KR20210149141A - Trispecific binding proteins, methods and uses thereof - Google Patents

Abstract

Provided herein are trispecific and/or trivalent binding proteins comprising four polypeptide chains forming three antigen binding sites that specifically bind to one or more target proteins, wherein a first polypeptide forming a binding protein is provided herein. The pair has dual variable domains with cross orientation and the second pair of polypeptides has a single variable domain that forms a single antigen binding site. In some embodiments, the binding protein comprises a binding site that binds a CD28 polypeptide, a binding site that binds a CDS polypeptide, and a binding site that binds a third polypeptide, such as a tumor target protein. The present invention also relates to methods for preparing trispecific and/or trivalent binding proteins and to the use of such binding proteins.

Description

Trispecific binding proteins, methods and uses thereof

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 62/831,572, filed on April 9, 2019, and to European Application, EP19306311.2, filed on October 8, 2019, the disclosures of each of which are incorporated herein by reference in their entirety. is incorporated by reference.

Submission of an ASCII text file sequence listing

The following submissions in ASCII text files are hereby incorporated by reference in their entirety: Sequence Listing in Computer-readable Format (CRF) (File Name: 183952032040SEQLIST.TXT, Recorded: April 6, 2020, Size: 526 KB).

technical field

The present invention relates to trispecific and/or trivalent binding proteins comprising four polypeptide chains forming three antigen binding sites that specifically bind to one or more target proteins, the first polypeptide forming the binding protein The pair has dual variable domains with cross orientation. The present invention also relates to methods for preparing trispecific and/or trivalent binding proteins and to the use of such binding proteins.

Monoclonal antibody-based biotherapeutics have become an important means of developing new drugs. Monoclonal antibody technology provides specific targeting, precise signal transduction, and/or payload to specific cell populations, and long-lasting biological effects through Fc function. Efforts in antibody engineering have enabled the development of bispecific antibodies that combine the specificities of two monoclonal antibodies for various biological applications, thereby expanding the field of antibody drug development. Newly discovered neutralizing antibodies with improved scope and efficacy could provide more options for biotherapeutic development to treat complex diseases such as cancer, arthritis, and/or inflammatory disorders.

Immunotherapy is a promising new therapeutic approach for disease management of cancer. The immune system is the first line of defense against the development and progression of cancer. Currently, there is a lot of evidence that T cells can control tumor growth and prolong the survival of cancer patients in the early and late stages of the disease. However, tumor-specific T cells may be restricted in several ways and thus fail to control the disease.

As part of human acquired immunity, T-cell immunity plays an important role in controlling viral infection and cancer, and has the potential to eliminate viral infection or cure cancer by eliminating infected and malignant cells. In chronic infectious diseases such as herpes virus infection (HSV, CMV, EBV, etc.), HIV, and HBV, the virus establishes persistence in humans through various mechanisms including immunosuppression, T cell depletion, and latent infection. Nevertheless, viral infection in general is viral antigen-specific, including antigen-specific CD8 T cells that can readily recognize infected cells to control or kill via cytokine release or cytotoxic T-cell (CTL)-mediated killing processes. Induces enemy immunity.

Thus, viral antigen-specific T cell activation and/or amplification in vivo and/or ex vivo may provide a therapeutic strategy for chronic viral infections.

All references cited herein, including patent applications, patent publications, and UniProtKB/Swiss-Prot accession numbers, are hereby incorporated by reference in their entirety as if each individual reference were specifically and individually indicated to be incorporated by reference.

To meet these and other needs, provided herein are trispecific binding proteins (eg, antibodies) that form three antigen binding sites. Such binding proteins may specifically bind one, two, or three antigenic targets or target proteins, such as CD28, CD3, and tumor target proteins. Some tumors express specific antigens. For example, HER2 amplification and overexpression can be found in molecular subtypes of breast cancer as well as gastric, ovarian, lung, and prostate carcinomas. Two factors are required for optimal activation of T cells: 1. antigen recognition and 2. costimulation. Using the trispecific HER2/CD28xCD3 trispecific binding proteins described herein, signal 1 is provided by an agonist anti-CD3 binding site and signal 2 is provided by an agonist anti-CD28 binding site. The trispecific binding protein recruits T cells to the tumor through a binding site that recognizes HER2, CD38, or other tumor target proteins, and activates binding T cells through anti-CD3 and anti-CD28. The resulting activation induces apoptosis potential of immune cells against nearby tumor cells. In addition, anti-CD3 binding sites are described as exhibiting high affinity binding to human CD3 polypeptides and eliminating potential manufacturing burdens (eg, deamidation sites).

Further provided herein are anti-CD38/CD28xCD3 trispecific antibodies developed and evaluated for their potential for T cell activation and subsequent proliferation and/or amplification of antigen specific T cells. Such trispecific Abs can effectively propagate CD4 and CD8 effector and memory populations in vitro, including antigen-specific CD8 T central memory and effector memory cells. Specifically, in vitro proliferation of CMV, EBV, HIV-1, influenza specific CD8 central memory and effector memory cells was demonstrated. The anti-CD38/CD28xCD3 trispecific antibodies described herein bind to CD3/CD28/CD38 and provide a signaling pathway that stimulates and proliferates T cells, thereby preventing infections such as HSV, CMV, EBV, HIV-1, and HBV infection. It has revealed novel properties that may provide an effective strategy for treating chronic infectious diseases.

To meet these and other needs, CD38 polypeptides (e.g., human and Provided herein are binding proteins that bind to cynomolgus monkey CD38 polypeptide). Advantageously, this binding protein has the ability to replenish T cells near cancer cells and subsequently activate T cells and promote activated T cells to kill adjacent cancer cells through a granzyme/perforin mechanism, which It provides a different mode of action for anti-tumor activity from anti-CD38 antibodies such as DARZALEX® (daratumumab). In addition, its ability to bind to both human and cynomolgus monkey CD38 polypeptides facilitates testing of the binding protein in preclinical toxicity studies, for example, to evaluate a safety profile for subsequent clinical use.

In some embodiments, provided herein is a binding protein comprising four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain comprises a structure represented by the formula

V _L2 -L ₁ -V _L1 -L ₂ -C _L [I]

The second polypeptide chain comprises a structure represented by the formula

V _H1 -L ₃ -V _H2 -L ₄ -C _{H1 -Hinge} -C _H2 -C _H3 [II]

The third polypeptide chain comprises a structure represented by the formula

V _H3 -C _{H1 -Hinge} -C _H2 -C _H3 [III]

The fourth polypeptide chain comprises a structure represented by the formula

V_L3-C_L [IV]

during the meal,

V _L1 is a first immunoglobulin light chain variable domain;

V _L2 is a second immunoglobulin light chain variable domain;

V _L3 is a third immunoglobulin light chain variable domain;

V _H1 is a first immunoglobulin heavy chain variable domain;

V _H2 is a second immunoglobulin heavy chain variable domain;

V _H3 is a third immunoglobulin heavy chain variable domain;

_CL is an immunoglobulin light chain constant domain;

C _H1 is an immunoglobulin C _H1 heavy chain constant domain;

C _H2 is an immunoglobulin C _H2 heavy chain constant domain;

C _H3 is an immunoglobulin C _H3 heavy chain constant domain;

The hinge is an immunoglobulin hinge region that connects the _{C H1} domain and the C _{H2 domain;}

L ₁ , L ₂ , L ₃ , and L ₄ are amino acid linkers;

the polypeptide of formula I and the polypeptide of formula II form a cross light chain-heavy chain pair;

V _H1 and V _L1 form a first antigen binding site;

V _H2 and V _L2 form a second antigen binding site that binds to a CD3 polypeptide, and the V _H2 domain is a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56) and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO: 57), wherein the V _L2 domain is QSLVHX ₁ NX ₂ X ₃ TY (X ₁ is E or Q, and X ₂ is A or L, and X ₃ is Q, R, or F) a CDR-L1 sequence comprising the amino acid sequence of (SEQ ID NO: 180), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64) , and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO: 65);

V _H3 and V _L3 form a third antigen binding site.

In some embodiments, the first binding site binds a CD28 polypeptide. In some embodiments, the V _H1 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYY (SEQ ID NO: 49), a CDR-H2 sequence comprising the amino acid sequence of IYPGNVNT (SEQ ID NO: 50), and TRSHYGLDWNFDV (SEQ ID NO: 51) in comprises a CDR-H3 sequence comprising the amino acid sequence, V _L1 domain is CDR-L2 comprising the amino acid sequence of CDR-L1 sequence, KAS (SEQ ID NO: 53) comprising the amino acid sequence of QNIYVW (SEQ ID NO: 52) sequence, and a CDR-L3 sequence comprising the amino acid sequence of QQGQTYPY (SEQ ID NO: 54). In some embodiments, V is _H1 domain comprises the amino acid sequence and / or, V _L1 domain of QVQLVQSGAEVVKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWIGSIYPGNVNTNYAQKFQGRATLTVDTSISTAYMELSRLRSDDTAVYYCTRSHYGLDWNFDVWGKGTTVTVSS (SEQ ID NO: 91) comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCQASQNIYVWLNWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTDFTLTISSLQPEDIATYYCQQGQTYPYTFGQGTKLEIK (SEQ ID NO: 92).

In some embodiments, _{the CDR-L1 sequence of the V L2} domain is an amino acid sequence selected from the group consisting of QSLVHQNAQTY (SEQ ID NO: 59), QSLVHENLQTY (SEQ ID NO: 60), QSLVHENLFTY (SEQ ID NO: 61), and QSLVHENLRTY (SEQ ID NO: 62) includes In some embodiments, a binding protein of the invention comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and RGVYYALSPFDY (SEQ ID NO: 56) 57) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of; and/or a CDR-L1 sequence comprising the amino acid sequence of QSLVHQNAQTY (SEQ ID NO: 59), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and an amino acid sequence of GQGTQYPFT (SEQ ID NO: 65) and an antigen binding site comprising an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, a binding protein of the invention comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and RGVYYALSPFDY (SEQ ID NO: 56) 57) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of; and/or a CDR-L1 sequence comprising the amino acid sequence of QSLVHENLQTY (SEQ ID NO: 60), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and an amino acid sequence of GQGTQYPFT (SEQ ID NO: 65) and an antigen binding site comprising an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, a binding protein of the invention comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and RGVYYALSPFDY (SEQ ID NO: 56) 57) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of; and/or a CDR-L1 sequence comprising the amino acid sequence of QSLVHENLFTY (SEQ ID NO: 61), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and an amino acid sequence of GQGTQYPFT (SEQ ID NO: 65) and an antigen binding site comprising an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, a binding protein of the invention comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and RGVYYALSPFDY (SEQ ID NO: 56) 57) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of; and/or a CDR-L1 sequence comprising the amino acid sequence of QSLVHENLRTY (SEQ ID NO: 62), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and an amino acid sequence of GQGTQYPFT (SEQ ID NO: 65) and an antigen binding site comprising an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, V _H2 domain QVQLVESGGGVVQPGRSLRLSCAASGFTFTKAWMHWVRQAPGKQLEWVAQIKDKSNSYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCRGVYYALSPFDYWGQGTLVTVSS (SEQ ID NO: 93) comprises the amino acid sequence and / or, V _L2 domain DIVMTQTPLSLSVTPGQPASISCKSSQSLVHQNAQTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 95) of, DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLQTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 96), DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLFTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 97), and DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLRTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 98). In some embodiments, V _H2 domain QVQLVESGGGVVQPGRSLRLSCAASGFTFTKAWMHWVRQAPGKQLEWVAQIKDKSNSYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCRGVYYALSPFDYWGQGTLVTVSS (SEQ ID NO: 93) or QVQLVESGGGVVQPGRSLRLSCAASGFTFTKAWMHWVRQAPGKQLEWVAQIKDKSNSYATYYASSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCRGVYYALSPFDYWGQGTLVTVSS comprises the amino acid sequence of (SEQ ID NO: 302) and / or, V _L2 domain DIVMTQTPLSLSVTPGQPASISCKSSQSLVHQNAQTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 95), DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLQTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 96), DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLFTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 97), and DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLRTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 98). In some embodiments, a binding protein of the invention comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 93, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 95 an antigen binding site. In some embodiments, a binding protein of the invention comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 302, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 95 an antigen binding site. In some embodiments, a binding protein of the invention comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 93, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 96 an antigen binding site. In some embodiments, a binding protein of the invention comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 93, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 97 an antigen binding site. In some embodiments, a binding protein of the invention comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 93, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 98 an antigen binding site.

In some embodiments, the third antigen binding site binds a tumor target protein. In some embodiments, the tumor target protein is a CD38 polypeptide (eg, a human CD38 polypeptide). In some embodiments, the tumor target protein is a HER2 polypeptide (eg, a human HER2 polypeptide). In some embodiments, a tumor target protein of the invention is A2AR, APRIL, ATPDase, BAFF, BAFFR, BCMA, BlyS, BTK, BTLA, B7DC, B7H1, B7H4 (also known as VTCN1), B7H5, B7H6, B7H7, B7RP1, B7 -4, C3, C5, CCL2 (also known as MCP-1), CCL3 (also known as MIP-1a), CCL4 (also known as MIP-1b), CCL5 (also known as RANTES), CCL7 (also known as MCP-3), CCL8 (also known as mcp-2), CCL11 (also known as eotaxin), CCL15 (also known as MIP-1d), CCL17 (also known as TARC), CCL19 (also known as MIP-3b), CCL20 (also known as MIP-3a) ), CCL21 (also known as MIP-2), CCL24 (also known as MPIF-2/eotaxin-2), CCL25 (also known as TECK), CCL26 (also known as eotaxin-3), CCR3, CCR4, CD3, CD19, CD20, CD23 (also known as FCER2, receptor for IgE), CD24, CD27, CD28, CD38, CD39, CD40, CD70, CD80 (also known as B7-1), CD86 (also known as B7-2), CD122, CD137 ( 41BB), CD137L, CD152 (also known as CTLA4), CD154 (also known as CD40L), CD160, CD272, CD273 (also known as PDL2), CD274 (also known as PDL1), CD275 (also known as B7H2), CD276 (also known as B7H3) ), CD278 (also known as ICOS), CD279 (also known as PD-1), CDH1 (also known as E-cadherin), chitinase, CLEC9, CLEC91, CRTH2, CSF-1 (also known as M-CSF), CSF-2 (also known as GM-CSF), CSF-3 (also known as GCSF), CX3CL1 (also known as SCYD1), CXCL12 (also known as SDF1), CXCL13, CXCR3, DNGR-1, ectonucleoside triphosphate diphospho Hyde Lolase 1, EGFR, ENTPD1, FCER1A, FCER1, FLAP, FOLH1, Gi24, GITR, GITRL, GM-CSF, Her2, HHLA2, HMGB1, HVEM, ICOSLG, IDO, IFNα, IgE, IGF1R, IL2Rbeta, IL1, IL1A , IL1B, IL1F10, IL2, IL4, IL4Ra, IL5, IL5R, IL6, IL7, IL7Ra, IL8, IL9, IL9R, IL10, rhIL10, IL12, IL13, IL13Ra1, IL13Ra2, IL15, IL17, IL17Rb (as a receptor for IL25 also known), IL18, IL22, IL23, IL25, IL27, IL33, IL35, ITGB4 (also known as b4 integrin), ITK, KIR, LAG3, LAMP1, leptin, LPFS2, MHC class II, MUC-1, NCR3LG1, NKG2D , NTPDase-1, OX40, OX40L, PD-1H, platelet receptor, PROM1, S152, SISP1, SLC, SPG64, ST2 (also known as receptor for IL33), STEAP2, Syk kinase, TACI, TDO, T14, TIGIT, TIM3, TLR, TLR2, TLR4, TLR5, TLR9, TMEF1, TNFa, TNFRSF7, Tp55, TREM1, TSLP (also known as a co-receptor for IL7Ra), TSLPR, TWEAK, VEGF, VISTA, Vstm3, WUCAM, and XCR1 (GPR5) /CCXCR1). In some embodiments, one or more of the antigen targets is a human antigen target.

In some embodiments, the third antigen binding site binds a human CD38 polypeptide. In some embodiments, the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYA (SEQ ID NO: 13), a CDR-H2 sequence comprising the amino acid sequence of IYPGQGGT (SEQ ID NO: 14), and ARTGGLRRAYFTY (SEQ ID NO: 15) in comprises a CDR-H3 sequence comprising the amino acid sequence, V _L3 domain is CDR-L2 comprising the amino acid sequence of CDR-L1 sequence, GAS (SEQ ID NO: 17) comprising the amino acid sequence of QSVSSYGQGF (SEQ ID NO: 16) sequence, and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO: 18). In some embodiments, the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTLTEFS (SEQ ID NO: 19), a CDR-H2 sequence comprising the amino acid sequence of FDPEDGET (SEQ ID NO: 20), and TTGRFFDWF (SEQ ID NO: 21) the inclusion of a CDR-H3 sequence comprising the amino acid sequence, and V _L3 domain is CDR-L2 comprising the amino acid sequence of CDR-L1 sequence, GAS (SEQ ID NO: 23) comprising the amino acid sequence of QSVISRF (SEQ ID NO: 22) sequence, and a CDR-L3 sequence comprising the amino acid sequence of QQDSNLPIT (SEQ ID NO: 24). In some embodiments, the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYAFTTYL (SEQ ID NO: 25), a CDR-H2 sequence comprising the amino acid sequence of INPGSGST (SEQ ID NO: 26), and ARYAYGY (SEQ ID NO: 27) in comprises a CDR-H3 sequence comprising the amino acid sequence, V _L3 domain is CDR-L2 comprising the amino acid sequence of CDR-L1 sequence, SAS (SEQ ID NO: 29) comprising the amino acid sequence of QNVGTA (SEQ ID NO: 28) sequence, and a CDR-L3 sequence comprising the amino acid sequence of QQYSTYPFT (SEQ ID NO: 30). In some embodiments, the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYSFTNYA (SEQ ID NO: 31), a CDR-H2 sequence comprising the amino acid sequence of ISPYYGDT (SEQ ID NO: 32), and ARRFEGFYYSMDY (SEQ ID NO: 33) in comprises a CDR-H3 sequence comprising the amino acid sequence, V _L3 domain is CDR-L2 comprising the amino acid sequence of CDR-L1 sequence, KVS (SEQ ID NO: 35) comprising the amino acid sequence of QSLVHSNGNTY (SEQ ID NO: 34) sequence, and a CDR-L3 sequence comprising the amino acid sequence of SQSTHVPLT (SEQ ID NO: 36).

In some embodiments, the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO: 37), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO: 38), and ARDPGLRYFDGGMDV (SEQ ID NO: 39) in comprises a CDR-H3 sequence comprising the amino acid sequence, V _L3 domain is CDR-L2 comprising the amino acid sequence of CDR-L1 sequence, AAS (SEQ ID NO: 41) comprising the amino acid sequence of QGISSY (SEQ ID NO: 40) sequence, and a CDR-L3 sequence comprising the amino acid sequence of QQLNSFPYT (SEQ ID NO: 42). In some embodiments, the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO: 43), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO: 44), and ARMFRGAFDY (SEQ ID NO: 45) in comprises a CDR-H3 sequence comprising the amino acid sequence, V _L3 domain is CDR-L2 comprising the amino acid sequence of CDR-L1 sequence, AAS (SEQ ID NO: 47) comprising the amino acid sequence of QGIRND (SEQ ID NO: 46) sequence, and a CDR-L3 sequence comprising the amino acid sequence of LQDYIYYPT (SEQ ID NO: 48). In some embodiments, V is _H3 domain comprises the amino acid sequence and / or, V _L3 of QVQLVQSGAEVVKPGASVKVSCKASGYTFTSYAMHWVKEAPGQRLEWIGYIYPGQGGTNYNQKFQGRATLTADTSASTAYMELSSLRSEDTAVYFCARTGGLRRAYFTYWGQGTLVTVSS domain (SEQ ID NO: 79) comprises the amino acid sequence of DIVLTQSPATLSLSPGERATISCRASQSVSSYGQGFMHWYQQKPGQPPRLLIYGASSRATGIPARFSGSGSGTDFTLTISPLEPEDFAVYYCQQNKEDPWTFGGGTKLEIK (SEQ ID NO: 80). In some embodiments, V is _H3 domain comprises the amino acid sequence and / or, V _L3 of QVQLVQSGAEVKKPGASVKVSCKVSGYTLTEFSIHWVRQAPGQGLEWMGGFDPEDGETIYAQKFQGRVIMTEDTSTDTAYMEMNSLRSEDTAIYYCTTGRFFDWFWGQGTLVTVSS domain (SEQ ID NO: 81) comprises the amino acid sequence of EIILTQSPAILSLSPGERATLSCRASQSVISRFLSWYQVKPGLAPRLLIYGASTRATGIPVRFSGSGSGTDFSLTISSLQPEDCAVYYCQQDSNLPITFGQGTRLEIK (SEQ ID NO: 82). In some embodiments, V is _H3 domain comprises the amino acid sequence and / or, V _L3 of QVQLVQSGAEVKKPGASVKVSCKASGYAFTTYLVEWIRQRPGQGLEWMGVINPGSGSTNYAQKFQGRVTMTVDRSSTTAYMELSRLRSDDTAVYYCARYAYGYWGQGTLVTVSS domain (SEQ ID NO: 83) comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQNVGTAVAWYQQKPGKSPKQLIYSASNRYTGVPSRFSGSGSGTDFTLTISSLQPEDLATYYCQQYSTYPFTFGQGTKLEIK (SEQ ID NO: 84). In some embodiments, V is _H3 domain comprises the amino acid sequence and / or, V _L3 of QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMYWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCARDPGLRYFDGGMDVWGQGTTVTVSS domain (SEQ ID NO: 87) comprises the amino acid sequence of DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIFAASTLHSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQLNSFPYTFGQGTKLEIK (SEQ ID NO: 88). In some embodiments, V is _H3 domain comprises the amino acid sequence and / or, V _L3 of QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISGDNSKNTLYLQMNSLRAEDTAVYYCARMFRGAFDYWGQGTLVTVSS domain (SEQ ID NO: 89) comprises the amino acid sequence of AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISGLQPEDSATYYCLQDYIYYPTFGQGTKVEIK (SEQ ID NO: 90). In some embodiments, V is _H3 domain comprises the amino acid sequence and / or, V _L3 of QVQLVQSGAEVKKPGASVKVSCKASGYSFTNYAVHWVRQAPGQGLEWMGVISPYYGDTTYAQKFQGRVTMTVDKSSSTAYMELSRLRSDDTAVYYCARRFEGFYYSMDYWGQGTLVTVSS domain (SEQ ID NO: 85) comprises the amino acid sequence of DVVMTQSPLSLPVTLGQPASISCRPSQSLVHSNGNTYLNWYQQRPGQSPKLLIYKVSKRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGGGTKVEIK (SEQ ID NO: 86).

In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 156 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 156; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 157 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 157; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 158 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 158; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 159 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 159. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 160 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 160; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 161 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 161; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 162 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 162; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:163 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:163. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 164 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 164; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 165 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 165; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 166 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 166; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 167 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 167. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 168 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 168; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 169 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 169; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 170 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 170; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 171 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 171. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 172 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 172; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 173 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 173; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 174 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 174; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 175 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 175. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 176 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 176; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 177 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 177; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 178 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 178; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 179 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 179. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 181 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 181; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 182 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 182; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 183 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 183; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 184 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 184. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 185 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 185; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 186 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 186; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:187 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:187; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 188 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 188.

In some embodiments, the third antigen binding site binds a human HER2 polypeptide. In some embodiments, the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIKDTY (SEQ ID NO: 1) or GFNIRDTY (SEQ ID NO: 2), IYPTNGYT (SEQ ID NO: 3), IYPTQGYT (SEQ ID NO: 4), or IYPTNAYT ( a CDR-H2 sequence comprising the amino acid sequence of SEQ ID NO: 5), and a CDR-H3 sequence comprising the amino acid sequence of SRWGGDGFYAMDY (SEQ ID NO: 6), SRWGGEGFYAMDY (SEQ ID NO: 7), or SRWGGSGFYAMDY (SEQ ID NO: 8); , the V _L3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9) or QDVQTA (SEQ ID NO: 10), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and QQHYTTP (SEQ ID NO: 11) and a CDR-L3 sequence comprising the amino acid sequence of number 12). In some embodiments, the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIKDTY (SEQ ID NO: 1), a CDR-H2 sequence comprising the amino acid sequence of IYPTNGYT (SEQ ID NO: 3), and SRWGGDGFYAMDY (SEQ ID NO: 6) in comprises a CDR-H3 sequence comprising the amino acid sequence, V _L3 domain is CDR-L2 comprising the amino acid sequence of CDR-L1 sequence, SAS (SEQ ID NO: 11) comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9) sequence, and a CDR-L3 sequence comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12). In some embodiments, the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTQGYT (SEQ ID NO: 4), and SRWGGEGFYAMDY (SEQ ID NO: 7) in comprises a CDR-H3 sequence comprising the amino acid sequence, V _L3 domain is CDR-L2 comprising the amino acid sequence of CDR-L1 sequence, SAS (SEQ ID NO: 11) comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9) sequence, and a CDR-L3 sequence comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12). In some embodiments, the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTNAYT (SEQ ID NO: 5), and SRWGGSGFYAMDY (SEQ ID NO: 8) in comprises a CDR-H3 sequence comprising the amino acid sequence, V _L3 domain is CDR-L2 comprising the amino acid sequence of CDR-L1 sequence, SAS (SEQ ID NO: 11) comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9) sequence, and a CDR-L3 sequence comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12). In some embodiments, the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTQGYT (SEQ ID NO: 4), and SRWGGSGFYAMDY (SEQ ID NO: 8) in comprises a CDR-H3 sequence comprising the amino acid sequence, V _L3 domain is CDR-L2 comprising the amino acid sequence of CDR-L1 sequence, SAS (SEQ ID NO: 11) comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9) sequence, and a CDR-L3 sequence comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12). In some embodiments, the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTNAYT (SEQ ID NO: 5), and SRWGGEGFYAMDY (SEQ ID NO: 7) in comprises a CDR-H3 sequence comprising the amino acid sequence, V _L3 domain is CDR-L2 comprising the amino acid sequence of CDR-L1 sequence, SAS (SEQ ID NO: 11) comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9) sequence, and a CDR-L3 sequence comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12). In some embodiments, the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIKDTY (SEQ ID NO: 1), a CDR-H2 sequence comprising the amino acid sequence of IYPTNGYT (SEQ ID NO: 3), and SRWGGDGFYAMDY (SEQ ID NO: 6) in comprises a CDR-H3 sequence comprising the amino acid sequence, V _L3 domain is CDR-L2 comprising the amino acid sequence of CDR-L1 sequence, SAS (SEQ ID NO: 11) comprising the amino acid sequence of QDVQTA (SEQ ID NO: 10) sequence, and a CDR-L3 sequence comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12). In some embodiments, V _H3 domain comprises the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (SEQ ID NO: 72), EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTQGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGEGFYAMDYWGQGTLVTVSS (SEQ ID NO: 73), EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTQGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGSGFYAMDYWGQGTLVTVSS (SEQ ID NO: 74), EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTNAYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGSGFYAMDYWGQGTLVTVSS (SEQ ID NO: 75), or EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTNAYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGEGFYAMDYWGQGTLVTVSS (SEQ ID NO: 76) / or, V and _L3 domain comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77) or DIQMTQSPSSLSASVGDRVTITCRASQDVQTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 78). In some embodiments, V is _H3 domain comprises the amino acid sequence and / or, V _L3 of EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS domain (SEQ ID NO: 72) comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77). In some embodiments, V is _H3 domain comprises the amino acid sequence and / or, V _L3 of EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTQGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGEGFYAMDYWGQGTLVTVSS domain (SEQ ID NO: 73) comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77). In some embodiments, V is _H3 domain comprises the amino acid sequence and / or, V _L3 of EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTNAYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGSGFYAMDYWGQGTLVTVSS domain (SEQ ID NO: 75) comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77). In some embodiments, V is _H3 domain comprises the amino acid sequence and / or, V _L3 of EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTQGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGSGFYAMDYWGQGTLVTVSS domain (SEQ ID NO: 74) comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77). In some embodiments, V is _H3 domain comprises the amino acid sequence and / or, V _L3 of EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTNAYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGEGFYAMDYWGQGTLVTVSS domain (SEQ ID NO: 76) comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77). In some embodiments, V is _H3 domain comprises the amino acid sequence and / or, V _L3 of EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS domain (SEQ ID NO: 72) comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVQTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 78).

In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 100 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 100; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 101 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 101; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 102 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 102; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 103 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 103. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 104 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 104; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 105 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 105; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 106 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 106; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 107 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 107. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 112 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 112; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 113 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 113; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 114 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 114; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 115 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 115. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 116 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 116; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 117 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 117; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 118 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 118; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 119 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 119. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 120 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 120; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 121 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 121; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 122 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 122; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:123 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:123. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 124 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 124; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 125 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 125; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 126 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 126; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 127 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 127. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 128 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 128; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 129 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 129; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 130 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 130; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 131. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 132 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 132; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 133 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 133; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 134 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 134; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 135 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 135. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 136 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 136; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 137 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 137; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 138; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 139 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 139. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 140 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 140; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 141 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 141; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 142 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 142; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 143 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 143. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 144 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 144; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 145 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 145; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 146 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 146; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 147 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 147. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 148 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 148; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 149 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 149; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 150 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 150; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 151 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 151. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 152 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 152; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 153 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 153; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 154 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 154; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 155 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 155. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 286 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 286; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 287 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 287; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 288 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 288; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 289 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 289. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 290 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 290; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 291 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 291; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 292 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 292; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 293 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 293. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 294 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 294; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 295 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 295; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 296 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 296; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 297 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 297. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 298 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 298; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 299 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 299; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 300 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 300; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 301 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 301.

In some embodiments that may be combined with any other embodiments described herein, _{at least one of L 1} , L ₂ , L ₃ , or L ₄ is independently 0 amino acids in length. In some embodiments, L ₁ , L ₂ , L ₃ , and L ₄ are each independently 0 amino acids in length or GGGGSGGGGS (SEQ ID NO: 69), GGGGSGGGGSGGGGS (SEQ ID NO: 70), S, RT, TKGPS (SEQ ID NO: 68) , GQPKAAP (SEQ ID NO: 67), and GGSGSSGSGG (SEQ ID NO: 71). In some embodiments, L ₁ , L ₂ , L ₃ , and L ₄ are each independently GGGGSGGGGS (SEQ ID NO: 69), GGGGSGGGGSGGGGS (SEQ ID NO: 70), S, RT, TKGPS (SEQ ID NO: 68), GQPKAAP (SEQ ID NO: 68) 67), and GGSGSSGSGG (SEQ ID NO: 71). In some embodiments, L ₁ comprises the sequence GQPKAAP (SEQ ID NO: 67), L ₂ comprises the sequence TKGPS (SEQ ID NO: 68), L ₃ comprises the sequence S, and L ₄ comprises the sequence RT . In some embodiments _{, at least one of L 1} , L ₂ , L ₃ , or L ₄ comprises the sequence DKTHT (SEQ ID NO: 66). In some embodiments, L ₁ , L ₂ , L ₃ , and L ₄ comprise the sequence DKTHT (SEQ ID NO: 66).

In some embodiments that may be combined with any other embodiments described herein, the hinge-C _H2 -C _H3 domains of the second and third polypeptide chains are human IgG4 hinge-C _H2 -C _H3 domains, and the hinge-C _{The H2-} C _H3 domain contains amino acid substitutions at positions corresponding to positions 234 and 235 of human IgG4 according to the EU index, respectively, and the amino acid substitutions are F234A and L235A. In some embodiments, the hinge-C _H2 -C _H3 domains of the second and third polypeptide chains are human IgG4 hinge-C _H2 -C _H3 domains, and the hinge-C _H2 -C _H3 domains are each human IgG4 according to the EU index. and an amino acid substitution at a position corresponding to positions 233 to 236 of In some embodiments, the hinge-C _H2 -C _H3 domains of the second and third polypeptide chains are human IgG4 hinge-C _H2 -C _H3 domains, and the hinge-C _H2 -C _H3 domains are each human IgG4 according to the EU index. and amino acid substitutions at positions corresponding to positions 228 and 409 of , and the amino acid substitutions are S228P and R409K. In some embodiments, the hinge-C _H2 -C _H3 domains of the second and third polypeptide chains are human IgG1 hinge-C _H2 -C _H3 domains, and the hinge-C _H2 -C _H3 domains are each human IgG1 according to the EU index. amino acid substitutions at positions corresponding to positions 234, 235, and 329 of In some embodiments, the hinge-C _H2 -C _H3 domains of the second and third polypeptide chains are human IgG1 hinge-C _H2 -C _H3 domains, and the hinge-C _H2 -C _H3 domains are each human IgG1 according to the EU index. and amino acid substitutions at positions corresponding to positions 298, 299, and 300 of , and the amino acid substitutions are S298N, T299A, and Y300S. In some embodiments, the hinge-C _H2- C _H3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to the EU index, substitutions are Y349C, T366S, L368A, and Y407V; The hinge-C _H2- C _H3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to the EU index, the amino acid substitutions being S354C and T366W. In some embodiments, the hinge-C _H2- C _H3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to the EU index, wherein the amino acid substitutions are S354C and T366W ego; the hinge-C _H2- C _H3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to the EU index, wherein the amino acid substitutions are Y349C, T366S , L368A, and Y407V.

In some embodiments, provided herein is an isolated nucleic acid molecule comprising a nucleotide sequence encoding a binding protein of any one of the above embodiments. In some embodiments, provided herein are expression vectors comprising a nucleic acid molecule of any one of the preceding embodiments. In some embodiments, provided herein is an isolated host cell comprising a nucleic acid molecule of any one of the above embodiments or an expression vector of any one of the above embodiments. In some embodiments, the host cell is a mammalian or insect cell.

In some embodiments, provided herein is a pharmaceutical composition comprising the binding protein of any one of the preceding embodiments and a pharmaceutically acceptable carrier.

In some embodiments, there is provided a method of preventing and/or treating cancer in a patient comprising administering to the patient a therapeutically effective amount of at least one binding protein or pharmaceutical composition of any one of the preceding embodiments. is provided on In some embodiments, provided herein is a binding protein or pharmaceutical composition according to any one of the above embodiments for use in a method of preventing and/or treating cancer in a patient, wherein the method comprises the binding protein or pharmaceutical composition. administering to the patient a therapeutically effective amount of the composition. In some embodiments, provided herein is a binding protein or pharmaceutical composition according to any one of the above embodiments for use in the manufacture of a medicament for preventing and/or treating cancer in a patient.

In some embodiments, at least one binding protein is co-administered with a chemotherapeutic agent. In some embodiments, the patient is a human.

In some embodiments, the third antigen binding site binds a human CD38 polypeptide and the cancer cell of the subject or patient expresses CD38. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or B-cell lymphoma. In some embodiments, prior to administration of the binding protein, the patient has received daratumumab treatment without a washout period.

In some embodiments, the third antigen binding site binds a human HER2 polypeptide and the cancer cell of the subject or patient expresses HER2. In some embodiments, the cancer is breast cancer, colorectal cancer, gastric cancer, or small cell lung cancer (NSCLC).

In some embodiments, provided herein is a method of propagating a virus-specific memory T cell comprising contacting the virus-specific memory T cell with a binding protein, wherein the binding protein binds three antigens. It comprises four polypeptide chains forming a site, and the first polypeptide chain comprises a structure represented by the following formula,

V _L2 -L ₁ -V _L1 -L ₂ -C _L [I]

The second polypeptide chain comprises a structure represented by the formula

V _H1 -L ₃ -V _H2 -L ₄ -C _{H1 -Hinge} -C _H2 -C _H3 [II]

The third polypeptide chain comprises a structure represented by the formula

V _H3 -C _{H1 -Hinge} -C _H2 -C _H3 [III]

The fourth polypeptide chain comprises a structure represented by the formula

V_L3-C_L [IV]

during the meal,

V _L1 is a first immunoglobulin light chain variable domain;

V _L2 is a second immunoglobulin light chain variable domain;

V _L3 is a third immunoglobulin light chain variable domain;

V _H1 is a first immunoglobulin heavy chain variable domain;

V _H2 is a second immunoglobulin heavy chain variable domain;

V _H3 is a third immunoglobulin heavy chain variable domain;

_CL is an immunoglobulin light chain constant domain;

C _H1 is an immunoglobulin C _H1 heavy chain constant domain;

C _H2 is an immunoglobulin C _H2 heavy chain constant domain;

C _H3 is an immunoglobulin C _H3 heavy chain constant domain;

The hinge is an immunoglobulin hinge region that connects the _{C H1} domain and the C _{H2 domain;}

L ₁ , L ₂ , L ₃ , and L ₄ are amino acid linkers;

the polypeptide of formula I and the polypeptide of formula II form a cross light chain-heavy chain pair;

V _H1 and V _L1 form a first antigen binding site that binds to a CD28 polypeptide, V _H2 and V _L2 form a second antigen binding site that binds to a CD3 polypeptide, and the V _H2 domain is GFTFTKAW (SEQ ID NO: 55) a CDR-H1 sequence comprising the amino acid sequence of, a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO: 57); _{the L2} domain is _{a CDR comprising the amino acid sequence of QSLVHX 1} NX ₂ X ₃ TY (X ₁ is E or Q, X ₂ is A or L, and X ₃ is Q, R, or F) (SEQ ID NO: 180) -L1 sequence, a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO: 65), wherein V _H3 and V _L3 are CD38 polypeptides to form a third antigen binding site that binds to

In some embodiments, provided herein is a binding protein comprising four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain comprises a structure represented by the formula

V _L2 -L ₁ -V _L1 -L ₂ -C _L [I]

The second polypeptide chain comprises a structure represented by the formula

V _H1 -L ₃ -V _H2 -L ₄ -C _{H1 -Hinge} -C _H2 -C _H3 [II]

The third polypeptide chain comprises a structure represented by the formula

V _H3 -C _{H1 -Hinge} -C _H2 -C _H3 [III]

The fourth polypeptide chain comprises a structure represented by the formula

V_L3-C_L [IV]

during the meal,

V _L1 is a first immunoglobulin light chain variable domain;

V _L2 is a second immunoglobulin light chain variable domain;

V _L3 is a third immunoglobulin light chain variable domain;

V _H1 is a first immunoglobulin heavy chain variable domain;

V _H2 is a second immunoglobulin heavy chain variable domain;

V _H3 is a third immunoglobulin heavy chain variable domain;

_CL is an immunoglobulin light chain constant domain;

C _H1 is an immunoglobulin C _H1 heavy chain constant domain;

C _H2 is an immunoglobulin C _H2 heavy chain constant domain;

C _H3 is an immunoglobulin C _H3 heavy chain constant domain;

The hinge is an immunoglobulin hinge region that connects the _{C H1} domain and the C _{H2 domain;}

L ₁ , L ₂ , L ₃ , and L ₄ are amino acid linkers;

the polypeptide of formula I and the polypeptide of formula II form a cross light chain-heavy chain pair;

V _H1 and V _L1 form a first antigen binding site that binds to a CD28 polypeptide, V _H2 and V _L2 form a second antigen binding site that binds to a CD3 polypeptide, and the V _H2 domain is GFTFTKAW (SEQ ID NO: 55) a CDR-H1 sequence comprising the amino acid sequence of, a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO: 57); _{the L2} domain is _{a CDR comprising the amino acid sequence of QSLVHX 1} NX ₂ X ₃ TY (X ₁ is E or Q, X ₂ is A or L, and X ₃ is Q, R, or F) (SEQ ID NO: 180) -L1 sequence, a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO: 65), wherein V _H3 and V _L3 are virus- form a third antigen binding site that binds to the CD38 polypeptide for use in proliferating specific memory T cells.

In some embodiments, the virus-specific memory T cell is contacted with the binding protein in vitro or ex vivo. In some embodiments, contacting the virus-specific memory T cell with the binding protein results in activation and/or proliferation of the virus-specific memory T cell.

In some embodiments, provided herein is a method of proliferating a T cell comprising contacting the T cell in vitro or ex vivo with a binding protein, wherein the binding protein forms three antigen binding sites. a polypeptide chain, wherein the first polypeptide chain comprises a structure represented by the following formula,

V _L2 -L ₁ -V _L1 -L ₂ -C _L [I]

The second polypeptide chain comprises a structure represented by the formula

V _H1 -L ₃ -V _H2 -L ₄ -C _{H1 -Hinge} -C _H2 -C _H3 [II]

The third polypeptide chain comprises a structure represented by the formula

V _H3 -C _{H1 -Hinge} -C _H2 -C _H3 [III]

The fourth polypeptide chain comprises a structure represented by the formula

V_L3-C_L [IV]

during the meal,

V _L1 is a first immunoglobulin light chain variable domain;

V _L2 is a second immunoglobulin light chain variable domain;

V _L3 is a third immunoglobulin light chain variable domain;

V _H1 is a first immunoglobulin heavy chain variable domain;

V _H2 is a second immunoglobulin heavy chain variable domain;

V _H3 is a third immunoglobulin heavy chain variable domain;

_CL is an immunoglobulin light chain constant domain;

C _H1 is an immunoglobulin C _H1 heavy chain constant domain;

C _H2 is an immunoglobulin C _H2 heavy chain constant domain;

C _H3 is an immunoglobulin C _H3 heavy chain constant domain;

The hinge is an immunoglobulin hinge region that connects the _{C H1} domain and the C _{H2 domain;}

L ₁ , L ₂ , L ₃ , and L ₄ are amino acid linkers;

the polypeptide of formula I and the polypeptide of formula II form a cross light chain-heavy chain pair;

V _H1 and V _L1 form a first antigen binding site that binds to a CD28 polypeptide, V _H2 and V _L2 form a second antigen binding site that binds to a CD3 polypeptide, and the V _H2 domain is GFTFTKAW (SEQ ID NO: 55) a CDR-H1 sequence comprising the amino acid sequence of, a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO: 57); _{the L2} domain is _{a CDR comprising the amino acid sequence of QSLVHX 1} NX ₂ X ₃ TY (X ₁ is E or Q, X ₂ is A or L, and X ₃ is Q, R, or F) (SEQ ID NO: 180) -L1 sequence, a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO: 65), wherein V _H3 and V _L3 are CD38 polypeptides to form a third antigen binding site that binds to

In some embodiments, provided herein is a binding protein comprising four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain comprises a structure represented by the formula

V _L2 -L ₁ -V _L1 -L ₂ -C _L [I]

The second polypeptide chain comprises a structure represented by the formula

V _H1 -L ₃ -V _H2 -L ₄ -C _{H1 -Hinge} -C _H2 -C _H3 [II]

The third polypeptide chain comprises a structure represented by the formula

V _H3 -C _{H1 -Hinge} -C _H2 -C _H3 [III]

The fourth polypeptide chain comprises a structure represented by the formula

V_L3-C_L [IV]

during the meal,

V _L1 is a first immunoglobulin light chain variable domain;

V _L2 is a second immunoglobulin light chain variable domain;

V _L3 is a third immunoglobulin light chain variable domain;

V _H1 is a first immunoglobulin heavy chain variable domain;

V _H2 is a second immunoglobulin heavy chain variable domain;

V _H3 is a third immunoglobulin heavy chain variable domain;

_CL is an immunoglobulin light chain constant domain;

C _H1 is an immunoglobulin C _H1 heavy chain constant domain;

C _H2 is an immunoglobulin C _H2 heavy chain constant domain;

C _H3 is an immunoglobulin C _H3 heavy chain constant domain;

The hinge is an immunoglobulin hinge region that connects the _{C H1} domain and the C _{H2 domain;}

L ₁ , L ₂ , L ₃ , and L ₄ are amino acid linkers;

the polypeptide of formula I and the polypeptide of formula II form a cross light chain-heavy chain pair;

V _H1 and V _L1 form a first antigen binding site that binds to a CD28 polypeptide, V _H2 and V _L2 form a second antigen binding site that binds to a CD3 polypeptide, and the V _H2 domain is GFTFTKAW (SEQ ID NO: 55) a CDR-H1 sequence comprising the amino acid sequence of, a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO: 57); _{the L2} domain is _{a CDR comprising the amino acid sequence of QSLVHX 1} NX ₂ X ₃ TY (X ₁ is E or Q, X ₂ is A or L, and X ₃ is Q, R, or F) (SEQ ID NO: 180) -L1 sequence, a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO: 65), V _H3 and V _L3 are T cells form a third antigen binding site that binds to a CD38 polypeptide for use in a method of propagating

In some embodiments, the T cell is a memory T cell or an effector T cell. In some embodiments, the T cell expresses a chimeric antigen receptor (CAR) on the cell surface or comprises a polynucleotide encoding a CAR.

In some embodiments, provided herein is a method of treating a chronic viral infection comprising administering to an individual or patient in need thereof an effective amount of a binding protein, wherein the binding protein forms three antigen binding sites. and four polypeptide chains, wherein the first polypeptide chain comprises a structure represented by the following formula,

V _L2 -L ₁ -V _L1 -L ₂ -C _L [I]

The second polypeptide chain comprises a structure represented by the formula

V _H1 -L ₃ -V _H2 -L ₄ -C _{H1 -Hinge} -C _H2 -C _H3 [II]

The third polypeptide chain comprises a structure represented by the formula

V _H3 -C _{H1 -Hinge} -C _H2 -C _H3 [III]

The fourth polypeptide chain comprises a structure represented by the formula

V_L3-C_L [IV]

during the meal,

V _L1 is a first immunoglobulin light chain variable domain;

V _L2 is a second immunoglobulin light chain variable domain;

V _L3 is a third immunoglobulin light chain variable domain;

V _H1 is a first immunoglobulin heavy chain variable domain;

V _H2 is a second immunoglobulin heavy chain variable domain;

V _H3 is a third immunoglobulin heavy chain variable domain;

_CL is an immunoglobulin light chain constant domain;

C _H1 is an immunoglobulin C _H1 heavy chain constant domain;

C _H2 is an immunoglobulin C _H2 heavy chain constant domain;

C _H3 is an immunoglobulin C _H3 heavy chain constant domain;

The hinge is an immunoglobulin hinge region that connects the _{C H1} domain and the C _{H2 domain;}

L ₁ , L ₂ , L ₃ , and L ₄ are amino acid linkers;

the polypeptide of formula I and the polypeptide of formula II form a cross light chain-heavy chain pair;

V _H1 and V _L1 form a first antigen binding site that binds to a CD28 polypeptide, V _H2 and V _L2 form a second antigen binding site that binds a CD3 polypeptide, and the V _H2 domain is GFTFTKAW (SEQ ID NO: 55) a CDR-H1 sequence comprising the amino acid sequence of, a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO: 57); _{the L2} domain is _{a CDR comprising the amino acid sequence of QSLVHX 1} NX ₂ X ₃ TY, wherein X ₁ is E or Q, X ₂ is A or L, and X ₃ is Q, R, or F (SEQ ID NO: 180) -L1 sequence, a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO: 65), wherein V _H3 and V _L3 are CD38 polypeptides to form a third antigen binding site that binds to

In some embodiments, provided herein is a binding protein comprising four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain comprises a structure represented by the formula

V _L2 -L ₁ -V _L1 -L ₂ -C _L [I]

The second polypeptide chain comprises a structure represented by the formula

V _H1 -L ₃ -V _H2 -L ₄ -C _{H1 -Hinge} -C _H2 -C _H3 [II]

The third polypeptide chain comprises a structure represented by the formula

V _H3 -C _{H1 -Hinge} -C _H2 -C _H3 [III]

The fourth polypeptide chain comprises a structure represented by the formula

V_L3-C_L [IV]

during the meal,

V _L1 is a first immunoglobulin light chain variable domain;

V _L2 is a second immunoglobulin light chain variable domain;

V _L3 is a third immunoglobulin light chain variable domain;

V _H1 is a first immunoglobulin heavy chain variable domain;

V _H2 is a second immunoglobulin heavy chain variable domain;

V _H3 is a third immunoglobulin heavy chain variable domain;

_CL is an immunoglobulin light chain constant domain;

C _H1 is an immunoglobulin C _H1 heavy chain constant domain;

C _H2 is an immunoglobulin C _H2 heavy chain constant domain;

C _H3 is an immunoglobulin C _H3 heavy chain constant domain;

The hinge is an immunoglobulin hinge region that connects the _{C H1} domain and the C _{H2 domain;}

L ₁ , L ₂ , L ₃ , and L ₄ are amino acid linkers;

the polypeptide of formula I and the polypeptide of formula II form a cross light chain-heavy chain pair;

V _H1 and V _L1 form a first antigen binding site that binds to a CD28 polypeptide, V _H2 and V _L2 form a second antigen binding site that binds a CD3 polypeptide, and the V _H2 domain is GFTFTKAW (SEQ ID NO: 55) a CDR-H1 sequence comprising the amino acid sequence of, a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO: 57); _{the L2} domain is _{a CDR comprising the amino acid sequence of QSLVHX 1} NX ₂ X ₃ TY, wherein X ₁ is E or Q, X ₂ is A or L, and X ₃ is Q, R, or F (SEQ ID NO: 180) -L1 sequence, a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO: 65), wherein V _H3 and V _L3 are chronic viruses Forms a third antigen binding site that binds to a CD38 polypeptide for use in a method of treating an infection, the method comprising administering to a subject or patient in need thereof an effective amount of the binding protein.

In some embodiments, the subject or patient is a human. In some embodiments, the binding protein is administered to a subject or patient in a pharmaceutical formulation comprising the binding protein and a pharmaceutically acceptable carrier. In some embodiments, administration of the binding protein results in activation and/or proliferation of virus-specific memory T cells in the subject or patient.

In some embodiments that may be combined with any other embodiments described herein, the memory T cell is a CD8+ or CD4+ memory T cell. In some embodiments, the memory T cell is a central memory T cell (T _CM ) or an effector memory T cell (T _EM ).

In some embodiments that may be combined with any other embodiments described herein, the virus is human immunodeficiency virus (HIV), influenza virus, cytomegalovirus (CMV), hepatitis B virus (HBV), human papillomavirus ( HPV), Epstein-Barr virus (EBV), human bubble virus (HFV), herpes simplex virus 1 (HSV-1), or herpes simplex virus 1 (HSV-2).

In some embodiments that may be combined with any of the other embodiments described herein, the CD28 polypeptide is a human CD28 polypeptide, the CD3 polypeptide is a human CD3 polypeptide, and the CD38 polypeptide is a human CD38 polypeptide.

In some embodiments, provided herein is a vector system comprising one or more vectors encoding the first, second, third, and fourth polypeptide chains of a binding protein of any one of the above embodiments. In some embodiments, the vector system comprises a first vector encoding a first polypeptide chain of a binding protein, a second vector encoding a second polypeptide chain of a binding protein, a third vector encoding a third polypeptide chain of a binding protein, and a fourth vector encoding a fourth polypeptide chain of the binding protein.

In some embodiments, provided herein is a kit comprising 1, 2, 3, or 4 polypeptide chains of a binding protein according to any one of the above embodiments. In some embodiments, the kit further comprises instructions for using the polypeptide chain or binding protein according to any of the methods or uses described herein, eg, described above.

In some embodiments, provided herein is a kit comprising 1, 2, 3, or 4 polynucleotides according to any one of the above embodiments. In some embodiments, provided herein is a polynucleotide kit comprising 1, 2, 3, or 4 polynucleotides of a polynucleotide kit comprising: (a) the polynucleotide sequence of SEQ ID NO: 189; A first polynucleotide comprising a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 190, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 191, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 192 polynucleotides; (b) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 193, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 194, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 195, and the sequence a fourth polynucleotide comprising the polynucleotide sequence of number 196; (c) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 197, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 198, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 199, and the sequence a fourth polynucleotide comprising the polynucleotide sequence of number 200; (d) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 201, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 202, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 203, and the sequence a fourth polynucleotide comprising the polynucleotide sequence of number 204; (e) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 205, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 206, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 207, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of No. 208; (f) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 209, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 210, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 211, and the sequence a fourth polynucleotide comprising the polynucleotide sequence of number 212; (g) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 213, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 214, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 215, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 216; (h) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 217, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 218, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 219, and the sequence a fourth polynucleotide comprising the polynucleotide sequence of No. 220; (i) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 221, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 222, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 223, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of No. 224; (j) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 225, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 226, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 227, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 228; (k) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 229, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 230, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 231, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 232; (l) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 233, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 234, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 235, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 236; (m) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 237, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 238, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 239, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 240; (n) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 241, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 242, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 243, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 244; (o) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 245, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 246, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 247, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 248; (p) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 249, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 250, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 251, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of No. 252; (q) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 253, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 254, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 255, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 256; (r) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 257, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 258, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 259, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 260; (s) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 261, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 262, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 263, and the sequence a fourth polynucleotide comprising the polynucleotide sequence of number 264; (t) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 265, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 266, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 267, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 268; (u) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 269, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 270, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 271, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 272; or (v) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 273, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 274, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 275, and A fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 276.

It should be understood that one, some, or all of the properties of the various embodiments described herein may be combined to form other embodiments of the invention. These and other aspects of the present invention will become apparent to those skilled in the art. These and other embodiments of the present invention are further described below in the Detailed Description for Practicing the Invention.

