RU2801824C2 - Chimeric antigen receptors targeting cd70 - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: invention relates to CARs (chimeric antigen receptors) that specifically bind to CD70. Also the following is disclosed: engineered immune cells containing CAR data, nucleic acids encoding CARs, and methods of producing CARs, engineered immune cells, and nucleic acids.

EFFECT: invention is effective in the treatment of a condition associated with malignant cells expressing CD70.

58 cl, 15 dwg, 13 tbl, 14 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority of U.S. Provisional Application No. 62/775246 filed December 4, 2018, U.S. Provisional Application No. 62/641869 filed March 12, 2018, U.S. Provisional Application No. 62/641873 filed 12 March 2018, U.S. Provisional Application No. 62/625009, filed February 1, 2018, and U.S. Provisional Application No. 62/625019, filed February 1, 2018, each of which is incorporated herein by reference in its full extent.

LINK TO SEQUENCE LISTING

This application is filed electronically via EFS-Web and includes a sequence listing filed electronically in txt format. The .txt file contains a sequence listing named "ALGN_014_03WO_SeqList_ST25.txt", created on January 24, 2019, and is ~725 kilobytes in size. The sequence listing contained in this .txt file is part of the specification and is incorporated herein by reference in its entirety.

FIELD OF TECHNOLOGY

The present invention relates to chimeric antigen receptors (CARs). CARs are able to redirect the specificity and reactivity of immune cells to a chosen target using the properties of the ligand-binding domain. In particular, the present invention relates to CARs that specifically bind to the 70 cassette of differentiation (CARs specific to CD70). The present invention also relates to polynucleotides encoding CD70-specific CARs and isolated cells expressing CD70-specific CARs on their surface. The present invention also relates to methods for constructing immune cells expressing CD70-specific CARs on their surface. The present invention is particularly applicable to the treatment of cancer, such as lymphoma, leukemia, glioma or renal cell carcinoma (RCC). The present invention also relates to immune cells containing CD70-specific CARs (CD70-specific CAR-T cells), compositions containing CD70-specific CAR-T cells, and methods of using CD70-specific CAR-T cells. CD70, for the treatment of conditions associated with malignant cells expressing CD70 (eg, cancer).

BACKGROUND OF THE INVENTION

The adaptive transfer of immune cells genetically modified to recognize cancer-associated antigens is a promising new approach to cancer treatment (see, e.g., Brenner et al., Current Opinion in Immunology, 22(2): 251-257 (2010) ; Rosenberg et al., Nature Reviews Cancer, 8(4): 299-308 (2008)). T cells can be genetically modified to express chimeric antigen receptors (CARs), fusion proteins consisting of an antigen recognition fragment and T cell activation domains (see, for example, Eshhar et al., Proc. Natl. Acad. sci. USA, 90(2): 720-724 (1993) and Sadelain et al., Curr. Opin. Immunol, 21(2): 215-223 (2009)).

Cluster 70 differentiation (CD70, CD27LG or TNFSF7) is a member of the tumor necrosis factor (TNF) superfamily and a ligand for CD27, the TNF superfamily receptor. The transient interaction between CD27 and CD70 provides T cell costimulation that is complementary to that provided by CD28. CD70 is expressed in hemoblastoses such as non-Hodgkin's lymphoma and Hodgkin's disease, as well as on solid tumors such as glioblastoma and renal cell carcinoma; while its expression on ccRCC is almost homogeneous (see, for example, Grewal I., et al., Expert Opinion on Therapeutic Targets, 12(3): 341-351 (2008)). The adaptive transfer of T cells genetically modified to recognize cancer-associated antigens is a promising new approach to cancer treatment (see, e.g., Brenner et al., Current Opinion in Immunology, 22(2): 251-257 (2010); Rosenberg et al., Nature Reviews Cancer, 8(4): 299-308 (2008)). T cells can be genetically modified to express chimeric antigen receptors (CARs), which are fusion proteins consisting of an antigen recognition fragment and T cell activation domains (see, e.g., Eshhar et al., Proc. Natl. Acad. sci. USA, 90(2): 720-724 (1993), and Sadelain et al., Current Opinion in Immunology, 21(2): 215-223 (2009)). Expression of CD70 in normal tissues is limited to activated T cells, B cells, NK cells, and dendritic cells. However, expression of CD70 on activated T cells may be of concern for CAR T cell production due to the potential for targeted T cell differentiation, depletion and mutual destruction during the production process.

Renal cell carcinoma (RCC) is a cancer that originates in the cortex of the kidney and accounts for approximately 90% of kidney cancers. Based on histology, RCC can be classified into several subtypes, of which clear cell renal cell carcinoma (ccRCC) is the most common and results in the highest mortality. Over 320,000 cases of RCC have been reported each year, resulting in approximately 140,000 deaths worldwide. Over the past 10 years, the incidence of RCC has steadily increased and is 2-3% of all malignant neoplasms in adults. Patients with localized tumors at an early stage may refuse surgical resection; however, localized disease may undergo early hematogenous dissemination leading to metastasis. Foci of early metastases include the lungs, lymph nodes, liver, bone, and brain; less often the adrenal glands and the contralateral kidney. Patients with advanced disease face high mortality rates, with a 5-year median survival of 53% for stage III disease and only 8% for disease with metastases. Current first-line treatments for advanced disease include small molecule tyrosine kinase inhibitors (TKIs) such as sunitinib and pazopanib, which target the vascular endothelial growth factor (VEGF) receptor, monoclonal antibodies that target VEGF, such as bevacizumab , a target for temsirolimus, a mammalian inhibitor of rapamycin (mTOR), and high doses of IL-2. Although these VEGF-targeting therapies are characterized as providing improved overall survival, long-term drug resistance leads to disease recurrence, and treatment of the disease at an advanced stage still remains an unmet need (see, e.g., Zarrabi, K. et al., Journal of Hematology and Oncology, 10:38 (2017)).

Accordingly, there is a need for alternative methods and agents for the treatment of cancer, and in particular malignancies, in which aberrant expression of CD70 is involved. Newer immunotherapies, such as CAR-T cell therapy, could significantly improve outcomes in patients with CD70-expressing cancers, such as those with mRCC. Accordingly, the treatment of cancer (such as, for example, mRCC) using CD70-specific CARs and CD70-specific CAR-T cells could be a promising therapeutic strategy. This document provides methods and compositions that meet such a need.

BRIEF DESCRIPTION OF THE INVENTION

This document presents chimeric antigen receptors (CARs) that bind to CD70, as well as methods for their preparation and methods for their use. This document also presents immune cells, such as T cells, containing such CD70-specific CARs. Certain CD70-specific CARs have been shown to be effective when expressed in T cells, with T cell activation upon contact with CD70. Advantageously, the CD70-specific CARs provided herein bind to human CD70. Also advantageously, the CD70-specific CAR-T cells provided herein exhibit cytotoxic activity when brought into contact with CD70-expressing cells. This document also presents antibodies that bind to CD70, as well as methods for their preparation and methods for their use. The anti-CD70 antibodies provided herein bind to human CD70.

In one aspect of the present invention, there is provided a chimeric cassette-of-differentiation 70 (CD70) specific antigen receptor (CAR) comprising an extracellular ligand-binding domain, a first transmembrane domain and an intracellular signaling domain, wherein the extracellular domain contains a single-stranded Fv fragment (scFv) that binds with the extracellular domain of CD70.

In some embodiments, the present invention provides a CD70-specific CAR, wherein the extracellular domain of the CAR provided herein comprises an scFv containing a heavy chain variable region (VH) containing three CDRs from a VH region containing the sequence shown under SEQ ID NO : 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 339 , 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379 or 381; and a light chain variable region (VL) comprising three CDRs from the VL region shown under SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, or 380. In some embodiments, the VH region contains the sequence shown under SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 , 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361 , 363, 365, 367, 369, 371, 373, 375, 377, 379, or 381, or a variant thereof with one or more conservative amino acid substitutions for residues that are not present in the CDR, and/or the VL region contains the amino acid sequence represented by under SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45 , 47, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, or 380, or a variation thereof with one or more amino acid substitutions for amino acids that are not present in the CDR.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 49, 50, or 51; CDR2 VH containing the amino acid sequence shown under SEQ ID NO: 52 or 53; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 54; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 193; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 194; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 195.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO: 2 and the VL region contains the amino acid sequence listed under SEQ ID NO: 1.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 55, 56, or 57; CDR2 VH containing the amino acid sequence shown under SEQ ID NO: 58 or 59; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 60; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 196; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 197; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 198.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO: 4 and the VL region contains the amino acid sequence listed under SEQ ID NO: 3.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 61, 62, or 63; CDR2 VH containing the amino acid sequence shown under SEQ ID NO: 64 or 65; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 66; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 199; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 200; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 201.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO:6 and the VL region contains the amino acid sequence listed under SEQ ID NO:5.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 67, 68, or 69; CDR2 VH containing the amino acid sequence shown under SEQ ID NO: 70 or 71; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 72; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 202; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 203; and CDR3 VL containing the amino acid sequence shown under SEQ ID NO: 204.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO: 8 and the VL region contains the amino acid sequence listed under SEQ ID NO: 7.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 73, 74, or 75; CDR2 VH containing the amino acid sequence shown under SEQ ID NO: 76 or 77; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 78; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 205; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 206; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 207.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO: 10 and the VL region contains the amino acid sequence listed under SEQ ID NO: 9.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 79, 80, or 81; CDR2 VH containing the amino acid sequence shown under SEQ ID NO: 82 or 83; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 84; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 208; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 209; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 210.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO: 12 and the VL region contains the amino acid sequence listed under SEQ ID NO: 11.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 85, 86, or 87; CDR2 VH containing the amino acid sequence shown under SEQ ID NO: 88 or 89; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 90; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 211; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 212; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 213.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO:14 and the VL region contains the amino acid sequence listed under SEQ ID NO:13.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 91, 92, or 93; CDR2 VH containing the amino acid sequence shown under SEQ ID NO: 94 or 95; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 96; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 214; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 215; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 216.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO: 16 and the VL region contains the amino acid sequence listed under SEQ ID NO: 15.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 97, 98, or 99; CDR2 VH containing the amino acid sequence shown under SEQ ID NO: 100 or 101; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 102; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 217; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 218; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 219.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO:18 and the VL region contains the amino acid sequence listed under SEQ ID NO:17.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 103, 104, or 105; CDR2 VH containing the amino acid sequence shown under SEQ ID NO: 106 or 107; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 108; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 220; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 221; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 222.

In some embodiments, the VH region contains the amino acid sequence shown under SEQ ID NO: 20 and the VL region contains the amino acid sequence shown under SEQ ID NO: 19.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 109, 110, or 111; CDR2 VH containing the amino acid sequence shown under SEQ ID NO: 112 or 113; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 114; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 223; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 224; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 225.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO:22 and the VL region contains the amino acid sequence listed under SEQ ID NO:21.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 115, 116, or 117; CDR2 VH containing the amino acid sequence shown under SEQ ID NO: 118 or 119; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 120; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 226; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 227; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 228.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO:24 and the VL region contains the amino acid sequence listed under SEQ ID NO:23.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 121, 122, or 123; CDR2 VH containing the amino acid sequence shown under SEQ ID NO: 124 or 125; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 126; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 229; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 230; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 231.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO:26 and the VL region contains the amino acid sequence listed under SEQ ID NO:25.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 127, 128, or 129; CDR2 VH containing the amino acid sequence shown under SEQ ID NO: 130 or 131; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 132; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 232; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 233; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 234.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO:28 and the VL region contains the amino acid sequence listed under SEQ ID NO:27.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 133, 134, or 135; CDR2 VH containing the amino acid sequence presented under SEQ ID NO: 136 or 137; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 138; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 235; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 236; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 237.

In some embodiments, the VH region contains the amino acid sequence shown under SEQ ID NO: 30 and the VL region contains the amino acid sequence shown under SEQ ID NO: 29.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 139, 140, or 141; CDR2 VH containing the amino acid sequence shown under SEQ ID NO: 142 or 143; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 144; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 238; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 239; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 240.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO:32 and the VL region contains the amino acid sequence listed under SEQ ID NO:31.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 145, 146, or 147; CDR2 VH containing the amino acid sequence presented under SEQ ID NO: 148 or 149; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 150; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 241; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 242; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 243.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO:34 and the VL region contains the amino acid sequence listed under SEQ ID NO:33.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 151, 152, or 153; CDR2 VH containing the amino acid sequence shown under SEQ ID NO: 154 or 155; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 156; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 244; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 245; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 246.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO:36 and the VL region contains the amino acid sequence listed under SEQ ID NO:35.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 157, 158, or 159; CDR2 VH containing the amino acid sequence shown under SEQ ID NO: 160 or 161; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 162; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 247; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 248; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 249.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO:38 and the VL region contains the amino acid sequence listed under SEQ ID NO:37.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 163, 164, or 165; CDR2 VH containing the amino acid sequence shown under SEQ ID NO: 166 or 167; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 168; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 250; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 251; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 252.

In some embodiments, the VH region contains the amino acid sequence shown under SEQ ID NO: 40 and the VL region contains the amino acid sequence shown under SEQ ID NO: 39.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 169, 170, or 171; CDR2 VH containing the amino acid sequence presented under SEQ ID NO: 172 or 173; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 174; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 253; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 254; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 255.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO:42 and the VL region contains the amino acid sequence listed under SEQ ID NO:41.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 175, 176, or 177; CDR2 VH containing the amino acid sequence presented under SEQ ID NO: 178 or 179; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 180; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 256; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 257; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 258.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO:44 and the VL region contains the amino acid sequence listed under SEQ ID NO:43.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 181, 182, or 183; CDR2 VH containing the amino acid sequence shown under SEQ ID NO: 184 or 185; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 186; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 259; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 260; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 261.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO:46 and the VL region contains the amino acid sequence listed under SEQ ID NO:45.

In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence shown under SEQ ID NO: 187, 188, or 189; CDR2 VH containing the amino acid sequence presented under SEQ ID NO: 190 or 191; and CDR3 VH containing the amino acid sequence shown under SEQ ID NO: 192; and the VL region contains a VL CDR1 containing the amino acid sequence shown under SEQ ID NO: 262; CDR2 VL containing the amino acid sequence shown under SEQ ID NO: 263; and a VL CDR3 containing the amino acid sequence shown under SEQ ID NO: 264.

In some embodiments, the VH region contains the amino acid sequence listed under SEQ ID NO:48 and the VL region contains the amino acid sequence listed under SEQ ID NO:47.

In some embodiments, each CDR is defined according to a Kabat definition, a Chothia definition, a combination of a Kabat definition and a Chothia definition, an AbM definition, or a contact CDR definition.

In some embodiments, each of the CDRs is defined according to a Kabat definition, a Chothia definition, an extended definition, a combination of a Kabat definition and a Chothia definition, an AbM definition, a contact definition, and/or a conformational CDR definition.

In some embodiments, the implementation of the intracellular signaling domain provides a signaling domain CD3ζ. In some embodiments, the intracellular signaling domain comprises a 4-1BB domain. In some embodiments, the CAR further comprises a second intracellular signaling domain. In some embodiments, the implementation of the second intracellular signaling domain provides a domain 4-1BB. In some embodiments, the implementation of the CAR contains the first intracellular signaling domain CD3ζ and the second intracellular signaling domain 4-1BB.

In some embodiments, the implementation of the intracellular signaling domain provides a signaling domain CD3ζ. In some embodiments, the intracellular signaling domain comprises a 4-1BB domain. In some embodiments, the CAR further comprises two intracellular signaling domains. In some embodiments, the CAR further comprises 3, 4, 5, or 6 intracellular signaling domains. In some embodiments, the CAR comprises a first intracellular signaling domain and a second intracellular signaling domain, wherein the second intracellular signaling domain comprises a 4-1BB domain. In some embodiments, the CAR contains a CD3ζ intracellular signaling domain and a 4-1BB intracellular signaling domain.

In some embodiments, the implementation of the CAR may contain a stem domain between the extracellular ligand-binding domain and the first transmembrane domain. In some embodiments, the stem domain is selected from the group consisting of a human CD8α hinge, an IgG1 hinge, and an FcγRIIIα hinge. In some embodiments, the stem domain is a human CD8α hinge, a human IgG1 hinge, or a human FcγRIIIα hinge.

In some embodiments, the CAR may contain a CD20 epitope. In some embodiments, the CD20 epitope comprises the amino acid sequence shown under SEQ ID NO: 293 or SEQ ID NO: 294 or SEQ ID NO: 609.

In some embodiments, the CAR may comprise the amino acid sequence listed under SEQ ID NO: 311-334 listed in Table 5. In some embodiments, the CAR may contain the amino acid sequence listed under SEQ ID NO: 319 or 327.

In some embodiments, the first transmembrane domain comprises a CD8α chain transmembrane domain.

In some embodiments, the implementation of the CAR may contain another extracellular ligand-binding domain that is not specific for CD70.

In some embodiments, the extracellular ligand-binding domain(s), the first transmembrane domain, and the intracellular signaling domain(s) are located in the same polypeptide.

In some embodiments, the CAR may comprise a second transmembrane domain, where the first transmembrane domain and the extracellular ligand-binding domain(s) are located in the first polypeptide, and where the second transmembrane domain and intracellular signaling domain(s) are located in the second polypeptide, where the first transmembrane domain contains a transmembrane domain from the α-chain of the high-affinity receptor for IgE (FcεRI), and the second transmembrane domain contains a transmembrane domain from the γ- or β-chain of FcεRI.

In some embodiments, the CAR may comprise a third polypeptide comprising a third transmembrane domain fused to an intracellular signaling domain from a costimulatory molecule, wherein the third transmembrane domain comprises a transmembrane domain from the γ or β chain of FcεRI.

In another aspect of the present invention, there is provided an isolated polynucleotide comprising a nucleic acid sequence encoding a CD70-specific CAR as described herein.

In another aspect of the present invention, there is provided an expression vector comprising a polynucleotide encoding a CD70-specific CAR as described herein.

In another aspect of the present invention, an engineered immune cell is provided that expresses on its outer cell membrane the CD70-specific CAR described herein. In some embodiments, the engineered immune cell may contain another CAR that is not specific for CD70. In some embodiments, the engineered immune cell may contain a polynucleotide encoding a "suicidal" polypeptide. In some embodiments, the "suicidal" polypeptide is RQR8.

In some embodiments, the engineered immune cell is derived from an inflammatory T lymphocyte, a cytotoxic T lymphocyte, a regulatory T lymphocyte, or a helper T lymphocyte.

In some embodiments, the engineered immune cell may be characterized by disruption of one or more endogenous genes, wherein the endogenous gene encodes TCRα, TCRβ, CD52, glucocorticoid receptor (GR), deoxycytidine kinase (dCK), CD70, or an immune response checkpoint protein such as, for example, programmed death protein-1 (PD-1).

In some embodiments, the engineered immune cell is from a healthy donor. In some embodiments, the engineered immune cell is from a patient.

In another aspect of the present invention, an engineered immune cell is provided that expresses on its outer cell membrane the CD70-specific CAR described herein for use as a drug. In some embodiments, the drug is for use in the treatment of cancer. In some embodiments, the drug is for the treatment of renal cell carcinoma, glioblastoma, glioma, e.g., low grade glioma, non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD), Waldenstrom's macroglobulinemia, acute myeloid leukemia, multiple myeloma, diffuse large cell lymphoma , follicular lymphoma, or non-small cell lung cancer.

In another aspect of the present invention, there is provided a method for constructing an immune cell comprising: providing the immune cell and allowing expression on the cell surface of at least one CD70-specific CAR described herein. In some embodiments, the method includes: providing an immune cell; introducing into the cell at least one polynucleotide encoding said CD70-specific CAR; and ensuring the expression of the specified polynucleotide in the cell.

In some embodiments, the method includes providing an immune cell; introducing into the cell at least one polynucleotide encoding said CD70-specific CAR; and introducing at least one other CAR that is not specific for CD70.

In another aspect, the present invention provides a method of treating a subject suffering from a condition associated with malignant cells, the method comprising: providing an immune cell expressing on the surface of the CD70-specific CAR described herein; and administering said immune cells to said patient.

In another aspect of the present invention, there is provided a pharmaceutical composition comprising the engineered immune cell described herein.

In another aspect, the present invention provides a method of treating a condition associated with CD70-expressing cancer cells in a subject, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising the engineered immune cell described herein. In some embodiments, the condition is cancer. In some embodiments, the cancer is renal cell carcinoma, glioblastoma, glioma such as low grade glioma, non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD), Waldenström's macroglobulinemia, acute myeloid leukemia, multiple myeloma, diffuse large cell lymphoma, follicular lymphoma or non-small cell lung cancer.

In another aspect, the present invention provides a method of inhibiting tumor growth or progression in a subject that has CD70-expressing cancer cells, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an engineered immune cell as described herein.

In another aspect, the present invention provides a method for inhibiting the metastasis of CD70-expressing cancer cells in a subject, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an engineered immune cell as described herein.

In another aspect, the present invention provides a method for inducing tumor regression in a subject that has CD70-expressing cancer cells, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising the engineered immune cell described herein.

In some embodiments, any of the above methods further comprises administering one or more additional therapeutic agents, such as a monoclonal antibody and/or a chemotherapeutic agent. In some embodiments, the monoclonal antibody may be, for example, an antibody that binds to a checkpoint inhibitor, such as, for example, an anti-PD-1 antibody or an anti-PD-L1 antibody. In some embodiments, any of the above methods further comprises administering a receptor tyrosine kinase inhibitor such as sunitinib or axitinib.

In some embodiments, the present invention provides a CD70-specific CAR comprising an extracellular ligand-binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular domain comprises a single chain Fv fragment (scFv) that binds to an extracellular domain of CD70 having a heavy chain variable region (VH) and light chain variable region (VL); where the VH region contains an amino acid sequence that is at least 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 18, and the VL region contains an amino acid sequence that is at least 95% , 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 17; or the VH region contains an amino acid sequence that is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 34, and the VL region contains an amino acid sequence that is at least 95% , 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 33.

In some embodiments, the extracellular domain contains an amino acid sequence that is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 319. In some embodiments, the extracellular domain contains an amino acid sequence that at least 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 327.

In some embodiments, the invention provides a polynucleotide encoding a CD70-specific CAR, wherein the polynucleotide contains a nucleic acid sequence that is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID. NO: 297 and at least 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 298 or at least 95%, 96%, 97%, 98%, 99 % or 100% identical to SEQ ID NO: 307 and at least 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 308.

In some embodiments, the present invention provides a CAR comprising an antigen-binding molecule that specifically binds to CD70, wherein the antigen-binding molecule comprises at least one of the following: A heavy chain variable region CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 49-51, 55-57, 61-63, 67-69, 73-75, 79-81, 85-87, 91-93, 97-99, 103-105, 109-111, 115-117, 121- 123, 127-129, 133-135, 139-141, 145-147, 151-153, 157-159, 163-165, 169-171, 175-177, 181-183, 187-189, 382-384, 388-390, 394-396, 400-402, 406-408, 412-414, 418-420, 424-426, 430-432, 436-438, 442-444, 448-450, 454-456, 460- 462, 466-468, 472-474, 478-480, 484-486, 490-492, 496-498, 502-504 and 508-510; A heavy chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ NOs: 52, 53, 58, 59, 64, 65, 70, 71, 76, 77, 82, 83, 88, 89, 94, 95 , 100,101,106,107,112,113,118,119,124,125,130,131,136,137,142,143,148,149,154,155,160,161,166,167, 172 173 178 179 184 185 190 191 385 386 391 392 397 398 403 404 409 410 415 416 421 422 427 428 433 434 , 439, 440, 445, 446, 451, 452, 457, 458, 463, 464, 469, 470, 475, 476, 481, 482, 487, 488, 493, 494, 499, 500, 505, 506, 511 and 512; A heavy chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 54, 60, 66, 72, 78, 84, 90, 96, 102, 108, 114, 120, 126, 132, 138, 144, 150, 156, 162, 168, 174, 180, 186, 192, 387, 393, 399, 405, 411, 417, 423, 429, 435, 441, 447, 453, 459, 465, 471, 4 77, 483, 489, 495, 501, 507 and 513; A light chain variable region CDR1 comprising an amino acid sequence selected from the group consisting of SEQ NOs: 193, 196, 199, 202, 205, 208, 211, 214, 217, 220, 223, 226, 229, 232, 235, 238 , 241 244 247 250 253 256 259 262 514 517 520 523 526 529 532 535 538 541 544 547 550 553 556 562 , 565, 568, 571, 574 and 577; A light chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 194, 197, 200, 203, 206, 209, 212, 215, 218, 221, 224, 227, 230, 233, 236, 239 242 245 248 251 254 257 260 263 515 518 521 524 527 530 533 536 539 542 545 548 551 554 557 5 60, 563, 566, 569, 572, 575 and 578; and a light chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 195, 198, 201, 204, 207, 210, 213, 216, 219, 222, 225, 228, 231, 234, 237 , 240, 243, 246, 249, 252, 255, 258, 261, 264, 516, 519, 522, 525, 528, 531, 534, 537, 540, 543, 546, 549, 552, 555, 558, 561 , 564, 567, 570, 573, 576 and 579.

In some embodiments, the antigen-binding molecule comprises a heavy chain variable domain comprising the amino acid sequences CDRH1, CDRH2, and CDRH3, respectively, selected from one of SEQ ID NOs: 49-51, 52-53, 54; 55-57, 58-59, 60; 61-63, 64-65, 66; 67-69, 70-71, 72; 73-75, 76-77, 78; 79-81, 82-83, 84; 85-87, 88-89, 90; 91-93, 94-95, 96; 97-99, 100-101, 102; 103-105, 106-107, 108; 109-111, 112-113, 114; 115-117, 118-119, 120; 121-123, 124-125, 126; 127-129, 130-131, 132; 133-135, 136-137, 138; 139-141, 142-143, 144; 145-147, 148-149, 150; 151-153, 154-155, 156; 157-159, 160-161, 162; 163-165, 166-167, 168; 169-171, 172-173, 174; 175-177, 178-179, 180; 181-183, 184-185, 186; 187-189, 190-191, 192; 382-384, 385-386, 387; 388-390, 391-392, 393; 394-396, 397-398, 399; 400-402, 403-404, 405; 406-408, 409-410, 411; 412-414, 415-416, 417; 418-420, 421-422, 423; 424-426, 427-428, 429; 430-432, 433-434, 435; 436-438, 439-440, 441; 442-444, 445-446, 447; 448-450, 451-452, 453; 454-456, 457-458, 459; 460-462, 463-464, 465; 466-468, 469-470, 471; 472-474, 475-476, 477; 478-480, 481-482, 483; 484-486, 487-488, 489; 490-492, 493-494, 495; 496-498, 499-500, 501; 502-504, 505-506, 507 or 508-510, 511-512, 513; and a light chain variable domain containing, respectively, the amino acid sequences CDRL1, CDRL2 and CDRL3 selected from one of SEQ ID NOs: 193, 194, 195; 196, 197, 198; 199, 200, 201; 202, 203, 204; 205, 206, 207; 208, 209, 210; 211, 212, 213; 214, 215, 216; 217, 218, 219; 220, 221, 222; 223, 224, 225; 226, 227, 228; 229, 230, 231; 232, 233, 234; 235, 236, 237; 238, 239, 240; 241, 242, 243; 244, 245, 246; 247, 248, 249; 250, 251, 252; 253, 254, 255; 256, 257, 258; 259, 260, 261; 262, 263, 264; 514, 515, 516; 517, 518, 519; 520, 521, 522; 523, 524, 525; 526, 527, 528; 529, 530, 531; 532, 533, 534; 535, 536, 537; 538, 539, 540; 541, 542, 543; 544, 545, 546; 547, 548, 549; 550, 551, 552; 553, 554, 555; 556, 557, 558; 559, 560, 561; 562, 563, 564; 565, 566, 567; 568, 569, 570; 571, 572, 573; 574, 575, 576 and 577, 578, 579.

In some embodiments, the antigen-binding molecule comprises the amino acid sequences CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, respectively, selected from one of SEQ ID NOs 49-51, 52-53, 54, 193, 194, 195; 55-57, 58-59, 60, 196, 197, 198; 61-63, 64-65, 66, 199, 200, 201; 67-69, 70-71, 72, 202, 203, 204; 73-75, 76-77, 78, 205, 206, 207; 79-81, 82-83, 84, 208, 209, 210; 85-87, 88-89, 90, 211, 212, 213; 91-93, 94-95, 96, 214, 215, 216; 97-99, 100-101, 102, 217, 218, 219; 103-105, 106-107, 108, 220, 221, 222; 109-111, 112-113, 114, 223, 224, 225; 115-117, 118-119, 120, 226, 227, 228; 121-123, 124-125, 126, 229, 230, 231; 127-129, 130-131, 132, 232, 233, 234; 133-135, 136-137, 138, 235, 236, 237; 139-141, 142-143, 144, 238, 239, 240; 145-147, 148-149, 150, 241, 242, 243; 151-153, 154-155, 156, 244, 245, 246; 157-159, 160-161, 162, 247, 248, 249; 163-165, 166-167, 168, 250, 251, 252; 169-171, 172-173, 174, 253, 254, 255; 175-177, 178-179, 180, 256, 257, 258; 181-183, 184-185, 186, 259, 260, 261; 187-189, 190-191, 192, 262, 263, 264; 382-384, 385-386, 387, 514, 515, 516; 388-390, 391-392, 393, 517, 518, 519; 394-396, 397-398, 399, 520, 521, 522; 400-402, 403-404, 405, 523, 524, 525; 406-408, 409-410, 411, 526, 527, 528; 412-414, 415-416, 417, 529, 530, 531; 418-420, 421-422, 423, 532, 533, 534; 424-426, 427-428, 429, 535, 536, 537; 430-432, 433-434, 435, 538, 539, 540; 436-438, 439-440, 441, 541, 542, 543; 442-444, 445-446, 447, 544, 545, 546; 448-450, 451-452, 453, 547, 548, 549; 454-456, 457-458, 459, 550, 551, 552; 460-462, 463-464, 465, 553, 554, 555; 466-468, 469-470, 471, 556, 557, 558; 472-474, 475-476, 477, 559, 560, 561; 478-480, 481-482, 483, 562, 563, 564; 484-486, 487-488, 489, 565, 566, 567; 490-492, 493-494, 495, 568, 569, 570; 496-498, 499-500, 501, 571, 572, 573; 502-504, 505-506, 507, 574, 575, 576 and 508-510, 511-512, 513, 577, 578, 579.

In some embodiments, the antigen-binding molecule comprises a light chain variable domain comprising the amino acid sequences CDRH1, CDRH2, and CDRH3, respectively, selected from one of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378 and 380; and a heavy chain variable domain comprising the amino acid sequences CDRL1, CDRL2, and CDRL3, respectively, selected from one of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379 and 381.

In some embodiments, the antigen-binding molecule comprises the amino acid sequences of the light chain variable domain and the heavy chain variable domain, respectively, selected from one of SEQ ID NOs: 1 and 2; 3 and 4; 5 and 6; 7 and 8; 9 and 10; 11 and 12; 13 and 14; 15 and 16; 17 and 18; 19 and 20; 21 and 22; 23 and 24; 25 and 26; 27 and 28; 29 and 30; 31 and 32; 33 and 34; 35 and 36; 37 and 38; 39 and 40; 41 and 42; 43 and 44; 45 and 46; 47 and 48; 338 and 339; 340 and 341; 342 and 343; 344 and 345; 346 and 347; 348 and 349; 350 and 351; 352 and 353; 354 and 355; 356 and 357; 358 and 359; 360 and 361; 362 and 363; 364 and 365; 366 and 367; 368 and 369; 370 and 371; 372 and 373; 374 and 375; 376 and 377; 378 and 379 and 380 and 381.

In another aspect of the present invention, antibodies are provided that specifically bind to the 70 cassette of differentiation (CD70).

In some embodiments, the antibody comprises a VH region shown under SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36 , 38, 40, 42, 44, 46, 48, 339, 341, 343, 345, 347, 349, 351, 353, 355, 662, 357, 359, 361, 363, 365, 367, 369, 371, 373 , 375, 377, 379 or 381; and/or the VL region shown under SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 338, 340, 342, 344, 346, 348, 350, 352, 354, 661, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378 or 380.

In some embodiments, the antibody comprises a heavy chain variable region (VH) comprising (i) a VH CDR1 comprising the sequence shown under SEQ ID NOs: 49, 50, 51, 55, 56, 57, 61, 62, 63, 67, 68, 69, 73, 74, 75, 79, 80, 81, 85, 86, 87, 91, 92, 93, 97, 98, 99, 103, 104, 105, 109, 110, 111, 115, 116, 117, 121, 122, 123, 127, 128, 129, 133, 134, 135, 139, 140, 141, 145, 146, 147, 151, 152, 153, 157, 158, 159, 163, 164, 1 65 169 170 171 175 176 177 181 182 183 187 188 189 382 383 384 388 389 390 394 395 396 400 401 402 4 06, 407, 408, 412, 413, 414, 418, 419, 420, 424, 425, 426, 430, 431, 432, 663, 664, 665, 436, 437, 438, 442, 443, 444, 448, 4 49, 450, 454, 455, 456, 460, 461, 462, 466, 467, 468, 472, 473, 474, 478, 479, 480, 484, 485, 486, 490, 491, 492, 496, 497, 4 98, 502, 503, 504, 508, 509 or 510; (ii) a VH CDR2 containing the sequence shown under SEQ ID NOs: 52, 53, 58, 59, 64, 65, 70, 71, 76, 77, 82, 83, 88, 89, 94, 95, 100, 101 , 106 107 112 113 118 119 124 125 130 131 136 137 142 143 148 149 154 155 160 161 166 167 172 173 178 , 179, 184, 185, 190, 191, 385, 386, 391, 392, 397, 398, 403, 404, 409, 410, 415, 416, 421, 422, 427, 428, 433, 434, 666, 667 , 439, 440, 445, 446, 451, 452, 457, 458, 463, 464, 469, 470, 475, 476, 481, 482, 487, 488, 493, 494, 499, 500, 505, 506, 511 or 512; and iii) a VH CDR3 containing the sequence shown under SEQ ID NOs: 54, 60, 66, 72, 78, 84, 90, 96, 102, 108, 114, 120, 126, 132, 138, 144, 150, 156 , 162 168 174 180 186 192 387 393 399 405 411 417 423 429 435 668 441 447 453 459 465 471 477 483 489 , 495, 501, 507 or 513; and/or a light chain variable region (VL) comprising (i) a VL CDR1 comprising the sequence shown under SEQ ID NOs: 193, 196, 199, 202, 205, 208, 211, 214, 217, 220, 223, 226 , 229, 232, 235, 238, 241, 244, 247, 250, 253, 256, 259, 262, 514, 517, 520, 523, 526, 529, 532, 535, 538, 669, 541, 544, 547 , 550, 553, 556, 559, 562, 565, 568, 571, 574 or 577; (ii) a VL CDR2 containing the sequence shown under SEQ ID NOs: 194, 197, 200, 203, 206, 209, 212, 215, 218, 221, 224, 227, 230, 233, 236, 239, 242, 245 , 248, 251, 254, 257, 260, 263, 515, 518, 521, 524, 527, 530, 533, 536, 539, 670, 542, 545, 548, 551, 554, 557, 560, 563, 566 , 569, 572, 575 or 578; and (iii) a VL CDR3 containing the sequence shown under SEQ ID NOs: 195, 198, 201, 204, 207, 210, 213, 216, 219, 222, 225, 228, 231, 234, 237, 240, 243, 246 249 252 255 258 261 264 516 519 522 525 528 531 534 537 540 671 543 546 549 552 555 558 561 5 64, 567, 570, 573, 576 or 579.

In some embodiments, the antibody comprises a VH region comprising VH CDR1, VH CDR2, and VH CDR3 from the VH sequence shown under SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 339, 341, 343, 345, 347, 349, 351, 353, 355, 662, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379 or 381; and/or a VL region comprising VL CDR1, VL CDR2 and VL CDR3 from the VL sequence shown under SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 , 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 338, 340, 342, 344, 346, 348, 350, 352, 354, 661, 356, 358, 360, 362 , 364, 366, 368, 370, 372, 374, 376, 378 or 380.

In additional aspects of the present invention, nucleic acids, vectors, host cells, pharmaceutical compositions, methods of making, and a method of treating conditions with the disclosed antibodies are provided.

BRIEF DESCRIPTION OF GRAPHICS

In FIG. 1 is a graph showing tumor volumes in mice treated with 4F11 CAR T cells at various doses in a subcutaneous xenograft model.

In FIG. 2 is a graph showing the body weights of mice treated with 4F11 CAR T cells at different doses in a subcutaneous xenograft model.

In FIG. 3 is a graph showing tumor volumes in mice treated with 4F11 and P08F08 CAR-T cells with or without CD70 KO in a subcutaneous xenograft model.

In FIG. 4 is a graph showing body weight scores in mice treated with 4F11 and P08F08 CAR-T cells with or without CD70 KO in a subcutaneous xenograft model.

In FIG. 5A-5C are a series of graphs showing tumor cell flux in mice treated with control cells, cells expressing 4F11 CAR with or without KO on CD70 and with or without KO on TCRa, and mice treated with cells expressing P08F08 CAR. , with or without KO on CD70 and with or without KO on TCRa, in 3 donors in an ACHN model with lung metastases.

In FIG. 5A shows the results obtained using control cells, cells expressing 4F11 CAR with CD70, TCRa or both KO to CD70 and KO to TCR, and cells expressing P08F08 CAR with KO to TCR; while the cells were obtained from a donor D419.

In FIG. 5B shows the results obtained using control cells, cells expressing 4F11 CAR with or without KO on CD70, and cells expressing P08F08 CAR; while the cells were obtained from a donor D710.

In FIG. 5C shows the results obtained using control cells, cells expressing the 4F11 CAR with or without KO on CD70, and cells expressing the P08F08 CAR; while the cells were obtained from a donor D503.

In FIG. 6A-6F show five exemplary non-limiting CAR-based designs. On each of the FIGS. 6A-6F, the approximate distance from the antigen-binding fragment of the CD70-specific domain to the cell membrane is indicated by the double arrowhead indicated by the number of amino acid residues (aa) between the scFv and the transmembrane domain.

In FIG. 6A shows a second generation CAR construct including an extracellular domain containing CD70-specific scFv, a hinge region, a transmembrane domain, a first intracellular domain (4-1BB domain), and a second intracellular domain (CD3ζ signaling domain).

In FIG. 6B shows the SR2 CAR format in which a "suicide" switch is created by inserting two RTX epitopes (i.e. CD20 epitopes) between the hinge and scFv.

In FIG. 6C shows the RSRQR CAR format with the addition of a third RTX epitope and a CD34 epitope.

In FIG. 6D shows an RSR format in which two RTX epitopes flank scFv.

In FIG. 6E shows a modification of the RSR CAR format in which the hinge domain is truncated (referred to as RSR-short).

In FIG. 6F shows the R2S CAR format in which two RTX epitopes of the R2 CAR format are moved to the N-terminus of the scFv.

In FIG. 7 shows target cell viability after exposure to CD70-specific CARs in four formats or non-transduced (NTD) control cells.

In FIG. 8A-8D are a series of graphs showing the killing of 786-0, ACHN, or REH cells using CD70-specific CAR T cells, where the extracellular domain of the CAR contains the scFvs indicated in the explanations in FIG. 8D.

In FIG. 8A shows the killing of 786-0 cells, where the CAR extracellular domain contains the scFvs indicated in the explanations in FIG. 8D.

In FIG. 8B shows the killing of ACHN cells where the CAR extracellular domain contains the scFvs indicated in the explanations in FIG. 8D.

In FIG. 8C shows killing of REH cells where the CAR extracellular domain contains the scFvs indicated in the explanations in FIG. 8D.

In FIG. 9A-9D are a series of graphs showing sequential killing of 786-0, ACHN, or REH cells using CD70-specific CAR T cells, where the extracellular domain of the CAR contains the scFvs indicated in the explanations in FIG. 9D.

In FIG. 9A is a graph showing the effectiveness of CD70-specific CARs on repeated exposure to luciferase-labeled 786-O target cells (every 2-3 days, CAR-T cells were transferred to a 96-well plate containing fresh targets). The E:T ratio was 3:1. CAR was expressed in cells from donor D503.

In FIG. 9B is a graph showing the efficacy of CD70-specific CARs on repeated exposure to luciferase-labeled ACHN target cells (every 2-3 days, CAR-T cells were transferred to a 96-well plate containing fresh targets). The E:T ratio was 10:1. CAR was expressed in cells from donor D503.

In FIG. 9C is a graph showing the efficacy of CD70-specific CARs on repeated exposure to luciferase-labeled REH target cells (2 x 10 ⁶ cells added at the indicated time points). The E:T ratio was 1:5. CAR was expressed in cells from donor D503.

In FIG. 10 is a series of graphs showing the efficacy of CD70 specific CARs in R2S, SR2 or RSRQR format upon repeated exposure to luciferase labeled REH target cells (2x10 ⁶ cells added at the indicated time points). The E:T ratio was 1:5. CAR was expressed in cells from donor D772.

In FIG. 11 is a graph showing tumor cell flux values in mice treated with control cells or cells expressing various scFv CARs in an ACHN model with lung metastases.

In FIG. 12A-12C are a series of graphs showing the quantification of CD70 expression in the context of anti-CD70 antibody (ABC) binding capacity on various cell lines studied or cell lines and cells derived from RCC patients. Also shown are data from cells obtained from patients with RCC.

In FIG. 12A shows the quantification of CD70 expression in the context of anti-CD70 antibody (ABC) binding capacity on various cell lines tested.

In FIG. 12B shows the quantification of CD70 expression in the context of anti-CD70 antibody (ABC) binding capacity on cells derived from RCC patients.

In FIG. 12C shows data from cells obtained from RCC patients.

In FIG. 13A-13C are a series of graphs showing target cell kill from RCC patient WD-59279, patient-derived cell lines, or ACHN, with antibody binding capacity indicated in each panel.

In FIG. 13A-B show target cell killing from RCC patients and antibody binding capacity.

In FIG. 13C shows ACHN target cell killing and antibody binding capacity.

In FIG. 14A-14B are a series of histograms showing CD70 receptor quantification and heme tumor cell killing by 4F11 CAR in QR3 format at 1:1 E:T for additional cell lines expressing CD70 at various levels.

In FIG. 14A is a bar graph showing CAR 4F11 CD70 receptor count quantification in QR3 format at 1:1 E:T for additional cell lines expressing CD70 at various levels.

In FIG. 14B is a bar graph showing CAR 4F11 kill heme tumor cells in QR3 format at 1:1 E:T for additional cell lines expressing CD70 at various levels.

In FIG. 15A-15B are a series of graphs showing tumor volume and body weight scores in mice treated with 4F11 and P08F08-CAR-T cells at a dose of 10 x 10 ⁶ cells or 5 x 10 ⁶ cells in a subcutaneous xenograft model.

In FIG. 15A is a graph showing tumor volume scores in mice treated with 4F11 and P08F08-CAR-T cells at 10 x 10 ⁶ cells or 5 x 10 ⁶ cells in a subcutaneous xenograft model.

In FIG. 15B is a graph showing the body weights of mice treated with 4F11 and P08F08-CAR-T cells at 10 x 10 ⁶ cells or 5 x 10 ⁶ cells in a subcutaneous xenograft model.

DETAILED DESCRIPTION

In the description disclosed in this document, chimeric antigen receptors (CARs) and immune cells containing CARs (for example, CAR-T cells) that specifically bind to CD70 (for example, human CD70). The description also provides polynucleotides encoding such CARs, compositions containing these CAR-T cells, as well as methods for obtaining and using these CARs and CAR-T cells. The specification also provides methods for treating a condition associated with CD70-expressing cancer cells, such as cancer, in a subject.

General Methods

The compositions and methods of the present invention, unless otherwise indicated, will use conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are within the skill of the art. Such techniques are fully explained in literature such as Molecular Cloning: A Laboratory Manual, second edition (Sambrook et al., 1989) Cold Spring Harbor Press; Oligonucleotide Synthesis (M. J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R.I. Freshney, ed., 1987); Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J. B. Griffiths, and D. G. Newell, eds., 1993-1998) J. Wiley and Sons; Methods in Enzymology (Academic Press, Inc.); Handbook of Experimental Immunology (D.M. Weir and C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987); Current Protocols in Molecular Biology (F.M. Ausubel et al., eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (J.E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C.A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: a practical approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal antibodies: a practical approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using antibodies: a laboratory manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J.D. Capra, eds., Harwood Academic Publishers, 1995).

Definitions

As used herein, the term "extracellular ligand-binding domain" refers to an oligo- or polypeptide that is capable of binding a ligand. In some exemplary embodiments, the domain will be capable of interacting with a cell surface molecule. For example, an extracellular ligand binding domain may be selected to recognize a ligand that acts as a cell surface marker on target cells associated with a particular pathological condition.

The term "stem domain" or "hinge domain" is used interchangeably herein to refer to any oligo or polypeptide that functions to link a transmembrane domain to an extracellular ligand binding domain in a CAR. In particular, stem domains are used to make the extracellular ligand-binding domain more flexible and accessible.

The term "intracellular signaling domain" refers to the portion of a protein that transduces an effector signaling function signal and directs the cell to perform a specialized function.

The term "costimulatory molecule" in the context of the present invention refers to a related binding partner on an immune cell, for example, A T cell that specifically binds to a costimulatory ligand, thereby mediating a costimulatory response of the cell, such as, but not limited to, proliferation. Costimulatory molecules include, but are not limited to, the MHC class I molecule, BTLA, and the Toll ligand receptor. Examples of co-stimulatory molecules include CD27, CD28, CD8, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C , B7-H3 and a ligand that specifically binds to CD83, etc.

"Costimulatory ligand" refers to a molecule on an antigen presenting cell that specifically binds a cognate costimulatory signal molecule on an immune cell, e.g., T cell, thereby providing a signal that, in addition to the primary signal, is provided, for example, by binding of the TCR/CD3 complex to the peptide-loaded MHC molecule, mediates the T cell response, including, without limitation, activation of proliferation, differentiation, and etc. The co-stimulatory ligand may include, without limitation, CD7, B7-1 (CD80), B7-2 (CD86), PD-L1, PD-L2, 4-1BBL, OX40L, inducible co-stimulatory ligand (ICOS-L), molecule intercellular adhesion (ICAM, CD30L, CD40, CD70, CD83, HLA-G, MICA, M1CB, HVEM, β-lymphotoxin receptor, 3/TR6, ILT3, ILT4, an agonist or antibody that binds a Toll-like receptor ligand, and a ligand which specifically binds to B7-H3 A costimulatory ligand also encompasses, among other things, an antibody that specifically binds to a costimulatory molecule present on a T cell, e.g., without limitation CD27, CD28, 4-1BB, OX40, CD30, CD40, PD- 1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LTGHT, NKG2C, B7-H3, a ligand that specifically binds to CD83.

An "antibody" is an immunoglobulin molecule capable of specifically binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., via at least one antigen recognition site located in the variable region of the immunoglobulin molecule. As used herein, the term encompasses not only intact polyclonal or monoclonal antibodies, but also fragments (such as Fab, Fab', F(ab') ₂ , Fv), single chain (scFv), and domain antibodies (including, for example, shark and camelid antibodies), and fusion proteins containing the antibody and any other modified configuration of an immunoglobulin molecule that contains an antigen recognition site. An antibody includes an antibody of any class, such as IgG, IgA, IgE, IgD, or IgM (or a subclass thereof), and the antibody need not be of any particular class. Depending on the amino acid sequence of the antibody constant region of its heavy chains, immunoglobulins can belong to different classes. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, some of which can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. The heavy chain constant regions that correspond to the different classes of immunoglobulins are respectively called alpha, delta, epsilon, gamma, and mu. The subunit structures and three-dimensional configurations of various classes of immunoglobulins are well known.

The terms "antigen-binding fragment" or "antigen-binding portion" of an antibody, as used herein, refers to one or more fragments of an intact antibody that retain the ability to specifically bind to a specified antigen (eg, CD70). The antigen-binding functions of an antibody can be performed by fragments of an intact antibody. Examples of binding fragments encompassed by the term "antigen-binding antibody fragment" include Fab; Fab';F(ab')₂; Fd fragment consisting of VH and CH1 domains; An Fv fragment consisting of the VL and VH domains of one antibody arm, a single domain (dAb) fragment (Ward et al., Nature 341:544-546, 1989) and a complementarity determining region (CDR).

An antibody, antigen-binding fragment, antibody-based conjugate, or polypeptide that "preferentially binds" or "specifically binds" (used interchangeably herein) to a target (e.g., CD70 protein) is a term well known in the art, and methods for determining such specific or preferred binding are also well known in the art. A molecule is said to exhibit "specific binding" or "predominant binding" if it reacts or binds more frequently, faster, for longer duration, and/or with greater affinity to a particular cell or substance than to alternative cells or substances. An antibody "specifically binds" or "predominantly binds" to a target if it binds with greater affinity, avidity, more easily and/or for a longer duration than it binds to other substances. For example, an antibody that specifically or preferentially binds to a CD70 epitope is one that binds to that epitope with greater affinity, avidity, more readily, and/or for longer duration than it binds to other CD70 epitopes or non-CD70 epitopes. . Also, in reading this definition, it should be understood that, for example, an antibody (or particle, or epitope) that specifically or preferentially binds to a first target may or may not bind specifically or preferentially to a second target. Thus, "specific binding" or "preferred binding" does not necessarily require (although it may include) exclusive binding. In general, but not necessarily, a link reference means a preferential link.

The "variable region" of an antibody refers to the variable region of an antibody light chain or the variable region of an antibody heavy chain, either alone or in combination. As is known in the art, each heavy and light chain variable region consists of four framework regions (FRs) connected by three complementarity determining regions (CDRs), also known as hypervariable regions. The CDRs in each strand are held together in close proximity by FRs and CDRs from the other strand, participating in the formation of the antigen-binding site of antibodies. There are at least two methods for determining CDRs: (1) the interspecies sequence variability approach (i.e. Kabat et al. Sequences of Proteins of Immunological Interest, (5th ed., 1991, National Institutes of Health, Bethesda Md. )); and (2) an approach based on crystallographic studies of antigen-antibody complexes (Al-lazikani et al. (1997) J. Molec. Biol. 273:927-948). As used herein, the CDR may refer to those CDRs that are determined either by any of the approaches, or by a combination of both approaches.

Variable domain “CDRs” are amino acid residues within a variable region that are identified according to the summation of definitions according to Kabat, Chothia, the summation of both Kabat and Chothia definitions, AbM, contact and/or conformational definitions, or according to any CDR determination technique well known in the art. Antibody CDRs can be identified as hypervariable regions, originally defined by Kabat et al. See, for example, Kabat et al., 1992, Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, NIH, Washington D.C. CDR positions can also be identified as structural loop structures, originally described by Chothia et al. See, for example, Chothia et al., Nature 342:877-883, 1989. Other approaches to CDR identification include "AbM definition", which is the optimal combination of Kabat and Chothia and generated using Oxford Molecular's AbM antibody modeling software (currently Accelrys®), or "contact determination" of CDRs based on observed contacts with antigens, as set forth in MacCallum et al., J. Mol. Biol., 262:732-745, 1996. In another approach, referred to herein as "determining the conformational position" of CDRs, CDR positions can be identified as residues that make enthalpy contributions to antigen binding. See, for example, Makabe et al., Journal of Biological Chemistry, 283:1156-1166, 2008. However, other definitions of CDR boundaries may not strictly follow one of the above approaches, but will nonetheless overlap with at least part of the CDR according to Kabat, although they may be shortened or lengthened in light of prediction or experimental evidence that particular residues or groups of residues, or even entire CDRs, do not significantly affect antigen binding. As used herein, the CDR may refer to those CDRs that are determined by any approach known in the art, including combinations of approaches. The methods used herein may use CDRs defined in accordance with any of these approaches. For any given embodiment providing for more than one CDR, the CDR may be defined according to any of the Kabat, Chothia, extended, AbM, contact, and/or conformational definitions.

As used herein, the term "monoclonal antibody" refers to an antibody derived from a population of substantially homogeneous antibodies, i.e. the individual antibodies that make up a population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, directed against a single antigenic site. In addition, unlike polyclonal antibody preparations, which typically contain different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed to a single determinant on the antigen. The term "monoclonal" indicates the nature of the antibody as being derived from a substantially homogeneous population of antibodies, and should not be construed as requiring the production of the antibody by any particular method. For example, monoclonal antibodies to be used in accordance with the present invention can be obtained using the hybridoma method first described by Kohler, Nature 256:495, 1975, or can be obtained using recombinant DNA methods such as those described in US patent No. 4816567. Monoclonal antibodies can also be isolated from phage libraries generated using the techniques described in, for example, McCafferty et al., Nature 348:552-554, 1990.

As used herein, the term "humanized" antibody refers to forms of antibodies other than human (e.g., murine), which are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab’, F(ab’)₂ or other antigen-binding antibody subsequences) that contain a minimal sequence derived from a non-human immunoglobulin. In some exemplary embodiments, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from the complementarity determining region (CDR) of the recipient are replaced with residues from a CDR of a non-human species (donor antibody), such as a mouse, rat, or rabbit , characterized by the required specificity, affinity and activity. In some instances, Fv framework region (FR) residues of a human immunoglobulin are replaced by corresponding non-human residues. In addition, the humanized antibody may contain residues that are not found in either the recipient antibody or the introduced CDR sequences or framework regions, but are included to further refine and optimize antibody performance. In general, a humanized antibody will contain substantially all of at least one, and typically two, variable domains in which all or substantially all of the CDR regions correspond to those found in a non-human immunoglobulin and all or substantially all of the FR regions. are those in the human immunoglobulin consensus sequence. An optimally humanized antibody will also contain at least a portion of an immunoglobulin (Fc) constant region or domain, typically a human immunoglobulin. Illustrative embodiments are antibodies having Fc regions modified as described in WO 99/58572. Other forms of humanized antibodies contain one or more CDRs (CDR L1, CDR L2, CDR L3, CDR H1, CDR H2, or CDR H3) that are altered from the parent antibody, which also designate one or more CDRs "derived from" one or more CDRs from the parent antibody.

As used herein, the term "human antibody" means an antibody having an amino acid sequence corresponding to that of a human-produced antibody and/or that has been generated using any of the human antibody production techniques known to those skilled in the art and disclosed herein. This definition of a human antibody includes antibodies comprising at least one human heavy chain polypeptide or at least one human light chain polypeptide. One such example is an antibody containing mouse light chain and human heavy chain polypeptides. Human antibodies can be obtained using various techniques known in the art. In some embodiments, the human antibody is selected from a phage library where human antibodies are expressed in the phage library (Vaughan et al., Nature Biotechnology, 14:309-314, 1996; Sheets et al., Proc. Natl. Acad. Sci. (USA ) 95:6157-6162, 1998; Hoogenboom and Winter, J. Mol. Biol., 227:381, 1991; Marks et al., J. Mol. Biol., 222:581, 1991). Human antibodies can also be obtained by immunizing animals that have been transgenically introduced with human immunoglobulin loci instead of endogenous loci, for example, mice in which endogenous immunoglobulin genes were partially or completely destroyed or inactivated. This approach is described in US Pat. Nos. 5,545,807; 5545806; 5569825; 5625126; 5,633,425 and 5,661,016. Alternatively, a human antibody can be obtained by immortalizing human B-lymphocytes that produce an antibody directed against the target antigen (such B-lymphocytes can be isolated from a subject or can be immunizedin vitro).See, for example, Cole et al. Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77, 1985; Boerner et al., J. Immunol., 147(1):86-95, 1991 and US Pat. No. 5,750,373.

The term "chimeric antibody" is intended to refer to antibodies in which the variable region sequences are derived from one species and the constant region sequences are derived from another species, such as an antibody in which the variable region sequences are derived from a mouse antibody and the constant region sequences are derived from a human antibody.

The terms "polypeptide", "oligopeptide", "peptide", and "protein" are used interchangeably herein to refer to chains of amino acids of any length - relatively short in some embodiments (e.g., 10-100 amino acids). The chain may be linear or branched, may contain modified amino acids, and/or may be interrupted by non-amino acid acids. The terms also cover an amino acid chain that has been naturally or tampered with; for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification such as conjugation with a labeling moiety. Also included in the definition are, for example, polypeptides containing one or more analogs of amino acids (including, for example, amino acids of non-natural origin, etc.), as well as other modifications known from in the art. It is understood that the polypeptides may occur as single chains or as associated chains.

A "monovalent antibody" contains one antigen-binding site per molecule (for example, IgG or Fab). In some cases, a monovalent antibody may contain more than one antigen-binding site, but binding sites from different antigens.

A "bivalent antibody" contains two antigen-binding sites per molecule (for example, IgG). In some cases, the two binding sites are characterized by the same kind of specificity for the antigen. However, bivalent antibodies can be bispecific.

Antibodies of the present invention can be obtained using techniques well known in the art, for example, recombinant technologies, phage display technologies, synthetic technologies or combinations of such technologies or other technologies well known in the art (see, for example, Jayasena, S.D., Clin. Chem., 45: 1628-50, 1999 and Fellouse, F.A., et al, J. MoI Biol., 373(4): 924-40, 2007).

It is known in the art that the terms "polynucleotide" or "nucleic acid", used interchangeably herein, refer to chains of nucleotides of any length and include DNA and RNA. Nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases and/or analogs thereof, or any support that can be inserted into the chain by DNA or RNA polymerase. The polynucleotide may contain modified nucleotides such as methylated nucleotides and their analogs. Modification of the nucleotide structure, if any, can be given before or after chain assembly. The nucleotide sequence may be interrupted by non-nucleotide components. The polynucleotide can be further modified after polymerization, for example by conjugation with a labeling moiety. Other types of modifications include, for example, "caps", the replacement of one or more naturally occurring nucleotides with an analog, internucleotide modifications, such as, for example, modifications with uncharged bonds (for example, methylphosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and with charged bonds (for example, phosphorothioates, phosphorodithioates, etc.) containing side fragments, such as, for example, proteins (for example, nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), with intercalators (for example, acridine, psoralen, etc.), with chelators (for example, metals, radioactive metals, boron, oxidizing metals, etc.), with alkylators, with modified bonds (for example, alpha-anomeric nucleic acids, etc.), as well as unmodified forms of the polynucleotide(s). In addition, any of the hydroxyl groups normally present in sugars may be substituted, for example, with phosphonate groups, phosphate groups, protected with standard protecting groups, or activated to form additional bonds to additional nucleotides, or may be conjugated to solid supports. The 5'- and 3'-terminal OH can be phosphorylated or substituted with amines or organic fragments of capping groups with 1-20 carbon atoms. Other hydroxyls can also be obtained in standard protecting groups. Polynucleotides may also contain similar forms of ribose or deoxyribose sugars generally known in the art, including, for example, 2'-O-methyl-, 2'-O-allyl, 2'-fluoro- or 2'- azidoribose, carbocyclic sugar analogs, alpha or beta anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs, and nitrogenous base removed nucleoside analogs such as methyl riboside. One or more phosphodiester bonds may be replaced by alternating linking groups. These alternative linking groups include, without limitation, those in which the phosphate is replaced by P(O)S ("thioatom"), P(S)S ("dithioatom"), (O)NR₂ ("amidate"), P(O)R, P(O)OR', CO or CH₂ ("formacetal"), in which each R or R' is independently H or substituted or unsubstituted alkyl (C1-20), optionally containing an ether (-O-) bond, aryl, alkenyl, cycloalkyl, cycloalkenyl, or araldyl. Not all bonds in a polynucleotide need to be identical. The previous description applies to all polynucleotides in this document, including RNA and DNA.

It is known in the art that the "constant region" of an antibody refers to an antibody light chain constant region or an antibody heavy chain constant region alone or in combination.

As used herein, the term "substantially pure" refers to material that is at least 50% pure (i.e., free of contaminants), at least 90% pure, at least 95% pure, at least 98% pure, and at least 99% pure.

A "host cell" includes a single cell or cell culture that can be or are the recipient of the vector(s) for incorporating polynucleotide inserts. Host cells include the progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or complementary genomic DNA) in the original parent cell due to natural, accidental or intentional mutation. The host cell includes cells transfected in vivo with the polynucleotide(s) of the present invention.

Used in this document, the term "immune cell" refers to a cell of hematopoietic origin, functionally involved in the initiation and/or functioning of the innate and/or adaptive immune response.

It is known in the art that the term "Fc region" is used to define the C-terminal region of an immunoglobulin heavy chain. An "Fc region" may be a sequence with a native Fc region or a variant Fc region. Although the boundaries of the Fc region of an immunoglobulin heavy chain may vary, the Fc region of a human IgG heavy chain is generally defined as a fragment of an amino acid residue at position Cys226 or from Pro230 to its carboxyl terminus. The numbering of residues in the Fc region corresponds to that according to the EU index, as in Kabat. Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991. The Fc region of an immunoglobulin typically contains two constant regions, CH2 and CH3.

As used in the art, the terms "Fc receptor" and "FcR" describe a receptor that binds to the Fc region of an antibody. In some embodiments, the FcR is a native sequence human FcR. Moreover, in some embodiments, the FcR is one that binds an IgG antibody (gamma receptor) and includes receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. FcγRII receptors include FcγRIIA ("activating receptor") and FcγRIIB ("inhibitory receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. FcRs are discussed in Ravetch and Kinet, Ann. Rev. Immunol. 9:457-92, 1991; Capel et al., Immunomethods, 4:25-34, 1994; and de Haas et al., J. Lab. Clin. Med., 126:330-41, 1995. "FcR" also includes the neonatal FcRn receptor, which is responsible for the transfer of maternal immunoglobulins to the fetus (Guyer et al., J. Immunol., 117:587, 1976; and Kim et al., J. Immunol., 24:249, 1994).

The term "competition" as used herein in relation to an antibody means that the first antibody, or an antigen-binding fragment (or portion) thereof, binds to an epitope in a manner substantially similar to the binding of a second antibody, or antigen-binding portion thereof, whereby the result of binding of the first an antibody with its cognate epitope is markedly reduced in the presence of the second antibody compared to the binding of the first antibody in the absence of the second antibody. There may be an alternative where the binding of the second antibody to its epitope is also detectably reduced in the presence of the first antibody, but not necessarily. That is, the first antibody can inhibit the binding of the second antibody to its epitope without the second antibody inhibiting the binding of the first antibody to its corresponding epitope. However, in cases where each antibody detectably inhibits the binding of another antibody to its cognate epitope or ligand, or to the same, greater or lesser extent, the antibodies are considered to "cross-compete" with each other to bind their respective epitope(s). The present invention encompasses both competing and cross-competing antibodies. Regardless of the mechanism by which such competition or cross-competition occurs (for example, steric mismatch, conformational change, or binding to a common epitope or part thereof), one skilled in the art would appreciate, based on the ideas presented herein, that such competing and/or cross-competing antibodies are covered and may be applicable to the methods disclosed in this document.

Used in this document, the term "autologous" means that the cells, cell line or population of cells used to treat patients obtained from the specified patient.

Used in this document, the term "allogeneic" means that the cells or population of cells used to treat patients are not obtained from the specified patient, but from a donor.

Used in this document, the term "treatment" is an approach to obtain favorable or desired clinical results. For the purposes of the present invention, beneficial or desired clinical results include, without limitation, one or more of the following: reduction in proliferation (or killing) of neoplastic or cancer cells, suppression of neoplastic cell metastasis, reduction or reduction in size of a CD70-expressing tumor, such as renal cell carcinoma (RCC), lymphoma, leukemia, or glioma, remission of CD70-associated disease (eg, cancer), reduction of symptoms resulting from CD70-associated disease (eg, cancer), improving the quality of life of patients suffering from a disease associated with CD70 (for example, cancer), reducing the dose of other drugs needed to treat a disease associated with CD70 (for example, cancer), delaying the progression of CD70-associated disease (eg, cancer), curing a CD70-associated disease (eg, cancer) and/or prolonging the survival of patients with a CD70-associated disease (eg, cancer).

"Reducing the severity" means the reduction or improvement of one or more symptoms compared to such symptoms in the absence of the introduction of CAR, specific for CD70, or CAR-T cells specific for CD70. "Reducing the severity" also includes reducing or reducing the duration of a symptom.

As used herein, the terms "effective dose" or "effective amount" of a drug, compound, or pharmaceutical composition is an amount sufficient to achieve any one or more favorable or desired results. In the case of prophylactic use, beneficial or desired results include the elimination or reduction of the risk of occurrence, reduction in the severity or delay in the onset of the disease, including the biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes that appear during the course of the disease. In the case of therapeutic use, beneficial or desired results include clinical results, such as a reduction in the incidence or severity of one or more symptoms of various diseases or conditions associated with CD70 (such as, for example, multiple myeloma), a reduction in the dose of other drugs necessary for treating a disease, enhancing the effect of another drug, and/or slowing the progression of a CD70-associated disease in patients. An effective dose may be administered in one or more administrations. For the purposes of the present invention, an effective dose of a drug, compound or pharmaceutical composition is an amount sufficient to effect prophylactic or therapeutic treatment directly or indirectly. In a clinical context, it is understood that an effective dose of a drug, compound, or pharmaceutical composition may or may not be provided in combination with another drug, compound, or pharmaceutical composition. Thus, an "effective dose" may be considered in the context of administering one or more therapeutic agents, and one agent may be considered to be administered in an effective amount if, in combination with one or more other agents, the desired result can be achieved or achieved.

An "individual", "patient", or "subject" is a mammal - in some embodiments, a human. Mammals include, without limitation, humans, monkeys, pigs and other farm animals, sports animals, pets, primates, horses, dogs, cats, rodents, including mice, rats, guinea pigs, etc. The subject is a mammal , and these terms are used interchangeably in this document. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human primate. In some embodiments, the subject is a human or a monkey, for example, the crabeater monkey.

As used herein, the term "vector" means a construct that is capable of delivering, and in some embodiments, allowing expression of one or more of the gene(s) or sequence(s) of interest in a host cell. Examples of vectors include, without limitation, viral vectors, naked DNA or RNA expression vectors, plasmids, cosmids or phage vectors, DNA or RNA expression vectors associated with cationic condensing agents, liposomal encapsulated vectors for DNA or RNA expression, and certain eukaryotic cells, such as producer cells.

As used herein, the term "expression control sequence" means a nucleic acid sequence that directs the transcription of a nucleic acid. The expression control sequence may be a promoter, such as a constitutive or inducible promoter, or an enhancer. The expression control sequence is operably linked to the nucleic acid sequence to be transcribed.

As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any material that, in combination with an active ingredient, allows the ingredient to remain biologically active and not react with the subject's immune system. Examples include, without limitation, any conventional pharmaceutical carriers such as phosphate buffered saline, water, emulsions such as an oil/water emulsion, and various types of wetting agents. Exemplary diluents for aerosol or parenteral administration are phosphate buffered saline (PBS) or normal (0.9%) saline. Compositions containing such carriers are formulated using well known conventional methods (see, for example, Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, ed., Mack Publishing Co., Easton, PA, 1990; and Remington, The Science and Practice of Pharmacy 21st Ed. Mack Publishing, 2005).

The term "k _on ", as used herein, refers to the rate constant of binding of an antibody, or scFv, or CAR to an antigen.

The term “k _off ” as used herein refers to the dissociation rate constant of an antibody, or scFv, or CAR from an antibody/antigen complex.

The term "K _D ", as used herein, refers to the equilibrium dissociation constant of an antibody-antigen interaction, or scFv antigen, or CAR antigen.

Reference to "about" in relation to a value or parameter herein includes (and describes) embodiments that are directed per se to that value or parameter. For example, a description referring to "about X" includes a description of "X". Numeric ranges include numbers that define the range.

It is understood that whatever embodiments are described herein with the wording "comprising", other similar embodiments are also contemplated, described by the terms "consisting of" and/or "consisting in fact of".

In cases where aspects or embodiments of the invention are described in terms of the Markush group or other group of alternatives, the present invention covers not only the entire group specified as a whole, but also each member of the group individually and all possible subgroups of the main group, but also in the main group one or more group members are missing. The present invention also provides for the express exclusion of any one or more of the members of the group in the claimed invention.

Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as generally understood by those skilled in the art to which the present invention pertains. In the event of a conflict, the present description, including definitions, shall prevail. Throughout the specification and claims, the word "comprise" or variations thereof such as "comprises" or "comprising" should be understood to mean the inclusion of the specified integer or group of integers, but not the exclusion of any other integer or group of integers. . Unless otherwise required by the context, the singular terms will cover the plural forms, and the plural terms will include the singular form.

This document describes illustrative methods and materials, although methods and materials similar or equivalent to those described in this document can also be used in the practice or testing of the present invention. These materials, methods and examples are illustrative only and are not intended to be limiting.

CD70 SPECIFIC CARS AND METHODS FOR THEIR PRODUCTION

The present invention provides CARs that bind to CD70 (for example, human CD70 (for example, SEQ ID NO: 335), for example, deposited in accordance with the provisions of the Budapest Treaty and assigned registration number: P32970-1. CD70-specific CARs provided herein include single-chain CARs and multi-chain CARs. In some embodiments, CARs are characterized by the ability to redirect T cell specificity and reactivity to CD70 without being limited to MHC, using the antigen-binding properties of monoclonal antibodies. Unrestricted MHC antigen recognition endows CAR-expressing T cells with the ability to recognize antigen independently of antigen processing, thus bypassing a major tumor avoidance mechanism.

In some embodiments, the CARs provided herein comprise an extracellular ligand-binding domain (e.g., single chain variable fragment (scFv)), a transmembrane domain and an intracellular signaling domain. In some embodiments, the CARs provided herein further comprise a "hinge" or "stem" domain that can be located between an extracellular ligand-binding domain and a transmembrane domain. In some embodiments, the extracellular ligand-binding domain, the transmembrane domain, and the intracellular signaling domain are located in the same polypeptide, i.e. in one chain. This document also presents multi-chain CARs and polypeptides. In some embodiments, multichain CARs comprise: a first polypeptide containing a transmembrane domain and at least one extracellular ligand-binding domain, and a second polypeptide containing a transmembrane domain and at least one intracellular signaling domain, where the polypeptides are assembled together to form a multichain CAR. In some embodiments, CARs are induced, e.g., by a small molecule (e.g., AP1903) or protein (for example, Epo, Tpo or PD-1). In some embodiments, the CD70-specific multichain CAR is based on a high affinity receptor for IgE (FcεRI). FcεRI, expressed on mast cells and basophils, causes allergic reactions. FcεRI is a tetrameric complex consisting of one α-subunit, one β-subunit and two disulfide-linked γ-subunits. The α-subunit contains an IgE binding domain. The β- and γ-subunits contain ITAMs that mediate signal transduction. In some embodiments, the extracellular domain of the FcRα chain has been removed and replaced with an extracellular ligand-binding domain specific for CD70. In some embodiments, the CD70-specific multi-chain CAR contains an scFv that specifically binds to CD70, the CD8α hinge, and the ITAM of the FcRβ chain. In some embodiments, the CAR may or may not contain an FcRγ chain.

In some embodiments, the extracellular ligand-binding domain comprises an scFv comprising a light chain variable region (VL) and a heavy chain variable region (VH) of a monoclonal antibody specific for the target antigen (i.e., CD70) linked by a flexible linker. Single chain variable region fragments are generated by linking the light and/or heavy chain variable regions using a short binding peptide (Bird et al., Science 242:423-426, 1988). An example of a binding peptide is a GS linker having the amino acid sequence (GGGGS) ₃ (SEQ ID NO: 296) which forms a bridge of about 3.5 nm between the carboxy terminus of one variable region and the amino terminus of another variable region. Other sequence linkers have been designed and used (Bird et al., 1988, supra). Other illustrative linkers generally may include other GS linkers, which may typically include (GGGGS)x where x is 1, 2, 3, 4, 5 (SEQ ID NO: 613). In some embodiments, x is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or any integer less than about 20. In some embodiments, the linker is (GGGGS) ₄ (SEQ ID NO: 602 ). In some embodiments, the linker is GSTSGSGKPGSGEGSTKG (SEQ ID NO: 612) as described in Whitlow et al, Protein Eng. (1993) 6(8): 989-895. Typically, linkers can be short, flexible polypeptides that, in some embodiments, consist of about 20 or fewer amino acid residues. Linkers, in turn, can be modified to give them additional functions, such as the attachment of drugs or attachment to a solid support. Single chain variants can be produced either recombinantly or synthetically. For the purpose of synthetically obtaining scFv, an automatic synthesizer can be used. For recombinant scFv production, a suitable plasmid containing a polynucleotide encoding an scFv can be introduced into a suitable host cell, either eukaryotic, such as yeast, plant, insect, or mammalian cells, or prokaryotic, such as E. coli. Polynucleotides encoding the scFv of interest can be obtained using standard manipulations, such as polynucleotide ligation. The resulting scFv can be isolated using standard protein purification techniques known in the art.

In another aspect, a CAR is provided that specifically binds to CD70, wherein the CAR comprises an extracellular ligand-binding domain comprising: a VH region containing VH CDR1, VH CDR2, and VH CDR3 from the VH sequence shown under SEQ ID NOs: 2, 4, 6 , 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46 or 48; and/or a VL region comprising VL CDR1, VL CDR2 and VL CDR3 from the VL sequence shown under SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 , 27, 29, 31, 33, 35, 37, 39, 41, 43, 45 or 47. In some embodiments, the VH and VL are connected to each other using a flexible linker. In some embodiments, the flexible linker contains the amino acid sequence shown under SEQ ID NO: 296.

In some embodiments, a CAR of the present invention comprises an extracellular ligand-binding domain having any one of the light chain partial sequences listed in Table 1 and/or any one of the heavy chain partial sequences listed in Table 1. In Table 1, underlined sequences are the CDR sequences according to Kabat and in bold type according to Chothia.

Also provided herein are portions of the CDRs of the extracellular ligand-binding domains of CARs to CD70 (including CDRs according to Chothia, Kabat and CDR contact regions). The definition of CDR regions is well known to those skilled in the art. It should be understood that in some embodiments, the CDRs may be a combination of CDRs according to Kabat and Chothia (also referred to as "combined CRs" or "extended CDRs"). In some embodiments, the CDRs are CDRs according to Kabat. In other embodiments, the CDRs are CDRs according to Chothia. In other words, in embodiments with more than one CDR, the CDRs can be any of Kabat, Chothia, combined CDRs, or combinations thereof. Tables 2A - 2B provide examples of the CDR sequences presented in this document.

Table 2A

heavy chain mAb CDRH1 CDRH2 CDRH3 31H1 SYGFS (SEQ ID NO: 49) (Kabat);
GGTFSSY (SEQ ID NO: 50) (Chothia);
GGTFSSYGFS (SEQ ID NO: 51) (extended) GIIPIFGSANYAQKFQG (SEQ ID NO: 52) (Kabat);
IPIFGS (SEQ ID NO: 53) (Chothia) GGSSSPFAY (SEQ ID NO: 54) 63B2 SYGFS (SEQ ID NO: 55) (Kabat);
GGTFSSY (SEQ ID NO: 56) (Chothia)
GGTFSSYGFS (extended) (SEQ ID NO: 57) GIIPIFGTANYAQKFQG (SEQ ID NO: 58) (Kabat);
IPIFGT (SEQ ID NO: 59) (Chothia) GGSSSPFAY (SEQ ID NO: 60) 40E3 SYYWN (SEQ ID NO: 61) (Kabat);
GGSISSY (SEQ ID NO: 62) (Chothia);
GGSISSYYWN (SEQ ID NO: 63) (extended) YIYYSGSTNYNPSLKS (SEQ ID NO: 64) (Kabat);
YYSGS (SEQ ID NO: 65) (Chothia) DIRTW (SEQ ID NO: 66) 42C3 NSWMS (SEQ ID NO: 67) (Kabat);
GFTFRNS (SEQ ID NO: 68) (Chothia);
GFTFRNSWMS (SEQ ID NO: 69) (extended) NIKRDGSEKYYVDSVKG (SEQ ID NO: 70) (Kabat);
KRDGSE (SEQ ID NO: 71) (Chothia) DQTGSFDY (SEQ ID NO: 72) 45F11 VYYWS (SEQ ID NO: 73) (Kabat;
DDSISVY (SEQ ID NO: 74) (Chothia);
DDSISVYYWS (SEQ ID NO: 75) (extended) VYSSGNINYNPSLES (SEQ ID NO: 76) (Kabat);
YSSGN (SEQ ID NO: 77) (Chothia) GLDAFDI (SEQ ID NO: 78) 64F9 SYAMS (SEQ ID NO: 79) (Kabat);
GFTFTSY (SEQ ID NO: 80) (Chothia);
GFTFTSYAMS (SEQ ID NO: 81) (extended) RVYSSGNINYNPSLES (SEQ ID NO: 82) (Kabat);
YSSGN (SEQ ID NO: 83) (Chothia) GLDAFDI (SEQ ID NO: 84) 72C2 TYAIS (SEQ ID NO: 85) (Kabat);
GGTFITY (SEQ ID NO: 86) (Chothia);
GGTFITYAIS (SEQ ID NO: 87) (extended) GIIPFFGTANYAQKFQG (SEQ ID NO: 88) (Kabat);
IPFFGT (SEQ ID NO: 89) (Chothia) WELFFFDF (SEQ ID NO: 90) 2F10 YYSMN (SEQ ID NO: 91) (Kabat);
GFTFTYY (SEQ ID NO: 92) (Chothia);
GFTFTYYSMN (SEQ ID NO: 93) (extended) HISIRSSTIYFADSAKG (SEQ ID NO: 94) (Kabat);
SIRSST (SEQ ID NO: 95) (Chothia) GSGWYGDYFDY (SEQ ID NO: 96) 4F11 NARMGVT (SEQ ID NO: 97) (Kabat);
GFSLSNARM (SEQ ID NO: 98) (Chothia);
GFSLSNARMGVT (SEQ ID NO: 99) (extended) HIFSNDEKSYSTSLKS (SEQ ID NO: 100) (Kabat);
FSNDE (SEQ ID NO: 101) (Chothia) IRDYYDISSYYDY (SEQ ID NO: 102) 10H10 NHNIH (SEQ ID NO: 103) (Kabat);
GFTFSNH (SEQ ID NO: 104) (Chothia);
GFTFSNHNIH (SEQ ID NO: 105) (extended) YISRSSSTIYYADSVKG (SEQ ID NO: 106) (Kabat);
SRSSST (SEQ ID NO: 107) (Chothia) DHAQWYGMDV (SEQ ID NO: 108) 17G6 SYWMS (SEQ ID NO: 109) (Kabat);
GFTFSSY (SEQ ID NO: 110) (Chothia);
GFTFSSYWMS (SEQ ID NO: 111) (extended) SIKQDGSEKYYVDSVKG (SEQ ID NO: 112) (Kabat);
KQDGSE (SEQ ID NO: 113) (Chothia) EGVNWGWRLYWHFDL (SEQ ID NO: 114) 65E11 SYSMN (SEQ ID NO: 115) (Kabat);
GFTFSSY (SEQ ID NO: 116) (Chothia);
GFTFSSYSMN (SEQ ID NO: 117) (extended) HSSISRGNIYFADSVKG (SEQ ID NO: 118) (Kabat);
SISRGN (SEQ ID NO: 119) (Chothia) GSGWYGDYFDY (SEQ ID NO: 120) P02B10 NYAMS (SEQ ID NO: 121) (Kabat);
GFAFSNY (SEQ ID NO: 122) (Chothia);
GFAFSNYAMS (SEQ ID NO: 123) (extended) AIRGGGGSTYYADSVKG (SEQ ID NO: 124) (Kabat);
RGGGGS (SEQ ID NO: 125) (Chothia) DFISGTWYPDY (SEQ ID NO: 126) P07D03 SYWIG (SEQ ID NO: 127) (Kabat);
GYRFTSY (SEQ ID NO: 128) (Chothia);
GYRFTSYWIG (SEQ ID NO: 129) (extended) SIYPDDSDTRYSPSFQG (SEQ ID NO: 130) (Kabat);
YPDDSD (SEQ ID NO: 131) (Chothia) STVDYPGYSYFDY (SEQ ID NO: 132) P08A02 NYWIA (SEQ ID NO: 133) (Kabat);
GYTFTNY (SEQ ID NO: 134) (Chothia);
GYTFTNYWIA (SEQ ID NO: 135) (extended) IIYPDGSDTRYSPSFQG (SEQ ID NO: 136) (Kabat);
YPDGSD (SEQ ID NO: 137) (Chothia) DITSWYYGEPAFDI
(SEQ ID NO: 138) P08E02 SSWIG (SEQ ID NO: 139) (Kabat);
GYSFTSS (SEQ ID NO: 140) (Chothia);
GYSFTSSWIG (SEQ ID NO: 141) (extended) IIYPGDSDTRYSPSFQG (SEQ ID NO: 142) (Kabat);
YPGDSD (SEQ ID NO: 143) (Chothia) GLSQAMTGGFFDY (SEQ ID NO: 144) P08F08 SYWIG (SEQ ID NO: 145) (Kabat);
GYGFTSY (SEQ ID NO: 146) (Chothia);
GYGFTSYWIG (SEQ ID NO: 147) (extended) IIHPDDSDTKYSPSFQG (SEQ ID NO: 148) (Kabat);
HPDDSD (SEQ ID NO: 149) (Chothia) SYLRGLWGGYFDY (SEQ ID NO: 150) P08G02 SSWIG (SEQ ID NO: 151) (Kabat);
GYTFPSS (SEQ ID NO: 152) (Chothia);
GYTFPSSWIG (SEQ ID NO: 153) (extended) IIYPDTSHTRYSPSFQ (SEQ ID NO: 154) (Kabat);
YPDTSH (SEQ ID NO: 155) (Chothia) ASYFDRGTGYSSWWMDV (SEQ ID NO: 156) P12B09 QYSMS (SEQ ID NO: 157) (Kabat);
GFTFSQY (SEQ ID NO: 158) (Chothia);
GFTFSQYSMS (SEQ ID NO: 159) (extended) AISGGGVSTYYADSVKG (SEQ ID NO: 160) (Kabat);
SGGGVS (SEQ ID NO: 161) (Chothia) DISDSGGSHWYFDY (SEQ ID NO: 162) P12F02 SYAMS (SEQ ID NO: 163) (Kabat);
GFTFSSY (SEQ ID NO: 164) (Chothia);
GFTFSSYAMS (SEQ ID NO: 165) (extended) TISGTGGTTYYADSVKG (SEQ ID NO: 166) (Kabat);
SGTGGT (SEQ ID NO: 167) (Chothia) VRAGIDPTASDV (SEQ ID NO: 168) P12G07 NFAMS (SEQ ID NO: 169) (Kabat);
GFTFNNF (SEQ ID NO: 170) (Chothia);
GFTFNNFAMS (SEQ ID NO: 171) (extended) GISGSGDNTYYADSVKG (SEQ ID NO: 172) (Kabat);
SGSGDN (SEQ ID NO: 173) (Chothia) DRDIGLGWYSYYLDV (SEQ ID NO: 174) P13F04 SYAIS (SEQ ID NO: 175) (Kabat);
GGTFSSY (SEQ ID NO: 176) (Chothia);
GGTFSSYAIS (SEQ ID NO: 177) (extended) EIIPIFGTASYAQKFQG (SEQ ID NO: 178) (Kabat);
IPIFGT (SEQ ID NO: 179) (Chothia) AGWDDSWFDY (SEQ ID NO: 180) P15D02 SYWIG (SEQ ID NO: 181) (Kabat);
GYSFASY (SEQ ID NO: 182) (Chothia);
GYSFASYWIG (SEQ ID NO: 183) (extended) VIYPGTSETRYSPSFQG (SEQ ID NO: 184) (Kabat);
YPGTSE (SEQ ID NO: 185) (Chothia) GLSASASGYSFQY (SEQ ID NO: 186) P16C05 DYWIG (SEQ ID NO: 187) (Kabat);
GYSFTDY (SEQ ID NO: 188) (Chothia);
GYSFTDYWIG (SEQ ID NO: 189) (extended) MISPGGSTTIYRPSFQG (SEQ ID NO: 190) (Kabat);
SPGGST (SEQ ID NO: 191) (Chothia) MYTGGYGGSWYFDY (SEQ ID NO: 192) 10A1 YYYWT (SEQ ID NO: 382) (Kabat);
GGSISYY (SEQ ID NO: 383) (Chothia);
GGSISYYYWT (SEQ ID NO: 384) (extended) HIYYSGSTNYNPSLKS (SEQ ID NO: 385) (Kabat);
YYSGS (SEQ ID NO: 386) (Chothia) AEGSlDAFDF (SEQ ID NO: 387) 10E2 SNYMT (SEQ ID NO: 388) (Kabat);
GFTVSSN (SEQ ID NO: 389) (Chothia);
GFTVSSNYMT (SEQ ID NO: 390) (extended) VIYSGGSTYYADSVKG (SEQ ID NO: 391) (Kabat);
YSGGS (SEQ ID NO: 392) (Chothia) NWGDYW (SEQ ID NO: 393) 11A1 YYFWN (SEQ ID NO: 394) (Kabat);
GGSIDYY (SEQ ID NO: 395) (Chothia);
GGSIDYYFWN (SEQ ID NO: 396) (extended) HVYDIGNTKYNPSLKS (SEQ ID NO: 397) (Kabat);
YDIGN (SEQ ID NO: 398) (Chothia) GEGAlDAFDI (SEQ ID NO: 399) 11C1 YYYWT (SEQ ID NO: 400) (Kabat);
GGSISYY (SEQ ID NO: 401) (Chothia);
GGSISYYYWT (SEQ ID NO: 402) (extended) HVIYSGTTNYNPSLKS (SEQ ID NO: 403) (Kabat);
IYSGT (SEQ ID NO: 404) (Chothia) AEGSlDAFDL (SEQ ID NO: 405) 11D1 DYGIH (SEQ ID NO: 406) (Kabat);
GFTFSDY (SEQ ID NO: 407) (Chothia);
GFTFSDYGIH (SEQ ID NO: 408) (extended) VIWYDGSiKKYSDSVKG (SEQ ID NO: 409) (Kabat);
WYDGSi (SEQ ID NO: 410) (Chothia) DEVGtfGADFF (SEQ ID NO: 411) 11E1 SdgYYWS (SEQ ID NO: 412) (Kabat);
GGSISSdgY (SEQ ID NO: 413) (Chothia);
GGSISSdgYYWS (SEQ ID NO: 414) (extended) YMYYSGSTYYNPSLKS (SEQ ID NO: 415) (Kabat);
YYSGS (SEQ ID NO: 416) (Chothia) DFGWYFDL (SEQ ID NO: 417) 12A2 SdgYYWS (SEQ ID NO: 418) (Kabat);
GGSVSSdgY (SEQ ID NO: 419) (Chothia);
GGSVSSdgYYWS (SEQ ID NO: 420) (extended) YIYYRRITDYNPSLKS (SEQ ID NO: 421) (Kabat);
YYRRI (SEQ ID NO: 422) (Chothia) DFGWYFDL (SEQ ID NO: 423) 12C4 GYYLH (SEQ ID NO: 424) (Kabat);
GYTFTGY (SEQ ID NO: 425) (Chothia);
GYTFTGYYLH (SEQ ID NO: 426) (extended) WINpNSGGTNYAQKFQG (SEQ ID NO: 427) (Kabat);
NpNSGG (SEQ ID NO: 428) (Chothia) DRGVtmivDGMDD (SEQ ID NO: 429) 12C5 DYGMH (SEQ ID NO: 430) (Kabat);
GFTFSDY (SEQ ID NO: 431) (Chothia);
GFTFSDYGMH (SEQ ID NO: 432) (extended) VIWYDGSnKYYADSVKG (SEQ ID NO: 433) (Kabat);
WYDGSn (SEQ ID NO: 434) (Chothia) DEVGfvGAFDI (SEQ ID NO: 435) 12C6 DYGMH (SEQ ID NO: 663) (Kabat);
GFTFSDY (SEQ ID NO: 664) (Chothia);
GFTFSDYGMH (SEQ ID NO: 665) (extended) VIWYDGSnKYYADSVKG (SEQ ID NO: 666) (Kabat);
WYDGSn (SEQ ID NO: 667) (Chothia) DEVGfvGAFDI (SEQ ID NO: 668) 12D3 SdgYYWS (SEQ ID NO: 436) (Kabat);
GGSISSdgY (SEQ ID NO: 437) (Chothia);
GGSISSdgYYWS (SEQ ID NO: 438) (extended) YMYYSGITYHNPSLKS (SEQ ID NO: 439) (Kabat);
YYSGI (SEQ ID NO: 440) (Chothia) DFGWYFDL (SEQ ID NO: 441) 12D6 SdaYYWS (SEQ ID NO: 442) (Kabat);
GGSISSdaY (SEQ ID NO: 443) (Chothia);
GGSISSdaYYWS (SEQ ID NO: 444) (extended) YMYYSGITYYNPSLKS (SEQ ID NO: 445) (Kabat);
YYSGI (SEQ ID NO: 446) (Chothia) DFGWYFDL (SEQ ID NO: 447) 12D7 DYGIH (SEQ ID NO: 448) (Kabat);
GFTFSDY (SEQ ID NO: 449) (Chothia);
GFTFSDYGIH (SEQ ID NO: 450) (extended) VIWYDGSiKKYSDSVKG (SEQ ID NO: 451) (Kabat);
WYDGSi (SEQ ID NO: 452) (Chothia) DEVGtfGADFF (SEQ ID NO: 453) 12F5 NAWMS (SEQ ID NO: 454) (Kabat);
GFTFSNA (SEQ ID NO: 455) (Chothia);
GFTFSNAWMS (SEQ ID NO: 456) (extended) RIKsktGGGTTDYAAPVKG (SEQ ID NO: 457) (Kabat);
KsktGGGT (SEQ ID NO: 458) (Chothia) LIVGaiSLFDY (SEQ ID NO: 459) 12H4 YYFWT (SEQ ID NO: 460) (Kabat);
GGSISYY (SEQ ID NO: 461) (Chothia);
GGSISYYFWT (SEQ ID NO: 462) (extended) QIYYSGNTNSNPSLKS (SEQ ID NO: 463) (Kabat);
YYSGN (SEQ ID NO: 464) (Chothia) AEGSlDAFDI (SEQ ID NO: 465) 8C8 SYSMN (SEQ ID NO: 466) (Kabat);
GFTFSSY (SEQ ID NO: 467) (Chothia);
GFTFSSYSMN (SEQ ID NO: 468) (extended) SIStSSNYIHYADSLQG (SEQ ID NO: 469) (Kabat);
StSSNY (SEQ ID NO: 470) (Chothia) DKGTtltnWYFDL (SEQ ID NO: 471) 8F7 SYGMH (SEQ ID NO: 472) (Kabat);
GFTFSSY (SEQ ID NO: 473) (Chothia);
GFTFSSYGMH (SEQ ID NO: 474) (extended) VIWYDGSnKYYADSLKG (SEQ ID NO: 475) (Kabat);
WYDGSn (SEQ ID NO: 476) (Chothia) DGYSgssDAFDI (SEQ ID NO: 477) 8F8 YYYWS (SEQ ID NO: 478) (Kabat);
GGSISYY (SEQ ID NO: 479) (Chothia);
GGSISYYYWS (SEQ ID NO: 480) (extended) NINYMGNTIYNPSLKS (SEQ ID NO: 481) (Kabat);
NYMGN (SEQ ID NO: 482) (Chothia) AEGSlDAFDF (SEQ ID NO: 483) 9D8 GYYIY (SEQ ID NO: 484) (Kabat);
GYIFTGY (SEQ ID NO: 485) (Chothia);
GYIFTGYYIY (SEQ ID NO: 486) (extended) WINpSSGGTNYAQKFQG (SEQ ID NO: 487) (Kabat);
NpSSGG (SEQ ID NO: 488) (Chothia) DRKReyyynFGMDV (SEQ ID NO: 489) 9E10 SHYIY (SEQ ID NO: 490) (Kabat);
GYTFTSH (SEQ ID NO: 491) (Chothia);
GYTFTSHYIY (SEQ ID NO: 492) (extended) WINpNSGGTNYAQKFQD (SEQ ID NO: 493) (Kabat);
NpNSGG (SEQ ID NO: 494) (Chothia) DRKReyyynFGMDV (SEQ ID NO: 495) 9E5 SHYIY (SEQ ID NO: 496) (Kabat);
GFTFTSH (SEQ ID NO: 497) (Chothia);
GFTFTSHYIY (SEQ ID NO: 498) (extended) WINpNSGGTKYAQKFQD (SEQ ID NO: 499) (Kabat);
NpNSGG (SEQ ID NO: 500) (Chothia) DRKReyyynFGMDV (SEQ ID NO: 501) 9F4 IYAIH (SEQ ID NO: 502) (Kabat);
GFTLSIY (SEQ ID NO: 503) (Chothia);
GFTLSIYAIH (SEQ ID NO: 504) (extended) SFGgRGSSTYFADSVKG (SEQ ID NO: 505) (Kabat);
GgRGSS (SEQ ID NO: 506) (Chothia) EKDWgRGFDY (SEQ ID NO: 507) 9F8 NYSMN (SEQ ID NO: 508) (Kabat);
GFTFSNY (SEQ ID NO: 509) (Chothia);
GFTFSNYSMN (SEQ ID NO: 510) (extended) SISsSTIYIYYADSVKG (SEQ ID NO: 511) (Kabat);
SsSTIY (SEQ ID NO: 512) (Chothia) DIGWevftLGFDY (SEQ ID NO: 513)

Table 2B

light chain mAb CDRL1 CDRL2 CDRL3 31H1 RSSQSLVHSDGNTYLS (SEQ ID NO: 193); KISNRFS (SEQ ID NO: 194) MQATQFPLT (SEQ ID NO: 195) 63B2 RSSQSLVHSDGNTYLS (SEQ ID NO: 196); KISNRFS (SEQ ID NO: 197) MQATQFPLT (SEQ ID NO: 198) 40E3 RASQGISNYLA (SEQ ID NO: 199); AASSLQS (SEQ ID NO: 200) QQYNSYPLT (SEQ ID NO: 201) 42C3 RSSQSLVYSDENTYLN (SEQ ID NO: 202); QVSNRDS (SEQ ID NO: 203) MQGTYWPPT (SEQ ID NO: 204) 45F11 RASQSVSSSLA (SEQ ID NO: 205); GASTRAT (SEQ ID NO: 206) QQYINWPH (SEQ ID NO: 207) 64F9 QASQDISNYLN (SEQ ID NO: 208); GASNLETS (SEQ ID NO: 209) QQYDNFPIT (SEQ ID NO: 210) 72C2 RASQSVSSNLA (SEQ ID NO: 211); SASTRAS (SEQ ID NO: 212) QQYDNWPPLT (SEQ ID NO: 213) 2F10 RASQSVSSSYLA (SEQ ID NO: 214); GASSRAT (SEQ ID NO: 215) QQYGSSPLT (SEQ ID NO: 216) 4F11 RASQDISNYLA (SEQ ID NO: 217); AASSLQS (SEQ ID NO: 218) LQLNSFPFT (SEQ ID NO: 219) 10H10 RASQGISSWLA (SEQ ID NO: 220); AASSLQS (SEQ ID NO: 221) QQAFSFPFT (SEQ ID NO: 222) 17G6 KSSQSVLYSYNNKNYVA (SEQ ID NO: 223); WASTRES (SEQ ID NO: 224) QQYYSTLT (SEQ ID NO: 225) 65E11 RASQSVSSSYLA (SEQ ID NO: 226); DASSRAT (SEQ ID NO: 227) QQYGSSPLT (SEQ ID NO: 228) P02B10 SGSSSNIGSNYVY (SEQ ID NO: 229); RNNQRPS (SEQ ID NO: 230) AAWDDSLSGVV (SEQ ID NO: 231) P07D03 SGSRSNIGSNYVY (SEQ ID NO: 232); RNNQRPS (SEQ ID NO: 233) ASWDGSLSAVV (SEQ ID NO: 234) P08A02 SGSSSNIGSNYVY (SEQ ID NO: 235); RNNQRPS (SEQ ID NO: 236) ATWDDSLGSPV (SEQ ID NO: 237) P08E02 RASQSISRYLN (SEQ ID NO: 238); AASILQT (SEQ ID NO: 239) QQSYSTTMWT (SEQ ID NO: 240) P08F08 SGSSSNIGSNYVN (SEQ ID NO: 241); GDYQRPS (SEQ ID NO: 242) ATRDDSLSGSVV (SEQ ID NO: 243) P08G02 RASQSIYDYLH (SEQ ID NO: 244); DASNLQS (SEQ ID NO: 245) QQSYTTPLFT (SEQ ID NO: 246) P12B09 RASQYIGRYLN (SEQ ID NO: 247); GATSLAS (SEQ ID NO: 248) QQSYSTTSPT (SEQ ID NO: 249) P12F02 SGSTSNIGRNYVY (SEQ ID NO: 250); RTNQRPS (SEQ ID NO: 251) AAWDDSLSGRV (SEQ ID NO: 252) P12G07 SGSSSNIGSNYVY (SEQ ID NO: 253); MNNQRPS (SEQ ID NO: 254) AAWDDSLSAVV (SEQ ID NO: 255) P13F04 SSGSNSNIGTNYVS (SEQ ID NO: 256); RSRRPS (SEQ ID NO: 257) AAWDGSLSGHWV (SEQ ID NO: 258) P15D02 RASQSIDTYLN (SEQ ID NO: 259); SASSLHS (SEQ ID NO: 260) QQSYSTTAWT (SEQ ID NO: 261) P16C05 RASQSIGQSLN (SEQ ID NO: 262); GASSLQS (SEQ ID NO: 263) QQSYSTPIT (SEQ ID NO: 264) 10A1 RASQSISTWLA (SEQ ID NO: 514); KASSLES (SEQ ID NO: 515) QQYKSYSHT (SEQ ID NO: 516) 10E2 RASQSISSWLA (SEQ ID NO: 517); KASSLES (SEQ ID NO: 518) QQYKSFSLT (SEQ ID NO: 519) 11A1 RASQSISSWLA (SEQ ID NO: 520); KASTLES (SEQ ID NO: 521) QQYNSYSYT (SEQ ID NO: 522) 11C1 RASQSVSSWLA (SEQ ID NO: 523); KASSLES (SEQ ID NO: 524) QQYNTYSHT (SEQ ID NO: 525) 11D1 RASQGIRNDLG (SEQ ID NO: 526); AASSLQS (SEQ ID NO: 527) LQDYNYPFT (SEQ ID NO: 528) 11E1 RASQDIDNYLA (SEQ ID NO: 529); AASALQS (SEQ ID NO: 530) QNYNSGPRT (SEQ ID NO: 531) 12A2 RASQDISNYLT (SEQ ID NO: 532); AASALQS (SEQ ID NO: 533) QNYNSAPRT (SEQ ID NO: 534) 12C4 RSSQSLLHSNGYNYLD (SEQ ID NO: 535); LGSNRAS (SEQ ID NO: 536) MQTLQTPFT (SEQ ID NO: 537) 12C5 RASQGINSHLA (SEQ ID NO: 538); YASTLPS (SEQ ID NO: 539) QQLNHYPIT (SEQ ID NO: 540) 12C6 RASQGINSHLA (SEQ ID NO: 669); YASTLPS (SEQ ID NO: 670) QQLNHYPIT (SEQ ID NO: 671) 12D3 RASQGISNYLA (SEQ ID NO: 541); AASTLHS (SEQ ID NO: 542) QKYNSAPRT (SEQ ID NO: 543) 12D6 RASQDISNYLA (SEQ ID NO: 544); AASTLHS (SEQ ID NO: 545) QKYNSAPRT (SEQ ID NO: 546) 12D7 RASQDISSFLA (SEQ ID NO: 547); VASTLQS (SEQ ID NO: 548) QQLHVYPIT (SEQ ID NO: 549) 12F5 RSSQSLLDSDDGNtYLD (SEQ ID NO: 550); TLSYRAS (SEQ ID NO: 551) MQRIEFPFT (SEQ ID NO: 552) 12H4 RASQTISTWLA (SEQ ID NO: 553); KASNLES (SEQ ID NO: 554) QQYQTFSHT (SEQ ID NO: 555) 8C8 RASQGISNYLA (SEQ ID NO: 556); AASTLQS (SEQ ID NO: 557) QKYNSAPLT (SEQ ID NO: 558) 8F7 RSSQTLVHSNGYNYLN (SEQ ID NO: 559); LGSNRAS (SEQ ID NO: 560) MQAIQTPYT (SEQ ID NO: 561) 8F8 RASQSISSWLA (SEQ ID NO: 562); KASNLES (SEQ ID NO: 563) QQYNSYSCT (SEQ ID NO: 564) 9D8 QASQDINNYLH (SEQ ID NO: 565); DASDWET (SEQ ID NO: 566) QQYDHLPIT (SEQ ID NO: 567) 9E10 QASQDISNYLH (SEQ ID NO: 568); DASDLET (SEQ ID NO: 569) QQYDHLPIT (SEQ ID NO: 570) 9E5 QASQDISNYLH (SEQ ID NO: 571); DASDLET (SEQ ID NO: 572) QQYDHLPIT (SEQ ID NO: 573) 9F4 QASQDISNYLN (SEQ ID NO: 574); DASNLETS (SEQ ID NO: 575) QQYDNLPYT (SEQ ID NO: 576) 9F8 RSSQSLLYSNGYNYLD (SEQ ID NO: 577); LNSNRAS (SEQ ID NO: 578) MQALQTPLT (SEQ ID NO: 579)

The present invention encompasses modifications to CARs and polypeptides containing the sequences shown in Tables 1 or 2A to 2B, including functionally equivalent CARs having modifications that do not significantly affect their properties, and variants that have increased or decreased activity and/or affinity. . For example, the amino acid sequence can be mutated to produce an antibody with the desired binding affinity for CD70. Modification of polypeptides is standard practice in the art and need not be detailed here. Examples of modified polypeptides include those with conservative amino acid residue substitutions, one or more deletions or additions of amino acids that do not substantially adversely affect functionality, or that mature (enhance) the affinity of the polypeptide for its ligand, or use chemical analogs.

Amino acid sequence insertions include amino and/or carboxy terminal fusions ranging in length from one residue to polypeptides containing one hundred or more residues, as well as intrasequence insertions of one or more amino acid residues. Examples of end inserts include an antibody with an N-terminal methionyl residue or an antibody fused to an epitope tag. Other insertion variants of an antibody molecule include the fusion of an enzyme or polypeptide to the N- or C-terminus of the antibody, which increases the circulating half-life of the antibody.

Substitutional variants have at least one amino acid residue removed from the antibody molecule and another residue inserted in place. Sites of greatest interest for displacement mutagenesis include hypervariable regions, but FR changes are also contemplated. Conservative substitutions are shown in Table 3 under the heading "conservative substitutions". If such substitutions result in a change in biological activity, then more significant changes, referred to in Table 3 as "exemplary substitutions", or as further described below in reference to amino acid classes, can be introduced and the products screened.

Table 3. Amino acid substitutions

original balance
(naturally occurring amino acid) Conservative substitutions Illustrative substitutions Ala (A) Val Val; Leu; ile Arg(R) Lys Lys; gln; Asn Asn(N) Gln gln; His; Asp, Lys; Arg Asp(D) Glu Glu; Asn Cys(C) Ser Ser; Ala Gln(Q) Asn asn; Glu Glu(E) asp asp; Gln Gly (G) Ala Ala His(H) Arg asn; gln; Lys; Arg Ile (I) Leu Leu; Val; met; Ala; Ph; norleucine Leu(L) ile Norleucine; Ile; Val; met; Ala; Phe Lys (K) Arg Arg; gln; Asn Met(M) Leu Leu; Ph; ile Phe(F) Tyr Leu; Val; Ile; Ala; Tyr Pro (P) Ala Ala Ser(S) Thr Thr Thr(T) Ser Ser TRP(W) Tyr Tyr; Phe Tyr (Y) Phe trp; Ph; Thr; Ser Val(V) Leu Ile; Leu; met; Ph; Ala; norleucine

In some embodiments, the present invention provides a CAR containing an extracellular ligand-binding domain that binds to CD70 and competes for binding to CD70 with the CAR described herein, including a CAR containing an extracellular domain that contains ScFv containing 31H1 sequences 63B2 40E3 42C3 45F11 64F9 72C2 2F10 4F11 10H10 17G6 65E11 P02B10 P07D03 P08A02 P08E02 P08F08 P08G02 P12B09 P1 2F02, P12G07, P13F04, P15D02, P16C05, 10A1, 10E2 , 11A1, 11C1, 11D1, 11E1, 12A2, 12C4, 12C5, 12D3, 12D6, 12D7, 12F5, 12H4, 8C8, 8F7, 8F8, 9D8, 9E10, 9E5, 9F4 or 9F8

In some embodiments, the present invention provides a CAR that specifically binds to CD70, where the CAR contains a VH region containing the sequence shown under SEQ ID NO: 20; and/or a VL region containing the sequence shown under SEQ ID NO: 19. In some embodiments, the present invention provides a CAR that specifically binds to CD70, where the CAR contains a VH region containing the sequence shown under SEQ ID NO: 22; and/or a VL region containing the sequence shown under SEQ ID NO: 21. In some embodiments, the present invention provides a CAR that specifically binds to CD70, where the CAR contains a VH region containing the sequence shown under SEQ ID NO: 28; and/or a VL region containing the sequence shown under SEQ ID NO: 27. In some embodiments, the present invention provides a CAR that specifically binds to CD70, where the CAR contains a VH region containing the sequence shown under SEQ ID NO: 36; and/or a VL region containing the sequence shown under SEQ ID NO: 35. In some embodiments, the present invention provides a CAR that specifically binds to CD70, where the CAR contains a VH region containing the sequence shown under SEQ ID NO: 46; and/or a VL region containing the sequence shown under SEQ ID NO: 45. In some embodiments, the present invention provides a CAR that specifically binds to CD70, where the CAR contains a VH region containing the sequence shown under SEQ ID NO: 18; and/or a VL region containing the sequence shown under SEQ ID NO: 17. In some embodiments, the present invention provides a CAR that specifically binds to CD70, where the CAR contains a VH region containing the sequence shown under SEQ ID NO: 34; and/or a VL region containing the sequence shown under SEQ ID NO: 33. In some embodiments, implementation of the present invention also provides CARs containing parts of the CDR antibodies to CD70 based on the contact regions of the CDR. CDR contact regions are regions of an antibody that confer specificity for an antibody to an antigen. In general, CDR contact regions include residue positions in the CDR and vernier zones that are restricted to maintain proper loop structure to allow binding of the antibody to a specific antigen. See, for example, Makabe et al., J. Biol. Chem., 283:1156-1166, 2007. The definition of CDR contact regions is well known to those skilled in the art.

The binding affinity (KD) of the ligand-binding domain in the CD70-specific CAR described herein to CD70 (e.g., human CD70) can be, for example, from about 0.1 to about 1000 nM, for example, from about 0, 5 nm to about 500 nm, or for example, from about 1 nm to about 250 nm. In some embodiments, the binding affinity is approximately any of 1000 nm, 750 nm, 500 nm, 400 nm, 300 nm, 250 nm, 200 nm, 100 nm, 90 nm, 80 nm, 70 nm, 60 nm, 50 nm, 45 nm, 40 nm, 35 nm, 30 nm, 25 nm, 20 nm, 19 nm, 18 nm, 17 nm, 16 nm, 15 nm, 10 nm, 8 nm, 7.5 nm, 7 nm, 6.5 nm, 6 nm, 5.5 nm, 5 nm, 4 nm, 3 nm, 2 nm, 1 nm, 0.5 nm, 0.3 nm or 0.1 nm.

In some embodiments, the binding affinity (KD) of the scFv ligand-binding domain in the CD70-specific CAR described herein for CD70 is from about 10 nM to about 100 nM, from about 10 nM to about 90 nM, from about 10 nM to about 80 nM, about 20 nM to about 70 nM, about 25 nM to about 75 nM, or about 40 nM to about 110 nM. In some embodiments, the scFv binding affinity described in this paragraph is for human CD70.

In some embodiments, the binding affinity is less than about any of 1000nM, 900nm, 800nm, 250nM, 200nM, 100nM, 50nM, 30nM, 20nM, 10nM, 7.5nM, 7nM, 6.5 nM, 6 nM, 5 nM.

The CAR intracellular signaling domain of the present invention is responsible for intracellular signaling after binding of the extracellular ligand-binding domain to a target, resulting in immune cell activation and immune response. The intracellular signaling domain has the ability to activate at least one of the normal immune cell effector functions in which CAR is expressed. For example, the effector function of a T cell may be a cytolytic activity or a helper activity involving the secretion of cytokines.

In some embodiments, an intracellular signaling domain for use in a CAR may be cytoplasmic sequences, such as, but not limited to, T-cell receptor and co-receptors that act together to initiate signal transduction upon interaction with an antigen receptor, as well as any derivative or variant of these sequences. and any synthetic sequence that has the same functionality. Intracellular signaling domains include two distinct classes of cytoplasmic signal sequences: those that initiate antigen-dependent primary activation and those that act in an antigen-independent manner to provide a secondary or costimulatory signal. Primary cytoplasmic signaling sequences may contain signaling motifs, which are known as immunoreceptor tyrosine activating motifs - ITAMs. ITAMs are well-defined signaling motifs found in the intracytoplasmic tail of a variety of receptors that serve as binding sites for tyrosine kinases of the syk/zap70 class. Examples of ITAMs used in the present invention may include, but are not limited to, those derived from TCRζ, FcRγ, FcRβ, FcRε, CD3γ, CD3δ, CD3ε, CD5, CD22, CD79a, CD79b, and CD66d. In some embodiments, an intracellular CAR signaling domain may comprise a CD3ζ signaling domain having an amino acid sequence that is at least about 70%, at least 80%, at least 90%, 95%, 97%, or 99% amino acid sequence identical. presented under SEQ ID NO: 272 or 683. In some embodiments, the implementation of the intracellular signaling domain of the CAR of the present invention contains the domain of costimulatory molecules.

In some embodiments, the CAR intracellular signaling domain of the present invention comprises part of a co-stimulatory molecule selected from the group consisting of the 41BB fragment (GenBank: AAA53133.) and CD28 (NP_006130.1). In some embodiments, the CAR intracellular signaling domain of the present invention comprises an amino acid sequence that is at least 70%, at least 80%, at least 90%, 95%, 97%, or 99% identical to the amino acid sequence shown under SEQ ID NO: 271 or 682 and SEQ ID NO: 275. In some embodiments, the CAR intracellular signaling domain of the present invention contains an amino acid sequence that is at least 70%, at least 80%, at least 90%, 95% , 97% or 99% identical to the amino acid sequence shown under SEQ ID NO: 271 or 682, and/or at least 70%, at least 80%, at least 90%, 95%, 97% or 99% identical to the amino acid sequence shown under SEQ ID NO: 276.

CARs are expressed on the cell membrane surface. Thus, a CAR may contain a transmembrane domain. Suitable transmembrane domains for the CAR disclosed herein are characterized by the ability to (a) be expressed on the surface of a cell, which in some embodiments is an immune cell, such as, for example, without limitation, a lymphocytic cell, for example, T-helper (T_h) cell, cytotoxic T (T_c) cell, regulatory T (T_reg) or natural killer (NK) cells, and/or (b) interact with a ligand-binding domain and an intracellular signaling domain to direct the immune cell's cellular response to a predetermined target cell. The transmembrane domain can be obtained from either a natural or synthetic source. The transmembrane domain can be derived from any membrane-bound or transmembrane protein. As non-limiting examples, a transmembrane polypeptide may be a subsequence or subunit of a T cell receptor, e.g. -chain, subunit chain of Fc receptors, in particular Fcγ receptor III or CD proteins. Alternatively, the transmembrane domain may be synthetic and may contain predominantly hydrophobic residues such as leucine and valine. In some embodiments, said transmembrane domain is derived from the human CD8α chain (e.g., NP_001139345.1). The transmembrane domain may further comprise a stem domain between the extracellular ligand binding domain and said transmembrane domain. The stem domain can contain up to 300 amino acids—in some embodiments, 10 to 100 amino acids, or in some embodiments, 25 to 50 amino acids. The stem region can be derived from all or part of naturally occurring molecules, e.g. from all or part of the extracellular region of CD8, CD4, CD28, 4-1BB or IgG (in particular the hinge region from IgG), or from all or part of the constant region the heavy chain of the antibody. Alternatively, the "stem" domain may be a synthetic sequence that corresponds to a naturally occurring stem sequence, or may be a fully synthetic stem sequence. In some embodiments, said stem domain is part of the human CD8α chain (e.g., NP_001139345.1). In another specific embodiment, said hinge and transmembrane domains comprise a portion of the human CD8α chain, which in some embodiments has at least 70%, at least 80%, at least 90%, 95%, 97%, or 99% sequence identity. with an amino acid sequence selected from the group consisting of SEQ ID NOs: 268 and 270. In some embodiments, the CAR stem domain described herein comprises a CD8α, IgG1, or FcγRIIIα subsequence, specifically a hinge region from any of CD8α, IgG1 or FcγRIIIα. In some embodiments, the stem domain comprises a human CD8α hinge, a human IgG1 hinge, or a human FcγRIIIα hinge. In some embodiments, the CARs disclosed herein may contain an extracellular ligand-binding domain that specifically binds to CD70. In some embodiments, the CARs disclosed herein comprise scFv, the human CD8α hinge and transmembrane domains, the CD3ζ signaling domain, and the 4-1BB signaling domain.

Table 4 lists exemplary domain sequences that can be used in the CARs described herein.

Table 4. Exemplary sequences of CAR components

Domain Amino acid sequence SEQID NO: CD8α signal peptide MALPVTALLLPLALLLHAARP 266 Hinge section of FcγRIIIα GLAVSTISSFFPPGYQ 267 Hinge section of CD8α TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD 268 Hinge section of IgG1 EPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 269 Transmembrane domain (TM) CD8α IYIWAPLAGTCGVLLLSLVITLYC 270 Intracellular signaling domain (ISD) 41BB KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL 271 Intracellular signaling domain (ISD) 41BB GRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL 682 Intracellular signaling domain (ISD) CD3ζ RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 272 Intracellular signaling domain (ISD) CD3ζ RVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 683 α-TM-IC FcεRI (transmembrane and intracellular domain of FcεRI α-chain) FFIPLLVVILFAVDTGLFISTQQQVTFLLKIKRTRKGFRLLNPHPKPNPKNN 273 FcεRIβ-ΔITAM (FcεRI β-chain without ITAM) MDTESNRRANLALPQEPSSVPAFEVLEISPQEVSSGRLLKSASSPPLHTWLTVLKKEQEFLGVTQILTAMICLCFGTVVCSVLDISHIEGDIFSSFKAGYPFWGAIFFSISGMLSIISERRNATYLVRGSLGANTASSIAGGTGITILIINLKKSLAYIHIHSCQKFFETKCFMASFSTEIVVMMLFLTILGLGSAVSLTICGAGEELKGNKV PE 274 CD28-IC (CD28 costimulatory domain) RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS 276 FcεRIγ-SP (signal peptide) MIPAVVLLLLLVEQAAA 277 FcεRI γ-ΔITAM (γ-chain FcεRI without ITAM) LGEPQLCYILDAILFLYGIVLTLLYCRLKIQVRKAAITSYEKS 278 GSG-P2A (GSG-P2A ribosomal slip polypeptide) GSGATNFSLLKQAGDVEENPGP 279 GSG-T2A (GSG-T2A ribosomal slip polypeptide) GSGEGRGSLLTCGDVEENPGP 280

Downregulation or mutation of target antigens is typically seen in cancer cells to form antigen-losing escape variants. Thus, to compensate for tumor escape and give the immune cell greater target specificity, a CD70-specific CAR may contain one or more additional extracellular ligand-binding domains designed to simultaneously bind different elements in the target, thereby increasing activation and function. immune cells. In some embodiments, the extracellular ligand-binding domains may be located in tandem on the same transmembrane polypeptide, optionally separated by a linker. In some embodiments, these different extracellular ligand-binding domains can be located on different transmembrane polypeptides that form CARs. In some embodiments, the present invention relates to a population of CARs, each of which contains a different extracellular ligand-binding domain. In particular, the present invention relates to a method for constructing immune cells, providing an immune cell and expression on the cell surface of a population of CARs, each of which contains different extracellular ligand-binding domains. In another specific embodiment, the present invention relates to a method for constructing an immune cell, comprising providing an immune cell and introducing into the cell polynucleotides encoding polypeptides constituting a CAR population, each of which contains different extracellular ligand-binding domains. By a CAR population is meant at least two, three, four, five, six or more CARs, each containing different extracellular ligand-binding domains. Different extracellular ligand-binding domains in accordance with the present invention can, in some embodiments, simultaneously bind different elements in the target, thereby increasing the activation and function of immune cells. The present invention also relates to an isolated immune cell that contains a population of CARs, each of which contains different extracellular ligand-binding domains.

In another aspect of the present invention, polynucleotides encoding any of the CARs and polypeptides described herein are provided. Polynucleotides can be generated and expressed using procedures known in the art.

In another aspect of the present invention, compositions (such as pharmaceutical compositions) containing any of the cells of the present invention are provided. In some embodiments, the composition comprises a cell containing a polynucleotide encoding any of the CARs described herein. In other embodiments, the composition comprises one or both of the polynucleotides shown under SEQ ID NO: 297 and SEQ ID NO: 298, SEQ ID NO: 299 and SEQ ID NO: 300, SEQ ID NO: 301 and SEQ ID NO: 302, SEQ ID NO: 303 and SEQ ID NO: 304, SEQ ID NO: 305 and SEQ ID NO: 306, SEQ ID NO: 307 and SEQ ID NO: 308 or SEQ ID NO: 309 and SEQ ID NO: 310 below:

heavy chain variable region 4F11

CAGGTCACCTTGAGGAGTCTGGTCCTGTGCTGGTGAAACCCACAGAGACCCTCACGCTGACCTGCACCGTCTCTGGGTTCTCACTCAGTAATGCTAGAATGGGTGTGACCTGGATCCGTCAGCCCCCAAGGGAAGGCCCTGGAGTGGCTTGCACACATTTTTTCGAATGACGAAAAATCCTACAGTACATCTCTGAAGAGCAGGCTCACCATCTCCAAGGACACT TCCAAAACCCAGGTGGTCCTTACCATGACCAACATGGACCCTGTGGACACAGCCACATATTACTGTGCACGGATACGAGATTACTATGACATTAGTAGTTATTATGACTACTGGGGCCAGGGAACCCTGGTCAGCGTCTCCTCA (SEQ ID NO: 297)

light chain variable region 4F11

GACATCCAGATGACCCAGTCTCCATCTGCCATGTCTGCATCTGTAGGAGACAAGTCACCATCACTTGTCGGCGAGTCAGGACATTAGCAATTATTTAGCCTGGTTTCAGCAGAAACCAGGGAAAGTCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCGGGGACAGAATTCACTCTCACAATCAGCAG CCTGCTGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCTTAATAGTTTCCCGTTCACTTTTGGCGGAGGGACCAAGGTGGAGATCAAC (SEQ ID NO: 298).

In still other embodiments, the composition comprises one or both of the polynucleotides shown under SEQ ID NO: 299 and SEQ ID NO: 300 below:

heavy chain variable region 17G6

GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGTAGCCTCTGGATTACACCTTTAGTAGTTATTGGATGAGCTGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAGCATAAAGCAAGATGGAAGTGAGAAATACTATGTGGACTCTGTGAAGGGCCGATTCACCATCTCCAG AGACAACGCCAAGAACTCAGTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGGTGTGTATTACTGTGCGAGAGAAGGAGTCAACTGGGGATGGAGACTCTACTGGCACTTCGATCTCTGGGGCCGTGGAACCCTGGTCACTGTCTCCTCA (SEQ ID NO: 299)

light chain variable region 17G6

GACATCGTGATGACCAGTCTCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTACAACAATAAGAACTACGTAGCTTGGTACCAGCAGAAACCAGGACAACCTCCTAACCTACTCATTTTCTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGA TTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTACTACTGTCAGCAATATTATAGTACGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 300).