1A provides a schematic diagram of a trispecific binding protein comprising four polypeptide chains forming three antigen binding sites that bind to three target proteins, CD28, CD3, and HER2. The first pair of polypeptides has dual variable domains (VH1-VH2 and VL2-VL1) with cross orientation forming two antigen binding sites that recognize CD3 and CD28, and the second pair of polypeptides have a single antigen that recognizes HER2. It has a single variable domain (VH3 and VL3) that forms the binding site. The trispecific binding protein depicted in FIG. 1A uses a constant region comprising "knobs-into-holes" mutations, wherein the knob is in a second pair of polypeptides with a single variable domain.
1B provides fold change in binding affinity (relative to parent) of anti-CD28/CD3/HER2 trispecific antibody variants using the indicated anti-HER2, anti-CD3, and anti-CD28 binding domains. Mutations 3233QQ to QEQ (top to bottom) represent mutations introduced at residues 32 to 35 of the VL domain of the anti-CD3 binding site (indicated by *); The remaining mutations were introduced in either the VH or VL domains of the trastuzumab anti-HER2 binding site (indicated by #; numbering according to Kabat). For mutations in the anti-HER2 binding site, mutation 30Q was introduced into the VL domain and the remaining mutations were introduced into the VH domain. Binding affinity was determined by ELISA and the values provided are relative to the parental trispecific antibody.
1C provides binding curves for the indicated trispecific antibodies that bind human HER2, human CD28, and CD3, as determined by ELISA.
1D provides a proposed mechanism of action for HER2/CD28xCD3 trispecific antibody-mediated T cell activation and HER2+ cancer cell killing.
2A provides a schematic diagram of a trispecific binding protein comprising four polypeptide chains forming three antigen binding sites that bind to three target proteins, CD28, CD3, and CD38. A first pair of polypeptides has dual variable domains (VH1-VH2 and VL2-VL1) with cross orientation forming two antigen binding sites that recognize CD3 and CD28, and a second pair of polypeptides have a single antigen that recognizes CD38. It has a single variable domain (VH3 and VL3) that forms the binding site. The trispecific binding protein shown in FIG. 2A uses an IgG4 constant region comprising a “knob-into-hole” mutation, wherein the knob is in a second pair of polypeptides with a single variable domain.
2B-2E show the indicated antigens for the target antigens human CD38 ( FIG. 2B ), cynomolgus monkey CD38 ( FIG. 2C ), human CD3 ( FIG. 2D ), and human CD28 ( FIG. 2E ), as determined by ELISA. -shows the binding affinity of CD38/CD28sup x CD3mid_ENLQ DKTHT IgG4 FALA trispecific antibody with CD38 binding domain.
3 shows an SPR competition assay of binding to CD38 by daratumumab and an anti-CD38 monospecific antibody having the indicated anti-CD38 binding domain. If the antibody recognized an epitope on CD38 different from that of daratumumab, injection of the antibody increased the SPR signal. If the antibody recognized an epitope overlapping with daratumumab, injection of the antibody did not increase the SPR signal.
4A and 4B show in vitro apoptosis activity of CD38/CD28sup x CD3mid_ENLQ DKTHT IgG4 FALA trispecific antibody with indicated anti-CD38 binding domains against human multiple myeloma NCI-H929 cells (CD38+/CD28+). Assays were performed in the presence of 5 nM isotype control antibody ( FIG. 4A ) or daratumumab ( FIG. 4B ). In the presence of daratumumab, the trispecific antibody continued to exhibit apoptotic activity.
5A and 5B show in vitro apoptosis activity of CD38/CD28sup x CD3mid_ENLQ DKTHT IgG4 FALA trispecific antibody with indicated anti-CD38 binding domains against human lymphoma OCI-Ly19 cells (CD38+/CD28-). Assays were performed in the presence of 5 nM isotype control antibody ( FIG. 5A ) or daratumumab ( FIG. 5B ). Daratumumab reduced the apoptotic activity of the anti-CD38/CD28xCD3 trispecific antibody.
6A-6J show in vitro T cell subset proliferation in PBMCs collected from CMV-infected donor D in response to CD38/CD28sup x CD3mid_ENLQ DKTHT IgG4 FALA trispecific antibody with indicated alternative anti-CD38 binding domains. show characterization. A trispecific antibody lacking the CD38VH1 anti-CD38 binding domain was used as a negative control (ACD38VH1/ACD28sup×ACD3mid IgG4 FALA). T cell populations were measured at the indicated time points (D3 and D7 represent days 3 and 7, respectively). The indicated trispecific antibodies were tested at the indicated concentrations of 0.2 nM and 1 nM. CMV-specific CD8+ T cells ( FIGS. 6A and 6B ), CMV-specific T _cm CD8+ cells ( FIGS. 6C and 6D ), and CMV-specific T _em CD8+ cells ( FIGS. 6E and FIG. 6E ) using flow cytometry analysis. 6f ) was quantified. _{In addition, the percentage of CMV-specific T cm} ( FIGS. 6G and 6H ) and T _em ( FIGS. 6I and 6J ) CD8+ cells at the indicated time points was quantified. All trispecific antibodies tested promoted proliferation of CMV-specific memory CD8+ T cells with different efficacy and kinetics in a dose-response manner.
7A-7J Characterization of in vitro T cell subset proliferation in PBMCs collected from CMV-infected donor E in response to CD38/CD28sup x CD3mid_ENLQ DKTHT IgG4 FALA trispecific antibody with indicated anti-CD38 binding domains. shows A trispecific antibody lacking the CD38VH1 anti-CD38 binding domain was used as a negative control (ACD38VH1/ACD28sup×ACD3mid IgG4 FALA). Antibodies shown in the legend from top to bottom are shown in the graph from left to right. T cell populations were measured at the indicated time points (D3 and D7 represent days 3 and 7, respectively). The indicated trispecific antibodies were tested at the indicated concentrations of 0.2 nM, 1 nM, and 2 nM. CMV-specific CD8+ T cells ( FIGS. 7A and 7B ), CMV-specific T _cm CD8+ cells ( FIGS. 7C and 7D ), and CMV-specific T _em CD8+ cells ( FIGS. 7E and 7D ) using flow cytometry analysis. 7f ) was quantified. In addition, the percentages of indicated CMV-specific T _cm ( FIGS. 7G and 7H ) and T _em ( FIGS. 7I and 7J ) CD8+ cells were quantified. All trispecific antibodies tested promoted proliferation of CMV-specific memory CD8+ T cells with different efficacy and kinetics in a dose-response manner.
8A-8J show in vitro T cell subset proliferation in PBMCs collected from EBV-infected donor C in response to CD38/CD28sup x CD3mid_ENLQ DKTHT IgG4 FALA trispecific antibody with indicated alternative anti-CD38 binding domains. show characterization. A trispecific antibody lacking the CD38VH1 anti-CD38 binding domain was used as a negative control (ACD38VH1/ACD28sup×ACD3mid IgG4 FALA). T cell populations were measured at the indicated time points (D3 and D7 represent days 3 and 7, respectively). The indicated trispecific antibodies were tested at the indicated concentrations of 0.2 nM and 1 nM. EBV-specific CD8+ T cells ( FIGS. 8A and 8B ), CMV-specific T _cm CD8+ cells ( FIGS. 8C and 8D ), and CMV-specific T _em CD8+ cells ( FIGS. 8E and FIG. 8D ) using flow cytometry analysis. 8f ) was quantified. In addition, the percentages of indicated EBV-specific T _cm ( FIGS. 8G and 8H ) and T _em ( FIGS. 8I and 8J ) CD8+ cells were quantified. All trispecific antibodies tested promoted proliferation of CMV-specific memory CD8+ T cells with different efficacy and kinetics in a dose-response manner.
9A-12 show in vitro T cell subset proliferation in PBMCs collected from EBV-infected donor D in response to CD38/CD28sup x CD3mid_ENLQ DKTHT IgG4 FALA trispecific antibody with indicated alternative anti-CD38 binding domains. show characterization. A trispecific antibody lacking the CD38VH1 anti-CD38 binding domain was used as a negative control (ACD38VH1/ACD28sup×ACD3mid IgG4 FALA). T cell populations were measured at the indicated time points (D3 and D7 represent days 3 and 7, respectively). The indicated trispecific antibodies were tested at the indicated concentrations of 0.2 nM and 1 nM. EBV-specific CD8+ T cells ( FIGS. 9A and 9B ), EBV-specific T _cm CD8+ cells ( FIGS. 9C and 9D ), and EBV-specific T _em CD8+ cells ( FIGS. 9E and FIG. 9D ) using flow cytometry analysis. 9f ) was quantified. In addition, the percentages of indicated EBV-specific T _cm ( FIGS. 9G-10 ) and T _em ( FIGS. 11 and 12 ) CD8+ cells were quantified. All trispecific antibodies tested promoted proliferation of EBV-specific memory CD8+ T cells with different potencies and kinetics in a dose-response manner.
13A to 13D show changes in tumor volume ( FIG. 13A ) and body weight over time (days) in NSG mice bearing ZR-75-1 tumors implanted with in vitro proliferated human CD3+ T cells ( FIG. 13A ) and body weight ( FIG. 13A ). 13b ). Groups of 10 mice were treated with vehicle or indicated doses of Her2/CD28 x CD3 trispecific antibody. The arrow tip indicates the dosing day. Tumor volume is expressed as mean ± SEM (mm ³ ). Changes in body weight are expressed as % change (mean ± SEM). The x-axis represents the number of days after transplantation of ZR-75-1 cells. ^{Tumor volume (mm 3} ) over time for individual mice in each treatment group is shown in FIG. 13C . Tumor weights (mg) for each treatment group are shown in FIG. 13D . ** = p<0.001; *** = p<0.0003 (two-way ANOVA, control vs. 100 & 10 ug/kg).
14A to 14C show the therapeutic effect of Her2/CD28 x CD3 trispecific antibody on whole blood T cells. 14A shows analysis of hCD45+, CD8+, CD4+, and mCD45+ cells by flow cytometry. 14B shows the effect of control or (indicated doses) Her2/CD28 x CD3 trispecific antibody treatment on hCD45+, CD8+, CD4+, and mCD45+ cell counts. 14C shows the effect of treatment with control or (indicated doses) Her2/CD28 x CD3 trispecific antibody on human cell ratios (CD4+/CD45+ and CD8+/CD45+). For each x-axis parameter shown in FIGS. 14b and 14c , the conditions are (left to right) as follows: control, 100 ug/kg of trispecific antibody, 10 ug/kg of trispecific antibody, 1 ug /kg of trispecific antibody, and 0.1 ug/kg of trispecific antibody. The percentages shown in FIGS. 14B and 14C are based on control samples versus 100 ug/kg.
15A-15C show the effect of Her2/CD28 x CD3 trispecific antibody treatment on tumor infiltrating lymphocytes (TIL), investigated by immunohistochemistry (IHC). Arrows indicate tumor-infiltrating T cells identified in ZR-75-1 breast tumors. The top image is at 1X magnification, and the bottom image is at 20X magnification. In both image sets, staining for human CD45, human CD4, and human CD8 is shown from left to right. Tumors of mice treated with vehicle control ( FIG. 15A ), 100 ug/kg of trispecific antibody ( FIG. 15B ), or 0.1 ug/kg of trispecific antibody ( FIG. 15C ) are shown.
16A-16C show quantification of the effect of Her2/CD28 x CD3 trispecific antibody treatment on TIL, as measured by IHC. Each dot represents one tumor from an individual mouse, the rectangle represents the group mean, and the error bars represent the standard deviation. * = p<0.05 versus vehicle control (ANOVA). The number of CD45+ ( FIG. 16A ), CD4+ ( FIG. 16B ), or CD8+ ( FIG. 16C ) cells are indicated. In Figure 16c , the $ area quantification approach was used for CD8+ cells instead of cell counting due to excessive non-specific signal in CD8 IHC slides.
17A-17F show anti-CD3 antigen binding without 32/35 QQ mutations in the VL domain, compared to Her2/CD28 x CD3 trispecific antibodies with mutations in the VL domain and anti-HER2 arm of the anti-CD3 arm. In vitro cytolysis of HER2+ breast cancer target cells in the presence of human CD8+ T cells by a Her2/CD28 x CD3 trispecific antibody having a domain (“ctl”) and a wild-type trastuzumab antigen binding domain (numbering is Table 1). as shown in ). Apoptotic activity against cell lines with various HER2 expression is shown: HCC1954 for high HER2 expression ( FIG. 17A ), BT20 for medium HER2 expression ( FIG. 17C ), and MDA-MD-231 for low HER2 expression ( FIG. 17C ). 17e ). Antibody concentration of apoptosis against target cells HCC1954 ( FIG. 17B ), BT20 ( FIG. 17D ), and MDA-MD-231 ( FIG. 17F ) by comparing binding protein #2 versus ctl or binding proteins #1 and #5 versus ctl A graph is shown as a function of .
18A and 18B summarize the mean EC50 (pM) of apoptosis in vitro by experimental or control Her2/CD28×CD3 trispecific antibodies against the indicated breast cancer ( FIG. 18A ) or gastric cancer cell lines ( FIG. 18B ). The amino acid sequences of the indicated trispecific antibodies are provided in Table 1.

The present invention provides trispecific and/or trivalent binding proteins comprising four polypeptide chains forming three antigen binding sites that specifically bind to one or more target proteins, wherein a first polypeptide forming a binding protein The pair has dual variable domains with cross orientation.

general definition

As used in accordance with the present invention, the following terms are understood to have the following meanings, unless otherwise specified. Unless the context requires otherwise, singular terms include the plural and plural terms include the singular.

Aspects and embodiments of the invention described herein are understood to include "comprising", "consisting of", and "consisting essentially of" the aspects and embodiments.

As used herein, the term “polynucleotide” refers to a single-stranded or double-stranded nucleic acid polymer of at least 10 nucleotides in length. In certain embodiments, nucleotides comprising polynucleotides may be ribonucleotides or deoxyribonucleotides, or modified forms of either type of nucleotide. Such modifications include base modifications such as bromouridine, ribose modifications such as arabinoside and 2',3'-dideoxyribose, and phosphorothioates, phosphorodithioates, phosphoroselenoates, phosphoros. internucleotide linkage modifications such as diselenoate, phosphoroanilothioate, phosphoraniladate, and phosphoroamidate. The term "polynucleotide" specifically includes single-stranded and double-stranded forms of DNA.

An "isolated polynucleotide" is a polynucleotide of genomic, cDNA, or synthetic origin, or some combination thereof, which (1) is not associated with all or part of a polynucleotide in which an isolated polynucleotide is found in nature, or (2) ) linked to a polynucleotide that is not linked in nature, or (3) does not exist as part of a larger sequence in nature.

An "isolated polypeptide" is defined as (1) essentially free of at least some other polypeptides with which it is normally found, (2) essentially free of other polypeptides from the same source (eg, the same species), (3) different expressed by the cells of the species, (4) separated from at least about 50% of the polynucleotide, lipid, carbohydrate, or other substance with which it in nature binds, (5) that in nature is associated with an “isolated polypeptide” not bound (by covalent or non-covalent interactions) to a portion of the polypeptide, (6) operably linked (by covalent or non-covalent interactions) to a polypeptide not associated with it in nature, or (7) in nature does not exist in Such isolated polypeptides may be encoded by genomic DNA, cDNA, mRNA or other RNA of synthetic origin, or any combination thereof. Preferably, the isolated polypeptide is substantially free of polypeptides or other contaminants found in its natural environment that could interfere with its use (therapeutic, diagnostic, prophylactic, research, etc.).

Naturally occurring antibodies generally comprise tetramers. Each of these tetramers is usually composed of two identical pairs of polypeptide chains, each pair having one full-length "light" chain (typically having a molecular weight of about 25 kDa) and a molecular weight (typically of about 50-70 kDa). having one full-length "heavy chain". As used herein, the terms “heavy chain” and “light chain” refer to any immunoglobulin polypeptide having sufficient variable domain sequence to confer specificity for a target antigen. In general, the amino-terminal portion of each light and heavy chain comprises a variable domain of about 100 to 110 or more amino acids, which is generally responsible for antigen recognition. In general, the carboxy-terminal portion of each chain defines a constant domain responsible for effector functions. Thus, in a naturally occurring antibody, a full-length heavy chain immunoglobulin polypeptide comprises one variable domain (V _H ) and three constant domains ( _CH1 , C _H2 , and C _H3 ), wherein the V _H domain is the amino-terminus of the polypeptide. a and C _H3 domains are carboxy- and at the terminal, full-length light chain immunoglobulin polypeptide comprises a variable domain (V _L) and a constant domain (C _L) and, V _L domain has the amino of the polypeptide - and the terminal The C _L domain is at the carboxy-terminus.

Human light chains are generally classified into kappa and lambda light chains, human heavy chains are generally classified as mu, delta, gamma, alpha, or epsilon, defining the isotypes of antibodies as IgM, IgD, IgG, IgA, and IgE, respectively do. There are several subclasses of IgG including, but not limited to, IgG1, IgG2, IgG3, and IgG4. There are subclasses of IgM including, but not limited to, IgM1 and IgM2. Similarly, IgA is subdivided into subclasses including, but not limited to, IgA1 and IgA2. Within full-length light and heavy chains, generally the variable and constant domains are joined by a “J” region of at least about 12 amino acids, and the heavy chain also includes a “D” region of greater than about 10 amino acids. See, eg, Fundamental Immunology (Paul, W., ed., Raven Press, 2nd ed., 1989), which is incorporated by reference in its entirety for all purposes. The variable regions of each light/heavy chain pair generally form an antigen binding site. In general, the variable domains of naturally occurring antibodies exhibit the same general structure of relatively conserved framework regions (FRs) joined by three hypervariable regions, also referred to as complementarity determining regions or CDRs. The CDRs from both chains of each pair are generally aligned by framework regions, which may allow binding to specific epitopes. From amino-terminus to carboxy-terminus, both light and heavy chain variable domains generally comprise domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

The term “CDR set” refers to a group of three CDRs present in a single variable region capable of binding antigen. The exact boundaries of these CDRs were defined differently depending on the system. The system described by Kabat (Kabat et al ., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) provides unambiguous residue numbering applicable to all variable regions of antibodies. Not only provides a system, but also provides precise residue boundaries defining three CDRs.These CDRs can be referred to as Kabat CDRs.Chothia and Lesk, 1987, J. Mol. Biol . 196: 901 -17; Chothia et al ., 1989, Nature 342: 877-83) found that certain sub-portions within the Kabat CDRs adopt nearly identical peptide framework structures despite great diversity at the amino acid sequence level. The parts are designated as L1, L2, and L3 or H1, H2, and H3, where "L" and "H" represent the light chain region and heavy chain region, respectively. This region has a border that overlaps with the Kabat CDR, Chothia Can be referred to as CDR.Other boundaries defining the CDR overlapping Kabat CDR are described in Padlan, 1995, FASEB J. 9: 133-39; MacCallum, 1996, J. Mol. Biol . 262(5): 732 -45; and Lefranc, 2003, Dev Comp Immunol 27 :.... 55-77] have been described in other CDR boundary definitions may not strictly follow this one system, and despite the specific residue or residue group Or even the whole CDR can be shortened or lengthened according to the prediction or experimental result that does not significantly affect antigen binding but overlaps with Kabat CDR.In certain embodiments, Kabat or Chothia defined CDR is used, but the method used herein is these cis CDRs defined according to any of the above systems may be used. Identification of predicted CDRs using amino acid sequences is described in Martin, AC "Protein sequence and structure analysis of antibody variable domains," In Antibody Engineering , Vol. 2. Kontermann R., Duebel S., eds. Springer-Verlag, Berlin, p. 33-51 (2010)] is well known in the art. The amino acid sequences of heavy and/or light chain variable domains are determined by other conventional methods to determine sequence hypervariable regions by confirming the sequence of the CDRs by, for example, comparison with the known amino acid sequences of other heavy and light chain variable regions. may be inspected. Numbered sequences can be obtained visually, or as described in Thompson, 1994, Nucleic Acids Res . 22: 4673-80]. Molecular models are typically used to accurately describe the framework and CDR regions, modifying sequence-based assignments accordingly.

The term “Fc,” as used herein, refers to a molecule comprising the sequence of a non-antigen-binding fragment generated from degradation of an antibody or by other means, whether in monomeric or multimeric form, and may include a hinge region. The original immunoglobulin source of the native Fc is preferably of human origin, preferably IgG1 and IgG2, but may be any immunoglobulin. Fc molecules consist of monomeric polypeptides that can be linked in dimeric or multimeric form by covalent (ie, disulfide bonds) and non-covalent bonds. The number of intermolecular disulfide bonds between monomeric subunits of native Fc molecules ranges from 1 to 4 depending on class (eg, IgG, IgA, and IgE) or subclass (eg, IgG1, IgG2, IgG3, IgA1, and IgGA2). is the range An example of an Fc is a disulfide linked dimer resulting from papain degradation of IgG. As used herein, the term “native Fc” is a generic term for monomeric, dimeric, and multimeric forms.

F(ab) fragments generally comprise one light chain and the V _H and C _{H1 domains of one heavy chain, wherein the V H} -C _H1 heavy chain portion of the F(ab) fragment forms a disulfide bond with another heavy chain polypeptide. Can not. As used herein, an F(ab) fragment is also defined as one light chain comprising two variable domains separated by an amino acid linker, and one comprising two variable domains and a C _H1 domain separated by an amino acid linker. may contain a heavy chain of

F(ab') fragments are generally constant (between the _{C H1} and C _H2 domains) such that an interchain disulfide bond is formed between one light chain and two heavy chains to form an F(ab') ₂ molecule. a portion of one heavy chain that further comprises a region.

As used herein, the term “binding protein” refers to a molecule that is not naturally occurring (or recombines or engineered) that specifically binds to at least one target antigen. Unless otherwise specified, trispecific binding proteins of the invention typically comprise four polypeptide chains forming three antigen binding sites, the first polypeptide chain having a structure represented by the formula

V _L2 -L ₁ -V _L1 -L ₂ -C _L [I]

The second polypeptide chain has a structure represented by the formula

V _H1 -L ₃ -V _H2 -L ₄ -C _{H1 -Hinge} -C _H2 -C _H3 [II]

The third polypeptide chain has a structure represented by the formula

V_H3-C_H1 [III]

The fourth polypeptide chain has a structure represented by the following formula,

V _L3 -C _L [IV]

during the meal,

V _L1 is a first immunoglobulin light chain variable domain;

V _L2 is a second immunoglobulin light chain variable domain;

V _L3 is a third immunoglobulin light chain variable domain;

V _H1 is a first immunoglobulin heavy chain variable domain;

V _H2 is a second immunoglobulin heavy chain variable domain;

V _H3 is a third immunoglobulin heavy chain variable domain;

_CL is an immunoglobulin light chain constant domain;

C _H1 is an immunoglobulin C _H1 heavy chain constant domain;

The hinge is an immunoglobulin hinge region that connects the _{C H1} domain and the C _{H2 domain;}

L ₁ , L ₂ , L ₃ , and L ₄ are amino acid linkers;

The polypeptide of formula I and the polypeptide of formula II form a cross light chain-heavy chain pair.

A “recombinant” molecule is one made, expressed, produced, or isolated by recombinant means.

One embodiment of the present invention provides binding proteins having biological and immunological specificity for 1 to 3 target antigens. Another embodiment of the invention provides a nucleic acid molecule comprising a nucleotide sequence encoding a polypeptide chain forming such a binding protein. Another embodiment of the invention provides an expression vector comprising a nucleic acid molecule comprising a nucleotide sequence encoding a polypeptide chain forming such a binding protein. Another embodiment of the invention provides a host cell expressing such a binding protein (ie, comprising a nucleic acid molecule or vector encoding a polypeptide chain forming such a binding protein).

As used herein, the term “swapability” refers to the interchangeability of variable domains in the form of a binding protein while maintaining folding and ultimate binding affinity. "Fully swappable" refers to reversing the order of the V _H1 and V _H2 domains in a polypeptide chain of Formula I or a polypeptide chain of Formula II, while maintaining the overall function of the binding protein, as evidenced by maintenance of binding affinity, resulting in _{V L1} and V _{refers to the ability to change the order of the L2} domains (ie, the ability to reverse the order). It is also noted that the notations V _H and V _L indicate only the position of the domain in a particular protein chain in the final form. For example, V _H1 and V _{H2 may be derived from the V L1} and V _L2 domains of a parent antibody and may be located at the V _H1 and V _H2 positions of the binding protein. Similarly, V _L1 and V _{L2 may be derived from the V H1} and V _H2 domains of the parent antibody and may be located at the V _H1 and V _H2 positions of the binding protein. Thus, the V _H and V _L notations refer to the current position and not the original position in the parent antibody. Thus, the V _H and V _L domains are “swappable”.

As used herein, the term “antigen” or “target antigen” or “antigen target” refers to a molecule capable of being bound by a binding protein and further used in an animal to generate an antibody capable of binding to an epitope of that antigen or Refers to a part of a molecule. A target antigen may have more than one epitope. For each target antigen recognized by the binding protein, the binding protein can compete with an intact antibody that recognizes the target antigen.

The term “Her2” refers to human epidermal growth factor receptor 2, a member of the epidermal growth factor receptor family.

"CD3" is a differentiation factor cluster 3 polypeptide and is a T cell surface protein that is generally part of the T cell receptor (TCR) complex.

"CD28" is a differentiation cluster 28 polypeptide, a T cell surface protein that provides a costimulatory signal for T cell activation and survival.

"CD38" is a differentiation cluster 38 polypeptide, a glycoprotein found on the surface of many immune cells.

The term "T-cell engager" refers to a binding protein directed against a tumor target protein as well as a binding protein directed against the cytotoxic activity of a host's immune system, more specifically, a T cell.

The term “monospecific binding protein” refers to a binding protein that specifically binds to one antigenic target.

The term “monovalent binding protein” refers to a binding protein having one antigen binding site.

The term “bispecific binding protein” refers to a binding protein that specifically binds to two different antigenic targets.

The term “bivalent binding protein” refers to a binding protein having two binding sites.

The term “trispecific binding protein” refers to a binding protein that specifically binds to three different antigenic targets.

The term “trivalent binding protein” refers to a binding protein having three binding sites. In certain embodiments, a trivalent binding protein is capable of binding one antigen target. In other embodiments, the trivalent binding protein is capable of binding two antigenic targets. In other embodiments, the trivalent binding protein is capable of binding three antigen targets.

An “isolated” binding protein is one that has been identified, separated and/or recovered from a component of its natural environment. Contaminant components of the natural environment are substances that would interfere with diagnostic or therapeutic uses of the binding protein, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. In some embodiments, the binding protein contains (1) greater than 95%, most preferably greater than 99% by weight of antibody as determined by the Lowry method, (2) N-terminal or internal amino acids using a spinning cup sequencer will be purified to homogeneity by SDS-PAGE in reducing or non-reducing conditions to a sufficient extent to obtain at least 15 residues of the sequence, or (3) using Coomassie blue or preferably silver staining. An isolated binding protein comprises the binding protein in situ within the recombinant cell since at least one component of the binding protein's natural environment will not be present.

As used herein, the term "substantially pure" or "substantially purified" refers to a species or compound that is the predominant species present (ie, more abundant than any other individual species in the composition on a molar basis). In some embodiments, the substantially purified fraction is a composition comprising at least about 50% (on a molar basis) of all macromolecular species present. In other embodiments, a substantially pure composition will comprise greater than about 80%, 85%, 90%, 95%, or 99% of all macromolecular species present in the composition. In another embodiment, purified to essentially homogeneity (contaminant species cannot be detected in the composition by conventional detection methods), and the composition consists essentially of a single macromolecular species.

The term "epitope" includes any determinant, preferably a polypeptide determinant, capable of specifically binding to an immunoglobulin or T cell receptor. In certain embodiments, epitope determinants include chemically active surface groups of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, which in certain embodiments will have specific three-dimensional structural properties and/or specific charge properties. can An epitope is a region of an antigen to which an antibody or binding protein binds. In certain embodiments, a binding protein is said to specifically bind an antigen when the binding protein preferentially recognizes a target antigen in a complex mixture of proteins and/or macromolecules. In some embodiments, the binding protein is antigen specific when the equilibrium dissociation constant is 10 ^-8 M or less, more preferably the equilibrium dissociation constant is 10 ^-9 M or less, and most preferably the dissociation constant is 10 ^{-10 M or less.} is said to be combined with

The dissociation constant (K _D ) of a binding protein can be determined, for example, by surface plasmon resonance. In general, surface plasmon resonance assays involve the use of a BIAcore system (Pharmacia Biosensor; Piscataway, NJ) between a ligand (target antigen on a biosensor matrix) and analyte (binding protein in solution) via surface plasmon resonance (SPR). Real-time binding interactions are measured. Surface plasmon analysis can also be performed by immobilization of an analyte (binding protein on a biosensor matrix) and presentation of a ligand (target antigen). As used herein, the term “K _D ” refers to the dissociation constant of an interaction between a particular binding protein and a target antigen.

As used herein, the term "specifically binding" refers to at least about 1 x 10 ^-6 M, 1 x 10 ^-7 M, 1 x 10 ^-8 M, 1 x 10 ^-9 M, 1 x 10 ^-10 M, of a binding protein or antigen-binding fragment thereof that binds to an epitope-containing antigen with a Kd of 1 x 10 ^-11 M, 1 x 10 ^-12 M or greater and/or binds to an epitope with an affinity that is at least 2-fold greater than the degree of substitution for a non-specific antigen indicates ability.

In some embodiments, antigen binding domains and/or binding proteins of the invention are human and cynomolgus monkey CD38 polypeptides, e.g., CD38 extracellular domain, human CD38 isoform A, human CD38 isoform E, and cynomolgus It "cross-reacts" with monkey CD38. A binding protein that binds antigen 1 (Ag1) is "cross-reactive" to antigen 2 (Ag2) when the EC50 is in a similar range for both antigens. In the present application, binding protein binding to Ag1 is cross-reactive to Ag2 when the ratio of the affinity of Ag2 to that of Ag1 is 20 or less (affinity is measured in the same way for both antigens).

As used herein, the term “linker” refers to one or more amino acid residues inserted between the immunoglobulin domains to provide the domains of the light and heavy chains with sufficient mobility to fold into a crossed double variable region immunoglobulin. A linker is inserted at the sequence level at the transition between the variable domains or between the variable domain and the constant domain, respectively. Transitions between domains can be identified because the approximate size of the immunoglobulin domains is well known. The exact location of the domain transition site is a region of peptide stretch that does not form secondary structural elements such as beta sheets or alpha helices, as evidenced by experimental data or can be estimated by modeling or secondary structure prediction techniques. can be found and determined. The linkers described herein include _{L 1} located in the light chain between the _{C-terminus of V L2} and the N-terminus of the V _L1 domain; and _{L 2} located in the light chain between the _{C-terminus of V L1} and the N-terminus of the C _L domain. The heavy chain linker is _{L 3} located between _{the C-terminus of V H1} and the N-terminus of the V _H2 domain; and _{L 4} located between the _{C-terminus of V H2} and the N-terminus of the C _H1 domain.

As used herein, the term “vector” refers to any molecule (eg, nucleic acid, plasmid, or virus) used to transfer coding information to a host cell. The term “vector” includes a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which represents a circular double-stranded DNA molecule into which additional DNA segments can be inserted. Another type of vector is a viral vector into which additional DNA segments can be inserted within the viral genome. Certain vectors (eg, bacterial vectors with a bacterial origin of replication and episomal mammalian vectors) are capable of autonomous replication in the host cell into which they are introduced. Other vectors (eg, non-episomal mammalian vectors) can integrate into the genome of a host cell upon introduction into the host cell and replicate along with the host genome. In addition, certain vectors are capable of directing the expression of operably linked genes. Such vectors are referred to herein as “recombinant expression vectors” (or simply “expression vectors”). In general, expression vectors useful in recombinant DNA technology are usually in the form of plasmids. Since a plasmid is the most commonly used form of vector, the terms "plasmid" and "vector" may be used interchangeably herein. However, the present invention is intended to include other forms of expression vectors, such as viral vectors (eg, replication defective retroviruses, adenoviruses, and adeno-associated viruses), which serve equivalent functions.

As used herein, the phrase “recombinant host cell” (or “host cell”) refers to a cell into which a recombinant expression vector has been introduced. Recombinant host cell or host cell is intended to refer to the particular subject cell as well as the progeny of such cell. Because certain modifications may occur in subsequent generations due to mutation or environmental influences, such progeny may not in fact be identical to the parent cell, but such cells are still included within the scope of the term "host cell" as used herein. A wide variety of host cell expression systems can be used to express the binding protein, including bacterial, yeast, baculovirus, and mammalian expression systems (as well as phage display expression systems). An example of a suitable bacterial expression vector is pUC19. For recombinant expression of the binding protein, the host cell is transformed or transfected with one or more recombinant expression vectors carrying a DNA fragment encoding the polypeptide chain of the binding protein, whereby the polypeptide chain is expressed in the host cell, preferably is secreted into the medium in which the host cells are cultured, and the binding protein can be recovered from the medium.

As used herein, the term “transformation” refers to a change in the genetic properties of a cell, wherein a cell has been transformed when it has been modified to contain new DNA. For example, a cell is transformed when it is genetically modified from its native state. After transformation, the transforming DNA can be physically integrated into the cell's chromosome and recombined with the cell's DNA, can be temporarily maintained as an episomal element without replication, or replicated independently as a plasmid. A cell is considered to be stably transformed when DNA replicates with cell division. As used herein, the term “transfection” refers to the uptake of foreign or exogenous DNA by a cell, and a cell is “transfected” when the exogenous DNA has been introduced inside the cell membrane. A number of transfection techniques are well known in the art. Such techniques can be used to introduce one or more exogenous DNA molecules into a suitable host cell.

The term "naturally occurring" as used herein and applied to a subject refers to the fact that the subject can be found in nature and has not been manipulated by humans. For example, a polynucleotide or polypeptide present in an organism (including viruses) that can be isolated from a source in nature and has not been intentionally modified by humans is naturally occurring. Similarly, "non-naturally occurring" as used herein refers to an object not found in nature or structurally modified or synthesized by humans.

As used herein, the twenty common amino acids and their abbreviations follow conventional usage. stereoisomers of the 20 common amino acids (eg, d-amino acids); Unnatural amino acids and analogs such as α-, α-disubstituted amino acids, N-alkyl amino acids, lactic acid, and other unconventional amino acids may also be suitable components of the polypeptide chain of a binding protein. Examples of unconventional amino acids include 4-hydroxyproline, γ-carboxyglutamate, ε-N,N,N-trimethyllysine, ε-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formyl methionine, 3-methylhistidine, 5-hydroxylysine, σ-N-methylarginine, and other similar amino acids and imino acids (eg, 4-hydroxyproline). In polypeptide notation as used herein, the left direction is the amino-terminal direction and the right direction is the carboxy-terminal direction according to standard usage and conventions.

Naturally occurring residues can be classified into the following classes according to their common side chain properties.

(1) hydrophobic: Met, Ala, Val, Leu, Ile, Phe, Trp, Tyr, Pro;

(2) polar hydrophilicity: Arg, Asn, Asp, Gin, Glu, His, Lys, Ser, Thr;

(3) aliphatic: Ala, Gly, Ile, Leu, Val, Pro;

(4) aliphatic hydrophobic: Ala, Ile, Leu, Val, Pro;

(5) neutral hydrophilicity: Cys, Ser, Thr, Asn, Gin;

(6) acidic: Asp, Glu;

(7) Basic: His, Lys, Arg;

(8) residues affecting chain orientation: Gly, Pro;

(9) aromatic: His, Trp, Tyr, Phe; and

(10) Aromatic hydrophobicity: Phe, Trp, Tyr.

Conservative amino acid substitutions may involve exchanging a member of one of these classes for another member of the same class. Non-conservative substitutions may include exchanging members of one of these classes for members of another class.

Those skilled in the art will be able to determine suitable variants of the polypeptide chain of the binding protein using well-known techniques. For example, one of ordinary skill in the art can identify suitable regions of a polypeptide chain that can be changed without disrupting activity by targeting regions that are not considered to be critical for activity. Alternatively, one of ordinary skill in the art can identify residues and portions of molecules that are conserved among similar polypeptides. Conservative amino acid substitutions can also be made without disrupting biological activity or adversely affecting polypeptide structure, even in regions that may be important for biological activity or structure.

As used herein, the term “patient” includes human and animal subjects.

As used herein, the term “treatment” refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those with the disorder as well as those prone to develop the disorder or those in which the disorder is to be prevented. In certain embodiments, the binding protein can be used to treat a human afflicted with or susceptible to cancer, or used to ameliorate cancer in a human subject. The binding protein can also be used to prevent cancer in human patients. In certain embodiments, the cancer is multiple myeloma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, lymphoma, breast cancer such as Her2+ breast cancer, germinal center B-cell lymphoma, or B-cell acute lymphoblastic leukemia. In another embodiment, the binding protein can be used to treat a human having an inflammatory disorder or a human prone to developing an inflammatory disorder, or used to ameliorate an inflammatory disorder in a human subject.

As used herein, the term “pharmaceutical composition” or “therapeutic composition” refers to a compound or composition capable of inducing a desired therapeutic effect when properly administered to a patient.

As used herein, the term “pharmaceutically acceptable carrier” or “physiologically acceptable carrier” refers to one or more formulation materials suitable for achieving or enhancing delivery of a binding protein.

The terms “effective amount” and “therapeutically effective amount” when used in reference to a pharmaceutical composition comprising one or more binding proteins refer to an amount or dosage sufficient to produce the desired therapeutic result. More specifically, a therapeutically effective amount is an amount of a binding protein sufficient to inhibit for a period of time one or more of the clinically defined pathological processes associated with the condition being treated. The effective amount will vary depending on the particular binding protein used, and will also depend on various factors associated with the patient being treated and the severity of the condition and disorder. For example, if the binding protein is to be administered in vivo, factors such as age, weight, and health of the patient, as well as dose response curves and toxicity data obtained from preclinical animal studies, will be among the factors considered. Determination of an effective or therapeutically effective amount of a given pharmaceutical composition is within the ability of one of ordinary skill in the art.

One embodiment of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a binding protein.

trispecific and/or trivalent binding proteins

Certain aspects of the present invention relate to trispecific and/or trivalent binding proteins comprising four polypeptide chains forming three antigen binding sites that specifically bind to one or more target proteins, comprising: A first pair of polypeptides has dual variable domains with cross orientation and a second pair of polypeptides that form the binding protein has a single variable domain. Any CDR or variable domain of any antigen binding protein described herein may be used in the trispecific binding protein of the invention.

In some embodiments, each of the three antigen binding sites binds a different target (eg, a polypeptide antigen). In some embodiments, the trispecific binding protein comprises four polypeptide chains forming three antigen binding sites, and the first polypeptide chain comprises a structure represented by the formula

V _L2 -L ₁ -V _L1 -L ₂ -C _L [I]

The second polypeptide chain comprises a structure represented by the formula

V _H1 -L ₃ -V _H2 -L ₄ -C _{H1 -Hinge} -C _H2 -C _H3 [II]

The third polypeptide chain comprises a structure represented by the formula

V _H3 -C _{H1 -Hinge} -C _H2 -C _H3 [III]

The fourth polypeptide chain comprises a structure represented by the formula

V_L3-C_L [IV]

during the meal,

V _L1 is a first immunoglobulin light chain variable domain;

V _L2 is a second immunoglobulin light chain variable domain;

V _L3 is a third immunoglobulin light chain variable domain;

V _H1 is a first immunoglobulin heavy chain variable domain;

V _H2 is a second immunoglobulin heavy chain variable domain;

V _H3 is a third immunoglobulin heavy chain variable domain;

_CL is an immunoglobulin light chain constant domain;

C _H1 is an immunoglobulin C _H1 heavy chain constant domain;

C _H2 is an immunoglobulin C _H2 heavy chain constant domain;

C _H3 is an immunoglobulin C _H3 heavy chain constant domain;

The hinge is an immunoglobulin hinge region that connects the _{C H1} domain and the C _{H2 domain;}

L ₁ , L ₂ , L ₃ , and L ₄ are amino acid linkers;

The polypeptide of formula I and the polypeptide of formula II form a cross light chain-heavy chain pair.

It is contemplated that any antigen binding site described herein may be used in a trispecific binding protein of the invention comprising, for example, four polypeptide chains having the structures described above. For example, in some embodiments, a trispecific binding protein of the invention comprises a _{pair of V H1} and V _{L1 domains forming a first antigen binding site, V H2} forming a second antigen binding site that binds a CD3 polypeptide, and a _{pair of V L2} domains, and a pair of V _H3 and V _L3 domains that form a third antigen binding site. In some embodiments, a trispecific binding protein of the invention comprises a _{pair of V H1} and V _{L1 domains that form a first antigen binding site that binds a CD28 polypeptide, V H2} that forms a second antigen binding site that binds a CD3 polypeptide and a _{pair of V L2} domains, and a pair of V _H3 and V _L3 domains that form a third antigen binding site. In some embodiments, a trispecific binding protein of the invention comprises a _{pair of V H1} and V _{L1 domains forming a first antigen binding site, a pair of V H2} and V _L2 domains forming a second antigen binding site that binds a CD3 polypeptide , and a pair of _{V H3} and V _L3 domains that form a third antigen binding site that binds a tumor target protein. In some embodiments, a trispecific binding protein of the invention comprises a _{pair of V H1} and V _{L1 domains that form a first antigen binding site that binds a CD28 polypeptide, V H2} that forms a second antigen binding site that binds a CD3 polypeptide and a _{pair of V L2 domains, and a pair of V H3} and V _L3 domains that form a third antigen binding site that binds a tumor target protein. In some embodiments, a trispecific binding protein of the invention comprises a _{pair of V H1} and V _{L1 domains that form a first antigen binding site that binds a CD28 polypeptide, V H2} that forms a second antigen binding site that binds a CD3 polypeptide and a _{pair of V L2 domains, and a pair of V H3} and V _L3 domains that form a third antigen binding site that binds the CD38 polypeptide. In some embodiments, a trispecific binding protein of the invention comprises a _{pair of V H1} and V _{L1 domains that form a first antigen binding site that binds a CD28 polypeptide, V H2} that forms a second antigen binding site that binds a CD3 polypeptide and a _{pair of V L2 domains, and a pair of V H3} and V _L3 domains that form a third antigen binding site that binds the HER2 polypeptide.

In some embodiments, a binding protein of the invention binds one or more tumor target proteins and one or more T cell target proteins. In some embodiments, a binding protein is capable of specifically binding one tumor target protein and two different epitopes on a single T cell target protein. In some embodiments, the binding protein is capable of specifically binding one tumor target protein and two different T cell target proteins (eg, CD28 and CD3). In some embodiments, the first and second polypeptide chains of the binding protein form two antigen binding sites that specifically target two T cell target proteins, and the third and fourth polypeptide chains of the binding protein are tumor targets Forms an antigen binding site that specifically binds to a protein. In some embodiments, the target protein is CD38 or HER2. Additional tumor target proteins are provided below. In some embodiments, the one or more T cell target proteins are one or more of CD3 and CD28. Exemplary, non-limiting polypeptides that can be used in any of the trispecific binding proteins described herein are provided in Table 1.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 156 or the amino acid sequence of SEQ ID NO: 156 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 157 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 157; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 158 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 158; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 159 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 159.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 160 or the amino acid sequence of SEQ ID NO: 160 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 161 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 161; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 162 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 162; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:163 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:163.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 164 or the amino acid sequence of SEQ ID NO: 164 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 165 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 165; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 166 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 166; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 167 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 167.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 168 or the amino acid sequence of SEQ ID NO: 168 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 169 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 169; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 170 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 170; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 171 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 171.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 172 or the amino acid sequence of SEQ ID NO: 172 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 173 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 173; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 174 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 174; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 175 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 175.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 176 or the amino acid sequence of SEQ ID NO: 176 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 177 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 177; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 178 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 178; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 179 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 179.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 181 or the amino acid sequence of SEQ ID NO: 181 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 182 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 182; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 183 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 183; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 184 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 184.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 185 or the amino acid sequence of SEQ ID NO: 185 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 186 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 186; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:187 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:187; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 188 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 188.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 100 or the amino acid sequence of SEQ ID NO: 100 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 101 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 101; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 102 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 102; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 103 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 103.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 104 or the amino acid sequence of SEQ ID NO: 104 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 105 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 105; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 106 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 106; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 107 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 107.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 112 or the amino acid sequence of SEQ ID NO: 112 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 113 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 113; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 114 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 114; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 115 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 115.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 116 or the amino acid sequence of SEQ ID NO: 116 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 117 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 117; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 118 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 118; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 119 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 119.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 120 or the amino acid sequence of SEQ ID NO: 120 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 121 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 121; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 122 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 122; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:123 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:123.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 124 or the amino acid sequence of SEQ ID NO: 124 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 125 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 125; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 126 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 126; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 127 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 127.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 128 or the amino acid sequence of SEQ ID NO: 128 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 129 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 129; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 130 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 130; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 131.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 132 or the amino acid sequence of SEQ ID NO: 132 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 133 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 133; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 134 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 134; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 135 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 135.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 136 or the amino acid sequence of SEQ ID NO: 136 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 137 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 137; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 138; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 139 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 139.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 140 or the amino acid sequence of SEQ ID NO: 140 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 141 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 141; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 142 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 142; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 143 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 143.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 144 or the amino acid sequence of SEQ ID NO: 144 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 145 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 145; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 146 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 146; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 147 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 147.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 148 or the amino acid sequence of SEQ ID NO: 148 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 149 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 149; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 150 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 150; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 151 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 151.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 152 or the amino acid sequence of SEQ ID NO: 152 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 153 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 153; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 154 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 154; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 155 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 155.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 286 or the amino acid sequence of SEQ ID NO: 286 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 287 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 287; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 288 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 288; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 289 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 289.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 290 or the amino acid sequence of SEQ ID NO: 290 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 291 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 291; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 292 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 292; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 293 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 293.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 294 or the amino acid sequence of SEQ ID NO: 294 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 295 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 295; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 296 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 296; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 297 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 297.

In some embodiments, a binding protein of the invention comprises four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is at least 95% identical to the amino acid sequence of SEQ ID NO: 298 or the amino acid sequence of SEQ ID NO: 298 comprising an amino acid sequence; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 299 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 299; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 300 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 300; The fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 301 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 301.

anti-CD38 binding site

Certain aspects of the invention relate to binding proteins comprising an antigen binding site that binds to a CD38 polypeptide. In some embodiments, the CD38 polypeptide is a human CD38 polypeptide, also known as ADPRC1. Human CD38 polypeptides are known in the art and include, without limitation, the polypeptide designated by NCBI accession number NP_001766.2, or a polypeptide produced from NCBI gene ID number 952. In some embodiments, the antigen binding site binds to a human CD38 polypeptide, a non-human primate (eg, cynomolgus monkey) CD38 polypeptide, or a human CD38 polypeptide and a non-human primate (eg, cynomolgus monkey) CD38 polypeptide . In some embodiments, the binding protein comprising an antigen binding site that binds to a CD38 polypeptide is monospecific and/or monovalent, bispecific and/or bivalent, trispecific and/or trivalent, or multispecific and/or polyvalent.

In some embodiments, any of the CDRs and/or variable domains of the following anti-CD38 binding sites can be used in monospecific antibodies.

In other embodiments, any of the following anti-CD38 binding sites of any of the CDRs and/or variable domains of a trispecific binding protein comprising four polypeptides forming three antigen binding sites, e.g., as described above It can be used at the binding site. In certain embodiments, the binding protein comprising an antigen binding site that binds to a CD38 polypeptide is a trispecific binding protein comprising four polypeptides forming three antigen binding sites as described above, wherein the V _H3 and V _L3 domains are pair to form a third antigen binding site that binds to the CD38 polypeptide.

Various characteristics of exemplary binding sites and binding proteins are described herein. For example, in some embodiments, the anti-CD38 binding site cross-reacts with human CD38 (eg, human CD38 isoform A and/or isoform E polypeptide) and cynomolgus monkey CD38. In some embodiments, a binding protein comprising an anti-CD38 binding site induces apoptosis of a CD38+ cell. In some embodiments, a binding protein comprising an anti-CD38 binding site recruits CD38+ cells to T cells and selectively activates T cells (eg, via TCR stimulation and/or costimulation).

In some embodiments, the binding site that binds CD38 comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYA (SEQ ID NO: 13), a CDR-H2 sequence comprising the amino acid sequence of IYPGQGGT (SEQ ID NO: 14), and ARTGGLRRAYFTY (SEQ ID NO: 14) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 15); and/or a CDR-L1 sequence comprising the amino acid sequence of QSVSSYGQGF (SEQ ID NO: 16), a CDR-L2 sequence comprising the amino acid sequence of GAS (SEQ ID NO: 17), and an amino acid sequence of QQNKEDPWT (SEQ ID NO: 18) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds CD38 comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYA (SEQ ID NO: 13), a CDR-H2 sequence comprising the amino acid sequence of IYPGQGGT (SEQ ID NO: 14), and ARTGGLRRAYFTY (SEQ ID NO: 14) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 15); and a CDR-L1 sequence comprising the amino acid sequence of QSVSSYGQGF (SEQ ID NO: 16), a CDR-L2 sequence comprising the amino acid sequence of GAS (SEQ ID NO: 17), and a CDR- comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO: 18)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the binding site that binds to CD38 comprises a CDR-H1 sequence comprising the amino acid sequence of GYTLTEFS (SEQ ID NO: 19), a CDR-H2 sequence comprising the amino acid sequence of FDPEDGET (SEQ ID NO: 20), and TTGRFFDWF (SEQ ID NO: 20) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of number 21); and/or a CDR-L1 sequence comprising the amino acid sequence of QSVISRF (SEQ ID NO: 22), a CDR-L2 sequence comprising the amino acid sequence of GAS (SEQ ID NO: 23), and an amino acid sequence of QQDSNLPIT (SEQ ID NO: 24) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds to CD38 comprises a CDR-H1 sequence comprising the amino acid sequence of GYTLTEFS (SEQ ID NO: 19), a CDR-H2 sequence comprising the amino acid sequence of FDPEDGET (SEQ ID NO: 20), and TTGRFFDWF (SEQ ID NO: 20) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of number 21); and a CDR-L1 sequence comprising the amino acid sequence of QSVISRF (SEQ ID NO: 22), a CDR-L2 sequence comprising the amino acid sequence of GAS (SEQ ID NO: 23), and a CDR- comprising the amino acid sequence of QQDSNLPIT (SEQ ID NO: 24)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the binding site that binds CD38 comprises a CDR-H1 sequence comprising the amino acid sequence of GYAFTTYL (SEQ ID NO: 25), a CDR-H2 sequence comprising the amino acid sequence of INPGSGST (SEQ ID NO: 26), and ARYAYGY (SEQ ID NO: 26) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of number 27); and/or a CDR-L1 sequence comprising the amino acid sequence of QNVGTA (SEQ ID NO: 28), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 29), and an amino acid sequence of QQYSTYPFT (SEQ ID NO: 30) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds CD38 comprises a CDR-H1 sequence comprising the amino acid sequence of GYAFTTYL (SEQ ID NO: 25), a CDR-H2 sequence comprising the amino acid sequence of INPGSGST (SEQ ID NO: 26), and ARYAYGY (SEQ ID NO: 26) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of number 27); and a CDR-L1 sequence comprising the amino acid sequence of QNVGTA (SEQ ID NO: 28), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 29), and a CDR- comprising the amino acid sequence of QQYSTYPFT (SEQ ID NO: 30)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the binding site that binds CD38 comprises a CDR-H1 sequence comprising the amino acid sequence of GYAFTTYL (SEQ ID NO: 31), a CDR-H2 sequence comprising the amino acid sequence of INPGSGST (SEQ ID NO: 32), and ARYAYGY (SEQ ID NO: 32) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 33); and/or a CDR-L1 sequence comprising the amino acid sequence of QSLVHSNGNTY (SEQ ID NO: 34), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 35), and an amino acid sequence of SQSTHVPLT (SEQ ID NO: 36) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds CD38 comprises a CDR-H1 sequence comprising the amino acid sequence of GYAFTTYL (SEQ ID NO: 31), a CDR-H2 sequence comprising the amino acid sequence of INPGSGST (SEQ ID NO: 32), and ARYAYGY (SEQ ID NO: 32) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 33); and a CDR-L1 sequence comprising the amino acid sequence of QSLVHSNGNTY (SEQ ID NO: 34), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 35), and a CDR- comprising the amino acid sequence of SQSTHVPLT (SEQ ID NO: 36)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the binding site that binds to CD38 comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO: 37), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO: 38), and ARDPGLRYFDGGMDV (SEQ ID NO: 38) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of number 39); and/or a CDR-L1 sequence comprising the amino acid sequence of QGISSY (SEQ ID NO: 40), a CDR-L2 sequence comprising the amino acid sequence of AAS (SEQ ID NO: 41), and an amino acid sequence of QQLNSFPYT (SEQ ID NO: 42) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds to CD38 comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO: 37), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO: 38), and ARDPGLRYFDGGMDV (SEQ ID NO: 38) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of number 39); and a CDR-L1 sequence comprising the amino acid sequence of QGISSY (SEQ ID NO: 40), a CDR-L2 sequence comprising the amino acid sequence of AAS (SEQ ID NO: 41), and a CDR- comprising the amino acid sequence of QQLNSFPYT (SEQ ID NO: 42)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the binding site that binds CD38 comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO: 43), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO: 44), and ARMFRGAFDY (SEQ ID NO: 44) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 45); and/or a CDR-L1 sequence comprising the amino acid sequence of QGIRND (SEQ ID NO: 46), a CDR-L2 sequence comprising the amino acid sequence of AAS (SEQ ID NO: 47), and an amino acid sequence of LQDYIYYPT (SEQ ID NO: 48) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds CD38 comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO: 43), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO: 44), and ARMFRGAFDY (SEQ ID NO: 44) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 45); and a CDR-L1 sequence comprising the amino acid sequence of QGIRND (SEQ ID NO: 46), a CDR-L2 sequence comprising the amino acid sequence of AAS (SEQ ID NO: 47), and a CDR- comprising the amino acid sequence of LQDYIYYPT (SEQ ID NO: 48)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the binding site that binds CD38 comprises at least 88%, at least 89%, at least 89%, 88%, at least 89%, at least 89%, at least 89%, at least 89%, at least 89%, at least 89% of the QVQLVQSGAEVVKPGASVKVSCKASGYTFTSYAMHWVKEAPGQRLEWIGYIYPGQGGTNYNQKFQGRATLTADTSASTAYMELSSLRSEDTAVYFCARTGGLRRAYFTYWGQGTLVTVSS amino acid sequence of the SEQ ID NO: an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or the amino acid sequence of DIVLTQSPATLSLSPGERATISCRASQSVSSYGQGFMHWYQQKPGQPPRLLIYGASSRATGIPARFSGSGSGTDFTLTISPLEPEDFAVYYCQQNKEDPWTFGGGTKLEIK (SEQ ID NO: 80) and at least 85%, at least 86%, at least 87%, at least 93%, at least 94% %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds CD38 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 79, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 80 do. In some embodiments, the binding site that binds CD38 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 79, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 80.

In some embodiments, the binding site that binds to CD38 has an amino acid sequence of at least 88%, at least 87%, 89%, at least 86%, at least 87%, 89%, at least 86%, at least 87%, 89%, at least 86%, at least 88%, at least 85%, 91, an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or the amino acid sequence of EIILTQSPAILSLSPGERATLSCRASQSVISRFLSWYQVKPGLAPRLIYGASTRATGIPVRFSGSGSGTDFSLTISSLQPEDCAVYYCQQDSNLPITFGQGTRLEIK (SEQ ID NO: 82) and at least 85%, at least 86%, at least 87%, at least 92%, at least 89%, at least 93%, at least 90%, at least 89% %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds CD38 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 81, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 82 do. In some embodiments, the binding site that binds CD38 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 81, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 82.

In some embodiments, the binding site that binds to CD38 comprises an amino acid sequence of at least 86%, at least 87%, 89%, at least 86%, at least 87%, 89%, at least 86%, at least 87%, 89%, 91 an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or at least 85%, at least 86%, at least 92%, at least 89%, at least 89%, at least 94%, at least 86%, at least 92%, at least 89%, at least 89% of %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds CD38 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 83, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 84 do. In some embodiments, the binding site that binds CD38 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 83, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 84.

In some embodiments, the binding site that binds CD38 comprises an amino acid sequence of at least 86%, at least 87%, at least 87%, at least 86%, at least 85%, 89%, at least 86%, at least 87%, 89%, an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or the amino acid sequence of DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIFAASTLHSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQLNSFPYTFGQGTKLEIK (SEQ ID NO: 88) and at least 90% 94, at least 86%, at least 92%, 87%, at least 89%, at least 94% %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds CD38 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 87, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 88 do. In some embodiments, the binding site that binds CD38 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 87, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 88.

In some embodiments, the binding site that binds CD38 comprises an amino acid sequence of QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISGDNSKNTLYLQMNSLRAEDTAVYYCARMFRGAFDYWGQGTLVTVSS (SEQ ID NO: 89), at least 86%, at least 85%, at least 89%, at least 89%, at least 89%, at least 89%, at least 89%, an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or the amino acid sequence of AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISGLQPEDSATYYCLQDYIYYPTFGQGTKVEIK (SEQ ID NO: 90) and at least 85%, at least 86%, at least 87%, at least 93%, at least 90%, at least 89%, at least 92%, at least 94% %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds CD38 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 89, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 90 do. In some embodiments, the binding site that binds CD38 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 89, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 90.

In some embodiments, the binding site that binds to CD38 comprises at least 88%, at least 87%, at least 85%, at least 86%, at least 87%, at least 85%, at least 86%, at least 87%, 89%, 86%, at least 86%, at least 87%, 89%, 91% of the amino acid sequence of QVQLVQSGAEVKKPGASVKVSCKASGYSFTNYAVHWVRQAPGQGLEWMGVISPYYGDTTYAQKFQGRVTMTVDKSSSTAYMELSRLRSDDTAVYYCARRFEGFYYSMDYWGQGTLVTVSS an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or the amino acid sequence of DVVMTQSPLSLPVTLGQPASISCRPSQSLVHSNGNTYLNWYQQRPGQSPKLLIYKVSKRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGGGTKVEIK (SEQ ID NO: 86) at least 85%, at least 86%, at least 92%, at least 89%, at least 93%, at least 86%, at least 92%, at least 87% %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds CD38 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 85, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 86 do. In some embodiments, the binding site that binds CD38 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO:85, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO:86.

In some embodiments, the binding site that binds to CD38 comprises an amino acid sequence of QVQLQQSGPELVRPGTSVKVSCKASGYAFTTYLVEWIKQRPGQGLEWIGVINPGSGSTNYNEKFKGKATLTVDRSSTTAYMHLSGLTSDDSAVYFCARYAYGYWGQGTTLTVSS (SEQ ID NO: 277), at least 86%, at least 89%, at least 89%, at least 89%, at least 89%, at least 89%, at least 85% an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or the amino acid sequence of DIVMTQSQKFMSASVGDRVSITCKASQNVGTAVAWYQQQPGHSPKQLIYSASNRYTGVPDRFTGSGAGTDFTLTISNIQSEDLADYFCQQYSTYPFTFGSGTKLEIK (SEQ ID NO: 278) and at least 90%, at least 86%, at least 92%, at least 87%, at least 89%, at least 94%, at least 86%, at least 92%, at least 87%, at least 89% %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds CD38 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 277, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 278 do. In some embodiments, the binding site that binds CD38 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 277, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 278. In some embodiments, the VH and/or VL domains are humanized.