In still other embodiments, the composition comprises one or both of the polynucleotides shown under SEQ ID NO: 301 and SEQ ID NO: 302 below:

heavy chain variable region 10H10

GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGTCAGTCTCTGGATTCACCTTCAGTAACCATAACATACACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATTTCATACATTAGTCGAAGTAGTAGTACCATATATTACGCAGACTCTGTGAAGGGCCGATTCACAATCTCCAGAGACA ATGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGACGAAGACACGGCTGTGTATTACTGTGCGAGAGATCACGCTCAGTGGTACGGTATGGACGTTTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 301).

Light chain variable region 10H10

GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCGGTAGGAGACAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGGTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCA GCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGCTTTCAGTTTCCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA (SEQ ID NO: 302).

In still other embodiments, the composition comprises one or both of the polynucleotides shown under SEQ ID NO: 303 and SEQ ID NO: 304 below:

heavy chain variable region P07D03

GAAGTGCAGCTTGTCCAGAGCGGAGCCGAAGTGAAGAAGCCTGGCGAGAGCCTGAAGATCAGCTGCAAGGGCTCCGGATATCGCTTCACAAGTTACTGGGATAGGGTGGGTGCGCCAGATGCCTGGTAAGGGACTGGAATGGATGGGCTCTATATATCCTGATGATTCCGACACACGTTATAGCCCAAGCTTTCAGGCCAGGTCACAATCAGCGCTGACAAGAG CATCAGCACCGCCTACCTTCAGTGGTCGTCTCTGAAGGCCAGCGACACCGCAATGTACTACTGCGCTCTAGCACAGTTGACTACCCGGGATACAGTTACTTCGACTACTGGGGCCAAGGTACACTGGTCACCGTCAGCAGC (SEQ ID NO: 303)

light chain variable region P07D03

GAGCTCCAGAGCGTGCTGACCCAGCCTCCTAGCGCAAGCGGCACCCCTGGACAGCGTGTGACAATTAGCTGTAGCGGAAGTCGTAGCAATATCGGATCAAACTATGTGTATTGGTATCAGCAATTGCCCGGTACAGCACCCAAATTGCTCATATAGAAATAATCAGAGACCTAGCGGAGTGCCTGATCGTTTTAGCGGTAGCAAAAGCGGCACCACGCATCACTGGC AATTTCAGGCCTGCGTAGCGAAGATGAGGCGGATTATTACTGTGCGAGTTGGGATGGTTCGCTGAGTGCTGTTGTGTTCGGCACCGGTACAAAACTGACCGTTCTG (SEQ ID NO: 304).

In still other embodiments, the composition comprises one or both of the polynucleotides shown under SEQ ID NO: 305 and SEQ ID NO: 306 below:

heavy chain variable region P08G02

GAAGTGCAGCTTGTCCAGAGCGGAGCCGAAGTGAAGAAGCCTGGCGAGAGCCTGAAGATCAGCTGCAAGGGCTCCGGATACACCTTTCCTTCATCATGGATAGGTTGGGTGCGCCAGATGCCTGGTAAGGGACTGGAATGGATGGGCATCATATACCCTGATACTAGCCATACCCGTTACAGCCCAAGCTTTTCAGGGCCAAGGTCACAATCAGCGCTGACAAGAGCAT CAGCACCGCCTACCTTCAGTGGTCGTCTCTGAAGGCCAGCGACACCGCAATGTACTACTGTGCCCGTGCGAGCTATTTCGATCGTGTGGAACAGGGTATAGTTCTTGGTGGATGGATGTGTGGGGCCAAGGTACACTGGTCACCGTCAGCAGC (SEQ ID NO: 305).

light chain variable region P08G02

GAGCTCGATATTCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCAAGCGTGGGCGATAGAGTGACCATTACCTGTAGGGCCTCACAATCCATATACGACTATTTGCACTGGTATCAGCAGAAACCCGGGAAAGCACCCAAACTGCTGATTTACGATGCTTCCAACCTACAGAGTGTGGTTCCTTCACGTTTTAGCGGTAGCGGTTCAGGCACCGATTTCACCCTGACCATTAGCAG CCTTCAGCCCGAAGATTTCGCTACGTATTATTGCCAGCAATCATACACCACGCCGTTGTTTACATTCGGCCAGGGTACCAAAGTGGAAATCAAA (SEQ ID NO: 306).

In still other embodiments, the composition comprises one or both of the polynucleotides shown under SEQ ID NO: 307 and SEQ ID NO: 308 below:

heavy chain variable region P08F08

GAAGTGCAGCTTGTCCAGAGCGGAGCCGAAGTGAAGAAGCCTGGCGAGAGCCTGAAGATCAGCTGCAAGGGCTCCGGATACGGATTCACAAGTTATTGGATAGGTTGGGTGCGCCAGATGCCTGGTAAGGGACTGGAATGGATGGGTATCATTCATCCCGATGATAGCGACACCAAATACAGCCCAAGCTTTCAGGCCAGGTCACAATCAGCGCTGACAAGAG CATCAGCACCGCCTACCTTCAGTGGTCGTCTCTGAAGGCCAGCGACACCGCAATGTACTACTGTGCCTCTAGCTATTTGCGTGGCTTGTGGGGAGGCTATTTTGACTATTGGGGCCAAGGTACACTGGTCACCGTCAGCAGC (SEQ ID NO: 307)

light chain variable region P08F08

GAGCTCCAGAGCGTGCTGACCCAGCCTCCTAGCGCAAGCGGCACCCCTGGACAGCGTGTGACAATTAGCTGTAGCGGATCAAGCTCAAACATTGGCTCAAATTATGTGAATTGGTATCAGCAATTGCCCGGTACAGCACCCAAACTGCTCATTTATGGAGATTATCAACGACCTAGCGGAGTGCCTGATCGTTTTAGCGGTAGCAAAAGCGGCACCAGCGCATCACTGGC AATTTCAGGCCTGCGTAGCGAAGATGAGGCGGATTATTACTGTGCTACCCGCGACGATTCGTTATCTGGGTCTGTCGTTTTTGGCACCGGTACAAAACTGACCGTGCTG (SEQ ID NO: 308).

In still other embodiments, the composition comprises one or both of the polynucleotides shown under SEQ ID NO: 309 and SEQ ID NO: 310 below:

heavy chain variable region P15D02

GAAGTGCAGCTTGTCCAGAGCGGAGCCGAAGTGAAGAAGCCTGGCGAGAGCCTGAAGATCAGCTGCAAGGGCTCCGGATACAGTTTTGCCTCATACTGGATCGGTTGGGTGCGCCAGATGCCTGGTAAGGGACTGGAATGGATGGGCGTAATTTACCCCGGAACTAGCGAGACACGTTACAGCCCAAGCTTTTCAGGCCAGGTCACAATCAGCGCTGACAAG AGCATCAGCACCGCCTACCTTCAGTGGTCGTCTCTGAAGGCCAGCGACACCGCAATGTACTACTGCCTAAAGGGTTGAGTGCGAGTGCAAGTGGATATTTCTTTCCAATATTGGGGCCAAGGTACACTGGTCACCGTCAGCAGC (SEQ ID NO: 309)

light chain variable region P15D032

GAGCTCGATATTCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCAAGCGTGGGCGATAGAGTGACCATTACCTGTAGGGCCTCACAAAGCATCGACACATATTTAAACTGGTATCAGCAGAAACCCGGGAAAGCACCCAAACTGCTGATTTATTCAGCTAGTAGCCTACACAGTGGCGTTCCTTCACGTTTTAGCGGTAGCGGTTCAGGCACCGATTTCACCCTGACCATTAGC AGCCTTCAGCCCGAAGATTTCGCTACGTATTATTGCCAACAATCATACAGCACAACTGCTTGGACATTCGGCCAGGGTACCAAAGTGGAAATCAAA (SEQ ID NO: 310).

This document further describes expression vectors and administration of polynucleotide compositions.

In another aspect of the present invention provides a method for obtaining any of the polynucleotides described in this document.

The present invention also encompasses polynucleotides complementary to any such sequences. Polynucleotides can be single stranded (coding or antisense) or double stranded and can be DNA (genomic, cDNA or synthetic) or RNA molecules. RNA molecules include HnRNA molecules, which contain introns and correspond one-to-one to the DNA molecule, and mRNA molecules, which do not contain introns. Additional coding or non-coding sequences may optionally be present in a polynucleotide of the present invention, and the polynucleotide may optionally be linked to other molecules and/or accessory materials.

Polynucleotides may contain a native sequence (i.e. an endogenous sequence that encodes an antibody or part thereof) or may contain a variant of such a sequence. Polynucleotide variants contain one or more substitutions, additions, deletions and/or insertions, provided that the immunoreactivity of the encoding polypeptide is not reduced compared to the native immunoreactive molecule. The effect on the immunoreactivity of the encoded polypeptide can generally be assessed as described herein. Variants in embodiments have at least about 70% identity, at least about 80% identity, at least about 90% identity, or at least about 95% identity with a polynucleotide sequence that encodes a native antibody or portion thereof.

Two polynucleotide or polypeptide sequences are said to be "identical" if the sequence of nucleotides or amino acids in the two sequences is the same when aligned to establish maximum similarity, as described below. Comparisons of two sequences are typically performed by comparing sequences in a comparison window to identify and compare local areas of sequence similarity. The term "comparison window" as used herein refers to a segment of at least about 20 contiguous positions, typically 30 to about 75 or 40 to about 50, in which the sequence can be compared to a reference sequence of the same number of contiguous positions after how two sequences are optimally aligned.

Optimal sequence alignment for comparison can be performed using the Megalign program in the Lasergene Bioinformatics Software Suite (DNASTAR, Inc., Madison, Wisconsin, USA) using standard parameters. This computer program implements several alignment schemes described in the following references: Dayhoff, M.O., 1978, A model of evolutionary change in proteins - Matrices for detecting distant relationships. In Dayhoff, M.O. (ed.) Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, Washington DC Vol. 5, Suppl. 3, pp. 345-358; Hein J., 1990, Unified Approach to Alignment and Phylogenes pp. 626-645 Methods in Enzymology vol. 183, Academic Press, Inc., San Diego, CA; Higgins, D.G. and Sharp, P.M., 1989, CABIOS 5:151-153; Myers, E.W. and Muller W., 1988, CABIOS 4:11-17; Robinson, E.D., 1971, Comb. Theor. 11:105; Santou, N., Nes, M., 1987, Mol. Biol. Evol. 4:406-425; Sneath, P.H.A. and Sokal, R.R., 1973, Numerical Taxonomy the Principles and Practice of Numerical Taxonomy, Freeman Press, San Francisco, CA; Wilbur, W.J. and Lipman, D.J., 1983, Proc. Natl. Acad. sci. USA 80:726-730.

"Percent sequence identity" is determined by comparing two optimally aligned sequences in a comparison window of at least 20 positions, where a portion of the polynucleotide or polypeptide sequence in the comparison window may contain additions or deletions (i.e., gaps) of 20 percent or less, typically 5 to 15 percent or 10 to 12 percent, compared to reference sequences (which contain no additions or deletions) to optimally align the two sequences. The percentage is calculated by determining the number of positions at which identical nucleic acid bases or amino acid residues occur in both sequences to obtain the number of positions that matched, dividing the number of positions that matched by the total number of positions in the reference sequence (i.e., window size) and multiplying the results by 100 to get the percent sequence identity.

Also or alternatively, the variants may be substantially homologous to the native gene or a portion thereof, or their complementary sequence. These polynucleotide variants are capable of hybridizing under moderately stringent conditions to a naturally occurring DNA sequence encoding a native antibody (or a complementary sequence).

Suitable "moderate-stringent conditions" include a pre-wash in a solution of 5 X SSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0); hybridization at 50°C - 65°C, 5X SSC overnight followed by washing twice at 65°C for 20 minutes with each of 2X, 0.5X and 0.2X SSC containing 0.1% SDS.

As used herein, "very stringent conditions" or "high stringency conditions" are as follows: (1) using low ionic strength and high temperature for washing, for example, 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50°C; (2) using during hybridization a denaturant such as formamide, e.g. 50% (v/v) formamide with 0.1% bovine serum albumin/0.1% ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750 mm sodium chloride, 75 mm sodium citrate at 42°C; or (3) using 50% formamide, 5 x SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5 x Denhardt's solution, exposed sonicated solution of salmon sperm DNA (50 µg/ml), 0.1% SDS and 10% dextran sulfate at 42°C with a wash at 42°C in 0.2 x SSC (sodium chloride/sodium citrate) and 50% formamide at 55°C followed by a high stringency wash consisting of 0.1 x SSC containing EDTA at 55°C. One skilled in the art will understand how to adjust the temperature, ionic strength, etc., if necessary, to accommodate factors such as probe length, etc.

Those skilled in the art will appreciate that, as a result of the degeneracy of the genetic code, there are multiple nucleotide sequences that encode for the polypeptide described herein. Some of these polynucleotides have minimal homology to the nucleotide sequence of any native gene. However, polynucleotides that differ due to differences in codon usage are specifically provided in the present invention. In addition, the alleles of the genes containing the polynucleotide sequences presented herein are within the scope of the present invention. Alleles are endogenous genes that are changed by one or more mutations such as deletions, additions and/or substitutions of nucleotides. The resulting mRNA and protein may, but need not, have an altered structure or function. Alleles can be identified using standard techniques (eg, hybridization, amplification, and/or sequence database comparison).

The polynucleotides of the present invention can be obtained using chemical synthesis, recombinant methods or PCR. Methods for the chemical synthesis of polynucleotides are well known in the art and need not be described in detail herein. One skilled in the art can use the sequences provided herein and a commercial DNA synthesizer to obtain the desired DNA sequence.

To obtain polynucleotides using recombinant methods, a polynucleotide containing the desired sequence can be placed in a suitable vector, and the vector, in turn, can be introduced into a suitable host cell for replication and amplification, as further discussed herein. Polynucleotides can be placed into host cells using methods known in the art. Cells are transformed by introducing an exogenous polynucleotide by direct injection, endocytosis, transfection, F-pairing, or electroporation. Once introduced, the exogenous polynucleotide can be maintained in the cell as a non-integrable vector (such as a plasmid) or integrated into the genome of the host cell. The thus amplified polynucleotide can be isolated from the host cell using methods well known in the art. See, for example, Sambrook et al., 1989.

Alternatively, PCR allows the reproduction of DNA sequences. PCR technology is well known in the art and is described in US Pat. Nos. 4,683,195; 4,800,159; eds., Birkauswer Press, Boston, 1994.

RNA can be obtained by using the isolated DNA in a suitable vector and introducing it into a suitable host cell. When cells reproduce by cell division and the DNA is transcribed into RNA, the RNA can then be isolated using methods well known to those skilled in the art, as presented previously, for example in Sambrook et al., 1989.

Suitable cloning vectors may be constructed according to standard techniques or may be selected from a wide variety of cloning vectors available in the art. Although the cloning vector selected may vary depending on the host cell to be used, useful cloning vectors will generally be capable of self-replication, may contain a separate target for a particular restriction endonuclease, and/or may carry genes for a marker that can be used. when selecting clones containing the vector. Suitable examples include plasmids and bacterial viruses, for example, pUC18, pUC19, Bluescript (for example, pBS SK+) and their derivatives, mp18, mp19, pBR322, pMB9, ColE1, pCR1, RP4, phage DNA and bifunctional vectors such as pSA3 and pAT28. These and many other cloning vectors are available from commercial manufacturers such as BioRad, Strategene and Invitrogen.

Expression vectors are typically replicable polynucleotide constructs that contain a polynucleotide according to the invention. The expression vector is expected to be capable of replication in host cells, either as episomes or as a component of chromosomal DNA. Suitable expression vectors include, but are not limited to, plasmids, viral vectors including adenoviruses, adeno-associated viruses, retroviruses, cosmids, and expression vector(s) disclosed in PCT Publication No. WO87/04462, or pLVX lentiviral vectors available from Clonetech. Vector components typically may include, without limitation, one or more of the following: a signal sequence; replication start point; one or more marker genes; suitable transcription control elements (such as promoters, enhancers and terminator). For expression (i.e. translation) also typically requires one or more transcription control elements, such as ribosome binding sites, translation initiation sites, and stop codons.

Vectors containing the polynucleotides of interest can be introduced into the host cell by any number of suitable methods, including electroporation, transfection using calcium chloride, rubidium chloride, calcium phosphate, DEAE-dextran, or other substances; microparticle bombardment; lipofection and infection (for example, where the vector is an infectious agent, such as vaccinia virus). The choice of vectors or polynucleotides to be administered will often depend on the properties of the host cell.

A polynucleotide encoding a CD70-specific CAR disclosed herein may be present in an expression cassette or expression vector (e.g., a plasmid for introduction into a bacterial host cell, or a viral vector such as a baculovirus vector for transfection of an insect host cell, or a plasmid or viral vector such as a lentivirus for transfection of a mammalian host cell). In some embodiments, the implementation of the polynucleotide or vector may include a nucleic acid sequence encoding sequences with ribosomal "breakthrough", such as, for example, without limitation, the sequence encoding the 2A peptide. 2A peptides, which have been identified in the aphthovirus subgroup of picornaviruses, induce ribosomal skipping from one codon to another without forming a peptide bond between the two amino acids encoded by the codons (see (Donnelly and Elliott 2001; Atkins, Wills et al. 2007; Doronina, Wu et al. 2008)). By "codon" is meant three nucleotides per mRNA (or on the sense strand of a DNA molecule) that are translated by the ribosome into one amino acid residue. Thus, two polypeptides can be synthesized from one contiguous open reading frame in mRNA when the polypeptides are separated by the 2A oligopeptide sequence that is in frame. Such ribosomal skipping mechanisms are well known in the art and are known to be used by multiple vectors to express multiple proteins encoded by a single messenger RNA.

To direct transmembrane polypeptides into the secretory pathway of a host cell, in some embodiments, a secretory signal sequence (also known as a leader sequence, prepro sequence, or pre sequence) is provided in a polynucleotide sequence or a vector sequence. The secretory signal sequence is operably linked to the transmembrane nucleic acid sequence, i.e. the two sequences are linked in the correct reading frame and positioned to direct the newly synthesized polypeptide into the secretory pathway of the host cell. Typically, secretory signal sequences are located 5' from the nucleic acid sequence encoding the polypeptide of interest, although some secretory signal sequences may be located elsewhere in the nucleic acid sequence of interest (see, e.g., Welch et al., US Pat. No. 5,037,743; Holland et al., US patent No. 5143830). In some embodiments, the signal peptide comprises the amino acid sequence shown under SEQ ID NO: 266 or 277. Those skilled in the art will appreciate that, due to the degeneracy of the genetic code, significant sequence variations are possible between these polynucleotide molecules. In some embodiments, the nucleic acid sequences of the present invention are codon-optimized for expression in mammalian cells, or in some embodiments, for expression in human cells. Codon optimization refers to the replacement of codons in a sequence of interest that are typically rare in highly expressed genes in a given species with codons that tend to be frequently found in highly expressed genes in that species by such codons encoding amino acids, like codons, that are exchanged.

ANTIBODIES SPECIFIC TO CD70 AND METHODS FOR THEIR PRODUCTION

This document provides antibodies to CD70.

In some embodiments, an anti-CD70 antibody of the present invention comprises any of the light chain partial sequences listed in Table 1 and/or any one of the heavy chain partial sequences listed in Table 1. In Table 1, the underlined sequences are CDR sequences according to Kabat and in bold type according to Chothia.

Tables 2A-2B provide examples of the CDR sequences of the anti-CD70 antibodies provided herein.

In some embodiments, the invention provides an antibody (e.g., comprising antibody fragments such as single chain variable fragments (scFv) that specifically bind to the 70 cassette of differentiation (CD70)), wherein the antibody comprises (a) a heavy chain variable region (VH) comprising (i) a first complementarity determining region (CDR1 ), VH containing the sequence shown under SEQ ID NOs: 49, 50, 51, 55, 56, 57, 61, 62, 63, 67, 68, 69, 73, 74, 75, 79, 80, 81, 85 , 86, 87, 91, 92, 93, 97, 98, 99, 103, 104, 105, 109, 110, 111, 115, 116, 117, 121, 122, 123, 127, 128, 129, 133, 134 , 135,139,140,141,145,146,147,151,152,153,157,158,159,163,164,165,169,170,171,175,176,177,181,182, 183 187 188 189 382 383 384 388 389 390 394 395 396 400 401 402 406 407 408 412 413 414 418 419 420 424 , 425, 426, 430, 431, 432, 663, 664, 665, 436, 437, 438, 442, 443, 444, 448, 449, 450, 454, 455, 456, 460, 461, 462, 466, 467 , 468, 472, 473, 474, 478, 479, 480, 484, 485, 486, 490, 491, 492, 496, 497, 498, 502, 503, 504, 508, 509 or 510; (ii) a VH CDR2 containing the sequence shown under SEQ ID NOs: 52, 53, 58, 59, 64, 65, 70, 71, 76, 77, 82, 83, 88, 89, 94, 95, 100, 101 , 106 107 112 113 118 119 124 125 130 131 136 137 142 143 148 149 154 155 160 161 166 167 172 173 178 , 179, 184, 185, 190, 191, 385, 386, 391, 392, 397, 398, 403, 404, 409, 410, 415, 416, 421, 422, 427, 428, 433, 434, 666, 667 , 439, 440, 445, 446, 451, 452, 457, 458, 463, 464, 469, 470, 475, 476, 481, 482, 487, 488, 493, 494, 499, 500, 505, 506, 511 or 512; and iii) a VH CDR3 containing the sequence shown under SEQ ID NOs: 54, 60, 66, 72, 78, 84, 90, 96, 102, 108, 114, 120, 126, 132, 138, 144, 150, 156 , 162 168 174 180 186 192 387 393 399 405 411 417 423 429 435 668 441 447 453 459 465 471 477 483 489 , 495, 501, 507 or 513; and/or a light chain variable region (VL) comprising (i) a VL CDR1 comprising the sequence shown under SEQ ID NOs: 193, 196, 199, 202, 205, 208, 211, 214, 217, 220, 223, 226 , 229, 232, 235, 238, 241, 244, 247, 250, 253, 256, 259, 262, 514, 517, 520, 523, 526, 529, 532, 535, 538, 669, 541, 544, 547 , 550, 553, 556, 559, 562, 565, 568, 571, 574 or 577; (ii) a VL CDR2 containing the sequence shown under SEQ ID NOs: 194, 197, 200, 203, 206, 209, 212, 215, 218, 221, 224, 227, 230, 233, 236, 239, 242, 245 , 248, 251, 254, 257, 260, 263, 515, 518, 521, 524, 527, 530, 533, 536, 539, 670, 542, 545, 548, 551, 554, 557, 560, 563, 566 , 569, 572, 575 or 578; and (iii) a VL CDR3 containing the sequence shown under SEQ ID NOs: 195, 198, 201, 204, 207, 210, 213, 216, 219, 222, 225, 228, 231, 234, 237, 240, 243, 246 249 252 255 258 261 264 516 519 522 525 528 531 534 537 540 671 543 546 549 552 555 558 561 5 64, 567, 570, 573, 576 or 579.

In some embodiments, the present invention provides an antibody (e.g., scFv) that specifically binds to the 70 cassette of differentiation (CD70), wherein said antibody comprises a heavy chain variable region (VH) comprising VH CDR1, VH CDR2, and VH CDR3 from a VH sequence, shown under SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 339, 341, 343, 345, 347, 349, 351, 353, 355, 662, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379 or 381 ; and/or a light chain variable region (VL) comprising VL CDR1, VL CDR2 and VL CDR3 from the VL sequence shown under SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 338, 340, 342, 344, 346, 348, 350, 352, 354, 661, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378 or 380.

In some embodiments, the present invention provides an isolated antibody that specifically binds to CD70 and competes with any of the above antibodies.

In some embodiments, the present invention provides an antibody that binds to CD70 and competes with an antibody described herein, including 31H1, 63B2, 40E3, 42C3, 45F11, 64F9, 72C2, 2F10, 4F11, 10H10, 17G6, 65E11, P02B10, P07D03 P08A02 P08E02 P08F08 P08G02 P12B09 P12F02 P12G07 P13F04 P15D02 P16C05 10A1 10E2 11A1 11C1 11D1 11E1 12A2 12 C4, 12C5, 12D3, 12D6, 12D7, 12F5, 12H4, 8C8, 8F7, 8F8, 9D8, 9E10, 9E5, 9F4 or 9F8.

In some embodiments, implementation of the present invention also provides parts of the CDR antibodies to CD70 based on the contact regions of the CDR. CDR contact regions are regions of an antibody that confer specificity for an antibody to an antigen. In general, CDR contact regions include residue positions in the CDR and vernier zones that are restricted to maintain proper loop structure to allow binding of the antibody to a specific antigen. See, for example, Makabe et al., J. Biol. Chem. , 283:1156-1166, 2007. The definition of CDR contact regions is well known to those skilled in the art.

The binding affinity (K _D ) of an anti-CD70 antibody described herein to CD70 (e.g., human CD70 (e.g., (SEQ ID NO: 335)) can be from about 0.001 to about 5000 nM. In some embodiments, the binding affinity is approximately 5000 nM, 4500 nM, 4000 nM, 3500 nM, 3000 nM, 2500 nM, 2000 nM, 1789 nM, 1583 nM, 1540 nM, 1500 nM, 1490 nM, 1064 nM, 100 0 nM, 933 nM, 894 nM, 750 nM, 705 nM, 678 nM, 532 nM, 500 nM, 494 nM, 400 nM, 349 nM, 340 nM, 353 nM, 300 nM, 250 nM, 244 nM, 231 nM, 225 nM, 207 n M, 200 nM, 186 nM, 172 nM, 136 nM, 113 nM, 104 nM, 101 nM, 100 nM, 90 nM, 83 nM, 79 nM, 74 nM, 54 nM, 50 nM, 45 nM, 42 nM, 40 nM, 35 nM , 32nM, 30nM, 25nM, 24nM, 22nM, 20nM, 19nM, 18nM, 17nM, 16nM, 15nM, 12nM, 10nM, 9nM, 8nM, 7.5nM , 7 nM, 6.5 nM, 6 nM, 5.5 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.3 nM, 0.1 nM, 0.01 NM or 0.001 nm. In some embodiments, the affiliation of binding is less than any of the values of 5000 nm, 4000 nm, 3000 nm, 2000 nm, 1000 nm, 900 nm, 800 nm, 250 nm, 100 nm, 100 nm, 50 nm, 30 nM, 20 nM, 10 nM, 7.5 nM, 7 nM, 6.5 nM, 6 nM, 5 nM, 4.5 nM, 4 nM, 3.5 nM, 3 nM, 2.5 nM, 2 nM, 1.5 nM, 1 nM or 0.5 nM.

In some embodiments, implementation of the present invention provides a nucleic acid encoding any of the above isolated antibodies. In some embodiments, implementation of the present invention provides a vector containing such a nucleic acid. In some embodiments, implementation of the present invention provides a host cell containing such a nucleic acid.

The present invention also provides any of the above antibodies for use as a drug. In some embodiments, the drug is for use in the treatment of cancers associated with CD70 selected from the group consisting of renal cell carcinoma, glioblastoma, glioma such as low grade glioma, non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD ), Waldenström's macroglobulinemia, acute myeloid leukemia, multiple myeloma, diffuse large cell lymphoma, follicular lymphoma, or non-small cell lung cancer.

In some embodiments, the present invention provides a method of treating a subject in need thereof, comprising providing any of the above antibodies and administering said antibody to said subject.

In some embodiments, implementation of the present invention provides a pharmaceutical composition containing any of the above antibodies.

In some embodiments, the present invention provides a method of treating a condition associated with CD70-expressing cancer cells in a subject, comprising administering to a subject in need thereof an effective amount of any of the foregoing antibodies or a pharmaceutical composition comprising any of the foregoing antibodies. In some embodiments, the condition is cancer. In some embodiments, the cancer is a CD70-associated cancer selected from the group consisting of renal cell carcinoma, glioblastoma, glioma such as low grade glioma, non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD), Waldenström's macroglobulinemia, acute myeloid leukemia, multiple myeloma, diffuse large cell lymphoma, follicular lymphoma, or non-small cell lung cancer.

In some embodiments, the present invention provides a method of inhibiting tumor growth or progression in a subject that has CD70-expressing cancer cells, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of the present invention.

In some embodiments, the present invention provides a method for inhibiting metastasis of CD70-expressing cancer cells in a subject, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of the present invention.

In some embodiments, the present invention provides a method of inducing tumor regression in a subject that has CD70-expressing cancer cells, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of the present invention.

In some embodiments, the production of an antibody involves culturing a host cell under conditions that result in antibody production and isolating the antibody from the host cell or cell culture.

Antibodies useful in the present invention may include monoclonal antibodies, polyclonal antibodies, antibody fragments (for example, Fab, Fab', F(ab')2, Fv, Fc, etc.), chimeric antibodies, bispecific antibodies, heteroconjugate antibodies, single-chain (ScFv) antibodies, their mutant forms, fusion proteins containing part of the antibody (for example, antibody domain), humanized antibodies, and any other modified configuration of an immunoglobulin molecule that contains an antigen recognition site of the desired specificity, including antibody glycosylation variants, antibody amino acid sequence variants, and covalently modified antibodies. Antibodies can be murine, rat, human or any other origin (including chimeric or humanized antibodies).

In some embodiments, the anti-CD70 monospecific antibody described herein is a monoclonal antibody. For example, an anti-CD70 monospecific antibody is a human monoclonal antibody.

The present invention also provides the following exemplary embodiments:

1. An isolated antibody that specifically binds to the 70 cassette of differentiation (CD70), wherein the antibody contains:

(a) a heavy chain variable region (VH) comprising (i) complementarity determining region one (CDR1), VH, which contains the sequence shown under SEQ ID NOs: 49, 50, 51, 55, 56, 57, 61, 62, 63, 67, 68, 69, 73, 74, 75, 79, 80, 81, 85, 86, 87, 91, 92, 93, 97, 98, 99, 103, 104, 105, 109, 110, 111, 115, 116, 117, 121, 122, 123, 127, 128, 129, 133, 134, 135, 139, 140, 141, 145, 146, 147, 151, 152, 153, 157, 158, 1 59, 163 164 165 169 170 171 175 176 177 181 182 183 187 188 189 382 383 384 388 389 390 394 395 396 4 00, 401, 402, 406, 407, 408, 412, 413, 414, 418, 419, 420, 424, 425, 426, 430, 431, 432, 663, 664, 665, 436, 437, 438, 442, 4 43, 444, 448, 449, 450, 454, 455, 456, 460, 461, 462, 466, 467, 468, 472, 473, 474, 478, 479, 480, 484, 485, 486, 490, 491, 4 92, 496 497 498 502 503 504 508 509 or 510 77, 82, 83, 88, 89, 94, 95, 100, 101, 106, 107, 112, 113, 118, 119, 124, 125, 130, 131, 136, 137, 142, 143, 148, 149, 154 155 160 161 166 167 172 173 178 179 184 185 190 191 385 386 391 392 397 398 403 404 409 410 4 15, 416, 421, 422, 427, 428, 433, 434, 666, 667, 439, 440, 445, 446, 451, 452, 457, 458, 463, 464, 469, 470, 475, 476, 481, 4 82, 487, 488, 493, 494, 499, 500, 505, 506, 511 or 512; and iii) a VH CDR3 containing the sequence shown under SEQ ID NOs: 54, 60, 66, 72, 78, 84, 90, 96, 102, 108, 114, 120, 126, 132, 138, 144, 150, 156 , 162 168 174 180 186 192 387 393 399 405 411 417 423 429 435 668 441 447 453 459 465 471 477 483 489 , 495, 501, 507 or 513; and/or

(b) a light chain variable region (VL) comprising (i) a VL CDR1 which contains the sequence shown under SEQ ID NOs: 193, 196, 199, 202, 205, 208, 211, 214, 217, 220, 223, 226, 229, 232, 235, 238, 241, 244, 247, 250, 253, 256, 259, 262, 514, 517, 520, 523, 526, 529, 532, 535, 538, 669, 541, 5 44, 547, 550, 553, 556, 559, 562, 565, 568, 571, 574 or 577; (ii) a VL CDR2 containing the sequence shown under SEQ ID NOs: 194, 197, 200, 203, 206, 209, 212, 215, 218, 221, 224, 227, 230, 233, 236, 239, 242, 245 , 248, 251, 254, 257, 260, 263, 515, 518, 521, 524, 527, 530, 533, 536, 539, 670, 542, 545, 548, 551, 554, 557, 560, 563, 566 , 569, 572, 575 or 578; and (iii) a VL CDR3 containing the sequence shown under SEQ ID NOs: 195, 198, 201, 204, 207, 210, 213, 216, 219, 222, 225, 228, 231, 234, 237, 240, 243, 246 249 252 255 258 261 264 516 519 522 525 528 531 534 537 540 671 543 546 549 552 555 558 561 5 64, 567, 570, 573, 576 or 579.

2. An isolated antibody that specifically binds to the 70 cassette of differentiation (CD70), wherein the antibody contains:

(a) a VH region containing VH CDR1, VH CDR2 and VH CDR3 from the VH sequence shown under SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 , 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 339, 341, 343, 345, 347, 349, 351, 353, 355, 662, 357, 359, 361, 363 , 365, 367, 369, 371, 373, 375, 377, 379 or 381; and/or

(b) a VL region containing VL CDR1, VL CDR2, and VL CDR3 from the VL sequence shown under SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 , 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 338, 340, 342, 344, 346, 348, 350, 352, 354, 661, 356, 358, 360, 362 , 364, 366, 368, 370, 372, 374, 376, 378 or 380.

3. An isolated antibody that specifically binds to CD70 and competes with the antibody of Embodiment 1.

4. Nucleic acid encoding an antibody according to any one of embodiments 1-3.

5. A vector containing a nucleic acid according to embodiment 4.

6. Host cell containing nucleic acid according to embodiment 4.

7. An antibody according to any one of embodiments 1-3 for use as a drug.

8. An antibody according to embodiment 7, wherein the drug is for use in the treatment of CD70 associated cancer selected from the group consisting of renal cell carcinoma, glioblastoma, glioma such as low grade glioma, non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD), Waldenström's macroglobulinemia, acute myeloid leukemia, multiple myeloma, diffuse large cell lymphoma, follicular lymphoma, or non-small cell lung cancer.

9. A method of treating a subject in need thereof, comprising:

providing an antibody according to any one of embodiments 1-3, and

administering said antibody to said subject.

10. A pharmaceutical composition containing an antibody according to any one of embodiments 1-3.

11. A method of treating a condition associated with CD70-expressing cancer cells in a subject, comprising administering to a subject in need thereof an effective amount of an antibody according to any one of embodiments 1-3 or a pharmaceutical composition according to embodiment 10.

12. The method according to embodiment 11, wherein the condition is cancer.

13. The method according to embodiment 12, wherein the cancer is a CD70 associated cancer selected from the group consisting of renal cell carcinoma, glioblastoma, glioma such as low grade glioma, non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD ), Waldenström's macroglobulinemia, acute myeloid leukemia, multiple myeloma, diffuse large cell lymphoma, follicular lymphoma, or non-small cell lung cancer.

14. A method for inhibiting tumor growth or progression in a subject having CD70-expressing cancer cells, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to Embodiment 10.

15. A method for inhibiting metastasis of CD70-expressing malignant cells in a subject, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to Embodiment 10.

16. A method for inducing tumor regression in a subject having CD70-expressing cancer cells, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to Embodiment 10.

17. A method for producing an antibody, comprising culturing a host cell according to Embodiment 6 under conditions that lead to the production of an antibody, and isolating the antibody from the host cell or cell culture.

Methods for constructing an immune cell

This document provides methods for obtaining immune cells for use in immunotherapy. In some embodiments, the methods involve introducing a CAR of the present invention into immune cells and expanding the cells. In some embodiments, the present invention relates to a method for constructing an immune cell comprising: providing the cell and allowing expression on the cell surface of at least one CAR as described above. Methods for constructing immune cells are described, for example, in PCT Patent Application Publication Nos. incorporated herein by reference in its entirety. In some embodiments, the method involves transfecting a cell with at least one CAR-encoding polynucleotide as described above and expressing the polynucleotides in the cell.

In some embodiments, the polynucleotides are present in lentiviral vectors for stable expression in cells.

In some embodiments, the method may further comprise the step of genetically modifying a cell by disrupting or inactivating at least one gene expressing, for example, without limitation, a TCR component, an immunosuppressive agent target, an HLA gene, CD70, and/or an immune response checkpoint protein such such as PDCD1 or CTLA-4. By disruption or inactivation of a gene is meant that the gene of interest is not expressed in a functional protein form. In some embodiments, the gene to be destroyed or inactivated is selected from the group consisting of, for example, without limitation, TCRα, TCRβ, CD52, GR, PD-1, CD70, and CTLA-4. In some embodiments, the method involves disrupting or inactivating one or more genes by introducing into cells a rare-cleaving endonuclease capable of selectively inactivating the gene by selectively cleaving DNA. In some embodiments, the rare-cleaving endonuclease can be, for example, a zinc finger nuclease (ZFN), a megaTAL nuclease, a meganuclease, a transcription activator-like effector nuclease (TALE-nuclease), or a CRISPR-associated endonuclease.

In some embodiments, an additional catalytic domain is used with a rare-cutting endonuclease to increase its ability to inactivate target genes. For example, the additional catalytic domain may be a DNA end processing enzyme. Non-limiting examples of DNA end processing enzymes include 5-3'-exonucleases, 3-5'-exonucleases, 5-3'-alkaline exonucleases, 5'-flap endonucleases, helicases, phosphatases, hydrolases, and template-independent DNA polymerases. Non-limiting examples of such a catalytic domain include a protein domain or a catalytically active derivative of a protein domain selected from the group consisting of hExoI (EXO1_HUMAN), Yeast ExoI (EXO1_YEAST), E. coli ExoI, human TREX2, mouse TREX1, human TREX1, bovine TREX1, rat TREX1, TdT (terminal deoxynucleotidyl transferase) human DNA2, yeast DNA2 (DNA2_YEAST). In some embodiments, the additional catalytic domain may have 3'-5' exonuclease activity, and in some embodiments, said additional catalytic domain is TREX, such as the TREX2 catalytic domain (WO2012/058458). In some embodiments, said catalytic domain is encoded by a single chain TREX polypeptide. The additional catalytic domain may be fused to a nuclease-hybridized protein or to a chimeric protein. In some embodiments, the additional catalytic domain is fused using, for example, a peptide linker.

In some embodiments, the method further comprises the step of introducing into the cells an exogenous nucleic acid comprising at least a sequence homologous to a portion of the target nucleic acid sequence such that homologous recombination occurs between the target nucleic acid sequence and the exogenous nucleic acid. In some embodiments, said exogenous nucleic acid comprises first and second portions that are homologous to the 5' and 3' regions of the target nucleic acid sequence, respectively. The exogenous nucleic acid may also contain a third portion located between the first and second portions that does not share homology with the 5' and 3' regions of the target nucleic acid sequence. After cleavage of the target nucleic acid sequence, a homologous recombination event between the target nucleic acid sequence and the exogenous nucleic acid is stimulated. In some embodiments, homologous sequences that are at least about 50 bp, greater than about 100 bp can be used in the donor matrix. or more than about 200 p. The size of the exogenous nucleic acid may be, for example, without limitation, from about 200 bp. up to approximately 6000 p. or from about 1000 p. up to about 2000 bp Plots of common nucleic acid homology are located in the regions flanking the site of insertion of the gap in the 3'-5'-direction and 5'-3'-direction, and the nucleic acid sequence to be introduced is located between the two arms.

In some embodiments, the implementation of the nucleic acid sequentially contains the first region of homology with sequences located above the specified cleavage site; a sequence for inactivating a target gene selected from the group consisting of TCRα, TCRβ, CD52, CD70, glucocorticoid receptor (GR), deoxycytidine kinase (DCK), and an immune response checkpoint protein such as, for example, programmed death-1 (PD- 1); and a second region of sequence homology below the cleavage site. The step of introducing the polynucleotide can be carried out simultaneously, before or after the introduction or expression of the rare-cutting endonuclease. Depending on the location of the target nucleic acid sequence in which the break event occurred, such an exogenous nucleic acid can be used to knock out a gene, for example, when the exogenous nucleic acid is in the open reading frame of a gene, or to introduce new sequences or genes of interest. Sequence insertions using such exogenous nucleic acid can be used to modify an existing target gene by making an adjustment or substitution of the gene (allele exchange - as a non-limiting example) or to increase or decrease the expression of the target gene (exchange of promoters - as a non-limiting example), to make an adjustment or replacement of the target gene. In some embodiments, inactivation of a gene selected from the group consisting of TCRα, TCRβ, CD52, CD70, GR, DCK, and immune checkpoint proteins can be performed at the precise genomic location that a specific TALE nuclease is targeting, where said specific TALE α-nuclease catalyzes cleavage, and wherein the exogenous nucleic acid sequentially comprises at least a region of homology and a sequence for inactivating one target gene selected from the group consisting of TCRα, TCRβ, CD52, CD70, GR, DCK, immune response checkpoint proteins that integrate through homologous recombination. In some embodiments, multiple genes can be sequentially or simultaneously disrupted or inactivated using multiple TALE nucleases, respectively, and specifically targeting one specific gene and multiple specific polynucleotides to inactivate a specific gene.

In some embodiments, the method involves inactivating one or more additional genes selected from the group consisting of TCRα, TCRβ, CD52, CD70, GR, DCK, and immune response checkpoint proteins. In some embodiments, gene inactivation can be achieved by introducing into cells at least one rare-cleaving endonuclease such that the rare-cleaving endonuclease specifically catalyzes cleavage of a target sequence of the cellular genome; and optionally introducing into the cells an exogenous nucleic acid sequentially containing a first region of homology with sequences upstream of the cleavage site, a sequence to be inserted into the genome of the cell, and a second region of homology with sequences below the cleavage site; where the introduced exogenous nucleic acid inactivates the gene and integrates at least one exogenous polynucleotide sequence encoding at least one recombinant protein of interest. In some embodiments, the exogenous polynucleotide sequence is integrated into a gene encoding a protein selected from the group consisting of TCRα, TCRβ, CD52, CD70, GR, DCK, and an immune response checkpoint protein.

In another aspect, the step of genetically modifying cells may include modifying T cells by destroying or inactivating at least one gene expressing a target for an immunosuppressive agent, and expanding the cells, optionally in the presence of an immunosuppressive agent. An immunosuppressive agent is an agent that suppresses immune function through one of several mechanisms of action. An immunosuppressive agent may reduce the activity and/or severity of an immune response. Non-limiting examples of immunosuppressive agents include calcineurin inhibitors, rapamycin targets, interleukin-2 α-chain blockers, inosine monophosphate dehydrogenase inhibitors, dihydrofolate reductase inhibitors, corticosteroids, and immunosuppressive antimetabolites. Some cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act by activating T cells or suppressing helper cell activation. The methods of the present invention confer immunosuppressive resistance on T cells in immunotherapy by destroying or inactivating the target of the immunosuppressive agent in the T cells. As non-limiting examples, targets for an immunosuppressive agent can be a receptor for an immunosuppressive agent, such as, for example, but not limited to CD52, the glucocorticoid receptor (GR), members of the FKBP gene family, and members of the cyclophilin gene family.

In some embodiments, the genetic modification according to the method includes expression in the cells provided for construction of one rare-cleavage endonuclease, whereby the rare-cleavage endonuclease specifically catalyzes cleavage in one target gene, thereby causing the destruction or inactivation of the target gene. In some embodiments, the method for constructing cells includes at least one of the following steps: providing a T cell, such as, for example, from a cell culture or from a blood sample; selecting a gene in a T cell expressing a target for an immunosuppressive agent; introducing into the T cell a rare-cleaving endonuclease capable, through DNA cleavage (in some embodiments, by introducing a double-strand break), to selectively inactivate a gene encoding a target for an immunosuppressive agent, and cell expansion optionally in the presence of an immunosuppressive agent.

In some embodiments, the method includes: providing a T cell, such as, for example, from a cell culture or from a blood sample; selecting a gene in a T cell where the gene expresses a target for an immunosuppressive agent; transfection of a T cell with a nucleic acid encoding a rare-cleaving endonuclease capable of, through DNA cleavage (in some embodiments, by introducing a double-strand break), to selectively inactivate a gene encoding a target for an immunosuppressive agent, and expression of rare-cleaving endonucleases in T cells; and cell expansion optionally in the presence of an immunosuppressive agent.

In some embodiments, a rare-cleaving endonuclease specifically targets CD52 or GR. In some embodiments, the gene selected for inactivation encodes CD52 and the immunosuppressive treatment comprises a humanized antibody that targets the CD52 antigen. In some embodiments, the gene selected for inactivation encodes for GR and the immunosuppressive treatment involves the use of a corticosteroid, such as dexamethasone. In some embodiments, the gene selected for inactivation is a member of the FKBP gene family or a variant thereof, and the immunosuppressive treatment involves the use of FK506, also known as tacrolimus or fujimycin. In some embodiments, a member of the FKBP gene family is FKBP12 or a variant thereof. In some embodiments, the gene selected for inactivation is a member of the cyclophilin gene family or a variant thereof, and the immunosuppressive treatment involves the use of cyclosporine.

In some embodiments, the rare-cleaving endonuclease can be, for example, a zinc finger nuclease (ZFN), a megaTAL nuclease, a meganuclease, a transcription activator-like effector nuclease (TALE-nuclease), or a CRISPR-associated endonuclease. In some embodiments, the rare-cleaving endonuclease is a TALE nuclease. In some embodiments, the rare-cleaving nuclease is a CRISPR nuclease with a guide RNA that is at least partially or fully complementary to the target site.

Typically, the CRISPR-associated nuclease is provided with a guide RNA (gRNA) or functional equivalent. gRNA has two parts; crispr-RNA (crRNA), which is specific to a target genomic DNA sequence, and transactivating RNA (tracrRNA), which promotes Cas binding to DNA. In some embodiments, crRNA and tracrRNA may be present in the same RNA oligonucleotide, referred to as a single guide RNA (sgRNA). In some embodiments, crRNA and tracrRNA may be present as separate RNA oligonucleotides. As used herein, the term "guide RNA" or "gRNA" refers to the combination of tracrRNA and crRNA, presented either as sgRNA or as a crRNA:tracrRNA duplex. In some embodiments, the CRISPR-associated nuclease is a Cas9 nuclease. In some embodiments, the implementation of the Cas9 protein can be obtained from Streptococcus pyogenes (SpCas9). In some embodiments, the implementation of the Cas9 protein can be obtained from other strains of bacteria, including Staphylococcus aureus (SaCas9). In some embodiments, the Cas endonuclease is selected from the group consisting of SpCas9, SpCas9-HF1, SpCas9-HF2, SpCas9-HF3, SpCas9-HF4, SaCas9, FnCpf, FnCas9, eSpCas9, C2C1, C2C3, Cpf1, Casl, CaslB, Cas2, Cas3 , Cas4, Cas5, Cas6, Cas7, Cas8, Cas9 (also known as Csnl and Csx12), Cas10, Csyl, Csy2, Csy3, Csel, Cse2, Cscl, Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6 , Cmrl, Cmr3, Cmr4, Cmr5, Cmr6, Csbl, Csb2, Csb3, Csxl7, Csxl4, Csx10, Csx16, CsaX, Csx3, Csxl, Csxl5, Csfl, Csf2, Csf3 or Csf4.

Research shows that adoptive transfer of T cells derived from less differentiated (i.e., T_SCM or T_CM) subpopulations, leads to long-term persistencein vivo(see, for example, Berger, C. et al., The Journal of Clinical Investigation, 118(1): 294-305 (2008)). Thus, genetic knockdown of CD70 in the CAR-T product is an important factor in preventing T cell differentiation.

In some embodiments, the genetic modification of the method comprises expression in the engineered cells of a single cleavage endonuclease such that the cleavage endonuclease specifically catalyzes cleavage at the CD70 gene, thereby causing the destruction or inactivation of the CD70 gene. In some embodiments, the method for constructing cells includes at least one of the following steps: providing a T cell, such as, for example, from a cell culture or from a blood sample; introducing into the T cell a rare-cleaving endonuclease capable of selectively inactivating (in some embodiments, by introducing a double-strand break) a gene encoding CD70 through DNA cleavage, and cell expansion.

In some embodiments, the method includes: providing a T cell, for example, from a cell culture or from a blood sample; transfecting a T cell with a nucleic acid encoding a rare-cleaving endonuclease capable of selectively inactivating, by DNA cleavage (in some embodiments, by introducing a double-strand break), a gene encoding CD70 and expression of rare-cleaving endonucleases in T cells; and cell reproduction.

In some embodiments, the rare-cleaving endonuclease can be, for example, a meganuclease, a zinc finger nuclease, or a TALE nuclease (TALEN). In some embodiments, the rare-cleaving endonuclease is a TALE nuclease. In some embodiments, the rare-cleaving nuclease is a CRISPR-associated nuclease, together with a guide RNA that is at least partially or fully complementary to the target site.

Also provided herein are methods for constructing T cells suitable for immunotherapy, the methods comprising genetically modifying T cells by destroying or inactivating at least an immune response checkpoint protein. In some embodiments, the immune response checkpoint protein is, for example, PD-1 and/or CTLA-4. In some embodiments, methods for genetically modifying a cell include modifying T cells by destroying or inactivating at least one immune response checkpoint protein and expanding the cells. Immune response checkpoint proteins include, but are not limited to, programmed death protein 1 (PD-1, also known as PDCD1 or CD279, accession number: NM _- 005018), cytotoxic T-lymphocyte antigen 4 (CTLA-4, also known as CD152, accession number AF414120.1 in GenBank), LAG3 (also known as CD223, accession number: NM _- 002286.5), Tim3 (also known as HAVCR2, accession number in GenBank: JX049979.1), BTLA (also known as CD272, accession number: NM _- 181780.3), BY55 (also known as CD160, GenBank accession number: CR541888.1), TIGIT (also known as VSTM3, accession number: NM _- 173799), B7H5 (also known as C10orf54, mouse vista gene homologue, accession number : NM _- 022153.1), LAIR1 (also known as CD305, GenBank accession number: CR542051.1), SIGLEC10 (GenBank accession number: AY358337.1), 2B4 (also known as CD244, accession number: NM _- 001166664.1), that directly suppress immune cells. For example, CTLA-4 is a cell surface protein expressed by some CD4 and CD8 T cells; when its ligands (B7-1 and B7-2) interact with antigen presenting cells, T cell activation and effector function are suppressed.

In some embodiments, said method for constructing cells includes at least one of the following steps: providing a T cell, such as, for example, from a cell culture or from a blood sample; introducing into the T cell a rare-cleaving endonuclease capable of selectively inactivating (in some embodiments by introducing a double-strand break) one gene encoding an immune response checkpoint protein through DNA cleavage, and cell expansion. In some embodiments, the method includes providing a T cell, for example, from a cell culture or from a blood sample; transfecting said T cell with a nucleic acid encoding a rare-cleaving endonuclease capable of selectively inactivating by DNA cleavage (in some embodiments, by introducing a double-strand break) a gene encoding an immune response checkpoint protein and expression of rare-cleaving endonucleases in T cells; cell reproduction. In some embodiments, a rare-cleaving endonuclease specifically targets a gene selected from the group consisting of: PD-1, CTLA-4, LAG3, Tim3, BTLA, BY55, TIGIT, B7H5, LAIR1, SIGLEC10, 2B4, TCRα, and TCRβ. In some embodiments, a rare-cleaving endonuclease can be a meganuclease, a zinc finger nuclease, or a TALE nuclease. In some embodiments, the rare-cleaving endonuclease is a TALE nuclease. In some embodiments, the rare-cleaving nuclease is Cas9 with a guide RNA that is at least partially or fully complementary to the target site.

In some embodiments, the present invention may be particularly suitable for allogeneic immunotherapy. In such embodiments, cells can be modified by a method that involves disrupting or inactivating at least one gene encoding a T cell receptor (TCR) component in T cells and expanding the T cells. In some embodiments, the genetic modification according to the method is due to the expression in the cells of the construct of a single cleavage endonuclease, whereby the cleavage endonuclease specifically catalyzes the cleavage of one target gene, thereby causing destruction or inactivation of the target gene. In some embodiments, said method for constructing cells includes at least one of the following steps: providing a T cell, such as, for example, from a cell culture or from a blood sample; introducing into the T cell a rare-cleaving endonuclease capable of selectively inactivating, via DNA cleavage (in some embodiments, by introducing a double-strand break), at least one gene encoding a T cell receptor (TCR) component; and cell reproduction.

In some embodiments, the method includes providing a T cell, such as, for example, from a cell culture or from a blood sample; transfecting said T cell with a nucleic acid encoding a rare-splitting endonuclease capable of selectively inactivating, by DNA cleavage (in some embodiments, by introducing a double strand break), at least one gene encoding a T cell receptor (TCR) component; expression of rare-splitting endonucleases in T-cells; sorting of transformed T cells that do not express TCR on their cell surface; and cell reproduction.

In some embodiments, a rare-cleaving endonuclease can be a meganuclease, zinc finger nucleases, or a TALE nuclease. In some embodiments, the rare-cleaving endonuclease is a TALE nuclease. In some embodiments, TALE nucleases recognize and cleave the sequence encoding TCRα or TCRβ. In some embodiments, the TALE nuclease comprises a polypeptide sequence selected from the amino acid sequence shown under SEQ ID NOs: 281, 282, 283, 284, 285, 286, 287, 288, 289, or 290.

Polypeptide sequences of TALE-nuclease:

repeat TRAC_T01-L

LTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASH DGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAH (SEQ ID NO: 281).

Repeat TRAC_T01-R

LTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDG GKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQ (SEQ ID NO: 282).

Repeat TRBC_T01-L

LTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNG GGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLC (SEQ ID NO: 283).

Repeat TRBC_T01-R

NPQRSTVWYLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLVLCQAHGLTPE QVVAIASHDGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGK QALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGRPALE (SEQ ID NO: 284 ).

Repeat TRBC_T02-L

LTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHD GGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQ (SEQ ID NO: 285).

Repeat TRBC_T02-R

LTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQA LETVQALLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAH (SEQ ID NO: 286).

Repeat CD52_T02-L

LTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAI ASHDGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQ RLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPQQVVAIASNGGGRPALE (SEQ ID NO: 287).

Repeat CD52_T02-R

LTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPQQVVAIAS NGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRL (SEQ ID NO: 288)

Repeat CD70-L

LTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNG GGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQ RLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGRPALE (SEQ ID NO: 289)

Repeat CD70-R

LTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGG KQALETVQALLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAH (SEQ ID NO: 290)

In another aspect, another step of genetically modifying the cell may be a method of expanding TCRα deficient T cells, comprising introducing pTα (also known as preTCRα) or a functional variant thereof into the T cell and expanding the cells, optionally by stimulating the CD3 complex. In some embodiments, the method comprises: a) transfecting cells with a nucleic acid encoding at least a pTα fragment to maintain expression on the surface of CD3; b) expression of said pTα in cells; and c) cell expansion, optionally by stimulation of the CD3 complex.

Methods for obtaining T cells for immunotherapy are also provided, comprising the steps of a method for expanding T cells. In some embodiments, the pTα polynucleotide sequence may be introduced randomly or by homologous recombination. In some embodiments, the implementation of the insert may be associated with inactivation of the TCRα gene.

Various functional variants of pTα can be used. A "functional variant" of a peptide refers to a molecule that is essentially similar to either a complete peptide or a fragment thereof. A "fragment" of pTα or a functional variant thereof refers to any subset of the molecule, ie a peptide shorter than the full length pTα. In some embodiments, pTα or functional variants may be, for example, a full-length pTα or a C-terminally truncated pTα variant. C-terminally truncated pTα lacks one or more C-terminal residues. As non-limiting examples, the C-terminally truncated version of pTα lacks 18, 48, 62, 78, 92, 110, or 114 residues from the C-terminus of the protein. Variants of the amino acid sequence of the peptide can be obtained by mutations in the DNA encoding the peptide. Such functional variants include, for example, deletions, insertions or substitutions of residues in the amino acid sequence. Any combination of deletion, insertion, and substitution can also be performed to obtain the final construct, provided that the final construct has the desired activity, in particular the restoration of a functional CD3 complex. In some embodiments, at least one mutation must be introduced into different pTα variants to affect dimerization, as described above. As a non-limiting example, the mutant residue can be at least W46R, D22A, K24A, R102A, or R117A from the human pTα protein, or positions aligned using the CLUSTALW method on a pTα family member or homologue member. In some embodiments, pTα or a variant thereof described above contains a mutant W46R residue or mutant residues D22A, K24A, R102A, and R117A. In some embodiments, said pTα or variants are also fused to a signaling domain such as, for example, CD28, OX40, ICOS, CD27, CD137 (4-1BB) and CD8, provided as non-limiting examples. The extracellular domain of pTα or the variants described above can be fused to a fragment of the TCRα protein, in particular the transmembrane and intracellular domain of TCRα. pTα variants can also be fused to the intracellular domain of TCRα.

In some embodiments, pTα variants may be fused to an extracellular ligand-binding domain. In some embodiments, pTα or a functional variant thereof is fused to a single chain antibody fragment (scFv) containing a variable fragment of the light and heavy chains of the target antigen-specific monoclonal antibody connected by a flexible linker.

The term "TCRα deficient T cell" refers to an isolated T cell that lacks the expression of a functional TCRα chain. This can be achieved in various ways, provided as non-limiting examples: by constructing the T cell such that it does not express any functional TCRα on its cell surface, or by constructing the T cell such that it produces only a small amount of functional TCRα chain on its surface, or by constructing a T cell to express a mutated or truncated form of the TCRα chain. Cells deficient in TCRα are no longer able to proliferate at the expense of the CD3 complex. Thus, to overcome this problem and allow TCRα deficient cells to proliferate, pTα or a functional variant thereof is introduced into the cells, whereby a functional CD3 complex is restored. In some embodiments, the method further comprises introducing into said T cells rare-cleaving endonucleases capable of selectively inactivating, by DNA cleavage, one gene encoding one component of the T cell receptor (TCR). In some embodiments, the rare-cleaving endonuclease is a TALE nuclease.

In another aspect, engineered T cells obtained by the methods described herein can be contacted with bispecific antibodies. For example, T cells can be contacted with the bispecific antibodies ex vivo prior to administration to a patient or in vivo after administration to a patient. Bispecific antibodies contain two variable regions with different antigenic properties that help the engineered cells approach the target antigen. As a non-limiting example, a bispecific antibody can be directed against a tumor marker and a lymphocyte antigen, such as, for example, but not limited to CD3, and can redirect and activate any circulating T cells against tumors.

In some embodiments, the implementation of the polynucleotide encoding the polypeptides of the present invention may be mRNA, which is introduced directly into cells, for example, by electroporation. In some embodiments, cytoPulse technology may be used to temporarily increase the permeability of living cells in order to deliver material to cells. The parameters can be modified to define conditions for high transfection efficiency with minimal mortality.