In some embodiments, the binding site that binds CD38 comprises an amino acid sequence of at least 86%, at least 87%, 89%, at least 86%, at least 87%, 89%, at least 86%, at least 87%, 89%, 91 an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or the amino acid sequence of DVVMIQTPLSLPVSLGDQASISCRPSQSLVHSNGNTYLNWYLQRPGQSPKLLIYKVSKRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYLCSQSTHVPLTFGSGTQLEIK (SEQ ID NO: 28089%) at least 85%, at least 86%, at least 92%, at least 91% %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds CD38 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 279, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 280 do. In some embodiments, the binding site that binds CD38 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 279, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 280. In some embodiments, the VH and/or VL domains are humanized.

In some embodiments of any of the above embodiments, the binding protein is a trispecific binding protein. In some embodiments, the trispecific binding protein comprises an antigen binding site that binds a CD38 polypeptide, an antigen binding site that binds a CD28 polypeptide, and an antigen binding site that binds a CD3 polypeptide. In some embodiments, the binding protein is a trispecific binding protein comprising four polypeptides comprising three antigen binding sites, wherein the polypeptide of formula I and the polypeptide of formula II are (eg, as described herein) form cross-light chain-heavy chain pairs. In some embodiments, the VH and VL domains of any of the anti-CD38 antigen binding sites described above represent V _H3 and V _L3 and form a third antigen binding site that binds the CD38 polypeptide. In some embodiments, V _H1 and V _L1 form a first antigen binding site that binds to a CD28 polypeptide, and V _H2 and V _L2 form a second antigen binding site that binds a CD3 polypeptide, The VH and VL domains of any of the anti-CD38 antigen binding sites described in 2 represent V _H3 and V _L3 and form a third antigen binding site that binds to the CD38 polypeptide.

The sequences of exemplary anti-CD38 antigen binding sites are provided in Table 2. In some embodiments, a binding protein comprising an anti-CD38 antigen binding site of the invention comprises one, two, three, four, five or six CDR sequences of an anti-CD38 antibody set forth in Table 2 includes In some embodiments, a binding protein comprising an anti-CD38 antigen binding site of the invention comprises a VH domain sequence and/or a VL domain sequence of an anti-CD38 antibody set forth in Table 2.

[Table 2]

Anti-CD38 binding protein sequence

Further provided herein are antibodies (eg, monospecific antibodies) comprising any of the anti-CD38 CDRs and/or variable domains described above.

In some embodiments, a binding protein of the invention comprises an antigen binding site that binds to the extracellular domain of a human CD38 polypeptide and an extracellular domain of a cynomolgus monkey CD38 polypeptide. Exemplary assays for determining whether an antigen binding site binds an antigen are described herein and known in the art, including (without limitation) ELISA, SPR, and flow cytometry assays.

anti-HER2 binding site

Certain aspects of the invention relate to binding proteins comprising an antigen binding site that binds to a HER2 polypeptide. In some embodiments, the HER2 polypeptide is a human HER2 polypeptide, also known as NEU, NGL, ERBB2, TKR1, CD340, HER-2, MLN19, and HER-2/neu. Human HER2 polypeptides are known in the art and are represented by NCBI accession numbers XP_024306411.1, XP_024306410.1, XP_024306409.1, NP_001276867.1, NP_001276866.1, NP_001276865.1, NP_001005862.1, or NP_004439.2; or a polypeptide produced from NCBI gene ID number 2064. In some embodiments, a binding protein comprising an antigen binding site that binds to a HER2 polypeptide is monospecific and/or monovalent, bispecific and/or bivalent, trispecific and/or trivalent, or multispecific and/or polyvalent. In some embodiments, the binding protein comprising an antigen binding site that binds to a HER2 polypeptide is a trispecific binding protein comprising four polypeptides forming three antigen binding sites as described above, wherein the V _H3 and V _L3 domains are pair to form a third antigen binding site that binds to the HER2 polypeptide.

In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIKDTY (SEQ ID NO: 1) or GFNIRDTY (SEQ ID NO: 2), IYPTNGYT (SEQ ID NO: 3), IYPTQGYT (SEQ ID NO: 4), or a CDR-H2 sequence comprising the amino acid sequence of IYPTNAYT (SEQ ID NO: 5), and a CDR-H3 sequence comprising the amino acid sequence of SRWGGDGFYAMDY (SEQ ID NO: 6), SRWGGEGFYAMDY (SEQ ID NO: 7), or SRWGGSGFYAMDY (SEQ ID NO: 8) an antibody heavy chain variable (VH) domain comprising a; and/or a CDR-L1 sequence comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9) or QDVQTA (SEQ ID NO: 10), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and QQHYTTP (SEQ ID NO: 12) ) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence comprising the amino acid sequence of In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIKDTY (SEQ ID NO: 1) or GFNIRDTY (SEQ ID NO: 2), IYPTNGYT (SEQ ID NO: 3), IYPTQGYT (SEQ ID NO: 4), or a CDR-H2 sequence comprising the amino acid sequence of IYPTNAYT (SEQ ID NO: 5), and a CDR-H3 sequence comprising the amino acid sequence of SRWGGDGFYAMDY (SEQ ID NO: 6), SRWGGEGFYAMDY (SEQ ID NO: 7), or SRWGGSGFYAMDY (SEQ ID NO: 8) an antibody heavy chain variable (VH) domain comprising a; and a CDR-L1 sequence comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9) or QDVQTA (SEQ ID NO: 10), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and QQHYTTP (SEQ ID NO: 12) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence comprising an amino acid sequence.

In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIKDTY (SEQ ID NO: 1), a CDR-H2 sequence comprising the amino acid sequence of IYPTNGYT (SEQ ID NO: 3), and SRWGGDGFYAMDY (SEQ ID NO: 3) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of number 6); and/or a CDR-L1 sequence comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and an amino acid sequence of QQHYTTP (SEQ ID NO: 12) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIKDTY (SEQ ID NO: 1), a CDR-H2 sequence comprising the amino acid sequence of IYPTNGYT (SEQ ID NO: 3), and SRWGGDGFYAMDY (SEQ ID NO: 3) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of number 6); and a CDR-L1 sequence comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and a CDR- comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTQGYT (SEQ ID NO: 4), and SRWGGEGFYAMDY (SEQ ID NO: 4) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 7); and/or a CDR-L1 sequence comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and an amino acid sequence of QQHYTTP (SEQ ID NO: 12) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTQGYT (SEQ ID NO: 4), and SRWGGEGFYAMDY (SEQ ID NO: 4) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 7); and a CDR-L1 sequence comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and a CDR- comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTNAYT (SEQ ID NO: 5), and SRWGGSGFYAMDY (SEQ ID NO: 5) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 8); and/or a CDR-L1 sequence comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and an amino acid sequence of QQHYTTP (SEQ ID NO: 12) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTNAYT (SEQ ID NO: 5), and SRWGGSGFYAMDY (SEQ ID NO: 5) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 8); and a CDR-L1 sequence comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and a CDR- comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTQGYT (SEQ ID NO: 4), and SRWGGSGFYAMDY (SEQ ID NO: 4) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 8); and/or a CDR-L1 sequence comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and an amino acid sequence of QQHYTTP (SEQ ID NO: 12) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTQGYT (SEQ ID NO: 4), and SRWGGSGFYAMDY (SEQ ID NO: 4) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 8); and a CDR-L1 sequence comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and a CDR- comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTNAYT (SEQ ID NO: 5), and SRWGGEGFYAMDY (SEQ ID NO: 5) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 7); and/or a CDR-L1 sequence comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and an amino acid sequence of QQHYTTP (SEQ ID NO: 12) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTNAYT (SEQ ID NO: 5), and SRWGGEGFYAMDY (SEQ ID NO: 5) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 7); and a CDR-L1 sequence comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and a CDR- comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIKDTY (SEQ ID NO: 1), a CDR-H2 sequence comprising the amino acid sequence of IYPTNGYT (SEQ ID NO: 3), and SRWGGDGFYAMDY (SEQ ID NO: 3) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 6); and/or a CDR-L1 sequence comprising the amino acid sequence of QDVQTA (SEQ ID NO: 10), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and an amino acid sequence of QQHYTTP (SEQ ID NO: 12) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIKDTY (SEQ ID NO: 1), a CDR-H2 sequence comprising the amino acid sequence of IYPTNGYT (SEQ ID NO: 3), and SRWGGDGFYAMDY (SEQ ID NO: 3) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 6); and a CDR-L1 sequence comprising the amino acid sequence of QDVQTA (SEQ ID NO: 10), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and a CDR- comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTQGYT (SEQ ID NO: 4), and SRWGGEGFYAMDY (SEQ ID NO: 4) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 7) and a CDR-H3 sequence comprising the amino acid sequence of SRWGGSGFYAMDY (SEQ ID NO: 8); and/or a CDR-L1 sequence comprising the amino acid sequence of QDVQTA (SEQ ID NO: 10), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and an amino acid sequence of QQHYTTP (SEQ ID NO: 12) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTQGYT (SEQ ID NO: 4), and SRWGGEGFYAMDY (SEQ ID NO: 4) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 7) and a CDR-H3 sequence comprising the amino acid sequence of SRWGGSGFYAMDY (SEQ ID NO: 8); and a CDR-L1 sequence comprising the amino acid sequence of QDVQTA (SEQ ID NO: 10), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and a CDR- comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTNAYT (SEQ ID NO: 5), and SRWGGSGFYAMDY (SEQ ID NO: 5) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 8); and/or a CDR-L1 sequence comprising the amino acid sequence of QDVQTA (SEQ ID NO: 10), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and an amino acid sequence of QQHYTTP (SEQ ID NO: 12) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTNAYT (SEQ ID NO: 5), and SRWGGSGFYAMDY (SEQ ID NO: 5) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 8); and a CDR-L1 sequence comprising the amino acid sequence of QDVQTA (SEQ ID NO: 10), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and a CDR- comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTQGYT (SEQ ID NO: 4), and SRWGGSGFYAMDY (SEQ ID NO: 4) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 8); and/or a CDR-L1 sequence comprising the amino acid sequence of QDVQTA (SEQ ID NO: 10), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and an amino acid sequence of QQHYTTP (SEQ ID NO: 12) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTQGYT (SEQ ID NO: 4), and SRWGGSGFYAMDY (SEQ ID NO: 4) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 8); and a CDR-L1 sequence comprising the amino acid sequence of QDVQTA (SEQ ID NO: 10), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and a CDR- comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTNAYT (SEQ ID NO: 5), and SRWGGEGFYAMDY (SEQ ID NO: 5) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 7); and/or a CDR-L1 sequence comprising the amino acid sequence of QDVQTA (SEQ ID NO: 10), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and an amino acid sequence of QQHYTTP (SEQ ID NO: 12) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds to HER2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTNAYT (SEQ ID NO: 5), and SRWGGEGFYAMDY (SEQ ID NO: 5) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 7); and a CDR-L1 sequence comprising the amino acid sequence of QDVQTA (SEQ ID NO: 10), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and a CDR- comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the amino acid sequence of the binding site is EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (SEQ ID NO: 72), EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTQGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGEGFYAMDYWGQGTLVTVSS (SEQ ID NO: 73), EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTQGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGSGFYAMDYWGQGTLVTVSS (SEQ ID NO: 74), EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTNAYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGSGFYAMDYWGQGTLVTVSS (SEQ ID NO: 75), or EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTNAYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGEGFYAMDYWGQGTLVTVSS (SEQ ID NO 76) that binds to HER2 and at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is 97%, at least 98%, at least 99%, or 100% identical; And / or DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77) or DIQMTQSPSSLSASVGDRVTITCRASQDVQTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK at least 85% identical to the amino acid sequence of (SEQ ID NO: 78), at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92 %, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds to HER2 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, or SEQ ID NO: 76; and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 77 or SEQ ID NO: 78. In some embodiments, the binding site that binds to HER2 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, or SEQ ID NO: 76; and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 77 or SEQ ID NO: 78.

In some embodiments, the binding site that binds to HER2 comprises an amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (SEQ ID NO: 72), at least 85%, at least 85%, at least 85%, at least 89%, at least 89%, an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77) and at least 90%, at least 86%, at least 87%, at least 89%, at least 94%, at least 86%, at least 87%, at least 89%, at least 88% %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds HER2 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 72, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 77 do. In some embodiments, the binding site that binds HER2 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 72, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 77.

In some embodiments, the binding site that binds to HER2 comprises an amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTQGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGEGFYAMDYWGQGTLVTVSS (SEQ ID NO. an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77) and at least 90%, at least 86%, at least 87%, at least 89%, at least 94%, at least 86%, at least 87%, at least 89%, at least 88% %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds HER2 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 73, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 77 do. In some embodiments, the binding site that binds HER2 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 73, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 77.

In some embodiments, the binding site that binds to HER2 comprises an amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTNAYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGSGFYAMDYWGQQGTLVTVSS (SEQ ID NO: 75), at least 89%, at least 86%, at least 85%, at least 89%, at least 89%, at least 89%, at least 88% an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77) and at least 90%, at least 86%, at least 87%, at least 89%, at least 94%, at least 86%, at least 87%, at least 89%, at least 88% %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds HER2 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 75, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 77 do. In some embodiments, the binding site that binds HER2 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO:75, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO:77.

In some embodiments, the binding site that binds to HER2 comprises an amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTQGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGSGFYAMDYWGQGTLVTVSS (SEQ ID NO. an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77) and at least 90%, at least 86%, at least 87%, at least 89%, at least 94%, at least 86%, at least 87%, at least 89%, at least 88% %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds HER2 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 74, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 77 do. In some embodiments, the binding site that binds HER2 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 74, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 77.

In some embodiments, the binding site that binds to HER2 comprises an amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTNAYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGEGFYAMDYWGQGTLVTVSS (SEQ ID NO: 76), at least 90%, at least 86%, at least 85%, at least 87%, 89%, at least 86%, an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77) and at least 90%, at least 86%, at least 87%, at least 89%, at least 94%, at least 86%, at least 87%, at least 89%, at least 88% %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds HER2 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 76, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 77 do. In some embodiments, the binding site that binds HER2 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 76, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 77.

In some embodiments, the binding site that binds to HER2 comprises an amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (SEQ ID NO: 72), at least 85%, at least 85%, at least 85%, at least 89%, at least 89%, an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or DIQMTQSPSSLSASVGDRVTITCRASQDVQTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 78) and at least 90%, at least 86%, at least 92%, at least 89%, at least 89%, %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds HER2 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 72, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 78 do. In some embodiments, the binding site that binds HER2 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 72, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 78.

In some embodiments, an anti-HER2 antigen binding site of the invention is of the anti-HER2 antibody trastuzumab, 30R/55Q/102E, 30R/56A/102S, 30R/55Q/102S, 30R/56A/102E, or 30Q. 1, 2, 3, 4, 5, or all 6 CDR sequences. In some embodiments, an anti-HER2 antigen binding site of the invention is of the anti-HER2 antibody trastuzumab, 30R/55Q/102E, 30R/56A/102S, 30R/55Q/102S, 30R/56A/102E, or 30Q. a VH domain sequence and/or a VL domain sequence.

The sequences of exemplary anti-HER2 antigen binding sites are provided in Table 3. In some embodiments, an anti-HER2 antigen binding site of the invention comprises one, two, three, four, five or all six CDR sequences of an anti-HER2 antibody set forth in Table 3. In some embodiments, an anti-HER2 antigen binding site of the invention comprises a VH domain sequence and/or a VL domain sequence of an anti-HER2 antibody set forth in Table 3.

[Table 3]

Anti-HER2 binding protein sequence

Other anti-tumor target binding sites

In some embodiments, a binding protein of the invention comprises an antigen binding site that binds to a tumor target protein. In some embodiments, the tumor target protein is a CD38 polypeptide (eg, a human CD38 polypeptide). In some embodiments, the tumor target protein is a HER2 polypeptide (eg, a human HER2 polypeptide). In some embodiments, a tumor target protein of the invention is A2AR, APRIL, ATPDase, BAFF, BAFFR, BCMA, BlyS, BTK, BTLA, B7DC, B7H1, B7H4 (also known as VTCN1), B7H5, B7H6, B7H7, B7RP1, B7 -4, C3, C5, CCL2 (also known as MCP-1), CCL3 (also known as MIP-1a), CCL4 (also known as MIP-1b), CCL5 (also known as RANTES), CCL7 (also known as MCP-3), CCL8 (also known as mcp-2), CCL11 (also known as eotaxin), CCL15 (also known as MIP-1d), CCL17 (also known as TARC), CCL19 (also known as MIP-3b), CCL20 (also known as MIP-3a) ), CCL21 (also known as MIP-2), CCL24 (also known as MPIF-2/eotaxin-2), CCL25 (also known as TECK), CCL26 (also known as eotaxin-3), CCR3, CCR4, CD3, CD19, CD20, CD23 (also known as FCER2, receptor for IgE), CD24, CD27, CD28, CD38, CD39, CD40, CD70, CD80 (also known as B7-1), CD86 (also known as B7-2), CD122, CD137 ( 41BB), CD137L, CD152 (also known as CTLA4), CD154 (also known as CD40L), CD160, CD272, CD273 (also known as PDL2), CD274 (also known as PDL1), CD275 (also known as B7H2), CD276 (also known as B7H3) CD278 (also known as ICOS), CD279 (also known as PD-1), CDH1 (also known as E-cadherin), chitinase, CLEC9, CLEC91, CRTH2, CSF-1 (also known as M-CSF), CSF-2 (also known as GM-CSF), CSF-3 (also known as GCSF), CX3CL1 (also known as SCYD1), CXCL12 (also known as SDF1), CXCL13, CXCR3, DNGR-1, ectonucleoside triphosphate diphospho Hyde Lolase 1, EGFR, ENTPD1, FCER1A, FCER1, FLAP, FOLH1, Gi24, GITR, GITRL, GM-CSF, Her2, HHLA2, HMGB1, HVEM, ICOSLG, IDO, IFNα, IgE, IGF1R, IL2Rbeta, IL1, IL1A , IL1B, IL1F10, IL2, IL4, IL4Ra, IL5, IL5R, IL6, IL7, IL7Ra, IL8, IL9, IL9R, IL10, rhIL10, IL12, IL13, IL13Ra1, IL13Ra2, IL15, IL17, IL17Rb (as a receptor for IL25 also known), IL18, IL22, IL23, IL25, IL27, IL33, IL35, ITGB4 (also known as b4 integrin), ITK, KIR, LAG3, LAMP1, leptin, LPFS2, MHC class II, MUC-1, NCR3LG1, NKG2D , NTPDase-1, OX40, OX40L, PD-1H, platelet receptor, PROM1, S152, SISP1, SLC, SPG64, ST2 (also known as receptor for IL33), STEAP2, Syk kinase, TACI, TDO, T14, TIGIT, TIM3, TLR, TLR2, TLR4, TLR5, TLR9, TMEF1, TNFa, TNFRSF7, Tp55, TREM1, TSLP (also known as a co-receptor for IL7Ra), TSLPR, TWEAK, VEGF, VISTA, Vstm3, WUCAM, and XCR1 (GPR5) /CCXCR1). In some embodiments, one or more of the antigen targets is a human antigen target.

anti-CD28 binding site

Certain aspects of the invention relate to binding proteins comprising an antigen binding site that binds to a CD28 polypeptide. In some embodiments, the CD28 polypeptide is a human CD28 polypeptide, also known as Tp44. Human CD28 polypeptides are known in the art and are produced from NCBI accession numbers XP_011510499.1, XP_011510497.1, XP_011510496.1, NP_001230007.1, NP_001230006.1, or NP_006130.1, or produced from NCBI gene ID number 940. Polypeptides are included without limitation. In some embodiments, a binding protein comprising an antigen binding site that binds to a CD28 polypeptide is monospecific and/or monovalent, bispecific and/or bivalent, trispecific and/or trivalent, or multispecific and/or polyvalent. In some embodiments, a binding protein comprising an antigen binding site that binds to a CD28 polypeptide is a trispecific binding protein comprising four polypeptides that form three antigen binding sites. In some embodiments, a binding protein comprising an antigen binding site that binds to a CD28 polypeptide comprises four polypeptides that form three antigen binding sites, one of which binds a CD28 polypeptide and one of which binds a CD3 polypeptide. It is a trispecific binding protein comprising In some embodiments, a binding protein comprising an antigen binding site that binds to a CD3 polypeptide has three antigen binding sites, one of which binds a CD28 polypeptide, one of which binds a CD3 polypeptide, and one that binds a CD38 polypeptide. ) is a trispecific binding protein comprising four polypeptides that form In some embodiments, a binding protein comprising an antigen binding site that binds to a CD3 polypeptide has three antigen binding sites, one of which binds a CD28 polypeptide, one of which binds a CD3 polypeptide, and one that binds a HER2 polypeptide. ) is a trispecific binding protein comprising four polypeptides that form In some embodiments, a binding protein comprising an antigen binding site that binds to a CD3 polypeptide has three antigen binding sites, one of which binds a CD28 polypeptide, one of which binds a CD3 polypeptide, and one that binds a tumor target protein. It is a trispecific binding protein comprising four polypeptides that form

In some embodiments, the binding site that binds to CD28 comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYY (SEQ ID NO: 49), a CDR-H2 sequence comprising the amino acid sequence of IYPGNVNT (SEQ ID NO: 50), and TRSHYGLDWNFDV (SEQ ID NO: 50) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 51); and/or a CDR-L1 sequence comprising the amino acid sequence of QNIYVW (SEQ ID NO: 52), a CDR-L2 sequence comprising the amino acid sequence of KAS (SEQ ID NO: 53), and an amino acid sequence of QQGQTYPY (SEQ ID NO: 54) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds to CD28 comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYY (SEQ ID NO: 49), a CDR-H2 sequence comprising the amino acid sequence of IYPGNVNT (SEQ ID NO: 50), and TRSHYGLDWNFDV (SEQ ID NO: 50) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 51); and a CDR-L1 sequence comprising the amino acid sequence of QNIYVW (SEQ ID NO: 52), a CDR-L2 sequence comprising the amino acid sequence of KAS (SEQ ID NO: 53), and a CDR- comprising the amino acid sequence of QQGQTYPY (SEQ ID NO: 54)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the binding site that binds to CD28 comprises at least 89%, at least 89%, at least 89%, 89%, 89%, at least 89%, 89%, 89%, SEQ ID NO: 91) of QVQLVQSGAEVVKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWIGSIYPGNVNTNYAQKFQGRATLTVDTSISTAYMELSRLRSDDTAVYYCTRSHYGLDWNFDVWG KGTTVTVSS an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCQASQNIYVWLNWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTDFTLTISSLQPEDIATYYCQQGQTYPYTFGQGTKLEIK (SEQ ID NO: 92) at least 85%, at least 86%, at least 92%, at least 89%, at least 93%, at least 86%, at least 92%, at least 87% %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds CD28 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 91, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 92 do. In some embodiments, the binding site that binds CD28 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 91, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 92.

In some embodiments of any of the above embodiments, the binding protein is a trispecific binding protein. In some embodiments, the trispecific binding protein comprises an antigen binding site that binds to a tumor target protein (including without limitation CD38 or HER2), an antigen binding site that binds a CD28 polypeptide, and an antigen binding site that binds a CD3 polypeptide. include In some embodiments, the binding protein is a trispecific binding protein comprising four polypeptides comprising three antigen binding sites, wherein the polypeptide of formula I and the polypeptide of formula II are (eg, as described herein) form cross-light chain-heavy chain pairs. In some embodiments, the VH and VL domains of any of the anti-CD28 antigen binding sites described above represent V _H1 and V _L1 and form a first antigen binding site that binds a CD28 polypeptide. In some embodiments, the VH and VL domains of any anti-CD28 antigen binding site described above and/or in Table 4 represent V _H1 and V _L1 and form a first antigen binding site that binds to a CD28 polypeptide, and _H2 and V _L2 form a second antigen binding site that binds to the CD3 polypeptide, and V _H3 and V _L3 form a third antigen binding site that binds to a tumor target protein (including without limitation CD38 or HER2).

The sequences of exemplary anti-CD28 antigen binding sites are provided in Table 4. In some embodiments, an anti-CD28 antigen binding site of the invention comprises one, two, three, four, five or all six CDR sequences of an anti-CD28 antibody set forth in Table 4. In some embodiments, an anti-CD28 antigen binding site of the invention comprises a VH domain sequence and/or a VL domain sequence of an anti-CD28 antibody set forth in Table 4.

[Table 4]

Anti-CD28 binding protein sequence

anti-CD3 binding site

Certain aspects of the invention relate to binding proteins comprising an antigen binding site that binds to a CD3 polypeptide. In some embodiments, the CD3 polypeptide comprises CD3-delta (also known as T3D, IMD19, and CD3-DELTA), CD3-epsilon (also known as T3E, IMD18, and TCRE), and CD3-gamma (T3G, IMD17, and CD3- also known as GAMMA). Human CD3 polypeptides are known in the art and include, without limitation, a polypeptide designated by NCBI Accession No. XP_006510029.1 or NP_031674.1, or a polypeptide produced from NCBI Gene ID Nos. 915, 916, or 917. In some embodiments, a binding protein comprising an antigen binding site that binds to a CD3 polypeptide is monospecific and/or monovalent, bispecific and/or bivalent, trispecific and/or trivalent, or multispecific and/or polyvalent. In some embodiments, a binding protein comprising an antigen binding site that binds to a CD3 polypeptide is a trispecific binding protein comprising four polypeptides that form three antigen binding sites. In some embodiments, a binding protein comprising an antigen binding site that binds to a CD3 polypeptide comprises four polypeptides that form three antigen binding sites, one of which binds a CD28 polypeptide and one of which binds a CD3 polypeptide. It is a trispecific binding protein comprising In some embodiments, a binding protein comprising an antigen binding site that binds to a CD3 polypeptide has three antigen binding sites, one of which binds a CD28 polypeptide, one of which binds a CD3 polypeptide, and one that binds a CD38 polypeptide. ) is a trispecific binding protein comprising four polypeptides that form In some embodiments, a binding protein comprising an antigen binding site that binds to a CD3 polypeptide has three antigen binding sites, one of which binds a CD28 polypeptide, one of which binds a CD3 polypeptide, and one that binds a HER2 polypeptide. ) is a trispecific binding protein comprising four polypeptides that form In some embodiments, a binding protein comprising an antigen binding site that binds to a CD3 polypeptide has three antigen binding sites, one of which binds a CD28 polypeptide, one of which binds a CD3 polypeptide, and one that binds a tumor target protein. It is a trispecific binding protein comprising four polypeptides that form

In some embodiments, the binding site that binds CD3 comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and RGVYYALSPFDY (SEQ ID NO: 56) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 57); and/or _{a CDR comprising the amino acid sequence of QSLVHX 1} NX ₂ X ₃ TY, wherein X ₁ is E or Q, X ₂ is A or L, and X ₃ is Q, R, or F (SEQ ID NO: 180). - an antibody light chain variable (VL) domain comprising a L1 sequence, a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO: 65) do. In some embodiments, _{the CDR-L1 sequence of the V L2} domain is an amino acid sequence selected from the group consisting of QSLVHQNAQTY (SEQ ID NO: 59), QSLVHENLQTY (SEQ ID NO: 60), QSLVHENLFTY (SEQ ID NO: 61), and QSLVHENLRTY (SEQ ID NO: 62) includes

In some embodiments, the binding site that binds CD3 comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and RGVYYALSPFDY (SEQ ID NO: 56) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 57); and/or a CDR-L1 sequence comprising the amino acid sequence of QSLVHQNAQTY (SEQ ID NO: 59), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and an amino acid sequence of GQGTQYPFT (SEQ ID NO: 65) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds CD3 comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and RGVYYALSPFDY (SEQ ID NO: 56) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 57); and a CDR-L1 sequence comprising the amino acid sequence of QSLVHQNAQTY (SEQ ID NO: 59), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and a CDR- comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO: 65)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the binding site that binds CD3 comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and RGVYYALSPFDY (SEQ ID NO: 56) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 57); and/or a CDR-L1 sequence comprising the amino acid sequence of QSLVHENLQTY (SEQ ID NO: 60), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and an amino acid sequence of GQGTQYPFT (SEQ ID NO: 65) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds CD3 comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and RGVYYALSPFDY (SEQ ID NO: 56) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 57); and a CDR-L1 sequence comprising the amino acid sequence of QSLVHENLQTY (SEQ ID NO: 60), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and a CDR- comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO: 65)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the binding site that binds CD3 comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and RGVYYALSPFDY (SEQ ID NO: 56) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 57); and/or a CDR-L1 sequence comprising the amino acid sequence of QSLVHENLFTY (SEQ ID NO: 61), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and an amino acid sequence of GQGTQYPFT (SEQ ID NO: 65) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds CD3 comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and RGVYYALSPFDY (SEQ ID NO: 56) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 57); and a CDR-L1 sequence comprising the amino acid sequence of QSLVHENLFTY (SEQ ID NO: 61), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and a CDR- comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO: 65)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the binding site that binds CD3 comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and RGVYYALSPFDY (SEQ ID NO: 56) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 57); and/or a CDR-L1 sequence comprising the amino acid sequence of QSLVHENLRTY (SEQ ID NO: 62), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and an amino acid sequence of GQGTQYPFT (SEQ ID NO: 65) an antibody light chain variable (VL) domain comprising a CDR-L3 sequence. In some embodiments, the binding site that binds CD3 comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and RGVYYALSPFDY (SEQ ID NO: 56) an antibody heavy chain variable (VH) domain comprising a CDR-H3 sequence comprising the amino acid sequence of No. 57); and a CDR-L1 sequence comprising the amino acid sequence of QSLVHENLRTY (SEQ ID NO: 62), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and a CDR- comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO: 65)- an antibody light chain variable (VL) domain comprising an L3 sequence.

In some embodiments, the binding site that binds to CD3 comprises an amino acid sequence of at least 86%, at least 87%, 89%, at least 86%, at least 87%, 89%, at least 86%, at least 87%, 89%, 91 an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or DIVMTQTPLSLSVTPGQPASISCKSSQSLVHQNAQTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 95), DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLQTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 96), DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLFTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 97), and DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLRTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 98), at least 85% to the amino acid sequence selected from the group consisting of, at least 86%, at least 87% , at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least an antibody light chain variable (VL) domain comprising an amino acid sequence that is 99%, or 100% identical. In some embodiments, the binding site that binds CD3 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO:93; and/or an antibody light chain variable (VL) domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, and SEQ ID NO: 98. In some embodiments, the binding site that binds CD3 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO:93; and an antibody light chain variable (VL) domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, and SEQ ID NO: 98.

In some embodiments, the binding site that binds CD3 comprises an amino acid sequence of QVQLVESGGGVVQPGRSLRLSCAASGFTFTKAWMHWVRQAPGKQLEWVAQIKDKSNSYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCRGVYYALSPFDYWGQGTLVTVSS (SEQ ID NO: 93), at least 86%, at least 87%, 89%, at least 86%, at least 87%, 89%, at least 86% an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or at least 85%, at least 86%, at least 92%, at least 89%, at least 93%, at least 90%, at least 86%, at least 92%, at least 89%, %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds CD3 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 93, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 95 do. In some embodiments, the binding site that binds CD3 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 93, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 95.

In some embodiments, the binding site that binds CD3 comprises an amino acid sequence of QVQLVESGGGVVQPGRSLRLSCAASGFTFTKAWMHWVRQAPGKQLEWVAQIKDKSNSYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCRGVYYALSPFDYWGQGTLVTVSS (SEQ ID NO: 93), at least 86%, at least 87%, 89%, at least 86%, at least 87%, 89%, at least 86% an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or at least 85%, at least 86%, at least 92%, at least 89%, at least 90%, at least 92%, at least 89%, at least 93%, at least 86%, at least 92%, at least 89%, %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds CD3 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 93, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 96 do. In some embodiments, the binding site that binds CD3 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 93, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 96.

In some embodiments, the binding site that binds CD3 comprises an amino acid sequence of QVQLVESGGGVVQPGRSLRLSCAASGFTFTKAWMHWVRQAPGKQLEWVAQIKDKSNSYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCRGVYYALSPFDYWGQGTLVTVSS (SEQ ID NO: 93), at least 86%, at least 87%, 89%, at least 86%, at least 87%, 89%, at least 86% an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or at least 85%, at least 86%, at least 92%, at least 89%, at least 90%, at least 92%, at least 89%, at least 89%, at least 86%, at least 92%, 91%, %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds CD3 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 93, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 97 do. In some embodiments, the binding site that binds CD3 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 93, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 97.

In some embodiments, the binding site that binds CD3 comprises an amino acid sequence of QVQLVESGGGVVQPGRSLRLSCAASGFTFTKAWMHWVRQAPGKQLEWVAQIKDKSNSYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCRGVYYALSPFDYWGQGTLVTVSS (SEQ ID NO: 93), at least 86%, at least 87%, 89%, at least 86%, at least 87%, 89%, at least 86% an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or at least 85%, at least 86%, at least 92%, at least 89%, at least 89%, at least 90%, at least 86%, at least 92%, at least 89%, %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds CD3 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 93, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 98 do. In some embodiments, the binding site that binds CD3 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 93, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 98.

In some embodiments, the binding site that binds CD3 comprises an amino acid sequence of QVQLVESGGGVVQPGRSLRLSCAASGFTFTKAWMHWVRQAPGKQLEWVAQIKDKSNSYATYYASSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCRGVYYALSPFDYWGQGTLVTVSS (SEQ ID NO: 302), at least 90%, at least 87%, 89%, at least 86%, at least 87%, 89%, at least 86% an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to, and / or at least 85%, at least 86%, at least 92%, at least 89%, at least 93%, at least 90%, at least 86%, at least 92%, at least 89%, %, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical amino acid sequence. In some embodiments, the binding site that binds CD3 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 302, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 95 do. In some embodiments, the binding site that binds CD3 comprises an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 302, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 95.

In some embodiments of any of the above embodiments, the binding protein is a trispecific binding protein. In some embodiments, the trispecific binding protein comprises an antigen binding site that binds to a tumor target protein (including without limitation CD38 or HER2), an antigen binding site that binds a CD28 polypeptide, and an antigen binding site that binds a CD3 polypeptide. include In some embodiments, the binding protein is a trispecific binding protein comprising four polypeptides comprising three antigen binding sites, wherein the polypeptide of formula I and the polypeptide of formula II are (eg, as described herein) form cross-light chain-heavy chain pairs. In some embodiments, the VH and VL domains of any of the anti-CD3 antigen binding sites described above represent V _H2 and V _L2 and form a second antigen binding site that binds a CD3 polypeptide. In some embodiments, V _H1 and V _L1 form a first antigen binding site that binds to a CD28 polypeptide, and the VH and VL domains of any anti-CD3 antigen binding site described above and/or in Table 5 are V _H2 and represents V _L2 and forms a second antigen binding site that binds to a CD3 polypeptide, and V _H3 and V _L3 form a third antigen binding site that binds to a tumor target protein (including without limitation CD38 or HER2).

The sequences of exemplary anti-CD3 antigen binding sites are provided in Table 5. In some embodiments, an anti-CD3 antigen binding site of the invention comprises one, two, three, four, five or all six CDR sequences of an anti-CD3 antibody set forth in Table 5. In some embodiments, an anti-CD3 antigen binding site of the invention comprises a VH domain sequence and/or a VL domain sequence of an anti-CD3 antibody set forth in Table 5.

[Table 5]

Anti-CD3 binding protein sequence

linker

In some embodiments, the linkers L ₁ , L ₂ , L ₃ , and L ₄ are 0 amino acids (length=0) to about 100 amino acids in length, or 100, 50, 40, 30, 20, or 15 or less amino acids in length. The linker may be 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid in length. In one binding protein, L ₁ , L ₂ , L ₃ , and L ₄ may all have the same amino acid sequence, or they may all have different amino acid sequences.

Examples of suitable linkers include, for example, GGGGSGGGGS (SEQ ID NO: 69), GGGGSGGGGSGGGGS (SEQ ID NO: 70), S, RT, TKGPS (SEQ ID NO: 68), GQPKAAP (SEQ ID NO: 67), GGSGSSGSGG (SEQ ID NO: 71), and DKTHT ( SEQ ID NO: 66), as well as those disclosed in International Publications WO2017/074878 and WO2017/180913. The above-listed examples are not intended to limit the scope of the invention in any way, and are not intended to limit the scope of the invention to valine, leucine, isoleucine, serine, threonine, lysine, arginine, histidine, aspartate, glutamate, asparagine, glutamine, glycine, and proline. Linkers comprising randomly selected amino acids selected from the group consisting of were shown to be suitable for binding proteins.

The identity and sequence of amino acid residues in the linker may vary depending on the type of secondary structural element that needs to be achieved in the linker. For example, glycine, serine, and alanine are best suited for linkers with maximum flexibility. When a stiffer extended linker is desired, some combinations of glycine, proline, threonine, and serine are useful. Any amino acid residue can be combined with other amino acid residues to form a larger peptide linker, if necessary depending on the desired properties, to be considered a linker.

In some embodiments, _{the length of L 1} is at least twice the length of L _{3 .} In some implementations, the length L ₂ is at least twice the length L _4. In some embodiments, _{the length of L 1} is at least twice the length of L _{3 and the length of L 2} is at least twice the length of L ₄ . In some embodiments, L ₁ is 3 to 12 amino acid residues in length, L ₂ is 3 to 14 amino acid residues in length, L ₃ is 1 to 8 amino acid residues in length, and L ₄ is 1 to 8 amino acid residues in length. It is three amino acid residues long. In some embodiments, L ₁ is 5 to 10 amino acid residues in length, L ₂ is 5 to 8 amino acid residues in length, L ₃ is 1 to 5 amino acid residues in length, and L ₄ is 1 to 5 amino acid residues in length. It is two amino acid residues long. In some embodiments, L ₁ is 7 amino acid residues long, L ₂ is 5 amino acid residues long, L ₃ is 1 amino acid residue long, and L ₄ is 2 amino acid residues long.

In some embodiments, L ₁ , L ₂ , L ₃ , and L ₄ are each independently 0 amino acids in length or GGGGSGGGGS (SEQ ID NO: 69), GGGGSGGGGSGGGGS (SEQ ID NO: 70), S, RT, TKGPS (SEQ ID NO: 68) , GQPKAAP (SEQ ID NO: 67), and GGSGSSGSGG (SEQ ID NO: 71). In some embodiments, L ₁ , L ₂ , L ₃ , and L ₄ are each independently GGGGSGGGGS (SEQ ID NO: 69), GGGGSGGGGSGGGGS (SEQ ID NO: 70), S, RT, TKGPS (SEQ ID NO: 68), GQPKAAP (SEQ ID NO: 68) 67), and GGSGSSGSGG (SEQ ID NO: 71). In some embodiments, L ₁ comprises the sequence GQPKAAP (SEQ ID NO: 67), L ₂ comprises the sequence TKGPS (SEQ ID NO: 68), L ₃ comprises the sequence S, and L ₄ comprises the sequence RT .

In some embodiments _{, at least one of L 1} , L ₂ , L ₃ , or L ₄ comprises the sequence DKTHT (SEQ ID NO: 66). In some embodiments, L ₁ , L ₂ , L ₃ , and L ₄ comprise the sequence DKTHT (SEQ ID NO: 66).

Fc region and constant domain

In some embodiments, a binding protein of the invention _{comprises a second polypeptide chain further comprising an Fc region linked to C H1} , wherein the Fc region comprises an immunoglobulin hinge region and C _H2 and C _H3 immunoglobulin heavy chain constant domains. do. In some embodiments, the binding protein of the present invention _{comprises a third polypeptide chain further comprising an Fc region linked to C H1} , wherein the Fc region comprises an immunoglobulin hinge region and C _H2 and C _H3 immunoglobulin heavy chain constant domains. do. In some embodiments, a binding protein of the invention _{comprises a second polypeptide chain further comprising an Fc region linked to C H1} , wherein the Fc region comprises an immunoglobulin hinge region and C _H2 and C _H3 immunoglobulin heavy chain constant domains; and _{a third polypeptide chain further comprising an Fc region linked to C H1} , wherein the Fc region comprises an immunoglobulin hinge region and C _H2 and C _H3 immunoglobulin heavy chain constant domains.

In some embodiments, a binding protein of the invention comprises a polypeptide chain comprising an Fc region or a full length antibody heavy chain. In some embodiments, the Fc region is a human Fc region, eg, a human IgG1, IgG2, IgG3, or IgG4 Fc region. In some embodiments, the Fc region comprises an antibody hinge, C _H1 , C _H2 , C _H3 , and optionally C _H4 domains. In some embodiments, the Fc region is a human IgG1 Fc region. In some embodiments, the Fc region is a human IgG4 Fc region. In some embodiments, the Fc region comprises one or more of the mutations described below. In some embodiments, the Fc region is the Fc region of one of the heavy chain polypeptides (eg, polypeptides 2 or 3) of the binding proteins shown in Table 4. In some embodiments, the heavy chain constant region is the constant region of one of the heavy chain polypeptides (eg, Polypeptide 2 or 3) of the binding protein shown in Table 4. In some embodiments, the light chain constant region is the constant region of one of the light chain polypeptides (eg, polypeptides 1 or 4) of the binding proteins shown in Table 4.

In some embodiments, a binding protein of the invention comprises one or two Fc variants. As used herein, the term “Fc variant” refers to a molecule or sequence that has been modified from a native Fc but still comprises a binding site for the repair receptor, FcRn (a neonatal Fc receptor). Exemplary Fc variants, and their interactions with repair receptors, are known in the art. Accordingly, the term “Fc variant” may include a humanized molecule or sequence from a non-human native Fc. In addition, native Fc comprises regions that can be removed as they provide structural features or biological activities that are not required for the antibody-like binding proteins of the invention. Thus, the term “Fc variant” refers to (1) disulfide bond formation, (2) incompatibility with the selected host cell, (3) N-terminal heterogeneity upon expression in the selected host cell, (4) glycosylation, (5) complement lacks one or more native Fc regions or residues that affect or are involved in (6) binding to Fc receptors other than repair receptors, or (7) antibody-dependent cytotoxicity (ADCC); and a molecule or sequence in which one or more Fc moieties or residues have been modified.

In some embodiments, a binding protein (eg, a trispecific binding protein) of the invention comprises a “knob” mutation on a second polypeptide chain and a “hole” mutation on a third polypeptide chain. In some embodiments, a binding protein of the invention comprises a “knob” mutation on a third polypeptide chain and a “hole” mutation on a second polypeptide chain. In some embodiments, the "knob" mutation comprises a substitution at a position corresponding to positions 354 and/or 366 of a human IgG1 or IgG4 according to the EU index. In some embodiments, the amino acid substitutions are S354C, T366W, T366Y, S354C, and T366W, or S354C and T366Y. In some embodiments, the "knob" mutation comprises a substitution at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to the EU index. In some embodiments, the amino acid substitutions are S354C and T366W. In some embodiments, a "hole" mutation comprises a substitution at a position corresponding to 407 and optionally positions 349, 366, and/or 368 of a human IgG1 or IgG4 according to the EU index. In some embodiments, the amino acid substitutions are Y407V or Y407T and optionally Y349C, T366S, and/or L368A. In some embodiments, a “hole” mutation comprises a substitution at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to the EU index. In some embodiments, the amino acid substitutions are Y349C, T366S, L368A, and Y407V.

In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, wherein the first Fc region comprises an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises: an amino acid substitution at a position corresponding to position 366 and optionally position 354 of human IgG1 or IgG4 according to the EU index, wherein the amino acid substitution is T366W or T366Y and optionally S354C; the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, the second Fc region comprising a human according to EU index and amino acid substitutions at positions corresponding to positions 407 and optionally positions 349, 366, and/or 368 of IgGl or IgG4, wherein the amino acid substitutions are Y407V or Y407T and optionally Y349C, T366S, and/or L368A.

In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, wherein the first Fc region comprises an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises: an amino acid substitution at a position corresponding to position 407 and optionally positions 349, 366, and/or 368 of human IgG1 or IgG4 according to the EU index, wherein the amino acid substitution is Y407V or Y407T and optionally Y349C, T366S, and/or L368A; the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, the second Fc region comprising a human according to EU index and amino acid substitutions at positions corresponding to positions 366 and optionally 354 of IgG1 or IgG4, wherein the amino acid substitutions are T366W or T366Y and optionally S354C.

In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, wherein the first Fc region comprises an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises: comprising an amino acid substitution at the position corresponding to position 366 of human IgG1 or IgG4 according to the EU index, wherein the amino acid substitution is T366W; the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, the second Fc region comprising a human according to EU index and an amino acid substitution at positions corresponding to positions 366, 368, and/or 407 of IgG1 or IgG4, wherein the amino acid substitutions are T366S, L368A, and/or Y407V.

In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, wherein the first Fc region comprises an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises: comprising an amino acid substitution at positions corresponding to positions 366, 368, and/or 407 of human IgG1 or IgG4 according to the EU index, wherein the amino acid substitutions are T366S, L368A, and/or Y407V; the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, the second Fc region comprising a human according to EU index and an amino acid substitution at the position corresponding to position 366 of IgG1 or IgG4, wherein the amino acid substitution is T366W.

In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, wherein the first Fc region comprises an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises: amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to the EU index, wherein the amino acid substitutions are S354C and T366W; the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, the second Fc region comprising a human according to EU index and amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of IgG1 or IgG4, wherein the amino acid substitutions are Y407V or Y349C and optionally Y349C, T366S, L368A, and Y407V. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, wherein the first Fc region comprises an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises: amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to the EU index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, the second Fc region comprising a human according to EU index and amino acid substitutions at positions corresponding to positions 354 and 366 of IgG1 or IgG4, the amino acid substitutions being S354C and T366W. In some embodiments, the first and/or second Fc region is a human IgG1 Fc region. In some embodiments, the first and/or second Fc region is a human IgG4 Fc region.

In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, wherein the first Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, the first Fc region comprises amino acid substitutions at positions corresponding to positions 228, 354, 366, and 409 of human IgG4 according to the EU index, the amino acid substitutions being S228P, S354C, T366W, and R409K; the third polypeptide chain further comprises a second Fc region linked to CH1, wherein the second Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, the second Fc region comprising: amino acid substitutions at positions corresponding to positions 228, 349, 366, 368, 407, and 409 of human IgG4 according to the EU index, the amino acid substitutions being S228P, Y349C, T366S, L368A, Y407V, and R409K. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, wherein the first Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, The first Fc region comprises amino acid substitutions at positions corresponding to positions 228, 349, 366, 368, 407, and 409 of human IgG4 according to the EU index, wherein the amino acid substitutions are S228P, Y349C, T366S, L368A, Y407V, and R409K; the third polypeptide chain further comprises a second Fc region linked to CH1, wherein the second Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, the second Fc region comprising: amino acid substitutions at positions corresponding to positions 228, 354, 366, and 409 of human IgG4 according to the EU index, the amino acid substitutions being S228P, S354C, T366W, and R409K.

In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, wherein the first Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, the first Fc region comprises amino acid substitutions at positions corresponding to positions 234, 235, 354, and 366 of human IgG4 according to the EU index, the amino acid substitutions being F234A, L235A, S354C, and T366W; the third polypeptide chain further comprises a second Fc region linked to CH1, wherein the second Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, the second Fc region comprising: amino acid substitutions at positions corresponding to positions 234, 235, 349, 366, 368, and 407 of human IgG4 according to the EU index, the amino acid substitutions being F234A, L235A, Y349C, T366S, L368A, and Y407V. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, wherein the first Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, The first Fc region comprises amino acid substitutions at positions corresponding to positions 234, 235, 349, 366, 368, and 407 of human IgG4 according to the EU index, wherein the amino acid substitutions are F234A, L235A, Y349C, T366S, L368A, and Y407V; the third polypeptide chain further comprises a second Fc region linked to CH1, wherein the second Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, the second Fc region comprising: amino acid substitutions at positions corresponding to positions 234, 235, 354, and 366 of human IgG4 according to the EU index, the amino acid substitutions being F234A, L235A, S354C, and T366W.

In some embodiments, the binding proteins of the invention have effector functions, e.g., Fc receptor-mediated antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and/or antibody-dependent cytotoxicity (ADCC). ) and one or more mutations that reduce In some embodiments, the second polypeptide chain further comprises _{a first Fc region linked to C H1} , wherein the first Fc region comprises an immunoglobulin hinge region and C _H2 and C _H3 immunoglobulin heavy chain constant domains; the third polypeptide chain further comprises _{a second Fc region linked to C H1} , wherein the second Fc region comprises an immunoglobulin hinge region and C _H2 and C _H3 immunoglobulin heavy chain constant domains; the first and second Fc regions are human IgG1 Fc regions; The first and second Fc regions contain amino acid substitutions at positions corresponding to positions 234 and 235 of human IgG1 according to the EU index, respectively, and the amino acid substitutions are L234A and L235A. In some embodiments, the Fc region of the second and third polypeptide chains is a human IgG1 Fc region, the Fc region comprising amino acid substitutions at positions corresponding to positions 234 and 235 of human IgG1 according to the EU index, respectively, an amino acid Substitutions are L234A and L235A. In some embodiments, the second polypeptide chain further comprises _{a first Fc region linked to C H1} , wherein the first Fc region comprises an immunoglobulin hinge region and C _H2 and C _H3 immunoglobulin heavy chain constant domains; the third polypeptide chain further comprises _{a second Fc region linked to C H1} , wherein the second Fc region comprises an immunoglobulin hinge region and C _H2 and C _H3 immunoglobulin heavy chain constant domains; the first and second Fc regions are human IgG1 Fc regions; The first and second Fc regions contain amino acid substitutions at positions corresponding to positions 234, 235, and 329 of human IgG1 according to the EU index, respectively, and the amino acid substitutions are L234A, L235A, and P329A. In some embodiments, the Fc region of the second and third polypeptide chains is a human IgG1 Fc region, wherein the Fc region comprises amino acid substitutions at positions corresponding to positions 234, 235, and 329 of human IgG1 according to the EU index, respectively and the amino acid substitutions are L234A, L235A, and P329A. In some embodiments, the Fc region of the second and third polypeptide chains is a human IgG4 Fc region, the Fc region comprising amino acid substitutions at positions corresponding to positions 234 and 235 of human IgG4 according to the EU index, respectively, and amino acid Substitutions are F234A and L235A. In some embodiments, the binding protein is _{a second polypeptide chain further comprising a first Fc region linked to C H1} , wherein the first Fc region comprises an immunoglobulin hinge region and C _H2 and C _H3 immunoglobulin heavy chain constant domains. and _{a third polypeptide chain further comprising a second Fc region linked to C H1} , wherein the second Fc region comprises an immunoglobulin hinge region and C _H2 and C _H3 immunoglobulin heavy chain constant domains; The first and second Fc regions contain amino acid substitutions at positions corresponding to positions 234 and 235 of human IgG4 according to the EU index, respectively, and the amino acid substitutions are F234A and L235A.

In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, wherein the first Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, The first Fc region comprises amino acid substitutions at positions corresponding to positions 228, 234, 235, 354, 366, and 409 of human IgG4 according to the EU index, wherein the amino acid substitutions are S228P, F234A, L235A, S354C, T366W, and R409K; the third polypeptide chain further comprises a second Fc region linked to CH1, wherein the second Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, the second Fc region comprising: and amino acid substitutions at positions corresponding to positions 228, 234, 235, 349, 366, 368, 407, and 409 of human IgG4 according to the EU index, wherein the amino acid substitutions are S228P, F234A, L235A, Y349C, T366S, L368A , Y407V, and R409K. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, wherein the first Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, The first Fc region comprises amino acid substitutions at positions corresponding to positions 228, 234, 235, 349, 366, 368, 407, and 409 of human IgG4 according to the EU index, wherein the amino acid substitutions are S228P, F234A, L235A, Y349C, T366S, L368A, Y407V, and R409K; the third polypeptide chain further comprises a second Fc region linked to CH1, wherein the second Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, the second Fc region comprising: and amino acid substitutions at positions corresponding to positions 228, 234, 235, 354, 366, and 409 of human IgG4 according to the EU index, the amino acid substitutions being S228P, F234A, L235A, S354C, T366W, and R409K.

In some embodiments, the Fc region is a human IgG4 Fc region comprising one or more mutations that reduce or eliminate FcγI and/or FcγII binding. In some embodiments, the Fc region is a human IgG4 Fc region comprising one or more mutations that reduce or eliminate FcγI and/or FcγII binding but do not affect FcRn binding. In some embodiments, the Fc region is a human IgG4 Fc region comprising an amino acid substitution at a position corresponding to positions 228 and/or 409 of a human IgG4 according to the EU index. In some embodiments, the amino acid substitution is S228P and/or R409K. In some embodiments, the Fc region is a human IgG4 Fc region comprising an amino acid substitution at positions corresponding to positions 234 and/or 235 of human IgG4 according to the EU index. In some embodiments, the amino acid substitution is F234A and/or L235A. In some embodiments, the Fc region is a human IgG4 Fc region comprising an amino acid substitution at positions corresponding to positions 228, 234, 235, and/or 409 of human IgG4 according to the EU index. In some embodiments, the amino acid substitution is S228P, F234A, L235A, and/or R409K. In some embodiments, the Fc region is a human IgG4 Fc region comprising an amino acid substitution at a position corresponding to positions 233 to 236 of a human IgG4 according to the EU index. In some embodiments, the amino acid substitution is a deletion at E233P, F234V, L235A, and 236. In some embodiments, the Fc region is a human IgG4 Fc region comprising an amino acid mutation in the substitution corresponding to positions 228, 233 to 236, and/or 409 of a human IgG4 according to the EU index. In some embodiments, the amino acid mutation is S228P; deletions at E233P, F234V, L235A, and 236; and/or R409K.

In some embodiments, the Fc region comprises Fc receptor binding and/or effector function of the Fc region (eg, Fc receptor-mediated antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and/or and one or more mutations that reduce or eliminate antibody-dependent cytotoxicity (ADCC).

In some embodiments, the Fc region is a human IgG1 Fc region comprising one or more amino acid substitutions at positions corresponding to positions 234, 235, and/or 329 of human IgG1 according to the EU index. In some embodiments, the amino acid substitution is L234A, L235A, and/or P329A. In some embodiments, the Fc region is a human IgG1 Fc region comprising an amino acid substitution at positions corresponding to positions 298, 299, and/or 300 of human IgG1 according to the EU index. In some embodiments, the amino acid substitutions are S298N, T299A, and/or Y300S.

In some embodiments, a binding protein of the invention comprises one or more mutations, e.g., to improve the stability of the hinge region and/or the dimer interface of IgG4 (e.g., Spiess, C. et al. Referring 26583-26593]): (2013) J. Biol Chem 288... In some embodiments, the mutation comprises a substitution at positions corresponding to positions 228 and 409 of human IgG4 according to the EU index, and the amino acid substitutions are S228P and R409K. In some embodiments, the binding protein is _{a second polypeptide chain further comprising a first Fc region linked to C H1} , wherein the first Fc region comprises an immunoglobulin hinge region and C _H2 and C _H3 immunoglobulin heavy chain constant domains. and _{a third polypeptide chain further comprising a second Fc region linked to C H1} , wherein the second Fc region comprises an immunoglobulin hinge region and C _H2 and C _H3 immunoglobulin heavy chain constant domains; the first and second Fc regions are human IgG4 Fc regions; The first and second Fc regions contain amino acid substitutions at positions corresponding to positions 228 and 409 of human IgG4 according to the EU index, respectively, and the amino acid substitutions are S228P and R409K. In some embodiments, the binding proteins of the invention comprise knob and hole mutations and one or more mutations to improve stability. In some embodiments, the first and/or second Fc region is a human IgG4 Fc region.

In some embodiments, the Fc region is a human IgG1 Fc region comprising one or more amino acid substitutions at positions corresponding to positions 234, 235, and/or 329 of human IgG1 according to the EU index. In some embodiments, the amino acid substitution is L234A, L235A, and/or P329A. In some embodiments, the Fc region is a human IgG1 Fc region comprising an amino acid substitution at positions corresponding to positions 298, 299, and/or 300 of human IgG1 according to the EU index. In some embodiments, the amino acid substitutions are S298N, T299A, and/or Y300S.

nucleic acid

Another aspect of the invention relates to an isolated nucleic acid molecule comprising a nucleotide sequence encoding any of the binding proteins described herein. Exemplary and non-limiting nucleic acid sequences are provided in Table 5.