This document also provides methods for transfecting T cells. In some embodiments, the method involves contacting a T cell with RNA and applying to the T cell a rapid pulse train consisting of: (a) an electrical pulse with a voltage range of about 2250 to 3000 volts per centimeter; (b) a pulse duration of 0.1 ms; (c) a pulse interval between the electrical pulses in steps (a) and (b) of about 0.2 to 10 ms; (d) an electrical pulse with a voltage range of approximately 2250 to 3000 V, with a pulse duration of approximately 100 ms and a pulse interval of approximately 100 ms between the electrical pulse in step (b) and the first electrical pulse in step ( c); and (e) four electrical pulses with a voltage of approximately 325 V, with a pulse duration of approximately 0.2 ms and a pulse interval of 2 ms between each of the 4 electrical pulses. In some embodiments, a method for transfecting a T cell involves bringing said T cell into contact with RNA and applying to the T cell a rapid pulse sequence comprising: (a) an electrical pulse with a voltage of approximately 2250, 2300, 2350, 2400, 2450 , 2500, 2550, 2400, 2450, 2500, 2600, 2700, 2800, 2900 or 3000 volts per centimeter; (b) a pulse duration of 0.1 ms; (c) and a pulse interval between the electrical pulses in steps (a) and (b) of approximately 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ms; (d) one electrical pulse with a voltage range of approximately 2250, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2400, 2450, 2500, 2600, 2700, 2800, 2900, or 3000 V, with pulse duration, a component of 100 ms, and a pulse interval of 100 ms between the electrical pulse in step (b) and the first electrical pulse in step (c); and (e) 4 electrical pulses with a voltage of approximately 325 V, with a pulse duration of approximately 0.2 ms and a pulse interval of approximately 2 ms between each of the 4 electrical pulses. Any values within the range of values described above are disclosed in this application. The electroporation medium may be any suitable medium known in the art, such as BTXpress ^{Cytoporation®} Media T4, available from BTX. In some embodiments, the electroporation medium has a conductivity in the range of about 0.01 to about 1.0 mS.

In some embodiments, as non-limiting examples, the RNA encodes a rare-cutting endonuclease, one monomer of a rare-cutting endonuclease, e.g., semi-TALE nuclease, CAR, at least one component of a multi-stranded chimeric antigen receptor, pTα or a functional variant thereof, an exogenous nucleic acid, and/or one additional catalytic domain.

Engineered immune cells

The present invention also provides engineered immune cells containing any of the CAR polynucleotides described herein. In some embodiments, the CAR can be introduced into an immune cell as a transgene via a plasmid vector. In some embodiments, the implementation of the plasmid vector may also contain, for example, a selection marker that allows identification and/or selection of cells that received the vector.

CAR polypeptides can be synthesized in situ in a cell after polynucleotides encoding CAR polypeptides are introduced into the cell. Alternatively, CAR polypeptides can be produced outside of cells and then introduced into cells. Methods for introducing a polynucleotide construct into cells are known in the art. In some embodiments, stable transformation methods can be used to integrate the polynucleotide construct into the genome of the cell. In other embodiments, transient transformation methods can be used to transiently express a polynucleotide construct without the polynucleotide construct being integrated into the cell's genome. In other embodiments, viral mediated methods can be used. The polynucleotides can be introduced into the cell by any suitable means, such as, for example, recombinant viral vectors (for example, retroviruses, adenoviruses), liposomes and the like. Temporal transformation techniques include, for example, without limitation, microinjection, electroporation, or particle bombardment. Polynucleotides can be included in vectors such as, for example, plasmid vectors or viral vectors.

This document also presents isolated cells and cell lines obtained by the above-described methods of constructing cells presented in this document. In some embodiments, the isolated cell contains at least one CAR as described above. In some embodiments, the isolated cell contains a population of CARs, with each CAR containing different extracellular ligand-binding domains.

This document also provides isolated immune cells obtained using any of the methods described above. Any immune cell capable of expressing heterologous DNA can be used to express the CAR of interest. In some embodiments, the immune cell is a T cell. In some embodiments, the implementation of the immune cell can be obtained from, for example, without limitation, a stem cell. The stem cells can be adult stem cells, non-human embryonic stem cells, such as non-human stem cells, cord blood stem cells, progenitor cells, bone marrow stem cells, induced pluripotent stem cells, totipotent stem cells, or hematopoietic stem cells. Typical human cells are CD34+ cells. The isolated cell may also be a dendritic cell, a killer dendritic cell, a mast cell, an NK cell, a B cell, or a T cell selected from the group consisting of inflammatory T lymphocytes, cytotoxic T lymphocytes, regulatory T lymphocytes, or helper T cells. T-lymphocytes. In some embodiments, the cell may be derived from the group consisting of CD4+ T lymphocytes and CD8+ T lymphocytes.

In some embodiments, engineered immune cells expressing on their cell surface membrane the CD70-specific CAR of the present invention contain a percentage of memory stem cells and central memory cells greater than 10%, 20%, 30%, 40%, 50% or 60%. In some embodiments, engineered immune cells expressing on their cell surface membrane the CD70-specific CAR of the present invention comprise a percentage of memory stem cells and central memory cells of from about 10% to about 60%, from about 10% to about 50%, about 10% to about 40%, about 15% to about 50%, about 15% to about 40%, about 20% to about 60%, or about 20% to about 70%.

In some embodiments, the immune cell is an inflammatory T lymphocyte that expresses any of the CARs described herein. In some embodiments, the immune cell is a cytotoxic T lymphocyte that expresses any of the CARs described herein. In some embodiments, the immune cell is a regulatory T lymphocyte that expresses any of the CARs described herein. In some embodiments, the immune cell is a helper T lymphocyte that expresses any of the CARs described herein.

Before propagation and genetic modification, the source of cells can be obtained from the subject through a number of non-limiting methods. Cells can be obtained from a number of non-limiting sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, site of infection, ascitic fluid, pleural effusion, spleen tissue, and tumors. In some embodiments, any number of T cell lines available and known to those skilled in the art may be used. In some embodiments, the cells may be obtained from a healthy donor, from a patient diagnosed with cancer, or from a patient diagnosed with an infection. In some embodiments, the cells may be part of a mixed population of cells that have different phenotypic characteristics.

This document also provides cell lines derived from transformed T cells in accordance with any of the methods described above. This document also presents modified cells resistant to immunosuppressive treatment. In some embodiments, the isolated cell of the present invention contains a polynucleotide encoding a CAR.

Immune cells of the present invention can be activated and propagated either before or after genetic modification of T cells using methods generally described, for example, without limitation in US patent No. 6352694; 6534055; 6905680; 6692964; 5858358; 6887466; 6905681; 7144575; 7067318; 7172869; 7232566; 7175843; 5883223; 6905874; 6797514; 6867041; as well as US Patent Application Publication No. 20060121005. T cells can be propagated in vitro or in vivo. Typically, T cells of the present invention can be expanded, for example, by contacting an agent that stimulates the CD3 TCR complex and a co-stimulatory molecule on the surface of the T cells to generate an activation signal for the T cell. For example, chemicals such as calcium ionophore A23187, phorbol 12-myristate-13-acetate (PMA), or mitogenic lectins such as phytohemagglutinin (PHA) can be used to generate an activation signal for the T cell.

In some embodiments, populations of T cells can be stimulated in vitro by contacting, for example, an anti-CD3 antibody or antigen-binding fragment thereof, or an anti-CD2 antibody immobilized on a surface, or by contacting a protein kinase C protein activator (for example , bryostatin) in combination with a calcium ionophore. To costimulate a helper molecule on the surface of T cells, a ligand is used that binds the helper molecule. For example, a population of T cells can be contacted with an anti-CD3 antibody and an anti-CD28 antibody under conditions suitable to stimulate T cell proliferation. The anti-CD3 antibody and the anti-CD28 antibody can be placed on a bead, plate, or other substrate. Suitable conditions for T cell culture include a suitable medium (e.g., Minimal Essential Media, or RPMI Media 1640, or X-vivo 5 (Lonza)), which may contain factors necessary for proliferation and viability, including blood serum (eg, fetal bovine or human serum), interleukin-2 (IL-2), insulin, IFN-γ, IL-4, IL-7, GM-CSF, IL-10, IL-2, IL-15, TGFp and TNF or any other cell growth supplements known to the person skilled in the art. Other cell growth additives include, but are not limited to, surfactant, plasmanate, and reducing agents such as N-acetylcysteine and 2-mercaptoethanol. Media may include RPMI 1640, A1M-V, DMEM, MEM, a-MEM, F-12, X-Vivo 1 and X-Vivo 20, Optimizer supplemented with amino acids, sodium pyruvate and vitamins, either without serum or supplemented with appropriate amount of blood serum (or blood plasma) or a certain set of hormones and / or an amount of cytokine (s) sufficient for the growth and reproduction of T cells (for example, IL-7 and/or IL-15). Antibiotics, for example penicillin and streptomycin are only added to the experimental cultures, not to the cell cultures to be administered to the subject. Target cells are maintained under conditions necessary to support growth, such as at an appropriate temperature (eg, 37°C) and atmosphere (e.g. ambient air plus 5% CO₂). T cells that have been exposed to different stimulation times may exhibit different characteristics.

In some embodiments, the implementation of the cells of the present invention can be propagated by co-culturing with tissue or cells. Cells can also be propagated in vivo, for example, in the blood of a subject after administration of the cell to the subject.

In some embodiments, the isolated cell of the present invention contains one disrupted or inactivated gene selected from the group consisting of CD52, CD70, GR, PD-1, CTLA-4, LAG3, Tim3, BTLA, BY55, TIGIT, B7H5, LAIR1, SIGLEC10, 2B4, HLA, TCRα and TCRβ, and/or expresses CAR, multi-chain CAR and/or pTα transgene. In some embodiments, the isolated cell contains polynucleotides encoding polypeptides containing a multi-stranded CAR. In some embodiments, an isolated cell of the present invention contains two disrupted or inactivated genes selected from the group consisting of: CD52 and GR, CD52 and TCRα, CDR52 and TCRβ, CD70 and CD52, CD70 and TCRα, CD70 and TCRβ, GR and TCRα , GR and TCRβ, TCRα and TCRβ, PD-1 and TCRα, PD-1 and TCRβ, CTLA-4 and TCRα, CTLA-4 and TCRβ, LAG3 and TCRα, LAG3 and TCRβ, Tim3 and TCRα, Tim3 and TCRβ, BTLA and TCRα, BTLA and TCRβ, BY55 and TCRα, BY55 and TCRβ, TIGIT and TCRα, TIGIT and TCRβ, B7H5 and TCRα, B7H5 and TCRβ, LAIR1 and TCRα, LAIR1 and TCRβ, SIGLEC10 and TCRα, SIGLEC10 and TCRβ, 2B4 and TCRα , 2B4 and TCRβ, and/or expresses CAR, multi-chain CAR and pTα transgene.

In some embodiments, the isolated cell of the present invention contains three degraded or inactivated genes selected from CD52, CD70 and TCRα or CD52, CD70 and TCRβ, and/or expresses CAR, a multi-stranded CAR and a pTα transgene.

In some embodiments, the implementation of the TCR becomes non-functional in the cells of the present invention by destroying or inactivating the TCRα gene and/or TCRβ gene(s). In some embodiments, a method is provided for obtaining modified cells derived from an individual, wherein the cells can proliferate independently of the major histocompatibility complex (MHC) signaling pathway. Modified cells that can proliferate independently of the MHC signaling pathway that are susceptible to production by this method are within the scope of the present invention. The modified cells disclosed herein can be used to treat patients in need thereof for host versus graft (HvG) rejection and graft versus host disease (GvHD); therefore, within the scope of the present invention is a method of treating patients in need thereof for host-versus-graft (HvG) rejection and graft-versus-host disease (GvHD), comprising treating said patient by administering to said patient an effective amount of the modified cells containing disrupted or inactivated TCRα and/or TCRβ genes.

In some embodiments, immune cells are engineered to be resistant to one or more chemotherapy drugs. The chemotherapeutic drug may be, for example, a purine nucleotide analog (PNA), which makes the immune cell suitable for anti-cancer therapy combining adoptive immunotherapy and chemotherapy. Exemplary PNAs include, for example, clofarabine, fludarabine, cyclophosphamide, and cytarabine, alone or in combination. PNAs are metabolized by deoxycytidine kinase (dCK) into mono-, di-, and triphosphate PNAs. Their triphosphate forms compete with ATP for DNA synthesis, act as pro-apoptotic agents, and are highly potent inhibitors of ribonucleotide reductase (RNR), which is involved in trinucleotide production. This document provides CD70 specific CAR-T cells containing a disrupted or inactivated dCK gene. In some embodiments, dCK knockout cells are obtained by transfecting T cells with polynucleotides encoding a specific TAL nuclease directed against dCK genes, such as by mRNA electroporation. CD70-specific dCK-knockout CAR-T cells can be resistant to PNAs, including, for example, clorofarabine and/or fludarabine, and maintain T cell cytotoxic activity against CD70-expressing cells.

In some embodiments, the isolated cells or cell lines of the present invention may contain pTα or a functional variant thereof. In some embodiments, the isolated cell or cell line may be further genetically modified by disruption or inactivation of the TCRα gene.

Epitopes specific for monoclonal antibodies

In some embodiments, the extracellular domain of any of the CD70-specific CARs described herein may contain one or more epitopes specific for (i.e., specifically recognizable) monoclonal antibodies. These epitopes are also referred to herein as mAb-specific epitopes. Illustrative mAb-specific epitopes are disclosed in International Patent Publication No. WO 2016/120126, which is incorporated herein in its entirety. In these embodiments, the extracellular domain comprises VH and VL polypeptides that specifically bind to CD70 and one or more epitopes that bind to one or more monoclonal antibodies (mAbs). CARs containing mAb-specific epitopes may be single-stranded or multi-stranded.

The incorporation of monoclonal antibody-specific epitopes into the extracellular domain of the CARs described herein allows sorting and depletion of engineered CAR-expressing immune cells. In some embodiments, this property also promotes the recovery of endogenous CD70-expressing cells that have been depleted by the introduction of CAR-expressing engineered immune cells.

Accordingly, in some embodiments, the present invention provides a method for sorting and/or depleting engineered immune cells having CARs containing mAb-specific epitopes, and a method for promoting the recovery of endogenous CD70-expressing cells, such as bone marrow progenitor cells.

To obtain CARs containing epitopes specific for monoclonal antibodies, several pairs of epitope-monoclonal antibody can be used; in particular, those already approved for medical use, such as the CD20 epitope/rituximab, as a non-limiting example.

The present invention also encompasses methods for sorting engineered immune cells having CD70-specific CARs expressing mAb-specific epitope(s) and therapeutic methods wherein activation of engineered immune cells having such CARs is modulated by cell depletion using an antibody that is targeted. on the external ligand-binding domain of these CARs.

Rituximab Mimotop SEQ ID NO: 293 CPYSNPSLC pavilizumab epitope SEQ ID NO: 660 NSELLSLINDMPITNDQKKLMSNN Cetuximab Mimotop 1 SEQ ID NO: 603 CQFDLSTRRLKC Mimotop 2 SEQ ID NO: 604 CQYNLSSRALKC Mimotop 3 SEQ ID NO: 605 CVWQRWQKSYVC Mimotop 4 SEQ ID NO: 606 CMWDRFSRWYKC Nivolumab Epitope 1 SEQ ID NO: 607 SFVLNWYRMSPSNQTDKLAAFPEDR Epitope 2 SEQ ID NO: 608 SGTYLCGAISLAPKAQIKE QBEND-10 Epitope 1 SEQ ID NO: 609 ELPTQGTFSNVSTNVS Epitope 2 SEQ ID NO: 295 ELPTQGTFSNVSTNVSPAKPTTTA Alemtuzumab epitope SEQ ID NO: 610 GQNDTSQTSSPS

In some embodiments, the implementation of the CAR-T cell contains a polynucleotide encoding a "suicidal" polypeptide, such as, for example, RQR8. See, for example, WO2013153391A, which is incorporated herein by reference in its entirety. In CAR-T cells containing the polynucleotide, the "suicidal" polypeptide is expressed on the surface of the CAR-T cell. In some embodiments, the suicide polypeptide comprises the amino acid sequence shown under SEQ ID NO: 291.

CPYSNPSLCSGGGGSELPTQGTFSNVSTNVSPAKPTTTACPYSNPSLCSGGGGSPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRRRVCKCPRPVV (SEQ ID NO: 291).

The "suicidal" polypeptide may also contain a signal peptide at the amino terminus, for example, MGTSLLCWMALCLLGADHADA (SEQ ID NO: 611). In some embodiments, the "suicidal" polypeptide comprises the amino acid sequence shown under SEQ ID NO: 292, which includes the signal sequence under SEQ ID NO: 611.

mgtsllcwmalcllgadhadacpysnpslcsggggselptqgtfsnvstnvspakptttacpysnpslcsggggspaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlycnhrnrrrvckcprpvv (SEQ ID NO: 292).

In some embodiments, the suicide polypeptide comprises the amino acid sequence of SEQ ID NO: 611

If the "suicidal" polypeptide is expressed on the surface of a CAR-T cell, binding of rituximab to the R-epitopes of the polypeptide causes cell lysis. More than one molecule of rituximab can bind to a single polypeptide expressed on the cell surface. Each R-epitope of the polypeptide can bind to a separate molecule of rituximab. Removal of CD70-specific CAR-T cells can occur in vivo, for example, by administering rituximab to a patient. The decision to remove the transferred cells may be driven by the discovery in the patient of undesirable effects that are associated with the transferred cells, for example, if unacceptable levels of toxicity are found.

In some embodiments, when administered to a patient, engineered immune cells expressing on their cell surface any of the CD70-specific CARs described herein can downregulate, kill, or lyse endogenous CD70-expressing cells in the patient. In one embodiment, the percentage reduction or lysis of endogenous CD70-expressing cells or cells from a CD70-expressing cell line by engineered immune cells expressing any of the CD70-specific CARs described herein is at least about 10 %, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% or more than the specified values. In one embodiment, the percentage reduction or lysis of endogenous CD70-expressing cells or cells from a CD70-expressing cell line by engineered immune cells expressing any of the CD70-specific CARs described herein is from about 5% to about 95%, about 10% to about 95%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, from about 10% to about 50%, about 10% to about 40%, about 20% to about 90%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 25% to about 75%, or about 25% to about 60%. In one embodiment, the endogenous CD70-expressing cells are endogenous CD70-expressing bone marrow cells.

In one embodiment, the percentage reduction in the level or lysis of target cells, for example, cell line expressing CD70 by engineered immune cells expressing on their cell surface membrane a CAR specific for CD70 of the present invention can be measured using the assay described herein.

Method for sorting CAR-positive immune cells

In one aspect, methods are provided for in vitro sorting of an immune cell population, wherein the immune cell subpopulation comprises engineered immune cells expressing any of the CD70-specific CARs containing epitopes specific for the monoclonal antibodies described herein. The method involves contacting a population of immune cells with an epitope-specific monoclonal antibody and selecting immune cells that bind to the monoclonal antibody to obtain a population of cells enriched in engineered immune cells expressing CD70-specific CAR.

In some embodiments, said monoclonal antibody specific for said epitope is optionally conjugated to a fluorophore. In this embodiment, the step of selecting cells that bind to the monoclonal antibody can be performed using fluorescence activated cell sorting (FACS). In some embodiments, said monoclonal antibody specific for said epitope is optionally conjugated to magnetic particles. In this embodiment, the step of selecting cells that bind to the monoclonal antibody can be performed using magnetic field activated cell sorting (MACS).

In some embodiments, the extracellular binding domain in the CAR contains a mAb-specific epitope with one or more of SEQ ID NOs: 294 or 601-610. In some embodiments, the extracellular binding domain in the CAR contains the mAb-specific epitope of SEQ ID NO: 609. In some embodiments, the extracellular binding domain in the CAR contains the mAb-specific epitope of SEQ ID NO: 295. In some embodiments, the extracellular binding domain in CAR contains a mAb-specific epitope of SEQ ID NO: 609 and the antibody used to contact the immune cell population is QBEND-10. In some embodiments, the extracellular binding domain in the CAR contains the mAb-specific epitope of SEQ ID NO: 295 and the antibody used to contact the immune cell population is QBEND-10.

In some embodiments, the extracellular binding domain in the CAR contains the mAb-specific epitope of SEQ ID NO: 294. In some embodiments, the extracellular binding domain in the CAR contains the mAb-specific epitope of SEQ ID NO: 294, and the antibody used to bring into contact with a population of immune cells, is rituximab.

In some embodiments, the population of CAR-expressing immune cells obtained using the in vitro immune cell sorting method described above contains at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95 % CAR-expressing immune cells. In some embodiments, the population of CD70 CAR-expressing immune cells obtained using the in vitro sorting of CAR-expressing immune cells described above contains at least 85% CAR-expressing immune cells.

According to the present invention, the cells to be administered to the recipient may be enriched in vitro from the original population. Methods for propagating initial populations are well known in the art and may include selecting cells that express an antigen, such as, for example, the CD34 antigen, using combinations of density gradient centrifugation, immunomagnetic bead purification, affinity chromatography, and sorting of fluorescently activated cells known to those skilled in the art. in this field of technology.

Flow cytometry is widely used in the art and is a technique well known to those skilled in the art for sorting and quantifying specific cell types in a population of cells. In general, flow cytometry is a method for quantifying the components or structural characteristics of cells, primarily by optical means. Because different cell types can be distinguished by quantifying structural characteristics, flow cytometry and cell sorting can be used to enumerate and sort cells with different phenotypes in a mixture.

Flow cytometry analysis involves two main steps: 1) labeling selected cell types with one or more labeling markers, and 2) determining the number of labeled cells relative to the total number of cells in the population.

The primary method of labeling cell types is by linking labeled antibodies to markers expressed by a particular cell type. The antibodies are either directly labeled with a fluorescent compound or indirectly labeled using, for example, a second antibody labeled with a fluorescent label that recognizes the first antibody.

In some embodiments, the method used to sort CAR-expressing immune cells is magnetic field-activated cell sorting (MACS). Magnetically activated cell sorting (MACS) is a method for separating different cell populations based on their surface antigens (CD molecules) using superparamagnetic nanoparticles and columns. To obtain pure cell populations, several simple steps must be followed. Cells in single cell suspension are labeled with microbeads using a magnetic field. The sample is applied to a column consisting of ferromagnetic spheres coated with a cell-friendly coating that ensures fast and gentle cell separation. Unlabeled cells pass, while magnetically labeled cells remain inside the column. The passing stream can be collected as an unlabeled cell fraction. After a short washing step, the column is removed from the separator and the magnetically labeled cells are eluted from the column.

In some embodiments, the mAb used in the method for sorting CAR-expressing immune cells is selected from alemtuzumab, ibritumomab tiuxetan, muromonab-CD3, tositumomab, abciximab, basiliximab, brentuximab vedotin, cetuximab, infliximab, rituximab, bevacizumab, certolizumab pegola, daclizumab, eculizumab , efalizumab, gemtuzumab, nalizumab, omalizumab, Palivizumab, Ranibizumab, Tocilizumab, Trastuzumab, Vedasolizumab, Adalimumab, Belimumab, Kanakinumab, Denosumab, Golimumab, Ipilyimumab, Opatumumab, Panitumab, Qbend-10 and Qbend-10 and Qbend-10 and Qbend-10 Ustekinumab. In some embodiments, said mAb is rituximab. In another embodiment, said mAb is QBEND-10.

In some embodiments, the implementation of the CAR-T cell contains a selected epitope in scFv, characterized by a specificity that is recognized by a particular antibody. See, for example, WO2016/120216, which is incorporated herein by reference in its entirety. Such an epitope facilitates sorting and/or depletion of CAR-T cells. The epitope may be selected from any number of epitopes known in the art. In some embodiments, the epitope may be targeted by a medically approved monoclonal antibody, such as, for example, without limitation, the CD20 epitope recognized by rituximab. In some embodiments, the epitope contains the amino acid sequence CPYSNPSLC (SEQ ID NO: 293)

In some embodiments, the implementation of the epitope is located in the CAR. For example, without limitation, an epitope may be located between the scFv and the CAR hinge region. In some embodiments, two instances of the same epitope separated by linkers can be used in a CAR. For example, a polypeptide containing the amino acid sequence shown under SEQ ID NO: 294 or SEQ ID NO: 609 or SEQ ID NO: 295 can be used in a CAR, located between the light chain variable region and the hinge region.

gsggggscpysnpslcsggggscpysnpslcsggggs (SEQ ID NO: 294)

ELPTQGTFSNVSTNVS (SEQ ID NO: 609)

ELPTQGTFSNVSTNVSPAKPTTTA (SEQ ID NO: 295)

In some embodiments, the CAR extracellular binding domain contains the following sequence:

V ₁ -L ₁ -V ₂ -(L) _x epitope 1-(L) _x -;

V ₁ -L ₁ -V ₂ -(L) _x epitope 1-(L) _x epitope 2-(L) _x -;

V ₁ -L ₁ -V ₂ -(L) _x epitope 1-(L) _x epitope 2-(L) _x epitope 3-(L) _x -;

(L) _x epitope 1-(L) _x -V ₁ -L ₁ -V ₂ ;

(L) _x epitope 1-(L) _x epitope 2-(L) _x -V ₁ -L ₁ -V ₂ ;

epitope 1-(L) _x epitope 2-(L) _x epitope 3-(L) _x -V ₁ -L ₁ -V ₂ ;

(L) _x epitope 1-(L) _x -V ₁ -L ₁ -V ₂ -(L) _x epitope 2-(L) _x ;

(L) _x epitope 1-(L) _x -V ₁ -L ₁ -V ₂ -(L) _x epitope 2-(L) _x epitope 3-(L) _x -;

(L) _x epitope 1-(L) _x -V ₁ -L ₁ -V ₂ -(L) _x epitope 2-(L) _x epitope 3-(L) _x epitope 4-(L) _x -;

(L) _x epitope 1-(L) _x epitope 2-(L) _x -V ₁ -L ₁ -V ₂ -(L) _x epitope 3-(L) _x -;

(L) _x epitope 1-(L) _x epitope 2-(L) _x -V ₁ -L ₁ -V ₂ -(L) _{x -} epitope 3-(L) _{x -} epitope 4-(L) _x -;

V ₁ -(L) _x epitope 1-(L) _x -V ₂ ;

V ₁ -(L) _x epitope 1-(L) _x -V ₂ -(L) _x epitope 2-(L) _x ;

V ₁ -(L) _x epitope 1-(L) _x -V ₂ -(L) _x epitope 2-(L) _x epitope 3-(L) _x ;

V ₁ -(L) _x epitope 1-(L) _x -V ₂ -(L) _x epitope 2-(L) _x epitope 3-(L) _x epitope 4-(L) _x ;

(L) _x epitope 1-(L) _x -V ₁ -(L) _x epitope 2-(L) _x -V ₂ or

(L) _x epitope 1-(L) _x -V ₁ -(L) _x epitope 2-(L) _x -V ₂ -(L) _x epitope 3-(L) _x ;

Where

V ₁ is V _L and V ₂ is V _H or V ₁ is V _H and V ₂ is V _L ;

L ₁ is a linker suitable for linking the V _H chain to the V _L chain;

L is a linker containing glycine and serine residues, and each occurrence of L in the extracellular binding domain may be identical to or different from another occurrence of L in the same extracellular binding domain, which in certain embodiments contains or is SGGGG (SEQ ID NO: 614), GGGGS (SEQ ID NO: 615) or SGGGGS (SEQ ID NO: 616), and

x is 0, or 1, or 2, and each case of x is chosen independently of the others; And

epitope 1, epitope 2, epitope 3 and epitope 4 are mAb-specific epitopes and may be identical or different, and where V _H is a heavy chain variable fragment and V _L is a light chain variable fragment. In some embodiments, epitope 1, epitope 2, and epitope 4 are the mAb-specific epitope having the amino acid sequence of SEQ ID NO: 293, and epitope 3 is the mAb-specific epitope having the amino acid sequence of SEQ ID NO: 295.

In some embodiments, the CAR extracellular binding domain contains the following sequence:

V ₁ -L ₁ -V ₂ -(L) _x epitope 1-(L) _x -;

V ₁ -L ₁ -V ₂ -(L) _x epitope 1-(L) _x epitope 2-(L) _x -;

V ₁ -L ₁ -V ₂ -(L) _x epitope 1-(L) _x epitope 2-(L) _x epitope 3-(L) _x -;

(L) _x epitope 1-(L) _x -V ₁ -L ₁ -V ₂ ;

(L) _x epitope 1-(L) _x epitope 2-(L) _x -V ₁ -L ₁ -V ₂ ;

epitope 1-(L) _x epitope 2-(L) _x epitope 3-(L) _x -V ₁ -L ₁ -V ₂ ;

(L) _x epitope 1-(L) _x -V ₁ -L ₁ -V ₂ -(L) _x epitope 2-(L) _x ;

(L) _x epitope 1-(L) _x -V ₁ -L ₁ -V ₂ -(L) _x epitope 2-(L) _x epitope 3-(L) _x -;

(L) _x epitope 1-(L) _x -V ₁ -L ₁ -V ₂ -(L) _x epitope 2-(L) _x epitope 3-(L) _x epitope 4-(L) _x -;

(L) _x epitope 1-(L) _x epitope 2-(L) _x -V ₁ -L ₁ -V ₂ -(L) _x epitope 3-(L) _x -;

(L) _x epitope 1-(L) _x epitope 2-(L) _x -V ₁ -L ₁ -V ₂ -(L) _{x -} epitope 3-(L) _{x -} epitope 4-(L) _x -;

V ₁ -(L) _x epitope 1-(L) _x -V ₂ ;

V ₁ -(L) _x epitope 1-(L) _x -V ₂ -(L) _x epitope 2-(L) _x ;

V ₁ -(L) _x epitope 1-(L) _x -V ₂ -(L) _x epitope 2-(L) _x epitope 3-(L) _x ;

V ₁ -(L) _x epitope 1-(L) _x -V ₂ -(L) _x epitope 2-(L) _x epitope 3-(L) _x epitope 4-(L) _x ;

(L) _x epitope 1-(L) _x -V ₁ -(L) _x epitope 2-(L) _x -V ₂ or

(L) _x epitope 1-(L) _x -V ₁ -(L) _x epitope 2-(L) _x -V ₂ -(L) _x epitope 3-(L) _x ;

Where

V ₁ is V _L and V ₂ is V _H or V ₁ is V _H and V ₂ is V _L ;

L ₁ is a linker suitable for linking the V _H chain to the V _L chain;

L is a linker containing glycine and serine residues, and each occurrence of L in the extracellular binding domain may be identical to or different from another occurrence of L in the same extracellular binding domain, which in certain embodiments contains or is SGGGG (SEQ ID NO: 614), GGGGS (SEQ ID NO: 615) or SGGGGS (SEQ ID NO: 616), and

x is 0, or 1, or 2, and each case of x is chosen independently of the others; And

epitope 1, epitope 2, epitope 3 and epitope 4 are mAb-specific epitopes and may be identical or different, and where V _H is a heavy chain variable fragment and V _L is a light chain variable fragment. In some embodiments, epitope 1, epitope 2, and epitope 4 are the mAb-specific epitope having the amino acid sequence of SEQ ID NO: 293 and epitope 3 is the mAb-specific epitope having the amino acid sequence of SEQ ID NO: 609.

In some embodiments, the CAR extracellular binding domain contains the following sequence:

V ₁ -L ₁ -V ₂ -(L) _x epitope 1-(L) _x epitope 2-(L) _x - or

(L) _x epitope 1-(L) _x -V ₁ -L ₁ -V ₂ -(L) _x epitope 2-(L) _x epitope 3-(L) _x epitope 4-(L) _x - where V _1, V _2, L _1, L, x and epitope 1, epitope 2, epitope 3 and epitope 4 are defined above.

In some embodiments, the CAR extracellular binding domain contains the following sequence:

(L) _x epitope 1-(L) _x -V ₁ -L ₁ -V ₂ -(L) _x epitope 2-(L) _x epitope 3-(L) _x epitope 4-(L) _x - where V _1, V _2, L _1, L, x are defined above, and where (L) _x epitope 1-(L) _x is GGGGSCPYSNPSLCSGGGGSGGGGS (SEQ ID NO: 617),

(L) _x epitope 2-(L) _x epitope 3-(L) _x epitope 4 is GSGGGGSCPYSNPSLCSGGGGSELPTQGTFSNVSTNVSPAKPTTTACPYSNPSLC (SEQ ID NO: 618)

and V _{1 ,} V _{2 ,} L _{1 ,} L, x are defined above.

In some embodiments, an epitope-specific antibody may be conjugated to a cytotoxic drug. There is also the possibility of enhancing CDC cytotoxicity using engineered antibodies that are grafted with component(s) of the complement system. In some embodiments, CAR-T cell activation can be modulated by cell depletion using an antibody that recognizes an epitope.

Applications in therapy

Isolated cells obtained by the methods described above, or cell lines obtained from such isolated cells, can be used as a drug. In some embodiments, such a drug may be used to treat cancer. In some embodiments, the cancer is renal cell carcinoma, glioblastoma, glioma such as low grade glioma, non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD), Waldenström's macroglobulinemia, acute myeloid leukemia, multiple myeloma, diffuse large cell lymphoma, follicular lymphoma or non-small cell lung cancer.

In some embodiments, the cancer is a cancer of hematopoietic origin, such as lymphoma or leukemia. In some embodiments, the cancer is selected from the group consisting of multiple myeloma, plasma cell malignancy, Hodgkin's lymphoma, lymphocyte-predominant nodular Hodgkin's lymphoma, Kahler's disease and myelomatosis, plasma cell leukemia, plasmacytoma, B-cell prolymphocytic leukemia, hairy cell leukemia , B-cell non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), follicular lymphoma, Burkitt's lymphoma, marginal zone cell lymphoma, mantle cell lymphoma, large cell lymphoma, progenitor B-lymphoblastic lymphoma, myeloid leukemia, Waldenström macroglobulinemia, diffuse large cell lymphoma, follicular lymphoma, mucosal lymphoid tissue lymphoma, small cell lymphocytic lymphoma, primary mediastinal (thymus) large cell lymphoma, lymphoplasmic lymphoma, nodular marginal zone B-cell lymphoma, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, T-cell/histiocytic large B-cell lymphoma, primary central nervous system lymphoma, primary cutaneous diffuse B large cell lymphoma (foot type), EBV-positive diffuse large B-cell lymphoma in the elderly, diffuse large B-cell lymphoma associated with inflammation, intravascular B-large cell lymphoma, ALK-positive B-large cell lymphoma, plasmablastic lymphoma, B-large cell HHV8-associated multifocal Castleman disease lymphoma, unclassified B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and Burkitt's lymphoma, unclassified B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin's lymphoma , and other cancers associated with hematopoietic cells, such as ALL or AML.

In some embodiments, the isolated cell of the present invention, or a cell line derived from the isolated cells, may be used in the manufacture of a medicament for the treatment of cancer in a patient in need thereof.

This document also provides methods for treating patients. In some embodiments, the method involves providing an immune cell of the present invention to a patient in need thereof. In some embodiments, the method includes the step of administering the transformed immune cells of the present invention to a patient in need thereof.

In some embodiments, the implementation of the T cells of the present invention can be subjected to sustained expansion of T cells in vivo and can be maintained for an extended period of time.

The methods of treatment of the present invention may be ameliorative, curative or prophylactic. The method of the present invention may be either part of an autologous immunotherapy or part of an allogeneic immunotherapy treatment. The present invention is particularly suitable for allogeneic immunotherapy. T cells from donors can be transformed into non-alloreactive cells using standard protocols and replicated as needed, thereby producing CAR-T cells that can be administered to one or more patients. Such CAR-T cell therapy can be made available as a commercially available therapeutic product.

Cells that can be used in the methods of the present invention are described in the previous section. This treatment can be used to treat patients diagnosed with, for example, cancer. Cancers that may be treated include, for example, without limitation, cancers that involve B-lymphocytes, including any of the cancers listed above. Cancer types to be treated with CARs and CAR-T cells of the present invention include, without limitation, certain leukemias or lymphoid malignancies. Also included are tumors/cancers in adults and tumors/cancers in children. In some embodiments, the treatment may be carried out in combination with one or more anti-cancer therapies selected from the group of antibody therapy, chemotherapy, cytokine therapy, dendritic cell therapy, gene therapy, hormonal therapy, laser radiation therapy. and radiation therapy.

In some embodiments, patients undergoing immunosuppressive therapy may be treated. Moreover, in some embodiments, the methods of the present invention are based on cells or cell populations that have become resistant to at least one immunosuppressive agent due to inactivation of a gene encoding a receptor for that immunosuppressive agent. In this aspect, immunosuppressive treatment should promote the selection and expansion of T cells in accordance with the present invention in the patient's body. The introduction of cells or populations of cells in accordance with the present invention can be carried out by any convenient method, including using aerosol inhalation, injection, oral administration, infusion, transfusion, implantation or transplantation. The compositions described herein can be administered to a patient subcutaneously, intradermally, intratumorally, intranodally, intramedullary, intramuscularly, via intravenous or intralymphatic injection or infusion, or intraperitoneally. In some embodiments, the cell compositions of the present invention are administered by intravenous injection or infusion.

In some embodiments, administration of cells or a population of cells may include administration of, for example, from about 10 ⁴ to about 10 ⁹ cells per kg of body weight, including all integer values of the number of cells in these ranges. In some embodiments, administration of cells or a population of cells may include administration of from about 10 ⁵ to about 10 ⁶ cells per kg of body weight, including all integer values of the number of cells in these ranges. Cells or a population of cells can be administered in one or more doses. In some embodiments, said effective amount of cells can be administered as a single dose. In some embodiments, the implementation of the specified effective number of cells can be administered in more than one dose over a certain period of time. Determining the timing of administration is the responsibility of the chief physician and depends on the clinical condition of the patient. The cells or population of cells can be obtained from any source, such as from a patient, from a blood bank, or from a donor. Although individual needs vary, determining the optimal ranges for effective amounts of a given cell type for a particular disease or condition is within the skill of the art. An effective amount means an amount that provides a therapeutic or prophylactic benefit. The dose administered will depend on the age, health and weight of the recipient, the type of concomitant treatment, if any, the frequency of treatment, and the nature of the desired effect. In some embodiments, an effective amount of cells or a composition containing these cells is administered parenterally. In some embodiments, the administration may be intravenous. In some embodiments, the implementation of the introduction can be carried out directly by injection into the tumor.

In some embodiments, the methods comprise (a) administering to a subject with a disease a first dose of allogeneic CAR-T cells. In some embodiments, the first dose contains about 1x10 ⁴ cells, about 5x10 ⁴ cells, about 1x10 ⁵ cells, about 5x10 ⁵ cells, about 1x10 ⁶ cells, about 5x10 ⁶ cells, about 6×10 ⁶ cells, approximately 1×10 ⁷ cells, approximately 6×10 ⁷ cells, approximately 1×10 ⁸ , approximately 1.8×10 ⁸ cells or approximately 4.8×10 ⁸ cells. In some embodiments, the methods further comprise (b) administering to the subject a subsequent dose of CAR-T cells at a time point that is at least or greater than about 5 weeks after and less than about 24 weeks from the start of administration in (a).

In some embodiments, a subject with a relapsed/refractory disease (e.g., relapsed/refractory RCC) are given a first and subsequent dose of allogeneic CAR-T cells, each containing approximately 6×10⁶cells, and a subsequent dose of CAR-T cells in (b) is administered approximately 99 days after the start of administration in (a).

In some embodiments, the methods further comprise administering additional subsequent or subsequent doses such that the first and subsequent doses are administered, for example, in accordance with the dose numbers and schedules indicated for the first and subsequent doses. In some embodiments, the first of one or more subsequent doses is administered at a time point that is at least or greater than 5 weeks from the start of the next dose. In some embodiments, the implementation of the introduction of the first, subsequent and subsequent doses include the introduction of at least three doses within 5 weeks or within about 5 weeks. In some embodiments, a subsequent dose is administered approximately 16 weeks from the start of the first dose, and an additional follow-up or follow-up dose is administered at 17 weeks from the start of the first dose. In some embodiments, additional subsequent doses are administered at 17 weeks and/or 34 weeks from the start of the first dose.

In some aspects, the time of administration of the subsequent dose(s) is additionally the time during which the subject does not show an immune response, e.g., does not show a detectable CAR-T-specific adaptive host immune response indicated for the first (or previous) dose. .

In some embodiments, the time between the first dose (initial dose), e.g., between the start of the first or previous dose and the start of the next dose (e.g., the start of the next dose), is greater than about 4 weeks, such as greater than about 5, 6, 7, 8, or 9 days, such as more than about 20 weeks, such as about 9 to about 35 weeks, about 14 to about 28 weeks, 15 to 27 weeks, or about 16 to about 18 weeks; and/or about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 weeks. In some embodiments, the next dose (eg, from the start of administration) is administered more than about 5 weeks after and less than about 24 weeks after the first or previous dose (eg, from the start of administration). In some embodiments, the next dose is started 17 weeks after the first dose. In some embodiments, the time between the first and subsequent doses (e.g., from the start of administration) or to and the subsequent dose is greater than about 5 weeks and less than about 24 weeks, such as 10 to 24 weeks, such as about 17 weeks. In some embodiments, the time between the first and subsequent doses (eg, from the start of administration) is approximately 17 weeks.

In some embodiments of the present invention, cells are administered to a patient in combination (for example, before, concurrently, or after) with any number of suitable treatments, including but not limited to treatment with agents such as CCR2 antagonist monoclonal antibody therapy (e.g., INC-8761), antiviral therapy, cidofovir and interleukin-2, cytarabine (also known as ARA-C), or treating patients with MS with natalizumab, or treating patients with psoriasis with efalizumab, or other treatment options for patients with PML. In some embodiments, CD70-specific CAR-T cells are administered to a patient in combination with one or more of the following: an anti-PD-1 antibody (e.g., nivolumab, pembrolizumab, or PF-06801591), an anti-PD-L1 antibody (such as avelumab, atezolizumab, or durvalumab), an anti-OX40 antibody (eg, PF-04518600), anti-4-1BB antibody (for example, PF-05082566), an anti-MCSF antibody (for example, PD-0360324), an anti-GITR antibody and/or an anti-TIGIT antibody. In some embodiments, a CD70-specific CAR comprising the amino acid sequence shown under SEQ ID NO: 319 or 327 is administered to a patient in combination with avelumab, which is an anti-PD-L1 antibody. In further embodiments, the T cells of the present invention may be used in combination with chemotherapy, radiation therapy, immunosuppressants such as cyclosporine, azathioprine, methotrexate, mycophenolate, and FK506, antibodies, or other immunodestructive agents such as CAMPATH, anti-CD3 antibodies, or other therapies with antibodies, cytoxin, fludarabine, cyclosporine, FK506, rapamycin, mycophenolic acid, steroids, FR901228, cytokines and/or ionizing radiation. These drugs inhibit calcineurin (cyclosporine and FK506) or calcium-dependent phosphatase, or inhibit p70S6 kinase, which is important in growth factor (rapamycin) induced signaling (Henderson, Naya et al. 1991; Liu, Albers et al. 1992; Bierer, Hollander et al. 1993). In additional embodiments, the T cells of the present invention can be used in combination with receptor tyrosine kinase inhibitors such as midostaurin, sunitinib and axitanib, mTOR inhibitors such as rapamacin and everolimus, epigenetic modulators such as vorinostat, proteasome inhibitors such as bortezomib, immunomodulatory agents such as lenalidomide, Hedgehog inhibitors such as erismodegib and PF-04449913, or isocitrate dehydrogenase (IDH) inhibitors such as AG-120 and AG-221. In a further embodiment, the cell compositions of the present invention are administered to a patient in combination with (e.g., before, at the same time or after) bone marrow transplantation, T cell destruction therapy using chemotherapeutic agents such as fludarabine, external beam radiation therapy (XRT), cyclophosphamide, or antibodies such as OKT3 or CAMPATH. In some embodiments, cell compositions of the present invention are administered following B cell destruction therapy, e.g., by means that interact with CD20, such as rituxan. For example, in some embodiments, subjects may receive standard treatment using high dose chemotherapy followed by peripheral blood stem cell transplantation. In some embodiments, after transplantation, subjects receive an infusion of expanded immune cells of the present invention. In some embodiments, expanded cells are administered before or after surgery.

In some embodiments, methods are provided for depleting engineered immune cells expressing CD70-specific CAR in a subject receiving said cells. Depletion can be accomplished by suppression or elimination.

In one aspect, a method for depleting engineered immune cells expressing a CD70-specific CAR containing an epitope specific for a monoclonal antibody comprises contacting said engineered immune cell with a monoclonal antibody specific for that epitope.

In some embodiments, a depletion method in a subject receiving engineered immune cells expressing a CAR specific for CD70 containing an epitope specific for a monoclonal antibody comprises administering to the subject a monoclonal antibody specific for the epitope. In these embodiments, administration to a subject of a monoclonal antibody specific for an epitope present in the extracellular domain of CAR abolishes or suppresses the activity of engineered CAR-expressing immune cells in the subject. In one aspect, depletion of engineered CAR-expressing immune cells allows the restoration of an endogenous population of CD70-expressing cells.

In one aspect, the present invention relates to a method of promoting the recovery of endogenous CD70-expressing cells in a subject who has been administered engineered immune cells expressing on the cell surface a CD70-specific CAR containing an epitope specific to a monoclonal antibody, the method comprising administering to the subject a monoclonal an antibody specific for the epitope. In some embodiments, the endogenous CD70-expressing cells are endogenous CD70-expressing bone marrow cells. In one aspect, the term "recovery" refers to an increase in endogenous CD70-expressing cells. The number of endogenous CD70-expressing cells may increase due to increased proliferation of endogenous CD70-expressing cells and/or due to decreased elimination of endogenous CD70-expressing cells by CAR-expressing engineered immune cells. In some embodiments, administering a monoclonal antibody to a subject depletes engineered immune cells expressing CAR and increases the amount of endogenous CD70-expressing cells in the subject, e.g. endogenous CD70-expressing bone marrow progenitor cells. In one embodiment, administration of a monoclonal antibody to a subject provides for an increase in endogenous CD70-expressing cells by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%. %, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% compared to the number of endogenous cells expressing CD70 before the introduction of the monoclonal antibody.

In one aspect, a method is provided for treating a CD70-mediated condition in a subject, the method comprising: (a) administering to the subject engineered immune cells expressing on the cell surface CARs specific for CD70 containing one or more epitopes specific for one or more monoclonal antibodies ; and (b) subsequent depletion of engineered immune cells in the subject by administering to the subject one or more monoclonal antibodies specific for the epitope.

In some embodiments, the mAbs used in the method of depleting engineered CAR-expressing immune cells are selected from alemtuzumab, ibritumomab tiuxetan, muromonab-CD3, tositumomab, abciximab, basiliximab, brentuximab vedotin, cetuximab, infliximab, rituximab, bevacizumab, certolys umaba pegola, daclizumab, eculizumab, efalizumab, gemtuzumab, natalizumab, omalizumab, palivizumab, ranibizumab, tocilizumab, trastuzumab, vedolizumab, adalimumab, belimumab, canakinumab, denosumab, golimumab, ipilimumab, ofatumumab, panitumumab, QBEND-10, ustekinum ba or their combinations.

In some embodiments, said monoclonal antibody-specific epitope (mAb-specific epitope) is a CD20 epitope or mimotope, for example, SEQ ID NO: 609, SEQ ID NO: 294, or SEQ ID NO: 295, and the epitope-specific mAb is rituximab.

In some embodiments, the step of administering the monoclonal antibody to the subject comprises infusing the subject with the monoclonal antibody. In some embodiments, the amount of the epitope-specific mAb administered to the subject is sufficient to eliminate at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of CAR-expressing immune cells in the subject.

In some embodiments, the step of administering the monoclonal antibody to the subject comprises infusing the subject with 375 mg/m2 of rituximab one or more times per week.

In some embodiments, if immune cells expressing a CAR containing a mAb-specific epitope (CAR-expressing immune cells) are depleted in a CDC assay using epitope-specific mAbs, then the number of viable CAR-expressing immune cells decreases, e.g., at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.

In some embodiments, the cytotoxic drug is associated with epitope-specific mAbs that are used to deplete CAR-expressing immune cells. By combining the targeting activities of monoclonal antibodies with the cytotoxic activity of cytotoxic drugs, the antibody-drug conjugate (ADC) allows fine discrimination between healthy and diseased tissue compared to the use of the drug alone. Several ADCs have received marketing authorizations; while the technology for their preparation, in particular on linkers, is widely represented in the following prior art (Payne, G. (2003) Cancer Cell 3:207-212; Trail et al (2003) Cancer Immunol. Immunother. 52:328-337; Syrigos and Epenetos (1999) Anticancer Research 19:605-614; Niculescu-Duvaz and Springer (1997) Adv. Drug Del. Rev. 26:151-172; U.S. Patent No. 4,975,278).

In some embodiments, the epitope-specific mAb to be infused is pre-conjugated to a molecule capable of stimulating complement-dependent cytotoxicity (CDC). Thus, the complement system aids or supplements the ability of antibodies to clear pathogens from the body. When stimulated by one of several, an activation cascade is launched in the form of a massive increase in response and activation of the membrane attack complex of cell destruction. Another molecule, such as glycans, can be used to conjugate the mAb [Courtois, A, Gac-Breton, S., Berthou, C, Guezennec, J., Bordron, A. and Boisset, C. (2012), Complement dependent cytotoxicity activity of therapeutic antibody fragments is acquired by immunogenic glycan coupling, Electronic Journal of Biotechnology ISSN: 0717-3458; http://www.ejbiotechnology.info DOI: 10.2225/voll5-issue5).

Sets

The present invention provides kits for use in the methods of the present invention. The kits of the present invention comprise one or more containers containing a CD70-specific CAR encoding polynucleotide or engineered immune cell containing a CD70-specific CAR encoding polynucleotide described herein and instructions for use in accordance with any of the methods. according to the present invention described in this document. As a rule, these instructions contain a description of the introduction of engineered immune cells for the types of therapeutic treatment described above. The kit may include one or more lymphodepletion agents (for example, alemtuzumab, cytoxan, fludarabine, cyclophosphamide or temozolomide).

Instructions relating to the use of the engineered immune cells described herein typically include information on dosage, dosing regimen, and route of administration for the intended treatment. Containers can be single doses, general packages (for example, multidose packs) or dose subunits. The instructions provided in the kit of the present invention are typically written instructions on a label or package insert (for example, paper sheet included in the kit), but machine-readable instructions are also acceptable (for example, instructions stored on a magnetic or optical disk for storage). In some embodiments, containers can be identified (for example, by label, barcode or radio frequency identification (RFID)), tracked or captured by a machine-readable container identifier.

The kits of the present invention are placed in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed mylar or plastic bags) and the like. In some embodiments, a container (for example, plastic bag) is suitable for intravenous infusion. Packages are also provided for use in combination with a special device such as an inhaler, a nasal device (e.g. nebulizer) or an infusion device such as a minipump. The kit may have a sterile access port (for example, the container may be an intravenous solution bag or a vial with a hypodermic stopper). The container may also have a sterile access port (for example, the container may be an intravenous solution bag or a vial with a hypodermic stopper). At least one active ingredient in the composition is a CD70 specific CAR. The container may further contain a second pharmaceutically active agent.

Kits may optionally provide additional components such as buffers and interpretive information. Typically, a kit contains a container and a label or leaflet(s) on or associated with the container.

The following examples are offered for illustrative purposes only and are not intended to limit the scope of the present invention. Indeed, various modifications of the present invention in addition to those shown and described herein will be apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims.

The deposits were created in accordance with the provisions of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure and its rules (Budapest Treaty). This guarantees the preservation of a viable culture in the deposit for 30 years from the date of deposit. The deposit will be made available through ATCC subject to the terms of the Budapest Agreement and subject to agreement between Pfizer, Inc. and ATCC, which guarantees permanent and unrestricted access to the progeny of the deposit culture to the public upon the grant of a relevant US patent or upon the publication of any US or foreign patent application, whichever comes first, and makes the progeny available to persons designated by the US Commissioner under patents and trademarks entitled to it under 35 USC Section 122 and the Commissioner's rules under it (including section 1.14 of 37 C.F.R. with specific reference to 886 OG 638).

The assignee of this application has agreed that if the culture of materials in the deposit dies, is lost or destroyed when cultivated under suitable conditions, the materials will be immediately replaced with the same upon notification. The availability of the deposited material should not be construed as a license to practice the present invention in violation of the rights granted under the authority of any government under its patent laws.

EXAMPLES

Example 1 Obtaining CAR-T Cells Specific for CD70

The following codon-optimized CD70-specific CAR sequences listed in Table 5 below were synthesized and subcloned into the following lentiviral vectors: pLVX-EF1a-TurboGFP-P2A-CD70 CAR (Clontech) or pCLS-EF1a-BFP-P2A-CD70 CAR ( Cellectis) using XmaI (5') and MluI (3') restriction sites (thus cloning CAR after the P2A site).

Table 5 Exemplary CD70-Specific CARs

CAR Amino acid sequence of CAR Components 31H1 MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGSSVKVSCKAS GGTFS SY GFS WVRQAPGQGLEWMG GI IPIFGS ANYAQKFQG RVTITADKSTSTVYMELISLRSEDTAVYYCAR GGSSSPFAY WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQNPLSSPVTLGQPASISC RSS QSLVHSDGNTYLS WLQQRPGQSPRLLIY KISNRFS GVPDRFSGSGAGTDFTLKISRVEAEDVGVYYC MQATQFPLT IGGGSKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVK FSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(SEQ ID NO: 311) Signal peptide CD8α;
VH 31H1;
linker GS;
VL 31H1;
linker GS;
hinge section of CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ 63B2 MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGSSVKVSCKAS GGTFS SY GFS WVRQAPGQGLEWMG GI IPIFGT ANYAQKFQG RVTITADKSTSTVFMELISLRSEYTAVYYCAR GGSSSPFAY WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQTPLSSPVTLGQPASISC R SSQSLVHSDGNTYLS WLQQRPGQSPRLLIY KISNRFS GVPDRFSGSGAGTDFTLKISRVEAEDVGVYYC MQATQFPLT IGGGSKVEIK TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRV KFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(SEQ ID NO: 312) Signal peptide CD8α;
VH 63B2;
linker GS;
VL 63B2;
linker GS;
hinge section from CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ 40E3 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVS GGSIS SY YWN WIRQPPGKGLEWIG YI YYSGS TNYNPSLKS RVTISVDTSKNQFSLKLRSVTAADTAVYYCAR DIRTW GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITC RASQGISNY LA WFQQKPGKAPKSLIY AASSLQS GVPSKFSGSGSGTDFTLTISSLQPEDFATYYC QQYNSYPLT FGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCFSPEEEEGGCELRVKRSADAPAYQQ GQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(SEQ ID NO: 313) Signal peptide CD8α;
VH40E3;
linker GS;
VL 40E3;
linker GS;
hinge section of CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ 42C3 RSS QSLVYSDENTYLN WFQQRPGQSLRRLIY QVSNRDS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYFC MQGTYWPPT FGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVK FSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR _ _
(SEQ ID NO: 314) Signal peptide CD8α;
VH42C3;
linker GS;
VL 42C3;
linker GS;
hinge section of CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ 45F11 MALPVTALLLPLALLLHAARPQVQLRGSGPGLVKPSETLSLTCTVS DDSIS VY YWS WIRQPAGKGLEWIG RV YSSGN INYNPSLES RVTMSVDTSKSRFSLNLSSVTAADTAVYYCAR GLDAFDI WGQGTMVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSMSLGERATLSC RASQSVSSSLA WY QQKPGQAPRLLIY GASTRAT GIPARFGGSGSGTEFTLTISSLQSEDFAVYYC QQYINWPH FGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQ LYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(SEQ ID NO: 315) Signal peptide CD8α;
VH45F11;
linker GS;
VL 45F11;
linker GS;
hinge section from CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ 64F9 MALPVTALLLPLALLLHAARPEVQLLESGGGLVQPGESLRLSCEVS GFTFT SY AMS WVRQVPGKGLEWVS II SGVAFT TYYADSVKG RFTISRDHSKNTLYLQMNGLRAEDTAVYYCVK VDGEVY WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITC QASQDI SNYLN WYQQKPGKAPKILIY GASNLET GVPSRFSGSGSGTDFTFAISSLQPEDVATYYC QQYDNFPIT FGQGTRLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFFSPEEEEGGCELRVKRSADAPAY QQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(SEQ ID NO: 316) Signal peptide CD8α;
VH 64F9;
linker GS;
VL 64F9;
linker GS;
hinge section from CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ 72C2 MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGSSVKVSCEAS GGTFI TY AIS WVRQAPGQGLEWMG GI IPFFGT ANYAQKFQG RVTITADKSTSTASMELRSLRSEDTAMYYCAQ WELFFFDF QSVSSNLA WYQQKPGQAPRLLIY SASTRAS GIPARFSGSGSGTEFTLSISSLQSEDFAVYYC QQYDNWPPLT FGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFFSPEEEEGGCELRVKRSADAPAY QQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(SEQ ID NO: 317) Signal peptide CD8α;
VH 72C2;
linker GS;
VL 72C2;
linker GS;
hinge section of CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ 2F10 R ASQSVSSSYLA WYQQQPGQAPRLLIY GASSRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAIYYC QQYGSSPLT FGGGTKVEIK TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADA PAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR _ _
(SEQ ID NO: 318) Signal peptide CD8α;
VH2F10;
linker GS;
VL2F10;
linker GS;
hinge section from CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ 4F11 RASQ DISNYLA WFQQKPGKVPKRLIY AASSLQS GVPSRFSGSGSGTEFTLTISSLLPEDFATYYC LQLNSFPFT FGGGTKVEIN TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFFSPEEEEGGCELRVKRSADAPAY QQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR _
(SEQ ID NO: 319) Signal peptide CD8α;
VH 4F11;
linker GS;
VL 4F11;
linker GS;
hinge section from CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ 10H10 MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAVS GFTFS NH NIH WVRQAPGKGLEWIS YI SRSSST IYYADSVKG RFTISRDNAKNSLYLQMNSLRDEDTAVYYCAR DHAQWYGMDV WGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITC RASQGISSWLA WYQQKPGKAPKVLIY AASSLQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQAFSFPFT FGPGTKVDIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFS RSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(SEQ ID NO: 320) Signal peptide CD8α;
VH 10H10;
linker GS;
VL 10H10;
linker GS;
hinge section of CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ 17G6 MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCVAS GFTFS SY WMS WVRQAPGKGLEWVA SI KQDGSE KYYVDSVKG RFTISRDNAKNSVYLQMNSLRAEDTGVYYCAR EGVNWGWRLYWHFDL WGRGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINC KSSQSVLYSYNNKNYVA WYQQKPGQPPNLLIF WASTRES GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC QQYYSTLT FGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(SEQ ID NO: 321) Signal peptide CD8α;
VH 17G6;
linker GS;
VL 17G6;
linker GS;
hinge section of CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ 65E11 R ASQSVSSSYLA WYQQKPGQAPRLLIY DASSRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QQYGSSPLT FGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADA PAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR _ _
(SEQ ID NO: 322) Signal peptide CD8α;
VH 65E11;
linker GS;
VL 65E11;
linker GS;
hinge section of CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ P02B10 MALPVTALLLPLALLLHAARPEVQLLESGGGLVQPGGSLRLSCAAS GFAFS NY AMS WVRQAPGKGLEWVS AI RGGGGS TYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DFISGTWYPDY WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELQSVLTQPPSASGTPGQRVTISC SGSSSNIGSNYVY WYQQLPGTAPKLLIY RNNQRPS GVPDRFSGSKSGTSASLAISGLRSEDEADYYC AAWDDSLSGVV FGGGTKLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVK FSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(SEQ ID NO: 323) Signal peptide CD8α;
VH P02B10;
linker GS;
VL P02B10;
linker GS;
hinge section of CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ P07D03 MALPVTALLLPLALLLHAARPEVQLVQSGAEVKKPGESLKISCKGS GYRFT SY WIG WVRQMPGKGLEWMG SI YPDDSD TRYSPSFQG QVTISADKSISTAYLQWSSLKASDTAMYYCAS STVDYPGYSYFDY WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELQSVLTQPPSASGTPGQRVTI SC SGSRSNIGSNYVY WYQQLPGTAPKLLIY RNNQRPS GVPDRFSGSKSGTSASLAISGLRSEDEADYYC ASWDGSLSAVV FGTGTKLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFS RSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(SEQ ID NO: 324) Signal peptide CD8α;
VH P07D03;
linker GS;
VL P07D03;
linker GS;
hinge section of CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ P08A02 MALPVTALLLPLALLLHAARPEVQLVQSGAEVKKPGESLKISCKGS GYTFT NY WIA WVRQMPGKGLEWMG II YPDGSD TRYSPSFQG QVTISADKSISTAYLQWSSLKASDTAMYYCAR DITSWYYGEPAFDI WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELQSVLTQPPSASGTPGQRVTISC SGSSSNIGSNYVY WYQQLPGTAPKLLIY RNNQRPS GVPDRFSGSKSGTSASLAISGLRSEDEADYYC ATWDDSLGSPV FGTGTKLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFS RSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(SEQ ID NO: 325) Signal peptide CD8α;
VH P08A02;
linker GS;
VL P08A02;
linker GS;
hinge section of CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ P08E02 MALPVTALLLPLALLLHAARPEVQLVQSGAEVKKPGESLKISCKGS GYSFT SS WIG WVRQMPGKGLEWMG II YPGDSD TRYSPSFQG QVTISADKSISTAYLQWSSLKASDTAMYYCAK GLSQAMTGFGFDY WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELDIQMTQSPSSLSASVGDRVTITC RASQSISRYLN WYQQKPGKAPKLLIY AASILQT GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYSTTMWT FGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRV KFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(SEQ ID NO: 326) Signal peptide CD8α;
VH P08E02;
linker GS;
VL P08E02;
linker GS;
hinge section from CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ P08F08 MALPVTALLLPLALLLHAARPEVQLVQSGAEVKKPGESLKISCKGS GYGFT S GSSSNIGSNYVN WYQQLPGTAPKLLIY GDYQRPS GVPDRFSGSKSGTSASLAISGLRSEDEADYYC ATRDDSLSGSVV FGTGTKLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVK FSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(SEQ ID NO: 327) Signal peptide CD8α;
VH P08F08;
linker GS;
VL P08F08;
linker GS;
hinge section from CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ P08G02 MALPVTALLLPLALLLHAARPEVQLVQSGAEVKKPGESLKISCKGS GYTFP SS WIG WVRQMPGKGLEWMG II YPDTSH TRYSPSFQG QVTISADKSISTAYLQWSSLKASDTAMYYCAR ASYFDRGTGYSSWWMDV WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELDIQMTQSPSSLSASVGDRVTITC RASQSIYDYLH WYQQKPGKAPKLLIY DASNLQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYTTPLFT FGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(SEQ ID NO: 328) Signal peptide CD8α;
VH P08G02;
linker GS;
VL P08G02;
linker GS;
hinge section from CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ P12B09 MALPVTALLLPLALLLHAARPEVQLLESGGGLVQPGGSLRLSCAAS GFTFS QY SMS WVRQAPGKGLEWVS AI SGGGVS TYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAS DISDSGGSHWYFDY WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELDIQMTQSPSSLSASVGDRV TITC RASQYIGRYLN WYQQKRGKAPKLLIH GATSLAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYSTTSPT FGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRV KFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(SEQ ID NO: 329) Signal peptide CD8α;
VH P12B09;
linker GS;
VL P12B09;
linker GS;
hinge section from CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ P12F02 MALPVTALLLPLALLLHAARPEVQLLESGGGLVQPGGSLRLSCAAS GFTFS SY AMS WVRQAPGKGLEWVS TI SGTGGT TYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK VRAGIDPTASDV WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELQSVLTQPPSASGTPGQRVTI SC SGSTSNIGRNYVY WYQQLPGTAPKLLIY RTNQRPS GVPDRFSGSKSGTSASLAISGLRSEDEADYYC AAWDDSLSGRV FGTGTKLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFS RSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(SEQ ID NO: 330) Signal peptide CD8α;
VH P12F02;
linker GS;
VL P12F02;
linker GS;
hinge section from CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ P12G07 MALPVTALLLPLALLLHAARPEVQLLESGGGLVQPGGSLRLSCAAS GFTFN NF AMS WVRQAPGKGLEWVS GI SGSGDN TYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK DRDIGLGWYSYYLDV WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELQSVLTQPPSASGTP GQRVTISC SGSSSNIGSNYVY WYQQLPGTAPKPLIY MNNQRPS GVPDRFSGSSKSGTSASLAISGLRSEDEADYYC AAWDDSLSAVV FGTGTKLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEGSCSCRFPEEEEG GCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(SEQ ID NO: 331) Signal peptide CD8α;
VH P12G07;
linker GS;
VL P12G07;
linker GS;
hinge section from CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ P13F04 MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGSSVKVSCKAS GGTFS SY AIS WVRQAPGQGLEWMG EI IPIFGT ASYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCAR AGWDDSWFDY WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELQSVLTQPPSASGTPGQRVTI SC SGSSNSNIGTNYVS WYQQLPGTAPKLLIY RSSRPS GVPDRFSGSSKSGTSASLAISGLRSEDEADYYC AAWDGSLSGHWV FGTGTKLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVK FSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(SEQ ID NO: 332) Signal peptide CD8α;
VH P13F04;
linker GS;
VL P13F04;
linker GS;
hinge section of CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ P15D02 MALPVTALLLPLALLLHAARPEVQLVQSGAEVKKPGESLKISCKGS GYSFA SY WIG WVRQMPGKGLEWMG VI YPGTSE TRYSPSFQG QVTISADKSISTAYLQWSSLKASDTAMYYCAK GLSASASGYSFQY WGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELDIQMTQSPSSLSASVGDRVTITC RASQSIDTYLN WYQQKPGKAPKLLIY SASSLHS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYSTTAWT FGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVK FSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(SEQ ID NO: 333) Signal peptide CD8α;
VH P15D02;
linker GS;
VL P15D02;
linker GS;
hinge section from CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ P16C05 MALPVTALLLPLALLLHAARPEVQLVQSGAEVKKPGESLKISCKGS GYSFT DY WIG WVRQMPGKGLEWMG MI SPGGST TIYRPSFQG QVTISADKSISTAYLQWSSLKASDTAMYYCAR EMYTGGYGGSWYFDY WGQGTLVTVSSGGGGSGGGGSGGGGGSGGGGSELDIQMTQSPSSLSASVGDR VTITC RASQSIGQSLN WYQQKPGKAPKLLIY GASSLQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYSTPIT FGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGC ELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(SEQ ID NO: 334) Signal peptide CD8α;
VH P16C05;
linker GS;
VL P16C05;
linker GS;
hinge section from CD8α;
TM domain from CD8α;
ISD 41BB;
ISD CD3ζ

CARs containing ScFv based on the sequences 10A1, 10E2, 11A1, 11C1, 11D1, 11E1, 12A2, 12C4, 12C5, 12D3, 12D6, 12D7, 12F5, 12H4, 8C8, 8F7, 8F8, 9D8, 9E10 were also obtained , 9E5, 9F4 or 9F8, and they contain the sequences shown under SEQ ID NOs: 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600 and 601.

Example 2 Screening with Jurkat Cells for In Vitro Characterization of Anti-CD70 CARs

Jurkat cells are an immortalized human T cell line and, like primary T cells, express CD70 when activated or transduced. Thus, these cells were selected for transduction by CAR to CD70 to study their activation profile. Jurkat cells modified with CRISPR/Cas9 with CD70 knockout ("KO Jurkat") or primary Jurkat cells ("WT Jurkat") were transduced with CAR to CD70. Their autoactivation profile was determined by comparing the percentage of CD69 expression on WT Jurkat (autoactivation and target-dependent activation, since WT Jurkat, when transduced, express the target, i.e. CD70) with the same indicator in KO Jurkat (only autoactivation in the absence of a target, i.e. CD70) by flow cytometry. Clones that showed target-specific activation and minimal auto-activation were then selected based on "activation factor" (see below for a definition of the term). Auto-activation is a term used to describe target-independent clustering and CAR activation. CAR autoactivation can range from minimal/nil to high and is considered an inherent characteristic or tendency of scFvs to aggregate and cluster. Autoactivation leads to prolonged signaling and can lead to T cell differentiation, depletion, and reduced cytolytic potential. Screening for and eliminating high-frequency autoactivating CARs is an important step in optimal CAR identification. Ideally, CARs have minimal auto-activation.

Binding of CARs to a recombinant antigen is one way to characterize CARs and group them into unique groups. Strong binding may indicate that CARs are highly expressed on the cell surface and have moderate to high affinity for their target antigen. Low or minimal binding may indicate low expression and/or weaker affinity. High and low binding CARs should be further characterized as optimal affinity and expression on the cell surface is unknown.

Materials and methods

CRISPR/Cas9 mediated CD70 knockout in Jurkat cells

Jurkat cells were transfected with CD70-targeting guide RNA vectors containing Cas9 and GFP derived from DNA 2.0 using Lipofectamine 3000 (Invitrogen). Forty-eight hours after transfection, single cells were sorted with fluorescence activation to select GFP+ CD70- cells. Individual clones were then expanded and genomic DNA for PCR was obtained by coarse cell lysis. PCR products were sequenced to identify clones with insertions/deletions or frameshifts indicative of CD70 knockout.

Transduction of Jurkat cells with CAR to CD70

HEK293T cells were seeded at 0.5 million cells per ml in 2 ml DMEM (Gibco) supplemented with 10% FBS (Hyclone or JR Scientific) per well in a 6-well plate on day 0. On day 1, lentivirus was obtained by mixing lentiviral packaging vectors: 1.5 μg psPAX2, 0.5 μg pMD2G and 2 μg of the appropriate GFP-tagged CAR transfer vector in 250 μl Opti-MEM (Gibco) per well in a 6-well plate ("DNA mix"). 10 μl Lipofectamine 2000 (Invitrogen) in 250 μl Opti-MEM was incubated at room temperature for 5 minutes and then added to the DNA mixture. The virus was incubated at room temperature for 20 minutes, and a total volume of 500 μl was slowly added along the walls to the wells containing HEK293T. On day 2, the medium from each well of the 6-well plate was replaced with 2 ml per well of Jurkat cell medium, i.e. RPMI (Gibco) supplemented with 10% FBS. On day 3, Jurkat cells (KO or WT) were resuspended at 0.5 million cells per ml in 2 ml of RPMI supplemented with 10% FBS per well of a 6-well plate. Lentiviral supernatants of HEK293T cells were collected and passed through a 0.45 micron filter (EMD Millipore) to remove cell debris and then added to Jurkat cells. On day 6, transduction efficiency was determined by detection of the GFP signal by flow cytometry. If necessary, cells were expanded in larger flasks using RPMI supplemented with 10% FBS.

Activation profile and ability to bind CD70 protein

On day 5, transduced cells were stained with human anti-CD69 antibody conjugated to PE-Cy7 and analyzed on a flow cytometer to obtain the percentage of the CD69+ population for each CAR. Cells were also incubated with recombinant biotinylated human CD70 protein, stained with PE-conjugated streptavidin, and analyzed on a flow cytometer to determine protein binding. Activation coefficients (WT activation/KO activation) and protein binding were used to rank CARs.

Table 6

CAR CD69+ in WT (%) CD69+ in KO (%) Activation factor
(WT/KO) Activation type Protein Binding (%) 31H1 37.2 16.1 2.31 Auto 1.75 63B2 11.1 1.85 6 Target 0.02 40E3 59.2 28.3 2.09 Auto 0.65 42C3 30.8 5.86 5.25 Target 1.48 45F11 16.4 2.46 6.67 Target 1.29 64F9 25.2 6.48 3.89 Target 6.24 72C2 7.85 1.27 6.18 Target 0.09 2F10 22.2 2.86 7.76 Target 0.00 4F11 27.6 2.32 11.90 Target 47.10 10H10 32.8 4.48 7.32 Target 17.90 17G6 78.7 11.5 6.84 Target 37.60 65E11 11.4 1.36 8.38 Target 0.05

Activation coefficient and CAR binding to hybridoma proteins were determined in screening using Jurkat cells and used for in vitro characterization of CARs. Activation coefficient was determined by calculating the ratio of percent expression of CD69 on wild type Jurkat cells transduced with CAR to CD70 (WT) and percent expression on Jurkat cells with CD70 knockout transduced with CAR to CD70 (KO). A higher activation coefficient indicates target-dependent activation. Protein binding was determined by binding to recombinant biotinylated hCD70 protein and was detected using phycoerythrin (PE) dye-conjugated streptavidin by flow cytometry. Protein binding values indicate the percentage of CD3+ CAR T cells that bind to the human CD70 protein.

Table 7

CAR %CD69+ in WT (%) CD69+ in KO (%) Activation factor
(WT/KO) Activation type Protein Binding (%) P02B10 22.50 8.01 2.81 Target 77.90 P07D03 14.40 4.73 3.04 Target 0.68 P08A02 67.60 4.69 14.41 Target 20.70 P08E02 43.70 13.30 3.29 Target 57.10 P08F08 34.90 10.20 3.42 Target 35.90 P08G02 54.70 25.90 2.11 Auto 77.80 P12B09 52.10 12.00 4.34 Target 5.74 P12F02 34.80 2.91 11.96 Target 2.39 P12G07 64.90 5.60 11.59 Target 15.50 P13F04 43.20 10.00 4.32 Target 37.50 P15D02 33.60 12.90 2.60 Target 62.00 P16C05 59.80 26.50 2.26 Auto 70.80

Table 7 . The activation coefficient and protein binding of phage CARs were determined by screening using Jurkat cells. The activation coefficient was used for in vitro characterization of CARs. Activation coefficient was determined by calculating the ratio of percent expression of CD69 on wild type Jurkat cells transduced with CAR to CD70 (WT) and percent expression on Jurkat cells with CD70 knockout transduced with CAR to CD70 (KO). A higher activation coefficient indicates target-dependent activation. Protein binding was determined by binding to recombinant biotinylated hCD70 protein and was detected using phycoerythrin (PE) dye-conjugated streptavidin by flow cytometry. Protein binding values indicate the percentage of CD3+ CAR T cells that bind to the human CD70 protein.

CARs that showed minimal autoactivation, i.e. minimal CD69 expression when transduced into Jurkat with KO on CD70 were considered more desirable than those that are highly upregulated even in the absence of a target, as this could result in a more depleted CAR phenotype. Similarly, CARs with a higher degree of binding to the human CD70 protein were considered to be more desirable as it was indicative of proper surface expression and folding of the CAR.

Example 3 Screening with Primary T Cells for In Vitro Characterization of Phage and Hybridoma CARs

Primary human T cells were transduced with CAR to CD70 to determine transduction efficiency, CD70 expression on T cells in culture, and T cell subpopulations. The transduced CAR T cells were then frozen for use in functional assays.

The transduction efficiency of CAR-based constructs can vary greatly between different clones. Greater transduction efficiency results in more CAR T cells and a more efficient production process, while CARs with low transduction efficiency may not be suitable for large scale production. In some embodiments, high transduction efficiency is preferred.

T cells have a range of phenotypes or subpopulations indicative of the state of differentiation and antigen exposure. Cell surface labels help identify T cell subpopulations, with the CD62L marker typically found on naïve, memory stem cells, and central memory T cells. These cells are less differentiated than other subpopulations such as memory effector T cells and effector T cells, so CAR T cells with a higher percentage of CD62L positive cells are preferred in some embodiments.

Surface expression of CD70 also varies between different transduced CARs, with some CAR T cells expressing 20-40% CD70 due to T cell activation and transduction, while others do not.

Materials and methods

Isolation of primary T cells

T cells were isolated from buffy coat samples obtained from Stanford University using Ficoll density gradient media (Ficoll Paque PLUS/GE Healthcare Life Sciences). The PBMC layer was isolated and T cells were purified using a commercially available T cell isolation kit (Miltenyi Biotec).

Transduction of T cells by CAR to CD70

HEK293T cells were seeded at 0.5 million cells per ml in 2 ml DMEM (Gibco) supplemented with 10% FBS (Hyclone or JR Scientific) per well in a 6-well plate on day 0. On day 1, lentivirus was obtained by mixing lentiviral packaging vectors: 1.5 μg psPAX2, 0.5 μg pMD2G and 2 μg of the appropriate GFP-tagged CAR transfer vector in 250 μl Opti-MEM (Gibco) per well in a 6-well plate ("DNA mix"). 10 μl Lipofectamine 2000 (Invitrogen) in 250 μl Opti-MEM was incubated at room temperature for 5 minutes and then added to the DNA mixture. The virus was incubated at room temperature for 20 minutes, and a total volume of 500 μl was slowly added along the walls to the wells containing HEK293T. Purified T cells were activated in X-Vivo-15 medium (Lonza) supplemented with 100 IU/ml human IL-2 (Miltenyi Biotec), 10% FBS (Hyclone or JR Scientific), and supplemented with CD2/CD3/CD28 beads for activation of human T cells at a ratio of granule:cell 1:2 (Miltenyi Biotec). On day 2, the medium from each well of the 6-well plate was replaced with 2 ml per well of T-cell transduction medium, i.e. X-Vivo-15 supplemented with 10% FBS. On day 3, T cells were resuspended at 0.5 million cells per ml in 2 ml of T cell transduction medium per well of a 6-well plate. Lentiviral supernatants of HEK293T cells were harvested and passed through a 0.45 micron filter (EMD Millipore) to remove cell debris and then added to T cells along with 100 IU/ml human IL-2. On day 6, transduction efficiency was determined by detection of the GFP signal by flow cytometry. Cells were expanded in large flasks or G-Rex flasks (Wilson Wolf) as needed using T cell expansion medium, ie X-Vivo-15 supplemented with 5% human AB serum (Gemini Bio).

Expression of CD70 and T cell subpopulations in CAR T cells

On day 13 after activation, transduced CAR T cells were stained with PE-conjugated anti-human CD70 antibody and BV605-conjugated anti-human CD62L antibody and analyzed on a flow cytometer to obtain the percentage of CD70+ and CD62L+ populations for each CAR. The expanded CAR T cells were then frozen in FBS containing 10% DMSO (Sigma Aldrich) for further use in functional assays.

Table 8

CAR CAR+
(%) CD70+
(%) CD62L+
(%) 31H1 58.7 16.0 53.4 63B2 4.1 30.0 76.3 40E3 60.0 31.3 54.5 42C3 51.5 35.9 58.9 45F11 26.8 33.6 78.8 64F9 57.3 27.3 79.1 72C2 32.2 32.2 83.2 2F10 1.1 27.9 32.3 4F11 89.3 0.1 78.0 10H10 37.4 1.7 49.0 17G6 71.7 0.2 69.0 65E11 56.9 5.0 76.1 P02B10 74.2 43.9 73.5 P07D03 81.0 17.7 76.1 P08A02 22.3 0.81 27.6 P08E02 48.1 1.25 35.6 P08F08 89.2 17.0 78.6 P08G02 66.9 1.22 58.8 P12B09 49.7 3.19 25.7 P12F02 59.8 12.8 27.1 P12G07 26.2 3.90 23.1 P13F04 6.47 6.78 32.9 P15D02 78.8 0.37 26.0 P16C05 60.3 11.8 34.4

TABLE 8 The CAR T cell phenotype at day 13 post-activation was used to characterize CAR phage and hybridoma in vitro . The CAR+ population was determined by gated CD3+ cells; the CD70 expressing population was determined by gating live CD3+ cells; the CD62L expressing population was determined by gated live CD3+ CAR+ CD8+ cells.

The CAR-based constructs under study showed different levels of transduction efficiency. Clones that resulted in poor transduction efficiency were considered less desirable as they would be less suitable for large scale production. The CAR T cell products also showed a different phenotype (measured by CD62L expression) and different levels of CD70 expression on the surface. Generally, CAR T cells that expressed higher levels of CD62L were considered more desirable because they were likely to be less differentiated.

Example 4 Phage CAR Stress Test

CAR T cells were prepared with 12 different scFvs from the phage library and frozen as described in the previous example. These CAR T cells were then thawed and mixed with Raji target cells known to express CD70 at a 1:1 effector:target (E:T) ratio in RPMI supplemented with 10% FBS. Thereafter, Raji cells were added to CAR-T cells every 2 days to maintain an E:T ratio of 1:1. The percentage of target cell lysis and the fold increase in the number of effector CAR T cells were determined at each time point.

The stress test is a screening assay that involves repeated exposure of CAR T cells to their target, which causes CAR proliferation and, in some cases, differentiation and depletion. A stress test was used to select optimal clones with a high level of target cell lysis and proliferative abilities after several cycles of exposure to target cells.

Materials and methods

On day 0, CAR T cells prepared with 12 different scFvs from the phage library were thawed and mixed with Raji cells at an E:T ratio of 1:1. On day 2, 200 µl of cells from the assay were mixed with 50 µl of cell count beads (CountBright, Invitrogen) and analyzed on a flow cytometer. Counting beads were used to determine the total number of GFP+ CAR T cells (CD3+ gated) and Raji cells (CD3− gated) for each CAR treatment. Based on the total number of CAR T cells, the number of Raji cells required to maintain an E:T ratio of 1:1 was calculated and added to the appropriate assay well. This process was repeated on day 5 and day 7. Percent target cell lysis was calculated at each time point by calculating the percentage of live Raji cells for each CAR treatment followed by normalization to a non-transduced control. The fold increase in the number of CAR T cells compared to the number of CAR T cells seeded on day 0 was calculated at each time point.

Clones with the highest level of target cell lysis and the highest fold increase in their number at the end of the analysis on day 7, for example, P08F08, were considered optimal clones.

Table 9

CAR Sequential killing analysis Target cell lysis (%) Multiplicity of increase in the number of CAR-T cells Day 2 Day 5 Day 7 Day 2 Day 5 Day 7 P02B10 61.6 -42.9 -12.0 1.56 0.97 0.49 P07D03 80.2 48.9 26.9 1.63 6.11 10.33 P08A02 91.8 12.5 6.9 0.69 1.69 2.65 P08E02 98.8 37.6 -5.7 0.50 0.45 1.06 P08F08 75.9 30.2 57.8 1.52 11.47 24.35 P08G02 98.9 49.9 27.4 0.75 0.56 3.05 P12B09 85.4 11.3 5.4 0.76 2.53 3.34 P12F02 82.8 -53.7 -46.3 2.18 0.96 0.26 P12G07 94.8 36.4 9.1 0.87 1.13 1.58 P13F04 89.3 44.8 41.3 2.15 3.61 5.67 P15D02 98.7 54.6 28.6 1.12 1.29 3.78 P16C05 92.7 18.9 -10.7 1.31 3.13 3.72

Table 9 . The lysis of target cells and the fold increase in the number of CAR T cells in the stress test were used for in vitro characterization of phage CARs. The phenotype of CAR-T cells was determined on day 13 after activation, and then on day 14 the cells were frozen. Stress testing was performed using thawed CAR T cells with Raji target cells at an E:T ratio of 1:1. Target cell lysis was determined by flow cytometry by gated CD3-γ target cells 2, 5 and 7 days after co-culture with CAR-T cells. The fold increase in the number of CAR-T cells was determined using cell count beads and calculation of the number of cells on days 2, 5 and 7 compared with the number of cells added at the beginning of the analysis. CARs in bold show high levels of target cell lysis and fold increase.

Example 5 Stress Test Repetition with Optimal CARs from a Second Donor

CAR T cells (P07D03, P08F08, P08G02, P15D02) were prepared and frozen with 4 scFv from the phage library and with 2 scFv from the hybridoma library (4F11, 17G6) as described in Example 3. CAR T cell data then thawed and mixed with Raji target cells known to express CD70 at a 1:1 effector:target ratio (E:T) in RPMI supplemented with 10% FBS. Thereafter, Raji cells were added to CAR-T cells every 2 days to maintain an E:T ratio of 1:1. The percentage of target cell lysis and the fold increase in the number of effector CAR T cells were determined at each time point.

All clones showed good results in terms of target cell lysis. P08F08 and 4F11 had excellent fold rates.

Table 10

CAR CAR+
(%) CD70+
(%) CD62L+
(%) Sequential killing analysis Target cell lysis (%) Multiplicity of increase in the number of CAR-T cells Day 2 Day 5 Day 7 Day 2 Day 5 Day 7 P07D03 48.8 3.2 63.4 95.1 98.1 98.7 1.2 8.1 11.8 P08F08 66.9 2.8 58.3 96.2 97.8 98.0 1.4 12.3 15.8 P08G02 37.9 0.1 35.0 98.6 97.2 99.5 0.9 2.4 5.7 P15D02 88.4 0.2 28.4 98.8 97.7 98.8 0.8 4.1 12.2 4F11 88.3 0.3 54.4 98.3 96.9 97.3 0.9 6.0 15.5 17G6 34.8 0.2 28.3 98.7 94.3 90.0 0.5 0.8 2.4

Table 10 . Target cell lysis and fold increase in CAR T cells in the stress test were used to characterize optimal CARs in vitro . The phenotype of CAR T cells was determined 14 days after activation, and then the cells were frozen on the same day. Stress testing was performed using thawed CAR T cells with Raji target cells at an E:T ratio of 1:1. Target cell lysis was determined by flow cytometry by gated CD3-γ target cells 2, 5 and 7 days after co-culture with CAR-T cells. The fold increase in the number of CAR-T cells was determined using cell count beads and calculation of the number of cells on days 2, 5 and 7 compared with the number of cells added at the beginning of the analysis. CARs in bold show high levels of target cell lysis and fold increase.

Example 6 Dose Dependent in vivo efficacy of CAR-T in a subcutaneous tumor model of RCC

CAR T cells were obtained from 4F11 scFv as described in Example 3. NOD scid gamma (NSG) mice were subcutaneously implanted with 786-O tumors, and once the tumors reached a volume of 200 mm ³ , the mice were treated with 4F11 CAR T cells. at various doses via intravenous injection into the tail vein to determine the optimal dose of CAR-T cells. 786-O cells are available from ATCC® under the name CRL-1932™. 4F11 CAR-T cells were highly effective in vivo and caused complete tumor regression at a dose of 5×10 ⁶ CAR-T cells.

Materials and methods

Fifty NOD scid gamma (NSG) mice were shaved and prepared for subcutaneous tumor implantation on the right flank. 786-O tumor cells known to express CD70 were expanded in RPMI supplemented with 10% FBS. On day 0, 786-O cells were resuspended in serum-free RPMI at the concentration required to inject 5 million cells per animal. Tumor cells were injected subcutaneously in 100 μl of serum-free RPMI in combination with 100 μl of Matrigel (Corning) per animal. Baseline body weights on day 0 in all animals were recorded immediately after tumor implantation. Tumor size was measured twice a week from day 9 using digital calipers (Mitutoyo) and body weight was recorded. On day 14, when tumors reached 200 mm ³ (standard error 8.39), 40 tumor-bearing mice were randomized into 4 groups of 10 mice each. 4F11 CAR T cells were thawed in RPMI supplemented with 10% FBS and resuspended in serum-free RPMI at the concentration required to inject 1, 3, or 5 million CAR+ T cells per animal (calculated based on a transduction efficiency of 4F11 of 57. 2%). The number of non-transduced T cells (NTD) required to maintain an equal total number of T cells in each group was calculated and added to the respective samples. CAR-T cells or control non-transduced T-cells were injected into 200 μl of serum-free RPMI per animal intravenously in the tail vein. Tumors were measured and body weights were recorded twice a week until day 43 when the NTD group reached the end point of the study (tumor volume 1500 mm ³ ).

Tumor volume scores (SEM mean and error) were plotted using GraphPad Prism, with statistics calculated using repeated measures one-way analysis of variance (see FIG. 1 and FIG. 2). Although the tumors were completely eliminated with the 5 million CAR dose, the 1 million CAR+ dose was not effective compared to the NTD group. Thus, the CAR+ dose of 3 million was chosen as the optimal dose for further in vivo studies.

Example 7 in vivo comparison of anti-CD70 CARs with or without TALEN-mediated CD70 knockout in 786-O cells

4F11 and P08F08 CAR T cells were generated as described in Example 1 with or without electroporation of TALEN CD70 DNA on day 6 post-activation. NSG mice were subcutaneously implanted with 786-O tumors, and after the tumors had reached a volume of 200 mm ³ , the mice were treated with CAR-T cells via tail vein intravenous injection to determine CAR and conditions with the most optimal efficacy. P08F08 CAR-T cells were highly effective in vivo and caused complete tumor regression at a dose of CAR-T cells of 3×10 ⁶ regardless of CD70 knockout (KO). 4F11 CAR T cells showed high efficiency in CD70 knockout, but in the absence of CD70 knockout, they only controlled tumor growth. These results suggest that CD70 knockout may increase anti-CD70 CAR activity.

Materials and methods

Seventy-five NSG mice were shaved and prepared for subcutaneous tumor implantation on the right flank. 786-O tumor cells known to express CD70 were expanded in RPMI supplemented with 10% FBS. On day 0, 786-O cells were resuspended in serum-free RPMI at the concentration required to inject 5 million cells per animal. Tumor cells were injected subcutaneously in 100 μl of serum-free RPMI in combination with 100 μl of Matrigel (Corning) per animal. Baseline body weights on day 0 in all animals were recorded immediately after tumor implantation. Tumor size was measured twice a week from day 7 using digital calipers (Mitutoyo) and body weight was recorded. On day 20, when tumors were 200 mm ³ (standard error 9.69), 60 tumor bearing mice were randomized into 6 groups of 10 mice each. On day 21, CAR T cells were thawed in RPMI supplemented with 10% FBS and resuspended in serum-free RPMI at 3 million CAR+ T cells per animal (calculated based on individual transduction efficiencies). The number of NTD cells required to maintain an equal percentage of CAR+ T cells as well as an equal number of total T cells in each group was calculated and added to the respective samples. CAR-T cells or control NTDs were injected into 200 μl of serum-free RPMI per animal intravenously via the tail vein. Tumors were measured and body weights were recorded twice a week until day 56 when the NTD group reached the end point of the study (tumor volume 1500 mm ³ ) (see Fig. 3 and Fig. 4).

Tumor volume scores (SEM mean and error) were plotted using GraphPad Prism, with statistics calculated using repeated measures one-way ANOVA. In the CAR-T P08F08 groups, both with and without CD70 knockout, complete tumor regression was achieved at a CAR+ dose of 3 million. The CD70 knockout CAR-T 4F11 group also achieved complete tumor regression at a CAR+ dose of 3 million. However, the CAR-T 4F11 group without CD70 knockout did not cause complete regression.

In FIG. 3 and FIG. 4, statistical significance compared to the corresponding NTD control is shown to the right of the legend (eg, P08F08 with CD70 KO versus NTD with CD70 KO). Statistical significance for each CAR group with CD70 KO compared to the corresponding CAR group without CD70 KO is shown to the left of the legend. The statistic is a one-way analysis of variance RM with Dunnett's posterior test (ns (not significant) p>0.05, *p<0.05, **p<0.01, ***p<0.001, ****p <0.0001).

Example 8 in vivo comparison of CAR to CD70 with or without TALEN-mediated CD70 knockout in an ACHN tumor model with metastases

4F11 CAR T cells and P08F08 from Example 7 were further tested on ACHN cells derived from renal cell carcinoma (RCC) cells. ACHN cells are described in Simmons et al. Animal Models of Bone Metastasis. Veterinary Pathology 52:827-841, 834 (2015). Each of the NSG mice were intravenously implanted with 1 million ACHN tumor cells, and 15 days after the tumor cell injection, the mice were intravenously injected with CAR-T cells via tail vein injection to determine CAR and the condition with the most optimal efficacy. 4F11 CAR T cells injected at 3 million CAR+ cells per mouse were effective in all 3 donors tested, regardless of CD70 knockout (KO). P08F08 CAR T cells did not show any efficacy and were only tested in the absence of CD70 knockout.

Materials and methods

Forty-five NSG mice were prepared for intravenous injection of the tumor via the tail vein. ACHN tumor cells known to express CD70 were expanded in MEM supplemented with 10% FBS. On day 0, ACHN tumor cells were resuspended in serum-free MEM at the concentration required to inject 1 million cells per animal. ACHN tumor cells were injected intravenously in 200 μl of serum-free MEM medium. Baseline body weights on day 4 were recorded for all animals. Tumor cell flux was measured twice a week starting on day 7 using bioluminescence (IVIS Spectrum Imager™ from PerkinElmer™; auto exposure with a maximum exposure time of 120 seconds) and body weights were recorded. On day 20, when tumors reached 200 mm ³ (standard error 9.69), 20 tumor-bearing mice were randomized into 4 groups of 5 mice each. On day 15, CAR T cells were thawed in MEM supplemented with 10% FBS and resuspended in serum free MEM at 3 million CAR+ T cells per animal (calculated based on individual transduction efficiencies). The number of NTD cells required to maintain an equal percentage of CAR+ T cells as well as an equal number of total T cells in each group was calculated and added to the respective samples. CAR-T cells or control NTDs were injected into 200 μl of serum-free MEM per animal intravenously via the tail vein. Tumor cell flux was measured and body weights were recorded twice a week until days 35-49 when the NTD group reached the endpoint of the study ( ^> 20% body weight loss) (see FIGS. 5a, 5b and 5c).

Bioluminescence scores (SEM mean and error) were plotted using GraphPad Prism, with statistics calculated using repeated measures one-way ANOVA. CAR-T 4F11 groups, both with and without CD70 knockout, demonstrated antitumor efficacy at a CAR+ dose of 3 million. The CAR-T P08F08 group without CD70 knockout showed little or no efficacy at the CAR+ dose of 3 million.

Example 9 Activity of CD70 Specific CAR T Cells Expressing CD20 Epitopes

Part A: in vitro activity

CD70 specific CAR T cells expressing CD20 epitopes are effective against 786-0 target cells in a cell killing assay.

Six CD70-specific CAR formats were constructed (FIGS. 6A-6F). The sequences of the constructed CARs are shown in Tables 11A - 11F:

table 11A

Format Clone name Complete amino acid sequence SEQID NO: No epitope
(Fig. 6A) 4F11 MALPVTALLLPLALLLHAARPQVTLKESGPVLVKPTETLTLTCTVSGFSLSNARMGVTWIRQPPGKALEWLAHIFSNDEKSYSTSLKSRLTISKDTSKTQVVLTMTNMDPVDPVTATYYCARIRDYYDISSYYDYWGQGTLVSVSSGGGGSGGGGSGGGGSDIQMTQSPSAMSASVGDRVTITCRASQDISNYLAWFQQKPG KVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLLPEDFATYYCLQLNSFPFTFGGTKVEINTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREE YDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 619 4F11-2 MALPVTALLLPLALLLHAARPQVTLKESGPVLVKPTETLTLTCTVSGFSLSNARMGVTWIRQPPGKALEWLAHIFSNDEKSYSTSLKSRLTISKDTSKTQVVLTMTNMDPVDPVDTATYYCARIRDYYDISSYYDYWGQGTLVSVSSGGGGGSGGGGSGGGGSGGGGSDIQMTQSPSAMSASVGDRVTITCRASQDISNYLAWF QQKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLLPEDFATYYCLQLNSFPFTFGGGTKVEINTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNEL NLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 672 P08F08 MALPVTALLLPLALLLHAARPEVQLVQSGAEVKKPGESLKISCKGSGYGFTSYWIGWVRQMPGKGLEWMGIIHPDDSDTKYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCASSYLRGLWGGYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELQSVLTQPPSASGTPGQRVTISCSGSSSNI GSNYVNWYQQLPGTAPKLLIYGDYQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATRDDSLSGSVVFGTGTKLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFFSPEEEEGGCELRVKRSADAPAYQ QGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 327 10A1 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGGSISYYYWTWIRQPPGKGLEWIGHIYYSGSTNYNPSLKSRVTISIDTSKNLFSLKLSSVTAADTAVYYCARAEGSlDAFDFWGQGTMVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCRASQSISTWLAW YQQKPGKAPKVLIYKASSLESGVPSRFSGSGSGTEFILTINSLQPDDFASYYCQQYKSYSHTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQ LYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 580 11C1 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLNCTVSGGSISYYYWTWIRQPPGKGLEWIGHVIYSGTTNYNPSLKSRVTISVDTSKNQFSLKLNSVTAADTAVYYCVRAEGSlDAFDLWGQGTMVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSILSASVGDRVTITCRASQSVSS WLAWYQQKPGKAPKVLIYKASSLESGVPSRFSGTGSGTEFTLTISSLQSDDFATYYCQQYNTYSHTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQG QNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 583 11E1 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPLQTLSLTCTVSGGSISSdgYYWSWIRQNPGKGLEWIGYMYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLRSVTAADTAVYYCTRDFGWYFDLWGRGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDSITITCRASQDID NYLAWYQQKTGKVPKVLIYAASALQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQNYNSGPRTFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQG QNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 585 12A2 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSQSLSLTCSVSGGSVSSdgYYWSWIRQHPGKGLEWIGYIYYRRITDYNPSLKSRVNISLDTSKNQFSLKLSSVTAADTAVYYCARDFGWYFDLWGRGTLVAVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDI SNYLTWYQQKPGRVPEVLIYAASALQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQNYNSAPRTFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQG QNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 586 12C5 MALPVTALLLPLALLLHAARPEVELVESGGGMVQPGRSLRLSCAASGFTFSDYGMHWVRQAPGMGLEWVTVIWYDGSnKYYADSVKGRFTISRDNSKNTVFLQMNSLRAEDTAVYYCARDEVGfvGAFDIWGQGTMVTVSSGGGGSGGGGSGGGGGSGGGGSDIQLTQSPSFLSASVGDRVIITCRASQGINSHLAW YQQKPGKAPKLLIYYASTLPSGVPSRFSGSGSGTEFTLTVTSLQPEDFATYYCQQLNHYPITFGQGTRLDINTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLY NELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 588 12C6 MALPVTALLLPLALLLHAARPEVELVESGGGMVQPGRSLRLSCAASGFTFSDYGMHWVRQAPGMGLEWVTVIWYDGSnKYYADSVKGRFTISRDNSKNTVFLQMNSLRAEDTAVYYCARDEVGfvGAFDIWGQGTMVTVSSGGGGSGGGGSGGGGGSGGGGSDIQLTQSPSFLSASVGDRVIITCRASQGINSHLAW YQQKPGKAPKLLIYYASTLPSGVPSRFSGSGSGTEFTLTVTSLQPEDFATYYCQQLNHYPITFGQGTRLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQ LYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 673 8F8 MALPVTALLLPLALLLHAARPQVQLQESGPGLVQPSETLSLTCTVSGGSISYYYWSWIRQPPGKGLEWIGNINYMGNTIYNPSLKSRVTISVDTSKDQFSLKLTSVSAADTAVYYCVRAEGSlDAFDFWGQGTLVAVSLGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCRASQSISS WLAWYQQKPGKAPKVLIYKASNLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSCTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQG QNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 596

Table 11B

Format clone name Complete amino acid sequence SEQID NO: SR2
(Fig. 6B) 4F11-SR2 MALPVTALLLPLALLLHAARPQVTLKESGPVLVKPTETLTLTCTVSGFSLSNARMGVTWIRQPPGKALEWLAHIFSNDEKSYSTSLKSRLTISKDTSKTQVVLTMTNMDPVDPVTATYYCARIRDYYDISSYYDYWGQGTLVSVSSGGGGSGGGGSGGGGSDIQMTQSPSAMSASVGDRVTITCRASQDISNYLAWFQQKPG KVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLLPEDFATYYCLQLNSFPFTFGGGTKVEINGSGGGGSCPYSNPSLCSGGGGSCPYSNPSLCSGGGGSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEE EGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 620 4F11-2-SR2 MALPVTALLLPLALLLHAARPQVTLKESGPVLVKPTETLTLTCTVSGFSLSNARMGVTWIRQPPGKALEWLAHIFSNDEKSYSTSLKSRLTISKDTSKTQVVLTMTNMDPVDPVDTATYYCARIRDYYDISSYYDYWGQGTLVSVSSGGGGGSGGGGSGGGGSGGGGSDIQMTQSPSAMSASVGDRVTITCRASQDISNYLAWF QQKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLLPEDFATYYCLQLNSFPFTFGGGTKVEINGSGGGSCPYSNPSLCSGGGGSCPYSNPSLCSGGGGSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGC SCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 674 P08F08-SR2 MALPVTALLLPLALLLHAARPEVQLVQSGAEVKKPGESLKISCKGSGYGFTSYWIGWVRQMPGKGLEWMGIIHPDDSDTKYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCASSYLRGLWGGYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELQSVLTQPPSASGTPGQRVTISCSGSSSNI GSNYVNWYQQLPGTAPKLLIYGDYQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATRDDSLSGSVVFGTGTKLTVLGSGGGGSCPYSNPSLCSGGGGSCPYSNPSLCSGGGGSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQ PFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 621 10A1-SR2 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGGSISYYYWTWIRQPPGKGLEWIGHIYYSGSTNYNPSLKSRVTISIDTSKNLFSLKLSSVTAADTAVYYCARAEGSlDAFDFWGQGTMVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCRASQSISTWLAW YQQKPGKAPKVLIYKASSLESGVPSRFSGSGSGTEFILTINSLQPDDFASYYCQQYKSYSHTFGQGTKLEIKGSGGGGSCPYSNPSLCSGGGGSCPYSNPSLCSGGGGSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQ EEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 622 11C1-SR2 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLNCTVSGGSISYYYWTWIRQPPGKGLEWIGHVIYSGTTNYNPSLKSRVTISVDTSKNQFSLKLNSVTAADTAVYYCVRAEGSlDAFDLWGQGTMVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSILSASVGDRVTITCRASQSVSS WLAWYQQKPGKAPKVLIYKASSLESGVPSRFSGTGSGTEFTLTISSLQSDDFATYYCQQYNTYSHTFGQGTKLEIKGSGGGGSCPYSNPSLCSGGGGSCPYSNPSLCSGGGGSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPV QTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 623 11E1-SR2 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPLQTLSLTCTVSGGSISSdgYYWSWIRQNPGKGLEWIGYMYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLRSVTAADTAVYYCTRDFGWYFDLWGRGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDSITITCRASQDID NYLAWYQQKTGKVPKVLIYAASALQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQNYNSGPPRTFGQGTKVEIKGSGGGSCPYSNPSLCSGGGGSCPYSNPSLCSGGGGSTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPV QTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 624 12A2-SR2 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSQSLSLTCSVSGGSVSSdgYYWSWIRQHPGKGLEWIGYIYYRRITDYNPSLKSRVNISLDTSKNQFSLKLSSVTAADTAVYYCARDFGWYFDLWGRGTLVAVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDI SNYLTWYQQKPGRVPEVLIYAASALQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQNYNSAPRTFGQGTKVEIKGSGGGGSCPYSNPSLCSGGGGSCPYSNPSLCSGGGGSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPV QTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 625 12C5-SR2 MALPVTALLLPLALLLHAARPEVELVESGGGMVQPGRSLRLSCAASGFTFSDYGMHWVRQAPGMGLEWVTVIWYDGSnKYYADSVKGRFTISRDNSKNTVFLQMNSLRAEDTAVYYCARDEVGfvGAFDIWGQGTMVTVSSGGGGSGGGGSGGGGGSGGGGSDIQLTQSPSFLSASVGDRVIITCRASQGINSHLAW YQQKPGKAPKLLIYYASTLPSGVPSRFSGSGSGTEFTLTVTSLQPEDFATYYCQQLNHYPITFGQGTRLDINGSGGGGSCPYSNPSLCSGGGGSCPYSNPSLCSGGGGSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQE EDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 626 12C6-SR2 MALPVTALLLPLALLLHAARPEVELVESGGGMVQPGRSLRLSCAASGFTFSDYGMHWVRQAPGMGLEWVTVIWYDGSnKYYADSVKGRFTISRDNSKNTVFLQMNSLRAEDTAVYYCARDEVGfvGAFDIWGQGTMVTVSSGGGGSGGGGSGGGGGSGGGGSDIQLTQSPSFLSASVGDRVIITCRASQGINSHLAW YQQKPGKAPKLLIYYASTLPSGVPSRFSGSGSGTEFTLTVTSLQPEDFATYYCQQLNHYPITFGQGTRLEIKGSGGGGSCPYSNPSLCSGGGGSCPYSNPSLCSGGGGSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQ EEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 675 8F8-SR2 MALPVTALLLPLALLLHAARPQVQLQESGPGLVQPSETLSLTCTVSGGSISYYYWSWIRQPPGKGLEWIGNINYMGNTIYNPSLKSRVTISVDTSKDQFSLKLTSVSAADTAVYYCVRAEGSlDAFDFWGQGTLVAVSLGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASVGDRVTITCRASQSISS WLAWYQQKPGKAPKVLIYKASNLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSCTFGQGTKLEIKGSGGGGSCPYSNPSLCSGGGGSCPYSNPSLCSGGGGSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPV QTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 627

Table 11C

Format clone name Complete amino acid sequence SEQID NO: RSRQR
(Fig. 6C) 4F11-RSRQR MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCSGGGGSGGGGSQVTLKESGPVLVKPTETLTLTCTVSGFSLSNARMGVTWIRQPPGKALEWLAHIFSNDEKSYSTSLKSRLTISKDTSKTQVVLTMTNMDPVDTATYYCARIRDYYDISSYYDYWGQGTLVSSGGGGSGGGGSGGGGSDIQMTQSPSAMSASVG DRVTITCRASQDISNYLAWFQQKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLLPEDFATYYCLQLNSFPFTFGGGTKVEINGSGGGGSCPYSNPSLCSGGGGSELPTQGTFSNVSTNVSPAKPTTTACPYSNPSLCCTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLL LSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 628 4F11-2-RSRQR MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCSGGGGSGGGGSQVTLKESGPVLVKPTETLTLTCTVSGFSLSNARMGVTWIRQPPGKALEWLAHIFSNDEKSYSTSLKSRLTISKDTSKTQVVLTMTNMDPVDTATYYCARIRDYYDISSYYDYWGQGTLVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSA MSASVGDRVTITCRASQDISNYLAWFQQKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLLPEDFATYYCLQLNSFPFTFGGGTKVEINGSGGGGSCPYSNPSLCSGGGGSELPTQGTFSNVSTNVSPAKPTTTACPYSNPSLCTTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTC GVLLLSLVITLYCKGRRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 676 P08F08-RSRQR MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCSGGGGSGGGSEVQLVQSGAEVKKPGESLKISCKGSGYGFTSYWIGWVRQMPGKGLEWMGIIHPDDSDTKYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCASSYLRGLWGGYFDYWGQGTLVTVSSGGGGGSGGGSGGGGGSGGGGSELQS VLTQPPSASGTPGQRVTISCSGSSSNIGSNYVNWYQQLPGTAPKLLIYGDYQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATRDDSLSGSVVFGTGTKLTVLGSGGGGSCPYSNPSLCSGGGGSELPTQGTFSNVSTNVSPAKPTTTACPYSNPSLCCTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGL DFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 629 10A1-RSRQR MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGGSISYYYWTWIRQPPGKGLEWIGHIYYSGSTNYNPSLKSRVTISIDTSKNLFSLKLSSVTAADTAVYYCARAEGSlDAFDFWGQGTMVTVSSGGGGSGGGGSGGGGSGGGDIQMTQSP STLSASVGDRVTITCRASQSISTWLAWYQQKPGKAPKVLIYKASSLESGVPSRFSGSGSGTEFILTINSLQPDDFASYYCQQYKSYSHTFGQGTKLEIKGSGGGGSCPYSNPSLCSGGGGSELPTQGTFSNVSTNVSPAKPTTTACPYSNPSLCTTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWA PLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 630 11C1-RSRQR MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCSGGGGSGGGGSQVQLQESGPGLVKPSETLSLNCTVSGGSISYYYWTWIRQPPGKGLEWIGHVIYSGTTNYNPSLKSRVTISVDTSKNQFSLKLNSVTAADTAVYYCVRAEGSlDAFDLWGQGTMVTVSSGGGGGSGGGSGGGGGSGGGGSDIQMT QSPSILSASVGDRVTITCRASQSVSSWLAWYQQKPGKAPKVLIYKASSLESGVPSRFSGTGSGTEFTLTISSLQSDDFATYYCQQYNTYSHTFGQGTKLEIKGSGGGGSCPYSNPSLCSGGGGSELPTQGTFSNVSTNVSPAKPTTTACPYSNPSLCTTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 631 11E1-RSRQR MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCSGGGGSGGGGSQVQLQESGPGLVKPLQTLSLTCTVSGGSISSdgYYWSWIRQNPGKGLEWIGYMYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLRSVTAADTAVYYCTRDFGWYFDLWGRGTLVTVSSGGGGSGGGGSGGGGGSGGGGSDIQ MTQSPSSLSASVGDSITITCRASQDIDNYLAWYQQKTGKVPKVLIYAASALQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQNYNSGPPRTFGQGTKVEIKGSGGGGSCPYSNPSLCSGGGGSELPTQGTFSNVSTNVSPAKPTTTACPYSNPSLCCTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 632 12A2-RSRQR MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCSGGGGSGGGGSQVQLQESGPGLVKPSQSLSLTCSVSGGSVSSdgYYWSWIRQHPGKGLEWIGYIYYRRITDYNPSLKSRVNISLDTSKNQFSLKLSSVTAADTAVYYCARDFGWYFDLWGRGTLVAVSSGGGGSGGGGSGGGGGGGSDI QMTQSPSSLSASVGDRVTITCRASQDISNYLTWYQQKPGRVPEVLIYAASALQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQNYNSAPRTFGQGTKVEIKGSGGGGSCPYSNPSLCSGGGGSELPTQGTFSNVSTNVSPAKPTTTACPYSNPSLCTTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 633 12C5-RSRQR MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCSGGGGSGGGGSEVELVESGGGMVQPGRSLRLSCAASGFTFSDYGMHWVRQAPGMGLEWVTVIWYDGSnKYYADSVKGRFTISRDNSKNTVFLQMNSLRAEDTAVYYCARDEVGfvGAFDIWGQGTMVTVSSGGGGGSGGGSGGGGGSGGGDIQLTQ SPSFLSASVGDRVIITCRASQGINSHLAWYQQKPGKAPKLLIYYASTLPSGVPSRFSGSGSGTEFTLTVTSLQPEDFATYYCQQLNHYPITFGQGTRLDINGSGGGGSCPYSNPSLCSGGGGSELPTQGTFSNVSTNVSPAKPTTTACPYSNPSLCTTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPL AGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 634 12C6-RSRQR MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCSGGGGSGGGGSEVELVESGGGMVQPGRSLRLSCAASGFTFSDYGMHWVRQAPGMGLEWVTVIWYDGSnKYYADSVKGRFTISRDNSKNTVFLQMNSLRAEDTAVYYCARDEVGfvGAFDIWGQGTMVTVSSGGGGGSGGGSGGGGGSGGGDIQLTQ SPSFLSASVGDRVIITCRASQGINSHLAWYQQKPGKAPKLLIYYASTLPSGVPSRFSGSGSGTEFTLTVTSLQPEDFATYYCQQLNHYPITFGQGTRLEIKGSGGGGSCPYSNPSLCSGGGGSELPTQGTFSNVSTNVSPAKPTTTACPYSNPSLCTTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWA PLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 677 8F8-RSRQR MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCSGGGGSGGGGSQVQLQESGPGLVQPSETLSLTCTVSGGSISYYYWSWIRQPPGKGLEWIGNINYMGNTIYNPSLKSRVTISVDTSKDQFSLKLTSVSAADTAVYYCVRAEGSlDAFDFWGQGTLVAVSLGGGGSGGGGSGGGGSGGGGSDIQ MTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKVLIYKASNLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSCTFGQGTKLEIKGSGGGGSCPYSNPSLCSGGGGSELPTQGTFSNVSTNVSPAKPTTTACPYSNPSLCCTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDI YIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 635

Table 11D

Format clone name Complete amino acid sequence SEQID NO: RSR
(Fig. 6D) 4F11-RSR MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCGGGGSVTLKESGPVLVKPTETLTLTCTVSGFSLSNARMGVTWIRQPPGKALEWLAHIFSNDEKSYSTSLKSRLTISKDTSKTQVVLTMTNMDPVDTATYYCARIRDYYDISSYYDYWGQGTLVSVSSGGGGSGGGGSGGGGSDIQMTQSPSAMSASVGDRVTITCR ASQDISNYLAWFQQKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLLPEDFATYYCLQLNSFPFTFGGGTKVEINGGGGSCPYSNPSLCGGGGSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRF PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 636 4F11-2-RSR MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCGGGGSVTLKESGPVLVKPTETLTLTCTVSGFSLSNARMGVTWIRQPPGKALEWLAHIFSNDEKSYSTSLKSRLTISKDTSKTQVVLTMTNMDPVDTATYYCARIRDYYDISSYYDYWGQGTLVSVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSAMSASVG DRVTITCRASQDISNYLAWFQQKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLLPEDFATYYCLQLNSFPFTFGGGTKVEINGGGGSCPYSNPSLCGGGGSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQE EDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 678 P08F08-RSR MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCGGGGSEVQLVQSGAEVKKPGESLKISCKGSGYGFTSYWIGWVRQMPGKGLEWMGIIHPDDSDTKYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCASSYLRGLWGGYFDYWGQGTLVTVSSGGGGSGGGGGSGGGSGGGGSELQSVLTQPP SASGTPGQRVTISCSGSSSNIGSNYVNWYQQLPGTAPKLLIYGDYQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATRDDSLSGSVVFGTGTKLTVLGGGSCPYSNPSLCGGGGSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIF KQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 637 10A1-RSR MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCGGGGSQVQLQESGPGLVKPSETLSLTCTVSGGSISYYYWTWIRQPPGKGLEWIGHIYYSGSTNYNPSLKSRVTISIDTSKNLFSLKLSSVTAADTAVYYCARAEGSlDAFDFWGQGTMVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASV GDRVTITCRASQSISTWLAWYQQKPGKAPKVLIYKASSLESGVPSRFSGSGSGTEFILTINSLQPDDFASYYCQQYKSYSHTFGQGTKLEIKGGGGSCPYSNPSLCGGGGSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQ TTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 638 11C1-RSR MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCGGGGSQVQLQESGPGLVKPSETLSLNCTVSGGSISYYYWTWIRQPPGKGLEWIGHVIYSGTTNYNPSLKSRVTISVDTSKNQFSLKLNSVTAADTAVYYCVRAEGSlDAFDLWGQGTMVTVSSGGGGSGGGGGSGGGGSGGGGSDIQMTQSPSILS ASVGDRVTITCRASQSVSSWLAWYQQKPGKAPKVLIYKASSLESGVPSRFSGTGTGTEFTLTISSLQSDDFATYYCQQYNTYSHTFGQGTKLEIKGGGGSCPYSNPSLCGGGGSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPF MRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 639 11E1-RSR MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCGGGGSQVQLQESGPGLVKPLQTLSLTCTVSGGSISSdgYYWSWIRQNPGKGLEWIGYMYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLRRSVTAADTAVYYCTRDFGWYFDLWGRGTLVTSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSS LSASVGDSITITCRASQDIDNYLAWYQQKTGKVPKVLIYAASALQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQNYNSGPRTFGQGTKVEIKGGGGSCPYSNPSLCGGGSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPF MRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 640 12A2-RSR MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCGGGGSQVQLQESGPGLVKPSQSLSLTCSVSGGSVSSdgYYWSWIRQHPGKGLEWIGYIYYRRITDYNPSLKSRVNISLDTSKNQFSLKLSSVTAADTAVYYCARDFGWYFDLWGRGTLVAVSSGGGGSGGGGSGGGGSGGGDIQMTQSP SSLSASVGDRVTITCRASQDISNYLTWYQQKPGRVPEVLIYAASALQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQNYNSAPRTFGQGTKVEIKGGGSCPYSNPSLCGGGGSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPF MRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 641 12C5-RSR MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCGGGGSEVELVESGGGMVQPGRSLRLSCAASGFTFSDYGMHWVRQAPGMGLEWVTVIWYDGSNKYYADSVKGRFTISRDNSKNTVFLQMNSLRAEDTAVYYCARDEVGFVGAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPSFLSASV GDRVIITCRASQGINSHLAWYQQKPGKAPKLLIYASTLPSGVPSRFSGSGSGTEFTLTVTSLQPEDFATYYCQQLNHYPITFGQGTRLDINGGGGSCPYSNPSLCGGGGSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQ EEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 642 12C6-RSR MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCGGGGSEVELVESGGGMVQPGRSLRLSCAASGFTFSDYGMHWVRQAPGMGLEWVTVIWYDGSNKYYADSVKGRFTISRDNSKNTVFLQMNSLRAEDTAVYYCARDEVGFVGAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPSFLSASV GDRVIITCRASQGINSHLAWYQQKPGKAPKLLIYYASTLPSGVPSRFSGSGSGTEFTLTVTSLQPEDFATYYCQQLNHYPITFGQGTRLEIKGGGGSCPYSNPSLCGGGSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTT QEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 679 8F8-RSR MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCGGGGSQVQLQESGPGLVQPSETLSLTCTVSGGSISYYYWSWIRQPPGKGLEWIGNINYMGNTIYNPSLKSRVTISVDTSKDQFSLKLTSVSAADTAVYYCVRAEGSlDAFDFWGQGTLVAVSLGGGGSGGGGSGGGGSGGGGSDIQMTQSPST LSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKVLIYKASNLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSCTFGQGTKLEIKGGGGSCPYSNPSLCGGGSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPF MRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 643

Table 11E

Format clone name Complete amino acid sequence SEQID NO: RSR-short
(FIG. 6E) 4F11-RSR-short MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCGGGGSVTLKESGPVLVKPTETLTLTCTVSGFSLSNARMGVTWIRQPPGKALEWLAHIFSNDEKSYSTSLKSRLTISKDTSKTQVVLTMTNMDPVDTATYYCARIRDYYDISSYYDYWGQGTLVSVSSGGGGSGGGGSGGGGSDIQMTQSPSAMSASVGDRVTITCR ASQDISNYLAWFQQKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLLPEDFATYYCLQLNSFPFTFGGGTKVEINGGGGSCPYSNPSLCTTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEDGCSCRFPEEEEGGC ELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 644 4F11-2-RSR-short MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCGGGGSVTLKESGPVLVKPTETLTLTCTVSGFSLSNARMGVTWIRQPPGKALEWLAHIFSNDEKSYSTSLKSRLTISKDTSKTQVVLTMTNMDPVDTATYYCARIRDYYDISSYYDYWGQGTLVSVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSAMSASVG DRVTITCRASQDISNYLAWFQQKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLLPEDFATYYCLQLNSFPFTFGGGTKVEINGGGGSCPYSNPSLCTTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRF PEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 680 P08F08-RSR-short MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCGGGGSEVQLVQSGAEVKKPGESLKISCKGSGYGFTSYWIGWVRQMPGKGLEWMGIIHPDDSDTKYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCASSYLRGLWGGYFDYWGQGTLVTVSSGGGGSGGGGGSGGGSGGGGSELQSVLTQPP SASGTPGQRVTISCSGSSSNIGSNYVNWYQQLPGTAPKLLIYGDYQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATRDDSLSGSVVFGTGTKLTVLGGGGSCPYSNPSLCCTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMR PVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 645 10A1-RSR-short MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCGGGGSQVQLQESGPGLVKPSETLSLTCTVSGGSISYYYWTWIRQPPGKGLEWIGHIYYSGSTNYNPSLKSRVTISIDTSKNLFSLKLSSVTAADTAVYYCARAEGSlDAFDFWGQGTMVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSTLSASV GDRVTITCRASQSISTWLAWYQQKPGKAPKVLIYKASSLESGVPSRFSGSGSGTEFILTINSLQPDDFASYYCQQYKSYSHTFGQGTKLEIKGGGGSCPYSNPSLCTTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEED GCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 646 11C1-RSR-short MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCGGGGSQVQLQESGPGLVKPSETLSLNCTVSGGSISYYYWTWIRQPPGKGLEWIGHVIYSGTTNYNPSLKSRVTISVDTSKNQFSLKLNSVTAADTAVYYCVRAEGSlDAFDLWGQGTMVTVSSGGGGSGGGGGSGGGGSGGGGSDIQMTQSPSILS ASVGDRVTITCRASQSVSSWLAWYQQKPGKAPKVLIYKASSLESGVPSRFSGTGSGTEFTLTISSLQSDDFATYYCQQYNTYSHTFGQGTKLEIKGGGGSCPYSNPSLCTTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKGRRKKLLYIFKQPFMRPVQTT QEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 647 11E1-RSR-short MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCGGGGSQVQLQESGPGLVKPLQTLSLTCTVSGGSISSDGYYWSWIRQNPGKGLEWIGYMYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLRRSVTAADTAVYYCTRDFGWYFDLWGRGTLVTSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSS LSASVGDSITITCRASQDIDNYLAWYQQKTGKVPKVLIYAASALQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQNYNSGPRTGQGTKVEIKGGGGSCPYSNPSLCTTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKGRRKKLLYIFKQPFMRPVQTT QEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 648 12A2-RSR-short MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCGGGGSQVQLQESGPGLVKPSQSLSLTCSVSGGSVSSDGYYWSWIRQHPGKGLEWIGYIYYRRITDYNPSLKSRVNISLDTSKNQFSLKLSSVTAADTAVYYCARDFGWYFDLWGRGTLVAVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSS LSASVGDRVTITCRASQDISNYLTWYQQKPGRVPEVLIYAASALQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQNYNSAPRTFGQGTKVEIKGGGGSCPYSNPSLCTTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQ EEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 649 12C5-RSR-short MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCGGGGSEVELVESGGGMVQPGRSLRLSCAASGFTFSDYGMHWVRQAPGMGLEWVTVIWYDGSNKYYADSVKGRFTISRDNSKNTVFLQMNSLRAEDTAVYYCARDEVGFVGAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPSFLSASV GDRVIITCRASQGINSHLAWYQQKPGKAPKLLIYASTLPSGVPSRFSGSGSGTEFTLTVTSLQPEDFATYYCQQLNHYPITFGQGTRLDINGGGGSCPYSNPSLCTTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSC RFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 650 12C6-RSR-short MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCGGGGSEVELVESGGGMVQPGRSLRLSCAASGFTFSDYGMHWVRQAPGMGLEWVTVIWYDGSNKYYADSVKGRFTISRDNSKNTVFLQMNSLRAEDTAVYYCARDEVGFVGAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSGGGGSDIQLTQSPSFLSASV GDRVIITCRASQGINSHLAWYQQKPGKAPKLLIYASTLPSGVPSRFSGSGSGTEFTLTVTSLQPEDFATYYCQQLNHYPITFGQGTRLEIKGGGGSCPYSNPSLCTTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGC SCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 681 8F8-RSR-short MALPVTALLLPLALLLHAARPGGGGSCPYSNPSLCGGGGSQVQLQESGPGLVQPSETLSLTCTVSGGSISYYYWSWIRQPPGKGLEWIGNINYMGNTIYNPSLKSRVTISVDTSKDQFSLKLTSVSAADTAVYYCVRAEGSlDAFDFWGQGTLVAVSLGGGGSGGGGSGGGGSGGGGSDIQMTQSPST LSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKVLIYKASNLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSCTFGQGTKLEIKGGGGSCPYSNPSLCTTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTT QEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 651

Testing was performed against the following: NTD control; RSRQR format (shown above and schematically in FIG. 6C) for 4F11 CAR; SR2 format (shown above and schematically in FIG. 6B) for P08F08 CAR; the R2S format (shown above and schematically in FIG. 6F) for the P08F08 CAR; and the RSR-short format (shown above and schematically in FIG. 6E) for the P08F08 CAR.