Another aspect of the invention relates to a kit of polynucleotides encoding one or more polypeptides of a binding protein, for example as described herein. In some embodiments, a polynucleotide kit of the present invention comprises 1, 2, 3, or 4 polynucleotides of a polynucleotide kit comprising: (a) comprising the polynucleotide sequence of SEQ ID NO: 189 A first polynucleotide comprising: nucleotides; (b) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 193, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 194, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 195, and the sequence a fourth polynucleotide comprising the polynucleotide sequence of number 196; (c) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 197, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 198, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 199, and the sequence a fourth polynucleotide comprising the polynucleotide sequence of number 200; (d) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 201, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 202, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 203, and the sequence a fourth polynucleotide comprising the polynucleotide sequence of number 204; (e) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 205, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 206, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 207, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of No. 208; (f) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 209, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 210, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 211, and the sequence a fourth polynucleotide comprising the polynucleotide sequence of number 212; (g) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 213, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 214, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 215, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 216; (h) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 217, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 218, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 219, and the sequence a fourth polynucleotide comprising the polynucleotide sequence of No. 220; (i) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 221, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 222, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 223, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of No. 224; (j) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 225, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 226, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 227, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 228; (k) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 229, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 230, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 231, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 232; (l) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 233, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 234, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 235, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 236; (m) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 237, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 238, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 239, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 240; (n) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 241, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 242, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 243, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 244; (o) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 245, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 246, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 247, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 248; (p) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 249, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 250, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 251, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of No. 252; (q) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 253, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 254, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 255, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 256; (r) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 257, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 258, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 259, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 260; (s) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 261, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 262, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 263, and the sequence a fourth polynucleotide comprising the polynucleotide sequence of number 264; (t) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 265, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 266, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 267, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 268; (u) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 269, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 270, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 271, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 272; or (v) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 273, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 274, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 275, and A fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 276.

Another aspect of the invention relates to a vector system comprising one or more vectors encoding the first, second, third, and fourth polypeptide chains of any of the binding proteins described herein. In some embodiments, the vector system comprises a first vector encoding a first polypeptide chain of a binding protein, a second vector encoding a second polypeptide chain of a binding protein, e.g., as shown in the polynucleotides of Table 6, binding a third vector encoding a third polypeptide chain of the protein, and a fourth vector encoding a fourth polypeptide chain of the binding protein. In some embodiments, the vector system comprises a first vector encoding first and second polypeptide chains of a binding protein, and a second vector encoding a third and fourth polypeptide chain of a binding protein. In some embodiments, the vector system comprises a first vector encoding a first and a third polypeptide chain of a binding protein, and a second vector encoding a second and a fourth polypeptide chain of a binding protein. In some embodiments, the vector system comprises a first vector encoding a first and a fourth polypeptide chain of a binding protein, and a second vector encoding a second and third polypeptide chain of a binding protein. In some embodiments, the vector system comprises a first vector encoding a first, second, third, and fourth polypeptide chain of a binding protein. One or more vectors in the vector system may be any of the vectors described herein. In some embodiments, the one or more vectors are expression vectors. In some embodiments, the first, second, third, and fourth polynucleotides are present in one or more expression vectors, eg, one, two, three, or four expression vectors.

Standard recombinant DNA methodologies are used to construct polynucleotides encoding the polypeptides forming the binding protein, incorporate such polynucleotides into recombinant expression vectors, and introduce such vectors into host cells. See, eg, Sambrook et al. , 2001, Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 3rd ed.)]. Enzymatic reactions and purification techniques may be performed according to the manufacturer's specifications, as commonly accomplished in the art, or as described herein. Unless specific definitions are provided, the nomenclature used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Similarly, conventional techniques may be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, delivery, and patient treatment.

In some embodiments, the isolated nucleic acid is operably linked to a heterologous promoter to direct transcription of the binding protein-encoding nucleic acid sequence. A promoter may refer to a nucleic acid control sequence that directs the transcription of a nucleic acid. A first nucleic acid sequence is operably linked to a second nucleic acid sequence when the first nucleic acid sequence is placed in functional association with the second nucleic acid sequence. For example, a promoter is operably linked to that coding sequence if it affects the transcription or expression of the coding sequence of the binding protein. Examples of promoters include viruses (eg, polyoma virus, fowlpox virus, adenovirus (eg, adenovirus 2), bovine papillomavirus, avian sarcoma virus, cytomegalovirus, retrovirus, hepatitis B virus, simian virus 40 ( SV40), etc.), heterologous eukaryotic promoters (eg, actin promoter, immunoglobulin promoter, heat shock promoter, etc.), CAG-promoter (Niwa et al., Gene 108(2):193-9, 1991) , phosphoglycerate kinase (PGK)-promoter, tetracycline-inducible promoter (Masui et al., Nucleic Acids Res. 33:e43, 2005), lac system, trp system, tac system, trc system, of phage lambda key operator and promoter regions, promoters for 3-phosphoglycerate kinase, promoters of yeast acid phosphatase, and promoters of yeast alpha-mating factors. A polynucleotide encoding a binding protein of the invention may be under the control of a constitutive promoter, an inducible promoter, or any other suitable promoter described herein or other suitable promoter readily recognized by one of ordinary skill in the art.

In some embodiments, the isolated nucleic acid is integrated into a vector. In some embodiments, the vector is an expression vector. An expression vector may comprise one or more regulatory sequences operably linked to the polynucleotide to be expressed. The term “regulatory sequences” includes promoters, enhancers, and other expression control elements (eg, polyadenylation signals). Examples of suitable enhancers include enhancer sequences from mammalian genes (eg, globin, elastase, albumin, α-fetoprotein, insulin, etc.), and enhancer sequences from eukaryotic viruses (eg, origin of replication late SV40 enhancer (bp 100) 270), cytomegalovirus early promoter enhancer, origin of replication late polyoma enhancer, adenovirus enhancer, etc.). Examples of suitable vectors include, for example, plasmids, cosmids, episomes, transposons, and viral vectors (eg, adenovirus, vaccinia virus, sindbis virus, measles virus, herpes virus, lentivirus, retrovirus, adenovirus). related viral vectors, etc.). Expression vectors can be used to transfect host cells such as, for example, bacterial cells, yeast cells, insect cells, and mammalian cells. Biologically functional viral and plasmid DNA vectors capable of expression and replication in a host are known in the art and can be used to transfect any cell of interest.

host cell

Another aspect of the invention relates to a host cell (eg, an isolated host cell) comprising one or more isolated polynucleotides, vectors, and/or vector systems described herein. In some embodiments, an isolated host cell of the invention is cultured in vitro. In some embodiments, the host cell is a bacterial cell (eg, an E. coli cell). In some embodiments, the host cell is a yeast cell (eg, S. cerevisiae cell). In some embodiments, the host cell is an insect cell. Examples of insect host cells include, for example, Drosophila cells (eg, S2 cells), Trichoplusia ni cells (eg, High Five ^™ cells), and Spodoptera frugiperda cells (eg, Sf21 or Sf9 cells). can do. In some embodiments, the host cell is a mammalian cell. Examples of mammalian host cells include, for example, human embryonic kidney cells (eg, 293 or 293 cells subcloned for growth in suspension culture), Expi293 ^™ cells, CHO cells, baby hamster kidney cells (eg, BHK). , ATCC CCL 10), mouse Sertoli cells (eg TM4 cells), monkey kidney cells (eg CV1 ATCC CCL 70), African green monkey kidney cells (eg VERO-76, ATCC CRL- 1587), human cervical carcinoma cells (eg HELA, ATCC CCL 2), canine kidney cells (eg MDCK, ATCC CCL 34), buffalo rat liver cells (eg BRL 3A, ATCC CRL 1442) ), human lung cells (eg W138, ATCC CCL 75), human liver cells (eg Hep G2, HB 8065), mouse mammary tumor cells (eg MMT 060562, ATCC CCL51), TRI cells , MRC 5 cells, FS4 cells, human liver cancer cell lines (eg, Hep G2), and myeloma cells (eg, NS0 and Sp2/0 cells).

Another aspect of the invention relates to a method of producing any of the binding proteins described herein. In some embodiments, the method comprises a) a host cell (eg, a host cell) comprising an isolated nucleic acid, vector, and/or vector system (eg, any isolated nucleic acid, vector, and/or vector system described herein). culturing the host cell (eg, any host cell described herein) under conditions such that the host cell expresses the binding protein; and b) isolating the binding protein from the host cell. Methods of culturing host cells under conditions to express a protein are well known to those skilled in the art. Methods for isolating proteins from cultured host cells are well known to those skilled in the art, including, for example, affinity chromatography (eg, protein A affinity chromatography followed by two-step affinity chromatography comprising size exclusion chromatography). is known

pharmaceutical composition

A therapeutic or pharmaceutical composition comprising a binding protein is within the scope of the present invention. Such therapeutic or pharmaceutical compositions may comprise a therapeutically effective amount of a binding protein, or binding protein-drug conjugate, admixed with a pharmaceutically or physiologically acceptable formulation agent selected to be suitable for the mode of administration.

Acceptable formulation materials are nontoxic to recipients at the dosages and concentrations employed.

A pharmaceutical composition is a formulation material for altering, maintaining, or preserving, for example, the pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution or release rate, adsorption or permeability of the composition may contain. Suitable formulating materials include amino acids (eg, glycine, glutamine, asparagine, arginine, or lysine), antibacterial agents, antioxidants (eg, ascorbic acid, sodium sulfite, or sodium hydrogen sulfite), buffers (eg, borate, bicarbonate, tris- HCl, citrate, phosphate, or other organic acids), bulking agents (such as mannitol or glycine), chelating agents (such as ethylenediamine tetraacetic acid (EDTA)), complexing agents (such as caffeine, polyvinylpyrrolidone, beta- cyclodextrin, or hydroxypropyl-beta-cyclodextrin), fillers, monosaccharides, disaccharides, and other carbohydrates (such as glucose, mannose, or dextrin), proteins (such as serum albumin, gelatin, or immunoglobulin), colorants, Flavoring and diluents, emulsifying agents, hydrophilic polymers (such as polyvinylpyrrolidone), low molecular weight polypeptides, salt-forming counterions (such as sodium), preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenol ethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide), a solvent (such as glycerin, propylene glycol, or polyethylene glycol), a sugar alcohol (such as mannitol or sorbitol), a suspending agent, a surfactant or wetting agent ( For example, pluronic; PEG; sorbitan esters; polysorbates such as polysorbate 20 or polysorbate 80; triton; tromethamine; lecithin; cholesterol or tyloxapol), stability enhancing agents such as sucrose or sorbitol ), tonicity enhancing agents (e.g., alkali metal halides (e.g., sodium or potassium chloride) or mannitol sorbitol), delivery vehicles, diluents, excipients and/or pharmaceutical adjuvants (e.g., See Remington's Pharmaceutical Sciences (18th Ed., AR Gennaro, ed., Mack Publishing Company 1990), and subsequent editions thereof, which are incorporated herein by reference for all purposes.

The optimal pharmaceutical composition will be determined by one of ordinary skill in the art depending on, for example, the intended route of administration, mode of delivery, and desired dosage. Such compositions can affect the physical state, stability, rate of release in vivo, and rate of clearance in vivo of the binding protein.

The primary vehicle or carrier in the pharmaceutical composition may be aqueous or non-aqueous in nature. For example, a vehicle or carrier suitable for injection may be water, physiological saline solution, or artificial cerebrospinal fluid, supplemented with other substances commonly used in compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are additional exemplary vehicles. Another exemplary pharmaceutical composition comprises a Tris buffer of about pH 7.0-8.5, or an acetate buffer of about pH 4.0-5.5, which may further comprise sorbitol or a suitable substitute. In one embodiment of the invention, a binding protein composition can be prepared for storage by mixing a selected composition having a desired degree of purity with an optional formulator in the form of a lyophilized cake or aqueous solution. In addition, the binding protein may be formulated as a lyophilisate using an appropriate excipient such as sucrose.

The pharmaceutical composition of the present invention may be selected for parenteral or subcutaneous delivery. Alternatively, the composition may be selected for inhalation or for delivery through the digestive tract, such as oral. The preparation of such pharmaceutically acceptable compositions is within the skill of the art.

The formulation components are present in concentrations that are acceptable at the site of administration. For example, a buffer is used to maintain the composition at a physiological pH or slightly lower pH, typically within a pH range of about 5 to about 8.

When parenteral administration is contemplated, therapeutic compositions for use may be in the form of a pyrogen-free, parenterally acceptable aqueous solution comprising the binding protein of interest in a pharmaceutically acceptable vehicle. A particularly suitable vehicle for parenteral injection is properly preserved sterile distilled water in which the binding protein is formulated as a sterile isotonic solution. Another formulation is an injectable microsphere, biodegradable particle, polymer compound (eg, polylactic or polyglycolic acid), bead, or formulation of the molecule of interest using agents such as liposomes. Hyaluronic acid may also be used, which may have the effect of promoting the continuation of the duration of circulation. Other suitable means for introducing a molecule of interest include implantable drug delivery devices.

In one embodiment, the pharmaceutical composition may be formulated for inhalation. For example, the binding protein may be formulated as a dry powder for inhalation. Binding protein inhalation solutions may also be formulated with propellants for aerosol delivery. In another embodiment, the solution may be nebulized.

It is also contemplated that certain formulations may be administered orally. In one embodiment of the invention, binding proteins administered in this manner may be formulated with or without carriers conventionally used in the formulation of solid dosage forms such as tablets and capsules. For example, the capsule may be designed to release the active portion of the formulation at a point in the gastrointestinal tract where bioavailability is maximized and systemic degradation is minimized. Additional agents may be included to facilitate absorption of the binding protein. Diluents, flavoring agents, low melting point waxes, vegetable oils, glidants, suspending agents, tablet disintegrating agents, and binders may also be used.

Other pharmaceutical compositions may include an effective amount of the binding protein in admixture with a non-toxic excipient suitable for the manufacture of tablets. Solutions can be prepared in unit dose form by dissolving the tablets in sterile water or other suitable vehicle. Suitable excipients include inert diluents such as calcium carbonate, sodium carbonate or sodium bicarbonate, lactose, or calcium phosphate; or a binder such as starch, gelatin, or acacia; or glidants such as magnesium stearate, stearic acid, or talc.

Additional pharmaceutical compositions of the present invention, including formulations comprising the binding protein in sustained delivery or controlled delivery formulations, will be apparent to those skilled in the art. Techniques for formulating various other sustained or controlled delivery means such as liposomal carriers, biodegradable microparticles or porous beads and depot injections are also known to those skilled in the art. Further examples of sustained release formulations include semipermeable polymer matrices in the form of molded articles, for example films or microcapsules. The sustained release matrix may be polyester, hydrogel, polylactide, a copolymer of L-glutamic acid and gamma ethyl-L-glutamate, poly(2-hydroxyethyl-methacrylate), ethylene vinyl acetate, or poly-D (-)-3-hydroxybutyric acid. Sustained release compositions may also include liposomes, which may be prepared by any of a number of methods known in the art.

Pharmaceutical compositions used for in vivo administration must generally be sterile. This may be accomplished by filtration through a sterile filtration membrane. Where the composition is lyophilized, sterilization using this method may be performed before or after lyophilization and reconstitution. The composition for parenteral administration may be stored in a lyophilized form or as a solution. In addition, parenteral compositions are generally placed in a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

Once formulated, the pharmaceutical composition may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored in ready-to-use form or in a form requiring reconstitution prior to administration (lyophilized form).

The present invention also includes kits for producing single-dose dosage units. The kits may each include both a first container with a dry protein and a second container with an aqueous formulation. Kits comprising single and multi-chamber prefilled syringes (eg, liquid syringes and lyosyringes) are also included within the scope of the present invention.

The effective amount of the binding protein pharmaceutical composition to be used therapeutically will depend, for example, on the therapeutic context and purpose. Thus, those skilled in the art will know how to determine, in part, the appropriate dosage level for treatment, the molecule delivered, the indication for which the binding protein is used, the route of administration, and the patient's physique (weight, body surface area, or organ size) and condition (age and general health). will understand that it will depend on Therefore, the clinician can titrate the dosage and modify the route of administration to obtain the optimal therapeutic effect.

Dosing frequency will depend on the pharmacokinetic parameters of the binding protein in the formulation used. In general, the clinician will administer the composition until a dosage is reached that achieves the desired effect. Thus, the composition may be administered as a single dose, in two or more doses over time (which may or may not contain the same amount of the molecule of interest), or as continuous infusion through an implantation device or catheter. . Further refinements of appropriate dosages are routinely made by those skilled in the art and are within the scope of work routinely performed by those skilled in the art. Appropriate dosages can be ascertained using appropriate dose-response data.

The route of administration of the pharmaceutical composition is according to known methods (eg, orally; intravenously, intraperitoneally, intracerebral (intraventricular), intraventricular, intramuscular, intraocular, intraarterial, intraportal, or intralesional. via injection by route; by a sustained release system; or by an implantable device). If desired, the composition may be administered by bolus injection, administered continuously by infusion, or administered by an implantable device.

The composition may also be administered topically via implantation of a membrane, sponge, or other suitable material in which the molecule of interest is absorbed or encapsulated. When an implantable device is used, the device may be implanted in any suitable tissue or organ, and the molecule of interest may be delivered via diffusion, timed release bolus, or continuous administration.

The pharmaceutical composition may be used for the prevention and/or treatment of HIV infection. The pharmaceutical composition may be used as a sole therapy or in combination with standard antiretroviral therapy.

The present invention also relates to kits comprising binding proteins and other reagents useful for detecting the level of a target antigen in a biological sample. Such reagents may include detectable labels, blocking sera, positive and negative control samples, and detection reagents. In some embodiments, a kit comprises a composition comprising any of the binding proteins, polynucleotides, vectors, vector systems, and/or host cells described herein. In some embodiments, a kit comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, and the like. The container may be formed from a variety of materials, such as glass or plastic. The container contains a composition, alone or in combination with other compositions effective for the treatment, prevention, and/or diagnosis of a condition (eg, HIV infection), and may have a sterile access port (eg, the container may have a subcutaneous may be an intravenous solution bag or vial with a stopper pierceable by a needle). In some embodiments, the label or package insert indicates that the composition is for use in the prevention, diagnosis, and/or treatment of a condition of choice. Alternatively or additionally, the article of manufacture or kit further comprises a second (or third) container comprising a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. may include It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

Methods and uses for binding proteins

virus

Certain aspects of the invention relate to methods of propagating virus-specific memory T cells. In some embodiments, the method binds a virus-specific memory T cell to a binding protein of the invention, e.g., a first antigen binding site that binds a CD28 polypeptide, a second antigen binding site that binds a CD3 polypeptide, and a CD38 polypeptide contacting with a trispecific binding protein comprising a third antigen binding site that binds to

In some embodiments, the virus-specific memory T cell is contacted with the binding protein in vitro or ex vivo.

In some embodiments, contacting the virus-specific memory T cell with the binding protein results in activation and/or proliferation of the virus-specific memory T cell.

Another aspect of the present invention relates to a method for proliferating T cells. In some embodiments, the method binds a T cell to a binding protein of the invention, e.g., a first antigen binding site that binds a CD28 polypeptide, a second antigen binding site that binds a CD3 polypeptide, and a third antigen binding site that binds a CD38 polypeptide contacting with a trispecific binding protein comprising an antigen binding site.

In some embodiments, the T cell is a memory T cell or an effector T cell.

In some embodiments, the T cell expresses a chimeric antigen receptor (CAR) on the cell surface or comprises a polynucleotide encoding a CAR.

Another aspect of the invention relates to a method of treating a chronic viral infection, eg, in an individual in need thereof. In some embodiments, the method comprises a first antigen binding site that binds a binding protein of the invention, e.g., a CD28 polypeptide, a second antigen binding site that binds a CD3 polypeptide, and a third antigen binding site that binds a CD38 polypeptide It comprises administering to an individual in need thereof an effective amount of a trispecific binding protein comprising a.

In some embodiments, the subject is a human.

In some embodiments, the binding protein is administered to a subject in a pharmaceutical formulation comprising the binding protein and a pharmaceutically acceptable carrier.

In some embodiments, administration of the binding protein results in activation and/or proliferation of virus-specific memory T cells in the subject.

In any of the above methods, the memory T cells may be CD8+ or CD4+ memory T cells. In any of the above methods, the memory T cells may be central memory T cells (T _CM ) or effector memory T cells (T _EM ).

cancer

Certain aspects of the invention relate to methods of preventing and/or treating cancer in a patient. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of a binding protein or pharmaceutical composition of the invention.

In some embodiments, a binding protein of the invention is administered to a patient in need thereof for the treatment or prevention of cancer. In some embodiments, the present invention relates to a method of preventing and/or treating a proliferative disease or disorder (eg, cancer). In some embodiments, the method comprises administering to the patient a therapeutically effective amount of at least one of the binding proteins described herein, or a pharmaceutical composition related thereto. In some embodiments, the present invention provides at least one of the binding proteins described herein for preventing and/or treating a proliferative disease or disorder (eg, cancer) in a patient in need thereof. , or to the use of a pharmaceutical composition related thereto. In some embodiments, the present invention provides herein for use in the manufacture of a medicament for preventing and/or treating a proliferative disease or disorder (eg, cancer) in a patient in need thereof. at least one of the described binding proteins, or pharmaceutical compositions related thereto. In some embodiments, the patient is a human.

In some embodiments, at least one binding protein is administered (or should be administered) in combination with one or more anti-cancer therapies (eg, chemotherapeutic agents or any anti-cancer therapy known in the art, such as therapy). In some embodiments, at least one binding protein is administered (or should be administered) prior to one or more anti-cancer therapies. In some embodiments, at least one binding protein is administered (or should be administered) concurrently with one or more anti-cancer therapies. In some embodiments, the at least one binding protein is administered (or should be administered) following one or more anti-cancer therapies.

In some embodiments, the binding protein comprises one or two antigen binding sites that bind a T cell surface protein, and another antigen binding site that binds the extracellular domain of a human HER2 polypeptide. In some embodiments, the binding protein comprises an antigen binding site that binds to the extracellular domain of a human HER2 polypeptide, an antigen binding site that binds a human CD28 polypeptide, and an antigen binding site that binds a human CD3 polypeptide.

In some embodiments, the cancer cells of the individual express HER2. In some embodiments, the patient is selected for treatment based on the cancer cells expressing human HER2 polypeptide. Assays known in the art suitable for detecting HER2 expression by cancer cells include, without limitation, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays.

In some embodiments, the cancer (eg, HER2-positive cancer) is breast cancer, colorectal cancer, gastric cancer, or small cell lung cancer (NSCLC).

In some embodiments, the binding protein comprises one or two antigen binding sites that bind a T cell surface protein, and another antigen binding site that binds the extracellular domain of the human CD38 polypeptide. In some embodiments, the binding protein comprises an antigen binding site that binds to the extracellular domain of a human CD38 polypeptide, an antigen binding site that binds a human CD28 polypeptide, and an antigen binding site that binds a human CD3 polypeptide.

In some embodiments, the cancer cells of the individual express CD38. In some embodiments, the cancer cell expresses a human CD38 isoform A polypeptide on the cell surface. In some embodiments, the cancer cell expresses a human CD38 isoform E polypeptide on the cell surface. In some embodiments, the patient is selected for treatment based on the cancer cells expressing human CD38 isoform E polypeptide on the cell surface. In some embodiments, the cancer cell expresses CD38 and CD28. In some embodiments, the cancer cell expresses CD38 and does not express CD28.

In some embodiments, the cancer (eg, CD38-positive cancer) is multiple myeloma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, lymphoma, breast cancer such as Her2+ breast cancer, prostate cancer, germinal center B cell Lymphoma, or B-cell acute lymphoblastic leukemia. In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or B-cell lymphoma.

In certain embodiments, the cancer is multiple myeloma. Anti-CD38 antibodies such as daratumumab have been tested for the treatment of multiple myeloma. However, although multiple myeloma is considered treatable, recurrence is inevitable in almost all patients, which develops into a refractory disease. In some embodiments, the cancer is relapsed or refractory multiple myeloma. In some embodiments, the patient has previously been treated for multiple myeloma. In some embodiments, a binding protein of the invention is administered to a patient as a first line, second line, or third line treatment for multiple myeloma. Without wishing to be bound by theory, the anti-CD38x anti-CD28x anti-CD3 binding proteins of the present invention recruit T cells to tumor cells via anti-CD38 (or anti-CD28/anti-CD38) and anti-CD3/anti-CD3 binding proteins. It is contemplated that it may be useful for treating multiple myeloma by activating binding T cells via anti-CD28 and/or killing tumor cells via a perforin/granzyme based mechanism. CD28 has been reported as a novel cancer marker for multiple myeloma. See Nair, JR et al. (2011) J. Immunol. 187:1243-1253].

Any of the binding proteins described herein can be used in the methods of the invention.

In some embodiments of any of the methods of the invention, prior to administration of the binding protein, the patient has been treated with daratumumab. As described herein, the present invention provides anti-CD38 binding proteins and sites that do not compete with daratumumab for CD38 binding. Without wishing to be bound by theory, it is believed that this is advantageous as a patient previously treated with daratumumab may receive treatment with the binding protein of the present invention without, for example, a pre-treatment washout period.

Binding proteins can be used in any known assay method, such as competitive binding assays for detection and quantification of one or more target antigens, direct and indirect sandwich assays, and immunoprecipitation assays. The binding protein will bind one or more target antigens with an affinity appropriate for the assay method used.

For diagnostic use, in certain embodiments, the binding protein may be labeled with a detectable moiety. A detectable moiety can be anything capable of directly or indirectly generating a detectable signal. For example, a detectable moiety may be a radioactive isotope such as ³ H, ¹⁴ C, ³² P, ³⁵ S, ¹²⁵ I, ⁹⁹ Tc, ¹¹¹ In, or ^{67 Ga;} fluorescent or chemiluminescent compounds such as fluorescein isothiocyanate, rhodamine, or luciferin; or an enzyme such as alkaline phosphatase, β-galactosidase, or horseradish peroxidase.

Binding proteins are also useful for in vivo imaging. The binding protein labeled with a detectable label can be administered to an animal, preferably into the bloodstream, and the presence and localization of the labeled antibody can be assayed in the host. The binding protein may be labeled with any moiety detectable in an animal by nuclear magnetic resonance, radiology, or other detection means known in the art.

For clinical or research use, in certain embodiments, the binding protein may be conjugated to a cytotoxic agent. A variety of antibodies (ie, antibody-drug conjugates) bound to cytotoxic agents have been used to target cytotoxic payloads to specific tumor cells. Cytotoxic agents and linkers for conjugating antibodies to such agents are known in the art (see, e.g., Parslow, AC et al. (2016) Biomedicines 4:14 and Kalim, M. et al. (2017) Drug Des. Devel. Ther. 11:2265-2276).

Binding protein therapeutic compositions and administration thereof

A therapeutic or pharmaceutical composition comprising a binding protein is within the scope of the present invention. Such therapeutic or pharmaceutical compositions may comprise a therapeutically effective amount of a binding protein, or binding protein-drug conjugate, admixed with a pharmaceutically or physiologically acceptable formulation agent selected to be suitable for the mode of administration. Such pharmaceutical compositions may be used in any of the methods and uses described herein (eg, ex vivo, in vitro, and/or in vivo).

It is preferred that acceptable formulation materials are nontoxic to recipients at the dosages and concentrations employed.

A pharmaceutical composition is a formulation material for altering, maintaining, or preserving, for example, the pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution or release rate, adsorption or permeability of the composition may contain. Suitable formulating materials include amino acids (eg, glycine, glutamine, asparagine, arginine, or lysine), antibacterial agents, antioxidants (eg, ascorbic acid, sodium sulfite, or sodium hydrogen sulfite), buffers (eg, borate, bicarbonate, tris- HCl, citrate, phosphate, or other organic acids), bulking agents (such as mannitol or glycine), chelating agents (such as ethylenediamine tetraacetic acid (EDTA)), complexing agents (such as caffeine, polyvinylpyrrolidone, beta- cyclodextrin, or hydroxypropyl-beta-cyclodextrin), fillers, monosaccharides, disaccharides, and other carbohydrates (such as glucose, mannose, or dextrin), proteins (such as serum albumin, gelatin, or immunoglobulin), colorants, Flavoring and diluents, emulsifying agents, hydrophilic polymers (such as polyvinylpyrrolidone), low molecular weight polypeptides, salt-forming counterions (such as sodium), preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenol ethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide), a solvent (such as glycerin, propylene glycol, or polyethylene glycol), a sugar alcohol (such as mannitol or sorbitol), a suspending agent, a surfactant or wetting agent ( For example, pluronic; PEG; sorbitan esters; polysorbates such as polysorbate 20 or polysorbate 80; triton; tromethamine; lecithin; cholesterol or tyloxapol), stability enhancing agents such as sucrose or sorbitol ), tonicity enhancing agents (such as alkali metal halides (preferably sodium or potassium chloride) or mannitol sorbitol), delivery vehicles, diluents, excipients and/or pharmaceutical adjuvants (e.g., See Remington's Pharmaceutical Sciences (18th Ed., AR Gennaro, ed., Mack Publishing Company 1990), and subsequent editions thereof, which are incorporated herein by reference for all purposes.

The optimal pharmaceutical composition will be determined by one of ordinary skill in the art depending on, for example, the intended route of administration, mode of delivery, and desired dosage. Such compositions can affect the physical state, stability, rate of release in vivo, and rate of clearance in vivo of the binding protein.

The primary vehicle or carrier in the pharmaceutical composition may be aqueous or non-aqueous in nature. For example, a vehicle or carrier suitable for injection may be water, physiological saline solution, or artificial cerebrospinal fluid, supplemented with other substances commonly used in compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are additional exemplary vehicles. Another exemplary pharmaceutical composition comprises a Tris buffer of about pH 7.0-8.5, or an acetate buffer of about pH 4.0-5.5, which may further comprise sorbitol or a suitable substitute. In one embodiment of the invention, a binding protein composition can be prepared for storage by mixing a selected composition having a desired degree of purity with an optional formulator in the form of a lyophilized cake or aqueous solution. In addition, the binding protein may be formulated as a lyophilisate using an appropriate excipient such as sucrose.

The pharmaceutical composition of the present invention may be selected for parenteral or subcutaneous delivery. Alternatively, the composition may be selected for inhalation or for delivery through the digestive tract, such as oral. The preparation of such pharmaceutically acceptable compositions is within the skill of the art.

The formulation components are present in concentrations that are acceptable at the site of administration. For example, a buffer is used to maintain the composition at a physiological pH or slightly lower pH, typically within a pH range of about 5 to about 8.

When parenteral administration is contemplated, therapeutic compositions for use may be in the form of a pyrogen-free, parenterally acceptable aqueous solution comprising the binding protein of interest in a pharmaceutically acceptable vehicle. A particularly suitable vehicle for parenteral injection is properly preserved sterile distilled water in which the binding protein is formulated as a sterile isotonic solution. Another formulation is an injectable microsphere, biodegradable particle, polymer compound (eg, polylactic or polyglycolic acid), bead, or formulation of the molecule of interest using agents such as liposomes. Hyaluronic acid may also be used, which may have the effect of promoting the continuation of the duration of circulation. Other suitable means for introducing a molecule of interest include implantable drug delivery devices.

In one embodiment, the pharmaceutical composition may be formulated for inhalation. For example, the binding protein may be formulated as a dry powder for inhalation. Binding protein inhalation solutions may also be formulated with propellants for aerosol delivery. In another embodiment, the solution may be nebulized.

It is also contemplated that certain formulations may be administered orally. In one embodiment of the invention, binding proteins administered in this manner may be formulated with or without carriers conventionally used in the formulation of solid dosage forms such as tablets and capsules. For example, the capsule may be designed to release the active portion of the formulation at a point in the gastrointestinal tract where bioavailability is maximized and systemic degradation is minimized. Additional agents may be included to facilitate absorption of the binding protein. Diluents, flavoring agents, low melting point waxes, vegetable oils, glidants, suspending agents, tablet disintegrating agents, and binders may also be used.

Other pharmaceutical compositions may include an effective amount of the binding protein in admixture with a non-toxic excipient suitable for the manufacture of tablets. Solutions can be prepared in unit dose form by dissolving the tablets in sterile water or other suitable vehicle. Suitable excipients include inert diluents such as calcium carbonate, sodium carbonate or sodium bicarbonate, lactose, or calcium phosphate; or a binder such as starch, gelatin, or acacia; or glidants such as magnesium stearate, stearic acid, or talc.

Additional pharmaceutical compositions of the present invention, including formulations comprising the binding protein in sustained delivery or controlled delivery formulations, will be apparent to those skilled in the art. Techniques for formulating various other sustained or controlled delivery means such as liposomal carriers, biodegradable microparticles or porous beads and depot injections are also known to those skilled in the art. Further examples of sustained release formulations include semipermeable polymer matrices in the form of molded articles, for example films or microcapsules. The sustained release matrix may be polyester, hydrogel, polylactide, a copolymer of L-glutamic acid and gamma ethyl-L-glutamate, poly(2-hydroxyethyl-methacrylate), ethylene vinyl acetate, or poly-D (-)-3-hydroxybutyric acid. Sustained release compositions may also include liposomes, which may be prepared by any of a number of methods known in the art.

Pharmaceutical compositions used for in vivo administration must generally be sterile. This may be accomplished by filtration through a sterile filtration membrane. Where the composition is lyophilized, sterilization using this method may be performed before or after lyophilization and reconstitution. The composition for parenteral administration may be stored in a lyophilized form or as a solution. In addition, parenteral compositions are generally placed in a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

Once formulated, the pharmaceutical composition may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored in ready-to-use form or in a form requiring reconstitution prior to administration (lyophilized form).

The present invention also relates to kits comprising binding proteins and other reagents useful for detecting the level of a target antigen in a biological sample. Such reagents may include detectable labels, blocking sera, positive and negative control samples, and detection reagents. In some embodiments, a kit comprises a composition comprising any of the binding proteins, polynucleotides, vectors, vector systems, and/or host cells described herein. In some embodiments, a kit comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, and the like. The container may be formed from a variety of materials, such as glass or plastic. The container holds a composition alone or in combination with other compositions effective for treating, preventing, and/or diagnosing a condition, and may have a sterile access port (eg, the container may have a stopper pierceable by a hypodermic injection needle). may be an intravenous solution bag or vial). In some embodiments, the label or package insert indicates that the composition is for use in the prevention, diagnosis, and/or treatment of a condition of choice. Alternatively or additionally, the article of manufacture or kit further comprises a second (or third) container comprising a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. may include It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

The present invention also includes kits for producing single-dose dosage units. The kits may each include both a first container with a dry protein and a second container with an aqueous formulation. Kits comprising single and multi-chamber prefilled syringes (eg, liquid syringes and lyosyringes) are also included within the scope of the present invention.

The effective amount of the binding protein pharmaceutical composition to be used therapeutically will depend, for example, on the therapeutic context and purpose. Thus, those skilled in the art will know how to determine, in part, the appropriate dosage level for treatment, the molecule delivered, the indication for which the binding protein is used, the route of administration, and the patient's physique (weight, body surface area, or organ size) and condition (age and general health). will understand that it will depend on Therefore, the clinician can titrate the dosage and modify the route of administration to obtain the optimal therapeutic effect.

Dosing frequency will depend on the pharmacokinetic parameters of the binding protein in the formulation used. In general, the clinician will administer the composition until a dosage is reached that achieves the desired effect. Thus, the composition may be administered as a single dose, in two or more doses over time (which may or may not contain the same amount of the molecule of interest), or as continuous infusion through an implantation device or catheter. . Further refinements of appropriate dosages are routinely made by those skilled in the art and are within the scope of work routinely performed by those skilled in the art. Appropriate dosages can be ascertained using appropriate dose-response data.

The route of administration of the pharmaceutical composition is according to known methods (eg, orally; intravenously, intraperitoneally, intracerebral (intraventricular), intraventricular, intramuscular, intraocular, intraarterial, intraportal, or intralesional. via injection by route; by a sustained release system; or by an implantable device). If desired, the composition may be administered by bolus injection, administered continuously by infusion, or administered by an implantable device.

The composition may also be administered topically via implantation of a membrane, sponge, or other suitable material in which the molecule of interest is absorbed or encapsulated. When an implantable device is used, the device may be implanted in any suitable tissue or organ, and the molecule of interest may be delivered via diffusion, timed release bolus, or continuous administration.

[Table 1]

Trispecific Binding Protein Polypeptide Sequence

[Table 6]

Trispecific binding protein polynucleotide sequence

Example

The following examples illustrate specific embodiments of the present invention and various uses thereof. These examples are presented for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

Example 1: Development of Trispecific HER2/CD28xCD3 Antibodies and Variant Anti-CD3 Binding Sites

Immunotherapy is a promising new therapeutic approach for disease management of cancer. The immune system is the first line of defense against the development and progression of cancer. Evidence is now great that T cells can control tumor growth and prolong the survival of cancer patients in the early and late stages of the disease. However, tumor-specific T cells may be restricted in several ways and thus fail to control the disease.

In order to remove the restriction on T cells induced by uncontrolled tumors, a novel antibody that specifically activates T cells to bind to HER2-expressing cancer cells was developed in the form of a trispecific antibody shown in FIG. 1A . This novel trispecific antibody is capable of binding three targets: HER2, CD3, and CD28. Anti-HER2 and anti-CD3 binding sites were further optimized for high affinity binding and reducing potential manufacturing burden.

HER2 amplification and overexpression can be found in molecular subtypes of breast cancer as well as gastric, ovarian, lung, and prostate carcinomas. Two factors are required for optimal activation of T cells: (1) antigen recognition and (2) co-stimulation. Using the trispecific HER2/CD28xCD3 trispecific binding proteins described herein, signal 1 is provided by an agonist anti-CD3 binding site and signal 2 is provided by an agonist anti-CD28 binding site (e.g., For example, see Figure 1d ). It is thought that the trispecific antibody described in the subsequent examples recruits T cells to the tumor via HER2 and activates binding T cells by binding to CD3 and CD28. The resulting activation induces apoptosis potential of immune cells against nearby tumor cells.

Materials and Methods

Generation and Characterization of Antibodies

The expression plasmid was transiently transfected into Expi293 cells to generate trispecific antibody variants. Five days after transfection, the supernatant from the transfected cells was collected, quantified and normalized to absorbance at 280 nm in a Nano Drop. Binding of the supernatant to the antigen was measured by ELISA, and the absorbance of the parental HER2 WT tri Ab was set to 1.0. The fold change of the other variants was calculated by dividing the corresponding absorbance by the absorbance of the parent Ab.

Protein A affinity purification followed by SEC purification was used to purify the trispecific antibody variants. Binding of the purified antibody to the antigen was measured by ELISA. EC50 was determined based on the binding curve generated by Graphpad Prism7.

result

To alleviate potential manufacturing burdens (eg, deamidation sites), trispecific Ab variants with multiple mutations in the binding arm were generated. A binding ELISA assay was performed to assess binding of the indicated trispecific antibodies to each of the three targets HER2, CD3, and CD28. In FIG. 1B , HER2/CD3×CD28 trispecific antibodies with the indicated anti-HER2 or anti-CD3 variants were compared to the parental trispecific Abs. Introduction of some sets of mutations (e.g., 32/33 QQ and 33/35QQ) into the VL domain of the anti-CD3 binding site resulted in a sharp decrease in binding to CD3, whereas the 32/35 QQ mutation was near wild-type binding. was maintained in MS peptide analysis showed that the binding site with a DNAQ mutation in CDR-L1 (SEQ ID NO: 63) still undergoes greater than 15% deamidation, whereas ENLQ (SEQ ID NO: 281), ENLF (SEQ ID NO: 282), and ENLR ( SEQ ID NO: 283) was shown to cause less than 5% deamidation. Importantly, these variants also retained binding to CD3.

In addition, binding curves for the indicated antibodies that bind human HER2, human CD28, and CD3 are provided in FIG. 1C . The EC50 values of selected trispecific antibody variants are provided in Table E.

[Table E]

Binding ELISA assays were performed on purified trispecific antibodies to determine binding affinities for HER2, human CD3, and human CD28

Without wishing to be bound by theory, it is believed that, as shown in FIG. 1D , the HER2/CD3/CD28 trispecific antibody recruits T cells to cancer cells via anti-HER2 and anti-CD3/CD28 arms. It is also believed that bound T cells are activated by the anti-CD28/CD3 arm. Without wishing to be bound by theory, it is believed that the death of cancer cells occurs through T cell-mediated mechanisms (eg, perforin, granzyme). Without wishing to be bound by theory, it is believed that, through a similar mechanism, other types of tumors can be killed by replacing antigen binding sites that recognize other tumor target proteins.

Example 2: Development of trispecific CD38/CD3xCD28 antibody

Trispecific CD38/CD3xCD28 antibodies were developed and characterized for binding to CD38, CD3, and CD28 polypeptides.

Materials and Methods

Generation of CD38/CD28xCD3 trispecific antibodies

A panel of anti-CD38, anti-CD3, and anti-CD28 antibodies, as well as the human IgG4 Fc domain, were used to generate the CD38/CD28xCD3 trispecific antibody in the form of the trispecific antibody shown in FIG. 2A .

Trispecific binding proteins were generated by transiently transfecting the four expression plasmids into Expi293 cells using the ExpiFectamine™ 293 transfection kit (Thermo Fisher Scientific) according to the manufacturer's protocol. Briefly, 25% (w/w) of each plasmid was diluted in Opti-MEM, mixed with pre-diluted ExpiFectamine reagent at room temperature (RT) for 20-30 minutes, and added to Expi293 cells (2.5x10 ⁶ pieces). cells/ml). In order to produce the trispecific binding protein in good yield and purity, optimization of transfection to determine the optimal ratio of plasmids is often used.

After 4-5 days of transfection, the supernatant from the transfected cells was collected and filtered through a 0.45 μm filter unit (Nalgene). The trispecific binding protein in the supernatant was purified using a three-step procedure. First, Protein A affinity purification was used, and the bound Ab was eluted using "IgG Elution Buffer" (Thermo Fisher Scientific). Second, the product was dialyzed against PBS (pH 7.4) overnight with two changes of PBS buffer. All precipitates were removed by filtration through a 0.45 μm filter unit (Nalgene) before the next step. Third, size exclusion chromatography (SEC) purification (Hiload 16/600 Superdex 200pg, or Hiload 26/600 Superdex 200pg, GE Healthcare) was used to remove aggregates and other species from the preparative column. Fractions were analyzed by reducing and non-reducing SDS-PAGE to identify fractions containing the monomeric trispecific binding protein, and then they were combined. Purified antibody can be aliquoted and stored at -80°C for a long time.

ELISA binding assay

The binding affinity for each target antigen by the CD38/CD28xCD3 T cell participant was measured by ELISA. Briefly, 96 well Immuno plates (Thermo Fisher Scientific) were coated with 200 ng/well of each antigen in PBS pH 7.4 overnight at 4°C. The coated plates were blocked with 5% skim milk+2% BSA in PBS for 1 hour at room temperature and then washed 3 times with PBS+0.25% Tween 20 (Aqua Max 400, Molecular Devices). Serial dilutions of antibodies (trispecific and control Ab) were prepared, added to ELISA plates (100 μl/well, in duplicate), incubated for 1 h at room temperature (RT), followed by PBS+0.25% Tween 20 Washed 5 times. After washing, HRP-conjugated secondary anti-human Fab (1:5000, Cat. No. 109-035-097, Jackson ImmunoResearch Inc) was added to each well and incubated for 30 minutes at room temperature. After washing 5 times with PBS+0.25% Tween 20, 100 μl of TMB microwell peroxidase substrate (KPL, Gaithersburg, MD, USA) was added to each well. 50 μl of 1 MH ₂ SO ₄ was added to terminate the reaction, and OD450 was measured using SpectraMax M5 (Molecular Devices) and analyzed using SoftMax Pro6.3 software (Molecular Devices). Final data were transferred to GraphPad Prism software (GraphPad Software, CA, USA) and plotted. EC50 was calculated using the same software.

Determination of trispecific antibody binding using SPR

Human CD38-His antigen was used for complete kinetic analysis (Cambridge Biologics, Cambridge, MA). Kinetic characterization of the purified antibody was performed using SPR technology in BIACORE 3000 (GE Healthcare). A capture assay using human IgG1 specific antibody capture and orientation of the investigated antibody was used. A human antibody capture kit (GE Healthcare) was used for the capture of Fc-containing protein constructs. An anti-His antibody capture kit (GE Healthcare) was used for the capture of His-tag antigen. Capture antibody was immobilized (11000 RU) via primary amine groups on a research grade CM5 chip (GE Life Sciences) using standard procedures. Assay antibody was captured at a flow rate of 10 μL/min using an adjusted RU value that typically produced a maximum analyte binding signal of 30 RU. Binding kinetics were determined for trispecific antibodies. Assay buffer HBS EP (10 mM HEPES, pH 7.4, 150 mM NaCl, 3 mM EDTA, and 0.005% surfactant P20) was used at a flow rate of 30 μl/min. The chip surface was regenerated using the regeneration solution of each capture kit. Kinetic parameters were analyzed and calculated in the BIA Assessment Program Package v4.1 using a 1:1 Langmuir binding model with mass transfer and a flow cell without capture antibody as reference.

Daratumumab Competition Binding Assay

For the daratumumab competition binding assay, daratumumab was amine bound to the active surface of the CM5 chip. The reference surface was left blank and was used to reject any non-specific binding of the injected molecule. Recombinant CD38-His (Sino Biological, Part# 10818-H08H) was injected onto the surface of daratumumab followed by injection of the test antibody. When the monospecific anti-CD38 antibody recognized an epitope of CD38 that was different from that of daratumumab, injection of the antibody increased the SPR signal. If the antibody recognized an epitope overlapping with daratumumab, injection of the antibody did not increase the SPR signal.

result

The binding properties of selected CD38/CD28sup x CD3mid_ENLQ DKTHT IgG4 FALA trispecific antibodies with alternative anti-CD38 binding domains to human CD38 were determined by SPR. The association rate constant (K _On ), dissociation rate constant (K _Off ), and K _D of selected trispecific antibodies are provided in Table A. The selected trispecific antibodies displayed varying degrees of affinity for the human CD38 antigen.

[Table A]

Binding properties of selected CD38/CD28sup x CD3mid_ENLQ DKTHT IgG4 FALA trispecific antibodies with alternative anti-CD38 binding domains to human CD38 as determined by SPR

The binding affinity of selected CD38/CD28sup x CD3mid_ENLQ DKTHT IgG4 FALA trispecific antibodies with alternative anti-CD38 binding domains to human CD3, human CD28, human CD38, and cynomolgus monkey CD38 was then analyzed by ELISA as described above. was measured with As shown in FIGS. 2B-2E , selected CD38/CD28sup x CD3mid_ENLQ DKTHT IgG4 FALA trispecific antibodies with alternative anti-CD38 binding domains were tested against human ( FIG. 2B ) and cynomolgus monkey CD38 ( FIG. 2C ). Although different affinities were shown, similar affinities were shown for human CD3 ( FIG. 2D ) and CD28 ( FIG. 2E ). EC50 values were then calculated with GraphPad Prism 7.02 using a variable slope model with a 4-parameter logistic curve. EC50 values of selected trispecific antibodies against human CD3, human CD28, human CD38, and cynomolgus monkey CD38 are provided in Table B. The control antibody was a human IgG4 isotype control.

[Table B]

EC50 values of selected CD38/CD28sup x CD3mid_ENLQ DKTHT IgG4 FALA trispecific antibodies with alternative anti-CD38 binding domains to human CD3, human CD28, human CD38, and cynomolgus monkey CD38

An SPR competition assay was performed to determine whether the anti-CD38 antibodies hhy6284, hhy992, hhy5379, or hhy1195 (tested in monospecific antibody form) competed with daratumumab for binding to CD38. After injection of CD38 onto daratumumab (immobilized on SPR sensor chip), test antibody (or daratumumab) was injected on daratumumab/CD38 complex. As shown in FIG. 3 , injections of Hyb6264, hhy992, Hyb5379, and Hhy1195 increased the SPR signal, indicating that these antibodies recognized an epitope of CD38 different from that recognized by daratumumab. As expected, injection of free daratumumab (competitive binding control) did not increase the SPR signal.

Binding of anti-CD38 antibodies to human or cynomolgus CD38 polypeptides is summarized in Table B2.

[Table B2]

Summary of Anti-CD38 Binding Properties to Human or Cynomolgus CD38

Anti-CD38 antibodies were also tested for competitive binding to daratumumab in an SPR assay. For the daratumumab competition binding assay, daratumumab was amine bound to the active surface of the CM5 chip. The reference surface was left blank and was used to reject any non-specific binding of the injected molecule. Recombinant CD38-His (Sino Biological, Part# 10818-H08H) was injected onto the surface of daratumumab followed by injection of the test antibody. If the antibody recognizes an epitope on CD38 that is different from that of daratumumab, injection of the antibody will increase the SPR signal. If the antibody recognizes an epitope that overlaps with daratumumab, injection of the antibody will not increase the SPR signal. According to the results of this assay, the tested antibodies hhy992, hyb6284, hhy1195, and hhy1370 did not compete with daratumumab.

Example 3: Trispecific CD38/CD3xCD28 Antibodies Promote Lysis of Human Multiple Myeloma and Lymphoma Tumor Cells.

An in vitro cell lysis assay was used to determine whether the trispecific CD38/CD3xCD28 antibody has anti-tumor cell activity using human multiple myeloma and lymphoma cells.

Materials and Methods

In vitro killing assay for tumor cells using human T cells

Target tumor cells were labeled with the membrane dye PKH-26 (Sigma) and an E:T ratio of 10:1 with human PBMCs or enriched CD8 T cells as effector cells in the presence of the indicated concentrations of the trispecific or related control antibody. (E:T=3:1 using concentrated CD8 T cells) was co-cultured for 24 hours. Peripheral blood mononuclear cells were isolated from normal human donors by Ficoll isolation, and autologous CD8+ or pan-T cells were enriched using a kit from Miltenyi Biotech (San Diego, CA). Cell lysis in target cells was determined by staining with LIVE/DEAD™ Fixable Violet Dead Cell Stain Kit (Life Technologies), and sample analysis was run on an LSRFortessa instrument (BD Biosciences) followed by analysis using Flowjo software (Treestar). This was measured as the number of dead cells in the labeled target cell population.

In vitro killing assay for tumor cells using human T cells in the presence of daratumumab

After pre-incubation of 5 nM of daratumumab or isotype control antibody with PKH-26 labeled target tumor cells (10 ⁵ cells/well) for 30 min, the indicated concentrations of trispecific TCE, and human PBMCs were was added (E:T=10:1). After 24 hours, staining with LIVE/DEAD™ Fixable Violet Dead Cell Stain Kit (Life Technologies) to determine the degree of cell lysis in target cells, running sample analysis on a LSRFortessa instrument (BD Biosciences) followed by Flowjo software (Treestar) was measured as the number of dead cells in the labeled target cell population by analysis using

result

The in vitro apoptotic activity of CD38/CD28sup x CD3mid_ENLQ DKTHT IgG4 FALA trispecific antibodies with alternative anti-CD38 binding domains was measured using the human multiple myeloma cell line NCI-H929 expressing both CD38 and CD28. Assays were performed in the presence of 5 nM daratumumab or isotype control antibody (present during the assay period). 4A and 4B , all trispecific antibodies tested induced cell lysis in a concentration-dependent manner in the presence and absence of daratumumab. EC50 values were then calculated in the presence and absence of daratumumab ( Table C ). The apoptotic activity of the trispecific antibody CD38/CD28sup x CD3mid_ENLQ DKTHT IgG4 FALA with CD38VH1 or CD38hhy1370 anti-CD38 binding domain was reduced by daratumumab, whereas CD38hyb5739, CD38hyb6284, or the trispecific antibody with CD38hhy1195 anti-CD38 binding domain. Specific antibodies showed a 3- to 8-fold decrease in apoptotic activity in the presence of daratumumab ( Table C ).

[Table C]

In vitro killing activity against human multiple myeloma cell line NCI-H929 (CD38+/CD28+) by CD38/CD28sup x CD3mid_ENLQ DKTHT IgG4 FALA trispecific antibody with alternative anti-CD38 binding domain in the presence of daratumumab

In addition, using the human lymphoma cell line OCI-LY19 expressing CD38 but not CD28, to determine the apoptotic activity of selected CD38/CD28sup x CD3mid_ENLQ DKTHT IgG4 FALA trispecific antibodies with alternative anti-CD38 binding domains. An in vitro cell lysis assay was used. The assay was performed in the presence of 5 nM of daratumumab or isotype control antibody present during the assay period. 5A and 5B , all trispecific antibodies tested induced cell lysis in a concentration-dependent manner in the presence and absence of daratumumab. EC50 values were then calculated in the presence and absence of daratumumab ( Table D ). The apoptotic activity of CD38/CD28sup x CD3mid_ENLQ DKTHT IgG4 FALA trispecific antibody with CD38VH1 anti-CD38 binding domain was decreased by about 24-fold by daratumumab, while CD38hhy992, CD38hyb5739, CD38hyb6284, CD38hhy1195, or CD38hhy1370 anti-CD38hhy1370 Trispecific antibodies with binding domains also showed a decrease in apoptotic activity in the presence of daratumumab ( Table D ).

[Table D]

In vitro killing activity against human lymphoma cell line OCI-LY19 (CD38+/CD28-) by selected CD38/CD28sup x CD3mid_ENLQ DKTHT IgG4 FALA trispecific antibodies with alternative anti-CD38 binding domains in the presence of daratumumab

Example 4: CD38/CD28xCD3 trispecific antibody promotes CMV-specific immune response

As part of acquired immunity, T-cell immunity plays an important role in controlling viral infection and cancer, and has the potential to eliminate viral infection or cure cancer by eliminating infected and malignant cells. In chronic infectious diseases such as herpes virus infection (HSV, CMV, EBV, etc.), HIV, and HBV, the virus establishes persistence in humans through various mechanisms including immunosuppression, T cell depletion, and latent infection. Nevertheless, viral infection in general is viral antigen-specific, including antigen-specific CD8 T cells that can readily recognize infected cells to control or kill via cytokine release or cytotoxic T-cell (CTL)-mediated killing processes. Induces enemy immunity. Thus, viral antigen specific T cell activation and/or amplification in vivo and/or ex vivo provides a therapeutic strategy for chronic viral infections.

Anti-CD38/CD28xCD3 trispecific antibodies were developed and evaluated for their potential to activate T cells and promote proliferation and/or amplification of antigen-specific T cells. Such trispecific Abs can effectively propagate CD4 and CD8 effector and memory populations in vitro, including antigen-specific CD8 T central memory and effector memory cells. Specifically, in vitro proliferation of CMV and EBV specific CD8 central memory and effector memory cells was demonstrated. The anti-CD38/CD28xCD3 trispecific antibodies described herein bind to CD3/CD28/CD38 and provide a signaling pathway that stimulates and proliferates T cells, thereby preventing infections such as HSV, CMV, EBV, HIV-1, and HBV infection. It has revealed novel properties that may provide an effective strategy for treating chronic infectious diseases.

In this example, the ability of the CD38/CD28xCD3 trispecific antibody to promote activation and proliferation of CMV-specific T cells was measured.

Materials and Methods

Measurement of T cell proliferation in vitro

T cells were isolated from human PBMC donors by negative selection using a magnetic Pan T Cell Isolation kit (Miltenyi Biotec GmbH, Germany). Antibodies were coated in 96-well cell culture plates by preparing the antibody in sterile PBS and dispensing 50 µL into each well (350 ng/well). The plates were then incubated at 37° C. for a minimum of 2 hours and then washed with sterile PBS. Intact T cells were added to antibody-coated plates ( ⁵ ×10 5 cells/mL) and incubated at 37° C. for several days. On day 4, cells were passaged with fresh cell culture medium on fresh antibody-coated plates. In certain experiments with 7 days of incubation, only fresh medium was added without changing to a new antibody-coated plate. Cells were collected at specific time points and cell counts were counted using CountBright™ counting beads.