Received CAR-T cells that express each of the CAR formats. These CAR T cells were then thawed and mixed with 786-0 target cells known to express CD70 at an effector:target (E:T) ratio of 3:1, 1:1, 1:3, or 1:9 (or 0 control), in RPMI supplemented with 10% FBS. The percentage of target cell lysis and the fold increase in the number of effector CAR-T cells were determined (Fig. 7).

Percentage lysis of target cells was calculated at each time point by calculating the percentage of viable 786-0 cells for each CAR treatment followed by normalization to an untreated control. The fold increase in the number of CAR T cells compared to the number of CAR T cells seeded on day 0 was calculated at each time point.

These results demonstrate that CD70-specific CAR-T cells expressing CD20 epitopes can effectively kill target cells at E:T ratios of 3:1, 1:1, 1:3, and 1:9 and at ratios in the ranges between them, as well as potentially at ratios outside the range from 3:1 to 1:9, which were not tested in this experiment.

Part B: Rituximab susceptibility in vivo

Depletion of CD70-specific CAR T cells following rituximab administration allows recovery of CD70-expressing lymphocytes in NSG mice.

Rituximab, an anti-CD20 antibody, was tested in mice for the ability to mediate the depletion of CD70-specific CAR T cells expressing CD20 epitopes and promote lymphocyte recovery. In this experiment, mice were treated with T cells expressing either a CD70-specific CAR that can bind to the mouse CD70 protein on the surface of lymphocytes (α-mouse CD70 CAR-T) and containing a CD20 epitope recognized by rituximab, or a control CAR that is slightly associated with the mouse FLT3 protein. Analysis of lymphocytes by flow cytometry was used to demonstrate the cytotoxic activity of CAR-T cells against lymphocytes expressing CD70, which is manifested in a decrease in the number of lymphocytes compared with mice treated with control CAR-T cells or with untreated mice. After confirming the killing activity of CAR T cells, mice were injected with rituximab for four consecutive days, and residual CAR T cells circulating in the blood were counted by flow cytometry on day 13. CAR T cells specific for CD70 in the blood these mice are malnourished compared to controls that did not receive rituximab. Finally, analysis of lymphocytes by flow cytometry showed that only mice treated with rituximab (day 20) showed lymphocyte recovery.

This experiment demonstrates that rituximab-dependent depletion of CD70-specific CAR T cells that express CD20 epitopes attenuates damage to CD70-expressing tissues, allowing rapid recovery of lymphocytes.

Example 10 CD70 Specific CAR T Cell Activity

Target cell kill was assessed using the same assay and experimental parameters similar to those described in Example 9, Part A. The lines tested were 786-0, ACHN and REH (human acute lymphocytic leukemia cell line). The REH cell line showed the best differentiation of CD70-specific CAR T cells, so it can be used for scFv ranking in all further experiments. In FIG. 8A-8D show killing of 786-0 (FIG. 8A), ACHN (FIG. 8B), or REH (FIG. 8C) cells using CD70-specific CAR T cells, where the extracellular domain of the CAR contains the scFv indicated in the legend. (Fig. 8D). The naked CAR format was used in all experiments.

Table 12 presents the basic data for FIG. 8A - 8D and additionally measured percentage of positive cells for fluorescently labeled antibodies to CD70, CD25 and 4-1BB (activation markers); percentage of memory stem T cells (TSCM), percentage of BFP (CAR+) before cytotoxicity analysis.

Table 12

Clone % REH lysis % ACHN lysis % 786-O lysis % CD70 D9 (with CAR gated) % CD25 4-1BB D9 (CAR gated) % Tscm D14 (with CAR gated) % BFP CAR D14 12D6 98.5 75.4 84.6 0.7 15.1 17.2 77.4 8F8 98.1 84.7 94.8 0.0 26.1 28.9 70.5 12H4 97.7 65.8 80.5 0.1 16.9 31.5 83.8 12A2 97.5 76.1 89.3 3.9 6.2 46.5 73.2 12C5 97.5 81.7 91.6 0.0 31.1 24.7 88.2 10A1 97.2 77.0 88.3 0.1 21.5 31.4 73.5 11E1 96.8 84.7 94.5 0.2 34.8 20.4 54.8 12D3 96.0 63.8 75.4 7.5 14.2 35.0 71.0 4F11 96.0 73.4 85.6 4.3 44.0 15.7 36.3 12D7 95.7 84.9 92.7 1.2 48.5 5.4 43.1 11C1 95.6 76.9 90.0 0.5 31.8 30.3 57.9 11A1 73.5 46.0 64.6 2.4 7.0 41.6 82.5 9E10 71.7 77.1 90.0 68.2 21.7 25.2 63.9 8C8 70.7 80.7 90.2 76.6 12.9 26.3 57.6 10E2 59.2 41.5 36.9 52.0 6.4 28.1 34.8 P08F08 45.8 78.0 94.5 30.6 7.8 48.4 43.1 8F7 38.6 39.3 55.4 46.4 3.0 32.3 63.5 12F5 21.7 14.5 16.2 50.9 7.1 29.9 44.7 9E5 13.9 7.0 11.9 13.1 1.3 77.0 63.9 11D1 12.7 -4.4 7.3 32.3 2.0 50.4 58.5 9F8 12.5 8.9 32.6 20.5 1.3 59.4 67.5 9F4 10.4 1.1 8.4 20.8 1.6 63.8 35.7 9D8 5.2 24.6 76.2 29.3 4.6 46.8 70.8 NTD 3.3 7.6 12.0

In FIG. 9A shows the efficacy of CD70-specific CARs on repeated exposure to luciferase labeled 786-O target cells (CAR-T cells were transferred to a 96-well plate containing fresh targets every 2-3 days). The E:T ratio was 3:1. CAR was expressed in cells from donor D503. Similar to the results described in Example 4, target cell lysis in a stress test was used to characterize CAR scFv in vitro .

In FIG. 9B shows the efficacy of CD70-specific CARs on repeated exposure to luciferase-labeled ACHN target cells (CAR-T cells were transferred to a 96-well plate containing fresh targets every 2-3 days). The E:T ratio was 10:1. CAR was expressed in cells from donor D503. Similar to the results described in Example 4, target cell lysis in a stress test was used to characterize CAR scFv in vitro .

In FIG. 9C shows the efficacy of CD70-specific CARs on repeated exposure to luciferase-labeled REH target cells (2×10 ⁶ cells added at the indicated time points). The E:T ratio was 1:5. CAR was expressed in cells from donor D503. Similar to the results described in Example 4, target cell lysis in a stress test was used to characterize CAR scFv in vitro .

In FIG. 10 shows the performance of CD70 specific CARs in various formats (as described in Example 9, Part A) on repeated exposure to luciferase labeled REH target cells (2x10 ⁶ cells added at the indicated time points). The E:T ratio was 1:5. Similar to the results described in Example 4, target cell lysis in a stress test was used to characterize CAR scFv in vitro .

Example 11. in vivo comparison of CAR CD70 in an ACHN model with metastases

CAR T cells containing various CD70 scFvs were generated and tested on ACHN cells, a cell line derived from renal cell carcinoma (RCC) cells. ACHN cells are described in Simmons et al. Animal Models of Bone Metastasis. Veterinary Pathology 52:827-841, 834 (2015). Each of the NSG mice were intravenously implanted with 1 million ACHN tumor cells, and 15 days after the tumor cell injection, the mice were intravenously injected with CAR-T cells via tail vein injection to determine CAR and the condition with the most optimal efficacy. 12C5 CAR T cells injected at 3 million CAR+ cells per mouse showed the best efficacy.

Materials and methods

forty-five NSG mice were prepared for intravenous injection of the tumor via the tail vein. ACHN tumor cells known to express CD70 were expanded in MEM supplemented with 10% FBS. On day 0, ACHN tumor cells were resuspended in serum-free MEM at the concentration required to inject 1 million cells per animal. ACHN tumor cells were injected intravenously in 200 μl of serum-free MEM medium. Baseline body weights on day 4 were recorded for all animals. Tumor cell flux was measured twice a week starting on day 7 using bioluminescence (IVIS Spectrum Imager™ from PerkinElmer™; auto exposure with a maximum exposure time of 120 seconds) and body weights were recorded. On day 20, when tumors reached 200 mm ³ (standard error 9.69), 35 tumor bearing mice were randomized into 7 groups of 5 mice each. On day 15, CAR T cells were thawed in MEM supplemented with 10% FBS and resuspended in serum free MEM at 3 million CAR+ T cells per animal (calculated based on individual transduction efficiencies). The number of NTD cells required to maintain an equal percentage of CAR+ T cells as well as an equal number of total T cells in each group was calculated and added to the respective samples. CAR-T cells or control NTDs were injected into 200 μl of serum-free MEM per animal intravenously via the tail vein. Tumor cell flux was measured and body weights were recorded twice a week until day 32 when the NTD group reached the end point of the study ( ^> 20% body weight loss) (see FIG. 11).

Bioluminescence scores (SEM mean and error) were plotted using GraphPad Prism, with statistics calculated using repeated measures one-way ANOVA. The CAR-T 12C5 group demonstrated antitumor efficacy at a CAR+ dose of 3 million.

Example 12 CD70 Expression Levels in Patient-Derived RCC Samples and Lysis of Patient-Derived RCC Samples by CD70-Specific CAR T Cells

Primary cell samples from RCC patients were obtained from Conversant Bio (frozen dissociated tumor cells) or from CHTN Western/NDRI (fresh tumor fragments, which were then dissociated at the point of collection in the laboratory using the Miltenyi MACS Human Tumor Dissociation Kit and GentleMACS) . Primary tumor cells were maintained in RPMI supplemented with 20% FBS. To determine cell surface CD70 protein expression in these cells, along with the respective RCC cell lines, the present inventors performed flow cytometry and receptor quantification using an anti-CD70 antibody conjugated to phycoerythrin at a 1:1 ratio. Cell surface receptors were quantified using Quantibrite beads from BD Biosciences and antibody binding capacity (ABC) values were calculated according to the manufacturer's recommendations. CD70-specific CAR T cells were generated as previously described and their cytotoxicity to primary RCC cells and the RCC ACHN cell line was assessed using the same assay and experimental parameters similar to those described in Example 9, Part A.

results

Primary RCC cells were confirmed to express CD70 with ABC values ranging from ~2000 CD70 receptors per cell (receptors/cell) to ~25000 receptors/cell (Fig. 12B), with expression on RCC cell lines ranging from ~25,000 receptors/cell to ~400,000 receptors/cell (FIG. 12A). The present inventors also confirmed that cells expressing 7,000 CD70 receptors per cell (receptors/cell) (Fig. 13B), 24,000 receptors/cell (Fig. 13A), or 40,000 receptors/cell (Fig. 13C) are effectively killed by CD70 -specific CAR T cells, in which CAR is derived from either scFv 4F11 or P08F08.

Example 13 CD70 Expression Levels on Various Hematologic Tumor Cell Lines and Lysis of These Cells by CD70 Specific CAR T Cells

The ability to target CD70 to a range of heme tumors, including lymphomas, leukemias, and myelomas, has been characterized. Characterization included analysis of both CD70 RNA and cell surface protein expression in multiple malignancies, followed by analysis of the efficacy of CAR T cells against cell lines.

results

Analysis of RNA expression in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM cells) using the Cancer Genome Atlas (TCGA) showed that CD70 expression can be observed for all 4 types of cancer , indicating the potential utility of targeting these cancers with CD70-specific CAR T cells. To determine cell surface CD70 protein expression in these cancers, the present inventors performed flow cytometry and receptor quantification on a panel of cell lines derived from selected tumor types. Expression patterns of cell surface proteins were similar to RNA analyzes, confirming that CD70 expression is widespread in cell lines of all tumor types (Fig. 14A). We then generated CD70-specific CAR T cells to test their performance in an in vitro cytotoxicity assay against the same cell lines. CAR T cells specific for CD70 showed sustained specific activity against target cells expressing the CD70 antigen (FIG. 14B). Various cell lines can be killed by CD70-specific CARs (FIG. 14B), indicating that CD70-specific CARs can kill even those cells that express CD70 at low levels. This demonstrates that the activity of CD70-specific CARs is not limited to particular cell types. Finally, the present inventors have shown that these CARs are effective against the MM1S cell line in an in vivo assay performed as shown in Example 7 (FIG. 15A and FIG. 15B). MM1S is a multiple myeloma cell line expressing a moderate amount of CD70 receptors per cell (FIG. 14A). Finally, it has been noted that CD70 has a broad expression profile in a range of hematologic malignancies. The use of CD70-specific CAR-T cells alone or in combination with other heme-associated targets enables tumor antigen to be targeted or escaped in a wide range of hematological malignancies.

Example 14 Determination of Kinetic Parameters and Affinity of Anti-Human CD70/CD70 Antibody Interactions at 37 ° C

In this example, the binding kinetic parameters and/or the affinity of various anti-human CD70 antibodies were determined. ScFvs were generated by cloning anti-CD70 antibody variable regions flanking linker (GGGGS) ₄ (SEQ ID NO: 602) and then the hinge portion and Fc from a modified human IgG2 sequence, resulting in an scFv-Fc fusion construct that was expressed using Expi293 and then purified by protein A binding affinity chromatography. Recombinant human CD70 was generated by fusing AviTag™, a polyhistidine tag, and chicken tenascin trimerization domain to the N-terminus of the extracellular domain (ECD) of human CD70, which was expressed using Expi293, then purified by immobilized metal ion affinity chromatography (IMAC) followed by size exclusion chromatography (SEC) if necessary.

Antibody binding kinetic parameters were determined using surface plasmon resonance (Biacore 8K, GE Healthcare Bio-Sciences, Pittsburgh, PA) at 37°C in HBS-T+ (0.01 M HEPES, pH 7.4, 0.15 M NaCl, 0.05% v/v Tween20, 1 mg/ml BSA). Recombinant human CD70 diluted in HBS-T+ was captured on a C1 chip immobilized with the AviTag™ labeled antibody. Purified anti-CD70 scFv-Fc fusions were serially diluted in HBS-T+, injected at a rate of 30 μl/min for 2-4 minutes, dissociation was monitored for 10 minutes, and then the surface was regenerated with 75 mM phosphoric acid between injections. Cycle buffers were selected for each CD70 scFv-Fc fusion to perform a dual control (“dual control” is described in Myszka, DG Improving biosensor analysis. J. Mol. Recognit. 12 , 279-284 (1999)) . Kinetic association rate constants (k _on ) and dissociation rate constants (k _off ) were obtained simultaneously by global matching of dual control sensorograms with Langmuir 1:1 mass transfer model using Biacore 8K Evaluation Software (GE Healthcare Bio-Sciences, Pittsburgh). , Pennsylvania) and then used to calculate the equilibrium dissociation constant (K _D ) from the kinetic rate constants of the reaction (K _D =k _off /k _on ). Data were matched to a 1:1 steady state affinity model using the Biacore 8K Evaluation Software to determine the equilibrium steady state dissociation constant (SS K _D ) as needed.

The kinetic binding parameters and affinity parameters for the anti-CD70 antibodies tested are shown in Table 13. The antibodies shown in Table 13 have the same scFv sequence as the CARs shown in Tables 5 and 11 with the same name.

Table 13

scFv format k _a (1/ms) k _d (1/s) t _1/2 (min) K _D (nm) SS KD (nm) 10A1 5.77E+05 7.73E-04 14.9 1.3 10H10 4.62E+04 3.20E-03 3.6 69.3 11C1 2.24E+05 1.86E-04 62.2 0.8 11E1 5.78E+05 1.00E-03 11.6 1.7 12A2 - - - indefinite 12C4 1.56E+06 4.55E-04 25.3 0.3 12D6 7.12E+04 1.94E-03 5.9 27.3 12D7 4.41E+05 7.55E-04 15.3 1.7 17G6 - - - Weak binding 4F11 8.25E+05 1.60E-03 7.2 1.9 8C8 1.03E+05 1.59E-03 7.3 15.4 8F8 3.48E+05 7.93E-04 14.6 2.3 9E10 8.25E+05 2.12E-03 5.4 2.6 P02B10 - - - 355 P07D03 - - - 1070 P08A02 - - - 1200 P08E02 8.23E+05 4.38E-03 2.6 5.3 P08F08 1.44E+06 1.53E-02 0.8 10.7 P08G02 2.39E+04 7.88E-03 1.5 330 P12B09 3.30E+05 1.35E-03 8.6 4.1 P12F02 2.75E+05 1.55E-03 7.4 5.7 P12G07 - - - Weak binding P13F04 9.77E+04 2.00E-02 0.6 205 P15D02 2.86E+05 <8.05E-05 >136 <0.3 P16C05 - - - Weak binding

While the teachings disclosed have been described with reference to various uses, methods, kits, and compositions, it should be understood that various changes and modifications may be made without departing from the teachings of this document and the claimed claims below. The above examples are provided to better illustrate the ideas disclosed and are not intended to limit the scope of the ideas presented herein. Although the present ideas have been described in the definitions of these illustrative embodiments, one skilled in the art will readily appreciate that numerous variations and modifications to these illustrative embodiments are possible without undue experimentation. All such variations and modifications are within the scope of current ideas.

All references cited in this document, including but not limited to patents, patent applications, scientific articles, manuals, etc., and the references cited therein, to the extent that they are no longer so, are incorporated herein. document by reference in their entirety. In the event that one or more of the references to the literature and similar materials differ or conflict with this application, including, without limitation, certain terms, terms of use, described techniques, and the like, this application shall prevail.

In the above description and examples, some specific embodiments of the present invention are defined in detail and the best mode of implementation proposed by the authors of the present invention is described. However, it will be understood that no matter how detailed the above may be in the text, the present invention may be practiced in many ways, and the present invention should be construed in accordance with the appended claims and any equivalents thereof.

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SEQUENCE LIST

<110> Pfizer Inc.

<120> CHIMERIC ANTIGEN RECEPTORS TARGETING CD70

<130> ALGN-014/03WO 333466-2233

<150> US 62/775246

<151> 2018-12-04

<150> US 62/641873

<151> 2018-03-12

<150> US 62/641869

<151> 2018-03-12

<150> US 62/625019

<151> 2018-02-01

<150> US 62/625009

<151> 2018-02-01

<160> 683

<170> PatentIn version 3.5

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35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Lys 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 Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 6

<211> 112

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 6

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1.5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr

20 25 30

Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asp Ile Arg Thr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

100 105 110

<210> 7

<211> 112

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 7

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 Ser Ser Gln Ser Leu Val Tyr Ser

20 25 30

Asp Glu Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser

35 40 45

Leu Arg Arg Leu Ile Tyr Gln Val Ser Asn Arg Asp 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 Phe Cys Met Gln Gly

85 90 95

Thr Tyr Trp Pro Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 8

<211> 117

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 8

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 Thr Phe Arg Asn Ser

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Asn Ile Lys Arg Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser 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 Asp Gln Thr Gly Ser Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 9

<211> 106

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 9

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Met Ser Leu Gly

1.5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Gly Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ile Asn Trp Pro His

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 10

<211> 115

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 10

Gln Val Gln Leu Arg Gly Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1.5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Asp Ser Ile Ser Val Tyr

20 25 30

Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Glu Trp Ile

35 40 45

Gly Arg Val Tyr Ser Ser Gly Asn Ile Asn Tyr Asn Pro Ser Leu Glu

50 55 60

Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Ser Arg Phe Ser Leu

65 70 75 80

Asn Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Gly Leu Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr

100 105 110

Val Ser Ser

115

<210> 11

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 11

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 Asp Ile Ser Asn Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ile Leu Ile

35 40 45

Tyr Gly Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Ala Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Phe Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 12

<211> 115

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 12

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Glu

1.5 10 15

Ser Leu Arg Leu Ser Cys Glu Val Ser Gly Phe Thr Phe Thr Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ile Ile Ser Gly Val Ala Phe Thr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp His Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Val Lys Val Asp Gly Glu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 13

<211> 108

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 13

Glu Ile Val Met Thr Gln Ser Pro Asp Thr Leu Ser Val Ser Pro Gly

1.5 10 15

Glu Arg Ala Ile Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Thr Arg Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Ser Ile Ser Ser Leu Gln Ser

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Asn Trp Pro Pro

85 90 95

Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 14

<211> 117

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 14

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1.5 10 15

Ser Val Lys Val Ser Cys Glu Ala Ser Gly Gly Thr Phe Ile Thr Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Phe Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Ser

65 70 75 80

Met Glu Leu Arg Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Gln Trp Glu Leu Phe Phe Phe Asp Phe Trp Gly Gln Gly Thr Pro

100 105 110

Val Thr Val Ser Ser

115

<210> 15

<211> 108

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 15

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1.5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Gln Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Ile Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 16

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 16

Ala 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 Thr Phe Thr Tyr Tyr

20 25 30

Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser His Ile Ser Ile Arg Ser Ser Thr Ile Tyr Phe Ala Asp Ser Ala

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Ser Gly Trp Tyr Gly Asp Tyr Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 17

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 17

Asp Ile Gln Met Thr Gln Ser Pro Ser Ala Met Ser Ala Ser Val Gly

1.5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr

20 25 30

Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Val Pro Lys Arg 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 Glu Phe Thr Leu Thr Ile Ser Ser Leu Leu Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Leu Asn Ser Phe Pro Phe

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Asn

100 105

<210> 18

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 18

Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu

1.5 10 15

Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn Ala

20 25 30

Arg Met Gly Val Thr Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu

35 40 45

Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser

50 55 60

Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Thr Gln Val

65 70 75 80

Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr

85 90 95

Cys Ala Arg Ile Arg Asp Tyr Tyr Asp Ile Ser Ser Tyr Tyr Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Leu Val Ser Val Ser Ser

115 120

<210> 19

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 19

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly

1.5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val 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 Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Phe Ser Phe Pro Phe

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

100 105

<210> 20

<211> 119

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 20

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 Val Ser Gly Phe Thr Phe Ser Asn His

20 25 30

Asn Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Ile

35 40 45

Ser Tyr Ile Ser Arg Ser Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp His Ala Gln Trp Tyr Gly Met Asp Val Trp Gly Gln Gly

100 105 110

Thr Thr Val Thr Val Ser Ser

115

<210> 21

<211> 112

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 21

Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1.5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser

20 25 30

Tyr Asn Asn Lys Asn Tyr Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Asn Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln

85 90 95

Tyr Tyr Ser Thr Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 22

<211> 124

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 22

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 Val Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Ser Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Gly Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Gly Val Asn Trp Gly Trp Arg Leu Tyr Trp His Phe Asp

100 105 110

Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 23

<211> 108

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 23

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1.5 10 15

Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 24

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 24

Glu Val Gln Val 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 Thr Phe Ser Ser Tyr

20 25 30

Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser His Ser Ser Ile Ser Arg Gly Asn Ile Tyr Phe Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Ser Gly Trp Tyr Gly Asp Tyr Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 25

<211> 112

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 25

Glu Leu Gln Ser Val Leu Thr Gln Pro Ser Ala Ser Gly Thr Pro

1.5 10 15

Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly

20 25 30

Ser Asn Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys

35 40 45

Leu Leu Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg

50 55 60

Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly

65 70 75 80

Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp

85 90 95

Ser Leu Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 26

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 26

Glu Val Gln Leu Leu 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 Ala Phe Ser Asn Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Arg Gly Gly Gly Gly Ser Thr 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 Tyr Cys

85 90 95

Ala Arg Asp Phe Ile Ser Gly Thr Trp Tyr Pro Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 27

<211> 112

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 27

Glu Leu Gln Ser Val Leu Thr Gln Pro Ser Ala Ser Gly Thr Pro

1.5 10 15

Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly

20 25 30

Ser Asn Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys

35 40 45

Leu Leu Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg

50 55 60

Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly

65 70 75 80

Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Asp Gly

85 90 95

Ser Leu Ser Ala Val Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 28

<211> 122

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 28

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1.5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Ser Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ser Ile Tyr Pro Asp Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Ser Ser Thr Val Asp Tyr Pro Gly Tyr Ser Tyr Phe Asp Tyr Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 29

<211> 112

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 29

Glu Leu Gln Ser Val Leu Thr Gln Pro Ser Ala Ser Gly Thr Pro

1.5 10 15

Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly

20 25 30

Ser Asn Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys

35 40 45

Leu Leu Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg

50 55 60

Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly

65 70 75 80

Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp

85 90 95

Ser Leu Gly Ser Pro Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 30

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 30

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1.5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Trp Ile Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Asp Gly Ser Asp Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Asp Ile Thr Ser Trp Tyr Tyr Gly Glu Pro Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 31

<211> 110

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 31

Glu Leu Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser

1.5 10 15

Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser

20 25 30

Arg Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu

35 40 45

Leu Ile Tyr Ala Ala Ser Ile Leu Gln Thr Gly Val Pro Ser Arg Phe

50 55 60

Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu

65 70 75 80

Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr

85 90 95

Thr Met Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 32

<211> 122

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 32

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1.5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Ser

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Lys Gly Leu Ser Gln Ala Met Thr Gly Phe Gly Phe Asp Tyr Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 33

<211> 113

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 33

Glu Leu Gln Ser Val Leu Thr Gln Pro Ser Ala Ser Gly Thr Pro

1.5 10 15

Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly

20 25 30

Ser Asn Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys

35 40 45

Leu Leu Ile Tyr Gly Asp Tyr Gln Arg Pro Ser Gly Val Pro Asp Arg

50 55 60

Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly

65 70 75 80

Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Arg Asp Asp

85 90 95

Ser Leu Ser Gly Ser Val Val Phe Gly Thr Gly Thr Lys Leu Thr Val

100 105 110

Leu

<210> 34

<211> 122

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 34

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1.5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Gly Phe Thr Ser Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile His Pro Asp Asp Ser Asp Thr Lys Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Ser Ser Tyr Leu Arg Gly Leu Trp Gly Gly Tyr Phe Asp Tyr Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 35

<211> 110

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 35

Glu Leu Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser

1.5 10 15

Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Tyr

20 25 30

Asp Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu

35 40 45

Leu Ile Tyr Asp Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe

50 55 60

Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu

65 70 75 80

Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr Thr

85 90 95

Pro Leu Phe Thr Phe Gly Glyn Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 36

<211> 126

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 36

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1.5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Pro Ser Ser

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Asp Thr Ser His Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Ala Ser Tyr Phe Asp Arg Gly Thr Gly Tyr Ser Ser Trp Trp

100 105 110

Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 37

<211> 110

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 37

Glu Leu Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser

1.5 10 15

Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Tyr Ile Gly

20 25 30

Arg Tyr Leu Asn Trp Tyr Gln Gln Lys Arg Gly Lys Ala Pro Lys Leu

35 40 45

Leu Ile His Gly Ala Thr Ser Leu Ala Ser Gly Val Pro Ser Arg Phe

50 55 60

Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu

65 70 75 80

Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr

85 90 95

Thr Ser Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 38

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 38

Glu Val Gln Leu Leu 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 Thr Phe Ser Gln Tyr

20 25 30

Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Gly Gly Val Ser Thr 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 Tyr Cys

85 90 95

Ala Ser Asp Ile Ser Asp Ser Gly Ser His Trp Tyr Phe Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 39

<211> 112

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 39

Glu Leu Gln Ser Val Leu Thr Gln Pro Ser Ala Ser Gly Thr Pro

1.5 10 15

Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Thr Ser Asn Ile Gly

20 25 30

Arg Asn Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys

35 40 45

Leu Leu Ile Tyr Arg Thr Asn Gln Arg Pro Ser Gly Val Pro Asp Arg

50 55 60

Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly

65 70 75 80

Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp

85 90 95

Ser Leu Ser Gly Arg Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 40

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 40

Glu Val Gln Leu Leu 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 Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Thr Ile Ser Gly Thr Gly Gly Thr Thr 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 Tyr Cys

85 90 95

Ala Lys Val Arg Ala Gly Ile Asp Pro Thr Ala Ser Asp Val Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 41

<211> 112

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 41

Glu Leu Gln Ser Val Leu Thr Gln Pro Ser Ala Ser Gly Thr Pro

1.5 10 15

Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly

20 25 30

Ser Asn Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys

35 40 45

Pro Leu Ile Tyr Met Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg

50 55 60

Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly

65 70 75 80

Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp

85 90 95

Ser Leu Ser Ala Val Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 42

<211> 124

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 42

Glu Val Gln Leu Leu 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 Thr Phe Asn Asn Phe

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Ser Gly Ser Gly Asp Asn Thr 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 Tyr Cys

85 90 95

Ala Lys Asp Arg Asp Ile Gly Leu Gly Trp Tyr Ser Tyr Tyr Leu Asp

100 105 110

Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 43

<211> 113

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 43

Glu Leu Gln Ser Val Leu Thr Gln Pro Ser Ala Ser Gly Thr Pro

1.5 10 15

Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Ile Gly

20 25 30

Thr Asn Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys

35 40 45

Leu Leu Ile Tyr Arg Ser Ser Arg Arg Pro Ser Gly Val Pro Asp Arg

50 55 60

Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly

65 70 75 80

Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Gly

85 90 95

Ser Leu Ser Gly His Trp Val Phe Gly Thr Gly Thr Lys Leu Thr Val

100 105 110

Leu

<210> 44

<211> 119

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 44

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1.5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Glu Ile Ile Pro Ile Phe Gly Thr Ala Ser Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Gly Trp Asp Asp Ser Trp Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 45

<211> 110

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 45

Glu Leu Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser

1.5 10 15

Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asp

20 25 30

Thr Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu

35 40 45

Leu Ile Tyr Ser Ala Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe

50 55 60

Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu

65 70 75 80

Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr

85 90 95

Thr Ala Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 46

<211> 122

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 46

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1.5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Ala Ser Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Val Ile Tyr Pro Gly Thr Ser Glu Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Lys Gly Leu Ser Ala Ser Ala Ser Gly Tyr Ser Phe Gln Tyr Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 47

<211> 109

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 47

Glu Leu Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser

1.5 10 15

Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly

20 25 30

Gln Ser Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu

35 40 45

Leu Ile Tyr Gly Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe

50 55 60

Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu

65 70 75 80

Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr

85 90 95

Pro Ile Thr Phe Gly Glyn Gly Thr Lys Val Glu Ile Lys

100 105

<210> 48

<211> 124

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 48

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1.5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asp Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Met Ile Ser Pro Gly Gly Ser Thr Thr Ile Tyr Arg Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Glu Met Tyr Thr Gly Gly Tyr Gly Gly Ser Trp Tyr Phe Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 49

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 49

Ser Tyr Gly Phe Ser

15

<210> 50

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 50

Gly Gly Thr Phe Ser Ser Tyr

15

<210> 51

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 51

Gly Gly Thr Phe Ser Tyr Gly Phe Ser

1.5 10

<210> 52

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 52

Gly Ile Ile Pro Ile Phe Gly Ser Ala Asn Tyr Ala Gln Lys Phe Gln

1.5 10 15

gly

<210> 53

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 53

Ile Pro Ile Phe Gly Ser

15

<210> 54

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 54

Gly Gly Ser Ser Ser Pro Phe Ala Tyr

15

<210> 55

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 55

Ser Tyr Gly Phe Ser

15

<210> 56

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 56

Gly Gly Thr Phe Ser Ser Tyr

15

<210> 57

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 57

Gly Gly Thr Phe Ser Tyr Gly Phe Ser

1.5 10

<210> 58

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 58

Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln

1.5 10 15

gly

<210> 59

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 59

Ile Pro Ile Phe Gly Thr

15

<210> 60

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 60

Gly Gly Ser Ser Ser Pro Phe Ala Tyr

15

<210> 61

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 61

Ser Tyr Tyr Trp Asn

15

<210> 62

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 62

Gly Gly Ser Ile Ser Ser Tyr

15

<210> 63

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 63

Gly Gly Ser Ile Ser Ser Tyr Tyr Trp Asn

1.5 10

<210> 64

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 64

Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser

1.5 10 15

<210> 65

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 65

Tyr Tyr Ser Gly Ser

15

<210> 66

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 66

Asp Ile Arg Thr Trp

15

<210> 67

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 67

Asn Ser Trp Met Ser

15

<210> 68

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 68

Gly Phe Thr Phe Arg Asn Ser

15

<210> 69

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 69

Gly Phe Thr Phe Arg Asn Ser Trp Met Ser

1.5 10

<210> 70

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 70

Asn Ile Lys Arg Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val Lys

1.5 10 15

gly

<210> 71

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 71

Lys Arg Asp Gly Ser Glu

15

<210> 72

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 72

Asp Gln Thr Gly Ser Phe Asp Tyr

15

<210> 73

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 73

Val Tyr Tyr Trp Ser

15

<210> 74

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 74

Asp Asp Ser Ile Ser Val Tyr

15

<210> 75

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 75

Asp Asp Ser Ile Ser Val Tyr Tyr Trp Ser

1.5 10

<210> 76

<211> 15

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 76

Val Tyr Ser Ser Gly Asn Ile Asn Tyr Asn Pro Ser Leu Glu Ser

1.5 10 15

<210> 77

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 77

Tyr Ser Ser Gly Asn

15

<210> 78

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 78

Gly Leu Asp Ala Phe Asp Ile

15

<210> 79

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 79

Ser Tyr Ala Met Ser

15

<210> 80

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 80

Gly Phe Thr Phe Thr Ser Tyr

15

<210> 81

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 81

Gly Phe Thr Phe Thr Ser Tyr Ala Met Ser

1.5 10

<210> 82

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 82

Arg Val Tyr Ser Ser Gly Asn Ile Asn Tyr Asn Pro Ser Leu Glu Ser

1.5 10 15

<210> 83

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 83

Tyr Ser Ser Gly Asn

15

<210> 84

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 84

Gly Leu Asp Ala Phe Asp Ile

15

<210> 85

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 85

Thr Tyr Ala Ile Ser

15

<210> 86

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 86

Gly Gly Thr Phe Ile Thr Tyr

15

<210> 87

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 87

Gly Gly Thr Phe Ile Thr Tyr Ala Ile Ser

1.5 10

<210> 88

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 88

Gly Ile Ile Pro Phe Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln

1.5 10 15

gly

<210> 89

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 89

Ile Pro Phe Phe Gly Thr

15

<210> 90

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 90

Trp Glu Leu Phe Phe Phe Asp Phe

15

<210> 91

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 91

Tyr Tyr Ser Met Asn

15

<210> 92

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 92

Gly Phe Thr Phe Thr Tyr Tyr

15

<210> 93

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 93

Gly Phe Thr Phe Thr Tyr Tyr Ser Met Asn

1.5 10

<210> 94

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 94

His Ile Ser Ile Arg Ser Ser Thr Ile Tyr Phe Ala Asp Ser Ala Lys

1.5 10 15

gly

<210> 95

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 95

Ser Ile Arg Ser Ser Thr

15

<210> 96

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 96

Gly Ser Gly Trp Tyr Gly Asp Tyr Phe Asp Tyr

1.5 10

<210> 97

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 97

Asn Ala Arg Met Gly Val Thr

15

<210> 98

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 98

Gly Phe Ser Leu Ser Asn Ala Arg Met

15

<210> 99

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 99

Gly Phe Ser Leu Ser Asn Ala Arg Met Gly Val Thr

1.5 10

<210> 100

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 100

His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser Leu Lys Ser

1.5 10 15

<210> 101

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 101

Phe Ser Asn Asp Glu

15

<210> 102

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 102

Ile Arg Asp Tyr Tyr Asp Ile Ser Ser Tyr Tyr Asp Tyr

1.5 10

<210> 103

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 103

Asn His Asn Ile His

15

<210> 104

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 104

Gly Phe Thr Phe Ser Asn His

15

<210> 105

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 105

Gly Phe Thr Phe Ser Asn His Asn Ile His

1.5 10

<210> 106

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 106

Tyr Ile Ser Arg Ser Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val Lys

1.5 10 15

gly

<210> 107

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 107

Ser Arg Ser Ser Ser Thr

15

<210> 108

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 108

Asp His Ala Gln Trp Tyr Gly Met Asp Val

1.5 10

<210> 109

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 109

Ser Tyr Trp Met Ser

15

<210> 110

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 110

Gly Phe Thr Phe Ser Ser Tyr

15

<210> 111

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 111

Gly Phe Thr Phe Ser Tyr Trp Met Ser

1.5 10

<210> 112

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 112

Ser Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val Lys

1.5 10 15

gly

<210> 113

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 113

Lys Gln Asp Gly Ser Glu

15

<210> 114

<211> 15

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 114

Glu Gly Val Asn Trp Gly Trp Arg Leu Tyr Trp His Phe Asp Leu

1.5 10 15

<210> 115

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 115

Ser Tyr Ser Met Asn

15

<210> 116

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 116

Gly Phe Thr Phe Ser Ser Tyr

15

<210> 117

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 117

Gly Phe Thr Phe Ser Ser Tyr Ser Met Asn

1.5 10

<210> 118

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 118

His Ser Ser Ile Ser Arg Gly Asn Ile Tyr Phe Ala Asp Ser Val Lys

1.5 10 15

gly

<210> 119

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 119

Ser Ile Ser Arg Gly Asn

15

<210> 120

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 120

Gly Ser Gly Trp Tyr Gly Asp Tyr Phe Asp Tyr

1.5 10

<210> 121

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 121

Asn Tyr Ala Met Ser

15

<210> 122

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 122

Gly Phe Ala Phe Ser Asn Tyr

15

<210> 123

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 123

Gly Phe Ala Phe Ser Asn Tyr Ala Met Ser

1.5 10

<210> 124

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 124

Ala Ile Arg Gly Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1.5 10 15

gly

<210> 125

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 125

Arg Gly Gly Gly Gly Ser

15

<210> 126

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 126

Asp Phe Ile Ser Gly Thr Trp Tyr Pro Asp Tyr

1.5 10

<210> 127

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 127

Ser Tyr Trp Ile Gly

15

<210> 128

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 128

Gly Tyr Arg Phe Thr Ser Tyr

15

<210> 129

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 129

Gly Tyr Arg Phe Thr Ser Tyr Trp Ile Gly

1.5 10

<210> 130

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 130

Ser Ile Tyr Pro Asp Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln

1.5 10 15

gly

<210> 131

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 131

Tyr Pro Asp Asp Ser Asp

15

<210> 132

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 132

Ser Thr Val Asp Tyr Pro Gly Tyr Ser Tyr Phe Asp Tyr

1.5 10

<210> 133

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 133

Asn Tyr Trp Ile Ala

15

<210> 134

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 134

Gly Tyr Thr Phe Thr Asn Tyr

15

<210> 135

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 135

Gly Tyr Thr Phe Thr Asn Tyr Trp Ile Ala

1.5 10

<210> 136

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 136

Ile Ile Tyr Pro Asp Gly Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln

1.5 10 15

gly

<210> 137

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 137

Tyr Pro Asp Gly Ser Asp

15

<210> 138

<211> 14

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 138

Asp Ile Thr Ser Trp Tyr Tyr Gly Glu Pro Ala Phe Asp Ile

1.5 10

<210> 139

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 139

Ser Ser Trp Ile Gly

15

<210> 140

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 140

Gly Tyr Ser Phe Thr Ser Ser

15

<210> 141

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 141

Gly Tyr Ser Phe Thr Ser Ser Trp Ile Gly

1.5 10

<210> 142

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 142

Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln

1.5 10 15

gly

<210> 143

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 143

Tyr Pro Gly Asp Ser Asp

15

<210> 144

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 144

Gly Leu Ser Gln Ala Met Thr Gly Phe Gly Phe Asp Tyr

1.5 10

<210> 145

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 145

Ser Tyr Trp Ile Gly

15

<210> 146

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 146

Gly Tyr Gly Phe Thr Ser Tyr

15

<210> 147

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 147

Gly Tyr Gly Phe Thr Ser Tyr Trp Ile Gly

1.5 10

<210> 148

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 148

Ile Ile His Pro Asp Asp Ser Asp Thr Lys Tyr Ser Pro Ser Phe Gln

1.5 10 15

gly

<210> 149

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 149

His Pro Asp Asp Ser Asp

15

<210> 150

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 150

Ser Tyr Leu Arg Gly Leu Trp Gly Gly Tyr Phe Asp Tyr

1.5 10

<210> 151

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 151

Ser Ser Trp Ile Gly

15

<210> 152

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 152

Gly Tyr Thr Phe Pro Ser Ser

15

<210> 153

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 153

Gly Tyr Thr Phe Pro Ser Ser Trp Ile Gly

1.5 10

<210> 154

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 154

Ile Ile Tyr Pro Asp Thr Ser His Thr Arg Tyr Ser Pro Ser Phe Gln

1.5 10 15

<210> 155

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 155

Tyr Pro Asp Thr Ser His

15

<210> 156

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 156

Ala Ser Tyr Phe Asp Arg Gly Thr Gly Tyr Ser Ser Trp Trp Met Asp

1.5 10 15

Val

<210> 157

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 157

Gln Tyr Ser Met Ser

15

<210> 158

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 158

Gly Phe Thr Phe Ser Gln Tyr

15

<210> 159

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 159

Gly Phe Thr Phe Ser Gln Tyr Ser Met Ser

1.5 10

<210> 160

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 160

Ala Ile Ser Gly Gly Gly Val Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1.5 10 15