In vitro T cell proliferation assay and T cell subset determination

Peripheral blood mononuclear cells were isolated from the blood of healthy human donors collected by Research Blood Components, LLC (Boston, MA). ^{PBMCs were added (5} ×10 5 cells/mL) to antibody-coated plates (350 ng/well) as described above and incubated at 37° C. for 3 and 7 days. Cells were harvested at specific time points and analyzed for T cell subsets naïve (CCR7+ CD45RO-), Tcm (CCR7+ CD45RO+), Tem (CCR7- CD45RO+), Tregs (CD4+ Foxp3+ CD25hi) by flow cytometry. CMV pp65-specific and EBV BMLF-specific CD8+ T cells were transfected with HLA/viral peptides (A*02:01/NLLVPMVATV, SEQ ID NO: 284), (A*02:01/GLCTLVAML, SEQ ID NO: 285) of PBMC donors, respectively. was detected using a fluorescence-conjugated pentamer limited to (ProImmune, Oxford, UK). PBMCs were obtained from HemaCare (Van Nuys, CA) for donors with known CMV or EBV infection. PMBCs from donors negative for the restriction HLA type were used as negative controls. Staining was performed according to the manufacturer's protocol.

Quantification of CMV-specific T cells

As indicated above, peripheral blood mononuclear cells (PBMCs) were isolated from the blood of human donors infected with known CMV and added to plates containing trispecific antibodies or control antibodies. Plates were incubated at 37°C. Cells were collected at specific time points and analyzed by flow cytometry.

result

CD38/CD28sup x CD3mid_ENLQ DKTHT IgG4 FALA trispecific antibody with alternative anti-CD38 binding domains ΔVH1CD38 (control), CD38VH1, CD38hhy992, CD38hyb5739, CD38hyb6284, CD38hhy1195, and CD38hhy1370 with CMV-infected human donor D ( Figure 6a to DKTHT IgG4 FALA trispecific antibody ) and PBMCs isolated from CMV-infected human donor E ( FIGS. 7A-7J ) were tested as described above. All CD38 trispecific Abs tested activated and promoted proliferation of CMV-specific T cells, resulting in CMV-specific CD8+ T cells (cells/well) with different potencies and kinetics in a dose-response manner over a 7-day experiment. (CMV donor D, FIGS. 6A and 6B ; CMV donor E, FIGS. 7A and 7B ). In addition, all CD38 trispecific Abs tested were CMV-specific central memory (T _cm ) (CMV donor D, FIGS. 6C and 6D ; CMV donor E, FIGS. 7C and 7D ) and effector memory (T _em ) CD8+ Expansion (cells/well) of T cells (CMV donor D, FIGS. 6E and 6F ; CMV donor E, FIGS. 7E and 7F ), both expanded rapidly within 7 days. 6G-6J (CMV Donor D) and 7G-7J (CMV Donor E) show the percentage of _{CMV-specific T cm} and T _em cells on days 0, 3, and 7 of the aforementioned 7-day experiment. It provides a time lapse showing.

Taken together, these data show that the CD38/CD28xCD3 trispecific antibody was administered to CMV-specific CD8+ T cells, CMV-specific effector memory (T _em ) CD8+ T cells, and CMV-specific central memory (T _cm ) CD8+ T cells. It indicates that it promotes the activation and proliferation of CMV-specific T cells, such as

Example 5: CD38/CD28xCD3 trispecific antibody promotes EBV-specific immune response

Next, the ability of the CD38/CD28xCD3 trispecific antibody to promote the activation and proliferation of Epstein-Barr virus (EBV)-specific T cells was measured.

Materials and Methods

Quantification of EBV-specific T cells

As indicated above, peripheral blood mononuclear cells (PBMCs) were isolated from the blood of human donors infected with known EBV and added to plates containing trispecific antibodies or control antibodies. Plates were incubated at 37° C. for up to 11 days. Cells were collected at specific time points and analyzed by flow cytometry.

result

CD38/CD28sup x CD3mid_ENLQ DKTHT IgG4 FALA trispecific antibody with alternative anti-CD38 binding domains AVH1CD38 (control), CD38VH1, CD38hhy992, CD38hyb5739, CD38hyb6284, CD38hhy1195, and CD38hhy1370 ( Figure 8a to DKTHT IgG4 FALA trispecific antibody also donated to EBV- ) and PBMCs isolated from EBV-infected donor D ( FIGS. 9A-12 ) were tested as described above. All CD38 trispecific Abs tested activated T cells and promoted proliferation of EBV-specific T cells, resulting in EBV-specific CD8+ T cells (cells) with different potencies and kinetics in a dose-response manner over the 7-day experiment. /well) (EBV donor C, FIGS. 8A and 8B ; EBV donor D, FIGS. 9A and 9B ). In addition, all CD38 trispecific Abs tested were EBV-specific central memory (T _cm ) (EBV donor C, FIGS. 8C and 8D ; EBV donor D, FIGS. 9C and 9D ) and effector memory (T _em ) CD8+ Expansion (cells/well) of T cells (EBV donor C, FIGS. 8E and 8F ; EBV donor D, FIGS. 9E and 9F ), both expanded rapidly within 7 days. 8G-8J (EBV Donor C) and 9G-12 (EBV Donor D) show the percentage of _{EBV-specific T cm} and T _em cells on days 0, 3, and 7 of the aforementioned 7-day experiment. It provides a time lapse showing.

Taken together, these data suggest that the CD38/CD28xCD3 trispecific antibody was administered to EBV-specific CD8+ T cells, EBV-specific effector memory (T _em ) CD8+ T cells, and EBV-specific central memory (T _cm ) CD8+ T cells. It indicates that it promotes the activation and proliferation of EBV-specific T cells, such as

Example 6: Antitumor Effect of Her2/CD28 x CD3 Trispecific Antibodies in Tumor-bearing Mice

In this example, the Her2/CD28 x CD3 trispecific antibody was tested for its antitumor effect in a Nod scid gamma (NSG) mouse model with ZR-75-1 tumors implanted with in vitro proliferated T cells.

Materials and Methods

NSG mice were divided into 5 groups of 10 mice each. On day 0, ZR-75-1 human breast cancer cells were transplanted into the mammary gland fat pad of each mouse at 5 million cells per mouse using 50% matrigel. On day 17/18, proliferation of human CD3+ T cells started. Randomization of mice on day 24 with tumors approximately 150 mm ^{3 occurred.} On day 25, all mice were implanted with in vitro proliferated human CD3+ T cells (10 million cells/mouse in 300 μL) (1QW, 1 IP injection).

From day 25, one group of mice received a dose of vehicle alone (8% w/v sucrose, 0.05% w/v polysorbate 80, 10 mM histidine, pH 5.5), while the remaining four groups received a dose of Her2/ CD28 x CD3 trispecific antibody was administered (both 10 mL/kg). The trispecific antibody administration group was administered at 100, 10, 1, or 0.1 μg/kg. Antibody or vehicle is administered 1QW intravenously in two doses (eg, day 25 and day 32). Blood and tumor tissues were collected on day 38 or 39.

result

The effect of Her2/CD28 x CD3 trispecific antibody (binding protein #2 in Table 1, corresponding to SEQ ID NOs: 104-107) on human breast tumor growth in the NSG mouse model transplanted with the in vitro proliferated human T cells. compared to vehicle control. The 10 ug/kg dose also showed an antitumor effect, but as a result of treatment with the highest dose (100 ug/kg) of the Her2/CD28 x CD3 trispecific antibody, tumor growth inhibition and regression were most pronounced ( FIG. 13a ). and FIG. 13d ). No significant weight loss was observed ( FIG. 13B ). Individual tumor volumes over time from each trispecific antibody treatment group are provided in FIG. 13C .

Next, the effect of trispecific antibody treatment on individual immune cell subsets was investigated. In addition to mouse CD45+ cells, human CD45+, human CD8+, and human CD4+ cell populations were determined by flow cytometry ( FIGS. 14A and 14C ). The highest dose of trispecific antibody (100 ug/kg) led to depletion of human CD4+ cells, and this effect was dose dependent ( FIGS. 14B and 14C ). The number of human CD8+ cells was not significantly affected by trispecific antibody administration.

The effect of trispecific antibody treatment on tumor infiltrating lymphocytes (TIL) was also assessed by immunohistochemical (IHC) staining for human CD45, CD4, and CD8. Using H&E staining, tumors in the low dose group (trispecific antibody at 1 ug/kg or 0.1 ug/kg) were generally comparable in size to the vehicle control group. 15A to 15C , human TIL was increased in the group administered with the low dose of Her2/CD28 x CD3 trispecific antibody, but human TIL was sparse in the high dose group. IHC images were also quantitatively investigated ( FIGS. 16A-16C ). These results indicated a significant reduction in CD45+ and CD8+ cells in the higher trispecific antibody dose groups (100 ug/kg and 10 ug/kg).

Compared to vehicle control, tumors in the high-dose trispecific antibody treatment group (100 ug/kg or 10 ug/kg) were characterized by lean TIL. Moderate to high numbers of CD45+, CD4+, or CD8+ human TILs were observed in the trispecific antibody-treated groups at 1 ug/kg and 0.1 ug/kg. These TILs were mostly present at the tumor margins, but occasionally extended deeper into the tumor core.

In conclusion, these results showed that NSG mice bearing ZR-75-1 breast tumors implanted with in vitro activated T cells were treated with 100 ug/kg or 10 ug/kg of HER2-targeted T-cell-engaged trispecific antibody twice. Treatment using the intravenous dose showed a significant reduction in tumor volume and a significant reduction in TIL at the same time. At 1 ug/kg of trispecific antibody, there was a slight and inconsistent trend for increased TIL compared to vehicle control.

Example 7: Effect of anti-HER2 and anti-CD3 antigen binding domain sequences in Her2/CD28 x CD3 trispecific antibody on cancer cell killing

This example describes the effect of anti-Her2 and anti-CD3 variable domain sequences on target cell death. In this example, a Her2/CD28 x CD3 trispecific antibody (“control”) having a wild-type trastuzumab antigen binding domain and an anti-CD3 antigen binding domain without a 32/35 QQ mutation in the VL domain (see Examples) It was compared with Her2/CD28 x CD3 trispecific antibodies #1 to 6 of Table 1 corresponding to SEQ ID NOs: 100-103, 104-107, 286-289, 290-293, 294-297, and 298-301, respectively.

Materials and Methods

CD8+ T cells were isolated from human PBMCs from healthy donors using a magnetic bead isolation kit (Miltenyi Biotec). T cells were used as effector cells for breast cancer cell lines expressing various levels of HER2 in a 3:1 (effector:target) ratio. Cells were incubated with experimental or control trispecific antibodies for 2 days prior to acquisition by flow cytometry using viability dye (Invitrogen) and PKH26 target cell stain (Sigma). Mean EC50 for target cell lysis was calculated from 2-3 PBMC donors for each trispecific Ab.

result

All trispecific antibodies were characterized for in vitro cell lysis of the three HER2+ breast cancer target cell lines HCC1954, BT20, and MDA-MB-231. The HCC1954 breast cancer cell line was found to express high levels of HER2 as assessed by flow cytometry (up to about 150,000 receptors/cell), IHC (3+), or HercepTest HER2 expression assay (3+) ( FIG. 17A ). ). The BT20 breast cancer cell line was found to express moderate levels of HER2 as assessed by flow cytometry (approximately 60,000 receptors/cell), IHC (1+), or HercepTest HER2 expression assay (1+) ( FIG. 17C ). . The MDA-MD-231 breast cancer cell line was found to express low levels of HER2 as assessed by flow cytometry (approximately 9,000 receptors/cell), IHC (0+), or HercepTest HER2 expression assay (0) ( 17e ). Results of cell death assays targeting HCC1954, BT20, or MDA-MB-231 were compared binding protein #2 versus control or binding proteins #1 and #5 versus control, respectively, in Figures 17B , 17D , and 17F . is shown in The results showed that Her2/CD28 x CD3 trispecific antibodies with 30R/55Q/102E mutations in the anti-HER2 arm and 32/35 QQ mutations in the VL domain of the anti-CD3 arm were 3, especially at lower antibody concentrations. showed improved target cell killing for all branch cell lines.

Cells in vitro against all trispecific antibodies targeting the above-mentioned three breast cancer cell lines (HCC1954, BT20, and MDA-MB-231) as well as gastric cancer cell lines OE19 (high HER2 expression) and GSU (medium HER2 expression) Mean EC50 (pM) for killing was determined. In general, Her2/CD28 x CD3 trispecific antibodies with mutations in the VL domain of the anti-CD3 arm and the anti-HER2 arm were directed against all three breast cancer cell lines ( FIG. 18A ) and against both gastric cancer cell lines ( FIG. 18B ). showed a lower E50 (and hence better cell death). These results show that although all trispecific antibodies are capable of inducing apoptosis of HER2+ cells, the mutated trispecific antibody consistently exhibits improved apoptosis efficacy against several target cell types.

SEQUENCE LISTING <110> Sanofi <120> TRISPECIFIC BINDING PROTEINS, METHODS, AND USES THEREOF <130> 18395-20320.40 <140> Not Yet Assigned <141> Concurrently Herewith <150> EP 19306311.2 <151> 2019-10-08 <150> US 62/831,572 <151> 2019-04-09 <160> 302 <170> FastSEQ for Windows Version 4.0 <210> 1 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 1 Gly Phe Asn Ile Lys Asp Thr Tyr 1 5 <210> 2 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 2 Gly Phe Asn Ile Arg Asp Thr Tyr 1 5 <210> 3 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 3 Ile Tyr Pro Thr Asn Gly Tyr Thr 1 5 <210> 4 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 4 Ile Tyr Pro Thr Gln Gly Tyr Thr 1 5 <210> 5 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 5 Ile Tyr Pro Thr Asn Ala Tyr Thr 1 5 <210> 6 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 6 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr 1 5 10 <210> 7 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 7 Ser Arg Trp Gly Gly Glu Gly Phe Tyr Ala Met Asp Tyr 1 5 10 <210> 8 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 8 Ser Arg Trp Gly Gly Ser Gly Phe Tyr Ala Met Asp Tyr 1 5 10 <210> 9 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 9 Gln Asp Val Asn Thr Ala 1 5 <210> 10 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 10 Gln Asp Val Gln Thr Ala 1 5 <210> 11 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 11 Ser Ala Ser One <210> 12 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 12 Gln Gln His Tyr Thr Thr Pro 1 5 <210> 13 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 13 Gly Tyr Thr Phe Thr Ser Tyr Ala 1 5 <210> 14 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 14 Ile Tyr Pro Gly Gln Gly Gly Thr 1 5 <210> 15 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 15 Ala Arg Thr Gly Gly Leu Arg Arg Ala Tyr Phe Thr Tyr 1 5 10 <210> 16 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 16 Gln Ser Val Ser Ser Tyr Gly Gln Gly Phe 1 5 10 <210> 17 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 17 Gly Ala Ser One <210> 18 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 18 Gln Gln Asn Lys Glu Asp Pro Trp Thr 1 5 <210> 19 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 19 Gly Tyr Thr Leu Thr Glu Phe Ser 1 5 <210> 20 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 20 Phe Asp Pro Glu Asp Gly Glu Thr 1 5 <210> 21 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 21 Thr Thr Gly Arg Phe Phe Asp Trp Phe 1 5 <210> 22 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 22 Gln Ser Val Ile Ser Arg Phe 1 5 <210> 23 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 23 Gly Ala Ser One <210> 24 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 24 Gln Gln Asp Ser Asn Leu Pro Ile Thr 1 5 <210> 25 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 25 Gly Tyr Ala Phe Thr Thr Tyr Leu 1 5 <210> 26 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 26 Ile Asn Pro Gly Ser Gly Ser Thr 1 5 <210> 27 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 27 Ala Arg Tyr Ala Tyr Gly Tyr 1 5 <210> 28 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 28 Gln Asn Val Gly Thr Ala 1 5 <210> 29 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 29 Ser Ala Ser One <210> 30 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 30 Gln Gln Tyr Ser Thr Tyr Pro Phe Thr 1 5 <210> 31 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 31 Gly Tyr Ser Phe Thr Asn Tyr Ala 1 5 <210> 32 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 32 Ile Ser Pro Tyr Tyr Gly Asp Thr 1 5 <210> 33 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 33 Ala Arg Arg Phe Glu Gly Phe Tyr Tyr Ser Met Asp Tyr 1 5 10 <210> 34 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 34 Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr 1 5 10 <210> 35 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 35 Lys Val Ser One <210> 36 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 36 Ser Gln Ser Thr His Val Pro Leu Thr 1 5 <210> 37 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 37 Gly Phe Thr Phe Ser Ser Tyr Gly 1 5 <210> 38 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 38 Ile Trp Tyr Asp Gly Ser Asn Lys 1 5 <210> 39 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 39 Ala Arg Asp Pro Gly Leu Arg Tyr Phe Asp Gly Gly Met Asp Val 1 5 10 15 <210> 40 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 40 Gln Gly Ile Ser Ser Tyr 1 5 <210> 41 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 41 Ala Ala Ser One <210> 42 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 42 Gln Gln Leu Asn Ser Phe Pro Tyr Thr 1 5 <210> 43 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 43 Gly Phe Thr Phe Ser Ser Tyr Gly 1 5 <210> 44 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 44 Ile Trp Tyr Asp Gly Ser Asn Lys 1 5 <210> 45 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 45 Ala Arg Met Phe Arg Gly Ala Phe Asp Tyr 1 5 10 <210> 46 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 46 Gln Gly Ile Arg Asn Asp 1 5 <210> 47 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 47 Ala Ala Ser One <210> 48 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 48 Leu Gln Asp Tyr Ile Tyr Tyr Pro Thr 1 5 <210> 49 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 49 Gly Tyr Thr Phe Thr Ser Tyr Tyr 1 5 <210> 50 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 50 Ile Tyr Pro Gly Asn Val Asn Thr 1 5 <210> 51 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 51 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val 1 5 10 <210> 52 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 52 Gln Asn Ile Tyr Val Trp 1 5 <210> 53 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 53 Lys Ala Ser One <210> 54 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 54 Gln Gln Gly Gln Thr Tyr Pro Tyr 1 5 <210> 55 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 55 Gly Phe Thr Phe Thr Lys Ala Trp 1 5 <210> 56 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 56 Ile Lys Asp Lys Ser Asn Ser Tyr Ala Thr 1 5 10 <210> 57 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 57 Arg Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr 1 5 10 <210> 58 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 58 Gln Ser Leu Val His Asn Asn Ala Asn Thr Tyr 1 5 10 <210> 59 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 59 Gln Ser Leu Val His Gln Asn Ala Gln Thr Tyr 1 5 10 <210> 60 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 60 Gln Ser Leu Val His Glu Asn Leu Gln Thr Tyr 1 5 10 <210> 61 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 61 Gln Ser Leu Val His Glu Asn Leu Phe Thr Tyr 1 5 10 <210> 62 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 62 Gln Ser Leu Val His Glu Asn Leu Arg Thr Tyr 1 5 10 <210> 63 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 63 Gln Ser Leu Val His Asp Asn Ala Gln Thr Tyr 1 5 10 <210> 64 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 64 Lys Val Ser One <210> 65 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 65 Gly Gln Gly Thr Gln Tyr Pro Phe Thr 1 5 <210> 66 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 66 Asp Lys Thr His Thr 1 5 <210> 67 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 67 Gly Gln Pro Lys Ala Ala Pro 1 5 <210> 68 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 68 Thr Lys Gly Pro Ser 1 5 <210> 69 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 69 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 <210> 70 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 70 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 <210> 71 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 71 Gly Gly Ser Gly Ser Ser Gly Ser Gly Gly 1 5 10 <210> 72 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 72 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 73 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 73 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Arg Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Gln Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Glu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 74 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 74 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Arg Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Gln Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Ser Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 75 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 75 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Arg Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Ala Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Ser Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 76 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 76 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Arg Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Ala Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Glu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 77 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 77 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 78 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 78 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Gln Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 79 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 79 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Ala Met His Trp Val Lys Glu Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Pro Gly Gln Gly Gly Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Ala Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Thr Gly Gly Leu Arg Arg Ala Tyr Phe Thr Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 80 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 80 Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30 Gly Gln Gly Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Pro Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Asn Lys 85 90 95 Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 81 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 81 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Phe 20 25 30 Ser Ile His Trp Val Arg Gln Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45 Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Ile Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Thr Thr Gly Arg Phe Phe Asp Trp Phe Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 82 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 82 Glu Ile Ile Leu Thr Gln Ser Pro Ala Ile Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ile Ser Arg 20 25 30 Phe Leu Ser Trp Tyr Gln Val Lys Pro Gly Leu Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Val Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile Ser Ser Leu Gln 65 70 75 80 Pro Glu Asp Cys Ala Val Tyr Tyr Cys Gln Gln Asp Ser Asn Leu Pro 85 90 95 Ile Thr Phe Gly Gin Gly Thr Arg Leu Glu Ile Lys 100 105 <210> 83 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 83 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Thr Tyr 20 25 30 Leu Val Glu Trp Ile Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Val Ile Asn Pro Gly Ser Gly Ser Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Val Asp Arg Ser Ser Thr Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Ala Tyr Gly Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser <210> 84 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 84 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Val Gly Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Gln Leu Ile 35 40 45 Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Tyr Pro Phe 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 85 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 85 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr 20 25 30 Ala Val His Trp Val Arg Gln Ala Pro Gly Gly Gly Leu Glu Trp Met 35 40 45 Gly Val Ile Ser Pro Tyr Tyr Gly Asp Thr Thr Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Phe Glu Gly Phe Tyr Tyr Ser Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 86 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 86 Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Arg Pro Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Asn Trp Tyr Gln Gln Arg Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Lys Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser 85 90 95 Thr His Val Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 87 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 87 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr His Cys 85 90 95 Ala Arg Asp Pro Gly Leu Arg Tyr Phe Asp Gly Gly Met Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 88 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 88 Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Phe Ala Ala Ser Thr Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Phe Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 89 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 89 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gly Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Met Phe Arg Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 90 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 90 Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Gly Leu Gln Pro 65 70 75 80 Glu Asp Ser Ala Thr Tyr Tyr Cys Leu Gln Asp Tyr Ile Tyr Tyr Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 91 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 91 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 92 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 92 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asn Ile Tyr Val Trp 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Thr Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 93 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 93 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Ala 20 25 30 Trp Met His Trp Val Arg Gln Ala Pro Gly Lys Gln Leu Glu Trp Val 35 40 45 Ala Gln Ile Lys Asp Lys Ser Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Arg Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 94 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 94 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Asn 20 25 30 Asn Ala Asn Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 95 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 95 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Gln 20 25 30 Asn Ala Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 96 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 96 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Glu 20 25 30 Asn Leu Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 97 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 97 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Glu 20 25 30 Asn Leu Phe Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 98 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 98 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Glu 20 25 30 Asn Leu Arg Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 99 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 99 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Asp 20 25 30 Asn Ala Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 100 <211> 336 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 100 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Gln 20 25 30 Asn Ala Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Asp Lys Thr His Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 115 120 125 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln 130 135 140 Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 145 150 155 160 Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro 165 170 175 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 180 185 190 Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly 195 200 205 Gln Thr Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 210 215 220 Asp Lys Thr His Thr Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 245 250 255 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 260 265 270 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 275 280 285 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 290 295 300 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 305 310 315 320 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 325 330 335 <210> 101 <211> 577 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 101 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Asp Lys Thr His Thr Gln Val Gln 115 120 125 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg 130 135 140 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His 145 150 155 160 Trp Val Arg Gln Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile 165 170 175 Lys Asp Lys Ser Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg 210 215 220 Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser Asp Lys Thr His Thr Ala Ser Thr Lys Gly 245 250 255 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 260 265 270 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 275 280 285 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 290 295 300 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 305 310 315 320 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 325 330 335 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 340 345 350 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 355 360 365 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 370 375 380 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 385 390 395 400 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 405 410 415 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 420 425 430 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 435 440 445 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 450 455 460 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 465 470 475 480 Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 485 490 495 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 500 505 510 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 515 520 525 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 530 535 540 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 545 550 555 560 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 565 570 575 Gly <210> 102 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 102 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 103 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 103 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 104 <211> 336 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 104 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Gln 20 25 30 Asn Ala Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Asp Lys Thr His Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 115 120 125 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln 130 135 140 Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 145 150 155 160 Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro 165 170 175 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 180 185 190 Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly 195 200 205 Gln Thr Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 210 215 220 Asp Lys Thr His Thr Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 245 250 255 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 260 265 270 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 275 280 285 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 290 295 300 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 305 310 315 320 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 325 330 335 <210> 105 <211> 577 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 105 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Asp Lys Thr His Thr Gln Val Gln 115 120 125 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg 130 135 140 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His 145 150 155 160 Trp Val Arg Gln Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile 165 170 175 Lys Asp Lys Ser Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg 210 215 220 Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser Asp Lys Thr His Thr Ala Ser Thr Lys Gly 245 250 255 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 260 265 270 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 275 280 285 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 290 295 300 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 305 310 315 320 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 325 330 335 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 340 345 350 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 355 360 365 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 370 375 380 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 385 390 395 400 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 405 410 415 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 420 425 430 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 435 440 445 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 450 455 460 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 465 470 475 480 Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 485 490 495 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 500 505 510 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 515 520 525 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 530 535 540 Lys Ser Arg Trp Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His 545 550 555 560 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 565 570 575 Gly <210> 106 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 106 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Arg Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Gln Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Glu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 107 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 107 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 108 <211> 336 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 108 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Asp 20 25 30 Asn Ala Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Asp Lys Thr His Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 115 120 125 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln 130 135 140 Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 145 150 155 160 Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro 165 170 175 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 180 185 190 Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly 195 200 205 Gln Thr Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 210 215 220 Asp Lys Thr His Thr Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 245 250 255 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 260 265 270 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 275 280 285 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 290 295 300 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 305 310 315 320 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 325 330 335 <210> 109 <211> 577 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 109 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Asp Lys Thr His Thr Gln Val Gln 115 120 125 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg 130 135 140 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His 145 150 155 160 Trp Val Arg Gln Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile 165 170 175 Lys Asp Lys Ser Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg 210 215 220 Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser Asp Lys Thr His Thr Ala Ser Thr Lys Gly 245 250 255 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 260 265 270 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 275 280 285 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 290 295 300 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 305 310 315 320 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 325 330 335 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 340 345 350 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 355 360 365 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 370 375 380 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 385 390 395 400 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 405 410 415 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 420 425 430 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 435 440 445 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 450 455 460 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 465 470 475 480 Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 485 490 495 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 500 505 510 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 515 520 525 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 530 535 540 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 545 550 555 560 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 565 570 575 Gly <210> 110 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 110 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Arg Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Gln Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Glu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 111 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 111 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 112 <211> 338 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 112 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Gln 20 25 30 Asn Ala Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Gly Gln Pro Lys Ala Ala Pro Asp Ile Gln Met Thr Gln Ser Pro Ser 115 120 125 Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala 130 135 140 Ser Gln Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly 145 150 155 160 Lys Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly 165 170 175 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190 Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 195 200 205 Gln Gly Gln Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu 210 215 220 Ile Lys Thr Lys Gly Pro Ser Arg Thr Val Ala Ala Pro Ser Val Phe 225 230 235 240 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val 245 250 255 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp 260 265 270 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr 275 280 285 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr 290 295 300 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val 305 310 315 320 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly 325 330 335 Glu Cys <210> 113 <211> 570 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 113 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ser Gln Val Gln Leu Val Glu Ser 115 120 125 Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala 130 135 140 Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His Trp Val Arg Gln 145 150 155 160 Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile Lys Asp Lys Ser 165 170 175 Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr 180 185 190 Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser 195 200 205 Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg Gly Val Tyr Tyr 210 215 220 Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 225 230 235 240 Ser Ser Arg Thr Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 245 250 255 Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu 260 265 270 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 275 280 285 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 290 295 300 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 305 310 315 320 Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr 325 330 335 Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 340 345 350 Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro 355 360 365 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 370 375 380 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 385 390 395 400 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 405 410 415 Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 420 425 430 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 435 440 445 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 450 455 460 Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu 465 470 475 480 Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe 485 490 495 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 500 505 510 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 515 520 525 Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 530 535 540 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 545 550 555 560 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 565 570 <210> 114 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 114 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Arg Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Gln Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Glu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 115 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 115 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 116 <211> 338 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 116 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Asn 20 25 30 Asn Ala Asn Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Gly Gln Pro Lys Ala Ala Pro Asp Ile Gln Met Thr Gln Ser Pro Ser 115 120 125 Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala 130 135 140 Ser Gln Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly 145 150 155 160 Lys Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly 165 170 175 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190 Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 195 200 205 Gln Gly Gln Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu 210 215 220 Ile Lys Thr Lys Gly Pro Ser Arg Thr Val Ala Ala Pro Ser Val Phe 225 230 235 240 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val 245 250 255 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp 260 265 270 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr 275 280 285 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr 290 295 300 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val 305 310 315 320 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly 325 330 335 Glu Cys <210> 117 <211> 570 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 117 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ser Gln Val Gln Leu Val Glu Ser 115 120 125 Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala 130 135 140 Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His Trp Val Arg Gln 145 150 155 160 Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile Lys Asp Lys Ser 165 170 175 Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr 180 185 190 Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser 195 200 205 Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg Gly Val Tyr Tyr 210 215 220 Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 225 230 235 240 Ser Ser Arg Thr Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 245 250 255 Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu 260 265 270 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 275 280 285 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 290 295 300 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 305 310 315 320 Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr 325 330 335 Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 340 345 350 Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro 355 360 365 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 370 375 380 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 385 390 395 400 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 405 410 415 Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 420 425 430 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 435 440 445 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 450 455 460 Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu 465 470 475 480 Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe 485 490 495 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 500 505 510 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 515 520 525 Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 530 535 540 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 545 550 555 560 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 565 570 <210> 118 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 118 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Arg Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Gln Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Ser Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 119 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 119 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 120 <211> 338 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 120 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Asn 20 25 30 Asn Ala Asn Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Gly Gln Pro Lys Ala Ala Pro Asp Ile Gln Met Thr Gln Ser Pro Ser 115 120 125 Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala 130 135 140 Ser Gln Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly 145 150 155 160 Lys Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly 165 170 175 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190 Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 195 200 205 Gln Gly Gln Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu 210 215 220 Ile Lys Thr Lys Gly Pro Ser Arg Thr Val Ala Ala Pro Ser Val Phe 225 230 235 240 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val 245 250 255 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp 260 265 270 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr 275 280 285 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr 290 295 300 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val 305 310 315 320 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly 325 330 335 Glu Cys <210> 121 <211> 570 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 121 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ser Gln Val Gln Leu Val Glu Ser 115 120 125 Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala 130 135 140 Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His Trp Val Arg Gln 145 150 155 160 Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile Lys Asp Lys Ser 165 170 175 Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr 180 185 190 Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser 195 200 205 Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg Gly Val Tyr Tyr 210 215 220 Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 225 230 235 240 Ser Ser Arg Thr Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 245 250 255 Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu 260 265 270 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 275 280 285 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 290 295 300 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 305 310 315 320 Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr 325 330 335 Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 340 345 350 Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro 355 360 365 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 370 375 380 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 385 390 395 400 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 405 410 415 Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 420 425 430 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 435 440 445 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 450 455 460 Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu 465 470 475 480 Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe 485 490 495 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 500 505 510 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 515 520 525 Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 530 535 540 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 545 550 555 560 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 565 570 <210> 122 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 122 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Arg Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Ala Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Ser Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 123 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 123 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 124 <211> 338 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 124 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Asn 20 25 30 Asn Ala Asn Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Gly Gln Pro Lys Ala Ala Pro Asp Ile Gln Met Thr Gln Ser Pro Ser 115 120 125 Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala 130 135 140 Ser Gln Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly 145 150 155 160 Lys Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly 165 170 175 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190 Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 195 200 205 Gln Gly Gln Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu 210 215 220 Ile Lys Thr Lys Gly Pro Ser Arg Thr Val Ala Ala Pro Ser Val Phe 225 230 235 240 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val 245 250 255 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp 260 265 270 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr 275 280 285 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr 290 295 300 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val 305 310 315 320 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly 325 330 335 Glu Cys <210> 125 <211> 570 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 125 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ser Gln Val Gln Leu Val Glu Ser 115 120 125 Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala 130 135 140 Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His Trp Val Arg Gln 145 150 155 160 Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile Lys Asp Lys Ser 165 170 175 Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr 180 185 190 Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser 195 200 205 Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg Gly Val Tyr Tyr 210 215 220 Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 225 230 235 240 Ser Ser Arg Thr Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 245 250 255 Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu 260 265 270 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 275 280 285 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 290 295 300 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 305 310 315 320 Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr 325 330 335 Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 340 345 350 Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro 355 360 365 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 370 375 380 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 385 390 395 400 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 405 410 415 Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 420 425 430 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 435 440 445 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 450 455 460 Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu 465 470 475 480 Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe 485 490 495 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 500 505 510 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 515 520 525 Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 530 535 540 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 545 550 555 560 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 565 570 <210> 126 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 126 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Arg Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Ala Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Glu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 127 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 127 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 128 <211> 338 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 128 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Gln 20 25 30 Asn Ala Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Gly Gln Pro Lys Ala Ala Pro Asp Ile Gln Met Thr Gln Ser Pro Ser 115 120 125 Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala 130 135 140 Ser Gln Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly 145 150 155 160 Lys Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly 165 170 175 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190 Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 195 200 205 Gln Gly Gln Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu 210 215 220 Ile Lys Thr Lys Gly Pro Ser Arg Thr Val Ala Ala Pro Ser Val Phe 225 230 235 240 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val 245 250 255 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp 260 265 270 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr 275 280 285 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr 290 295 300 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val 305 310 315 320 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly 325 330 335 Glu Cys <210> 129 <211> 570 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 129 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ser Gln Val Gln Leu Val Glu Ser 115 120 125 Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala 130 135 140 Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His Trp Val Arg Gln 145 150 155 160 Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile Lys Asp Lys Ser 165 170 175 Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr 180 185 190 Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser 195 200 205 Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg Gly Val Tyr Tyr 210 215 220 Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 225 230 235 240 Ser Ser Arg Thr Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 245 250 255 Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu 260 265 270 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 275 280 285 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 290 295 300 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 305 310 315 320 Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr 325 330 335 Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 340 345 350 Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro 355 360 365 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 370 375 380 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 385 390 395 400 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 405 410 415 Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 420 425 430 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 435 440 445 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 450 455 460 Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu 465 470 475 480 Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe 485 490 495 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 500 505 510 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 515 520 525 Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 530 535 540 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 545 550 555 560 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 565 570 <210> 130 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 130 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 131 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 131 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 132 <211> 336 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 132 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Asn 20 25 30 Asn Ala Asn Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Asp Lys Thr His Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 115 120 125 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln 130 135 140 Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 145 150 155 160 Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro 165 170 175 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 180 185 190 Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly 195 200 205 Gln Thr Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 210 215 220 Asp Lys Thr His Thr Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 245 250 255 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 260 265 270 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 275 280 285 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 290 295 300 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 305 310 315 320 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 325 330 335 <210> 133 <211> 577 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 133 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Asp Lys Thr His Thr Gln Val Gln 115 120 125 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg 130 135 140 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His 145 150 155 160 Trp Val Arg Gln Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile 165 170 175 Lys Asp Lys Ser Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg 210 215 220 Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser Asp Lys Thr His Thr Ala Ser Thr Lys Gly 245 250 255 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 260 265 270 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 275 280 285 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 290 295 300 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 305 310 315 320 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 325 330 335 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 340 345 350 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 355 360 365 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 370 375 380 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 385 390 395 400 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 405 410 415 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 420 425 430 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 435 440 445 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 450 455 460 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 465 470 475 480 Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 485 490 495 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 500 505 510 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 515 520 525 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 530 535 540 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 545 550 555 560 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 565 570 575 Gly <210> 134 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 134 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 135 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 135 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 136 <211> 336 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 136 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Glu 20 25 30 Asn Leu Arg Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Asp Lys Thr His Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 115 120 125 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln 130 135 140 Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 145 150 155 160 Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro 165 170 175 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 180 185 190 Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly 195 200 205 Gln Thr Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 210 215 220 Asp Lys Thr His Thr Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 245 250 255 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 260 265 270 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 275 280 285 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 290 295 300 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 305 310 315 320 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 325 330 335 <210> 137 <211> 577 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 137 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Asp Lys Thr His Thr Gln Val Gln 115 120 125 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg 130 135 140 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His 145 150 155 160 Trp Val Arg Gln Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile 165 170 175 Lys Asp Lys Ser Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg 210 215 220 Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser Asp Lys Thr His Thr Ala Ser Thr Lys Gly 245 250 255 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 260 265 270 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 275 280 285 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 290 295 300 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 305 310 315 320 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 325 330 335 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 340 345 350 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 355 360 365 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 370 375 380 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 385 390 395 400 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 405 410 415 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 420 425 430 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 435 440 445 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 450 455 460 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 465 470 475 480 Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 485 490 495 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 500 505 510 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 515 520 525 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 530 535 540 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 545 550 555 560 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 565 570 575 Gly <210> 138 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 138 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 139 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 139 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 140 <211> 336 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 140 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Glu 20 25 30 Asn Leu Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Asp Lys Thr His Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 115 120 125 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln 130 135 140 Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 145 150 155 160 Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro 165 170 175 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 180 185 190 Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly 195 200 205 Gln Thr Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 210 215 220 Asp Lys Thr His Thr Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 245 250 255 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 260 265 270 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 275 280 285 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 290 295 300 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 305 310 315 320 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 325 330 335 <210> 141 <211> 577 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 141 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Asp Lys Thr His Thr Gln Val Gln 115 120 125 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg 130 135 140 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His 145 150 155 160 Trp Val Arg Gln Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile 165 170 175 Lys Asp Lys Ser Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg 210 215 220 Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser Asp Lys Thr His Thr Ala Ser Thr Lys Gly 245 250 255 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 260 265 270 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 275 280 285 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 290 295 300 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 305 310 315 320 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 325 330 335 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 340 345 350 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 355 360 365 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 370 375 380 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 385 390 395 400 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 405 410 415 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 420 425 430 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 435 440 445 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 450 455 460 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 465 470 475 480 Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 485 490 495 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 500 505 510 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 515 520 525 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 530 535 540 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 545 550 555 560 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 565 570 575 Gly <210> 142 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 142 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 143 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 143 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 144 <211> 336 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 144 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Glu 20 25 30 Asn Leu Phe Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Asp Lys Thr His Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 115 120 125 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln 130 135 140 Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 145 150 155 160 Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro 165 170 175 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 180 185 190 Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly 195 200 205 Gln Thr Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 210 215 220 Asp Lys Thr His Thr Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 245 250 255 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 260 265 270 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 275 280 285 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 290 295 300 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 305 310 315 320 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 325 330 335 <210> 145 <211> 577 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 145 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Asp Lys Thr His Thr Gln Val Gln 115 120 125 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg 130 135 140 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His 145 150 155 160 Trp Val Arg Gln Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile 165 170 175 Lys Asp Lys Ser Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg 210 215 220 Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser Asp Lys Thr His Thr Ala Ser Thr Lys Gly 245 250 255 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 260 265 270 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 275 280 285 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 290 295 300 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 305 310 315 320 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 325 330 335 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 340 345 350 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 355 360 365 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 370 375 380 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 385 390 395 400 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 405 410 415 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 420 425 430 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 435 440 445 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 450 455 460 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 465 470 475 480 Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 485 490 495 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 500 505 510 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 515 520 525 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 530 535 540 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 545 550 555 560 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 565 570 575 Gly <210> 146 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 146 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 147 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 147 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 148 <211> 338 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 148 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Asn 20 25 30 Asn Ala Asn Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Gly Gln Pro Lys Ala Ala Pro Asp Ile Gln Met Thr Gln Ser Pro Ser 115 120 125 Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala 130 135 140 Ser Gln Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly 145 150 155 160 Lys Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly 165 170 175 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190 Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 195 200 205 Gln Gly Gln Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu 210 215 220 Ile Lys Thr Lys Gly Pro Ser Arg Thr Val Ala Ala Pro Ser Val Phe 225 230 235 240 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val 245 250 255 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp 260 265 270 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr 275 280 285 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr 290 295 300 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val 305 310 315 320 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly 325 330 335 Glu Cys <210> 149 <211> 570 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 149 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ser Gln Val Gln Leu Val Glu Ser 115 120 125 Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala 130 135 140 Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His Trp Val Arg Gln 145 150 155 160 Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile Lys Asp Lys Ser 165 170 175 Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr 180 185 190 Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser 195 200 205 Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg Gly Val Tyr Tyr 210 215 220 Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 225 230 235 240 Ser Ser Arg Thr Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 245 250 255 Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu 260 265 270 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 275 280 285 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 290 295 300 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 305 310 315 320 Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr 325 330 335 Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 340 345 350 Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro 355 360 365 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 370 375 380 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 385 390 395 400 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 405 410 415 Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 420 425 430 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 435 440 445 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 450 455 460 Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu 465 470 475 480 Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe 485 490 495 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 500 505 510 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 515 520 525 Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 530 535 540 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 545 550 555 560 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 565 570 <210> 150 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 150 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 151 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 151 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 152 <211> 336 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 152 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Glu 20 25 30 Asn Leu Arg Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Asp Lys Thr His Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 115 120 125 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln 130 135 140 Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 145 150 155 160 Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro 165 170 175 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 180 185 190 Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly 195 200 205 Gln Thr Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 210 215 220 Asp Lys Thr His Thr Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 245 250 255 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 260 265 270 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 275 280 285 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 290 295 300 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 305 310 315 320 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 325 330 335 <210> 153 <211> 577 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 153 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Asp Lys Thr His Thr Gln Val Gln 115 120 125 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg 130 135 140 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His 145 150 155 160 Trp Val Arg Gln Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile 165 170 175 Lys Asp Lys Ser Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg 210 215 220 Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser Asp Lys Thr His Thr Ala Ser Thr Lys Gly 245 250 255 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 260 265 270 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 275 280 285 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 290 295 300 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 305 310 315 320 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 325 330 335 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 340 345 350 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 355 360 365 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 370 375 380 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 385 390 395 400 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 405 410 415 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 420 425 430 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 435 440 445 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 450 455 460 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 465 470 475 480 Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 485 490 495 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 500 505 510 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 515 520 525 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 530 535 540 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 545 550 555 560 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 565 570 575 Gly <210> 154 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 154 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Arg Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Gln Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Glu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 155 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 155 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 156 <211> 336 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 156 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Glu 20 25 30 Asn Leu Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Asp Lys Thr His Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 115 120 125 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln 130 135 140 Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 145 150 155 160 Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro 165 170 175 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 180 185 190 Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly 195 200 205 Gln Thr Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 210 215 220 Asp Lys Thr His Thr Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 245 250 255 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 260 265 270 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 275 280 285 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 290 295 300 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 305 310 315 320 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 325 330 335 <210> 157 <211> 577 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 157 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Asp Lys Thr His Thr Gln Val Gln 115 120 125 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg 130 135 140 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His 145 150 155 160 Trp Val Arg Gln Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile 165 170 175 Lys Asp Lys Ser Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg 210 215 220 Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser Asp Lys Thr His Thr Ala Ser Thr Lys Gly 245 250 255 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 260 265 270 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 275 280 285 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 290 295 300 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 305 310 315 320 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 325 330 335 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 340 345 350 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 355 360 365 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 370 375 380 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 385 390 395 400 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 405 410 415 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 420 425 430 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 435 440 445 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 450 455 460 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 465 470 475 480 Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 485 490 495 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 500 505 510 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 515 520 525 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 530 535 540 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 545 550 555 560 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 565 570 575 Gly <210> 158 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 158 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Ala Met His Trp Val Lys Glu Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Pro Gly Gln Gly Gly Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Ala Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Thr Gly Gly Leu Arg Arg Ala Tyr Phe Thr Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 159 <211> 218 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 159 Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30 Gly Gln Gly Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Pro Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Asn Lys 85 90 95 Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 160 <211> 336 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 160 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Glu 20 25 30 Asn Leu Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Asp Lys Thr His Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 115 120 125 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln 130 135 140 Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 145 150 155 160 Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro 165 170 175 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 180 185 190 Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly 195 200 205 Gln Thr Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 210 215 220 Asp Lys Thr His Thr Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 245 250 255 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 260 265 270 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 275 280 285 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 290 295 300 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 305 310 315 320 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 325 330 335 <210> 161 <211> 577 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 161 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Asp Lys Thr His Thr Gln Val Gln 115 120 125 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg 130 135 140 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His 145 150 155 160 Trp Val Arg Gln Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile 165 170 175 Lys Asp Lys Ser Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg 210 215 220 Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser Asp Lys Thr His Thr Ala Ser Thr Lys Gly 245 250 255 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 260 265 270 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 275 280 285 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 290 295 300 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 305 310 315 320 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 325 330 335 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 340 345 350 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 355 360 365 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 370 375 380 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 385 390 395 400 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 405 410 415 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 420 425 430 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 435 440 445 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 450 455 460 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 465 470 475 480 Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 485 490 495 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 500 505 510 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 515 520 525 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 530 535 540 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 545 550 555 560 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 565 570 575 Gly <210> 162 <211> 442 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 162 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Phe 20 25 30 Ser Ile His Trp Val Arg Gln Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45 Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Ile Met Thr Glu Asp Thr Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Thr Thr Gly Arg Phe Phe Asp Trp Phe Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 260 265 270 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 305 310 315 320 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu 340 345 350 Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 405 410 415 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 <210> 163 <211> 215 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 163 Glu Ile Ile Leu Thr Gln Ser Pro Ala Ile Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ile Ser Arg 20 25 30 Phe Leu Ser Trp Tyr Gln Val Lys Pro Gly Leu Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Val Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile Ser Ser Leu Gln 65 70 75 80 Pro Glu Asp Cys Ala Val Tyr Tyr Cys Gln Gln Asp Ser Asn Leu Pro 85 90 95 Ile Thr Phe Gly Gin Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 164 <211> 336 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 164 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Glu 20 25 30 Asn Leu Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Asp Lys Thr His Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 115 120 125 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln 130 135 140 Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 145 150 155 160 Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro 165 170 175 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 180 185 190 Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly 195 200 205 Gln Thr Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 210 215 220 Asp Lys Thr His Thr Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 245 250 255 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 260 265 270 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 275 280 285 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 290 295 300 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 305 310 315 320 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 325 330 335 <210> 165 <211> 577 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 165 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Asp Lys Thr His Thr Gln Val Gln 115 120 125 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg 130 135 140 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His 145 150 155 160 Trp Val Arg Gln Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile 165 170 175 Lys Asp Lys Ser Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg 210 215 220 Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser Asp Lys Thr His Thr Ala Ser Thr Lys Gly 245 250 255 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 260 265 270 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 275 280 285 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 290 295 300 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 305 310 315 320 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 325 330 335 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 340 345 350 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 355 360 365 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 370 375 380 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 385 390 395 400 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 405 410 415 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 420 425 430 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 435 440 445 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 450 455 460 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 465 470 475 480 Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 485 490 495 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 500 505 510 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 515 520 525 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 530 535 540 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 545 550 555 560 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 565 570 575 Gly <210> 166 <211> 440 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 166 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Thr 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Thr Tyr 20 25 30 Leu Val Glu Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Asn Pro Gly Ser Gly Ser Thr Asn Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Arg Ser Ser Thr Thr Ala Tyr 65 70 75 80 Met His Leu Ser Gly Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Tyr Ala Tyr Gly Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val 100 105 110 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys 115 120 125 Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys 130 135 140 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 145 150 155 160 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 165 170 175 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 180 185 190 Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val 195 200 205 Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro 210 215 220 Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Lys 225 230 235 240 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 245 250 255 Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 260 265 270 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 275 280 285 Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 290 295 300 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 305 310 315 320 Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 325 330 335 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met 340 345 350 Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro 355 360 365 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 370 375 380 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 385 390 395 400 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val 405 410 415 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 420 425 430 Lys Ser Leu Ser Leu Ser Leu Gly 435 440 <210> 167 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 167 Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Gln Pro Gly His Ser Pro Lys Gln Leu Ile 35 40 45 Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ala Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Ile Gln Ser 65 70 75 80 Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Thr Tyr Pro Phe 85 90 95 Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 168 <211> 336 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 168 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Glu 20 25 30 Asn Leu Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Asp Lys Thr His Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 115 120 125 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln 130 135 140 Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 145 150 155 160 Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro 165 170 175 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 180 185 190 Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly 195 200 205 Gln Thr Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 210 215 220 Asp Lys Thr His Thr Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 245 250 255 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 260 265 270 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 275 280 285 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 290 295 300 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 305 310 315 320 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 325 330 335 <210> 169 <211> 577 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 169 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Asp Lys Thr His Thr Gln Val Gln 115 120 125 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg 130 135 140 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His 145 150 155 160 Trp Val Arg Gln Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile 165 170 175 Lys Asp Lys Ser Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg 210 215 220 Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser Asp Lys Thr His Thr Ala Ser Thr Lys Gly 245 250 255 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 260 265 270 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 275 280 285 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 290 295 300 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 305 310 315 320 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 325 330 335 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 340 345 350 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 355 360 365 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 370 375 380 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 385 390 395 400 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 405 410 415 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 420 425 430 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 435 440 445 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 450 455 460 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 465 470 475 480 Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 485 490 495 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 500 505 510 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 515 520 525 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 530 535 540 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 545 550 555 560 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 565 570 575 Gly <210> 170 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 170 Gln Val Gln Leu Leu Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Val 1 5 10 15 Ser Val Lys Ile Ser Cys Thr Gly Ser Gly Tyr Ser Phe Thr Asn Tyr 20 25 30 Ala Val His Trp Val Lys Gln Ser His Val Lys Ser Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Pro Tyr Tyr Gly Asp Thr Thr Tyr Asn Gln Lys Phe 50 55 60 Thr Gly Lys Ala Thr Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ala Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Phe Cys 85 90 95 Ala Arg Arg Phe Glu Gly Phe Tyr Tyr Ser Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 171 <211> 219 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 171 Asp Val Val Met Ile Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Pro Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Asn Trp Tyr Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Lys Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Leu Cys Ser Gln Ser 85 90 95 Thr His Val Pro Leu Thr Phe Gly Ser Gly Thr Gln Leu Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 172 <211> 336 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 172 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Glu 20 25 30 Asn Leu Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Asp Lys Thr His Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 115 120 125 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln 130 135 140 Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 145 150 155 160 Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro 165 170 175 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 180 185 190 Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly 195 200 205 Gln Thr Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 210 215 220 Asp Lys Thr His Thr Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 245 250 255 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 260 265 270 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 275 280 285 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 290 295 300 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 305 310 315 320 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 325 330 335 <210> 173 <211> 577 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 173 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Asp Lys Thr His Thr Gln Val Gln 115 120 125 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg 130 135 140 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His 145 150 155 160 Trp Val Arg Gln Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile 165 170 175 Lys Asp Lys Ser Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg 210 215 220 Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser Asp Lys Thr His Thr Ala Ser Thr Lys Gly 245 250 255 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 260 265 270 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 275 280 285 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 290 295 300 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 305 310 315 320 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 325 330 335 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 340 345 350 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 355 360 365 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 370 375 380 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 385 390 395 400 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 405 410 415 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 420 425 430 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 435 440 445 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 450 455 460 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 465 470 475 480 Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 485 490 495 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 500 505 510 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 515 520 525 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 530 535 540 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 545 550 555 560 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 565 570 575 Gly <210> 174 <211> 448 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 174 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr His Cys 85 90 95 Ala Arg Asp Pro Gly Leu Arg Tyr Phe Asp Gly Gly Met Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 175 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 175 Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Phe Ala Ala Ser Thr Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Phe Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 176 <211> 336 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 176 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Glu 20 25 30 Asn Leu Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Asp Lys Thr His Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 115 120 125 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln 130 135 140 Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 145 150 155 160 Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro 165 170 175 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 180 185 190 Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly 195 200 205 Gln Thr Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 210 215 220 Asp Lys Thr His Thr Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 245 250 255 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 260 265 270 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 275 280 285 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 290 295 300 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 305 310 315 320 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 325 330 335 <210> 177 <211> 577 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 177 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Asp Lys Thr His Thr Gln Val Gln 115 120 125 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg 130 135 140 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His 145 150 155 160 Trp Val Arg Gln Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile 165 170 175 Lys Asp Lys Ser Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg 210 215 220 Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser Asp Lys Thr His Thr Ala Ser Thr Lys Gly 245 250 255 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 260 265 270 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 275 280 285 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 290 295 300 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 305 310 315 320 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 325 330 335 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 340 345 350 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 355 360 365 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 370 375 380 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 385 390 395 400 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 405 410 415 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 420 425 430 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 435 440 445 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 450 455 460 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 465 470 475 480 Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 485 490 495 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 500 505 510 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 515 520 525 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 530 535 540 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 545 550 555 560 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 565 570 575 Gly <210> 178 <211> 443 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 178 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gly Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Met Phe Arg Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro 210 215 220 Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe 225 230 235 240 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255 Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 260 265 270 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285 Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320 Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Gln 340 345 350 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly 355 360 365 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 385 390 395 400 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu 405 410 415 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 <210> 179 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 179 Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Gly Leu Gln Pro 65 70 75 80 Glu Asp Ser Ala Thr Tyr Tyr Cys Leu Gln Asp Tyr Ile Tyr Tyr Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 180 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <220> <221> VARIANT <222> 6 <223> Xaa = Glu or Gln <220> <221> VARIANT <222> 8 <223> Xaa = Ala or Leu <220> <221> VARIANT <222> 9 <223> Xaa = Gln, Arg, or Phe <400> 180 Gln Ser Leu Val His Xaa Asn Xaa Xaa Thr Tyr 1 5 10 <210> 181 <211> 336 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 181 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Glu 20 25 30 Asn Leu Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Asp Lys Thr His Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 115 120 125 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln 130 135 140 Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 145 150 155 160 Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro 165 170 175 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 180 185 190 Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly 195 200 205 Gln Thr Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 210 215 220 Asp Lys Thr His Thr Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 245 250 255 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 260 265 270 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 275 280 285 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 290 295 300 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 305 310 315 320 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 325 330 335 <210> 182 <211> 577 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 182 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Asp Lys Thr His Thr Gln Val Gln 115 120 125 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg 130 135 140 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His 145 150 155 160 Trp Val Arg Gln Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile 165 170 175 Lys Asp Lys Ser Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg 210 215 220 Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser Asp Lys Thr His Thr Ala Ser Thr Lys Gly 245 250 255 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 260 265 270 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 275 280 285 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 290 295 300 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 305 310 315 320 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 325 330 335 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 340 345 350 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 355 360 365 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 370 375 380 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 385 390 395 400 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 405 410 415 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 420 425 430 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 435 440 445 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 450 455 460 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 465 470 475 480 Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 485 490 495 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 500 505 510 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 515 520 525 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 530 535 540 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 545 550 555 560 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 565 570 575 Gly <210> 183 <211> 440 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 183 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Thr Tyr 20 25 30 Leu Val Glu Trp Ile Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Val Ile Asn Pro Gly Ser Gly Ser Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Val Asp Arg Ser Ser Thr Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Ala Tyr Gly Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys 115 120 125 Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys 130 135 140 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 145 150 155 160 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 165 170 175 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 180 185 190 Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val 195 200 205 Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro 210 215 220 Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Lys 225 230 235 240 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 245 250 255 Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 260 265 270 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 275 280 285 Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 290 295 300 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 305 310 315 320 Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 325 330 335 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met 340 345 350 Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro 355 360 365 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 370 375 380 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 385 390 395 400 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val 405 410 415 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 420 425 430 Lys Ser Leu Ser Leu Ser Leu Gly 435 440 <210> 184 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 184 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Val Gly Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Gln Leu Ile 35 40 45 Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Tyr Pro Phe 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 185 <211> 336 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 185 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Glu 20 25 30 Asn Leu Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Asp Lys Thr His Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 115 120 125 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln 130 135 140 Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 145 150 155 160 Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro 165 170 175 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 180 185 190 Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly 195 200 205 Gln Thr Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 210 215 220 Asp Lys Thr His Thr Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 245 250 255 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 260 265 270 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 275 280 285 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 290 295 300 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 305 310 315 320 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 325 330 335 <210> 186 <211> 577 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 186 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Asp Lys Thr His Thr Gln Val Gln 115 120 125 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg 130 135 140 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His 145 150 155 160 Trp Val Arg Gln Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile 165 170 175 Lys Asp Lys Ser Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg 210 215 220 Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser Asp Lys Thr His Thr Ala Ser Thr Lys Gly 245 250 255 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 260 265 270 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 275 280 285 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 290 295 300 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 305 310 315 320 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 325 330 335 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 340 345 350 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 355 360 365 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 370 375 380 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 385 390 395 400 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 405 410 415 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 420 425 430 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 435 440 445 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 450 455 460 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 465 470 475 480 Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 485 490 495 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 500 505 510 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 515 520 525 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 530 535 540 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 545 550 555 560 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 565 570 575 Gly <210> 187 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 187 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr 20 25 30 Ala Val His Trp Val Arg Gln Ala Pro Gly Gly Gly Leu Glu Trp Met 35 40 45 Gly Val Ile Ser Pro Tyr Tyr Gly Asp Thr Thr Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Phe Glu Gly Phe Tyr Tyr Ser Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 188 <211> 219 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 188 Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Arg Pro Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Asn Trp Tyr Gln Gln Arg Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Lys Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser 85 90 95 Thr His Val Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 189 <211> 1008 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 189 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg caccagaacg cccagaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaaggaca aaacccatac cgacatccag 360 atgacccaga gccccagcag cctgtctgcc agcgtgggcg acagagtgac catcacctgt 420 caggccagcc agaacatcta cgtgtggctg aactggtatc agcagaagcc cggcaaggcc 480 cccaagctgc tgatctacaa ggccagcaac ctgcacaccg gcgtgcccag cagattttct 540 ggcagcggct ccggcaccga cttcaccctg acaatcagct ccctgcagcc cgaggacatt 600 gccacctact actgccagca gggccagacc tacccctaca cctttggcca gggcaccaag 660 ctggaaatca aggataagac ccacacccgt acggtggccg ctcccagcgt gttcatcttc 720 ccacctagcg acgagcagct gaagtccggc acagcctctg tcgtgtgcct gctgaacaac 780 ttctaccccc gcgaggccaa agtgcagtgg aaggtggaca acgccctgca gagcggcaac 840 agccaggaaa gcgtgaccga gcaggacagc aaggactcca cctacagcct gagcagcacc 900 ctgacactga gcaaggccga ctacgagaag cacaaggtgt acgcctgcga agtgacccac 960 cagggcctgt ctagccccgt gaccaagagc ttcaaccggg gcgagtgt 1008 <210> 190 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 190 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 191 <211> 1338 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 191 gaagtgcagc tggtggaatc tggcggcgga ctggtgcagc ctggcggatc tctgagactg 60 agctgtgccg ccagcggctt caacatcaag gacacctaca tccactgggt gcgccaggcc 120 cctggcaagg gactggaatg ggtggccaga atctacccca ccaacggcta caccagatac 180 gccgacagcg tgaagggccg gttcaccatc agcgccgaca ccagcaagaa caccgcctac 240 ctgcagatga acagcctgcg ggccgaggac accgccgtgt actactgtag tagatgggga 300 ggcgacggct tctacgccat ggactattgg ggccagggca ccctcgtgac cgtgtctagt 360 gcgtcgacca agggcccatc ggtgttccct ctggcccctt gcagcagaag caccagcgaa 420 tctacagccg ccctgggctg cctcgtgaag gactactttc ccgagcccgt gaccgtgtcc 480 tggaactctg gcgctctgac aagcggcgtg cacacctttc cagccgtgct ccagagcagc 540 ggcctgtact ctctgagcag cgtcgtgaca gtgcccagca gcagcctggg caccaagacc 600 tacacctgta acgtggacca caagcccagc aacaccaagg tggacaagcg ggtggaatct 660 aagtacggcc ctccctgccc tccttgccca gcccctgaag ctgccggcgg accctccgtg 720 ttcctgttcc ccccaaagcc caaggacacc ctgatgatca gccggacccc cgaagtgacc 780 tgcgtggtgg tggatgtgtc ccaggaagat cccgaggtgc agttcaattg gtacgtggac 840 ggcgtggaag tgcacaacgc caagccaag cccagagagg aacagttcaa cagcacctac 900 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 960 tgcaaggtgt ccaacaaggg cctgcccagc tccatcgaga aaaccatcag caaggccaag 1020 ggccagcccc gcgagcctca agtgtatacc ctgccccctt gccaggaaga gatgaccaag 1080 aaccaggtgt ccctgtggtg tctcgtgaaa ggcttctacc ccagcgacat tgccgtggaa 1140 tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggacagc 1200 gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcaggaaggc 1260 aacgtgttca gctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1320 ctgtctctgt ccctgggc 1338 <210> 192 <211> 642 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 192 gacatccaga tgacccagag ccccagcagc ctgtctgcca gcgtgggcga cagagtgacc 60 atcacctgta gagccagcca ggacgtgaac accgccgtgg cctggtatca gcagaagcct 120 ggcaaggccc ccaagctgct gatctacagc gccagcttcc tgtacagcgg cgtgcccagc 180 agattcagcg gaagcagaag cggcaccgac ttcaccctga ccatcagctc cctgcagccc 240 gaggacttcg ccacctacta ctgccagcag cactacacca ccccccccac atttggccag 300 ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttcccacct 360 agcgacgagc agctgaagtc cggcacagcc tctgtcgtgt gcctgctgaa caacttctac 420 ccccgcgagg ccaaagtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gaaagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgaca 540 ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccaccagggc 600 ctgtctagcc ccgtgaccaa gagcttcaac cggggcgagt gt 642 <210> 193 <211> 1008 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 193 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg caccagaacg cccagaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaaggaca aaacccatac cgacatccag 360 atgacccaga gccccagcag cctgtctgcc agcgtgggcg acagagtgac catcacctgt 420 caggccagcc agaacatcta cgtgtggctg aactggtatc agcagaagcc cggcaaggcc 480 cccaagctgc tgatctacaa ggccagcaac ctgcacaccg gcgtgcccag cagattttct 540 ggcagcggct ccggcaccga cttcaccctg acaatcagct ccctgcagcc cgaggacatt 600 gccacctact actgccagca gggccagacc tacccctaca cctttggcca gggcaccaag 660 ctggaaatca aggataagac ccacacccgt acggtggccg ctcccagcgt gttcatcttc 720 ccacctagcg acgagcagct gaagtccggc acagcctctg tcgtgtgcct gctgaacaac 780 ttctaccccc gcgaggccaa agtgcagtgg aaggtggaca acgccctgca gagcggcaac 840 agccaggaaa gcgtgaccga gcaggacagc aaggactcca cctacagcct gagcagcacc 900 ctgacactga gcaaggccga ctacgagaag cacaaggtgt acgcctgcga agtgacccac 960 cagggcctgt ctagccccgt gaccaagagc ttcaaccggg gcgagtgt 1008 <210> 194 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 194 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 195 <211> 1338 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 195 gaagtgcagc tggtggaatc tggcggcgga ctggtgcagc ctggcggatc tctgagactg 60 agctgtgccg ccagcggctt caacatccgg gacacctaca tccactgggt gcgccaggcc 120 cctggcaagg gactggaatg ggtggccaga atctacccca cccagggcta caccagatac 180 gccgacagcg tgaagggccg gttcaccatc agcgccgaca ccagcaagaa caccgcctac 240 ctgcagatga acagcctgcg ggccgaggac accgccgtgt actactgtag tagatgggga 300 ggcgaaggct tctacgccat ggactattgg ggccagggca ccctcgtgac cgtgtctagt 360 gcgtcgacca agggcccatc ggtgttccct ctggcccctt gcagcagaag caccagcgaa 420 tctacagccg ccctgggctg cctcgtgaag gactactttc ccgagcccgt gaccgtgtcc 480 tggaactctg gcgctctgac aagcggcgtg cacacctttc cagccgtgct ccagagcagc 540 ggcctgtact ctctgagcag cgtcgtgaca gtgcccagca gcagcctggg caccaagacc 600 tacacctgta acgtggacca caagcccagc aacaccaagg tggacaagcg ggtggaatct 660 aagtacggcc ctccctgccc tccttgccca gcccctgaag ctgccggcgg accctccgtg 720 ttcctgttcc ccccaaagcc caaggacacc ctgatgatca gccggacccc cgaagtgacc 780 tgcgtggtgg tggatgtgtc ccaggaagat cccgaggtgc agttcaattg gtacgtggac 840 ggcgtggaag tgcacaacgc caagccaag cccagagagg aacagttcaa cagcacctac 900 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 960 tgcaaggtgt ccaacaaggg cctgcccagc tccatcgaga aaaccatcag caaggccaag 1020 ggccagcccc gcgagcctca agtgtatacc ctgccccctt gccaggaaga gatgaccaag 1080 aaccaggtgt ccctgtggtg tctcgtgaaa ggcttctacc ccagcgacat tgccgtggaa 1140 tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggacagc 1200 gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcaggaaggc 1260 aacgtgttca gctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1320 ctgtctctgt ccctgggc 1338 <210> 196 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 196 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 197 <211> 1008 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 197 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg cacgacaacg cccagaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaaggaca aaacccatac cgacatccag 360 atgacccaga gccccagcag cctgtctgcc agcgtgggcg acagagtgac catcacctgt 420 caggccagcc agaacatcta cgtgtggctg aactggtatc agcagaagcc cggcaaggcc 480 cccaagctgc tgatctacaa ggccagcaac ctgcacaccg gcgtgcccag cagattttct 540 ggcagcggct ccggcaccga cttcaccctg acaatcagct ccctgcagcc cgaggacatt 600 gccacctact actgccagca gggccagacc tacccctaca cctttggcca gggcaccaag 660 ctggaaatca aggataagac ccacacccgt acggtggccg ctcccagcgt gttcatcttc 720 ccacctagcg acgagcagct gaagtccggc acagcctctg tcgtgtgcct gctgaacaac 780 ttctaccccc gcgaggccaa agtgcagtgg aaggtggaca acgccctgca gagcggcaac 840 agccaggaaa gcgtgaccga gcaggacagc aaggactcca cctacagcct gagcagcacc 900 ctgacactga gcaaggccga ctacgagaag cacaaggtgt acgcctgcga agtgacccac 960 cagggcctgt ctagccccgt gaccaagagc ttcaaccggg gcgagtgt 1008 <210> 198 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 198 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 199 <211> 1338 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 199 gaagtgcagc tggtggaatc tggcggcgga ctggtgcagc ctggcggatc tctgagactg 60 agctgtgccg ccagcggctt caacatccgg gacacctaca tccactgggt gcgccaggcc 120 cctggcaagg gactggaatg ggtggccaga atctacccca cccagggcta caccagatac 180 gccgacagcg tgaagggccg gttcaccatc agcgccgaca ccagcaagaa caccgcctac 240 ctgcagatga acagcctgcg ggccgaggac accgccgtgt actactgtag tagatgggga 300 ggcgaaggct tctacgccat ggactattgg ggccagggca ccctcgtgac cgtgtctagt 360 gcgtcgacca agggcccatc ggtgttccct ctggcccctt gcagcagaag caccagcgaa 420 tctacagccg ccctgggctg cctcgtgaag gactactttc ccgagcccgt gaccgtgtcc 480 tggaactctg gcgctctgac aagcggcgtg cacacctttc cagccgtgct ccagagcagc 540 ggcctgtact ctctgagcag cgtcgtgaca gtgcccagca gcagcctggg caccaagacc 600 tacacctgta acgtggacca caagcccagc aacaccaagg tggacaagcg ggtggaatct 660 aagtacggcc ctccctgccc tccttgccca gcccctgaag ctgccggcgg accctccgtg 720 ttcctgttcc ccccaaagcc caaggacacc ctgatgatca gccggacccc cgaagtgacc 780 tgcgtggtgg tggatgtgtc ccaggaagat cccgaggtgc agttcaattg gtacgtggac 840 ggcgtggaag tgcacaacgc caagccaag cccagagagg aacagttcaa cagcacctac 900 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 960 tgcaaggtgt ccaacaaggg cctgcccagc tccatcgaga aaaccatcag caaggccaag 1020 ggccagcccc gcgagcctca agtgtatacc ctgccccctt gccaggaaga gatgaccaag 1080 aaccaggtgt ccctgtggtg tctcgtgaaa ggcttctacc ccagcgacat tgccgtggaa 1140 tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggacagc 1200 gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcaggaaggc 1260 aacgtgttca gctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1320 ctgtctctgt ccctgggc 1338 <210> 200 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 200 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 201 <211> 1014 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 201 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg caccagaacg cccagaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaagggcc agcccaaggc cgccccccgac 360 atccagatga cccagagccc cagcagcctg tctgccagcg tgggcgacag agtgaccatc 420 acctgtcagg ccagccagaa catctacgtg tggctgaact ggtatcagca gaagcccggc 480 aaggccccca agctgctgat ctacaaggcc agcaacctgc acaccggcgt gcccagcaga 540 ttttctggca gcggctccgg caccgacttc accctgacaa tcagctccct gcagcccgag 600 gacattgcca cctactactg ccagcagggc cagacctacc cctacacctt tggccagggc 660 accaagctgg aaatcaagac caagggcccc agccgtacgg tggccgctcc cagcgtgttc 720 atcttcccac ctagcgacga gcagctgaag tccggcacag cctctgtcgt gtgcctgctg 780 aacaacttct acccccgcga ggccaaagtg cagtggaagg tggacaacgc cctgcagagc 840 ggcaacagcc aggaaagcgt gaccgagcag gacagcaagg actccaccta cagcctgagc 900 agcaccctga cactgagcaa ggccgactac gagaagcaca aggtgtacgc ctgcgaagtg 960 acccaccagg gcctgtctag ccccgtgacc aagagcttca accggggcga gtgt 1014 <210> 202 <211> 1710 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 202 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 agccaggtgc agctggtgga atctggcggc ggagtggtgc agcctggcag aagcctgaga 420 ctgagctgtg ccgccagcgg cttcaccttc accaaggcct ggatgcactg ggtgcgccag 480 gcccctggaa agcagctgga atgggtggcc cagatcaagg acaagagcaa cagctacgcc 540 acctactacg ccgacagcgt gaagggccgg ttcaccatca gccgggacga cagcaagaac 600 accctgtacc tgcagatgaa cagcctgcgg gccgaggaca ccgccgtgta ctactgtcgg 660 ggcgtgtact atgccctgag ccccttcgat tactggggcc agggaaccct cgtgaccgtg 720 tctagtcgga ccgccagcac aaagggccca tcggtgttcc ctctggcccc ttgcagcaga 780 agcaccagcg aatctacagc cgccctgggc tgcctcgtga aggactactt tcccgagccc 840 gtgaccgtgt cctggaactc tggcgctctg acaagcggcg tgcacacctt tccagccgtg 900 ctccagagca gcggcctgta ctctctgagc agcgtcgtga cagtgcccag cagcagcctg 960 ggcaccaaga cctacacctg taacgtggac cacaagccca gcaacaccaa ggtggacaag 1020 cgggtggaat ctaagtacgg ccctccctgc cctccttgcc cagcccctga agctgccggc 1080 ggaccctccg tgttcctgtt ccccccaaag cccaaggaca ccctgatgat cagccggacc 1140 cccgaagtga cctgcgtggt ggtggatgtg tcccaggaag atcccgaggt gcagttcaat 1200 tggtacgtgg acggcgtgga agtgcacaac gccaagacca agcccagaga ggaacagttc 1260 aacagcacct accgggtggt gtccgtgctg accgtgctgc accaggactg gctgaacggc 1320 aaagagtaca agtgcaaggt gtccaacaag ggcctgccca gctccatcga gaaaaccatc 1380 agcaaggcca agggccagcc ccgcgagcct caagtgtgta ccctgccccc tagccaggaa 1440 gagatgacca agaaccaggt gtccctgagc tgtgccgtga aaggcttcta ccccagcgac 1500 attgccgtgg aatgggagag caacggccag cccgagaaca actacaagac caccccccct 1560 gtgctggaca gcgacggctc attcttcctg gtgtccaagc tgaccgtgga caagagccgg 1620 tggcaggaag gcaacgtgtt cagctgctcc gtgatgcacg aggccctgca caaccactac 1680 acccagaagt ccctgtctct gtccctgggc 1710 <210> 203 <211> 1338 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 203 gaagtgcagc tggtggaatc tggcggcgga ctggtgcagc ctggcggatc tctgagactg 60 agctgtgccg ccagcggctt caacatccgg gacacctaca tccactgggt gcgccaggcc 120 cctggcaagg gactggaatg ggtggccaga atctacccca cccagggcta caccagatac 180 gccgacagcg tgaagggccg gttcaccatc agcgccgaca ccagcaagaa caccgcctac 240 ctgcagatga acagcctgcg ggccgaggac accgccgtgt actactgtag tagatgggga 300 ggcgaaggct tctacgccat ggactattgg ggccagggca ccctcgtgac cgtgtctagt 360 gcgtcgacca agggcccatc ggtgttccct ctggcccctt gcagcagaag caccagcgaa 420 tctacagccg ccctgggctg cctcgtgaag gactactttc ccgagcccgt gaccgtgtcc 480 tggaactctg gcgctctgac aagcggcgtg cacacctttc cagccgtgct ccagagcagc 540 ggcctgtact ctctgagcag cgtcgtgaca gtgcccagca gcagcctggg caccaagacc 600 tacacctgta acgtggacca caagcccagc aacaccaagg tggacaagcg ggtggaatct 660 aagtacggcc ctccctgccc tccttgccca gcccctgaag ctgccggcgg accctccgtg 720 ttcctgttcc ccccaaagcc caaggacacc ctgatgatca gccggacccc cgaagtgacc 780 tgcgtggtgg tggatgtgtc ccaggaagat cccgaggtgc agttcaattg gtacgtggac 840 ggcgtggaag tgcacaacgc caagccaag cccagagagg aacagttcaa cagcacctac 900 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 960 tgcaaggtgt ccaacaaggg cctgcccagc tccatcgaga aaaccatcag caaggccaag 1020 ggccagcccc gcgagcctca agtgtatacc ctgccccctt gccaggaaga gatgaccaag 1080 aaccaggtgt ccctgtggtg tctcgtgaaa ggcttctacc ccagcgacat tgccgtggaa 1140 tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggacagc 1200 gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcaggaaggc 1260 aacgtgttca gctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1320 ctgtctctgt ccctgggc 1338 <210> 204 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 204 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 205 <211> 1014 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 205 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg cacaacaacg ccaacaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaagggcc agcccaaggc cgccccccgac 360 atccagatga cccagagccc cagcagcctg tctgccagcg tgggcgacag agtgaccatc 420 acctgtcagg ccagccagaa catctacgtg tggctgaact ggtatcagca gaagcccggc 480 aaggccccca agctgctgat ctacaaggcc agcaacctgc acaccggcgt gcccagcaga 540 ttttctggca gcggctccgg caccgacttc accctgacaa tcagctccct gcagcccgag 600 gacattgcca cctactactg ccagcagggc cagacctacc cctacacctt tggccagggc 660 accaagctgg aaatcaagac caagggcccc agccgtacgg tggccgctcc cagcgtgttc 720 atcttcccac ctagcgacga gcagctgaag tccggcacag cctctgtcgt gtgcctgctg 780 aacaacttct acccccgcga ggccaaagtg cagtggaagg tggacaacgc cctgcagagc 840 ggcaacagcc aggaaagcgt gaccgagcag gacagcaagg actccaccta cagcctgagc 900 agcaccctga cactgagcaa ggccgactac gagaagcaca aggtgtacgc ctgcgaagtg 960 acccaccagg gcctgtctag ccccgtgacc aagagcttca accggggcga gtgt 1014 <210> 206 <211> 1710 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 206 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 agccaggtgc agctggtgga atctggcggc ggagtggtgc agcctggcag aagcctgaga 420 ctgagctgtg ccgccagcgg cttcaccttc accaaggcct ggatgcactg ggtgcgccag 480 gcccctggaa agcagctgga atgggtggcc cagatcaagg acaagagcaa cagctacgcc 540 acctactacg ccgacagcgt gaagggccgg ttcaccatca gccgggacga cagcaagaac 600 accctgtacc tgcagatgaa cagcctgcgg gccgaggaca ccgccgtgta ctactgtcgg 660 ggcgtgtact atgccctgag ccccttcgat tactggggcc agggaaccct cgtgaccgtg 720 tctagtcgga ccgccagcac aaagggccca tcggtgttcc ctctggcccc ttgcagcaga 780 agcaccagcg aatctacagc cgccctgggc tgcctcgtga aggactactt tcccgagccc 840 gtgaccgtgt cctggaactc tggcgctctg acaagcggcg tgcacacctt tccagccgtg 900 ctccagagca gcggcctgta ctctctgagc agcgtcgtga cagtgcccag cagcagcctg 960 ggcaccaaga cctacacctg taacgtggac cacaagccca gcaacaccaa ggtggacaag 1020 cgggtggaat ctaagtacgg ccctccctgc cctccttgcc cagcccctga agctgccggc 1080 ggaccctccg tgttcctgtt ccccccaaag cccaaggaca ccctgatgat cagccggacc 1140 cccgaagtga cctgcgtggt ggtggatgtg tcccaggaag atcccgaggt gcagttcaat 1200 tggtacgtgg acggcgtgga agtgcacaac gccaagacca agcccagaga ggaacagttc 1260 aacagcacct accgggtggt gtccgtgctg accgtgctgc accaggactg gctgaacggc 1320 aaagagtaca agtgcaaggt gtccaacaag ggcctgccca gctccatcga gaaaaccatc 1380 agcaaggcca agggccagcc ccgcgagcct caagtgtgta ccctgccccc tagccaggaa 1440 gagatgacca agaaccaggt gtccctgagc tgtgccgtga aaggcttcta ccccagcgac 1500 attgccgtgg aatgggagag caacggccag cccgagaaca actacaagac caccccccct 1560 gtgctggaca gcgacggctc attcttcctg gtgtccaagc tgaccgtgga caagagccgg 1620 tggcaggaag gcaacgtgtt cagctgctcc gtgatgcacg aggccctgca caaccactac 1680 acccagaagt ccctgtctct gtccctgggc 1710 <210> 207 <211> 1338 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 207 gaagtgcagc tggtggaatc tggcggcgga ctggtgcagc ctggcggatc tctgagactg 60 agctgtgccg ccagcggctt caacatccgg gacacctaca tccactgggt gcgccaggcc 120 cctggcaagg gactggaatg ggtggccaga atctacccca cccagggcta caccagatac 180 gccgacagcg tgaagggccg gttcaccatc agcgccgaca ccagcaagaa caccgcctac 240 ctgcagatga acagcctgcg ggccgaggac accgccgtgt actactgtag tagatgggga 300 ggctccggct tctacgccat ggactattgg ggccagggca ccctcgtgac cgtgtctagt 360 gcgtcgacca agggcccatc ggtgttccct ctggcccctt gcagcagaag caccagcgaa 420 tctacagccg ccctgggctg cctcgtgaag gactactttc ccgagcccgt gaccgtgtcc 480 tggaactctg gcgctctgac aagcggcgtg cacacctttc cagccgtgct ccagagcagc 540 ggcctgtact ctctgagcag cgtcgtgaca gtgcccagca gcagcctggg caccaagacc 600 tacacctgta acgtggacca caagcccagc aacaccaagg tggacaagcg ggtggaatct 660 aagtacggcc ctccctgccc tccttgccca gcccctgaat ttctgggcgg accctccgtg 720 ttcctgttcc ccccaaagcc caaggacacc ctgatgatca gccggacccc cgaagtgacc 780 tgcgtggtgg tggatgtgtc ccaggaagat cccgaggtgc agttcaattg gtacgtggac 840 ggcgtggaag tgcacaacgc caagccaag cccagagagg aacagttcaa cagcacctac 900 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 960 tgcaaggtgt ccaacaaggg cctgcccagc tccatcgaga aaaccatcag caaggccaag 1020 ggccagcccc gcgagcctca agtgtatacc ctgccccctt gccaggaaga gatgaccaag 1080 aaccaggtgt ccctgtggtg tctcgtgaaa ggcttctacc ccagcgacat tgccgtggaa 1140 tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggacagc 1200 gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcaggaaggc 1260 aacgtgttca gctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1320 ctgtctctgt ccctgggc 1338 <210> 208 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 208 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 209 <211> 1014 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 209 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg cacaacaacg ccaacaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaagggcc agcccaaggc cgccccccgac 360 atccagatga cccagagccc cagcagcctg tctgccagcg tgggcgacag agtgaccatc 420 acctgtcagg ccagccagaa catctacgtg tggctgaact ggtatcagca gaagcccggc 480 aaggccccca agctgctgat ctacaaggcc agcaacctgc acaccggcgt gcccagcaga 540 ttttctggca gcggctccgg caccgacttc accctgacaa tcagctccct gcagcccgag 600 gacattgcca cctactactg ccagcagggc cagacctacc cctacacctt tggccagggc 660 accaagctgg aaatcaagac caagggcccc agccgtacgg tggccgctcc cagcgtgttc 720 atcttcccac ctagcgacga gcagctgaag tccggcacag cctctgtcgt gtgcctgctg 780 aacaacttct acccccgcga ggccaaagtg cagtggaagg tggacaacgc cctgcagagc 840 ggcaacagcc aggaaagcgt gaccgagcag gacagcaagg actccaccta cagcctgagc 900 agcaccctga cactgagcaa ggccgactac gagaagcaca aggtgtacgc ctgcgaagtg 960 acccaccagg gcctgtctag ccccgtgacc aagagcttca accggggcga gtgt 1014 <210> 210 <211> 1710 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 210 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 agccaggtgc agctggtgga atctggcggc ggagtggtgc agcctggcag aagcctgaga 420 ctgagctgtg ccgccagcgg cttcaccttc accaaggcct ggatgcactg ggtgcgccag 480 gcccctggaa agcagctgga atgggtggcc cagatcaagg acaagagcaa cagctacgcc 540 acctactacg ccgacagcgt gaagggccgg ttcaccatca gccgggacga cagcaagaac 600 accctgtacc tgcagatgaa cagcctgcgg gccgaggaca ccgccgtgta ctactgtcgg 660 ggcgtgtact atgccctgag ccccttcgat tactggggcc agggaaccct cgtgaccgtg 720 tctagtcgga ccgccagcac aaagggccca tcggtgttcc ctctggcccc ttgcagcaga 780 agcaccagcg aatctacagc cgccctgggc tgcctcgtga aggactactt tcccgagccc 840 gtgaccgtgt cctggaactc tggcgctctg acaagcggcg tgcacacctt tccagccgtg 900 ctccagagca gcggcctgta ctctctgagc agcgtcgtga cagtgcccag cagcagcctg 960 ggcaccaaga cctacacctg taacgtggac cacaagccca gcaacaccaa ggtggacaag 1020 cgggtggaat ctaagtacgg ccctccctgc cctccttgcc cagcccctga agctgccggc 1080 ggaccctccg tgttcctgtt ccccccaaag cccaaggaca ccctgatgat cagccggacc 1140 cccgaagtga cctgcgtggt ggtggatgtg tcccaggaag atcccgaggt gcagttcaat 1200 tggtacgtgg acggcgtgga agtgcacaac gccaagacca agcccagaga ggaacagttc 1260 aacagcacct accgggtggt gtccgtgctg accgtgctgc accaggactg gctgaacggc 1320 aaagagtaca agtgcaaggt gtccaacaag ggcctgccca gctccatcga gaaaaccatc 1380 agcaaggcca agggccagcc ccgcgagcct caagtgtgta ccctgccccc tagccaggaa 1440 gagatgacca agaaccaggt gtccctgagc tgtgccgtga aaggcttcta ccccagcgac 1500 attgccgtgg aatgggagag caacggccag cccgagaaca actacaagac caccccccct 1560 gtgctggaca gcgacggctc attcttcctg gtgtccaagc tgaccgtgga caagagccgg 1620 tggcaggaag gcaacgtgtt cagctgctcc gtgatgcacg aggccctgca caaccactac 1680 acccagaagt ccctgtctct gtccctgggc 1710 <210> 211 <211> 1338 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 211 gaagtgcagc tggtggaatc tggcggcgga ctggtgcagc ctggcggatc tctgagactg 60 agctgtgccg ccagcggctt caacatccgg gacacctaca tccactgggt gcgccaggcc 120 cctggcaagg gactggaatg ggtggccaga atctacccca ccaacgccta caccagatac 180 gccgacagcg tgaagggccg gttcaccatc agcgccgaca ccagcaagaa caccgcctac 240 ctgcagatga acagcctgcg ggccgaggac accgccgtgt actactgtag tagatgggga 300 ggctccggct tctacgccat ggactattgg ggccagggca ccctcgtgac cgtgtctagt 360 gcgtcgacca agggcccatc ggtgttccct ctggcccctt gcagcagaag caccagcgaa 420 tctacagccg ccctgggctg cctcgtgaag gactactttc ccgagcccgt gaccgtgtcc 480 tggaactctg gcgctctgac aagcggcgtg cacacctttc cagccgtgct ccagagcagc 540 ggcctgtact ctctgagcag cgtcgtgaca gtgcccagca gcagcctggg caccaagacc 600 tacacctgta acgtggacca caagcccagc aacaccaagg tggacaagcg ggtggaatct 660 aagtacggcc ctccctgccc tccttgccca gcccctgaat ttctgggcgg accctccgtg 720 ttcctgttcc ccccaaagcc caaggacacc ctgatgatca gccggacccc cgaagtgacc 780 tgcgtggtgg tggatgtgtc ccaggaagat cccgaggtgc agttcaattg gtacgtggac 840 ggcgtggaag tgcacaacgc caagccaag cccagagagg aacagttcaa cagcacctac 900 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 960 tgcaaggtgt ccaacaaggg cctgcccagc tccatcgaga aaaccatcag caaggccaag 1020 ggccagcccc gcgagcctca agtgtatacc ctgccccctt gccaggaaga gatgaccaag 1080 aaccaggtgt ccctgtggtg tctcgtgaaa ggcttctacc ccagcgacat tgccgtggaa 1140 tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggacagc 1200 gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcaggaaggc 1260 aacgtgttca gctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1320 ctgtctctgt ccctgggc 1338 <210> 212 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 212 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 213 <211> 1014 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 213 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg cacaacaacg ccaacaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaagggcc agcccaaggc cgccccccgac 360 atccagatga cccagagccc cagcagcctg tctgccagcg tgggcgacag agtgaccatc 420 acctgtcagg ccagccagaa catctacgtg tggctgaact ggtatcagca gaagcccggc 480 aaggccccca agctgctgat ctacaaggcc agcaacctgc acaccggcgt gcccagcaga 540 ttttctggca gcggctccgg caccgacttc accctgacaa tcagctccct gcagcccgag 600 gacattgcca cctactactg ccagcagggc cagacctacc cctacacctt tggccagggc 660 accaagctgg aaatcaagac caagggcccc agccgtacgg tggccgctcc cagcgtgttc 720 atcttcccac ctagcgacga gcagctgaag tccggcacag cctctgtcgt gtgcctgctg 780 aacaacttct acccccgcga ggccaaagtg cagtggaagg tggacaacgc cctgcagagc 840 ggcaacagcc aggaaagcgt gaccgagcag gacagcaagg actccaccta cagcctgagc 900 agcaccctga cactgagcaa ggccgactac gagaagcaca aggtgtacgc ctgcgaagtg 960 acccaccagg gcctgtctag ccccgtgacc aagagcttca accggggcga gtgt 1014 <210> 214 <211> 1710 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 214 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 agccaggtgc agctggtgga atctggcggc ggagtggtgc agcctggcag aagcctgaga 420 ctgagctgtg ccgccagcgg cttcaccttc accaaggcct ggatgcactg ggtgcgccag 480 gcccctggaa agcagctgga atgggtggcc cagatcaagg acaagagcaa cagctacgcc 540 acctactacg ccgacagcgt gaagggccgg ttcaccatca gccgggacga cagcaagaac 600 accctgtacc tgcagatgaa cagcctgcgg gccgaggaca ccgccgtgta ctactgtcgg 660 ggcgtgtact atgccctgag ccccttcgat tactggggcc agggaaccct cgtgaccgtg 720 tctagtcgga ccgccagcac aaagggccca tcggtgttcc ctctggcccc ttgcagcaga 780 agcaccagcg aatctacagc cgccctgggc tgcctcgtga aggactactt tcccgagccc 840 gtgaccgtgt cctggaactc tggcgctctg acaagcggcg tgcacacctt tccagccgtg 900 ctccagagca gcggcctgta ctctctgagc agcgtcgtga cagtgcccag cagcagcctg 960 ggcaccaaga cctacacctg taacgtggac cacaagccca gcaacaccaa ggtggacaag 1020 cgggtggaat ctaagtacgg ccctccctgc cctccttgcc cagcccctga agctgccggc 1080 ggaccctccg tgttcctgtt ccccccaaag cccaaggaca ccctgatgat cagccggacc 1140 cccgaagtga cctgcgtggt ggtggatgtg tcccaggaag atcccgaggt gcagttcaat 1200 tggtacgtgg acggcgtgga agtgcacaac gccaagacca agcccagaga ggaacagttc 1260 aacagcacct accgggtggt gtccgtgctg accgtgctgc accaggactg gctgaacggc 1320 aaagagtaca agtgcaaggt gtccaacaag ggcctgccca gctccatcga gaaaaccatc 1380 agcaaggcca agggccagcc ccgcgagcct caagtgtgta ccctgccccc tagccaggaa 1440 gagatgacca agaaccaggt gtccctgagc tgtgccgtga aaggcttcta ccccagcgac 1500 attgccgtgg aatgggagag caacggccag cccgagaaca actacaagac caccccccct 1560 gtgctggaca gcgacggctc attcttcctg gtgtccaagc tgaccgtgga caagagccgg 1620 tggcaggaag gcaacgtgtt cagctgctcc gtgatgcacg aggccctgca caaccactac 1680 acccagaagt ccctgtctct gtccctgggc 1710 <210> 215 <211> 1338 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 215 gaagtgcagc tggtggaatc tggcggcgga ctggtgcagc ctggcggatc tctgagactg 60 agctgtgccg ccagcggctt caacatccgg gacacctaca tccactgggt gcgccaggcc 120 cctggcaagg gactggaatg ggtggccaga atctacccca ccaacgccta caccagatac 180 gccgacagcg tgaagggccg gttcaccatc agcgccgaca ccagcaagaa caccgcctac 240 ctgcagatga acagcctgcg ggccgaggac accgccgtgt actactgtag tagatgggga 300 ggcgaaggct tctacgccat ggactattgg ggccagggca ccctcgtgac cgtgtctagt 360 gcgtcgacca agggcccatc ggtgttccct ctggcccctt gcagcagaag caccagcgaa 420 tctacagccg ccctgggctg cctcgtgaag gactactttc ccgagcccgt gaccgtgtcc 480 tggaactctg gcgctctgac aagcggcgtg cacacctttc cagccgtgct ccagagcagc 540 ggcctgtact ctctgagcag cgtcgtgaca gtgcccagca gcagcctggg caccaagacc 600 tacacctgta acgtggacca caagcccagc aacaccaagg tggacaagcg ggtggaatct 660 aagtacggcc ctccctgccc tccttgccca gcccctgaat ttctgggcgg accctccgtg 720 ttcctgttcc ccccaaagcc caaggacacc ctgatgatca gccggacccc cgaagtgacc 780 tgcgtggtgg tggatgtgtc ccaggaagat cccgaggtgc agttcaattg gtacgtggac 840 ggcgtggaag tgcacaacgc caagccaag cccagagagg aacagttcaa cagcacctac 900 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 960 tgcaaggtgt ccaacaaggg cctgcccagc tccatcgaga aaaccatcag caaggccaag 1020 ggccagcccc gcgagcctca agtgtatacc ctgccccctt gccaggaaga gatgaccaag 1080 aaccaggtgt ccctgtggtg tctcgtgaaa ggcttctacc ccagcgacat tgccgtggaa 1140 tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggacagc 1200 gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcaggaaggc 1260 aacgtgttca gctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1320 ctgtctctgt ccctgggc 1338 <210> 216 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 216 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 217 <211> 1014 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 217 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg caccagaacg cccagaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaagggcc agcccaaggc cgccccccgac 360 atccagatga cccagagccc cagcagcctg tctgccagcg tgggcgacag agtgaccatc 420 acctgtcagg ccagccagaa catctacgtg tggctgaact ggtatcagca gaagcccggc 480 aaggccccca agctgctgat ctacaaggcc agcaacctgc acaccggcgt gcccagcaga 540 ttttctggca gcggctccgg caccgacttc accctgacaa tcagctccct gcagcccgag 600 gacattgcca cctactactg ccagcagggc cagacctacc cctacacctt tggccagggc 660 accaagctgg aaatcaagac caagggcccc agccgtacgg tggccgctcc cagcgtgttc 720 atcttcccac ctagcgacga gcagctgaag tccggcacag cctctgtcgt gtgcctgctg 780 aacaacttct acccccgcga ggccaaagtg cagtggaagg tggacaacgc cctgcagagc 840 ggcaacagcc aggaaagcgt gaccgagcag gacagcaagg actccaccta cagcctgagc 900 agcaccctga cactgagcaa ggccgactac gagaagcaca aggtgtacgc ctgcgaagtg 960 acccaccagg gcctgtctag ccccgtgacc aagagcttca accggggcga gtgt 1014 <210> 218 <211> 1710 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 218 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 agccaggtgc agctggtgga atctggcggc ggagtggtgc agcctggcag aagcctgaga 420 ctgagctgtg ccgccagcgg cttcaccttc accaaggcct ggatgcactg ggtgcgccag 480 gcccctggaa agcagctgga atgggtggcc cagatcaagg acaagagcaa cagctacgcc 540 acctactacg ccgacagcgt gaagggccgg ttcaccatca gccgggacga cagcaagaac 600 accctgtacc tgcagatgaa cagcctgcgg gccgaggaca ccgccgtgta ctactgtcgg 660 ggcgtgtact atgccctgag ccccttcgat tactggggcc agggaaccct cgtgaccgtg 720 tctagtcgga ccgccagcac aaagggccca tcggtgttcc ctctggcccc ttgcagcaga 780 agcaccagcg aatctacagc cgccctgggc tgcctcgtga aggactactt tcccgagccc 840 gtgaccgtgt cctggaactc tggcgctctg acaagcggcg tgcacacctt tccagccgtg 900 ctccagagca gcggcctgta ctctctgagc agcgtcgtga cagtgcccag cagcagcctg 960 ggcaccaaga cctacacctg taacgtggac cacaagccca gcaacaccaa ggtggacaag 1020 cgggtggaat ctaagtacgg ccctccctgc cctccttgcc cagcccctga agctgccggc 1080 ggaccctccg tgttcctgtt ccccccaaag cccaaggaca ccctgatgat cagccggacc 1140 cccgaagtga cctgcgtggt ggtggatgtg tcccaggaag atcccgaggt gcagttcaat 1200 tggtacgtgg acggcgtgga agtgcacaac gccaagacca agcccagaga ggaacagttc 1260 aacagcacct accgggtggt gtccgtgctg accgtgctgc accaggactg gctgaacggc 1320 aaagagtaca agtgcaaggt gtccaacaag ggcctgccca gctccatcga gaaaaccatc 1380 agcaaggcca agggccagcc ccgcgagcct caagtgtgta ccctgccccc tagccaggaa 1440 gagatgacca agaaccaggt gtccctgagc tgtgccgtga aaggcttcta ccccagcgac 1500 attgccgtgg aatgggagag caacggccag cccgagaaca actacaagac caccccccct 1560 gtgctggaca gcgacggctc attcttcctg gtgtccaagc tgaccgtgga caagagccgg 1620 tggcaggaag gcaacgtgtt cagctgctcc gtgatgcacg aggccctgca caaccactac 1680 acccagaagt ccctgtctct gtccctgggc 1710 <210> 219 <211> 1338 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 219 gaagtgcagc tggtggaatc tggcggcgga ctggtgcagc ctggcggatc tctgagactg 60 agctgtgccg ccagcggctt caacatcaag gacacctaca tccactgggt gcgccaggcc 120 cctggcaagg gactggaatg ggtggccaga atctacccca ccaacggcta caccagatac 180 gccgacagcg tgaagggccg gttcaccatc agcgccgaca ccagcaagaa caccgcctac 240 ctgcagatga acagcctgcg ggccgaggac accgccgtgt actactgtag tagatgggga 300 ggcgacggct tctacgccat ggactattgg ggccagggca ccctcgtgac cgtgtctagt 360 gcgtcgacca agggcccatc ggtgttccct ctggcccctt gcagcagaag caccagcgaa 420 tctacagccg ccctgggctg cctcgtgaag gactactttc ccgagcccgt gaccgtgtcc 480 tggaactctg gcgctctgac aagcggcgtg cacacctttc cagccgtgct ccagagcagc 540 ggcctgtact ctctgagcag cgtcgtgaca gtgcccagca gcagcctggg caccaagacc 600 tacacctgta acgtggacca caagcccagc aacaccaagg tggacaagcg ggtggaatct 660 aagtacggcc ctccctgccc tccttgccca gcccctgaag ctgccggcgg accctccgtg 720 ttcctgttcc ccccaaagcc caaggacacc ctgatgatca gccggacccc cgaagtgacc 780 tgcgtggtgg tggatgtgtc ccaggaagat cccgaggtgc agttcaattg gtacgtggac 840 ggcgtggaag tgcacaacgc caagccaag cccagagagg aacagttcaa cagcacctac 900 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 960 tgcaaggtgt ccaacaaggg cctgcccagc tccatcgaga aaaccatcag caaggccaag 1020 ggccagcccc gcgagcctca agtgtatacc ctgccccctt gccaggaaga gatgaccaag 1080 aaccaggtgt ccctgtggtg tctcgtgaaa ggcttctacc ccagcgacat tgccgtggaa 1140 tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggacagc 1200 gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcaggaaggc 1260 aacgtgttca gctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1320 ctgtctctgt ccctgggc 1338 <210> 220 <211> 642 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 220 gacatccaga tgacccagag ccccagcagc ctgtctgcca gcgtgggcga cagagtgacc 60 atcacctgta gagccagcca ggacgtgaac accgccgtgg cctggtatca gcagaagcct 120 ggcaaggccc ccaagctgct gatctacagc gccagcttcc tgtacagcgg cgtgcccagc 180 agattcagcg gaagcagaag cggcaccgac ttcaccctga ccatcagctc cctgcagccc 240 gaggacttcg ccacctacta ctgccagcag cactacacca ccccccccac atttggccag 300 ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttcccacct 360 agcgacgagc agctgaagtc cggcacagcc tctgtcgtgt gcctgctgaa caacttctac 420 ccccgcgagg ccaaagtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gaaagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgaca 540 ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccaccagggc 600 ctgtctagcc ccgtgaccaa gagcttcaac cggggcgagt gt 642 <210> 221 <211> 1008 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 221 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg cacaacaacg ccaacaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaaggaca aaacccatac cgacatccag 360 atgacccaga gccccagcag cctgtctgcc agcgtgggcg acagagtgac catcacctgt 420 caggccagcc agaacatcta cgtgtggctg aactggtatc agcagaagcc cggcaaggcc 480 cccaagctgc tgatctacaa ggccagcaac ctgcacaccg gcgtgcccag cagattttct 540 ggcagcggct ccggcaccga cttcaccctg acaatcagct ccctgcagcc cgaggacatt 600 gccacctact actgccagca gggccagacc tacccctaca cctttggcca gggcaccaag 660 ctggaaatca aggataagac ccacacccgt acggtggccg ctcccagcgt gttcatcttc 720 ccacctagcg acgagcagct gaagtccggc acagcctctg tcgtgtgcct gctgaacaac 780 ttctaccccc gcgaggccaa agtgcagtgg aaggtggaca acgccctgca gagcggcaac 840 agccaggaaa gcgtgaccga gcaggacagc aaggactcca cctacagcct gagcagcacc 900 ctgacactga gcaaggccga ctacgagaag cacaaggtgt acgcctgcga agtgacccac 960 cagggcctgt ctagccccgt gaccaagagc ttcaaccggg gcgagtgt 1008 <210> 222 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 222 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 223 <211> 1338 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 223 gaagtgcagc tggtggaatc tggcggcgga ctggtgcagc ctggcggatc tctgagactg 60 agctgtgccg ccagcggctt caacatcaag gacacctaca tccactgggt gcgccaggcc 120 cctggcaagg gactggaatg ggtggccaga atctacccca ccaacggcta caccagatac 180 gccgacagcg tgaagggccg gttcaccatc agcgccgaca ccagcaagaa caccgcctac 240 ctgcagatga acagcctgcg ggccgaggac accgccgtgt actactgtag tagatgggga 300 ggcgacggct tctacgccat ggactattgg ggccagggca ccctcgtgac cgtgtctagt 360 gcgtcgacca agggcccatc ggtgttccct ctggcccctt gcagcagaag caccagcgaa 420 tctacagccg ccctgggctg cctcgtgaag gactactttc ccgagcccgt gaccgtgtcc 480 tggaactctg gcgctctgac aagcggcgtg cacacctttc cagccgtgct ccagagcagc 540 ggcctgtact ctctgagcag cgtcgtgaca gtgcccagca gcagcctggg caccaagacc 600 tacacctgta acgtggacca caagcccagc aacaccaagg tggacaagcg ggtggaatct 660 aagtacggcc ctccctgccc tccttgccca gcccctgaag ctgccggcgg accctccgtg 720 ttcctgttcc ccccaaagcc caaggacacc ctgatgatca gccggacccc cgaagtgacc 780 tgcgtggtgg tggatgtgtc ccaggaagat cccgaggtgc agttcaattg gtacgtggac 840 ggcgtggaag tgcacaacgc caagccaag cccagagagg aacagttcaa cagcacctac 900 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 960 tgcaaggtgt ccaacaaggg cctgcccagc tccatcgaga aaaccatcag caaggccaag 1020 ggccagcccc gcgagcctca agtgtatacc ctgccccctt gccaggaaga gatgaccaag 1080 aaccaggtgt ccctgtggtg tctcgtgaaa ggcttctacc ccagcgacat tgccgtggaa 1140 tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggacagc 1200 gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcaggaaggc 1260 aacgtgttca gctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1320 ctgtctctgt ccctgggc 1338 <210> 224 <211> 642 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 224 gacatccaga tgacccagag ccccagcagc ctgtctgcca gcgtgggcga cagagtgacc 60 atcacctgta gagccagcca ggacgtgaac accgccgtgg cctggtatca gcagaagcct 120 ggcaaggccc ccaagctgct gatctacagc gccagcttcc tgtacagcgg cgtgcccagc 180 agattcagcg gaagcagaag cggcaccgac ttcaccctga ccatcagctc cctgcagccc 240 gaggacttcg ccacctacta ctgccagcag cactacacca ccccccccac atttggccag 300 ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttcccacct 360 agcgacgagc agctgaagtc cggcacagcc tctgtcgtgt gcctgctgaa caacttctac 420 ccccgcgagg ccaaagtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gaaagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgaca 540 ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccaccagggc 600 ctgtctagcc ccgtgaccaa gagcttcaac cggggcgagt gt 642 <210> 225 <211> 1008 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 225 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg cacgagaacc tgcgtaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaaggaca aaacccatac cgacatccag 360 atgacccaga gccccagcag cctgtctgcc agcgtgggcg acagagtgac catcacctgt 420 caggccagcc agaacatcta cgtgtggctg aactggtatc agcagaagcc cggcaaggcc 480 cccaagctgc tgatctacaa ggccagcaac ctgcacaccg gcgtgcccag cagattttct 540 ggcagcggct ccggcaccga cttcaccctg acaatcagct ccctgcagcc cgaggacatt 600 gccacctact actgccagca gggccagacc tacccctaca cctttggcca gggcaccaag 660 ctggaaatca aggataagac ccacacccgt acggtggccg ctcccagcgt gttcatcttc 720 ccacctagcg acgagcagct gaagtccggc acagcctctg tcgtgtgcct gctgaacaac 780 ttctaccccc gcgaggccaa agtgcagtgg aaggtggaca acgccctgca gagcggcaac 840 agccaggaaa gcgtgaccga gcaggacagc aaggactcca cctacagcct gagcagcacc 900 ctgacactga gcaaggccga ctacgagaag cacaaggtgt acgcctgcga agtgacccac 960 cagggcctgt ctagccccgt gaccaagagc ttcaaccggg gcgagtgt 1008 <210> 226 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 226 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 227 <211> 1338 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 227 gaagtgcagc tggtggaatc tggcggcgga ctggtgcagc ctggcggatc tctgagactg 60 agctgtgccg ccagcggctt caacatcaag gacacctaca tccactgggt gcgccaggcc 120 cctggcaagg gactggaatg ggtggccaga atctacccca ccaacggcta caccagatac 180 gccgacagcg tgaagggccg gttcaccatc agcgccgaca ccagcaagaa caccgcctac 240 ctgcagatga acagcctgcg ggccgaggac accgccgtgt actactgtag tagatgggga 300 ggcgacggct tctacgccat ggactattgg ggccagggca ccctcgtgac cgtgtctagt 360 gcgtcgacca agggcccatc ggtgttccct ctggcccctt gcagcagaag caccagcgaa 420 tctacagccg ccctgggctg cctcgtgaag gactactttc ccgagcccgt gaccgtgtcc 480 tggaactctg gcgctctgac aagcggcgtg cacacctttc cagccgtgct ccagagcagc 540 ggcctgtact ctctgagcag cgtcgtgaca gtgcccagca gcagcctggg caccaagacc 600 tacacctgta acgtggacca caagcccagc aacaccaagg tggacaagcg ggtggaatct 660 aagtacggcc ctccctgccc tccttgccca gcccctgaag ctgccggcgg accctccgtg 720 ttcctgttcc ccccaaagcc caaggacacc ctgatgatca gccggacccc cgaagtgacc 780 tgcgtggtgg tggatgtgtc ccaggaagat cccgaggtgc agttcaattg gtacgtggac 840 ggcgtggaag tgcacaacgc caagccaag cccagagagg aacagttcaa cagcacctac 900 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 960 tgcaaggtgt ccaacaaggg cctgcccagc tccatcgaga aaaccatcag caaggccaag 1020 ggccagcccc gcgagcctca agtgtatacc ctgccccctt gccaggaaga gatgaccaag 1080 aaccaggtgt ccctgtggtg tctcgtgaaa ggcttctacc ccagcgacat tgccgtggaa 1140 tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggacagc 1200 gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcaggaaggc 1260 aacgtgttca gctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1320 ctgtctctgt ccctgggc 1338 <210> 228 <211> 642 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 228 gacatccaga tgacccagag ccccagcagc ctgtctgcca gcgtgggcga cagagtgacc 60 atcacctgta gagccagcca ggacgtgaac accgccgtgg cctggtatca gcagaagcct 120 ggcaaggccc ccaagctgct gatctacagc gccagcttcc tgtacagcgg cgtgcccagc 180 agattcagcg gaagcagaag cggcaccgac ttcaccctga ccatcagctc cctgcagccc 240 gaggacttcg ccacctacta ctgccagcag cactacacca ccccccccac atttggccag 300 ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttcccacct 360 agcgacgagc agctgaagtc cggcacagcc tctgtcgtgt gcctgctgaa caacttctac 420 ccccgcgagg ccaaagtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gaaagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgaca 540 ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccaccagggc 600 ctgtctagcc ccgtgaccaa gagcttcaac cggggcgagt gt 642 <210> 229 <211> 1008 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 229 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg cacgagaacc tgcagaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaaggaca aaacccatac cgacatccag 360 atgacccaga gccccagcag cctgtctgcc agcgtgggcg acagagtgac catcacctgt 420 caggccagcc agaacatcta cgtgtggctg aactggtatc agcagaagcc cggcaaggcc 480 cccaagctgc tgatctacaa ggccagcaac ctgcacaccg gcgtgcccag cagattttct 540 ggcagcggct ccggcaccga cttcaccctg acaatcagct ccctgcagcc cgaggacatt 600 gccacctact actgccagca gggccagacc tacccctaca cctttggcca gggcaccaag 660 ctggaaatca aggataagac ccacacccgt acggtggccg ctcccagcgt gttcatcttc 720 ccacctagcg acgagcagct gaagtccggc acagcctctg tcgtgtgcct gctgaacaac 780 ttctaccccc gcgaggccaa agtgcagtgg aaggtggaca acgccctgca gagcggcaac 840 agccaggaaa gcgtgaccga gcaggacagc aaggactcca cctacagcct gagcagcacc 900 ctgacactga gcaaggccga ctacgagaag cacaaggtgt acgcctgcga agtgacccac 960 cagggcctgt ctagccccgt gaccaagagc ttcaaccggg gcgagtgt 1008 <210> 230 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 230 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 231 <211> 1338 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 231 gaagtgcagc tggtggaatc tggcggcgga ctggtgcagc ctggcggatc tctgagactg 60 agctgtgccg ccagcggctt caacatcaag gacacctaca tccactgggt gcgccaggcc 120 cctggcaagg gactggaatg ggtggccaga atctacccca ccaacggcta caccagatac 180 gccgacagcg tgaagggccg gttcaccatc agcgccgaca ccagcaagaa caccgcctac 240 ctgcagatga acagcctgcg ggccgaggac accgccgtgt actactgtag tagatgggga 300 ggcgacggct tctacgccat ggactattgg ggccagggca ccctcgtgac cgtgtctagt 360 gcgtcgacca agggcccatc ggtgttccct ctggcccctt gcagcagaag caccagcgaa 420 tctacagccg ccctgggctg cctcgtgaag gactactttc ccgagcccgt gaccgtgtcc 480 tggaactctg gcgctctgac aagcggcgtg cacacctttc cagccgtgct ccagagcagc 540 ggcctgtact ctctgagcag cgtcgtgaca gtgcccagca gcagcctggg caccaagacc 600 tacacctgta acgtggacca caagcccagc aacaccaagg tggacaagcg ggtggaatct 660 aagtacggcc ctccctgccc tccttgccca gcccctgaag ctgccggcgg accctccgtg 720 ttcctgttcc ccccaaagcc caaggacacc ctgatgatca gccggacccc cgaagtgacc 780 tgcgtggtgg tggatgtgtc ccaggaagat cccgaggtgc agttcaattg gtacgtggac 840 ggcgtggaag tgcacaacgc caagccaag cccagagagg aacagttcaa cagcacctac 900 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 960 tgcaaggtgt ccaacaaggg cctgcccagc tccatcgaga aaaccatcag caaggccaag 1020 ggccagcccc gcgagcctca agtgtatacc ctgccccctt gccaggaaga gatgaccaag 1080 aaccaggtgt ccctgtggtg tctcgtgaaa ggcttctacc ccagcgacat tgccgtggaa 1140 tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggacagc 1200 gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcaggaaggc 1260 aacgtgttca gctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1320 ctgtctctgt ccctgggc 1338 <210> 232 <211> 642 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 232 gacatccaga tgacccagag ccccagcagc ctgtctgcca gcgtgggcga cagagtgacc 60 atcacctgta gagccagcca ggacgtgaac accgccgtgg cctggtatca gcagaagcct 120 ggcaaggccc ccaagctgct gatctacagc gccagcttcc tgtacagcgg cgtgcccagc 180 agattcagcg gaagcagaag cggcaccgac ttcaccctga ccatcagctc cctgcagccc 240 gaggacttcg ccacctacta ctgccagcag cactacacca ccccccccac atttggccag 300 ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttcccacct 360 agcgacgagc agctgaagtc cggcacagcc tctgtcgtgt gcctgctgaa caacttctac 420 ccccgcgagg ccaaagtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gaaagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgaca 540 ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccaccagggc 600 ctgtctagcc ccgtgaccaa gagcttcaac cggggcgagt gt 642 <210> 233 <211> 1008 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 233 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg cacgagaacc tgttcaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaaggaca aaacccatac cgacatccag 360 atgacccaga gccccagcag cctgtctgcc agcgtgggcg acagagtgac catcacctgt 420 caggccagcc agaacatcta cgtgtggctg aactggtatc agcagaagcc cggcaaggcc 480 cccaagctgc tgatctacaa ggccagcaac ctgcacaccg gcgtgcccag cagattttct 540 ggcagcggct ccggcaccga cttcaccctg acaatcagct ccctgcagcc cgaggacatt 600 gccacctact actgccagca gggccagacc tacccctaca cctttggcca gggcaccaag 660 ctggaaatca aggataagac ccacacccgt acggtggccg ctcccagcgt gttcatcttc 720 ccacctagcg acgagcagct gaagtccggc acagcctctg tcgtgtgcct gctgaacaac 780 ttctaccccc gcgaggccaa agtgcagtgg aaggtggaca acgccctgca gagcggcaac 840 agccaggaaa gcgtgaccga gcaggacagc aaggactcca cctacagcct gagcagcacc 900 ctgacactga gcaaggccga ctacgagaag cacaaggtgt acgcctgcga agtgacccac 960 cagggcctgt ctagccccgt gaccaagagc ttcaaccggg gcgagtgt 1008 <210> 234 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 234 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 235 <211> 1338 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 235 gaagtgcagc tggtggaatc tggcggcgga ctggtgcagc ctggcggatc tctgagactg 60 agctgtgccg ccagcggctt caacatcaag gacacctaca tccactgggt gcgccaggcc 120 cctggcaagg gactggaatg ggtggccaga atctacccca ccaacggcta caccagatac 180 gccgacagcg tgaagggccg gttcaccatc agcgccgaca ccagcaagaa caccgcctac 240 ctgcagatga acagcctgcg ggccgaggac accgccgtgt actactgtag tagatgggga 300 ggcgacggct tctacgccat ggactattgg ggccagggca ccctcgtgac cgtgtctagt 360 gcgtcgacca agggcccatc ggtgttccct ctggcccctt gcagcagaag caccagcgaa 420 tctacagccg ccctgggctg cctcgtgaag gactactttc ccgagcccgt gaccgtgtcc 480 tggaactctg gcgctctgac aagcggcgtg cacacctttc cagccgtgct ccagagcagc 540 ggcctgtact ctctgagcag cgtcgtgaca gtgcccagca gcagcctggg caccaagacc 600 tacacctgta acgtggacca caagcccagc aacaccaagg tggacaagcg ggtggaatct 660 aagtacggcc ctccctgccc tccttgccca gcccctgaag ctgccggcgg accctccgtg 720 ttcctgttcc ccccaaagcc caaggacacc ctgatgatca gccggacccc cgaagtgacc 780 tgcgtggtgg tggatgtgtc ccaggaagat cccgaggtgc agttcaattg gtacgtggac 840 ggcgtggaag tgcacaacgc caagccaag cccagagagg aacagttcaa cagcacctac 900 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 960 tgcaaggtgt ccaacaaggg cctgcccagc tccatcgaga aaaccatcag caaggccaag 1020 ggccagcccc gcgagcctca agtgtatacc ctgccccctt gccaggaaga gatgaccaag 1080 aaccaggtgt ccctgtggtg tctcgtgaaa ggcttctacc ccagcgacat tgccgtggaa 1140 tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggacagc 1200 gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcaggaaggc 1260 aacgtgttca gctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1320 ctgtctctgt ccctgggc 1338 <210> 236 <211> 642 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 236 gacatccaga tgacccagag ccccagcagc ctgtctgcca gcgtgggcga cagagtgacc 60 atcacctgta gagccagcca ggacgtgaac accgccgtgg cctggtatca gcagaagcct 120 ggcaaggccc ccaagctgct gatctacagc gccagcttcc tgtacagcgg cgtgcccagc 180 agattcagcg gaagcagaag cggcaccgac ttcaccctga ccatcagctc cctgcagccc 240 gaggacttcg ccacctacta ctgccagcag cactacacca ccccccccac atttggccag 300 ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttcccacct 360 agcgacgagc agctgaagtc cggcacagcc tctgtcgtgt gcctgctgaa caacttctac 420 ccccgcgagg ccaaagtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gaaagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgaca 540 ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccaccagggc 600 ctgtctagcc ccgtgaccaa gagcttcaac cggggcgagt gt 642 <210> 237 <211> 1014 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 237 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg cacaacaacg ccaacaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaagggcc agcccaaggc cgccccccgac 360 atccagatga cccagagccc cagcagcctg tctgccagcg tgggcgacag agtgaccatc 420 acctgtcagg ccagccagaa catctacgtg tggctgaact ggtatcagca gaagcccggc 480 aaggccccca agctgctgat ctacaaggcc agcaacctgc acaccggcgt gcccagcaga 540 ttttctggca gcggctccgg caccgacttc accctgacaa tcagctccct gcagcccgag 600 gacattgcca cctactactg ccagcagggc cagacctacc cctacacctt tggccagggc 660 accaagctgg aaatcaagac caagggcccc agccgtacgg tggccgctcc cagcgtgttc 720 atcttcccac ctagcgacga gcagctgaag tccggcacag cctctgtcgt gtgcctgctg 780 aacaacttct acccccgcga ggccaaagtg cagtggaagg tggacaacgc cctgcagagc 840 ggcaacagcc aggaaagcgt gaccgagcag gacagcaagg actccaccta cagcctgagc 900 agcaccctga cactgagcaa ggccgactac gagaagcaca aggtgtacgc ctgcgaagtg 960 acccaccagg gcctgtctag ccccgtgacc aagagcttca accggggcga gtgt 1014 <210> 238 <211> 1710 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 238 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 agccaggtgc agctggtgga atctggcggc ggagtggtgc agcctggcag aagcctgaga 420 ctgagctgtg ccgccagcgg cttcaccttc accaaggcct ggatgcactg ggtgcgccag 480 gcccctggaa agcagctgga atgggtggcc cagatcaagg acaagagcaa cagctacgcc 540 acctactacg ccgacagcgt gaagggccgg ttcaccatca gccgggacga cagcaagaac 600 accctgtacc tgcagatgaa cagcctgcgg gccgaggaca ccgccgtgta ctactgtcgg 660 ggcgtgtact atgccctgag ccccttcgat tactggggcc agggaaccct cgtgaccgtg 720 tctagtcgga ccgccagcac aaagggccca tcggtgttcc ctctggcccc ttgcagcaga 780 agcaccagcg aatctacagc cgccctgggc tgcctcgtga aggactactt tcccgagccc 840 gtgaccgtgt cctggaactc tggcgctctg acaagcggcg tgcacacctt tccagccgtg 900 ctccagagca gcggcctgta ctctctgagc agcgtcgtga cagtgcccag cagcagcctg 960 ggcaccaaga cctacacctg taacgtggac cacaagccca gcaacaccaa ggtggacaag 1020 cgggtggaat ctaagtacgg ccctccctgc cctccttgcc cagcccctga agctgccggc 1080 ggaccctccg tgttcctgtt ccccccaaag cccaaggaca ccctgatgat cagccggacc 1140 cccgaagtga cctgcgtggt ggtggatgtg tcccaggaag atcccgaggt gcagttcaat 1200 tggtacgtgg acggcgtgga agtgcacaac gccaagacca agcccagaga ggaacagttc 1260 aacagcacct accgggtggt gtccgtgctg accgtgctgc accaggactg gctgaacggc 1320 aaagagtaca agtgcaaggt gtccaacaag ggcctgccca gctccatcga gaaaaccatc 1380 agcaaggcca agggccagcc ccgcgagcct caagtgtgta ccctgccccc tagccaggaa 1440 gagatgacca agaaccaggt gtccctgagc tgtgccgtga aaggcttcta ccccagcgac 1500 attgccgtgg aatgggagag caacggccag cccgagaaca actacaagac caccccccct 1560 gtgctggaca gcgacggctc attcttcctg gtgtccaagc tgaccgtgga caagagccgg 1620 tggcaggaag gcaacgtgtt cagctgctcc gtgatgcacg aggccctgca caaccactac 1680 acccagaagt ccctgtctct gtccctgggc 1710 <210> 239 <211> 1338 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 239 gaagtgcagc tggtggaatc tggcggcgga ctggtgcagc ctggcggatc tctgagactg 60 agctgtgccg ccagcggctt caacatcaag gacacctaca tccactgggt gcgccaggcc 120 cctggcaagg gactggaatg ggtggccaga atctacccca ccaacggcta caccagatac 180 gccgacagcg tgaagggccg gttcaccatc agcgccgaca ccagcaagaa caccgcctac 240 ctgcagatga acagcctgcg ggccgaggac accgccgtgt actactgtag tagatgggga 300 ggcgacggct tctacgccat ggactattgg ggccagggca ccctcgtgac cgtgtctagt 360 gcgtcgacca agggcccatc ggtgttccct ctggcccctt gcagcagaag caccagcgaa 420 tctacagccg ccctgggctg cctcgtgaag gactactttc ccgagcccgt gaccgtgtcc 480 tggaactctg gcgctctgac aagcggcgtg cacacctttc cagccgtgct ccagagcagc 540 ggcctgtact ctctgagcag cgtcgtgaca gtgcccagca gcagcctggg caccaagacc 600 tacacctgta acgtggacca caagcccagc aacaccaagg tggacaagcg ggtggaatct 660 aagtacggcc ctccctgccc tccttgccca gcccctgaag ctgccggcgg accctccgtg 720 ttcctgttcc ccccaaagcc caaggacacc ctgatgatca gccggacccc cgaagtgacc 780 tgcgtggtgg tggatgtgtc ccaggaagat cccgaggtgc agttcaattg gtacgtggac 840 ggcgtggaag tgcacaacgc caagccaag cccagagagg aacagttcaa cagcacctac 900 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 960 tgcaaggtgt ccaacaaggg cctgcccagc tccatcgaga aaaccatcag caaggccaag 1020 ggccagcccc gcgagcctca agtgtatacc ctgccccctt gccaggaaga gatgaccaag 1080 aaccaggtgt ccctgtggtg tctcgtgaaa ggcttctacc ccagcgacat tgccgtggaa 1140 tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggacagc 1200 gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcaggaaggc 1260 aacgtgttca gctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1320 ctgtctctgt ccctgggc 1338 <210> 240 <211> 642 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 240 gacatccaga tgacccagag ccccagcagc ctgtctgcca gcgtgggcga cagagtgacc 60 atcacctgta gagccagcca ggacgtgaac accgccgtgg cctggtatca gcagaagcct 120 ggcaaggccc ccaagctgct gatctacagc gccagcttcc tgtacagcgg cgtgcccagc 180 agattcagcg gaagcagaag cggcaccgac ttcaccctga ccatcagctc cctgcagccc 240 gaggacttcg ccacctacta ctgccagcag cactacacca ccccccccac atttggccag 300 ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttcccacct 360 agcgacgagc agctgaagtc cggcacagcc tctgtcgtgt gcctgctgaa caacttctac 420 ccccgcgagg ccaaagtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gaaagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgaca 540 ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccaccagggc 600 ctgtctagcc ccgtgaccaa gagcttcaac cggggcgagt gt 642 <210> 241 <211> 1008 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 241 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg cacgagaacc tgcgtaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaaggaca aaacccatac cgacatccag 360 atgacccaga gccccagcag cctgtctgcc agcgtgggcg acagagtgac catcacctgt 420 caggccagcc agaacatcta cgtgtggctg aactggtatc agcagaagcc cggcaaggcc 480 cccaagctgc tgatctacaa ggccagcaac ctgcacaccg gcgtgcccag cagattttct 540 ggcagcggct ccggcaccga cttcaccctg acaatcagct ccctgcagcc cgaggacatt 600 gccacctact actgccagca gggccagacc tacccctaca cctttggcca gggcaccaag 660 ctggaaatca aggataagac ccacacccgt acggtggccg ctcccagcgt gttcatcttc 720 ccacctagcg acgagcagct gaagtccggc acagcctctg tcgtgtgcct gctgaacaac 780 ttctaccccc gcgaggccaa agtgcagtgg aaggtggaca acgccctgca gagcggcaac 840 agccaggaaa gcgtgaccga gcaggacagc aaggactcca cctacagcct gagcagcacc 900 ctgacactga gcaaggccga ctacgagaag cacaaggtgt acgcctgcga agtgacccac 960 cagggcctgt ctagccccgt gaccaagagc ttcaaccggg gcgagtgt 1008 <210> 242 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 242 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 243 <211> 1338 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 243 gaagtgcagc tggtggaatc tggcggcgga ctggtgcagc ctggcggatc tctgagactg 60 agctgtgccg ccagcggctt caacatccgg gacacctaca tccactgggt gcgccaggcc 120 cctggcaagg gactggaatg ggtggccaga atctacccca cccagggcta caccagatac 180 gccgacagcg tgaagggccg gttcaccatc agcgccgaca ccagcaagaa caccgcctac 240 ctgcagatga acagcctgcg ggccgaggac accgccgtgt actactgtag tagatgggga 300 ggcgaaggct tctacgccat ggactattgg ggccagggca ccctcgtgac cgtgtctagt 360 gcgtcgacca agggcccatc ggtgttccct ctggcccctt gcagcagaag caccagcgaa 420 tctacagccg ccctgggctg cctcgtgaag gactactttc ccgagcccgt gaccgtgtcc 480 tggaactctg gcgctctgac aagcggcgtg cacacctttc cagccgtgct ccagagcagc 540 ggcctgtact ctctgagcag cgtcgtgaca gtgcccagca gcagcctggg caccaagacc 600 tacacctgta acgtggacca caagcccagc aacaccaagg tggacaagcg ggtggaatct 660 aagtacggcc ctccctgccc tccttgccca gcccctgaag ctgccggcgg accctccgtg 720 ttcctgttcc ccccaaagcc caaggacacc ctgatgatca gccggacccc cgaagtgacc 780 tgcgtggtgg tggatgtgtc ccaggaagat cccgaggtgc agttcaattg gtacgtggac 840 ggcgtggaag tgcacaacgc caagccaag cccagagagg aacagttcaa cagcacctac 900 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 960 tgcaaggtgt ccaacaaggg cctgcccagc tccatcgaga aaaccatcag caaggccaag 1020 ggccagcccc gcgagcctca agtgtatacc ctgccccctt gccaggaaga gatgaccaag 1080 aaccaggtgt ccctgtggtg tctcgtgaaa ggcttctacc ccagcgacat tgccgtggaa 1140 tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggacagc 1200 gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcaggaaggc 1260 aacgtgttca gctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1320 ctgtctctgt ccctgggc 1338 <210> 244 <211> 642 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 244 gacatccaga tgacccagag ccccagcagc ctgtctgcca gcgtgggcga cagagtgacc 60 atcacctgta gagccagcca ggacgtgaac accgccgtgg cctggtatca gcagaagcct 120 ggcaaggccc ccaagctgct gatctacagc gccagcttcc tgtacagcgg cgtgcccagc 180 agattcagcg gaagcagaag cggcaccgac ttcaccctga ccatcagctc cctgcagccc 240 gaggacttcg ccacctacta ctgccagcag cactacacca ccccccccac atttggccag 300 ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttcccacct 360 agcgacgagc agctgaagtc cggcacagcc tctgtcgtgt gcctgctgaa caacttctac 420 ccccgcgagg ccaaagtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gaaagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgaca 540 ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccaccagggc 600 ctgtctagcc ccgtgaccaa gagcttcaac cggggcgagt gt 642 <210> 245 <211> 1008 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 245 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg cacgagaacc tgttcaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaaggaca aaacccatac cgacatccag 360 atgacccaga gccccagcag cctgtctgcc agcgtgggcg acagagtgac catcacctgt 420 caggccagcc agaacatcta cgtgtggctg aactggtatc agcagaagcc cggcaaggcc 480 cccaagctgc tgatctacaa ggccagcaac ctgcacaccg gcgtgcccag cagattttct 540 ggcagcggct ccggcaccga cttcaccctg acaatcagct ccctgcagcc cgaggacatt 600 gccacctact actgccagca gggccagacc tacccctaca cctttggcca gggcaccaag 660 ctggaaatca aggataagac ccacacccgt acggtggccg ctcccagcgt gttcatcttc 720 ccacctagcg acgagcagct gaagtccggc acagcctctg tcgtgtgcct gctgaacaac 780 ttctaccccc gcgaggccaa agtgcagtgg aaggtggaca acgccctgca gagcggcaac 840 agccaggaaa gcgtgaccga gcaggacagc aaggactcca cctacagcct gagcagcacc 900 ctgacactga gcaaggccga ctacgagaag cacaaggtgt acgcctgcga agtgacccac 960 cagggcctgt ctagccccgt gaccaagagc ttcaaccggg gcgagtgt 1008 <210> 246 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 246 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 247 <211> 1338 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 247 caggtgcagc tggtgcagtc tggcgccgaa gtcgtgaaac ctggcgcctc cgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctacgcca tgcactgggt caaagaggcc 120 cctggccaga gactggaatg gatcggctac atctaccccg gccagggcgg caccaactac 180 aaccagaagt tccagggcag agccaccctg accgccgata caagcgccag caccgcctac 240 atggaactga gcagcctgcg gagcgaggat accgccgtgt acttctgtgc cagaacaggc 300 ggcctgaggc gggcctactt tacctattgg ggccagggca ccctcgtgac cgtgtctagc 360 gctagcacaa agggcccatc ggtgttccct ctggcccctt gcagcagaag caccagcgaa 420 tctacagccg ccctgggctg cctcgtgaag gactactttc ccgagcccgt gaccgtgtcc 480 tggaactctg gcgctctgac aagcggcgtg cacacctttc cagccgtgct ccagagcagc 540 ggcctgtact ctctgagcag cgtcgtgaca gtgcccagca gcagcctggg caccaagacc 600 tacacctgta acgtggacca caagcccagc aacaccaagg tggacaagcg ggtggaatct 660 aagtacggcc ctccctgccc tccttgccca gcccctgaag ctgccggcgg accctccgtg 720 ttcctgttcc ccccaaagcc caaggacacc ctgatgatca gccggacccc cgaagtgacc 780 tgcgtggtgg tggatgtgtc ccaggaagat cccgaggtgc agttcaattg gtacgtggac 840 ggcgtggaag tgcacaacgc caagccaag cccagagagg aacagttcaa cagcacctac 900 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 960 tgcaaggtgt ccaacaaggg cctgcccagc tccatcgaga aaaccatcag caaggccaag 1020 ggccagcccc gcgagcctca agtgtatacc ctgccccctt gccaggaaga gatgaccaag 1080 aaccaggtgt ccctgtggtg tctcgtgaaa ggcttctacc ccagcgacat tgccgtggaa 1140 tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggacagc 1200 gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcaggaaggc 1260 aacgtgttca gctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1320 ctgtctctgt ccctgggc 1338 <210> 248 <211> 654 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 248 gacatcgtgc tgacacagag ccctgccacc ctgtctctga gccctggcga gagagccacc 60 atcagctgta gagccagcca gagcgtgtcc agctacggcc agggcttcat gcactggtat 120 cagcagaagc ccggccagcc ccccagactg ctgatctatg gcgccagcag cagagccaca 180 ggcatccccg ccagattttc tggctctggc agcggcaccg acttcaccct gacaatcagc 240 cccctggaac ccgaggactt cgccgtgtac tactgccagc agaacaaaga ggacccctgg 300 accttcggcg gaggcaccaa gctggaaatc aagcgtacgg tggccgctcc cagcgtgttc 360 atcttcccac ctagcgacga gcagctgaag tccggcacag cctctgtcgt gtgcctgctg 420 aacaacttct acccccgcga ggccaaggtg cagtggaagg tggacaatgc cctgcagagc 480 ggcaacagcc aggaaagcgt gaccgagcag gacagcaagg actccaccta cagcctgagc 540 agcaccctga ccctgtccaa ggccgattac gagaagcaca aggtgtacgc ctgcgaagtg 600 acccaccagg gcctgtctag ccccgtgacc aagagcttca accggggcga gtgc 654 <210> 249 <211> 1008 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 249 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg cacgagaacc tgcagaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaaggaca aaacccatac cgacatccag 360 atgacccaga gccccagcag cctgtctgcc agcgtgggcg acagagtgac catcacctgt 420 caggccagcc agaacatcta cgtgtggctg aactggtatc agcagaagcc cggcaaggcc 480 cccaagctgc tgatctacaa ggccagcaac ctgcacaccg gcgtgcccag cagattttct 540 ggcagcggct ccggcaccga cttcaccctg acaatcagct ccctgcagcc cgaggacatt 600 gccacctact actgccagca gggccagacc tacccctaca cctttggcca gggcaccaag 660 ctggaaatca aggataagac ccacacccgt acggtggccg ctcccagcgt gttcatcttc 720 ccacctagcg acgagcagct gaagtccggc acagcctctg tcgtgtgcct gctgaacaac 780 ttctaccccc gcgaggccaa agtgcagtgg aaggtggaca acgccctgca gagcggcaac 840 agccaggaaa gcgtgaccga gcaggacagc aaggactcca cctacagcct gagcagcacc 900 ctgacactga gcaaggccga ctacgagaag cacaaggtgt acgcctgcga agtgacccac 960 cagggcctgt ctagccccgt gaccaagagc ttcaaccggg gcgagtgt 1008 <210> 250 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 250 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 251 <211> 1326 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 251 caggttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg tgtccggcta caccctgacc gagttcagca tccactgggt ccgacaggct 120 ccaggacaag gcttggaatg gatgggcggc ttcgatcccg aggacggcga aacaatctac 180 gcccagaaat tccagggccg cgtgatcatg accgaggaca cctctaccga caccgcctac 240 atggaaatga acagcctgcg gagcgaggat accgccatct actactgtac caccggcaga 300 ttcttcgact ggttctgggg ccagggcacc ctggttacag tctcttctgc gtcgaccaag 360 ggcccatcgg tgttccctct ggccccttgc agcagaagca ccagcgaatc tacagccgcc 420 ctgggctgcc tcgtgaagga ctactttccc gagcccgtga ccgtgtcctg gaactctggc 480 gctctgacaa gcggcgtgca cacctttcca gccgtgctcc agagcagcgg cctgtactct 540 ctgagcagcg tcgtgacagt gcccagcagc agcctgggca ccaagaccta cacctgtaac 600 gtggaccaca agcccagcaa caccaaggtg gacaagcggg tggaatctaa gtacggccct 660 ccctgccctc cttgcccagc ccctgaagct gccggcggac cctccgtgtt cctgttcccc 720 ccaaagccca aggacaccct gatgatcagc cggacccccg aagtgacctg cgtggtggtg 780 gatgtgtccc aggaagatcc cgaggtgcag ttcaattggt acgtggacgg cgtggaagtg 840 cacaacgcca agaccaagcc cagagaggaa cagttcaaca gcacctaccg ggtggtgtcc 900 gtgctgaccg tgctgcacca ggactggctg aacggcaaag agtacaagtg caaggtgtcc 960 aacaagggcc tgcccagctc catcgagaaa accatcagca aggccaaggg ccagccccgc 1020 gagcctcaag tgtataccct gcccccttgc caggaagaga tgaccaagaa ccaggtgtcc 1080 ctgtggtgtc tcgtgaaagg cttctacccc agcgacattg ccgtggaatg ggagagcaac 1140 ggccagcccg agaacaacta caagaccacc ccccctgtgc tggacagcga cggctcattc 1200 ttcctgtact ccaagctgac cgtggacaag agccggtggc aggaaggcaa cgtgttcagc 1260 tgctccgtga tgcacgaggc cctgcacaac cactacaccc agaagtccct gtctctgtcc 1320 ctgggc 1326 <210> 252 <211> 645 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 252 gagatcatcc tgacacagag ccccgccatc ctgtcactgt ctccaggcga aagagccaca 60 ctgagctgta gagccagcca gagcgtgatc agcagattcc tgagctggta tcaagtgaag 120 cccggactgg cccctcggct gttgatatat ggcgcctcta cacgcgccac aggcatccct 180 gttagatttt ctggcagcgg ctccggcacc gacttcagcc tgacaattag cagcctgcag 240 cctgaggact gcgccgtgta ctactgtcag caggacagca acctgcctat caccttcggc 300 cagggcacca gactggaaat caagcgtacg gtggccgctc ccagcgtgtt catcttccca 360 cctagcgacg agcagctgaa gtccggcaca gcctctgtcg tgtgcctgct gaacaacttc 420 tacccccgcg aggccaaagt gcagtggaag gtggacaacg ccctgcagag cggcaacagc 480 caggaaagcg tgaccgagca ggacagcaag gactccacct acagcctgag cagcaccctg 540 acactgagca aggccgacta cgagaagcac aaggtgtacg cctgcgaagt gacccaccag 600 ggcctgtcta gccccgtgac caagagcttc aaccggggcg agtgt 645 <210> 253 <211> 1008 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 253 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg cacgagaacc tgcagaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaaggaca aaacccatac cgacatccag 360 atgacccaga gccccagcag cctgtctgcc agcgtgggcg acagagtgac catcacctgt 420 caggccagcc agaacatcta cgtgtggctg aactggtatc agcagaagcc cggcaaggcc 480 cccaagctgc tgatctacaa ggccagcaac ctgcacaccg gcgtgcccag cagattttct 540 ggcagcggct ccggcaccga cttcaccctg acaatcagct ccctgcagcc cgaggacatt 600 gccacctact actgccagca gggccagacc tacccctaca cctttggcca gggcaccaag 660 ctggaaatca aggataagac ccacacccgt acggtggccg ctcccagcgt gttcatcttc 720 ccacctagcg acgagcagct gaagtccggc acagcctctg tcgtgtgcct gctgaacaac 780 ttctaccccc gcgaggccaa agtgcagtgg aaggtggaca acgccctgca gagcggcaac 840 agccaggaaa gcgtgaccga gcaggacagc aaggactcca cctacagcct gagcagcacc 900 ctgacactga gcaaggccga ctacgagaag cacaaggtgt acgcctgcga agtgacccac 960 cagggcctgt ctagccccgt gaccaagagc ttcaaccggg gcgagtgt 1008 <210> 254 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 254 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 255 <211> 1320 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 255 caggttcagc tgcagcagtc tggccccgaa ctcgttagac ctggcacctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cgcctttacc acctacctgg tggaatggat caagcagagg 120 cctggacagg gcctcgagtg gatcggagtg atcaatcctg gcagcggcag caccaactac 180 aacgagaagt tcaagggcaa agccacactg accgtggaca gaagcagcac cacagcctac 240 atgcacctga gcggcctgac ctctgatgac agcgccgtgt acttctgcgc cagatacgcc 300 tatggctatt ggggccaggg cacaaccctg accgttagct ctgcgtcgac caagggccca 360 tcggtgttcc ctctggcccc ttgcagcaga agcaccagcg aatctacagc cgccctgggc 420 tgcctcgtga aggactactt tcccgagccc gtgaccgtgt cctggaactc tggcgctctg 480 acaagcggcg tgcacacctt tccagccgtg ctccagagca gcggcctgta ctctctgagc 540 agcgtcgtga cagtgcccag cagcagcctg ggcaccaaga cctacacctg taacgtggac 600 cacaagccca gcaacaccaa ggtggacaag cgggtggaat ctaagtacgg ccctccctgc 660 cctccttgcc cagcccctga agctgccggc ggaccctccg tgttcctgtt ccccccaaag 720 cccaaggaca ccctgatgat cagccggacc cccgaagtga cctgcgtggt ggtggatgtg 780 tcccaggaag atcccgaggt gcagttcaat tggtacgtgg acggcgtgga agtgcacaac 840 gccaagcca agcccagaga ggaacagttc aacagcacct accgggtggt gtccgtgctg 900 accgtgctgc accaggactg gctgaacggc aaagagtaca agtgcaaggt gtccaacaag 960 ggcctgccca gctccatcga gaaaaccatc agcaaggcca agggccagcc ccgcgagcct 1020 caagtgtata ccctgccccc ttgccaggaa gagatgacca agaaccaggt gtccctgtgg 1080 tgtctcgtga aaggcttcta ccccagcgac attgccgtgg aatgggagag caacggccag 1140 cccgagaaca actacaagac caccccccct gtgctggaca gcgacggctc attcttcctg 1200 tactccaagc tgaccgtgga caagagccgg tggcaggaag gcaacgtgtt cagctgctcc 1260 gtgatgcacg aggccctgca caaccactac acccagaagt ccctgtctct gtccctgggc 1320 <210> 256 <211> 642 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 256 gacatcgtga tgacccagag ccagaaattc atgagcgcca gcgtgggcga cagagtgtcc 60 atcacatgta aagccagcca gaacgtgggc acagccgtgg cttggtatca gcagcagcct 120 ggccactctc ctaagcagct gatctacagc gccagcaaca gatacaccgg cgtgcccgat 180 agattcacag gatctggcgc cggaaccgac ttcaccctga ccatcagcaa catccagagc 240 gaggacctgg ccgactactt ctgccagcag tacagcacat accccttcac ctttggcagc 300 ggcaccaagc tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttcccacct 360 agcgacgagc agctgaagtc cggcacagcc tctgtcgtgt gcctgctgaa caacttctac 420 ccccgcgagg ccaaagtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gaaagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgaca 540 ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccaccagggc 600 ctgtctagcc ccgtgaccaa gagcttcaac cggggcgagt gt 642 <210> 257 <211> 1008 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 257 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg cacgagaacc tgcagaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaaggaca aaacccatac cgacatccag 360 atgacccaga gccccagcag cctgtctgcc agcgtgggcg acagagtgac catcacctgt 420 caggccagcc agaacatcta cgtgtggctg aactggtatc agcagaagcc cggcaaggcc 480 cccaagctgc tgatctacaa ggccagcaac ctgcacaccg gcgtgcccag cagattttct 540 ggcagcggct ccggcaccga cttcaccctg acaatcagct ccctgcagcc cgaggacatt 600 gccacctact actgccagca gggccagacc tacccctaca cctttggcca gggcaccaag 660 ctggaaatca aggataagac ccacacccgt acggtggccg ctcccagcgt gttcatcttc 720 ccacctagcg acgagcagct gaagtccggc acagcctctg tcgtgtgcct gctgaacaac 780 ttctaccccc gcgaggccaa agtgcagtgg aaggtggaca acgccctgca gagcggcaac 840 agccaggaaa gcgtgaccga gcaggacagc aaggactcca cctacagcct gagcagcacc 900 ctgacactga gcaaggccga ctacgagaag cacaaggtgt acgcctgcga agtgacccac 960 cagggcctgt ctagccccgt gaccaagagc ttcaaccggg gcgagtgt 1008 <210> 258 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 258 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 259 <211> 1338 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 259 caggttcagc tgctgcagtc tggcgccgaa cttgtcagac ctggcgtgtc cgtgaagatc 60 agctgtacag gcagcggcta cagcttcacc aactacgccg tgcactgggt caagcagagc 120 cacgtgaagt ccctggaatg gatcggcgtg atcagcccct actacggcga caccacctac 180 aaccagaagt tcaccggcaa ggccaccatg accgtggaca agtctagcag caccgcctac 240 atggaactgg ccagactgac cagcgaggac agcgccatct acttttgcgc cagaagattc 300 gagggcttct actacagcat ggactactgg ggccagggca ccagcgtgac agtttcttct 360 gcgtcgacca agggcccatc ggtgttccct ctggcccctt gcagcagaag caccagcgaa 420 tctacagccg ccctgggctg cctcgtgaag gactactttc ccgagcccgt gaccgtgtcc 480 tggaactctg gcgctctgac aagcggcgtg cacacctttc cagccgtgct ccagagcagc 540 ggcctgtact ctctgagcag cgtcgtgaca gtgcccagca gcagcctggg caccaagacc 600 tacacctgta acgtggacca caagcccagc aacaccaagg tggacaagcg ggtggaatct 660 aagtacggcc ctccctgccc tccttgccca gcccctgaag ctgccggcgg accctccgtg 720 ttcctgttcc ccccaaagcc caaggacacc ctgatgatca gccggacccc cgaagtgacc 780 tgcgtggtgg tggatgtgtc ccaggaagat cccgaggtgc agttcaattg gtacgtggac 840 ggcgtggaag tgcacaacgc caagccaag cccagagagg aacagttcaa cagcacctac 900 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 960 tgcaaggtgt ccaacaaggg cctgcccagc tccatcgaga aaaccatcag caaggccaag 1020 ggccagcccc gcgagcctca agtgtatacc ctgccccctt gccaggaaga gatgaccaag 1080 aaccaggtgt ccctgtggtg tctcgtgaaa ggcttctacc ccagcgacat tgccgtggaa 1140 tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggacagc 1200 gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcaggaaggc 1260 aacgtgttca gctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1320 ctgtctctgt ccctgggc 1338 <210> 260 <211> 657 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 260 gacgtggtca tgatccagac acctctgagc ctgcctgtgt ctctgggaga tcaggccagc 60 atcagctgca gacctagcca gtctctggtg cacagcaacg gcaacaccta cctgaactgg 120 tatctgcaga ggcccggaca gagccccaag ctgctgatct acaaggtgtc caagcggttc 180 agcggcgtgc ccgatagatt ttctggcagc ggctctggca ccgacttcac cctgaagatt 240 agcagagtgg aagccgagga cctgggcgtg tacctgtgtt ctcagagcac acacgtgccc 300 ctgacctttg gcagcggaac ccagctggaa atcaagcgta cggtggccgc tcccagcgtg 360 ttcatcttcc cacctagcga cgagcagctg aagtccggca cagcctctgt cgtgtgcctg 420 ctgaacaact tctacccccg cgaggccaaa gtgcagtgga aggtggacaa cgccctgcag 480 agcggcaaca gccaggaaag cgtgaccgag caggacagca aggactccac ctacagcctg 540 agcagcaccc tgacactgag caaggccgac tacgagaagc acaaggtgta cgcctgcgaa 600 gtgacccacc agggcctgtc tagccccgtg accaagagct tcaaccgggg cgagtgt 657 <210> 261 <211> 1008 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 261 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg cacgagaacc tgcagaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaaggaca aaacccatac cgacatccag 360 atgacccaga gccccagcag cctgtctgcc agcgtgggcg acagagtgac catcacctgt 420 caggccagcc agaacatcta cgtgtggctg aactggtatc agcagaagcc cggcaaggcc 480 cccaagctgc tgatctacaa ggccagcaac ctgcacaccg gcgtgcccag cagattttct 540 ggcagcggct ccggcaccga cttcaccctg acaatcagct ccctgcagcc cgaggacatt 600 gccacctact actgccagca gggccagacc tacccctaca cctttggcca gggcaccaag 660 ctggaaatca aggataagac ccacacccgt acggtggccg ctcccagcgt gttcatcttc 720 ccacctagcg acgagcagct gaagtccggc acagcctctg tcgtgtgcct gctgaacaac 780 ttctaccccc gcgaggccaa agtgcagtgg aaggtggaca acgccctgca gagcggcaac 840 agccaggaaa gcgtgaccga gcaggacagc aaggactcca cctacagcct gagcagcacc 900 ctgacactga gcaaggccga ctacgagaag cacaaggtgt acgcctgcga agtgacccac 960 cagggcctgt ctagccccgt gaccaagagc ttcaaccggg gcgagtgt 1008 <210> 262 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 262 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 263 <211> 1344 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 263 caggtgcagc tggtggaatc tggcggcgga gtggtgcagc ctggcagaag cctgagactg 60 agctgtgccg ccagcggctt caccttcagc agctacggca tgtactgggt gcgccaggcc 120 cctggcaaag gcctggaatg ggtggccgtg atttggtacg acggcagcaa caagtactac 180 gccgacagcg tgaagggccg gttcaccatc tcccgggaca acagcaagaa caccctgtac 240 ctgcagatga acagcctgcg ggccgaggac acagccgtgt atcactgcgc cagagatccc 300 ggcctgcggt actttgacgg cggcatggat gtgtggggcc agggcacaac cgtgaccgtg 360 tcatctgcgt cgaccaaggg cccatcggtg ttccctctgg ccccttgcag cagaagcacc 420 agcgaatcta cagccgccct gggctgcctc gtgaaggact actttcccga gcccgtgacc 480 gtgtcctgga actctggcgc tctgacaagc ggcgtgcaca cctttccagc cgtgctccag 540 agcagcggcc tgtactctct gagcagcgtc gtgacagtgc ccagcagcag cctgggcacc 600 aagacctaca cctgtaacgt ggaccacaag cccagcaaca ccaaggtgga caagcgggtg 660 gaatctaagt acggccctcc ctgccctcct tgcccagccc ctgaagctgc cggcggaccc 720 tccgtgttcc tgttcccccc aaagcccaag gacaccctga tgatcagccg gacccccgaa 780 gtgacctgcg tggtggtgga tgtgtcccag gaagatcccg aggtgcagtt caattggtac 840 gtggacggcg tggaagtgca caacgccaag accaagccca gagaggaaca gttcaacagc 900 acctaccggg tggtgtccgt gctgaccgtg ctgcaccagg actggctgaa cggcaaagag 960 tacaagtgca aggtgtccaa caagggcctg cccagctcca tcgagaaaac catcagcaag 1020 gccaagggcc agccccgcga gcctcaagtg tataccctgc ccccttgcca ggaagagatg 1080 accaagaacc aggtgtccct gtggtgtctc gtgaaaggct tctaccccag cgacattgcc 1140 gtggaatggg agagcaacgg ccagcccgag aacaactaca agaccacccc ccctgtgctg 1200 gacagcgacg gctcattctt cctgtactcc aagctgaccg tggacaagag ccggtggcag 1260 gaaggcaacg tgttcagctg ctccgtgatg cacgaggccc tgcacaacca ctacacccag 1320 aagtccctgt ctctgtccct gggc 1344 <210> 264 <211> 642 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 264 gacatccagc tgacccagag ccccagcttt ctgagcgcca gcgtgggcga cagagtgacc 60 atcacctgta gagccagcca gggcatcagc agctacctgg cctggtatca gcagaagccc 120 ggcaaggccc ccaaactgct gatctttgcc gccagcacac tgcacagcgg cgtgcccagc 180 agattttctg gcagcggctc cggcaccgag ttcaccctga caatcagcag cctgcagccc 240 gaggacttcg ccacctacta ctgccagcag ctgaacagct tcccctacac cttcggccag 300 ggcaccaagc tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttcccacct 360 agcgacgagc agctgaagtc cggcacagcc tctgtcgtgt gcctgctgaa caacttctac 420 ccccgcgagg ccaaagtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gaaagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgaca 540 ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccaccagggc 600 ctgtctagcc ccgtgaccaa gagcttcaac cggggcgagt gt 642 <210> 265 <211> 1008 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 265 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg cacgagaacc tgcagaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaaggaca aaacccatac cgacatccag 360 atgacccaga gccccagcag cctgtctgcc agcgtgggcg acagagtgac catcacctgt 420 caggccagcc agaacatcta cgtgtggctg aactggtatc agcagaagcc cggcaaggcc 480 cccaagctgc tgatctacaa ggccagcaac ctgcacaccg gcgtgcccag cagattttct 540 ggcagcggct ccggcaccga cttcaccctg acaatcagct ccctgcagcc cgaggacatt 600 gccacctact actgccagca gggccagacc tacccctaca cctttggcca gggcaccaag 660 ctggaaatca aggataagac ccacacccgt acggtggccg ctcccagcgt gttcatcttc 720 ccacctagcg acgagcagct gaagtccggc acagcctctg tcgtgtgcct gctgaacaac 780 ttctaccccc gcgaggccaa agtgcagtgg aaggtggaca acgccctgca gagcggcaac 840 agccaggaaa gcgtgaccga gcaggacagc aaggactcca cctacagcct gagcagcacc 900 ctgacactga gcaaggccga ctacgagaag cacaaggtgt acgcctgcga agtgacccac 960 cagggcctgt ctagccccgt gaccaagagc ttcaaccggg gcgagtgt 1008 <210> 266 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 266 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 267 <211> 1329 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 267 caggtgcagc tggtggaaag cggcggaggc gtggtgcagc ctggcaggtc tctgagactg 60 agctgtgccg ccagcggctt caccttcagc agctacggaa tgcactgggt gcgccaggcc 120 cctggcaaag gactggaatg ggtggccgtg atttggtacg acggcagcaa caagtactac 180 gccgacagcg tgaagggccg gttcaccatc agcggcgaca acagcaagaa caccctgtac 240 ctgcagatga acagcctgcg ggccgaggac accgccgtgt actactgcgc cagaatgttc 300 agaggcgcct tcgactactg gggccagggc acactcgtga ccgtgtctag tgcgtcgacc 360 aagggcccat cggtgttccc tctggcccct tgcagcagaa gcaccagcga atctacagcc 420 gccctgggct gcctcgtgaa ggactacttt cccgagcccg tgaccgtgtc ctggaactct 480 ggcgctctga caagcggcgt gcacaccttt ccagccgtgc tccagagcag cggcctgtac 540 tctctgagca gcgtcgtgac agtgcccagc agcagcctgg gcaccaagac ctacacctgt 600 aacgtggacc acaagcccag caacaccaag gtggacaagc gggtggaatc taagtacggc 660 cctccctgcc ctccttgccc agcccctgaa gctgccggcg gaccctccgt gttcctgttc 720 cccccaaagc ccaaggacac cctgatgatc agccggaccc ccgaagtgac ctgcgtggtg 780 gtggatgtgt cccaggaaga tcccgaggtg cagttcaatt ggtacgtgga cggcgtggaa 840 gtgcacaacg ccaagaccaa gcccagagag gaacagttca acagcaccta ccgggtggtg 900 tccgtgctga ccgtgctgca ccaggactgg ctgaacggca aagagtacaa gtgcaaggtg 960 tccaacaagg gcctgcccag ctccatcgag aaaaccatca gcaaggccaa gggccagccc 1020 cgcgagcctc aagtgtatac cctgccccct tgccaggaag agatgaccaa gaaccaggtg 1080 tccctgtggt gtctcgtgaa aggcttctac cccagcgaca ttgccgtgga atgggagagc 1140 aacggccagc ccgagaacaa ctacaagacc accccccctg tgctggacag cgacggctca 1200 ttcttcctgt actccaagct gaccgtggac aagagccggt ggcaggaagg caacgtgttc 1260 agctgctccg tgatgcacga ggccctgcac aaccactaca cccagaagtc cctgtctctg 1320 tccctgggc 1329 <210> 268 <211> 642 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 268 gccatccaga tgacccagag ccccagcagc ctgtctgcca gcgtgggcga cagagtgacc 60 atcacctgta gagccagcca gggcatccgg aacgacctgg gctggtatca gcagaagcct 120 ggcaaggccc ccaagctgct gatctacgcc gctagctctc tgcagtccgg cgtgcccagc 180 agattttctg gcagcggctc cggcaccgac ttcaccctga caatctctgg cctgcagccc 240 gaggacagcg ccacctacta ctgtctgcaa gactacatct actaccccac cttcggccag 300 ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttcccacct 360 agcgacgagc agctgaagtc cggcacagcc tctgtcgtgt gcctgctgaa caacttctac 420 ccccgcgagg ccaaagtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gaaagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgaca 540 ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccaccagggc 600 ctgtctagcc ccgtgaccaa gagcttcaac cggggcgagt gt 642 <210> 269 <211> 1008 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 269 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg cacgagaacc tgcagaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaaggaca aaacccatac cgacatccag 360 atgacccaga gccccagcag cctgtctgcc agcgtgggcg acagagtgac catcacctgt 420 caggccagcc agaacatcta cgtgtggctg aactggtatc agcagaagcc cggcaaggcc 480 cccaagctgc tgatctacaa ggccagcaac ctgcacaccg gcgtgcccag cagattttct 540 ggcagcggct ccggcaccga cttcaccctg acaatcagct ccctgcagcc cgaggacatt 600 gccacctact actgccagca gggccagacc tacccctaca cctttggcca gggcaccaag 660 ctggaaatca aggataagac ccacacccgt acggtggccg ctcccagcgt gttcatcttc 720 ccacctagcg acgagcagct gaagtccggc acagcctctg tcgtgtgcct gctgaacaac 780 ttctaccccc gcgaggccaa agtgcagtgg aaggtggaca acgccctgca gagcggcaac 840 agccaggaaa gcgtgaccga gcaggacagc aaggactcca cctacagcct gagcagcacc 900 ctgacactga gcaaggccga ctacgagaag cacaaggtgt acgcctgcga agtgacccac 960 cagggcctgt ctagccccgt gaccaagagc ttcaaccggg gcgagtgt 1008 <210> 270 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 270 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 271 <211> 1320 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 271 caggttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg cctctggcta cgccttcacc acctacctgg tggaatggat cagacagagg 120 cctggacagg gcctcgaatg gatgggcgtg atcaatcctg gcagcggcag caccaattac 180 gcccagaaat tccagggcag agtgaccatg accgtggaca gaagcagcac caccgcctac 240 atggaactga gcagactgag aagcgacgac accgccgtgt actactgtgc cagatacgcc 300 tacggctatt ggggccaggg aaccctggtt accgttagct ctgcgtcgac caagggccca 360 tcggtgttcc ctctggcccc ttgcagcaga agcaccagcg aatctacagc cgccctgggc 420 tgcctcgtga aggactactt tcccgagccc gtgaccgtgt cctggaactc tggcgctctg 480 acaagcggcg tgcacacctt tccagccgtg ctccagagca gcggcctgta ctctctgagc 540 agcgtcgtga cagtgcccag cagcagcctg ggcaccaaga cctacacctg taacgtggac 600 cacaagccca gcaacaccaa ggtggacaag cgggtggaat ctaagtacgg ccctccctgc 660 cctccttgcc cagcccctga agctgccggc ggaccctccg tgttcctgtt ccccccaaag 720 cccaaggaca ccctgatgat cagccggacc cccgaagtga cctgcgtggt ggtggatgtg 780 tcccaggaag atcccgaggt gcagttcaat tggtacgtgg acggcgtgga agtgcacaac 840 gccaagcca agcccagaga ggaacagttc aacagcacct accgggtggt gtccgtgctg 900 accgtgctgc accaggactg gctgaacggc aaagagtaca agtgcaaggt gtccaacaag 960 ggcctgccca gctccatcga gaaaaccatc agcaaggcca agggccagcc ccgcgagcct 1020 caagtgtata ccctgccccc ttgccaggaa gagatgacca agaaccaggt gtccctgtgg 1080 tgtctcgtga aaggcttcta ccccagcgac attgccgtgg aatgggagag caacggccag 1140 cccgagaaca actacaagac caccccccct gtgctggaca gcgacggctc attcttcctg 1200 tactccaagc tgaccgtgga caagagccgg tggcaggaag gcaacgtgtt cagctgctcc 1260 gtgatgcacg aggccctgca caaccactac acccagaagt ccctgtctct gtccctgggc 1320 <210> 272 <211> 642 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 272 gacatccaga tgacacagag ccctagcagc ctgtctgcca gcgtgggaga cagagtgacc 60 atcacctgta gagccagcca gaatgtggga acagccgtgg cctggtatca gcagaagcct 120 ggcaagagcc ccaagcagct gatctacagc gccagcaaca gatacaccgg cgtgcccagc 180 agattttctg gcagcggctc tggcaccgac ttcaccctga ccatatctag cctgcagcct 240 gaggacctgg ccacctacta ctgtcagcag tacagcacat accccttcac cttcggccag 300 ggcaccaagc tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttcccacct 360 agcgacgagc agctgaagtc cggcacagcc tctgtcgtgt gcctgctgaa caacttctac 420 ccccgcgagg ccaaagtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480 gaaagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgaca 540 ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccaccagggc 600 ctgtctagcc ccgtgaccaa gagcttcaac cggggcgagt gt 642 <210> 273 <211> 1008 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 273 gacatcgtga tgacccagac ccccctgagc ctgagcgtga cacctggaca gcctgccagc 60 atcagctgca agagcagcca gagcctggtg cacgagaacc tgcagaccta cctgagctgg 120 tatctgcaga agcccggcca gagcccccag tccctgatct acaaggtgtc caacagattc 180 agcggcgtgc ccgacagatt ctccggcagc ggctctggca ccgacttcac cctgaagatc 240 agccgggtgg aagccgagga cgtgggcgtg tactattgtg gccagggcac ccagtacccc 300 ttcacctttg gcagcggcac caaggtggaa atcaaggaca aaacccatac cgacatccag 360 atgacccaga gccccagcag cctgtctgcc agcgtgggcg acagagtgac catcacctgt 420 caggccagcc agaacatcta cgtgtggctg aactggtatc agcagaagcc cggcaaggcc 480 cccaagctgc tgatctacaa ggccagcaac ctgcacaccg gcgtgcccag cagattttct 540 ggcagcggct ccggcaccga cttcaccctg acaatcagct ccctgcagcc cgaggacatt 600 gccacctact actgccagca gggccagacc tacccctaca cctttggcca gggcaccaag 660 ctggaaatca aggataagac ccacacccgt acggtggccg ctcccagcgt gttcatcttc 720 ccacctagcg acgagcagct gaagtccggc acagcctctg tcgtgtgcct gctgaacaac 780 ttctaccccc gcgaggccaa agtgcagtgg aaggtggaca acgccctgca gagcggcaac 840 agccaggaaa gcgtgaccga gcaggacagc aaggactcca cctacagcct gagcagcacc 900 ctgacactga gcaaggccga ctacgagaag cacaaggtgt acgcctgcga agtgacccac 960 cagggcctgt ctagccccgt gaccaagagc ttcaaccggg gcgagtgt 1008 <210> 274 <211> 1731 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 274 caggtgcagc tggtgcagtc tggcgccgag gtcgtgaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cacctttacc agctactaca tccactgggt gcgccaggcc 120 cctggacagg gactggaatg gatcggcagc atctaccccg gcaacgtgaa caccaactac 180 gcccagaagt tccagggcag agccaccctg accgtggaca ccagcatcag caccgcctac 240 atggaactga gccggctgag aagcgacgac accgccgtgt actactgcac ccggtcccac 300 tacggcctgg attggaactt cgacgtgtgg ggcaagggca ccaccgtgac agtgtctagc 360 gacaaaaccc atacccaggt gcagctggtg gaatctggcg gcggagtggt gcagcctggc 420 agaagcctga gactgagctg tgccgccagc ggcttcacct tcaccaaggc ctggatgcac 480 tgggtgcgcc aggcccctgg aaagcagctg gaatgggtgg cccagatcaa ggacaagagc 540 aacagctacg ccacctacta cgccgacagc gtgaagggcc ggttcaccat cagccgggac 600 gacagcaaga acaccctgta cctgcagatg aacagcctgc gggccgagga caccgccgtg 660 tactactgtc ggggcgtgta ctatgccctg agccccttcg attactgggg ccagggaacc 720 ctcgtgaccg tgtctagtga taagacccac accgccagca caaagggccc atcggtgttc 780 cctctggccc cttgcagcag aagcaccagc gaatctacag ccgccctggg ctgcctcgtg 840 aaggactact ttcccgagcc cgtgaccgtg tcctggaact ctggcgctct gacaagcggc 900 gtgcacacct ttccagccgt gctccagagc agcggcctgt actctctgag cagcgtcgtg 960 acagtgccca gcagcagcct gggcaccaag acctacacct gtaacgtgga ccacaagccc 1020 agcaacacca aggtggacaa gcgggtggaa tctaagtacg gccctccctg ccctccttgc 1080 ccagcccctg aagctgccgg cggaccctcc gtgttcctgt tccccccaaa gcccaaggac 1140 accctgatga tcagccggac ccccgaagtg acctgcgtgg tggtggatgt gtcccaggaa 1200 gatcccgagg tgcagttcaa ttggtacgtg gacggcgtgg aagtgcacaa cgccaagacc 1260 aagcccagag aggaacagtt caacagcacc taccgggtgg tgtccgtgct gaccgtgctg 1320 caccaggact ggctgaacgg caaagagtac aagtgcaagg tgtccaacaa gggcctgccc 1380 agctccatcg agaaaaccat cagcaaggcc aagggccagc cccgcgagcc tcaagtgtgt 1440 accctgcccc ctagccagga agagatgacc aagaaccagg tgtccctgag ctgtgccgtg 1500 aaaggcttct accccagcga cattgccgtg gaatgggaga gcaacggcca gcccgagaac 1560 aactacaaga ccaccccccc tgtgctggac agcgacggct cattcttcct ggtgtccaag 1620 ctgaccgtgg acaagagccg gtggcaggaa ggcaacgtgt tcagctgctc cgtgatgcac 1680 gaggccctgc acaaccacta cacccagaag tccctgtctc tgtccctggg c 1731 <210> 275 <211> 1338 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 275 caggttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgcctc tgtgaaggtg 60 tcctgcaagg ccagcggcta cagcttcacc aattacgccg tgcactgggt ccgacaggct 120 ccaggacaag gactggaatg gatgggcgtg atcagcccct actacggcga taccacatac 180 gcccagaaat tccagggcag agtgaccatg accgtggaca agagcagcag caccgcctac 240 atggaactga gcagactgag aagcgacgac accgccgtgt actactgcgc cagaagattc 300 gagggcttct actacagcat ggactactgg ggccagggca ccctggttac agtctcttct 360 gcgtcgacca agggcccatc ggtgttccct ctggcccctt gcagcagaag caccagcgaa 420 tctacagccg ccctgggctg cctcgtgaag gactactttc ccgagcccgt gaccgtgtcc 480 tggaactctg gcgctctgac aagcggcgtg cacacctttc cagccgtgct ccagagcagc 540 ggcctgtact ctctgagcag cgtcgtgaca gtgcccagca gcagcctggg caccaagacc 600 tacacctgta acgtggacca caagcccagc aacaccaagg tggacaagcg ggtggaatct 660 aagtacggcc ctccctgccc tccttgccca gcccctgaag ctgccggcgg accctccgtg 720 ttcctgttcc ccccaaagcc caaggacacc ctgatgatca gccggacccc cgaagtgacc 780 tgcgtggtgg tggatgtgtc ccaggaagat cccgaggtgc agttcaattg gtacgtggac 840 ggcgtggaag tgcacaacgc caagccaag cccagagagg aacagttcaa cagcacctac 900 cgggtggtgt ccgtgctgac cgtgctgcac caggactggc tgaacggcaa agagtacaag 960 tgcaaggtgt ccaacaaggg cctgcccagc tccatcgaga aaaccatcag caaggccaag 1020 ggccagcccc gcgagcctca agtgtatacc ctgccccctt gccaggaaga gatgaccaag 1080 aaccaggtgt ccctgtggtg tctcgtgaaa ggcttctacc ccagcgacat tgccgtggaa 1140 tgggagagca acggccagcc cgagaacaac tacaagacca ccccccctgt gctggacagc 1200 gacggctcat tcttcctgta ctccaagctg accgtggaca agagccggtg gcaggaaggc 1260 aacgtgttca gctgctccgt gatgcacgag gccctgcaca accactacac ccagaagtcc 1320 ctgtctctgt ccctgggc 1338 <210> 276 <211> 657 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 276 gacgtggtca tgacacagag ccctctgagc ctgcctgtga cactgggaca gcctgccagc 60 atcagctgta gacctagcca gagcctggtg cacagcaacg gcaacaccta cctgaactgg 120 tatcagcaga ggcccggaca gagccccaag ctgctgatct acaaggtgtc caagcggttc 180 agcggcgtgc ccgatagatt ttctggcagc ggctctggca ccgacttcac cctgaagatt 240 agcagagtgg aagccgagga cgtgggcgtg tactactgta gccagtctac ccacgtgcca 300 ctgacctttg gcggcggaac aaaggtggaa atcaagcgta cggtggccgc tcccagcgtg 360 ttcatcttcc cacctagcga cgagcagctg aagtccggca cagcctctgt cgtgtgcctg 420 ctgaacaact tctacccccg cgaggccaaa gtgcagtgga aggtggacaa cgccctgcag 480 agcggcaaca gccaggaaag cgtgaccgag caggacagca aggactccac ctacagcctg 540 agcagcaccc tgacactgag caaggccgac tacgagaagc acaaggtgta cgcctgcgaa 600 gtgacccacc agggcctgtc tagccccgtg accaagagct tcaaccgggg cgagtgt 657 <210> 277 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 277 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Thr 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Thr Tyr 20 25 30 Leu Val Glu Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Ile Asn Pro Gly Ser Gly Ser Thr Asn Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Arg Ser Ser Thr Thr Ala Tyr 65 70 75 80 Met His Leu Ser Gly Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Tyr Ala Tyr Gly Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val 100 105 110 Ser Ser <210> 278 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 278 Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Gln Pro Gly His Ser Pro Lys Gln Leu Ile 35 40 45 Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ala Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Ile Gln Ser 65 70 75 80 Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Thr Tyr Pro Phe 85 90 95 Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 279 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 279 Gln Val Gln Leu Leu Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Val 1 5 10 15 Ser Val Lys Ile Ser Cys Thr Gly Ser Gly Tyr Ser Phe Thr Asn Tyr 20 25 30 Ala Val His Trp Val Lys Gln Ser His Val Lys Ser Leu Glu Trp Ile 35 40 45 Gly Val Ile Ser Pro Tyr Tyr Gly Asp Thr Thr Tyr Asn Gln Lys Phe 50 55 60 Thr Gly Lys Ala Thr Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ala Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Phe Cys 85 90 95 Ala Arg Arg Phe Glu Gly Phe Tyr Tyr Ser Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 280 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 280 Asp Val Val Met Ile Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Pro Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Asn Trp Tyr Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Lys Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Leu Cys Ser Gln Ser 85 90 95 Thr His Val Pro Leu Thr Phe Gly Ser Gly Thr Gln Leu Glu Ile Lys 100 105 110 <210> 281 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 281 Glu Asn Leu Gln One <210> 282 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 282 Glu Asn Leu Phe One <210> 283 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 283 Glu Asn Leu Arg One <210> 284 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 284 Asn Leu Val Pro Met Val Ala Thr Val 1 5 <210> 285 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 285 Gly Leu Cys Thr Leu Val Ala Met Leu 1 5 <210> 286 <211> 336 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 286 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Gln 20 25 30 Asn Ala Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Asp Lys Thr His Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 115 120 125 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln 130 135 140 Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 145 150 155 160 Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro 165 170 175 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 180 185 190 Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly 195 200 205 Gln Thr Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 210 215 220 Asp Lys Thr His Thr Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 245 250 255 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 260 265 270 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 275 280 285 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 290 295 300 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 305 310 315 320 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 325 330 335 <210> 287 <211> 577 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 287 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Asp Lys Thr His Thr Gln Val Gln 115 120 125 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg 130 135 140 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His 145 150 155 160 Trp Val Arg Gln Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile 165 170 175 Lys Asp Lys Ser Asn Ser Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg 210 215 220 Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser Asp Lys Thr His Thr Ala Ser Thr Lys Gly 245 250 255 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 260 265 270 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 275 280 285 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 290 295 300 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 305 310 315 320 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 325 330 335 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 340 345 350 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 355 360 365 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 370 375 380 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 385 390 395 400 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 405 410 415 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 420 425 430 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 435 440 445 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 450 455 460 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 465 470 475 480 Thr Leu Pro Pro Ser Gin Glu Glu Met Thr Lys Asn Gln Val Ser Leu 485 490 495 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 500 505 510 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 515 520 525 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 530 535 540 Lys Ser Arg Trp Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His 545 550 555 560 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 565 570 575 Gly <210> 288 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 288 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Arg Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Ala Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Ser Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 289 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 289 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 290 <211> 338 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 290 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Gln 20 25 30 Asn Ala Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Gly Gln Pro Lys Ala Ala Pro Asp Ile Gln Met Thr Gln Ser Pro Ser 115 120 125 Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala 130 135 140 Ser Gln Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly 145 150 155 160 Lys Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly 165 170 175 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190 Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 195 200 205 Gln Gly Gln Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu 210 215 220 Ile Lys Thr Lys Gly Pro Ser Arg Thr Val Ala Ala Pro Ser Val Phe 225 230 235 240 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val 245 250 255 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp 260 265 270 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr 275 280 285 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr 290 295 300 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val 305 310 315 320 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly 325 330 335 Glu Cys <210> 291 <211> 577 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 291 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Asp Lys Thr His Thr Gln Val Gln 115 120 125 Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg 130 135 140 Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His 145 150 155 160 Trp Val Arg Gln Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile 165 170 175 Lys Asp Lys Ser Asn Ser Tyr Ala Thr Tyr Tyr Ala Glu Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu 195 200 205 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg 210 215 220 Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr 225 230 235 240 Leu Val Thr Val Ser Ser Asp Lys Thr His Thr Ala Ser Thr Lys Gly 245 250 255 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 260 265 270 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 275 280 285 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 290 295 300 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 305 310 315 320 Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val 325 330 335 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 340 345 350 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 355 360 365 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 370 375 380 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 385 390 395 400 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 405 410 415 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 420 425 430 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 435 440 445 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 450 455 460 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 465 470 475 480 Thr Leu Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 485 490 495 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 500 505 510 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 515 520 525 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 530 535 540 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 545 550 555 560 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 565 570 575 Gly <210> 292 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 292 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Arg Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Gln Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Glu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 293 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 293 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 294 <211> 338 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 294 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Gln 20 25 30 Asn Ala Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Gly Gln Pro Lys Ala Ala Pro Asp Ile Gln Met Thr Gln Ser Pro Ser 115 120 125 Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala 130 135 140 Ser Gln Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly 145 150 155 160 Lys Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly 165 170 175 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190 Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 195 200 205 Gln Gly Gln Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu 210 215 220 Ile Lys Thr Lys Gly Pro Ser Arg Thr Val Ala Ala Pro Ser Val Phe 225 230 235 240 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val 245 250 255 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp 260 265 270 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr 275 280 285 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr 290 295 300 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val 305 310 315 320 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly 325 330 335 Glu Cys <210> 295 <211> 570 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 295 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ser Gln Val Gln Leu Val Glu Ser 115 120 125 Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala 130 135 140 Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His Trp Val Arg Gln 145 150 155 160 Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile Lys Asp Lys Ser 165 170 175 Asn Ser Tyr Ala Thr Tyr Tyr Ala Ser Ser Val Lys Gly Arg Phe Thr 180 185 190 Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser 195 200 205 Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg Gly Val Tyr Tyr 210 215 220 Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 225 230 235 240 Ser Ser Arg Thr Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 245 250 255 Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu 260 265 270 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 275 280 285 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 290 295 300 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 305 310 315 320 Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr 325 330 335 Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 340 345 350 Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro 355 360 365 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 370 375 380 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 385 390 395 400 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 405 410 415 Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 420 425 430 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 435 440 445 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 450 455 460 Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu 465 470 475 480 Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe 485 490 495 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 500 505 510 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 515 520 525 Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 530 535 540 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 545 550 555 560 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 565 570 <210> 296 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 296 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Arg Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Gln Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Glu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 297 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 297 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 298 <211> 338 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 298 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Gln 20 25 30 Ser Ala Gln Thr Tyr Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Gln Gly 85 90 95 Thr Gln Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Val Glu Ile Lys 100 105 110 Gly Gln Pro Lys Ala Ala Pro Asp Ile Gln Met Thr Gln Ser Pro Ser 115 120 125 Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala 130 135 140 Ser Gln Asn Ile Tyr Val Trp Leu Asn Trp Tyr Gln Gln Lys Pro Gly 145 150 155 160 Lys Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly 165 170 175 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 180 185 190 Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln 195 200 205 Gln Gly Gln Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu 210 215 220 Ile Lys Thr Lys Gly Pro Ser Arg Thr Val Ala Ala Pro Ser Val Phe 225 230 235 240 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val 245 250 255 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp 260 265 270 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr 275 280 285 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr 290 295 300 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val 305 310 315 320 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly 325 330 335 Glu Cys <210> 299 <211> 570 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 299 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Pro Gly Asn Val Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Ser His Tyr Gly Leu Asp Trp Asn Phe Asp Val Trp Gly Lys 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Ser Gln Val Gln Leu Val Glu Ser 115 120 125 Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala 130 135 140 Ala Ser Gly Phe Thr Phe Thr Lys Ala Trp Met His Trp Val Arg Gln 145 150 155 160 Ala Pro Gly Lys Gln Leu Glu Trp Val Ala Gln Ile Lys Asp Lys Ser 165 170 175 Asn Ser Tyr Ala Thr Tyr Tyr Ala Ser Ser Val Lys Gly Arg Phe Thr 180 185 190 Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser 195 200 205 Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Arg Gly Val Tyr Tyr 210 215 220 Ala Leu Ser Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 225 230 235 240 Ser Ser Arg Thr Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 245 250 255 Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu 260 265 270 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 275 280 285 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 290 295 300 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 305 310 315 320 Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr 325 330 335 Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 340 345 350 Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro 355 360 365 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 370 375 380 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 385 390 395 400 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 405 410 415 Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 420 425 430 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 435 440 445 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 450 455 460 Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu 465 470 475 480 Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe 485 490 495 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 500 505 510 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 515 520 525 Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 530 535 540 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 545 550 555 560 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 565 570 <210> 300 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 300 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Arg Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Gln Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Glu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Cys Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 <210> 301 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 301 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 302 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 302 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Lys Ala 20 25 30 Trp Met His Trp Val Arg Gln Ala Pro Gly Lys Gln Leu Glu Trp Val 35 40 45 Ala Gln Ile Lys Asp Lys Ser Asn Ser Tyr Ala Thr Tyr Tyr Ala Ser 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Arg Gly Val Tyr Tyr Ala Leu Ser Pro Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120

Claims (89)

A binding protein comprising four polypeptide chains forming three antigen-binding sites, wherein the first polypeptide chain comprises a structure represented by the formula
V_L2-L_One-V_L1-L₂-C_L [I]
The second polypeptide chain comprises a structure represented by the formula
V_H1-L₃-V_H2-L₄-C_H1-Hinge-C_H2-C_H3 [II]
The third polypeptide chain comprises a structure represented by the formula
V_H3-C_H1-Hinge-C_H2-C_H3 [III]
The fourth polypeptide chain comprises a structure represented by the formula
V_L3-C_L [IV]
during the meal,
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1Silver Immunoglobulin C_H1 heavy chain constant domain;
C_H2is immunoglobulin C_H2 heavy chain constant domain;
C_H3Silver Immunoglobulin C_H3 heavy chain constant domain;
Hinge is C_H1 domain and c_H2 an immunoglobulin hinge region that connects domains;
L_One, L₂, L₃, and L₄is an amino acid linker;
the polypeptide of formula I and the polypeptide of formula II form a cross light chain-heavy chain pair;
V_H1and V_L1forms a first antigen binding site;
V_H2and V_L2forms a second antigen binding site that binds to the CD3 polypeptide, and V_H2 The domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and a CDR comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO: 57) -H3 sequence, and V_L2 The domain is QSLVHX_OneNX₂X₃TY(X_Oneis E or Q, and X₂is A or L, and X₃is Q, R, or F) (SEQ ID NO: 180), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and GQGTQYPFT (SEQ ID NO: 65) a CDR-L3 sequence comprising an amino acid sequence;
V_H3and V_L3forms a third antigen binding site. The binding protein of claim 1 , wherein the first binding site binds to a CD28 polypeptide. 3. The method of claim 2, wherein the V _H1 domain is a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYY (SEQ ID NO: 49), a CDR-H2 sequence comprising the amino acid sequence of IYPGNVNT (SEQ ID NO: 50), and TRSHYGLDWNFDV (SEQ ID NO: 51) ), wherein the V _L1 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QNIYVW (SEQ ID NO: 52), a CDR-L1 sequence comprising the amino acid sequence of KAS (SEQ ID NO: 53)- A binding protein comprising a L2 sequence and a CDR-L3 sequence comprising the amino acid sequence of QQGQTYPY (SEQ ID NO: 54). 4. The method of claim 3, V _H1 domains, binding protein comprising the amino acid sequence and / or, V _L1 domain of QVQLVQSGAEVVKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWIGSIYPGNVNTNYAQKFQGRATLTVDTSISTAYMELSRLRSDDTAVYYCTRSHYGLDWNFDVWGKGTTVTVSS (SEQ ID NO: 91) comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCQASQNIYVWLNWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTDFTLTISSLQPEDIATYYCQQGQTYPYTFGQGTKLEIK (SEQ ID NO: 92). 5. The method of any one of claims 1 to 4, wherein _{the CDR-L1 sequence of the V L2} domain is QSLVHQNAQTY (SEQ ID NO: 59), QSLVHENLQTY (SEQ ID NO: 60), QSLVHENLFTY (SEQ ID NO: 61), and QSLVHENLRTY (SEQ ID NO: 62) ), a binding protein comprising an amino acid sequence selected from the group consisting of. 6. The method of claim 5, V _H2 domain QVQLVESGGGVVQPGRSLRLSCAASGFTFTKAWMHWVRQAPGKQLEWVAQIKDKSNSYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCRGVYYALSPFDYWGQGTLVTVSS (SEQ ID NO: 93) or QVQLVESGGGVVQPGRSLRLSCAASGFTFTKAWMHWVRQAPGKQLEWVAQIKDKSNSYATYYASSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCRGVYYALSPFDYWGQGTLVTVSS comprises the amino acid sequence of (SEQ ID NO: 302) and / or, V _L2 domain DIVMTQTPLSLSVTPGQPASISCKSSQSLVHQNAQTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 95), DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLQTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 96), DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLFTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 97), and DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLRTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK, binding protein comprising an amino acid sequence selected from the group consisting of (SEQ ID NO: 98). 7. The binding protein of any one of claims 1-6, wherein the third antigen binding site binds a tumor target protein. 7. The binding protein of any one of claims 1-6, wherein the third antigen binding site binds to a human CD38 polypeptide. 9. The method of claim 8,
(a) the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYA (SEQ ID NO: 13), a CDR-H2 sequence comprising the amino acid sequence of IYPGQGGT (SEQ ID NO: 14), and an amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO: 15) a CDR-H3 sequence comprising the sequence, wherein the V _L3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVSSYGQGF (SEQ ID NO: 16), a CDR-L2 sequence comprising the amino acid sequence of GAS (SEQ ID NO: 17), and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO: 18);
(b) the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTLTEFS (SEQ ID NO: 19), a CDR-H2 sequence comprising the amino acid sequence of FDPEDGET (SEQ ID NO: 20), and an amino acid sequence of TTGRFFDWF (SEQ ID NO: 21) a CDR-H3 sequence comprising the sequence, wherein the V _L3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVISRF (SEQ ID NO: 22), a CDR-L2 sequence comprising the amino acid sequence of GAS (SEQ ID NO: 23), and a CDR-L3 sequence comprising the amino acid sequence of QQDSNLPIT (SEQ ID NO: 24);
(c) the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYAFTTYL (SEQ ID NO: 25), a CDR-H2 sequence comprising the amino acid sequence of INPGSGST (SEQ ID NO: 26), and amino acids of ARYAYGY (SEQ ID NO: 27) a CDR-H3 sequence comprising the sequence, wherein the V _L3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QNVGTA (SEQ ID NO: 28), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 29); and a CDR-L3 sequence comprising the amino acid sequence of QQYSTYPFT (SEQ ID NO: 30);
(d) the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYSFTNYA (SEQ ID NO: 31), a CDR-H2 sequence comprising the amino acid sequence of ISPYYGDT (SEQ ID NO: 32), and amino acids of ARRFEGFYYSMDY (SEQ ID NO: 33) a CDR-H3 sequence comprising the sequence, wherein the V _L3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSLVHSNGNTY (SEQ ID NO: 34), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 35), and a CDR-L3 sequence comprising the amino acid sequence of SQSTHVPLT (SEQ ID NO: 36);
(e) the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO: 37), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO: 38), and an amino acid of ARDPGLRYFDGGMDV (SEQ ID NO: 39) a CDR-H3 sequence comprising the sequence, wherein the V _L3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QGISSY (SEQ ID NO: 40), a CDR-L2 sequence comprising the amino acid sequence of AAS (SEQ ID NO: 41); and a CDR-L3 sequence comprising the amino acid sequence of QQLNSFPYT (SEQ ID NO: 42);
(f) the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO: 43), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO: 44), and an amino acid of ARMFRGAFDY (SEQ ID NO: 45) a CDR-H3 sequence comprising the sequence, wherein the V _L3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QGIRND (SEQ ID NO: 46), a CDR-L2 sequence comprising the amino acid sequence of AAS (SEQ ID NO: 47); and a CDR-L3 sequence comprising the amino acid sequence of LQDYIYYPT (SEQ ID NO: 48). 10. The method of claim 9,
(a) V _H3 QVQLVQSGAEVVKPGASVKVSCKASGYTFTSYAMHWVKEAPGQRLEWIGYIYPGQGGTNYNQKFQGRATLTADTSASTAYMELSSLRSEDTAVYFCARTGGLRRAYFTYWGQGTLVTVSS domain comprises the amino acid sequence of (SEQ ID NO: 79) and / or, V _L3 domain comprises the amino acid sequence of DIVLTQSPATLSLSPGERATISCRASQSVSSYGQGFMHWYQQKPGQPPRLLIYGASSRATGIPARFSGSGSGTDFTLTISPLEPEDFAVYYCQQNKEDPWTFGGGTKLEIK (SEQ ID NO: 80) or;
(b) V is QVQLVQSGAEVKKPGASVKVSCKVSGYTLTEFSIHWVRQAPGQGLEWMGGFDPEDGETIYAQKFQGRVIMTEDTSTDTAYMEMNSLRSEDTAIYYCTTGRFFDWFWGQGTLVTVSS _H3 domain comprises the amino acid sequence of (SEQ ID NO: 81) and / or, V _L3 domain comprises the amino acid sequence of EIILTQSPAILSLSPGERATLSCRASQSVISRFLSWYQVKPGLAPRLLIYGASTRATGIPVRFSGSGSGTDFSLTISSLQPEDCAVYYCQQDSNLPITFGQGTRLEIK (SEQ ID NO: 82) or;
(c) V domain QVQLVQSGAEVKKPGASVKVSCKASGYAFTTYLVEWIRQRPGQGLEWMGVINPGSGSTNYAQKFQGRVTMTVDRSSTTAYMELSRLRSDDTAVYYCARYAYGYWGQGTLVTVSS _H3 (SEQ ID NO: 83) comprising the amino acid sequence and / or the, V _L3 domain comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQNVGTAVAWYQQKPGKSPKQLIYSASNRYTGVPSRFSGSGSGTDFTLTISSLQPEDLATYYCQQYSTYPFTFGQGTKLEIK (SEQ ID NO: 84) or;
(d) V is QVQLVQSGAEVKKPGASVKVSCKASGYSFTNYAVHWVRQAPGQGLEWMGVISPYYGDTTYAQKFQGRVTMTVDKSSSTAYMELSRLRSDDTAVYYCARRFEGFYYSMDYWGQGTLVTVSS _H3 domain comprises the amino acid sequence of (SEQ ID NO: 85) and / or, V _L3 domain comprises the amino acid sequence of DVVMTQSPLSLPVTLGQPASISCRPSQSLVHSNGNTYLNWYQQRPGQSPKLLIYKVSKRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGGGTKVEIK (SEQ ID NO: 86) or;
(e) V is QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMYWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCARDPGLRYFDGGMDVWGQGTTVTVSS _H3 domain comprises the amino acid sequence of (SEQ ID NO: 87) and / or, V _L3 domain comprises the amino acid sequence of DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIFAASTLHSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQLNSFPYTFGQGTKLEIK (SEQ ID NO: 88) or;
(f) V _H3 domains, binding protein comprising the amino acid sequence and / or, V _L3 of QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISGDNSKNTLYLQMNSLRAEDTAVYYCARMFRGAFDYWGQGTLVTVSS domain (SEQ ID NO: 89) comprises the amino acid sequence of AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISGLQPEDSATYYCLQDYIYYPTFGQGTKVEIK (SEQ ID NO: 90). 9. The method of claim 8,
(a) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 156 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 156; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 157 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 157; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 158 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 158; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 159 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 159;
(b) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 160 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 160; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 161 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 161; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 162 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 162; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:163 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:163;
(c) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 164 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 164; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 165 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 165; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 166 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 166; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 167 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 167;
(d) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 168 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 168; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 169 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 169; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 170 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 170; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 171 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 171;
(e) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 172 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 172; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 173 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 173; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 174 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 174; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 175 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 175;
(f) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 176 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 176; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 177 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 177; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 178 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 178; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 179 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 179;
(g) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 181 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 181; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 182 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 182; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 183 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 183; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 184 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 184;
(h) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 185 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 185; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 186 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 186; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:187 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:187; wherein the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 188 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 188. 8. The binding protein of any one of claims 1-7, wherein the third antigen binding site binds a human HER2 polypeptide. 13. The method of claim 12,
(a) the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIKDTY (SEQ ID NO: 1) or GFNIRDTY (SEQ ID NO: 2), IYPTNGYT (SEQ ID NO: 3), IYPTQGYT (SEQ ID NO: 4), or IYPTNAYT (SEQ ID NO: 2) 5) a CDR-H2 sequence comprising the amino acid sequence of, and a CDR-H3 sequence comprising the amino acid sequence of SRWGGDGFYAMDY (SEQ ID NO: 6), SRWGGEGFYAMDY (SEQ ID NO: 7), or SRWGGSGFYAMDY (SEQ ID NO: 8); _{The L3} domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9) or QDVQTA (SEQ ID NO: 10), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and QQHYTTP (SEQ ID NO: 12) ) comprises a CDR-L3 sequence comprising the amino acid sequence of;
(b) the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIKDTY (SEQ ID NO: 1), a CDR-H2 sequence comprising the amino acid sequence of IYPTNGYT (SEQ ID NO: 3), and an amino acid sequence of SRWGGDGFYAMDY (SEQ ID NO: 6) a CDR-H3 sequence comprising the sequence, wherein the V _L3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and a CDR-L3 sequence comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12);
(c) the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTQGYT (SEQ ID NO: 4), and an amino acid sequence of SRWGGEGFYAMDY (SEQ ID NO: 7) a CDR-H3 sequence comprising the sequence, wherein the V _L3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and a CDR-L3 sequence comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12);
(d) the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTNAYT (SEQ ID NO: 5), and an amino acid sequence of SRWGGSGFYAMDY (SEQ ID NO: 8) a CDR-H3 sequence comprising the sequence, wherein the V _L3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and a CDR-L3 sequence comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12);
(e) the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTQGYT (SEQ ID NO: 4), and an amino acid sequence of SRWGGSGFYAMDY (SEQ ID NO: 8) a CDR-H3 sequence comprising the sequence, wherein the V _L3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and a CDR-L3 sequence comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12);
(f) the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence comprising the amino acid sequence of IYPTNAYT (SEQ ID NO: 5), and an amino acid sequence of SRWGGEGFYAMDY (SEQ ID NO: 7) a CDR-H3 sequence comprising the sequence, wherein the V _L3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDVNTA (SEQ ID NO: 9), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and a CDR-L3 sequence comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12);
(g) the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFNIKDTY (SEQ ID NO: 1), a CDR-H2 sequence comprising the amino acid sequence of IYPTNGYT (SEQ ID NO: 3), and an amino acid sequence of SRWGGDGFYAMDY (SEQ ID NO: 6) a CDR-H3 sequence comprising the sequence, wherein the V _L3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDVQTA (SEQ ID NO: 10), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 11), and a CDR-L3 sequence comprising the amino acid sequence of QQHYTTP (SEQ ID NO: 12). 14. The method of claim 13,
(a) V _H3 domains EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (SEQ ID NO: 72), EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTQGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGEGFYAMDYWGQGTLVTVSS (SEQ ID NO: 73), EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTQGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGSGFYAMDYWGQGTLVTVSS (SEQ ID NO: 74), EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTNAYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGSGFYAMDYWGQGTLVTVSS (SEQ ID NO: 75), or EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTNAYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGEGFYAMDYWGQGTLVTVSS comprises the amino acid sequence of (SEQ ID NO: 76) and / or , V _L3 domain comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77) or DIQMTQSPSSLSASVGDRVTITCRASQDVQTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 78) or;
(b) V is EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS _H3 domain comprises the amino acid sequence of (SEQ ID NO: 72) and / or, V _L3 domain comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77) or;
(c) V domain EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTQGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGEGFYAMDYWGQGTLVTVSS _H3 comprises the amino acid sequence of (SEQ ID NO: 73) and / or, V _L3 domain comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77) or;
(d) V is EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTNAYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGSGFYAMDYWGQGTLVTVSS _H3 domain comprises the amino acid sequence of (SEQ ID NO: 75) and / or, V _L3 domain comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77) or;
(e) V is EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTQGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGSGFYAMDYWGQGTLVTVSS _H3 domain comprises the amino acid sequence of (SEQ ID NO: 74) and / or, V _L3 domain comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77) or;
(f) V _H3 EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTNAYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGEGFYAMDYWGQGTLVTVSS domain comprises the amino acid sequence of (SEQ ID NO: 76) and / or, V _L3 domain comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77) or;
(g) V _H3 domains, binding protein comprising the amino acid sequence and / or, V _L3 of EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS domain (SEQ ID NO: 72) comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVQTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 78). 13. The method of claim 12,
(a) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 100 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 100; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 101 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 101; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 102 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 102; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 103 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 103;
(b) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 104 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 104; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 105 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 105; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 106 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 106; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 107 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 107;
(c) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 112 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 112; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 113 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 113; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 114 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 114; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 115 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 115;
(d) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 116 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 116; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 117 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 117; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 118 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 118; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 119 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 119;
(e) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 120 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 120; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 121 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 121; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 122 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 122; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 123 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 123;
(f) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 124 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 124; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 125 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 125; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 126 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 126; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 127 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 127;
(g) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 128 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 128; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 129 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 129; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 130 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 130; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 131;
(h) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 132 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 132; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 133 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 133; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 134 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 134; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 135 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 135;
(i) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 136 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 136; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 137 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 137; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 138; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 139 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 139;
(j) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 140 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 140; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 141 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 141; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 142 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 142; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 143 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 143;
(k) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 144 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 144; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 145 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 145; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 146 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 146; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 147 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 147;
(l) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 148 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 148; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 149 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 149; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 150 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 150; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 151 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 151;
(m) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 152 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 152; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 153 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 153; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 154 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 154; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 155 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 155;
(n) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 286 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 286; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 287 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 287; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 288 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 288; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 289 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 289;
(o) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 290 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 290; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 291 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 291; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 292 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 292; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 293 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 293;
(p) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 294 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 294; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 295 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 295; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 296 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 296; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 297 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 297;
(q) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 298 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 298; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 299 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 299; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 300 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 300; wherein the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 301 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 301. 16. The binding protein of any one of claims 1-15, wherein _{at least one of L 1} , L ₂ , L ₃ , or L ₄ is independently 0 amino acids in length. 16. The method of any one of claims 1 to 15, wherein (a) L ₁ , L ₂ , L ₃ , and L ₄ are each independently 0 amino acids in length or GGGGSGGGGS (SEQ ID NO: 69), GGGGSGGGGSGGGGS (SEQ ID NO: 70) ), S, RT, TKGPS (SEQ ID NO: 68), GQPKAAP (SEQ ID NO: 67), and GGSGSSGSGG (SEQ ID NO: 71); (b) L ₁ , L ₂ , L ₃ , and L ₄ are each independently GGGGSGGGGS (SEQ ID NO: 69), GGGGSGGGGSGGGGS (SEQ ID NO: 70), S, RT, TKGPS (SEQ ID NO: 68), GQPKAAP (SEQ ID NO: 67) , and a sequence selected from the group consisting of GGSGSSGSGG (SEQ ID NO: 71). 16. The method of any one of claims 1 to 15, wherein L ₁ comprises the sequence GQPKAAP (SEQ ID NO: 67), L ₂ comprises the sequence TKGPS (SEQ ID NO: 68), L ₃ comprises the sequence S, and , L ₄ comprises the sequence RT. 16. The binding protein of any one of claims 1-15, wherein _{at least one of L 1} , L ₂ , L ₃ , or L ₄ comprises the sequence DKTHT (SEQ ID NO: 66). The binding protein of claim 19 , wherein L ₁ , L ₂ , L ₃ , and L ₄ comprise the sequence DKTHT (SEQ ID NO: 66). _{21. The hinge-C H2-} C _H3 domain of any one of claims 1-20, wherein the hinge-C H2-C H3 domains of the second and third polypeptide chains are human IgG4 hinge-C _H2 -C _H3 domains, and the hinge-C _H2- C _{H3 domains.} wherein the domain comprises amino acid substitutions at positions corresponding to positions 234 and 235 of human IgG4 according to the EU index, respectively, wherein the amino acid substitutions are F234A and L235A. _{21. The hinge-C H2-} C _H3 domain of any one of claims 1-20, wherein the hinge-C H2-C H3 domains of the second and third polypeptide chains are human IgG4 hinge-C _H2- C _H3 domains, and the hinge-C _H2- C _{H3 domains.} wherein the domain comprises an amino acid substitution at a position corresponding to positions 233 to 236 of human IgG4 according to the EU index, respectively, wherein the amino acid substitution is a deletion at E233P, F234V, L235A, and 236. 23. The method of any one of claims 1-22, wherein the hinge-C _H2 -C _H3 domains of the second and third polypeptide chains are human IgG4 hinge-C _H2 -C _H3 domains, and the hinge-C _H2 -C _{H3 domains.} and the domain comprises amino acid substitutions at positions corresponding to positions 228 and 409 of human IgG4 according to the EU index, respectively, wherein the amino acid substitutions are S228P and R409K. _{21. The hinge-C H2} -C _H3 domain of any one of claims 1-20, wherein the hinge-C H2 -C H3 domains of the second and third polypeptide chains are human IgG1 hinge-C _H2 -C _H3 domains, and the hinge-C _H2 -C _{H3 domains.} wherein the domain comprises amino acid substitutions at positions corresponding to positions 234, 235, and 329 of human IgG1 according to the EU index, respectively, wherein the amino acid substitutions are L234A, L235A, and P329A. _{21. The hinge-C H2} -C _H3 domain of any one of claims 1-20, wherein the hinge-C H2 -C H3 domains of the second and third polypeptide chains are human IgG1 hinge-C _H2 -C _H3 domains, and the hinge-C _H2 -C _{H3 domains.} wherein the domain comprises amino acid substitutions at positions corresponding to positions 298, 299, and 300 of human IgG1 according to the EU index, respectively, wherein the amino acid substitutions are S298N, T299A, and Y300S. 26. The method according to any one of claims 1 to 25, wherein the hinge-C _H2- C _H3 domain of the second polypeptide chain corresponds to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to the EU index. an amino acid substitution at the position, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; The hinge-C _H2- C _H3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to the EU index, the amino acid substitutions being S354C and T366W. 26. The method according to any one of claims 1 to 25, wherein the hinge-C _H2- C _H3 domain of the second polypeptide chain has amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to the EU index. wherein the amino acid substitutions are S354C and T366W; the hinge-C _H2- C _H3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to the EU index, wherein the amino acid substitutions are Y349C, T366S , L368A, and Y407V. 28. An isolated nucleic acid molecule comprising a nucleotide sequence encoding the binding protein of any one of claims 1-27. An expression vector comprising the nucleic acid molecule of claim 28 . 30. An isolated host cell comprising the nucleic acid molecule of claim 28 or the expression vector of claim 29. 31. The isolated host cell of claim 30, wherein the host cell is a mammalian or insect cell. 28. A pharmaceutical composition comprising the binding protein of any one of claims 1 to 27 and a pharmaceutically acceptable carrier. A method of preventing and/or treating cancer in a patient comprising administering to the patient a therapeutically effective amount of at least one binding protein of any one of claims 1-27 or a pharmaceutical composition of claim 32 . 34. The method of claim 33, wherein the at least one binding protein is co-administered with a chemotherapeutic agent. 35. The method of claim 33 or 34, wherein the patient is a human. 36. The method of any one of claims 33-35, wherein the third antigen binding site binds a human CD38 polypeptide, and wherein the cancer cells of the patient express CD38. 37. The method of claim 36, wherein the cancer is multiple myeloma. 37. The method of claim 36, wherein the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or B-cell lymphoma. 39. The method of any one of claims 36-38, wherein prior to administration of the binding protein, the patient has received daratumumab treatment without a washout period. 36. The method of any one of claims 33-35, wherein the third antigen binding site binds a human HER2 polypeptide and the patient's cancer cells express HER2. 41. The method of claim 40, wherein the cancer is breast cancer, colorectal cancer, gastric cancer, or small cell lung cancer (NSCLC). The binding protein or pharmaceutical composition of any one of claims 7 to 27 or the pharmaceutical composition of claim 32 , for use in preventing and/or treating cancer in a patient. 43. The binding protein or composition of claim 42, wherein the at least one binding protein is co-administered with a chemotherapeutic agent. 44. The binding protein or composition of claim 42 or 43, wherein the patient is a human. 45. The binding protein or composition of any one of claims 42-44, wherein the third antigen binding site binds a human CD38 polypeptide and the cancer cell of the patient expresses CD38. 46. The binding protein or composition of claim 45, wherein the cancer is multiple myeloma. 46. The binding protein or composition of claim 45, wherein the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or B-cell lymphoma. 48. The binding protein or composition of any one of claims 45-47, wherein prior to administration of the binding protein, the patient has received daratumumab treatment without a washout period. 45. The binding protein or composition of any one of claims 42-44, wherein the third antigen binding site binds a human HER2 polypeptide and the cancer cell of the patient expresses HER2. 50. The binding protein or composition of claim 49, wherein the cancer is breast cancer, colorectal cancer, gastric cancer, or small cell lung cancer (NSCLC). A method for proliferating a T cell, comprising the step of contacting the T cell with a binding protein comprising four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain comprises a structure represented by the formula ,
V_L2-L_One-V_L1-L₂-C_L [I]
The second polypeptide chain comprises a structure represented by the formula
V_H1-L₃-V_H2-L₄-C_H1-Hinge-C_H2-C_H3 [II]
The third polypeptide chain comprises a structure represented by the formula
V_H3-C_H1-Hinge-C_H2-C_H3 [III]
The fourth polypeptide chain comprises a structure represented by the formula
V_L3-C_L [IV]
during the meal,
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1Silver Immunoglobulin C_H1 heavy chain constant domain;
C_H2is immunoglobulin C_H2 heavy chain constant domain;
C_H3Silver Immunoglobulin C_H3 heavy chain constant domain;
Hinge is C_H1 domain and c_H2 an immunoglobulin hinge region that connects domains;
L_One, L₂, L₃, and L₄is an amino acid linker;
the polypeptide of formula I and the polypeptide of formula II form a cross light chain-heavy chain pair;
V_H1and V_L1forms a first antigen binding site that binds to the CD28 polypeptide;
V_H2and V_L2forms a second antigen binding site that binds to the CD3 polypeptide, and V_H2 The domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and a CDR comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO: 57) -H3 sequence, and V_L2 The domain is QSLVHX_OneNX₂X₃TY(X_Oneis E or Q, and X₂is A or L, and X₃is Q, R, or F) (SEQ ID NO: 180), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and GQGTQYPFT (SEQ ID NO: 65) a CDR-L3 sequence comprising an amino acid sequence;
V_H3and V_L3forms a third antigen binding site that binds to the CD38 polypeptide. 52. The method of claim 51, wherein the T cell expresses a chimeric antigen receptor (CAR) on the cell surface or comprises a polynucleotide encoding a CAR. 53. The method of claim 51 or 52, wherein the T cells are memory T cells or effector T cells. A method of propagating virus-specific memory T cells, the method comprising contacting the virus-specific memory T cells with a binding protein comprising four polypeptide chains forming three antigen binding sites, the first polypeptide chain comprising: includes a structure represented by the following formula,
V_L2-L_One-V_L1-L₂-C_L [I]
The second polypeptide chain comprises a structure represented by the formula
V_H1-L₃-V_H2-L₄-C_H1-Hinge-C_H2-C_H3 [II]
The third polypeptide chain comprises a structure represented by the formula
V_H3-C_H1-Hinge-C_H2-C_H3 [III]
The fourth polypeptide chain comprises a structure represented by the formula
V_L3-C_L [IV]
during the meal,
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1Silver Immunoglobulin C_H1 heavy chain constant domain;
C_H2is immunoglobulin C_H2 heavy chain constant domain;
C_H3Silver Immunoglobulin C_H3 heavy chain constant domain;
Hinge is C_H1 domain and c_H2 an immunoglobulin hinge region that connects domains;
L_One, L₂, L₃, and L₄is an amino acid linker;
the polypeptide of formula I and the polypeptide of formula II form a cross light chain-heavy chain pair;
V_H1and V_L1forms a first antigen binding site that binds to the CD28 polypeptide;
V_H2and V_L2forms a second antigen binding site that binds to the CD3 polypeptide, and V_H2 The domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and a CDR comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO: 57) -H3 sequence, and V_L2 The domain is QSLVHX_OneNX₂X₃TY(X_Oneis E or Q, and X₂is A or L, and X₃is Q, R, or F) (SEQ ID NO: 180), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and GQGTQYPFT (SEQ ID NO: 65) a CDR-L3 sequence comprising an amino acid sequence;
V_H3and V_L3forms a third antigen binding site that binds to the CD38 polypeptide. 55. The method of claim 54, wherein the virus-specific memory T cells are contacted with the binding protein in vitro or ex vivo. 56. The method of claim 54 or 55, wherein contacting the virus-specific memory T cell with the binding protein results in activation and/or proliferation of the virus-specific memory T cell. A method of treating a chronic viral infection comprising administering to a patient in need thereof an effective amount of a binding protein comprising four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is represented by the formula including a structure that becomes
V_L2-L_One-V_L1-L₂-C_L [I]
The second polypeptide chain comprises a structure represented by the formula
V_H1-L₃-V_H2-L₄-C_H1-Hinge-C_H2-C_H3 [II]
The third polypeptide chain comprises a structure represented by the formula
V_H3-C_H1-Hinge-C_H2-C_H3 [III]
The fourth polypeptide chain comprises a structure represented by the formula
V_L3-C_L [IV]
during the meal,
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1Silver Immunoglobulin C_H1 heavy chain constant domain;
C_H2is immunoglobulin C_H2 heavy chain constant domain;
C_H3Silver Immunoglobulin C_H3 heavy chain constant domain;
Hinge is C_H1 domain and c_H2 an immunoglobulin hinge region that connects domains;
L_One, L₂, L₃, and L₄is an amino acid linker;
the polypeptide of formula I and the polypeptide of formula II form a cross light chain-heavy chain pair;
V_H1and V_L1forms a first antigen binding site that binds to the CD28 polypeptide;
V_H2and V_L2forms a second antigen binding site that binds to the CD3 polypeptide, and V_H2 The domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and a CDR comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO: 57) -H3 sequence, and V_L2 The domain is QSLVHX_OneNX₂X₃TY(X_Oneis E or Q, and X₂is A or L, and X₃is Q, R, or F) (SEQ ID NO: 180), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and GQGTQYPFT (SEQ ID NO: 65) a CDR-L3 sequence comprising an amino acid sequence;
V_H3and V_L3forms a third antigen binding site that binds to the CD38 polypeptide. 58. The method of claim 57, wherein the patient is a human. 59. The method of claim 57 or 58, wherein the binding protein is administered to the patient in a pharmaceutical formulation comprising the binding protein and a pharmaceutically acceptable carrier. 60. The method of any one of claims 57-59, wherein administration of the binding protein results in activation and/or proliferation of virus-specific memory T cells in the patient. 61. The method of any one of claims 53-56 and 60, wherein the memory T cells are CD8+ or CD4+ memory T cells. 62. The method of any one of claims 53-56, 60, and 61, wherein the memory T cells are central memory T cells (T _CM ) or effector memory T cells (T _EM ). 63. The virus of any one of claims 54 to 62, wherein the virus is human immunodeficiency virus (HIV), influenza virus, cytomegalovirus (CMV), hepatitis B virus (HBV), human papillomavirus (HPV), Epstein. - bar virus (EBV), human foam virus (HFV), herpes simplex virus 1 (HSV-1), or herpes simplex virus 1 (HSV-2). 64. The method of any one of claims 51-63, wherein the CD28 polypeptide is a human CD28 polypeptide, the CD3 polypeptide is a human CD3 polypeptide, and the CD38 polypeptide is a human CD38 polypeptide. A binding protein for use in proliferating T cells, wherein the binding protein is contacted with the T cell, the binding protein comprising four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain is represented by the formula including a structure that becomes
V_L2-L_One-V_L1-L₂-C_L [I]
The second polypeptide chain comprises a structure represented by the formula
V_H1-L₃-V_H2-L₄-C_H1-Hinge-C_H2-C_H3 [II]
The third polypeptide chain comprises a structure represented by the formula
V_H3-C_H1-Hinge-C_H2-C_H3 [III]
The fourth polypeptide chain comprises a structure represented by the formula
V_L3-C_L [IV]
during the meal,
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1Silver Immunoglobulin C_H1 heavy chain constant domain;
C_H2is immunoglobulin C_H2 heavy chain constant domain;
C_H3Silver Immunoglobulin C_H3 heavy chain constant domain;
Hinge is C_H1 domain and c_H2 an immunoglobulin hinge region that connects domains;
L_One, L₂, L₃, and L₄is an amino acid linker;
the polypeptide of formula I and the polypeptide of formula II form a cross light chain-heavy chain pair;
V_H1and V_L1forms a first antigen binding site that binds to the CD28 polypeptide;
V_H2and V_L2forms a second antigen binding site that binds to the CD3 polypeptide, and V_H2 The domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and a CDR comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO: 57) -H3 sequence, and V_L2 The domain is QSLVHX_OneNX₂X₃TY(X_Oneis E or Q, and X₂is A or L, and X₃is Q, R, or F) (SEQ ID NO: 180), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and GQGTQYPFT (SEQ ID NO: 65) a CDR-L3 sequence comprising an amino acid sequence;
V_H3and V_L3and forms a third antigen binding site that binds to the CD38 polypeptide. 66. The binding protein of claim 65, wherein the T cell expresses a chimeric antigen receptor (CAR) on the cell surface or comprises a polynucleotide encoding a CAR. 67. The binding protein of claim 65 or 66, wherein the T cell is a memory T cell or an effector T cell. A binding protein for use in propagating virus-specific memory T cells, wherein the binding protein is contacted with a virus-specific memory T cell, the binding protein comprising four polypeptide chains forming three antigen binding sites; , the first polypeptide chain comprises a structure represented by the following formula,
V_L2-L_One-V_L1-L₂-C_L [I]
The second polypeptide chain comprises a structure represented by the formula
V_H1-L₃-V_H2-L₄-C_H1-Hinge-C_H2-C_H3 [II]
The third polypeptide chain comprises a structure represented by the formula
V_H3-C_H1-Hinge-C_H2-C_H3 [III]
The fourth polypeptide chain comprises a structure represented by the formula
V_L3-C_L [IV]
during the meal,
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1Silver Immunoglobulin C_H1 heavy chain constant domain;
C_H2is immunoglobulin C_H2 heavy chain constant domain;
C_H3Silver Immunoglobulin C_H3 heavy chain constant domain;
Hinge is C_H1 domain and c_H2 an immunoglobulin hinge region that connects domains;
L_One, L₂, L₃, and L₄is an amino acid linker;
the polypeptide of formula I and the polypeptide of formula II form a cross light chain-heavy chain pair;
V_H1and V_L1forms a first antigen binding site that binds to the CD28 polypeptide;
V_H2and V_L2forms a second antigen binding site that binds to the CD3 polypeptide, and V_H2 The domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and a CDR comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO: 57) -H3 sequence, and V_L2 The domain is QSLVHX_OneNX₂X₃TY(X_Oneis E or Q, and X₂is A or L, and X₃is Q, R, or F) (SEQ ID NO: 180), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and GQGTQYPFT (SEQ ID NO: 65) a CDR-L3 sequence comprising an amino acid sequence;
V_H3and V_L3and forms a third antigen binding site that binds to the CD38 polypeptide. 69. The binding protein of claim 68, wherein the virus-specific memory T cell is contacted with the binding protein in vitro or ex vivo. 70. The binding protein of claim 68 or 69, wherein contacting the virus-specific memory T cell with the trispecific binding protein results in activation and/or proliferation of the virus-specific memory T cell. A binding protein for use in treating a chronic viral infection, wherein the binding protein is administered to a patient in need thereof, the binding protein comprising four polypeptide chains forming three antigen binding sites, wherein the first polypeptide chain comprises: It contains a structure represented by the following formula,
V_L2-L_One-V_L1-L₂-C_L [I]
The second polypeptide chain comprises a structure represented by the formula
V_H1-L₃-V_H2-L₄-C_H1-Hinge-C_H2-C_H3 [II]
The third polypeptide chain comprises a structure represented by the formula
V_H3-C_H1-Hinge-C_H2-C_H3 [III]
The fourth polypeptide chain comprises a structure represented by the formula
V_L3-C_L [IV]
during the meal,
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1Silver Immunoglobulin C_H1 heavy chain constant domain;
C_H2is immunoglobulin C_H2 heavy chain constant domain;
C_H3Silver Immunoglobulin C_H3 heavy chain constant domain;
Hinge is C_H1 domain and c_H2 an immunoglobulin hinge region that connects domains;
L_One, L₂, L₃, and L₄is an amino acid linker;
the polypeptide of formula I and the polypeptide of formula II form a cross light chain-heavy chain pair;
V_H1and V_L1forms a first antigen binding site that binds to the CD28 polypeptide;
V_H2and V_L2forms a second antigen binding site that binds to the CD3 polypeptide, and V_H2 The domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO: 56), and a CDR comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO: 57) -H3 sequence, and V_L2 The domain is QSLVHX_OneNX₂X₃TY(X_Oneis E or Q, and X₂is A or L, and X₃is Q, R, or F) (SEQ ID NO: 180), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 64), and GQGTQYPFT (SEQ ID NO: 65) a CDR-L3 sequence comprising an amino acid sequence;
V_H3and V_L3and forms a third antigen binding site that binds to the CD38 polypeptide. 72. The binding protein of claim 71, wherein the patient is a human. 73. The binding protein of claim 71 or 72, wherein the binding protein is administered to the patient in a pharmaceutical formulation comprising the binding protein and a pharmaceutically acceptable carrier. 74. The binding protein according to any one of claims 71 to 73, wherein administration of the binding protein results in activation and/or proliferation of virus-specific memory T cells in the patient. 75. The binding protein of any one of claims 67-70 or 74, wherein the memory T cell is a CD8+ or CD4+ memory T cell. 76. The binding protein of any one of claims 67-70, 74, and 75, wherein the memory T cell is a central memory T cell (T _CM ) or an effector memory T cell (T _{EM ).} 77. The method of any one of claims 68-76, wherein the virus is human immunodeficiency virus (HIV), influenza virus, cytomegalovirus (CMV), hepatitis B virus (HBV), human papillomavirus (HPV), Epstein. - a binding protein, which is bar virus (EBV), human foam virus (HFV), herpes simplex virus 1 (HSV-1), or herpes simplex virus 1 (HSV-2). 78. The binding protein of any one of claims 65-77, wherein the CD28 polypeptide is a human CD28 polypeptide, the CD3 polypeptide is a human CD3 polypeptide, and the CD38 polypeptide is a human CD38 polypeptide. 79. The method of any one of claims 51 to 78, wherein the V _H1 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYY (SEQ ID NO: 49), a CDR-H2 comprising the amino acid sequence of IYPGNVNT (SEQ ID NO: 50). sequence, and a CDR-H3 sequence comprising the amino acid sequence of TRSHYGLDWNFDV (SEQ ID NO: 51), wherein the V _L1 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QNIYVW (SEQ ID NO: 52), KAS (SEQ ID NO: 53) A method or binding protein comprising a CDR-L2 sequence comprising the amino acid sequence of, and a CDR-L3 sequence comprising the amino acid sequence of QQGQTYPY (SEQ ID NO: 54). The method of claim 79 wherein, V _H1 QVQLVQSGAEVVKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWIGSIYPGNVNTNYAQKFQGRATLTVDTSISTAYMELSRLRSDDTAVYYCTRSHYGLDWNFDVWGKGTTVTVSS domain comprises the amino acid sequence of (SEQ ID NO: 91) and / or, V _L1 domain, methods or binding protein comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCQASQNIYVWLNWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTDFTLTISSLQPEDIATYYCQQGQTYPYTFGQGTKLEIK (SEQ ID NO: 92). 81. The method of any one of claims _{51-80, wherein the CDR-L1 sequence of the V L2} domain is QSLVHQNAQTY (SEQ ID NO: 59), QSLVHENLQTY (SEQ ID NO: 60), QSLVHENLFTY (SEQ ID NO: 61), and QSLVHENLRTY (SEQ ID NO: 62) ), a method or binding protein comprising an amino acid sequence selected from the group consisting of The method of claim 81 wherein, V _H2 domain QVQLVESGGGVVQPGRSLRLSCAASGFTFTKAWMHWVRQAPGKQLEWVAQIKDKSNSYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCRGVYYALSPFDYWGQGTLVTVSS (SEQ ID NO: 93) or QVQLVESGGGVVQPGRSLRLSCAASGFTFTKAWMHWVRQAPGKQLEWVAQIKDKSNSYATYYASSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCRGVYYALSPFDYWGQGTLVTVSS comprises the amino acid sequence of (SEQ ID NO: 302) and / or, V _L2 domain DIVMTQTPLSLSVTPGQPASISCKSSQSLVHQNAQTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 95), DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLQTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 96), DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLFTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 97), and DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLRTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 98), the method or binding protein comprising an amino acid sequence selected from the group consisting of. 83. The method of any one of claims 51 to 82,
(a) the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYA (SEQ ID NO: 13), a CDR-H2 sequence comprising the amino acid sequence of IYPGQGGT (SEQ ID NO: 14), and an amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO: 15) a CDR-H3 sequence comprising the sequence, wherein the V _L3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVSSYGQGF (SEQ ID NO: 16), a CDR-L2 sequence comprising the amino acid sequence of GAS (SEQ ID NO: 17), and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO: 18);
(b) the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTLTEFS (SEQ ID NO: 19), a CDR-H2 sequence comprising the amino acid sequence of FDPEDGET (SEQ ID NO: 20), and an amino acid sequence of TTGRFFDWF (SEQ ID NO: 21) a CDR-H3 sequence comprising the sequence, wherein the V _L3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVISRF (SEQ ID NO: 22), a CDR-L2 sequence comprising the amino acid sequence of GAS (SEQ ID NO: 23), and a CDR-L3 sequence comprising the amino acid sequence of QQDSNLPIT (SEQ ID NO: 24);
(c) the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYAFTTYL (SEQ ID NO: 25), a CDR-H2 sequence comprising the amino acid sequence of INPGSGST (SEQ ID NO: 26), and amino acids of ARYAYGY (SEQ ID NO: 27) a CDR-H3 sequence comprising the sequence, wherein the V _L3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QNVGTA (SEQ ID NO: 28), a CDR-L2 sequence comprising the amino acid sequence of SAS (SEQ ID NO: 29); and a CDR-L3 sequence comprising the amino acid sequence of QQYSTYPFT (SEQ ID NO: 30);
(d) the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYSFTNYA (SEQ ID NO: 31), a CDR-H2 sequence comprising the amino acid sequence of ISPYYGDT (SEQ ID NO: 32), and amino acids of ARRFEGFYYSMDY (SEQ ID NO: 33) a CDR-H3 sequence comprising the sequence, wherein the V _L3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSLVHSNGNTY (SEQ ID NO: 34), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO: 35), and a CDR-L3 sequence comprising the amino acid sequence of SQSTHVPLT (SEQ ID NO: 36);
(e) the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO: 37), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO: 38), and an amino acid of ARDPGLRYFDGGMDV (SEQ ID NO: 39) a CDR-H3 sequence comprising the sequence, wherein the V _L3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QGISSY (SEQ ID NO: 40), a CDR-L2 sequence comprising the amino acid sequence of AAS (SEQ ID NO: 41); and a CDR-L3 sequence comprising the amino acid sequence of QQLNSFPYT (SEQ ID NO: 42);
(f) the V _H3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO: 43), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO: 44), and an amino acid of ARMFRGAFDY (SEQ ID NO: 45) a CDR-H3 sequence comprising the sequence, wherein the V _L3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QGIRND (SEQ ID NO: 46), a CDR-L2 sequence comprising the amino acid sequence of AAS (SEQ ID NO: 47); and a CDR-L3 sequence comprising the amino acid sequence of LQDYIYYPT (SEQ ID NO: 48). 84. The method of claim 83,
(a) V _H3 QVQLVQSGAEVVKPGASVKVSCKASGYTFTSYAMHWVKEAPGQRLEWIGYIYPGQGGTNYNQKFQGRATLTADTSASTAYMELSSLRSEDTAVYFCARTGGLRRAYFTYWGQGTLVTVSS domain comprises the amino acid sequence of (SEQ ID NO: 79) and / or, V _L3 domain comprises the amino acid sequence of DIVLTQSPATLSLSPGERATISCRASQSVSSYGQGFMHWYQQKPGQPPRLLIYGASSRATGIPARFSGSGSGTDFTLTISPLEPEDFAVYYCQQNKEDPWTFGGGTKLEIK (SEQ ID NO: 80) or;
(b) V is QVQLVQSGAEVKKPGASVKVSCKVSGYTLTEFSIHWVRQAPGQGLEWMGGFDPEDGETIYAQKFQGRVIMTEDTSTDTAYMEMNSLRSEDTAIYYCTTGRFFDWFWGQGTLVTVSS _H3 domain comprises the amino acid sequence of (SEQ ID NO: 81) and / or, V _L3 domain comprises the amino acid sequence of EIILTQSPAILSLSPGERATLSCRASQSVISRFLSWYQVKPGLAPRLLIYGASTRATGIPVRFSGSGSGTDFSLTISSLQPEDCAVYYCQQDSNLPITFGQGTRLEIK (SEQ ID NO: 82) or;
(c) V domain QVQLVQSGAEVKKPGASVKVSCKASGYAFTTYLVEWIRQRPGQGLEWMGVINPGSGSTNYAQKFQGRVTMTVDRSSTTAYMELSRLRSDDTAVYYCARYAYGYWGQGTLVTVSS _H3 (SEQ ID NO: 83) comprising the amino acid sequence and / or the, V _L3 domain comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQNVGTAVAWYQQKPGKSPKQLIYSASNRYTGVPSRFSGSGSGTDFTLTISSLQPEDLATYYCQQYSTYPFTFGQGTKLEIK (SEQ ID NO: 84) or;
(d) V is QVQLVQSGAEVKKPGASVKVSCKASGYSFTNYAVHWVRQAPGQGLEWMGVISPYYGDTTYAQKFQGRVTMTVDKSSSTAYMELSRLRSDDTAVYYCARRFEGFYYSMDYWGQGTLVTVSS _H3 domain comprises the amino acid sequence of (SEQ ID NO: 85) and / or, V _L3 domain comprises the amino acid sequence of DVVMTQSPLSLPVTLGQPASISCRPSQSLVHSNGNTYLNWYQQRPGQSPKLLIYKVSKRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGGGTKVEIK (SEQ ID NO: 86) or;
(e) V is QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMYWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCARDPGLRYFDGGMDVWGQGTTVTVSS _H3 domain comprises the amino acid sequence of (SEQ ID NO: 87) and / or, V _L3 domain comprises the amino acid sequence of DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIFAASTLHSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQLNSFPYTFGQGTKLEIK (SEQ ID NO: 88) or;
(f) V _H3 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISGDNSKNTLYLQMNSLRAEDTAVYYCARMFRGAFDYWGQGTLVTVSS domain comprises the amino acid sequence of (SEQ ID NO: 89) and / or, V _L3 domain, method or binding protein comprising the amino acid sequence of AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISGLQPEDSATYYCLQDYIYYPTFGQGTKVEIK (SEQ ID NO: 90). 83. The method of any one of claims 51 to 82,
(a) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 156 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 156; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 157 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 157; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 158 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 158; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 159 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 159;
(b) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 160 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 160; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 161 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 161; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 162 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 162; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 163 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 163;
(c) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 164 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 164; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 165 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 165; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 166 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 166; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 167 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 167;
(d) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 168 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 168; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 169 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 169; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 170 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 170; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 171 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 171;
(e) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 172 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 172; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 173 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 173; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 174 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 174; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 175 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 175;
(f) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 176 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 176; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 177 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 177; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 178 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 178; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 179 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 179;
(g) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 181 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 181; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 182 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 182; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 183 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 183; the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 184 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 184;
(h) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 185 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 185; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 186 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 186; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:187 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:187; wherein the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 188 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 188. 28. A vector system comprising one or more vectors encoding the first, second, third, and fourth polypeptide chains of the binding protein of any one of claims 1-27. 87. The binding protein of claim 86, wherein a first vector encoding a first polypeptide chain of a binding protein, a second vector encoding a second polypeptide chain of a binding protein, a third vector encoding a third polypeptide chain of a binding protein, and binding A vector system comprising a fourth vector encoding a fourth polypeptide chain of a protein. (a) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 189, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 190, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 191, and the sequence a fourth polynucleotide comprising the polynucleotide sequence of number 192;
(b) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 193, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 194, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 195, and the sequence a fourth polynucleotide comprising the polynucleotide sequence of number 196;
(c) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 197, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 198, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 199, and the sequence a fourth polynucleotide comprising the polynucleotide sequence of number 200;
(d) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 201, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 202, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 203, and the sequence a fourth polynucleotide comprising the polynucleotide sequence of number 204;
(e) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 205, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 206, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 207, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of No. 208;
(f) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 209, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 210, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 211, and the sequence a fourth polynucleotide comprising the polynucleotide sequence of number 212;
(g) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 213, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 214, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 215, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 216;
(h) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 217, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 218, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 219, and the sequence a fourth polynucleotide comprising the polynucleotide sequence of No. 220;
(i) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 221, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 222, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 223, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of No. 224;
(j) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 225, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 226, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 227, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 228;
(k) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 229, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 230, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 231, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 232;
(l) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 233, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 234, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 235, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 236;
(m) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 237, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 238, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 239, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 240;
(n) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 241, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 242, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 243, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 244;
(o) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 245, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 246, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 247, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 248;
(p) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 249, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 250, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 251, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of No. 252;
(q) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 253, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 254, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 255, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 256;
(r) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 257, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 258, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 259, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 260;
(s) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 261, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 262, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 263, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 264;
(t) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 265, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 266, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 267, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 268;
(u) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 269, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 270, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 271, and the sequence a fourth polynucleotide comprising the polynucleotide sequence of number 272; or
(v) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 273, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 274, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 275, and a sequence a fourth polynucleotide comprising the polynucleotide sequence of number 276
A kit of polynucleotides comprising a. 89. The kit of claim 88, wherein the first, second, third, and fourth polynucleotides are present in one or more expression vectors.

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