gly

<210> 161

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 161

Ser Gly Gly Gly Val Ser

15

<210> 162

<211> 14

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 162

Asp Ile Ser Asp Ser Gly Ser His Trp Tyr Phe Asp Tyr

1.5 10

<210> 163

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 163

Ser Tyr Ala Met Ser

15

<210> 164

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 164

Gly Phe Thr Phe Ser Ser Tyr

15

<210> 165

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 165

Gly Phe Thr Phe Ser Tyr Ala Met Ser

1.5 10

<210> 166

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 166

Thr Ile Ser Gly Thr Gly Gly Thr Thr Tyr Tyr Ala Asp Ser Val Lys

1.5 10 15

gly

<210> 167

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 167

Ser Gly Thr Gly Gly Thr

15

<210> 168

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 168

Val Arg Ala Gly Ile Asp Pro Thr Ala Ser Asp Val

1.5 10

<210> 169

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 169

Asn Phe Ala Met Ser

15

<210> 170

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 170

Gly Phe Thr Phe Asn Asn Phe

15

<210> 171

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 171

Gly Phe Thr Phe Asn Asn Phe Ala Met Ser

1.5 10

<210> 172

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 172

Gly Ile Ser Gly Ser Gly Asp Asn Thr Tyr Tyr Ala Asp Ser Val Lys

1.5 10 15

gly

<210> 173

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 173

Ser Gly Ser Gly Asp Asn

15

<210> 174

<211> 15

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 174

Asp Arg Asp Ile Gly Leu Gly Trp Tyr Ser Tyr Tyr Leu Asp Val

1.5 10 15

<210> 175

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 175

Ser Tyr Ala Ile Ser

15

<210> 176

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 176

Gly Gly Thr Phe Ser Ser Tyr

15

<210> 177

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 177

Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser

1.5 10

<210> 178

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 178

Glu Ile Ile Pro Ile Phe Gly Thr Ala Ser Tyr Ala Gln Lys Phe Gln

1.5 10 15

gly

<210> 179

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 179

Ile Pro Ile Phe Gly Thr

15

<210> 180

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 180

Ala Gly Trp Asp Asp Ser Trp Phe Asp Tyr

1.5 10

<210> 181

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 181

Ser Tyr Trp Ile Gly

15

<210> 182

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 182

Gly Tyr Ser Phe Ala Ser Tyr

15

<210> 183

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 183

Gly Tyr Ser Phe Ala Ser Tyr Trp Ile Gly

1.5 10

<210> 184

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 184

Val Ile Tyr Pro Gly Thr Ser Glu Thr Arg Tyr Ser Pro Ser Phe Gln

1.5 10 15

gly

<210> 185

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 185

Tyr Pro Gly Thr Ser Glu

15

<210> 186

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 186

Gly Leu Ser Ala Ser Ala Ser Gly Tyr Ser Phe Gln Tyr

1.5 10

<210> 187

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 187

Asp Tyr Trp Ile Gly

15

<210> 188

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 188

Gly Tyr Ser Phe Thr Asp Tyr

15

<210> 189

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 189

Gly Tyr Ser Phe Thr Asp Tyr Trp Ile Gly

1.5 10

<210> 190

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 190

Met Ile Ser Pro Gly Gly Ser Thr Thr Ile Tyr Arg Pro Ser Phe Gln

1.5 10 15

gly

<210> 191

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 191

Ser Pro Gly Gly Ser Thr

15

<210> 192

<211> 14

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 192

Met Tyr Thr Gly Gly Tyr Gly Gly Ser Trp Tyr Phe Asp Tyr

1.5 10

<210> 193

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 193

Arg Ser Ser Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr Leu Ser

1.5 10 15

<210> 194

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 194

Lys Ile Ser Asn Arg Phe Ser

15

<210> 195

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 195

Met Gln Ala Thr Gln Phe Pro Leu Thr

15

<210> 196

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 196

Arg Ser Ser Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr Leu Ser

1.5 10 15

<210> 197

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 197

Lys Ile Ser Asn Arg Phe Ser

15

<210> 198

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 198

Met Gln Ala Thr Gln Phe Pro Leu Thr

15

<210> 199

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 199

Arg Ala Ser Gln Gly Ile Ser Asn Tyr Leu Ala

1.5 10

<210> 200

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 200

Ala Ala Ser Ser Leu Gln Ser

15

<210> 201

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 201

Gln Gln Tyr Asn Ser Tyr Pro Leu Thr

15

<210> 202

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 202

Arg Ser Ser Gln Ser Leu Val Tyr Ser Asp Glu Asn Thr Tyr Leu Asn

1.5 10 15

<210> 203

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 203

Gln Val Ser Asn Arg Asp Ser

15

<210> 204

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 204

Met Glyn Gly Thr Tyr Trp Pro Pro Thr

15

<210> 205

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 205

Arg Ala Ser Gln Ser Val Ser Ser Ser Leu Ala

1.5 10

<210> 206

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 206

Gly Ala Ser Thr Arg Ala Thr

15

<210> 207

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 207

Gln Gln Tyr Ile Asn Trp Pro His

15

<210> 208

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 208

Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn

1.5 10

<210> 209

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 209

Gly Ala Ser Asn Leu Glu Thr

15

<210> 210

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 210

Gln Gln Tyr Asp Asn Phe Pro Ile Thr

15

<210> 211

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 211

Arg Ala Ser Gln Ser Val Ser Ser Asn Leu Ala

1.5 10

<210> 212

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 212

Ser Ala Ser Thr Arg Ala Ser

15

<210> 213

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 213

Gln Gln Tyr Asp Asn Trp Pro Pro Leu Thr

1.5 10

<210> 214

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 214

Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala

1.5 10

<210> 215

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 215

Gly Ala Ser Ser Arg Ala Thr

15

<210> 216

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 216

Gln Gln Tyr Gly Ser Ser Pro Leu Thr

15

<210> 217

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 217

Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Ala

1.5 10

<210> 218

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 218

Ala Ala Ser Ser Leu Gln Ser

15

<210> 219

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 219

Leu Gln Leu Asn Ser Phe Pro Phe Thr

15

<210> 220

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 220

Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala

1.5 10

<210> 221

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 221

Ala Ala Ser Ser Leu Gln Ser

15

<210> 222

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 222

Gln Gln Ala Phe Ser Phe Pro Phe Thr

15

<210> 223

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 223

Lys Ser Ser Gln Ser Val Leu Tyr Ser Tyr Asn Asn Lys Asn Tyr Val

1.5 10 15

Ala

<210> 224

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 224

Trp Ala Ser Thr Arg Glu Ser

15

<210> 225

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 225

Gln Gln Tyr Tyr Ser Thr Leu Thr

15

<210> 226

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 226

Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala

1.5 10

<210> 227

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 227

Asp Ala Ser Ser Arg Ala Thr

15

<210> 228

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 228

Gln Gln Tyr Gly Ser Ser Pro Leu Thr

15

<210> 229

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 229

Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Tyr

1.5 10

<210> 230

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 230

Arg Asn Asn Gln Arg Pro Ser

15

<210> 231

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 231

Ala Ala Trp Asp Asp Ser Leu Ser Gly Val Val

1.5 10

<210> 232

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 232

Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn Tyr Val Tyr

1.5 10

<210> 233

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 233

Arg Asn Asn Gln Arg Pro Ser

15

<210> 234

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 234

Ala Ser Trp Asp Gly Ser Leu Ser Ala Val Val

1.5 10

<210> 235

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 235

Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Tyr

1.5 10

<210> 236

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 236

Arg Asn Asn Gln Arg Pro Ser

15

<210> 237

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 237

Ala Thr Trp Asp Asp Ser Leu Gly Ser Pro Val

1.5 10

<210> 238

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 238

Arg Ala Ser Gln Ser Ile Ser Arg Tyr Leu Asn

1.5 10

<210> 239

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 239

Ala Ala Ser Ile Leu Gln Thr

15

<210> 240

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 240

Gln Gln Ser Tyr Ser Thr Thr Met Trp Thr

1.5 10

<210> 241

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 241

Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Asn

1.5 10

<210> 242

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 242

Gly Asp Tyr Gln Arg Pro Ser

15

<210> 243

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 243

Ala Thr Arg Asp Asp Ser Leu Ser Gly Ser Val Val

1.5 10

<210> 244

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 244

Arg Ala Ser Gln Ser Ile Tyr Asp Tyr Leu His

1.5 10

<210> 245

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 245

Asp Ala Ser Asn Leu Gln Ser

15

<210> 246

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 246

Gln Gln Ser Tyr Thr Thr Pro Leu Phe Thr

1.5 10

<210> 247

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 247

Arg Ala Ser Gln Tyr Ile Gly Arg Tyr Leu Asn

1.5 10

<210> 248

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 248

Gly Ala Thr Ser Leu Ala Ser

15

<210> 249

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 249

Gln Gln Ser Tyr Ser Thr Thr Ser Pro Thr

1.5 10

<210> 250

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 250

Ser Gly Ser Thr Ser Asn Ile Gly Arg Asn Tyr Val Tyr

1.5 10

<210> 251

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 251

Arg Thr Asn Gln Arg Pro Ser

15

<210> 252

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 252

Ala Ala Trp Asp Asp Ser Leu Ser Gly Arg Val

1.5 10

<210> 253

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 253

Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Tyr

1.5 10

<210> 254

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 254

Met Asn Asn Gln Arg Pro Ser

15

<210> 255

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 255

Ala Ala Trp Asp Asp Ser Leu Ser Ala Val Val

1.5 10

<210> 256

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 256

Ser Gly Ser Asn Ser Asn Ile Gly Thr Asn Tyr Val Ser

1.5 10

<210> 257

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 257

Arg Ser Ser Arg Arg Pro Ser

15

<210> 258

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 258

Ala Ala Trp Asp Gly Ser Leu Ser Gly His Trp Val

1.5 10

<210> 259

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 259

Arg Ala Ser Gln Ser Ile Asp Thr Tyr Leu Asn

1.5 10

<210> 260

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 260

Ser Ala Ser Ser Leu His Ser

15

<210> 261

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 261

Gln Gln Ser Tyr Ser Thr Thr Ala Trp Thr

1.5 10

<210> 262

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 262

Arg Ala Ser Gln Ser Ile Gly Gln Ser Leu Asn

1.5 10

<210> 263

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 263

Gly Ala Ser Ser Leu Gln Ser

15

<210> 264

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 264

Gln Gln Ser Tyr Ser Thr Pro Ile Thr

15

<210> 265

<400> 265

000

<210> 266

<211> 21

<212> PROTEIN

<213> Homo sapiens

<400> 266

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro

20

<210> 267

<211> 16

<212> PROTEIN

<213> Homo sapiens

<400> 267

Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro Pro Gly Tyr Gln

1.5 10 15

<210> 268

<211> 45

<212> PROTEIN

<213> Homo sapiens

<400> 268

Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala

1.5 10 15

Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly

20 25 30

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

35 40 45

<210> 269

<211> 231

<212> PROTEIN

<213> Homo sapiens

<400> 269

Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

1.5 10 15

Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

20 25 30

Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val

35 40 45

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

50 55 60

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

65 70 75 80

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

85 90 95

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

100 105 110

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

115 120 125

Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu Thr Lys

130 135 140

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

145 150 155 160

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

165 170 175

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

180 185 190

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

195 200 205

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

210 215 220

Leu Ser Leu Ser Pro Gly Lys

225 230

<210> 270

<211> 24

<212> PROTEIN

<213> Homo sapiens

<400> 270

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

1.5 10 15

Ser Leu Val Ile Thr Leu Tyr Cys

20

<210> 271

<211> 42

<212> PROTEIN

<213> Homo sapiens

<400> 271

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

1.5 10 15

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

20 25 30

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

35 40

<210> 272

<211> 112

<212> PROTEIN

<213> Homo sapiens

<400> 272

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly

1.5 10 15

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

20 25 30

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

35 40 45

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

50 55 60

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

65 70 75 80

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

85 90 95

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

100 105 110

<210> 273

<211> 52

<212> PROTEIN

<213> Homo sapiens

<400> 273

Phe Phe Ile Pro Leu Leu Val Val Ile Leu Phe Ala Val Asp Thr Gly

1.5 10 15

Leu Phe Ile Ser Thr Gln Gln Gln Val Thr Phe Leu Leu Lys Ile Lys

20 25 30

Arg Thr Arg Lys Gly Phe Arg Leu Leu Asn Pro His Pro Lys Pro Asn

35 40 45

Pro Lys Asn Asn

50

<210> 274

<211> 215

<212> PROTEIN

<213> Homo sapiens

<400> 274

Met Asp Thr Glu Ser Asn Arg Arg Ala Asn Leu Ala Leu Pro Gln Glu

1.5 10 15

Pro Ser Ser Val Pro Ala Phe Glu Val Leu Glu Ile Ser Pro Gln Glu

20 25 30

Val Ser Ser Gly Arg Leu Leu Lys Ser Ala Ser Ser Pro Pro Leu His

35 40 45

Thr Trp Leu Thr Val Leu Lys Lys Glu Gln Glu Phe Leu Gly Val Thr

50 55 60

Gln Ile Leu Thr Ala Met Ile Cys Leu Cys Phe Gly Thr Val Val Cys

65 70 75 80

Ser Val Leu Asp Ile Ser His Ile Glu Gly Asp Ile Phe Ser Ser Phe

85 90 95

Lys Ala Gly Tyr Pro Phe Trp Gly Ala Ile Phe Phe Ser Ile Ser Gly

100 105 110

Met Leu Ser Ile Ile Ser Glu Arg Arg Asn Ala Thr Tyr Leu Val Arg

115 120 125

Gly Ser Leu Gly Ala Asn Thr Ala Ser Ser Ile Ala Gly Gly Thr Gly

130 135 140

Ile Thr Ile Leu Ile Ile Asn Leu Lys Lys Ser Leu Ala Tyr Ile His

145 150 155 160

Ile His Ser Cys Gln Lys Phe Phe Glu Thr Lys Cys Phe Met Ala Ser

165 170 175

Phe Ser Thr Glu Ile Val Val Met Met Leu Phe Leu Thr Ile Leu Gly

180 185 190

Leu Gly Ser Ala Val Ser Leu Thr Ile Cys Gly Ala Gly Glu Glu Leu

195 200 205

Lys Gly Asn Lys Val Pro Glu

210 215

<210> 275

<211> 42

<212> PROTEIN

<213> Homo sapiens

<400> 275

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

1.5 10 15

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

20 25 30

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

35 40

<210> 276

<211> 41

<212> PROTEIN

<213> Homo sapiens

<400> 276

Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr

1.5 10 15

Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro

20 25 30

Pro Arg Asp Phe Ala Ala Tyr Arg Ser

35 40

<210> 277

<211> 18

<212> PROTEIN

<213> Homo sapiens

<400> 277

Met Ile Pro Ala Val Val Leu Leu Leu Leu Leu Leu Val Glu Gln Ala

1.5 10 15

Ala Ala

<210> 278

<211> 43

<212> PROTEIN

<213> Homo sapiens

<400> 278

Leu Gly Glu Pro Gln Leu Cys Tyr Ile Leu Asp Ala Ile Leu Phe Leu

1.5 10 15

Tyr Gly Ile Val Leu Thr Leu Leu Tyr Cys Arg Leu Lys Ile Gln Val

20 25 30

Arg Lys Ala Ala Ile Thr Ser Tyr Glu Lys Ser

35 40

<210> 279

<211> 22

<212> PROTEIN

<213> Homo sapiens

<400> 279

Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val

1.5 10 15

Glu Glu Asn Pro Gly Pro

20

<210> 280

<211> 21

<212> PROTEIN

<213> Homo sapiens

<400> 280

Gly Ser Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu

1.5 10 15

Glu Asn Pro Gly Pro

20

<210> 281

<211> 530

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 281

Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys

1.5 10 15

Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala

20 25 30

His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly

35 40 45

Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys

50 55 60

Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn

65 70 75 80

Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val

85 90 95

Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala

100 105 110

Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu

115 120 125

Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala

130 135 140

Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg

145 150 155 160

Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val

165 170 175

Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val

180 185 190

Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu

195 200 205

Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu

210 215 220

Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr

225 230 235 240

Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala

245 250 255

Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly

260 265 270

Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys

275 280 285

Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala

290 295 300

His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly

305 310 315 320

Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys

325 330 335

Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn

340 345 350

Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val

355 360 365

Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala

370 375 380

Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu

385 390 395 400

Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala

405 410 415

Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala

420 425 430

Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val

435 440 445

Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val

450 455 460

Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu

465 470 475 480

Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu

485 490 495

Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr

500 505 510

Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Arg Pro Ala

515 520 525

Leu Glu

530

<210> 282

<211> 530

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 282

Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys

1.5 10 15

Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala

20 25 30

His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly

35 40 45

Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys

50 55 60

Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His

65 70 75 80

Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val

85 90 95

Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala

100 105 110

Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu

115 120 125

Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala

130 135 140

Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg

145 150 155 160

Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val

165 170 175

Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val

180 185 190

Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln

195 200 205

Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu

210 215 220

Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr

225 230 235 240

Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala

245 250 255

Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly

260 265 270

Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys

275 280 285

Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala

290 295 300

His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly

305 310 315 320

Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys

325 330 335

Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn

340 345 350

Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val

355 360 365

Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala

370 375 380

Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu

385 390 395 400

Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala

405 410 415

Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala

420 425 430

Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val

435 440 445

Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val

450 455 460

Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln

465 470 475 480

Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu

485 490 495

Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr

500 505 510

Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Arg Pro Ala

515 520 525

Leu Glu

530

<210> 283

<211> 530

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 283

Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys

1.5 10 15

Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala

20 25 30

His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly

35 40 45

Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys

50 55 60

Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn

65 70 75 80

Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val

85 90 95

Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala

100 105 110

Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu

115 120 125

Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala

130 135 140

Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg

145 150 155 160

Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val

165 170 175

Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val

180 185 190

Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln

195 200 205

Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu

210 215 220

Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr

225 230 235 240

Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala

245 250 255

Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly

260 265 270

Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys

275 280 285

Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala

290 295 300

His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly

305 310 315 320

Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys

325 330 335

Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His

340 345 350

Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val

355 360 365

Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala

370 375 380

Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu

385 390 395 400

Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala

405 410 415

Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg

420 425 430

Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val

435 440 445

Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val

450 455 460

Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu

465 470 475 480

Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu

485 490 495

Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr

500 505 510

Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Arg Pro Ala

515 520 525

Leu Glu

530

<210> 284

<211> 539

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 284

Asn Pro Gln Arg Ser Thr Val Trp Tyr Leu Thr Pro Gln Gln Val Val

1.5 10 15

Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln

20 25 30

Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln

35 40 45

Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr

50 55 60

Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro

65 70 75 80

Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu

85 90 95

Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu

100 105 110

Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln

115 120 125

Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His

130 135 140

Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly

145 150 155 160

Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln

165 170 175

Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp

180 185 190

Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu

195 200 205

Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser

210 215 220

Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro

225 230 235 240

Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile

245 250 255

Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu

260 265 270

Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val

275 280 285

Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln

290 295 300

Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln

305 310 315 320

Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr

325 330 335

Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro

340 345 350

Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu

355 360 365

Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu

370 375 380

Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln

385 390 395 400

Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His

405 410 415

Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly

420 425 430

Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln

435 440 445

Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly

450 455 460

Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu

465 470 475 480

Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser

485 490 495

Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro

500 505 510

Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile

515 520 525

Ala Ser Asn Gly Gly Gly Arg Pro Ala Leu Glu

530 535

<210> 285

<211> 530

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 285

Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys

1.5 10 15

Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala

20 25 30

His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly

35 40 45

Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys

50 55 60

Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His

65 70 75 80

Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val

85 90 95

Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala

100 105 110

Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu

115 120 125

Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala

130 135 140

Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg

145 150 155 160

Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val

165 170 175

Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val

180 185 190

Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu

195 200 205

Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu

210 215 220

Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr

225 230 235 240

Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala

245 250 255

Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly

260 265 270

Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys

275 280 285

Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala

290 295 300

His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly

305 310 315 320

Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys

325 330 335

Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn

340 345 350

Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val

355 360 365

Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala

370 375 380

Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu

385 390 395 400

Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala

405 410 415

Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg

420 425 430

Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val

435 440 445

Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val

450 455 460

Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu

465 470 475 480

Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu

485 490 495

Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr

500 505 510

Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Arg Pro Ala

515 520 525

Leu Glu

530

<210> 286

<211> 530

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 286

Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys

1.5 10 15

Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala

20 25 30

His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly

35 40 45

Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys

50 55 60

Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn

65 70 75 80

Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val

85 90 95

Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala

100 105 110

Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu

115 120 125

Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala

130 135 140

Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg

145 150 155 160

Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val

165 170 175

Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val

180 185 190

Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln

195 200 205

Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu

210 215 220

Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr

225 230 235 240

Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala

245 250 255

Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly

260 265 270

Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys

275 280 285

Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala

290 295 300

His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly

305 310 315 320

Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys

325 330 335

Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn

340 345 350

Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val

355 360 365

Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala

370 375 380

Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu

385 390 395 400

Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala

405 410 415

Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg

420 425 430

Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val

435 440 445

Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val

450 455 460

Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln

465 470 475 480

Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu

485 490 495

Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr

500 505 510

Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Arg Pro Ala

515 520 525

Leu Glu

530

<210> 287

<211> 530

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 287

Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys

1.5 10 15

Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala

20 25 30

His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly

35 40 45

Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys

50 55 60

Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His

65 70 75 80

Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val

85 90 95

Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala

100 105 110

Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu

115 120 125

Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala

130 135 140

Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg

145 150 155 160

Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val

165 170 175

Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val

180 185 190

Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln

195 200 205

Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu

210 215 220

Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr

225 230 235 240

Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala

245 250 255

Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly

260 265 270

Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys

275 280 285

Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala

290 295 300

His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly

305 310 315 320

Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys

325 330 335

Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His

340 345 350

Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val

355 360 365

Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala

370 375 380

Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu

385 390 395 400

Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala

405 410 415

Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg

420 425 430

Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val

435 440 445

Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val

450 455 460

Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu

465 470 475 480

Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu

485 490 495

Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr

500 505 510

Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Arg Pro Ala

515 520 525

Leu Glu

530

<210> 288

<211> 530

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 288

Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys

1.5 10 15

Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala

20 25 30

His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly

35 40 45

Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys

50 55 60

Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His

65 70 75 80

Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val

85 90 95

Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala

100 105 110

Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu

115 120 125

Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala

130 135 140

Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg

145 150 155 160

Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val

165 170 175

Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val

180 185 190

Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln

195 200 205

Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu

210 215 220

Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr

225 230 235 240

Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala

245 250 255

Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly

260 265 270

Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys

275 280 285

Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala

290 295 300

His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly

305 310 315 320

Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys

325 330 335

Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn

340 345 350

Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val

355 360 365

Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala

370 375 380

Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu

385 390 395 400

Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala

405 410 415

Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg

420 425 430

Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val

435 440 445

Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val

450 455 460

Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu

465 470 475 480

Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu

485 490 495

Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr

500 505 510

Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Arg Pro Ala

515 520 525

Leu Glu

530

<210> 289

<211> 530

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 289

Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys

1.5 10 15

Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala

20 25 30

His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly

35 40 45

Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys

50 55 60

Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn

65 70 75 80

Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val

85 90 95

Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala

100 105 110

Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu

115 120 125

Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala

130 135 140

Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg

145 150 155 160

Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val

165 170 175

Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val

180 185 190

Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln

195 200 205

Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu

210 215 220

Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr

225 230 235 240

Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala

245 250 255

Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly

260 265 270

Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys

275 280 285

Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala

290 295 300

His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly

305 310 315 320

Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys

325 330 335

Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn

340 345 350

Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val

355 360 365

Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala

370 375 380

Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu

385 390 395 400

Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala

405 410 415

Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg

420 425 430

Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val

435 440 445

Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val

450 455 460

Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln

465 470 475 480

Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu

485 490 495

Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr

500 505 510

Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Arg Pro Ala

515 520 525

Leu Glu

530

<210> 290

<211> 530

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 290

Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys

1.5 10 15

Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala

20 25 30

His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly

35 40 45

Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys

50 55 60

Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn

65 70 75 80

Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val

85 90 95

Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala

100 105 110

Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu

115 120 125

Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala

130 135 140

Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg

145 150 155 160

Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val

165 170 175

Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val

180 185 190

Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln

195 200 205

Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu

210 215 220

Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr

225 230 235 240

Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala

245 250 255

Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly

260 265 270

Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys

275 280 285

Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala

290 295 300

His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly

305 310 315 320

Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys

325 330 335

Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn

340 345 350

Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val

355 360 365

Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala

370 375 380

Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu

385 390 395 400

Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala

405 410 415

Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg

420 425 430

Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val

435 440 445

Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val

450 455 460

Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu

465 470 475 480

Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu

485 490 495

Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr

500 505 510

Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Arg Pro Ala

515 520 525

Leu Glu

530

<210> 291

<211> 136

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 291

Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Glu

1.5 10 15

Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser Pro

20 25 30

Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys

35 40 45

Ser Gly Gly Gly Gly Ser Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

50 55 60

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

65 70 75 80

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

85 90 95

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

100 105 110

Ser Leu Val Ile Thr Leu Tyr Cys Asn His Arg Asn Arg Arg Arg Val

115 120 125

Cys Lys Cys Pro Arg Pro Val Val

130 135

<210> 292

<211> 157

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 292

Met Gly Thr Ser Leu Leu Cys Trp Met Ala Leu Cys Leu Leu Gly Ala

1.5 10 15

Asp His Ala Asp Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly

20 25 30

Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser

35 40 45

Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Thr Ala Cys Pro Tyr Ser

50 55 60

Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Pro Ala Pro Arg Pro

65 70 75 80

Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro

85 90 95

Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu

100 105 110

Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys

115 120 125

Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn His Arg

130 135 140

Asn Arg Arg Arg Val Cys Lys Cys Pro Arg Pro Val Val

145 150 155

<210> 293

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 293

Cys Pro Tyr Ser Asn Pro Ser Leu Cys

15

<210> 294

<211> 37

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 294

Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys

1.5 10 15

Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser

20 25 30

Gly Gly Gly Gly Ser

35

<210> 295

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

peptide

<400> 295

Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser

1.5 10 15

Pro Ala Lys Pro Thr Thr Thr Ala

20

<210> 296

<211> 15

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 296

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

1.5 10 15

<210> 297

<211> 369

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 297

caggtcacct tgaaggagtc tggtcctgtg ctggtgaaac ccacagagac cctcacgctg

60

acctgcaccg tctctgggtt ctcactcagt aatgctagaa tgggtgtgac ctggatccgt

120

cagcccccag ggaaggccct ggagtggctt gcacacattt tttcgaatga cgaaaaatcc

180

tacagtacat ctctgaagag caggctcacc atctccaagg acacttccaa aacccaggtg

240

gtccttacca tgaccaacat ggaccctgtg gacacagcca catattactg tgcacggata

300

cgagattact atgacattag tagttattat gactactggg gccagggaac cctggtcagc

360

gtctcctca

369

<210> 298

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 298

gacatccaga tgacccagtc tccatctgcc atgtctgcat ctgtaggaga cagagtcacc

60

atcacttgtc gggcgagtca ggacattagc aattatttag cctggtttca gcagaaacca

120

gggaaagtcc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca

180

aggttcagcg gcagtggatc ggggacagaa ttcactctca caatcagcag cctgctgcct

240

gaagattttg caacttatta ctgtctacag cttaatagtt tcccgttcac ttttggcgga

300

gggaccaagg tggagatcaa c

321

<210> 299

<211> 372

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 299

gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc

60

tcctgtgtag ccctctggatt cacctttagt agttattggga tgagctgggt ccgccaggct

120

ccagggaagg ggctggagtg ggtggccagc ataaagcaag atggaagtga gaaatactat

180

gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcagtgtat

240

ctgcaaatga acagcctgag agccgaggac acgggtgtgt attactgtgc gagagaagga

300

gtcaactggg gatggagact ctactggcac ttcgatctct ggggccgtgg aaccctggtc

360

actgtctcct ca

372

<210> 300

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 300

gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc

60

atcaactgca agtccagcca gagtgtttta tacagctaca acaataagaa ctacgtagct

120

tggtaccagc agaaaccagg acaacctcct aacctactca ttttctgggc atctacccgg

180

gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc

240

atcagcagcc tgcaggctga agatgtggca gtttactact gtcagcaata ttatagtacg

300

ctcactttcg gcggagggac caaggtggag atcaaa

336

<210> 301

<211> 357

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 301

gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc

60

tcctgtgcag tctctggatt caccttcagt aaccataaca tacactgggt ccgccaggct

120

ccagggaagg ggctggagtg gatttcatac attagtcgaa gtagtagtac catatattac

180

gcagactctg tgaagggccg attcacaatc tccagagaca atgccaagaa ctcactgtat

240

ctgcaaatga acagcctgag agacgaagac acggctgtgt attactgtgc gagagatcac

300

gctcagtggt acggtatgga cgtttggggc caagggacca cggtcaccgt ctcctca

357

<210> 302

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 302

gacatccaga tgacccagtc tccatcttcc gtgtctgcat cggtaggaga cagagtcacc

60

atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca

120

gggaaagccc ctaaggtcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca

180

aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct

240

gaagattttg caacttacta ttgtcaacag gctttcagtt tcccattcac tttcggccct

300

gggaccaaag tggatatcaa a

321

<210> 303

<211> 366

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 303

gaagtgcagc ttgtccagag cggagccgaa gtgaagaagc ctggcgagag cctgaagatc

60

agctgcaagg gctccggata tcgcttcaca agttactgga tagggtgggt gcgccagatg

120

cctggtaagg gactggaatg gatgggctct atatatcctg atgattccga cacacgttat

180

agcccaagct ttcaggggcca ggtcacaatc agcgctgaca agagcatcag caccgcctac

240

cttcagtggt cgtctctgaa ggccagcgac accgcaatgt actactgcgc ctctagcaca

300

gttgactacc cgggatacag ttacttcgac tactggggcc aaggtacact ggtcaccgtc

360

agcagc

366

<210> 304

<211> 336

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 304

gagctccaga gcgtgctgac ccagcctcct agcgcaagcg gcacccctgg acagcgtgtg

60

acaattagct gtagcggaag tcgtagcaat atcggatcaa actatgtgta ttggtatcag

120

caattgcccg gtacagcacc caaattgctc atatatagaa ataatcagag acctagcgga

180

gtgcctgatc gttttagcgg tagcaaaagc ggcaccagcg catcactggc aatttcaggc

240

ctgcgtagcg aagatgaggc ggattattac tgtgcgagtt gggatggttc gctgagtgct

300

gttgtgttcg gcaccggtac aaaactgacc gttctg

336

<210> 305

<211> 378

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 305

gaagtgcagc ttgtccagag cggagccgaa gtgaagaagc ctggcgagag cctgaagatc

60

agctgcaagg gctccggata cacctttcct tcatcatgga taggttgggt gcgccagatg

120

cctggtaagg gactggaatg gatgggcatc atataccctg atactagcca tacccgttac

180

agcccaagct ttcaggggcca ggtcacaatc agcgctgaca agagcatcag caccgcctac

240

cttcagtggt cgtctctgaa ggccagcgac accgcaatgt actactgtgc ccgtgcgagc

300

tatttcgatc gtggaacagg gtatagttct tggtggatgg atgtgtgggg ccaaggtaca

360

ctggtcaccg tcagcagc

378

<210> 306

<211> 330

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 306

gagctcgata ttcagatgac ccagagccct agcagcctga gcgcaagcgt gggcgataga

60

gtgaccatta cctgtagggc ctcacaatcc atatacgact atttgcactg gtatcagcag

120

aaacccggga aagcacccaa actgctgatt tacgatgctt ccaacctaca gagtggcgtt

180

ccttcacgtt ttagcggtag cggttcaggc accgatttca ccctgaccat tagcagcctt

240

cagcccgaag atttcgctac gtattattgc cagcaatcat acaccacgcc gttgtttaca

300

ttcggccagg gtaccaaagt ggaaatcaaa

330

<210> 307

<211> 366

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 307

gaagtgcagc ttgtccagag cggagccgaa gtgaagaagc ctggcgagag cctgaagatc

60

agctgcaagg gctccggata cggattcaca agttattgga taggttggggt gcgccagatg

120

cctggtaagg gactggaatg gatgggtatc attcatcccg atgatagcga caccaaatac

180

agcccaagct ttcaggggcca ggtcacaatc agcgctgaca agagcatcag caccgcctac

240

cttcagtggt cgtctctgaa ggccagcgac accgcaatgt actactgtgc ctctagctat

300

ttgcgtggct tgtggggagg ctattttgac tattggggcc aaggtacact ggtcaccgtc

360

agcagc

366

<210> 308

<211> 339

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 308

gagctccaga gcgtgctgac ccagcctcct agcgcaagcg gcacccctgg acagcgtgtg

60

acaattagct gtagcggatc aagctcaaac attggctcaa attatgtgaa ttggtatcag

120

caattgcccg gtacagcacc caaactgctc atttatggag attatcaacg acctagcgga

180

gtgcctgatc gttttagcgg tagcaaaagc ggcaccagcg catcactggc aatttcaggc

240

ctgcgtagcg aagatgaggc ggattattac tgtgctaccc gcgacgattc gttatctggg

300

tctgtcgttt ttggcaccgg tacaaaactg accgtgctg

339

<210> 309

<211> 366

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 309

gaagtgcagc ttgtccagag cggagccgaa gtgaagaagc ctggcgagag cctgaagatc

60

agctgcaagg gctccggata cagttttgcc tcatactgga tcggttgggt gcgccagatg

120

cctggtaagg gactggaatg gatgggcgta atttaccccg gaactagcga gacacgttac

180

agcccaagct ttcaggggcca ggtcacaatc agcgctgaca agagcatcag caccgcctac

240

cttcagtggt cgtctctgaa ggccagcgac accgcaatgt actactgcgc taaagggttg

300

agtgcgagtg caagtggata ttctttccaa tattggggcc aaggtacact ggtcaccgtc

360

agcagc

366

<210> 310

<211> 330

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 310

gagctcgata ttcagatgac ccagagccct agcagcctga gcgcaagcgt gggcgataga

60

gtgaccatta cctgtagggc ctcacaaagc atcgacacat atttaaactg gtatcagcag

120

aaacccggga aagcacccaa actgctgatt tattcagcta gtagcctaca cagtggcgtt

180

ccttcacgtt ttagcggtag cggttcaggc accgatttca ccctgaccat tagcagcctt

240

cagcccgaag atttcgctac gtattattgc caacaatcat acagcacaac tgcttggaca

300

ttcggccagg gtaccaaagt ggaaatcaaa

330

<210> 311

<211> 494

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 311

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val

20 25 30

Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly

35 40 45

Thr Phe Ser Ser Tyr Gly Phe Ser Trp Val Arg Gln Ala Pro Gly Gln

50 55 60

Gly Leu Glu Trp Met Gly Gly Ile Ile Pro Ile Phe Gly Ser Ala Asn

65 70 75 80

Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser

85 90 95

Thr Ser Thr Val Tyr Met Glu Leu Ile Ser Leu Arg Ser Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Gly Gly Ser Ser Ser Pro Phe Ala Tyr

115 120 125

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

145 150 155 160

Ile Val Met Thr Gln Asn Pro Leu Ser Ser Pro Val Thr Leu Gly Gln

165 170 175

Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser Asp

180 185 190

Gly Asn Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Ser Pro

195 200 205

Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser Gly Val Pro Asp

210 215 220

Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile Ser

225 230 235 240

Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala Thr

245 250 255

Gln Phe Pro Leu Thr Ile Gly Gly Gly Ser Lys Val Glu Ile Lys Thr

260 265 270

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

275 280 285

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

290 295 300

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

305 310 315 320

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

325 330 335

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

340 345 350

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

355 360 365

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

370 375 380

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn

385 390 395 400

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

405 410 415

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

420 425 430

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

435 440 445

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

450 455 460

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

465 470 475 480

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 312

<211> 494

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 312

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val

20 25 30

Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly

35 40 45

Thr Phe Ser Ser Tyr Gly Phe Ser Trp Val Arg Gln Ala Pro Gly Gln

50 55 60

Gly Leu Glu Trp Met Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn

65 70 75 80

Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser

85 90 95

Thr Ser Thr Val Phe Met Glu Leu Ile Ser Leu Arg Ser Glu Tyr Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Gly Gly Ser Ser Ser Pro Phe Ala Tyr

115 120 125

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

145 150 155 160

Ile Val Met Thr Gln Thr Pro Leu Ser Ser Pro Val Thr Leu Gly Gln

165 170 175

Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser Asp

180 185 190

Gly Asn Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Ser Pro

195 200 205

Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser Gly Val Pro Asp

210 215 220

Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile Ser

225 230 235 240

Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala Thr

245 250 255

Gln Phe Pro Leu Thr Ile Gly Gly Gly Ser Lys Val Glu Ile Lys Thr

260 265 270

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

275 280 285

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

290 295 300

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

305 310 315 320

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

325 330 335

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

340 345 350

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

355 360 365

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

370 375 380

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn

385 390 395 400

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

405 410 415

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

420 425 430

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

435 440 445

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

450 455 460

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

465 470 475 480

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 313

<211> 483

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 313

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu

20 25 30

Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly

35 40 45

Ser Ile Ser Ser Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys

50 55 60

Gly Leu Glu Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr

65 70 75 80

Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys

85 90 95

Asn Gln Phe Ser Leu Lys Leu Arg Ser Val Thr Ala Ala Asp Thr Ala

100 105 110

Val Tyr Tyr Cys Ala Arg Asp Ile Arg Thr Trp Gly Gln Gly Thr Leu

115 120 125

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser

145 150 155 160

Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys

165 170 175

Arg Ala Ser Gln Gly Ile Ser Asn Tyr Leu Ala Trp Phe Gln Gln Lys

180 185 190

Pro Gly Lys Ala Pro Lys Ser Leu Ile Tyr Ala Ala Ser Ser Leu Gln

195 200 205

Ser Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

210 215 220

Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr

225 230 235 240

Cys Gln Gln Tyr Asn Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys

245 250 255

Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

260 265 270

Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg

275 280 285

Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys

290 295 300

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

305 310 315 320

Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu

325 330 335

Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln

340 345 350

Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly

355 360 365

Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

370 375 380

Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

385 390 395 400

Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met

405 410 415

Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu

420 425 430

Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys

435 440 445

Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu

450 455 460

Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu

465 470 475 480

Pro Pro Arg

<210> 314

<211> 493

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 314

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Thr Phe Arg Asn Ser Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Asn Ile Lys Arg Asp Gly Ser Glu Lys Tyr

65 70 75 80

Tyr Val Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Asp Gln Thr Gly Ser Phe Asp Tyr Trp

115 120 125

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Val

145 150 155 160

Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly Gln Pro

165 170 175

Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser Asp Glu

180 185 190

Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser Leu Arg

195 200 205

Arg Leu Ile Tyr Gln Val Ser Asn Arg Asp Ser Gly Val Pro Asp Arg

210 215 220

Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg

225 230 235 240

Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Met Gln Gly Thr Tyr

245 250 255

Trp Pro Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Thr Thr

260 265 270

Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln

275 280 285

Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala

290 295 300

Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala

305 310 315 320

Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr

325 330 335

Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln

340 345 350

Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser

355 360 365

Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys

370 375 380

Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln

385 390 395 400

Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu

405 410 415

Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg

420 425 430

Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met

435 440 445

Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly

450 455 460

Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp

465 470 475 480

Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 315

<211> 485

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 315

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Arg Gly Ser Gly Pro Gly Leu

20 25 30

Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Asp

35 40 45

Ser Ile Ser Val Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys

50 55 60

Gly Leu Glu Trp Ile Gly Arg Val Tyr Ser Ser Gly Asn Ile Asn Tyr

65 70 75 80

Asn Pro Ser Leu Glu Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys

85 90 95

Ser Arg Phe Ser Leu Asn Leu Ser Ser Val Thr Ala Ala Asp Thr Ala

100 105 110

Val Tyr Tyr Cys Ala Arg Gly Leu Asp Ala Phe Asp Ile Trp Gly Gln

115 120 125

Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met

145 150 155 160

Thr Gln Ser Pro Ala Thr Leu Ser Met Ser Leu Gly Glu Arg Ala Thr

165 170 175

Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Leu Ala Trp Tyr

180 185 190

Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser

195 200 205

Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Gly Gly Ser Gly Ser Gly

210 215 220

Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala

225 230 235 240

Val Tyr Tyr Cys Gln Gln Tyr Ile Asn Trp Pro His Phe Gly Gly Gly

245 250 255

Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr

260 265 270

Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala

275 280 285

Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe

290 295 300

Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val

305 310 315 320

Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys

325 330 335

Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr

340 345 350

Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu

355 360 365

Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro

370 375 380

Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly

385 390 395 400

Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro

405 410 415

Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr

420 425 430

Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly

435 440 445

Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln

450 455 460

Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln

465 470 475 480

Ala Leu Pro Pro Arg

485

<210> 316

<211> 486

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 316

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Glu Ser Leu Arg Leu Ser Cys Glu Val Ser Gly Phe

35 40 45

Thr Phe Thr Ser Tyr Ala Met Ser Trp Val Arg Gln Val Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ser Ile Ile Ser Gly Val Ala Phe Thr Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp His Ser

85 90 95

Lys Asn Thr Leu Tyr Leu Gln Met Asn Gly Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Val Lys Val Asp Gly Glu Val Tyr Trp Gly Gln

115 120 125

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met

145 150 155 160

Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr

165 170 175

Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr

180 185 190

Gln Gln Lys Pro Gly Lys Ala Pro Lys Ile Leu Ile Tyr Gly Ala Ser

195 200 205

Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

210 215 220

Thr Asp Phe Thr Phe Ala Ile Ser Ser Leu Gln Pro Glu Asp Val Ala

225 230 235 240

Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Phe Pro Ile Thr Phe Gly Gln

245 250 255

Gly Thr Arg Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro

260 265 270

Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu

275 280 285

Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp

290 295 300

Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly

305 310 315 320

Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg

325 330 335

Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln

340 345 350

Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu

355 360 365

Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala

370 375 380

Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu

385 390 395 400

Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp

405 410 415

Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu

420 425 430

Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile

435 440 445

Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr

450 455 460

Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met

465 470 475 480

Gln Ala Leu Pro Pro Arg

485

<210> 317

<211> 489

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 317

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val

20 25 30

Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Glu Ala Ser Gly Gly

35 40 45

Thr Phe Ile Thr Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln

50 55 60

Gly Leu Glu Trp Met Gly Gly Ile Ile Pro Phe Phe Gly Thr Ala Asn

65 70 75 80

Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser

85 90 95

Thr Ser Thr Ala Ser Met Glu Leu Arg Ser Leu Arg Ser Glu Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Gln Trp Glu Leu Phe Phe Phe Asp Phe Trp

115 120 125

Gly Glyn Gly Thr Pro Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile

145 150 155 160

Val Met Thr Gln Ser Pro Asp Thr Leu Ser Val Ser Pro Gly Glu Arg

165 170 175

Ala Ile Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn Leu Ala

180 185 190

Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Ser

195 200 205

Ala Ser Thr Arg Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly

210 215 220

Ser Gly Thr Glu Phe Thr Leu Ser Ile Ser Ser Leu Gln Ser Glu Asp

225 230 235 240

Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Asn Trp Pro Pro Leu Thr

245 250 255

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro

260 265 270

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

275 280 285

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

290 295 300

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

305 310 315 320

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

325 330 335

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

340 345 350

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

355 360 365

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

370 375 380

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

385 390 395 400

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

405 410 415

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

420 425 430

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

435 440 445

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

450 455 460

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

465 470 475 480

Leu His Met Gln Ala Leu Pro Pro Arg

485

<210> 318

<211> 492

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 318

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Ala Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Thr Phe Thr Tyr Tyr Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ser His Ile Ser Ile Arg Ser Ser Thr Ile Tyr

65 70 75 80

Phe Ala Asp Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Gly Ser Gly Trp Tyr Gly Asp Tyr Phe

115 120 125

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

145 150 155 160

Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro

165 170 175

Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser

180 185 190

Ser Tyr Leu Ala Trp Tyr Gln Gln Gln Pro Gly Gln Ala Pro Arg Leu

195 200 205

Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe

210 215 220

Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu

225 230 235 240

Glu Pro Glu Asp Phe Ala Ile Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser

245 250 255

Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Thr Thr Thr

260 265 270

Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro

275 280 285

Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val

290 295 300

His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro

305 310 315 320

Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu

325 330 335

Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro

340 345 350

Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys

355 360 365

Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe

370 375 380

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu

385 390 395 400

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

405 410 415

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

420 425 430

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

435 440 445

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

450 455 460

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

465 470 475 480

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 319

<211> 494

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 319

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu

20 25 30

Val Lys Pro Thr Glu Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe

35 40 45

Ser Leu Ser Asn Ala Arg Met Gly Val Thr Trp Ile Arg Gln Pro Pro

50 55 60

Gly Lys Ala Leu Glu Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys

65 70 75 80

Ser Tyr Ser Thr Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr

85 90 95

Ser Lys Thr Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp

100 105 110

Thr Ala Thr Tyr Tyr Cys Ala Arg Ile Arg Asp Tyr Tyr Asp Ile Ser

115 120 125

Ser Tyr Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Ser Val Ser Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

145 150 155 160

Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ala Met Ser

165 170 175

Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp

180 185 190

Ile Ser Asn Tyr Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Val Pro

195 200 205

Lys Arg Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser

210 215 220

Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser

225 230 235 240

Ser Leu Leu Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Leu Asn

245 250 255

Ser Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Asn Thr

260 265 270

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

275 280 285

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

290 295 300

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

305 310 315 320

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

325 330 335

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

340 345 350

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

355 360 365

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

370 375 380

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn

385 390 395 400

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

405 410 415

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

420 425 430

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

435 440 445

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

450 455 460

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

465 470 475 480

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 320

<211> 490

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 320

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe

35 40 45

Thr Phe Ser Asn His Asn Ile His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Ile Ser Tyr Ile Ser Arg Ser Ser Ser Thr Ile Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Asp His Ala Gln Trp Tyr Gly Met Asp

115 120 125

Val Trp Gly Gly Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly

130 135 140

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

145 150 155 160

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly

165 170 175

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp

180 185 190

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile

195 200 205

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

210 215 220

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

225 230 235 240

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Phe Ser Phe Pro Phe

245 250 255

Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Thr Thr Thr Pro Ala

260 265 270

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

275 280 285

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

290 295 300

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

305 310 315 320

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

325 330 335

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

340 345 350

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

355 360 365

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

370 375 380

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn

385 390 395 400

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

405 410 415

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

420 425 430

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

435 440 445

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

450 455 460

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

465 470 475 480

Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 321

<211> 500

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 321

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe

35 40 45

Thr Phe Ser Ser Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Ser Ile Lys Gln Asp Gly Ser Glu Lys Tyr

65 70 75 80

Tyr Val Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Ser Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Gly Val Tyr Tyr Cys Ala Arg Glu Gly Val Asn Trp Gly Trp Arg Leu

115 120 125

Tyr Trp His Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser

130 135 140

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

145 150 155 160

Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu

165 170 175

Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln

180 185 190

Ser Val Leu Tyr Ser Tyr Asn Asn Lys Asn Tyr Val Ala Trp Tyr Gln

195 200 205

Gln Lys Pro Gly Gln Pro Pro Asn Leu Leu Ile Phe Trp Ala Ser Thr

210 215 220

Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr

225 230 235 240

Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val

245 250 255

Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Leu Thr Phe Gly Gly Gly Thr

260 265 270

Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

275 280 285

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

290 295 300

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

305 310 315 320

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

325 330 335

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys

340 345 350

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

355 360 365

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

370 375 380

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

385 390 395 400

Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

405 410 415

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

420 425 430

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

435 440 445

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

450 455 460

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

465 470 475 480

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

485 490 495

Leu Pro Pro Arg

500

<210> 322

<211> 492

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 322

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Val Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Thr Phe Ser Ser Tyr Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ser His Ser Ser Ile Ser Arg Gly Asn Ile Tyr

65 70 75 80

Phe Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Gly Ser Gly Trp Tyr Gly Asp Tyr Phe

115 120 125

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

145 150 155 160

Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro

165 170 175

Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser

180 185 190

Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu

195 200 205

Leu Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe

210 215 220

Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu

225 230 235 240

Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser

245 250 255

Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Thr Thr Thr

260 265 270

Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro

275 280 285

Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val

290 295 300

His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro

305 310 315 320

Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu

325 330 335

Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro

340 345 350

Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys

355 360 365

Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe

370 375 380

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu

385 390 395 400

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

405 410 415

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

420 425 430

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

435 440 445

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

450 455 460

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

465 470 475 480

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 323

<211> 496

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 323

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Ala Phe Ser Asn Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ser Ala Ile Arg Gly Gly Gly Gly Ser Thr Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser

85 90 95

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Asp Phe Ile Ser Gly Thr Trp Tyr Pro

115 120 125

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

145 150 155 160

Ser Glu Leu Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr

165 170 175

Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile

180 185 190

Gly Ser Asn Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro

195 200 205

Lys Leu Leu Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp

210 215 220

Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser

225 230 235 240

Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp

245 250 255

Asp Ser Leu Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val

260 265 270

Leu Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile

275 280 285

Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala

290 295 300

Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr

305 310 315 320

Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu

325 330 335

Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile

340 345 350

Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp

355 360 365

Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

370 375 380

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly

385 390 395 400

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

405 410 415

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

420 425 430

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

435 440 445

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

450 455 460

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

465 470 475 480

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490 495

<210> 324

<211> 498

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 324

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val

20 25 30

Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr

35 40 45

Arg Phe Thr Ser Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys

50 55 60

Gly Leu Glu Trp Met Gly Ser Ile Tyr Pro Asp Asp Ser Asp Thr Arg

65 70 75 80

Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser

85 90 95

Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Ser Ser Thr Val Asp Tyr Pro Gly Tyr Ser

115 120 125

Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

145 150 155 160

Gly Gly Ser Glu Leu Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser

165 170 175

Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser

180 185 190

Asn Ile Gly Ser Asn Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr

195 200 205

Ala Pro Lys Leu Leu Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val

210 215 220

Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala

225 230 235 240

Ile Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser

245 250 255

Trp Asp Gly Ser Leu Ser Ala Val Val Phe Gly Thr Gly Thr Lys Leu

260 265 270

Thr Val Leu Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

275 280 285

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

290 295 300

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

305 310 315 320

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

325 330 335

Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu

340 345 350

Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu

355 360 365

Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys

370 375 380

Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln

385 390 395 400

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

405 410 415

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

420 425 430

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

435 440 445

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

450 455 460

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

465 470 475 480

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

485 490 495

Pro Arg

<210> 325

<211> 499

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 325

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val

20 25 30

Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr

35 40 45

Thr Phe Thr Asn Tyr Trp Ile Ala Trp Val Arg Gln Met Pro Gly Lys

50 55 60

Gly Leu Glu Trp Met Gly Ile Ile Tyr Pro Asp Gly Ser Asp Thr Arg

65 70 75 80

Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser

85 90 95

Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Arg Asp Ile Thr Ser Trp Tyr Tyr Gly Glu

115 120 125

Pro Ala Phe Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

145 150 155 160

Gly Gly Gly Ser Glu Leu Gln Ser Val Leu Thr Gln Pro Pro Ser Ala

165 170 175

Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser

180 185 190

Ser Asn Ile Gly Ser Asn Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly

195 200 205

Thr Ala Pro Lys Leu Leu Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly

210 215 220

Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu

225 230 235 240

Ala Ile Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala

245 250 255

Thr Trp Asp Asp Ser Leu Gly Ser Pro Val Phe Gly Thr Gly Thr Lys

260 265 270

Leu Thr Val Leu Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

275 280 285

Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg

290 295 300

Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys

305 310 315 320

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

325 330 335

Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu

340 345 350

Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln

355 360 365

Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly

370 375 380

Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

385 390 395 400

Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

405 410 415

Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met

420 425 430

Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu

435 440 445

Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys

450 455 460

Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu

465 470 475 480

Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu

485 490 495

Pro Pro Arg

<210> 326

<211> 496

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 326

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val

20 25 30

Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr

35 40 45

Ser Phe Thr Ser Ser Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys

50 55 60

Gly Leu Glu Trp Met Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg

65 70 75 80

Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser

85 90 95

Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Lys Gly Leu Ser Gln Ala Met Thr Gly Phe

115 120 125

Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

145 150 155 160

Gly Gly Ser Glu Leu Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu

165 170 175

Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln

180 185 190

Ser Ile Ser Arg Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala

195 200 205

Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ile Leu Gln Thr Gly Val Pro

210 215 220

Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile

225 230 235 240

Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser

245 250 255

Tyr Ser Thr Thr Met Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

260 265 270

Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile

275 280 285

Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala

290 295 300

Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr

305 310 315 320

Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu

325 330 335

Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile

340 345 350

Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp

355 360 365

Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

370 375 380

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly

385 390 395 400

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

405 410 415

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

420 425 430

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

435 440 445

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

450 455 460

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

465 470 475 480

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490 495

<210> 327

<211> 499

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 327

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val

20 25 30

Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr

35 40 45

Gly Phe Thr Ser Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys

50 55 60

Gly Leu Glu Trp Met Gly Ile Ile His Pro Asp Asp Ser Asp Thr Lys

65 70 75 80

Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser

85 90 95

Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Ser Ser Tyr Leu Arg Gly Leu Trp Gly Gly

115 120 125

Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

145 150 155 160

Gly Gly Ser Glu Leu Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser

165 170 175

Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser

180 185 190

Asn Ile Gly Ser Asn Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr

195 200 205

Ala Pro Lys Leu Leu Ile Tyr Gly Asp Tyr Gln Arg Pro Ser Gly Val

210 215 220

Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala

225 230 235 240

Ile Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr

245 250 255

Arg Asp Asp Ser Leu Ser Gly Ser Val Val Phe Gly Thr Gly Thr Lys

260 265 270

Leu Thr Val Leu Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

275 280 285

Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg

290 295 300

Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys

305 310 315 320

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

325 330 335

Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu

340 345 350

Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln

355 360 365

Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly

370 375 380

Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

385 390 395 400

Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

405 410 415

Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met

420 425 430

Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu

435 440 445

Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys

450 455 460

Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu

465 470 475 480

Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu

485 490 495

Pro Pro Arg

<210> 328

<211> 500

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 328

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val

20 25 30

Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr

35 40 45

Thr Phe Pro Ser Ser Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys

50 55 60

Gly Leu Glu Trp Met Gly Ile Ile Tyr Pro Asp Thr Ser His Thr Arg

65 70 75 80

Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser

85 90 95

Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Arg Ala Ser Tyr Phe Asp Arg Gly Thr Gly

115 120 125

Tyr Ser Ser Trp Trp Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr

130 135 140

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

145 150 155 160

Gly Ser Gly Gly Gly Gly Ser Glu Leu Asp Ile Gln Met Thr Gln Ser

165 170 175

Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys

180 185 190

Arg Ala Ser Gln Ser Ile Tyr Asp Tyr Leu His Trp Tyr Gln Gln Lys

195 200 205

Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Gln

210 215 220

Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

225 230 235 240

Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr

245 250 255

Cys Gln Gln Ser Tyr Thr Thr Pro Leu Phe Thr Phe Gly Gln Gly Thr

260 265 270

Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

275 280 285

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

290 295 300

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

305 310 315 320

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

325 330 335

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys

340 345 350

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

355 360 365

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

370 375 380

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

385 390 395 400

Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

405 410 415

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

420 425 430

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

435 440 445

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

450 455 460

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

465 470 475 480

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

485 490 495

Leu Pro Pro Arg

500

<210> 329

<211> 497

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 329

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Thr Phe Ser Gln Tyr Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ser Ala Ile Ser Gly Gly Gly Val Ser Thr Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser

85 90 95

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Ser Asp Ile Ser Asp Ser Gly Gly Ser His

115 120 125

Trp Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

145 150 155 160

Gly Gly Gly Ser Glu Leu Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

165 170 175

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser

180 185 190

Gln Tyr Ile Gly Arg Tyr Leu Asn Trp Tyr Gln Gln Lys Arg Gly Lys

195 200 205

Ala Pro Lys Leu Leu Ile His Gly Ala Thr Ser Leu Ala Ser Gly Val

210 215 220

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

225 230 235 240

Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln

245 250 255

Ser Tyr Ser Thr Thr Ser Pro Thr Phe Gly Gln Gly Thr Lys Val Glu

260 265 270

Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

275 280 285

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

290 295 300

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

305 310 315 320

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

325 330 335

Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr

340 345 350

Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu

355 360 365

Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu

370 375 380

Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln

385 390 395 400

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu

405 410 415

Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly

420 425 430

Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln

435 440 445

Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu

450 455 460

Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr

465 470 475 480

Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro

485 490 495

Arg

<210> 330

<211> 497

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 330

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Thr Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ser Thr Ile Ser Gly Thr Gly Gly Thr Thr Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser

85 90 95

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Lys Val Arg Ala Gly Ile Asp Pro Thr Ala

115 120 125

Ser Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

130 135 140

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

145 150 155 160

Gly Ser Glu Leu Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly

165 170 175

Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Thr Ser Asn

180 185 190

Ile Gly Arg Asn Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala

195 200 205

Pro Lys Leu Leu Ile Tyr Arg Thr Asn Gln Arg Pro Ser Gly Val Pro

210 215 220

Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile

225 230 235 240

Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp

245 250 255

Asp Asp Ser Leu Ser Gly Arg Val Phe Gly Thr Gly Thr Lys Leu Thr

260 265 270

Val Leu Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

275 280 285

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

290 295 300

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

305 310 315 320

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

325 330 335

Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr

340 345 350

Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu

355 360 365

Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu

370 375 380

Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln

385 390 395 400

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu

405 410 415

Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly

420 425 430

Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln

435 440 445

Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu

450 455 460

Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr

465 470 475 480

Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro

485 490 495

Arg

<210> 331

<211> 500

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 331

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Thr Phe Asn Asn Phe Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ser Gly Ile Ser Gly Ser Gly Asp Asn Thr Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser

85 90 95

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Lys Asp Arg Asp Ile Gly Leu Gly Trp Tyr

115 120 125

Ser Tyr Tyr Leu Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser

130 135 140

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

145 150 155 160

Gly Gly Gly Gly Ser Glu Leu Gln Ser Val Leu Thr Gln Pro Pro Ser

165 170 175

Ala Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser

180 185 190

Ser Ser Asn Ile Gly Ser Asn Tyr Val Tyr Trp Tyr Gln Gln Leu Pro

195 200 205

Gly Thr Ala Pro Lys Pro Leu Ile Tyr Met Asn Asn Gln Arg Pro Ser

210 215 220

Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser

225 230 235 240

Leu Ala Ile Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys

245 250 255

Ala Ala Trp Asp Asp Ser Leu Ser Ala Val Val Phe Gly Thr Gly Thr

260 265 270

Lys Leu Thr Val Leu Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

275 280 285

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

290 295 300

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

305 310 315 320

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

325 330 335

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys

340 345 350

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

355 360 365

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

370 375 380

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

385 390 395 400

Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

405 410 415

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

420 425 430

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

435 440 445

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

450 455 460

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

465 470 475 480

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

485 490 495

Leu Pro Pro Arg

500

<210> 332

<211> 496

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 332

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val

20 25 30

Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly

35 40 45

Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln

50 55 60

Gly Leu Glu Trp Met Gly Glu Ile Ile Pro Ile Phe Gly Thr Ala Ser

65 70 75 80

Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser

85 90 95

Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Ala Gly Trp Asp Asp Ser Trp Phe Asp

115 120 125

Tyr Trp Gly Glyn Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

130 135 140

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

145 150 155 160

Glu Leu Gln Ser Val Leu Thr Gln Pro Ser Ala Ser Gly Thr Pro

165 170 175

Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Ile Gly

180 185 190

Thr Asn Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys

195 200 205

Leu Leu Ile Tyr Arg Ser Ser Arg Arg Pro Ser Gly Val Pro Asp Arg

210 215 220

Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly

225 230 235 240

Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Gly

245 250 255

Ser Leu Ser Gly His Trp Val Phe Gly Thr Gly Thr Lys Leu Thr Val

260 265 270

Leu Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile

275 280 285

Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala

290 295 300

Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr

305 310 315 320

Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu

325 330 335

Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile

340 345 350

Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp

355 360 365

Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

370 375 380

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly

385 390 395 400

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

405 410 415

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

420 425 430

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

435 440 445

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

450 455 460

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

465 470 475 480

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490 495

<210> 333

<211> 496

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 333

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val

20 25 30

Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr

35 40 45

Ser Phe Ala Ser Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys

50 55 60

Gly Leu Glu Trp Met Gly Val Ile Tyr Pro Gly Thr Ser Glu Thr Arg

65 70 75 80

Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser

85 90 95

Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Lys Gly Leu Ser Ala Ser Ala Ser Gly Tyr

115 120 125

Ser Phe Gln Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

145 150 155 160

Gly Gly Ser Glu Leu Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu

165 170 175

Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln

180 185 190

Ser Ile Asp Thr Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala

195 200 205

Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu His Ser Gly Val Pro

210 215 220

Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile

225 230 235 240

Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser

245 250 255

Tyr Ser Thr Thr Ala Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

260 265 270

Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile

275 280 285

Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala

290 295 300

Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr

305 310 315 320

Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu

325 330 335

Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile

340 345 350

Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp

355 360 365

Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

370 375 380

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly

385 390 395 400

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

405 410 415

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

420 425 430

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

435 440 445

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

450 455 460

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

465 470 475 480

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490 495

<210> 334

<211> 497

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 334

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val

20 25 30

Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr

35 40 45

Ser Phe Thr Asp Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys

50 55 60

Gly Leu Glu Trp Met Gly Met Ile Ser Pro Gly Gly Ser Thr Thr Ile

65 70 75 80

Tyr Arg Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser

85 90 95

Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Arg Glu Met Tyr Thr Gly Gly Tyr Gly Gly

115 120 125

Ser Trp Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

130 135 140

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

145 150 155 160

Gly Gly Gly Gly Ser Glu Leu Asp Ile Gln Met Thr Gln Ser Pro Ser

165 170 175

Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala

180 185 190

Ser Gln Ser Ile Gly Gln Ser Leu Asn Trp Tyr Gln Gln Lys Pro Gly

195 200 205

Lys Ala Pro Lys Leu Leu Ile Tyr Gly Ala Ser Ser Leu Gln Ser Gly

210 215 220

Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu

225 230 235 240

Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln

245 250 255

Gln Ser Tyr Ser Thr Pro Ile Thr Phe Gly Gln Gly Thr Lys Val Glu

260 265 270

Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

275 280 285

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

290 295 300

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

305 310 315 320

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

325 330 335

Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr

340 345 350

Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu

355 360 365

Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu

370 375 380

Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln

385 390 395 400

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu

405 410 415

Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly

420 425 430

Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln

435 440 445

Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu

450 455 460

Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr

465 470 475 480

Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro

485 490 495

Arg

<210> 335

<211> 193

<212> PROTEIN

<213> Homo sapiens

<400> 335

Met Pro Glu Glu Gly Ser Gly Cys Ser Val Arg Arg Arg Pro Tyr Gly

1.5 10 15

Cys Val Leu Arg Ala Ala Leu Val Pro Leu Val Ala Gly Leu Val Ile

20 25 30

Cys Leu Val Val Cys Ile Gln Arg Phe Ala Gln Ala Gln Gln Gln Leu

35 40 45

Pro Leu Glu Ser Leu Gly Trp Asp Val Ala Glu Leu Gln Leu Asn His

50 55 60

Thr Gly Pro Gln Gln Asp Pro Arg Leu Tyr Trp Gln Gly Gly Pro Ala

65 70 75 80

Leu Gly Arg Ser Phe Leu His Gly Pro Glu Leu Asp Lys Gly Gln Leu

85 90 95

Arg Ile His Arg Asp Gly Ile Tyr Met Val His Ile Gln Val Thr Leu

100 105 110

Ala Ile Cys Ser Ser Thr Thr Ala Ser Arg His His Pro Thr Thr Leu

115 120 125

Ala Val Gly Ile Cys Ser Pro Ala Ser Arg Ser Ile Ser Leu Leu Arg

130 135 140

Leu Ser Phe His Gln Gly Cys Thr Ile Ala Ser Gln Arg Leu Thr Pro

145 150 155 160

Leu Ala Arg Gly Asp Thr Leu Cys Thr Asn Leu Thr Gly Thr Leu Leu

165 170 175

Pro Ser Arg Asn Thr Asp Glu Thr Phe Phe Gly Val Gln Trp Val Arg

180 185 190

Pro

<210> 336

<211> 933

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<220>

<221> modified_base

<222> (793)..(793)

<223> a, c, t or g

<220>

<221> modified_base

<222> (797)..(797)

<223> a, c, t or g

<400> 336

atggctctcc cggtcacggc cctgctgctg cctctggcgc tgctcctgca cgcggcgcgc

60

ccgcaggtca ccttgaagga gtctggtcct gtgctggtga aacccacaga gaccctcacg

120

ctgacctgca ccgtctctgg gttctcactc agtaatgcta gaatgggtgt gacctggatc

180

cgtcagcccc cagggaaggc cctggagtgg cttgcacaca ttttttcgaa tgacgaaaaa

240

tcctacagta catctctgaa gagcaggctc accatctcca aggacacttc caaaacccag

300

gtggtcctta ccatgaccaa catggaccct gtggacacag ccacatatta ctgtgcacgg

360

atacgagatt actatgacat tagtagttat tatgactact ggggccaggg aaccctggtc

420

agcgtctcct caggcggagg cggttctggc ggaggtggca gcggtggtgg cggaagtgggg

480

ggtggcggct ccgacatcca gatgacccag tctccatctg ccatgtctgc atctgtagga

540

gacagagtca ccatcacttg tcgggcgagt caggacatta gcaattattt agcctggttt

600

cagcagaaac cagggaaagt ccctaagcgc ctgatctatg ctgcatccag tttgcaaagt

660

ggggtcccat caaggttcag cggcagtgga tcggggacag aattcactct cacaatcagc

720

agcctgctgc ctgaagattt tgcaacttat tactgtctac agcttaatag tttcccgttc

780

acttttggcg ganggancaa ggtggagatc aacactacca caccagcacc tcgaccacca

840

actccagcac caaccattgc atcacagcca ctgagcctgc gaccagaggc ctgtagacct

900

gctgcaggag gagctgtgca tacccgagga ctg

933

<210> 337

<211> 948

<212> DNA

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 337

atggctctcc cggtcacggc cctgctgctg cctctggcgc tgctcctgca cgcggcgcgc

60

ccggaagtgc agcttgtcca gagcggagcc gaagtgaaga agcctggcga gagcctgaag

120

atcagctgca agggctccgg atacggattc acaagttatt ggataggttg ggtgcgccag

180

atgcctggta agggactgga atggatgggt atcattcatc ccgatgatag cgacaccaaa

240

tacagcccaa gctttcaggg ccaggtcaca atcagcgctg acaagagcat cagcaccgcc

300

taccttcagt ggtcgtctct gaaggccagc gacaccgcaa tgtactactg tgcctctagc

360

tatttgcgtg gcttgtgggg aggctatttt gactattggg gccaaggtac actggtcacc

420

gtcagcagcg gcggaggcgg ttctggcgga ggtggcagcg gtggtggcgg aagtgggggt

480

ggcggctccg agctccagag cgtgctgacc cagcctccta gcgcaagcgg cacccctgga

540

cagcgtgtga caattagctg tagcggatca agctcaaaca ttggctcaaa ttatgtgaat

600

tggtatcagc aattgcccgg tacagcaccc aaactgctca tttatggaga ttatcaacga

660

cctagcggag tgcctgatcg ttttagcggt agcaaaagcg gcaccagcgc atcactggca

720

atttcaggcc tgcgtagcga agatgaggcg gattattact gtgctacccg cgacgattcg

780

ttatctgggt ctgtcgtttt tggcaccggt acaaaactga ccgtgctgac taccacacca

840

gcacctcgac caccaactcc agcaccaacc attgcatcac agccactgag cctgcgacca

900

gaggcctgta gacctgctgc aggaggagct gtgcataccc gaggactg

948

<210> 338

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 338

Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly

1.5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Thr Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile

35 40 45

Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Ile Leu Thr Ile Asn Ser Leu Gln Pro

65 70 75 80

Asp Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Tyr Lys Ser Tyr Ser His

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 339

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 339

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1.5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Tyr Tyr

20 25 30

Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly His Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Ile Asp Thr Ser Lys Asn Leu Phe Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Ala Glu Gly Ser Leu Asp Ala Phe Asp Phe Trp Gly Gln Gly Thr

100 105 110

Met Val Thr Val Ser Ser

115

<210> 340

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 340

Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly

1.5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile

35 40 45

Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro

65 70 75 80

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Lys Ser Phe Ser Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 341

<211> 113

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 341

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly

1.5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn

20 25 30

Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ser

<210> 342

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 342

Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly

1.5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile

35 40 45

Tyr Lys Ala Ser Thr Leu Glu 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

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser Tyr

85 90 95

Thr Phe Gly His Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 343

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 343

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly

1.5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Asp Tyr Tyr

20 25 30

Phe Trp Asn Trp Phe Arg Gln Ser Pro Val Lys Gly Leu Glu Trp Ile

35 40 45

Gly His Val Tyr Asp Ile Gly Asn Thr Lys Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Ile Asp Thr Ser Glu Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Gly Glu Gly Ala Leu Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr

100 105 110

Met Val Thr Val Ser Ser

115

<210> 344

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 344

Asp Ile Gln Met Thr Gln Ser Pro Ser Ile Leu Ser Ala Ser Val Gly

1.5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile

35 40 45

Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Thr Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser

65 70 75 80

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Thr Tyr Ser His

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 345

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 345

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1.5 10 15

Thr Leu Ser Leu Asn Cys Thr Val Ser Gly Gly Ser Ile Ser Tyr Tyr

20 25 30

Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly His Val Ile Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Val

85 90 95

Arg Ala Glu Gly Ser Leu Asp Ala Phe Asp Leu Trp Gly Gln Gly Thr

100 105 110

Met Val Thr Val Ser Ser

115

<210> 346

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 346

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 Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Tyr Asn Tyr Pro Phe

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

100 105

<210> 347

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 347

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 Val Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Gly Ile His Trp Val Arg Gln Ala Pro Gly Met Gly Gln Glu Trp Val

35 40 45

Ala Val Ile Trp Tyr Asp Gly Ser Ile Lys Lys Tyr Ser Asp Ser Val

50 55 60

Lys Gly Arg Phe Ile Ile Ser Arg Asp Asn Ser Glu Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Gly Glu Asp Thr Ala Ile Tyr Tyr Cys

85 90 95

Ala Arg Asp Glu Val Gly Thr Phe Gly Ala Phe Asp Phe Trp Gly Gln

100 105 110

Gly Thr Lys Val Thr Val Ser Ser

115 120

<210> 348

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 348

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1.5 10 15

Asp Ser Ile Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Asp Asn Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Thr Gly Lys Val Pro Lys Val Leu Ile

35 40 45

Tyr Ala Ala Ser Ala 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 Ser Leu Gln Pro

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Asn Tyr Asn Ser Gly Pro Arg

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 349

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 349

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Leu Gln

1.5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asp

20 25 30

Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Asn Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Tyr Met Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Thr Arg Asp Phe Gly Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 350

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 350

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 Ile Ser Asn Tyr

20 25 30

Leu Thr Trp Tyr Gln Gln Lys Pro Gly Arg Val Pro Glu Val Leu Ile

35 40 45

Tyr Ala Ala Ser Ala 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 Ser Leu Gln Pro

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Asn Tyr Asn Ser Ala Pro Arg

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 351

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 351

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1.5 10 15

Ser Leu Ser Leu Thr Cys Ser Val Ser Gly Gly Ser Val Ser Ser Asp

20 25 30

Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Tyr Ile Tyr Tyr Arg Arg Ile Thr Asp Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Asn Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Phe Gly Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr

100 105 110

Leu Val Ala Val Ser Ser

115

<210> 352

<211> 112

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 352

Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly

1.5 10 15

Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser

20 25 30

Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Val Leu Ile Leu Leu Gly Ser Asn Arg Ala Ser Gly Val Pro

50 55 60

Asp Arg Val Ser Ala Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Met Gln Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln Thr

85 90 95

Leu Gln Thr Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 353

<211> 122

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 353

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 Thr Phe Thr Gly Tyr

20 25 30

Tyr Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Thr Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Arg Leu Arg Ile Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Arg Gly Val Thr Met Ile Val Asp Gly Met Asp Asp Trp

100 105 110

Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 354

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 354

Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly

1.5 10 15

Asp Arg Val Ile Ile Thr Cys Arg Ala Ser Gln Gly Ile Asn Ser His

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Ala Ser Thr Leu Pro Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Val Thr Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn His Tyr Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Asp Ile Asn

100 105

<210> 355

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 355

Glu Val Glu Leu Val Glu Ser Gly Gly Gly Met Val Gln Pro Gly Arg

1.5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Gly Met His Trp Val Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val

35 40 45

Thr 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 Val Phe

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 Asp Glu Val Gly Phe Val Gly Ala Phe Asp Ile Trp Gly Gln

100 105 110

Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 356

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 356

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 Gly Ile Ser Asn Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Thr Leu His Ser 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 Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Asn Ser Ala Pro Arg

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 357

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 357

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1.5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asp

20 25 30

Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Tyr Met Tyr Tyr Ser Gly Ile Thr Tyr His Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Phe Gly Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 358

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 358

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 Ile Ser Asn Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Thr Leu His Ser 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

Asp Asp Phe Ala Ala Tyr Tyr Cys Gln Lys Tyr Asn Ser Ala Pro Arg

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 359

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 359

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1.5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asp

20 25 30

Ala Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Tyr Met Tyr Tyr Ser Gly Ile Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Asp Phe Gly Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 360

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 360

Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly

1.5 10 15

Asp Arg Val Ser Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Phe

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Val Leu Leu Ile

35 40 45

Tyr Val Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Val Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu His Val Tyr Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Arg

100 105

<210> 361

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 361

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 Val Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Gly Ile His Trp Val Arg Gln Ala Pro Gly Met Gly Gln Glu Trp Val

35 40 45

Ala Val Ile Trp Tyr Asp Gly Ser Ile Lys Lys Tyr Ser Asp Ser Val

50 55 60

Lys Gly Arg Phe Ile Ile Ser Arg Asp Asn Ser Glu Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Gly Glu Asp Thr Ala Ile Tyr Tyr Cys

85 90 95

Ala Arg Asp Glu Val Gly Thr Phe Gly Ala Phe Asp Phe Trp Gly Gln

100 105 110

Gly Thr Lys Val Thr Val Ser Ser

115 120

<210> 362

<211> 113

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 362

Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly

1.5 10 15

Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Asp Asp Gly Asn Thr Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln

35 40 45

Ser Pro Gln Leu Leu Ile Tyr Thr Leu Ser Tyr Arg Ala Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys

65 70 75 80

Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln

85 90 95

Arg Ile Glu Phe Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile

100 105 110

Lys

<210> 363

<211> 122

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 363

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1.5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Lys Ser Lys Thr Gly Gly Gly Thr Thr Asp Tyr Ala Ala

50 55 60

Pro 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 Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Thr Ser Leu Ile Val Gly Ala Ile Ser Leu Phe Asp Tyr Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 364

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 364

Asp Ile Gln Met Thr Gln Ser Pro Ser Ala Leu Ser Ala Ser Val Gly

1.5 10 15

Asp Arg Val Ala Ile Thr Cys Arg Ala Ser Gln Thr Ile Ser Thr Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile

35 40 45

Tyr Lys Ala Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro

65 70 75 80

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Gln Thr Phe Ser His

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 365

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 365

Gln Val Gln Leu Arg Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1.5 10 15

Thr Leu Ser Leu Thr Cys Thr Ile Ser Gly Gly Ser Ile Ser Tyr Tyr

20 25 30

Phe Trp Thr Trp Ile Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile

35 40 45

Gly Gln Ile Tyr Tyr Ser Gly Asn Thr Asn Ser Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Ile Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Thr Ser Val Thr Val Ala Asp Thr Ala Val Tyr Tyr Cys Val

85 90 95

Arg Ala Glu Gly Ser Leu Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr

100 105 110

Met Val Ala Val Ser Ser

115

<210> 366

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 366

Asp Met Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1.5 10 15

Asp Arg Val Thr Leu Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr

20 25 30

Leu Ala Trp Phe Gln Leu Lys Pro Gly Lys Val Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Ala Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Asn Ser Ala Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 367

<211> 122

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 367

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1.5 10 15

Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ser Met Asn Trp Val Arg Gln Phe Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Thr Ser Ser Asn Tyr Ile His Tyr Ala Asp Ser Leu

50 55 60

Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Val Arg Asp Lys Gly Thr Thr Leu Thr Asn Trp Tyr Phe Asp Leu Trp

100 105 110

Gly Arg Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 368

<211> 112

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 368

Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly

1.5 10 15

Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Thr Leu Val His Ser

20 25 30

Asn Gly Tyr Asn Tyr Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Ser Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Met Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala

85 90 95

Ile Gln Thr Pro Tyr Thr Phe Gly Gln Gly Thr Asn Val Glu Ile Lys

100 105 110

<210> 369

<211> 121

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 369

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 Gly 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 Leu

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 Tyr Cys

85 90 95

Ala Arg Asp Gly Tyr Ser Gly Ser Ser Asp Ala Phe Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 370

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 370

Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly

1.5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile

35 40 45

Tyr Lys Ala Ser Asn Leu Glu 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

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser Cys

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 371

<211> 118

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 371

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Gln Pro Ser Glu

1.5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Tyr Tyr

20 25 30

Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Asn Ile Asn Tyr Met Gly Asn Thr Ile Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asp Gln Phe Ser Leu

65 70 75 80

Lys Leu Thr Ser Val Ser Ala Ala Asp Thr Ala Val Tyr Tyr Cys Val

85 90 95

Arg Ala Glu Gly Ser Leu Asp Ala Phe Asp Phe Trp Gly Gln Gly Thr

100 105 110

Leu Val Ala Val Ser Leu

115

<210> 372

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 372

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1.5 10 15

Asp Arg Ile Ile Phe Thr Cys Gln Ala Ser Gln Asp Ile Asn Asn Tyr

20 25 30

Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asp Trp Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp His Leu Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Val Glu Ile Lys

100 105

<210> 373

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 373

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Thr Lys Pro Gly Ala

1.5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Gly Tyr

20 25 30

Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Pro Ser Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Ala Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Arg Lys Arg Glu Tyr Tyr Tyr Asn Phe Gly Met Asp Val

100 105 110

Trp Gly Glyn Gly Thr Thr Val Thr Val Ser Thr

115 120

<210> 374

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 374

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1.5 10 15

Asp Arg Val Ile Leu Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr

20 25 30

Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asp Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Ala Asp Phe Thr Phe Thr Ile Ser Asn Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp His Leu Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 375

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 375

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Thr Lys Pro Gly Ala

1.5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His

20 25 30

Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Met Ala Arg 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

Ala Lys Asp Arg Lys Arg Glu Tyr Tyr Tyr Asn Phe Gly Met Asp Val

100 105 110

Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ala

115 120

<210> 376

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 376

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1.5 10 15

Asp Arg Val Ile Leu Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr

20 25 30

Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asp Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Ala Asp Phe Thr Phe Thr Ile Ser Asn Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp His Leu Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 377

<211> 123

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 377

Gln Val Gln Leu Val Gln Phe Gly Val Glu Val Arg Lys Pro Gly Ala

1.5 10 15

Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Thr Phe Thr Ser His

20 25 30

Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Met Ala Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ser Val Tyr Tyr Cys

85 90 95

Val Lys Asp Arg Lys Arg Glu Tyr Tyr Tyr Asn Phe Gly Met Asp Val

100 105 110

Trp Gly Glyn Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 378

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 378

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 Asp Ile Ser Asn Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 379

<211> 119

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 379

Glu Val Gln Met Leu Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly

1.5 10 15

Ser Leu Arg Leu Ser Cys Lys Thr Ser Gly Phe Thr Leu Ser Ile Tyr

20 25 30

Ala Ile His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val

35 40 45

Ser Ser Phe Gly Gly Arg Gly Ser Ser Thr Tyr Phe Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Ala Ser Glu Asn Ser Leu Tyr

65 70 75 80

Leu His Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Glu Lys Asp Trp Gly Arg Gly Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 380

<211> 112

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 380

Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly

1.5 10 15

Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr Ser

20 25 30

Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Phe Leu Asn Ser Asn Arg Ala 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 Phe Cys Met Gln Ala

85 90 95

Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 381

<211> 122

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 381

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1.5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr

20 25 30

Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Ser Ser Thr Ile Tyr Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser 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 Asp Ile Gly Trp Glu Val Phe Thr Leu Gly Phe Asp Tyr Trp

100 105 110

Gly Gln Gly Thr Gln Val Thr Val Ser Ser

115 120

<210> 382

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 382

Tyr Tyr Tyr Trp Thr

15

<210> 383

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 383

Gly Gly Ser Ile Ser Tyr Tyr

15

<210> 384

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 384

Gly Gly Ser Ile Ser Tyr Tyr Tyr Trp Thr

1.5 10

<210> 385

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 385

His Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser

1.5 10 15

<210> 386

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 386

Tyr Tyr Ser Gly Ser

15

<210> 387

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 387

Ala Glu Gly Ser Leu Asp Ala Phe Asp Phe

1.5 10

<210> 388

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 388

Ser Asn Tyr Met Thr

15

<210> 389

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 389

Gly Phe Thr Val Ser Ser Asn

15

<210> 390

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 390

Gly Phe Thr Val Ser Ser Asn Tyr Met Thr

1.5 10

<210> 391

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 391

Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly

1.5 10 15

<210> 392

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 392

Tyr Ser Gly Gly Ser

15

<210> 393

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 393

Asn Trp Gly Asp Tyr Trp

15

<210> 394

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 394

Tyr Tyr Phe Trp Asn

15

<210> 395

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 395

Gly Gly Ser Ile Asp Tyr Tyr

15

<210> 396

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 396

Gly Gly Ser Ile Asp Tyr Tyr Phe Trp Asn

1.5 10

<210> 397

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 397

His Val Tyr Asp Ile Gly Asn Thr Lys Tyr Asn Pro Ser Leu Lys Ser

1.5 10 15

<210> 398

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 398

Tyr Asp Ile Gly Asn

15

<210> 399

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 399

Gly Glu Gly Ala Leu Asp Ala Phe Asp Ile

1.5 10

<210> 400

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 400

Tyr Tyr Tyr Trp Thr

15

<210> 401

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 401

Gly Gly Ser Ile Ser Tyr Tyr

15

<210> 402

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 402

Gly Gly Ser Ile Ser Tyr Tyr Tyr Trp Thr

1.5 10

<210> 403

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 403

His Val Ile Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys Ser

1.5 10 15

<210> 404

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 404

Ile Tyr Ser Gly Thr

15

<210> 405

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 405

Ala Glu Gly Ser Leu Asp Ala Phe Asp Leu

1.5 10

<210> 406

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 406

Asp Tyr Gly Ile His

15

<210> 407

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 407

Gly Phe Thr Phe Ser Asp Tyr

15

<210> 408

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 408

Gly Phe Thr Phe Ser Asp Tyr Gly Ile His

1.5 10

<210> 409

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 409

Val Ile Trp Tyr Asp Gly Ser Ile Lys Lys Tyr Ser Asp Ser Val Lys

1.5 10 15

gly

<210> 410

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 410

Trp Tyr Asp Gly Ser Ile

15

<210> 411

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 411

Asp Glu Val Gly Thr Phe Gly Ala Phe Asp Phe

1.5 10

<210> 412

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 412

Ser Asp Gly Tyr Tyr Trp Ser

15

<210> 413

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 413

Gly Gly Ser Ile Ser Ser Asp Gly Tyr

15

<210> 414

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 414

Gly Gly Ser Ile Ser Ser Asp Gly Tyr Tyr Trp Ser

1.5 10

<210> 415

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 415

Tyr Met Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser

1.5 10 15

<210> 416

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 416

Tyr Tyr Ser Gly Ser

15

<210> 417

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 417

Asp Phe Gly Trp Tyr Phe Asp Leu

15

<210> 418

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 418

Ser Asp Gly Tyr Tyr Trp Ser

15

<210> 419

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 419

Gly Gly Ser Val Ser Ser Asp Gly Tyr

15

<210> 420

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 420

Gly Gly Ser Val Ser Ser Asp Gly Tyr Tyr Trp Ser

1.5 10

<210> 421

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 421

Tyr Ile Tyr Tyr Arg Arg Ile Thr Asp Tyr Asn Pro Ser Leu Lys Ser

1.5 10 15

<210> 422

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 422

Tyr Tyr Arg Arg Ile

15

<210> 423

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 423

Asp Phe Gly Trp Tyr Phe Asp Leu

15

<210> 424

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 424

Gly Tyr Tyr Leu His

15

<210> 425

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 425

Gly Tyr Thr Phe Thr Gly Tyr

15

<210> 426

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 426

Gly Tyr Thr Phe Thr Gly Tyr Tyr Leu His

1.5 10

<210> 427

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 427

Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe Gln

1.5 10 15

gly

<210> 428

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 428

Asn Pro Asn Ser Gly Gly

15

<210> 429

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 429

Asp Arg Gly Val Thr Met Ile Val Asp Gly Met Asp Asp

1.5 10

<210> 430

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 430

Asp Tyr Gly Met His

15

<210> 431

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 431

Gly Phe Thr Phe Ser Asp Tyr

15

<210> 432

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 432

Gly Phe Thr Phe Ser Asp Tyr Gly Met His

1.5 10

<210> 433

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 433

Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys

1.5 10 15

gly

<210> 434

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 434

Trp Tyr Asp Gly Ser Asn

15

<210> 435

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 435

Asp Glu Val Gly Phe Val Gly Ala Phe Asp Ile

1.5 10

<210> 436

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 436

Ser Asp Gly Tyr Tyr Trp Ser

15

<210> 437

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 437

Gly Gly Ser Ile Ser Ser Asp Gly Tyr

15

<210> 438

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 438

Gly Gly Ser Ile Ser Ser Asp Gly Tyr Tyr Trp Ser

1.5 10

<210> 439

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 439

Tyr Met Tyr Tyr Ser Gly Ile Thr Tyr His Asn Pro Ser Leu Lys Ser

1.5 10 15

<210> 440

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 440

Tyr Tyr Ser Gly Ile

15

<210> 441

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 441

Asp Phe Gly Trp Tyr Phe Asp Leu

15

<210> 442

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 442

Ser Asp Ala Tyr Tyr Trp Ser

15

<210> 443

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 443

Gly Gly Ser Ile Ser Ser Asp Ala Tyr

15

<210> 444

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 444

Gly Gly Ser Ile Ser Ser Asp Ala Tyr Tyr Trp Ser

1.5 10

<210> 445

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 445

Tyr Met Tyr Tyr Ser Gly Ile Thr Tyr Tyr Asn Pro Ser Leu Lys Ser

1.5 10 15

<210> 446

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 446

Tyr Tyr Ser Gly Ile

15

<210> 447

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 447

Asp Phe Gly Trp Tyr Phe Asp Leu

15

<210> 448

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 448

Asp Tyr Gly Ile His

15

<210> 449

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 449

Gly Phe Thr Phe Ser Asp Tyr

15

<210> 450

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 450

Gly Phe Thr Phe Ser Asp Tyr Gly Ile His

1.5 10

<210> 451

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 451

Val Ile Trp Tyr Asp Gly Ser Ile Lys Lys Tyr Ser Asp Ser Val Lys

1.5 10 15

gly

<210> 452

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 452

Trp Tyr Asp Gly Ser Ile

15

<210> 453

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 453

Asp Glu Val Gly Thr Phe Gly Ala Phe Asp Phe

1.5 10

<210> 454

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 454

Asn Ala Trp Met Ser

15

<210> 455

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 455

Gly Phe Thr Phe Ser Asn Ala

15

<210> 456

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 456

Gly Phe Thr Phe Ser Asn Ala Trp Met Ser

1.5 10

<210> 457

<211> 19

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 457

Arg Ile Lys Ser Lys Thr Gly Gly Gly Thr Thr Asp Tyr Ala Ala Pro

1.5 10 15

Val Lys Gly

<210> 458

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 458

Lys Ser Lys Thr Gly Gly Gly Thr

15

<210> 459

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 459

Leu Ile Val Gly Ala Ile Ser Leu Phe Asp Tyr

1.5 10

<210> 460

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 460

Tyr Tyr Phe Trp Thr

15

<210> 461

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 461

Gly Gly Ser Ile Ser Tyr Tyr

15

<210> 462

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 462

Gly Gly Ser Ile Ser Tyr Tyr Phe Trp Thr

1.5 10

<210> 463

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 463

Gln Ile Tyr Tyr Ser Gly Asn Thr Asn Ser Asn Pro Ser Leu Lys Ser

1.5 10 15

<210> 464

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 464

Tyr Tyr Ser Gly Asn

15

<210> 465

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 465

Ala Glu Gly Ser Leu Asp Ala Phe Asp Ile

1.5 10

<210> 466

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 466

Ser Tyr Ser Met Asn

15

<210> 467

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 467

Gly Phe Thr Phe Ser Ser Tyr

15

<210> 468

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 468

Gly Phe Thr Phe Ser Ser Tyr Ser Met Asn

1.5 10

<210> 469

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 469

Ser Ile Ser Thr Ser Ser Asn Tyr Ile His Tyr Ala Asp Ser Leu Gln

1.5 10 15

gly

<210> 470

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 470

Ser Thr Ser Ser Asn Tyr

15

<210> 471

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 471

Asp Lys Gly Thr Thr Leu Thr Asn Trp Tyr Phe Asp Leu

1.5 10

<210> 472

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 472

Ser Tyr Gly Met His

15

<210> 473

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 473

Gly Phe Thr Phe Ser Ser Tyr

15

<210> 474

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 474

Gly Phe Thr Phe Ser Ser Tyr Gly Met His

1.5 10

<210> 475

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 475

Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Leu Lys

1.5 10 15

gly

<210> 476

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 476

Trp Tyr Asp Gly Ser Asn

15

<210> 477

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 477

Asp Gly Tyr Ser Gly Ser Ser Asp Ala Phe Asp Ile

1.5 10

<210> 478

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 478

Tyr Tyr Tyr Trp Ser

15

<210> 479

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 479

Gly Gly Ser Ile Ser Tyr Tyr

15

<210> 480

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 480

Gly Gly Ser Ile Ser Tyr Tyr Tyr Trp Ser

1.5 10

<210> 481

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 481

Asn Ile Asn Tyr Met Gly Asn Thr Ile Tyr Asn Pro Ser Leu Lys Ser

1.5 10 15

<210> 482

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 482

Asn Tyr Met Gly Asn

15

<210> 483

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 483

Ala Glu Gly Ser Leu Asp Ala Phe Asp Phe

1.5 10

<210> 484

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 484

Gly Tyr Tyr Ile Tyr

15

<210> 485

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 485

Gly Tyr Ile Phe Thr Gly Tyr

15

<210> 486

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 486

Gly Tyr Ile Phe Thr Gly Tyr Tyr Ile Tyr

1.5 10

<210> 487

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 487

Trp Ile Asn Pro Ser Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe Gln

1.5 10 15

gly

<210> 488

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 488

Asn Pro Ser Ser Gly Gly

15

<210> 489

<211> 14

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 489

Asp Arg Lys Arg Glu Tyr Tyr Tyr Asn Phe Gly Met Asp Val

1.5 10

<210> 490

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 490

Ser His Tyr Ile Tyr

15

<210> 491

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 491

Gly Tyr Thr Phe Thr Ser His

15

<210> 492

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 492

Gly Tyr Thr Phe Thr Ser His Tyr Ile Tyr

1.5 10

<210> 493

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 493

Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe Gln

1.5 10 15

asp

<210> 494

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 494

Asn Pro Asn Ser Gly Gly

15

<210> 495

<211> 14

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 495

Asp Arg Lys Arg Glu Tyr Tyr Tyr Asn Phe Gly Met Asp Val

1.5 10

<210> 496

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 496

Ser His Tyr Ile Tyr

15

<210> 497

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 497

Gly Phe Thr Phe Thr Ser His

15

<210> 498

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 498

Gly Phe Thr Phe Thr Ser His Tyr Ile Tyr

1.5 10

<210> 499

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 499

Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe Gln

1.5 10 15

asp

<210> 500

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 500

Asn Pro Asn Ser Gly Gly

15

<210> 501

<211> 14

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 501

Asp Arg Lys Arg Glu Tyr Tyr Tyr Asn Phe Gly Met Asp Val

1.5 10

<210> 502

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 502

Ile Tyr Ala Ile His

15

<210> 503

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 503

Gly Phe Thr Leu Ser Ile Tyr

15

<210> 504

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 504

Gly Phe Thr Leu Ser Ile Tyr Ala Ile His

1.5 10

<210> 505

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 505

Ser Phe Gly Gly Arg Gly Ser Ser Thr Tyr Phe Ala Asp Ser Val Lys

1.5 10 15

gly

<210> 506

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 506

Gly Gly Arg Gly Ser Ser

15

<210> 507

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 507

Glu Lys Asp Trp Gly Arg Gly Phe Asp Tyr

1.5 10

<210> 508

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 508

Asn Tyr Ser Met Asn

15

<210> 509

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 509

Gly Phe Thr Phe Ser Asn Tyr

15

<210> 510

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 510

Gly Phe Thr Phe Ser Asn Tyr Ser Met Asn

1.5 10

<210> 511

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 511

Ser Ile Ser Ser Ser Thr Ile Tyr Ile Tyr Tyr Ala Asp Ser Val Lys

1.5 10 15

gly

<210> 512

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 512

Ser Ser Ser Thr Ile Tyr

15

<210> 513

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 513

Asp Ile Gly Trp Glu Val Phe Thr Leu Gly Phe Asp Tyr

1.5 10

<210> 514

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 514

Arg Ala Ser Gln Ser Ile Ser Thr Trp Leu Ala

1.5 10

<210> 515

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 515

Lys Ala Ser Ser Leu Glu Ser

15

<210> 516

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 516

Gln Gln Tyr Lys Ser Tyr Ser His Thr

15

<210> 517

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 517

Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala

1.5 10

<210> 518

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 518

Lys Ala Ser Ser Leu Glu Ser

15

<210> 519

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 519

Gln Gln Tyr Lys Ser Phe Ser Leu Thr

15

<210> 520

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 520

Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala

1.5 10

<210> 521

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 521

Lys Ala Ser Thr Leu Glu Ser

15

<210> 522

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 522

Gln Gln Tyr Asn Ser Tyr Ser Tyr Thr

15

<210> 523

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 523

Arg Ala Ser Gln Ser Val Ser Ser Trp Leu Ala

1.5 10

<210> 524

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 524

Lys Ala Ser Ser Leu Glu Ser

15

<210> 525

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 525

Gln Gln Tyr Asn Thr Tyr Ser His Thr

15

<210> 526

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 526

Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly

1.5 10

<210> 527

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 527

Ala Ala Ser Ser Leu Gln Ser

15

<210> 528

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 528

Leu Gln Asp Tyr Asn Tyr Pro Phe Thr

15

<210> 529

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 529

Arg Ala Ser Gln Asp Ile Asp Asn Tyr Leu Ala

1.5 10

<210> 530

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 530

Ala Ala Ser Ala Leu Gln Ser

15

<210> 531

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 531

Gln Asn Tyr Asn Ser Gly Pro Arg Thr

15

<210> 532

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 532

Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Thr

1.5 10

<210> 533

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 533

Ala Ala Ser Ala Leu Gln Ser

15

<210> 534

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 534

Gln Asn Tyr Asn Ser Ala Pro Arg Thr

15

<210> 535

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 535

Arg Ser Ser Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp

1.5 10 15

<210> 536

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 536

Leu Gly Ser Asn Arg Ala Ser

15

<210> 537

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 537

Met Gln Thr Leu Gln Thr Pro Phe Thr

15

<210> 538

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 538

Arg Ala Ser Gln Gly Ile Asn Ser His Leu Ala

1.5 10

<210> 539

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 539

Tyr Ala Ser Thr Leu Pro Ser

15

<210> 540

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 540

Gln Gln Leu Asn His Tyr Pro Ile Thr

15

<210> 541

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 541

Arg Ala Ser Gln Gly Ile Ser Asn Tyr Leu Ala

1.5 10

<210> 542

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 542

Ala Ala Ser Thr Leu His Ser

15

<210> 543

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 543

Gln Lys Tyr Asn Ser Ala Pro Arg Thr

15

<210> 544

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 544

Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Ala

1.5 10

<210> 545

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 545

Ala Ala Ser Thr Leu His Ser

15

<210> 546

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 546

Gln Lys Tyr Asn Ser Ala Pro Arg Thr

15

<210> 547

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 547

Arg Ala Ser Gln Asp Ile Ser Ser Phe Leu Ala

1.5 10

<210> 548

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 548

Val Ala Ser Thr Leu Gln Ser

15

<210> 549

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 549

Gln Gln Leu His Val Tyr Pro Ile Thr

15

<210> 550

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 550

Arg Ser Ser Gln Ser Leu Leu Asp Ser Asp Asp Gly Asn Thr Tyr Leu

1.5 10 15

asp

<210> 551

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 551

Thr Leu Ser Tyr Arg Ala Ser

15

<210> 552

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 552

Met Gln Arg Ile Glu Phe Pro Phe Thr

15

<210> 553

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 553

Arg Ala Ser Gln Thr Ile Ser Thr Trp Leu Ala

1.5 10

<210> 554

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 554

Lys Ala Ser Asn Leu Glu Ser

15

<210> 555

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 555

Gln Gln Tyr Gln Thr Phe Ser His Thr

15

<210> 556

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 556

Arg Ala Ser Gln Gly Ile Ser Asn Tyr Leu Ala

1.5 10

<210> 557

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 557

Ala Ala Ser Thr Leu Gln Ser

15

<210> 558

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 558

Gln Lys Tyr Asn Ser Ala Pro Leu Thr

15

<210> 559

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 559

Arg Ser Ser Gln Thr Leu Val His Ser Asn Gly Tyr Asn Tyr Leu Asn

1.5 10 15

<210> 560

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 560

Leu Gly Ser Asn Arg Ala Ser

15

<210> 561

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 561

Met Gln Ala Ile Gln Thr Pro Tyr Thr

15

<210> 562

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 562

Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala

1.5 10

<210> 563

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 563

Lys Ala Ser Asn Leu Glu Ser

15

<210> 564

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 564

Gln Gln Tyr Asn Ser Tyr Ser Cys Thr

15

<210> 565

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 565

Gln Ala Ser Gln Asp Ile Asn Asn Tyr Leu His

1.5 10

<210> 566

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 566

Asp Ala Ser Asp Trp Glu Thr

15

<210> 567

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 567

Gln Gln Tyr Asp His Leu Pro Ile Thr

15

<210> 568

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 568

Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu His

1.5 10

<210> 569

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 569

Asp Ala Ser Asp Leu Glu Thr

15

<210> 570

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 570

Gln Gln Tyr Asp His Leu Pro Ile Thr

15

<210> 571

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 571

Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu His

1.5 10

<210> 572

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 572

Asp Ala Ser Asp Leu Glu Thr

15

<210> 573

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 573

Gln Gln Tyr Asp His Leu Pro Ile Thr

15

<210> 574

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 574

Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn

1.5 10

<210> 575

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 575

Asp Ala Ser Asn Leu Glu Thr

15

<210> 576

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 576

Gln Gln Tyr Asp Asn Leu Pro Tyr Thr

15

<210> 577

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 577

Arg Ser Ser Gln Ser Leu Leu Tyr Ser Asn Gly Tyr Asn Tyr Leu Asp

1.5 10 15

<210> 578

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 578

Leu Asn Ser Asn Arg Ala Ser

15

<210> 579

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 579

Met Gln Ala Leu Gln Thr Pro Leu Thr

15

<210> 580

<211> 489

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 580

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu

20 25 30

Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly

35 40 45

Ser Ile Ser Tyr Tyr Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly Lys

50 55 60

Gly Leu Glu Trp Ile Gly His Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr

65 70 75 80

Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Ile Asp Thr Ser Lys

85 90 95

Asn Leu Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala

100 105 110

Val Tyr Tyr Cys Ala Arg Ala Glu Gly Ser Leu Asp Ala Phe Asp Phe

115 120 125

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Thr Trp Leu

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile Tyr

195 200 205

Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Glu Phe Ile Leu Thr Ile Asn Ser Leu Gln Pro Asp

225 230 235 240

Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Tyr Lys Ser Tyr Ser His Thr

245 250 255

Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro

260 265 270

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

275 280 285

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

290 295 300

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

305 310 315 320

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

325 330 335

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

340 345 350

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

355 360 365

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

370 375 380

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

385 390 395 400

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

405 410 415

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

420 425 430

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

435 440 445

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

450 455 460

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

465 470 475 480

Leu His Met Gln Ala Leu Pro Pro Arg

485

<210> 581

<211> 484

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 581

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Ile Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Thr Val Ser Ser Asn Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr

65 70 75 80

Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys

85 90 95

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala

100 105 110

Val Tyr Tyr Cys Ala Arg Asn Trp Gly Asp Tyr Trp Gly Gln Gly Thr

115 120 125

Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln

145 150 155 160

Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr

165 170 175

Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln

180 185 190

Lys Pro Gly Lys Ala Pro Lys Val Leu Ile Tyr Lys Ala Ser Ser Leu

195 200 205

Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu

210 215 220

Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr

225 230 235 240

Tyr Cys Gln Gln Tyr Lys Ser Phe Ser Leu Thr Phe Gly Gln Gly Thr

245 250 255

Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

260 265 270

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

275 280 285

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

290 295 300

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

305 310 315 320

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys

325 330 335

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

340 345 350

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

355 360 365

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

370 375 380

Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

385 390 395 400

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

405 410 415

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

420 425 430

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

435 440 445

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

450 455 460

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

465 470 475 480

Leu Pro Pro Arg

<210> 582

<211> 489

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 582

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu

20 25 30

Val Lys Pro Ser Gly Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly

35 40 45

Ser Ile Asp Tyr Tyr Phe Trp Asn Trp Phe Arg Gln Ser Pro Val Lys

50 55 60

Gly Leu Glu Trp Ile Gly His Val Tyr Asp Ile Gly Asn Thr Lys Tyr

65 70 75 80

Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Ile Asp Thr Ser Glu

85 90 95

Asn Gln Phe Ser Leu Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala

100 105 110

Val Tyr Tyr Cys Ala Arg Gly Glu Gly Ala Leu Asp Ala Phe Asp Ile

115 120 125

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile Tyr

195 200 205

Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp

225 230 235 240

Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser Tyr Thr

245 250 255

Phe Gly His Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro

260 265 270

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

275 280 285

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

290 295 300

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

305 310 315 320

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

325 330 335

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

340 345 350

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

355 360 365

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

370 375 380

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

385 390 395 400

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

405 410 415

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

420 425 430

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

435 440 445

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

450 455 460

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

465 470 475 480

Leu His Met Gln Ala Leu Pro Pro Arg

485

<210> 583

<211> 489

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 583

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu

20 25 30

Val Lys Pro Ser Glu Thr Leu Ser Leu Asn Cys Thr Val Ser Gly Gly

35 40 45

Ser Ile Ser Tyr Tyr Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly Lys

50 55 60

Gly Leu Glu Trp Ile Gly His Val Ile Tyr Ser Gly Thr Thr Asn Tyr

65 70 75 80

Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys

85 90 95

Asn Gln Phe Ser Leu Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala

100 105 110

Val Tyr Tyr Cys Val Arg Ala Glu Gly Ser Leu Asp Ala Phe Asp Leu

115 120 125

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ile Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Trp Leu

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile Tyr

195 200 205

Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Thr

210 215 220

Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser Asp

225 230 235 240

Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Thr Tyr Ser His Thr

245 250 255

Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro

260 265 270

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

275 280 285

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

290 295 300

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

305 310 315 320

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

325 330 335

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

340 345 350

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

355 360 365

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

370 375 380

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

385 390 395 400

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

405 410 415

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

420 425 430

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

435 440 445

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

450 455 460

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

465 470 475 480

Leu His Met Gln Ala Leu Pro Pro Arg

485

<210> 584

<211> 491

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 584

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val

20 25 30

Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe

35 40 45

Thr Phe Ser Asp Tyr Gly Ile His Trp Val Arg Gln Ala Pro Gly Met

50 55 60

Gly Gln Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Ile Lys Lys

65 70 75 80

Tyr Ser Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Asn Ser

85 90 95

Glu Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Gly Glu Asp Thr

100 105 110

Ala Ile Tyr Tyr Cys Ala Arg Asp Glu Val Gly Thr Phe Gly Ala Phe

115 120 125

Asp Phe Trp Gly Gln Gly Thr Lys Val Thr Val Ser Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

145 150 155 160

Ser Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val

165 170 175

Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn

180 185 190

Asp Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu

195 200 205

Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser

210 215 220

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln

225 230 235 240

Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Tyr Asn Tyr Pro

245 250 255

Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Thr Thr Thr Pro

260 265 270

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

275 280 285

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

290 295 300

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

305 310 315 320

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

325 330 335

Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

340 345 350

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

355 360 365

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser

370 375 380

Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr

385 390 395 400

Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys

405 410 415

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn

420 425 430

Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu

435 440 445

Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly

450 455 460

His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr

465 470 475 480

Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 585

<211> 489

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 585

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu

20 25 30

Val Lys Pro Leu Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly

35 40 45

Ser Ile Ser Ser Asp Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Asn Pro

50 55 60

Gly Lys Gly Leu Glu Trp Ile Gly Tyr Met Tyr Tyr Ser Gly Ser Thr

65 70 75 80

Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr

85 90 95

Ser Lys Asn Gln Phe Ser Leu Lys Leu Arg Ser Val Thr Ala Ala Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Thr Arg Asp Phe Gly Trp Tyr Phe Asp Leu

115 120 125

Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

165 170 175

Ser Ile Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Asp Asn Tyr Leu

180 185 190

Ala Trp Tyr Gln Gln Lys Thr Gly Lys Val Pro Lys Val Leu Ile Tyr

195 200 205

Ala Ala Ser Ala Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

225 230 235 240

Asp Val Ala Thr Tyr Tyr Cys Gln Asn Tyr Asn Ser Gly Pro Arg Thr

245 250 255

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro

260 265 270

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

275 280 285

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

290 295 300

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

305 310 315 320

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

325 330 335

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

340 345 350

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

355 360 365

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

370 375 380

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

385 390 395 400

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

405 410 415

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

420 425 430

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

435 440 445

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

450 455 460

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

465 470 475 480

Leu His Met Gln Ala Leu Pro Pro Arg

485

<210> 586

<211> 489

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 586

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu

20 25 30

Val Lys Pro Ser Gln Ser Leu Ser Leu Thr Cys Ser Val Ser Gly Gly

35 40 45

Ser Val Ser Ser Asp Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro

50 55 60

Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile Tyr Tyr Arg Arg Ile Thr

65 70 75 80

Asp Tyr Asn Pro Ser Leu Lys Ser Arg Val Asn Ile Ser Leu Asp Thr

85 90 95

Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Ala Arg Asp Phe Gly Trp Tyr Phe Asp Leu

115 120 125

Trp Gly Arg Gly Thr Leu Val Ala Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu

180 185 190

Thr Trp Tyr Gln Gln Lys Pro Gly Arg Val Pro Glu Val Leu Ile Tyr

195 200 205

Ala Ala Ser Ala Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

225 230 235 240

Asp Val Ala Thr Tyr Tyr Cys Gln Asn Tyr Asn Ser Ala Pro Arg Thr

245 250 255

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro

260 265 270

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

275 280 285

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

290 295 300

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

305 310 315 320

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

325 330 335

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

340 345 350

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

355 360 365

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

370 375 380

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

385 390 395 400

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

405 410 415

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

420 425 430

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

435 440 445

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

450 455 460

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

465 470 475 480

Leu His Met Gln Ala Leu Pro Pro Arg

485

<210> 587

<211> 498

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 587

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val

20 25 30

Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr

35 40 45

Thr Phe Thr Gly Tyr Tyr Leu His Trp Val Arg Gln Ala Pro Gly Gln

50 55 60

Gly Leu Glu Trp Met Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn

65 70 75 80

Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser

85 90 95

Ile Thr Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ile Asp Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Asp Arg Gly Val Thr Met Ile Val Asp

115 120 125

Gly Met Asp Asp Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

145 150 155 160

Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val

165 170 175

Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu

180 185 190

Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro

195 200 205

Gly Gln Ser Pro Gln Val Leu Ile Leu Leu Gly Ser Asn Arg Ala Ser

210 215 220

Gly Val Pro Asp Arg Val Ser Ala Ser Gly Ser Gly Thr Asp Phe Thr

225 230 235 240

Leu Lys Ile Ser Arg Met Gln Ala Glu Asp Val Gly Ile Tyr Tyr Cys

245 250 255

Met Gln Thr Leu Gln Thr Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu

260 265 270

Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

275 280 285

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

290 295 300

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

305 310 315 320

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

325 330 335

Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu

340 345 350

Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu

355 360 365

Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys

370 375 380

Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln

385 390 395 400

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

405 410 415

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

420 425 430

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

435 440 445

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

450 455 460

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

465 470 475 480

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

485 490 495

Pro Arg

<210> 588

<211> 491

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 588

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Glu Leu Val Glu Ser Gly Gly Gly Met

20 25 30

Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Thr Phe Ser Asp Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Met

50 55 60

Gly Leu Glu Trp Val Thr Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser

85 90 95

Lys Asn Thr Val Phe Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Asp Glu Val Gly Phe Val Gly Ala Phe

115 120 125

Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

145 150 155 160

Ser Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val

165 170 175

Gly Asp Arg Val Ile Ile Thr Cys Arg Ala Ser Gln Gly Ile Asn Ser

180 185 190

His Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu

195 200 205

Ile Tyr Tyr Ala Ser Thr Leu Pro Ser Gly Val Pro Ser Arg Phe Ser

210 215 220

Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Val Thr Ser Leu Gln

225 230 235 240

Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn His Tyr Pro

245 250 255

Ile Thr Phe Gly Gln Gly Thr Arg Leu Asp Ile Asn Thr Thr Thr Pro

260 265 270

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

275 280 285

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

290 295 300

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

305 310 315 320

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

325 330 335

Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

340 345 350

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

355 360 365

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser

370 375 380

Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr

385 390 395 400

Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys

405 410 415

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn

420 425 430

Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu

435 440 445

Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly

450 455 460

His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr

465 470 475 480

Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 589

<211> 489

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 589

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu

20 25 30

Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly

35 40 45

Ser Ile Ser Ser Asp Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro

50 55 60

Gly Lys Gly Leu Glu Trp Ile Gly Tyr Met Tyr Tyr Ser Gly Ile Thr

65 70 75 80

Tyr His Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr

85 90 95

Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser Ser Val Thr Ala Ala Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Ala Arg Asp Phe Gly Trp Tyr Phe Asp Leu

115 120 125

Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr Leu

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr

195 200 205

Ala Ala Ser Thr Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

225 230 235 240

Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Asn Ser Ala Pro Arg Thr

245 250 255

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro

260 265 270

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

275 280 285

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

290 295 300

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

305 310 315 320

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

325 330 335

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

340 345 350

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

355 360 365

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

370 375 380

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

385 390 395 400

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

405 410 415

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

420 425 430

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

435 440 445

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

450 455 460

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

465 470 475 480

Leu His Met Gln Ala Leu Pro Pro Arg

485

<210> 590

<211> 489

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 590

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu

20 25 30

Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly

35 40 45

Ser Ile Ser Ser Asp Ala Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro

50 55 60

Gly Lys Gly Leu Glu Trp Ile Gly Tyr Met Tyr Tyr Ser Gly Ile Thr

65 70 75 80

Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr

85 90 95

Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Ala Arg Asp Phe Gly Trp Tyr Phe Asp Leu

115 120 125

Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr

195 200 205

Ala Ala Ser Thr Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp

225 230 235 240

Asp Phe Ala Ala Tyr Tyr Cys Gln Lys Tyr Asn Ser Ala Pro Arg Thr

245 250 255

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro

260 265 270

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

275 280 285

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

290 295 300

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

305 310 315 320

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

325 330 335

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

340 345 350

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

355 360 365

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

370 375 380

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

385 390 395 400

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

405 410 415

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

420 425 430

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

435 440 445

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

450 455 460

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

465 470 475 480

Leu His Met Gln Ala Leu Pro Pro Arg

485

<210> 591

<211> 491

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 591

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val

20 25 30

Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe

35 40 45

Thr Phe Ser Asp Tyr Gly Ile His Trp Val Arg Gln Ala Pro Gly Met

50 55 60

Gly Gln Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Ile Lys Lys

65 70 75 80

Tyr Ser Asp Ser Val Lys Gly Arg Phe Ile Ile Ser Arg Asp Asn Ser

85 90 95

Glu Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Gly Glu Asp Thr

100 105 110

Ala Ile Tyr Tyr Cys Ala Arg Asp Glu Val Gly Thr Phe Gly Ala Phe

115 120 125

Asp Phe Trp Gly Gln Gly Thr Lys Val Thr Val Ser Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

145 150 155 160

Ser Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val

165 170 175

Gly Asp Arg Val Ser Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser

180 185 190

Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Val Leu Leu

195 200 205

Ile Tyr Val Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser

210 215 220

Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Val Ser Ser Leu Gln

225 230 235 240

Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu His Val Tyr Pro

245 250 255

Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Arg Thr Thr Thr Pro

260 265 270

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

275 280 285

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

290 295 300

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

305 310 315 320

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

325 330 335

Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

340 345 350

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

355 360 365

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser

370 375 380

Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr

385 390 395 400

Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys

405 410 415

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn

420 425 430

Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu

435 440 445

Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly

450 455 460

His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr

465 470 475 480

Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 592

<211> 499

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 592

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Thr Phe Ser Asn Ala Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Gly Arg Ile Lys Ser Lys Thr Gly Gly Gly Thr

65 70 75 80

Thr Asp Tyr Ala Ala Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

85 90 95

Asp Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu

100 105 110

Asp Thr Ala Val Tyr Tyr Cys Thr Ser Leu Ile Val Gly Ala Ile Ser

115 120 125

Leu Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

145 150 155 160

Gly Gly Ser Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val

165 170 175

Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu

180 185 190

Leu Asp Ser Asp Asp Gly Asn Thr Tyr Leu Asp Trp Tyr Leu Gln Lys

195 200 205

Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Thr Leu Ser Tyr Arg Ala

210 215 220

Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

225 230 235 240

Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr

245 250 255

Cys Met Gln Arg Ile Glu Phe Pro Phe Thr Phe Gly Pro Gly Thr Lys

260 265 270

Val Asp Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

275 280 285

Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg

290 295 300

Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys

305 310 315 320

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

325 330 335

Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu

340 345 350

Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln

355 360 365

Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly

370 375 380

Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

385 390 395 400

Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

405 410 415

Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met

420 425 430

Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu

435 440 445

Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys

450 455 460

Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu

465 470 475 480

Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu

485 490 495

Pro Pro Arg

<210> 593

<211> 489

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 593

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Arg Glu Ser Gly Pro Gly Leu

20 25 30

Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Ile Ser Gly Gly

35 40 45

Ser Ile Ser Tyr Tyr Phe Trp Thr Trp Ile Arg Gln Pro Pro Gly Arg

50 55 60

Gly Leu Glu Trp Ile Gly Gln Ile Tyr Tyr Ser Gly Asn Thr Asn Ser

65 70 75 80

Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Ile Asp Thr Ser Lys

85 90 95

Asn Gln Phe Ser Leu Lys Leu Thr Ser Val Thr Val Ala Asp Thr Ala

100 105 110

Val Tyr Tyr Cys Val Arg Ala Glu Gly Ser Leu Asp Ala Phe Asp Ile

115 120 125

Trp Gly Glyn Gly Thr Met Val Ala Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ala Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Ala Ile Thr Cys Arg Ala Ser Gln Thr Ile Ser Thr Trp Leu

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile Tyr

195 200 205

Lys Ala Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro Asp

225 230 235 240

Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Gln Thr Phe Ser His Thr

245 250 255

Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro

260 265 270

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

275 280 285

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

290 295 300

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

305 310 315 320

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

325 330 335

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

340 345 350

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

355 360 365

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

370 375 380

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

385 390 395 400

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

405 410 415

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

420 425 430

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

435 440 445

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

450 455 460

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

465 470 475 480

Leu His Met Gln Ala Leu Pro Pro Arg

485

<210> 594

<211> 493

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 594

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe

35 40 45

Thr Phe Ser Ser Tyr Ser Met Asn Trp Val Arg Gln Phe Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ser Ser Ile Ser Thr Ser Ser Asn Tyr Ile His

65 70 75 80

Tyr Ala Asp Ser Leu Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Ser Leu Tyr Leu Gln Met Ser Ser Leu Arg Val Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Val Arg Asp Lys Gly Thr Thr Leu Thr Asn Trp

115 120 125

Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

145 150 155 160

Gly Gly Ser Asp Met Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala

165 170 175

Ser Val Gly Asp Arg Val Thr Leu Thr Cys Arg Ala Ser Gln Gly Ile

180 185 190

Ser Asn Tyr Leu Ala Trp Phe Gln Leu Lys Pro Gly Lys Val Pro Lys

195 200 205

Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg

210 215 220

Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ala Leu Thr Ile Ser Ser

225 230 235 240

Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Asn Ser

245 250 255

Ala Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Thr Thr

260 265 270

Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln

275 280 285

Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala

290 295 300

Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala

305 310 315 320

Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr

325 330 335

Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln

340 345 350

Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser

355 360 365

Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys

370 375 380

Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln

385 390 395 400

Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu

405 410 415

Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg

420 425 430

Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met

435 440 445

Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly

450 455 460

Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp

465 470 475 480

Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 595

<211> 497

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 595

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val

20 25 30

Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Gly Ala Ser Gly Phe

35 40 45

Thr Phe Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr

65 70 75 80

Tyr Ala Asp Ser Leu Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser

85 90 95

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Asp Gly Tyr Ser Gly Ser Ser Asp Ala

115 120 125

Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly

130 135 140

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

145 150 155 160

Gly Ser Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr

165 170 175

Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Thr Leu Val

180 185 190

His Ser Asn Gly Tyr Asn Tyr Leu Asn Trp Tyr Leu Gln Lys Pro Gly

195 200 205

Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly

210 215 220

Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Ser Asp Phe Thr Leu

225 230 235 240

Lys Ile Ser Arg Met Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met

245 250 255

Gln Ala Ile Gln Thr Pro Tyr Thr Phe Gly Gln Gly Thr Asn Val Glu

260 265 270

Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

275 280 285

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

290 295 300

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

305 310 315 320

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

325 330 335

Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr

340 345 350

Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu

355 360 365

Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu

370 375 380

Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln

385 390 395 400

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu

405 410 415

Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly

420 425 430

Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln

435 440 445

Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu

450 455 460

Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr

465 470 475 480

Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro

485 490 495

Arg

<210> 596

<211> 489

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 596

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu

20 25 30

Val Gln Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly

35 40 45

Ser Ile Ser Tyr Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys

50 55 60

Gly Leu Glu Trp Ile Gly Asn Ile Asn Tyr Met Gly Asn Thr Ile Tyr

65 70 75 80

Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys

85 90 95

Asp Gln Phe Ser Leu Lys Leu Thr Ser Val Ser Ala Ala Asp Thr Ala

100 105 110

Val Tyr Tyr Cys Val Arg Ala Glu Gly Ser Leu Asp Ala Phe Asp Phe

115 120 125

Trp Gly Glyn Gly Thr Leu Val Ala Val Ser Leu Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile Tyr

195 200 205

Lys Ala Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp

225 230 235 240

Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser Cys Thr

245 250 255

Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro

260 265 270

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

275 280 285

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

290 295 300

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

305 310 315 320

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

325 330 335

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

340 345 350

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

355 360 365

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

370 375 380

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

385 390 395 400

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

405 410 415

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

420 425 430

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

435 440 445

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

450 455 460

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

465 470 475 480

Leu His Met Gln Ala Leu Pro Pro Arg

485

<210> 597

<211> 494

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 597

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val

20 25 30

Thr Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr

35 40 45

Ile Phe Thr Gly Tyr Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln

50 55 60

Gly Leu Glu Trp Met Gly Trp Ile Asn Pro Ser Ser Gly Gly Thr Asn

65 70 75 80

Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Ala Arg Asp Thr Ser

85 90 95

Ile Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Asp Arg Lys Arg Glu Tyr Tyr Tyr Asn

115 120 125

Phe Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Thr

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

145 150 155 160

Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser

165 170 175

Ala Ser Val Gly Asp Arg Ile Ile Phe Thr Cys Gln Ala Ser Gln Asp

180 185 190

Ile Asn Asn Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

195 200 205

Lys Leu Leu Ile Tyr Asp Ala Ser Asp Trp Glu Thr Gly Val Pro Ser

210 215 220

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser

225 230 235 240

Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp

245 250 255

His Leu Pro Ile Thr Phe Gly Gln Gly Thr Arg Val Glu Ile Lys Thr

260 265 270

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

275 280 285

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

290 295 300

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

305 310 315 320

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

325 330 335

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

340 345 350

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

355 360 365

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

370 375 380

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn

385 390 395 400

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

405 410 415

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

420 425 430

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

435 440 445

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

450 455 460

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

465 470 475 480

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 598

<211> 494

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 598

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val

20 25 30

Thr Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr

35 40 45

Thr Phe Thr Ser His Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln

50 55 60

Gly Leu Glu Trp Met Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn

65 70 75 80

Tyr Ala Gln Lys Phe Gln Asp Arg Val Thr Met Ala Arg Asp Thr Ser

85 90 95

Ile Ser Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Lys Asp Arg Lys Arg Glu Tyr Tyr Tyr Asn

115 120 125

Phe Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ala

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

145 150 155 160

Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser

165 170 175

Ala Ser Val Gly Asp Arg Val Ile Leu Thr Cys Gln Ala Ser Gln Asp

180 185 190

Ile Ser Asn Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

195 200 205

Lys Leu Leu Ile Tyr Asp Ala Ser Asp Leu Glu Thr Gly Val Pro Ser

210 215 220

Arg Phe Ser Gly Ser Gly Ser Gly Ala Asp Phe Thr Phe Thr Ile Ser

225 230 235 240

Asn Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp

245 250 255

His Leu Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Thr

260 265 270

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

275 280 285

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

290 295 300

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

305 310 315 320

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

325 330 335

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

340 345 350

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

355 360 365

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

370 375 380

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn

385 390 395 400

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

405 410 415

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

420 425 430

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

435 440 445

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

450 455 460

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

465 470 475 480

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 599

<211> 494

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 599

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Phe Gly Val Glu Val

20 25 30

Arg Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe

35 40 45

Thr Phe Thr Ser His Tyr Ile Tyr Trp Val Arg Gln Ala Pro Gly Gln

50 55 60

Gly Leu Glu Trp Met Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys

65 70 75 80

Tyr Ala Gln Lys Phe Gln Asp Arg Val Thr Met Ala Arg Asp Thr Ser

85 90 95

Ile Ser Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr

100 105 110

Ser Val Tyr Tyr Cys Val Lys Asp Arg Lys Arg Glu Tyr Tyr Tyr Asn

115 120 125

Phe Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

145 150 155 160

Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser

165 170 175

Ala Ser Val Gly Asp Arg Val Ile Leu Thr Cys Gln Ala Ser Gln Asp

180 185 190

Ile Ser Asn Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

195 200 205

Lys Leu Leu Ile Tyr Asp Ala Ser Asp Leu Glu Thr Gly Val Pro Ser

210 215 220

Arg Phe Ser Gly Ser Gly Ser Gly Ala Asp Phe Thr Phe Thr Ile Ser

225 230 235 240

Asn Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp

245 250 255

His Leu Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Thr

260 265 270

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

275 280 285

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

290 295 300

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

305 310 315 320

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

325 330 335

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

340 345 350

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

355 360 365

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

370 375 380

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn

385 390 395 400

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

405 410 415

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

420 425 430

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

435 440 445

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

450 455 460

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

465 470 475 480

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 600

<211> 490

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 600

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Met Leu Glu Ser Gly Gly Gly Leu

20 25 30

Ile Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Lys Thr Ser Gly Phe

35 40 45

Thr Leu Ser Ile Tyr Ala Ile His Trp Val Arg Gln Ala Pro Gly Arg

50 55 60

Gly Leu Glu Trp Val Ser Ser Phe Gly Gly Arg Gly Ser Ser Thr Tyr

65 70 75 80

Phe Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Ala Ser

85 90 95

Glu Asn Ser Leu Tyr Leu His Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Lys Glu Lys Asp Trp Gly Arg Gly Phe Asp

115 120 125

Tyr Trp Gly Glyn Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

130 135 140

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

145 150 155 160

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

165 170 175

Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr

180 185 190

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

195 200 205

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

210 215 220

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

225 230 235 240

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Tyr

245 250 255

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala

260 265 270

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

275 280 285

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

290 295 300

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

305 310 315 320

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

325 330 335

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

340 345 350

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

355 360 365

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

370 375 380

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn

385 390 395 400

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

405 410 415

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

420 425 430

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

435 440 445

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

450 455 460

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

465 470 475 480

Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 601

<211> 498

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic sequence description: synthetic

design

<400> 601

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Thr Phe Ser Asn Tyr Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ser Ser Ile Ser Ser Ser Thr Ile Tyr Ile Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Lys Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Asp Ile Gly Trp Glu Val Phe Thr Leu

115 120 125

Gly Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

145 150 155 160

Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val

165 170 175

Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu

180 185 190

Leu Tyr Ser Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro

195 200 205

Gly Gln Ser Pro Gln Leu Leu Ile Phe Leu Asn Ser Asn Arg Ala Ser

210 215 220

Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr

225 230 235 240

Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys

245 250 255

Met Gln Ala Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val

260 265 270

Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

275 280 285

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

290 295 300

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

305 310 315 320

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

325 330 335

Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu

340 345 350

Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu

355 360 365

Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys

370 375 380

Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln

385 390 395 400

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

405 410 415

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

420 425 430

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

435 440 445

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

450 455 460

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

465 470 475 480

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

485 490 495

Pro Arg

<210> 602

<211> 20

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 602

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

1.5 10 15

Gly Gly Gly Ser

20

<210> 603

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 603

Cys Gln Phe Asp Leu Ser Thr Arg Arg Leu Lys Cys

1.5 10

<210> 604

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 604

Cys Gln Tyr Asn Leu Ser Ser Arg Ala Leu Lys Cys

1.5 10

<210> 605

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 605

Cys Val Trp Gln Arg Trp Gln Lys Ser Tyr Val Cys

1.5 10

<210> 606

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 606

Cys Met Trp Asp Arg Phe Ser Arg Trp Tyr Lys Cys

1.5 10

<210> 607

<211> 25

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 607

Ser Phe Val Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp

1.5 10 15

Lys Leu Ala Ala Phe Pro Glu Asp Arg

20 25

<210> 608

<211> 19

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 608

Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala Gln

1.5 10 15

Ile Lys Glu

<210> 609

<211> 16

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 609

Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser

1.5 10 15

<210> 610

<211> 12

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 610

Gly Gln Asn Asp Thr Ser Gln Thr Ser Ser Pro Ser

1.5 10

<210> 611

<211> 21

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 611

Met Gly Thr Ser Leu Leu Cys Trp Met Ala Leu Cys Leu Leu Gly Ala

1.5 10 15

Asp His Ala Asp Ala

20

<210> 612

<211> 18

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 612

Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr

1.5 10 15

Lys Gly

<210> 613

<211> 25

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<220>

<221> OTHER CHARACTERISTICS

<222> (1)..(25)

<223> This sequence can cover 1-5 repeated

links "Gly Gly Gly Gly Ser"

<400> 613

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

1.5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Ser

20 25

<210> 614

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 614

Ser Gly Gly Gly Gly

15

<210> 615

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 615

Gly Gly Gly Gly Ser

15

<210> 616

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 616

Ser Gly Gly Gly Gly Ser

15

<210> 617

<211> 25

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 617

Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly

1.5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Ser

20 25

<210> 618

<211> 55

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 618

Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys

1.5 10 15

Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn

20 25 30

Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro

35 40 45

Tyr Ser Asn Pro Ser Leu Cys

50 55

<210> 619

<211> 489

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 619

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu

20 25 30

Val Lys Pro Thr Glu Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe

35 40 45

Ser Leu Ser Asn Ala Arg Met Gly Val Thr Trp Ile Arg Gln Pro Pro

50 55 60

Gly Lys Ala Leu Glu Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys

65 70 75 80

Ser Tyr Ser Thr Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr

85 90 95

Ser Lys Thr Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp

100 105 110

Thr Ala Thr Tyr Tyr Cys Ala Arg Ile Arg Asp Tyr Tyr Asp Ile Ser

115 120 125

Ser Tyr Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Ser Val Ser Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ala Met Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu

180 185 190

Ala Trp Phe Gln Gln Lys Pro Gly Lys Val Pro Lys Arg Leu Ile Tyr

195 200 205

Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Leu Pro Glu

225 230 235 240

Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Leu Asn Ser Phe Pro Phe Thr

245 250 255

Phe Gly Gly Gly Thr Lys Val Glu Ile Asn Thr Thr Thr Pro Ala Pro

260 265 270

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

275 280 285

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

290 295 300

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

305 310 315 320

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

325 330 335

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

340 345 350

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

355 360 365

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

370 375 380

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

385 390 395 400

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

405 410 415

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

420 425 430

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

435 440 445

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

450 455 460

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

465 470 475 480

Leu His Met Gln Ala Leu Pro Pro Arg

485

<210> 620

<211> 526

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 620

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu

20 25 30

Val Lys Pro Thr Glu Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe

35 40 45

Ser Leu Ser Asn Ala Arg Met Gly Val Thr Trp Ile Arg Gln Pro Pro

50 55 60

Gly Lys Ala Leu Glu Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys

65 70 75 80

Ser Tyr Ser Thr Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr

85 90 95

Ser Lys Thr Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp

100 105 110

Thr Ala Thr Tyr Tyr Cys Ala Arg Ile Arg Asp Tyr Tyr Asp Ile Ser

115 120 125

Ser Tyr Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Ser Val Ser Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ala Met Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu

180 185 190

Ala Trp Phe Gln Gln Lys Pro Gly Lys Val Pro Lys Arg Leu Ile Tyr

195 200 205

Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Leu Pro Glu

225 230 235 240

Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Leu Asn Ser Phe Pro Phe Thr

245 250 255

Phe Gly Gly Gly Thr Lys Val Glu Ile Asn Gly Ser Gly Gly Gly Gly

260 265 270

Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser

275 280 285

Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Thr

290 295 300

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

305 310 315 320

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

325 330 335

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

340 345 350

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

355 360 365

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

370 375 380

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

385 390 395 400

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

405 410 415

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn

420 425 430

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

435 440 445

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

450 455 460

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

465 470 475 480

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

485 490 495

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

500 505 510

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520 525

<210> 621

<211> 536

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 621

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val

20 25 30

Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr

35 40 45

Gly Phe Thr Ser Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys

50 55 60

Gly Leu Glu Trp Met Gly Ile Ile His Pro Asp Asp Ser Asp Thr Lys

65 70 75 80

Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser

85 90 95

Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Ser Ser Tyr Leu Arg Gly Leu Trp Gly Gly

115 120 125

Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

145 150 155 160

Gly Gly Ser Glu Leu Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser

165 170 175

Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser

180 185 190

Asn Ile Gly Ser Asn Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr

195 200 205

Ala Pro Lys Leu Leu Ile Tyr Gly Asp Tyr Gln Arg Pro Ser Gly Val

210 215 220

Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala

225 230 235 240

Ile Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr

245 250 255

Arg Asp Asp Ser Leu Ser Gly Ser Val Val Phe Gly Thr Gly Thr Lys

260 265 270

Leu Thr Val Leu Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn

275 280 285

Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

290 295 300

Ser Leu Cys Ser Gly Gly Gly Gly Ser Thr Thr Thr Pro Ala Pro Arg

305 310 315 320

Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg

325 330 335

Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly

340 345 350

Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr

355 360 365

Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg

370 375 380

Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro

385 390 395 400

Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu

405 410 415

Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala

420 425 430

Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu

435 440 445

Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly

450 455 460

Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu

465 470 475 480

Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser

485 490 495

Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly

500 505 510

Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu

515 520 525

His Met Gln Ala Leu Pro Pro Arg

530 535

<210> 622

<211> 526

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 622

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu

20 25 30

Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly

35 40 45

Ser Ile Ser Tyr Tyr Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly Lys

50 55 60

Gly Leu Glu Trp Ile Gly His Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr

65 70 75 80

Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Ile Asp Thr Ser Lys

85 90 95

Asn Leu Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala

100 105 110

Val Tyr Tyr Cys Ala Arg Ala Glu Gly Ser Leu Asp Ala Phe Asp Phe

115 120 125

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Thr Trp Leu

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile Tyr

195 200 205

Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Glu Phe Ile Leu Thr Ile Asn Ser Leu Gln Pro Asp

225 230 235 240

Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Tyr Lys Ser Tyr Ser His Thr

245 250 255

Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Ser Gly Gly Gly Gly

260 265 270

Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser

275 280 285

Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Thr

290 295 300

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

305 310 315 320

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

325 330 335

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

340 345 350

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

355 360 365

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

370 375 380

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

385 390 395 400

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

405 410 415

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn

420 425 430

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

435 440 445

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

450 455 460

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

465 470 475 480

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

485 490 495

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

500 505 510

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520 525

<210> 623

<211> 526

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 623

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu

20 25 30

Val Lys Pro Ser Glu Thr Leu Ser Leu Asn Cys Thr Val Ser Gly Gly

35 40 45

Ser Ile Ser Tyr Tyr Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly Lys

50 55 60

Gly Leu Glu Trp Ile Gly His Val Ile Tyr Ser Gly Thr Thr Asn Tyr

65 70 75 80

Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys

85 90 95

Asn Gln Phe Ser Leu Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala

100 105 110

Val Tyr Tyr Cys Val Arg Ala Glu Gly Ser Leu Asp Ala Phe Asp Leu

115 120 125

Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ile Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Trp Leu

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile Tyr

195 200 205

Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Thr

210 215 220

Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser Asp

225 230 235 240

Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Thr Tyr Ser His Thr

245 250 255

Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Ser Gly Gly Gly Gly

260 265 270

Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser

275 280 285

Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Thr

290 295 300

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

305 310 315 320

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

325 330 335

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

340 345 350

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

355 360 365

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

370 375 380

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

385 390 395 400

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

405 410 415

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn

420 425 430

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

435 440 445

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

450 455 460

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

465 470 475 480

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

485 490 495

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

500 505 510

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520 525

<210> 624

<211> 526

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 624

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu

20 25 30

Val Lys Pro Leu Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly

35 40 45

Ser Ile Ser Ser Asp Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Asn Pro

50 55 60

Gly Lys Gly Leu Glu Trp Ile Gly Tyr Met Tyr Tyr Ser Gly Ser Thr

65 70 75 80

Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr

85 90 95

Ser Lys Asn Gln Phe Ser Leu Lys Leu Arg Ser Val Thr Ala Ala Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Thr Arg Asp Phe Gly Trp Tyr Phe Asp Leu

115 120 125

Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

165 170 175

Ser Ile Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Asp Asn Tyr Leu

180 185 190

Ala Trp Tyr Gln Gln Lys Thr Gly Lys Val Pro Lys Val Leu Ile Tyr

195 200 205

Ala Ala Ser Ala Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

225 230 235 240

Asp Val Ala Thr Tyr Tyr Cys Gln Asn Tyr Asn Ser Gly Pro Arg Thr

245 250 255

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Ser Gly Gly Gly Gly

260 265 270

Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser

275 280 285

Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Thr

290 295 300

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

305 310 315 320

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

325 330 335

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

340 345 350

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

355 360 365

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

370 375 380

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

385 390 395 400

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

405 410 415

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn

420 425 430

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

435 440 445

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

450 455 460

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

465 470 475 480

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

485 490 495

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

500 505 510

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520 525

<210> 625

<211> 526

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 625

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu

20 25 30

Val Lys Pro Ser Gln Ser Leu Ser Leu Thr Cys Ser Val Ser Gly Gly

35 40 45

Ser Val Ser Ser Asp Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro

50 55 60

Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile Tyr Tyr Arg Arg Ile Thr

65 70 75 80

Asp Tyr Asn Pro Ser Leu Lys Ser Arg Val Asn Ile Ser Leu Asp Thr

85 90 95

Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Ala Arg Asp Phe Gly Trp Tyr Phe Asp Leu

115 120 125

Trp Gly Arg Gly Thr Leu Val Ala Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu

180 185 190

Thr Trp Tyr Gln Gln Lys Pro Gly Arg Val Pro Glu Val Leu Ile Tyr

195 200 205

Ala Ala Ser Ala Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

225 230 235 240

Asp Val Ala Thr Tyr Tyr Cys Gln Asn Tyr Asn Ser Ala Pro Arg Thr

245 250 255

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Ser Gly Gly Gly Gly

260 265 270

Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser

275 280 285

Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Thr

290 295 300

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

305 310 315 320

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

325 330 335

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

340 345 350

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

355 360 365

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

370 375 380

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

385 390 395 400

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

405 410 415

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn

420 425 430

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

435 440 445

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

450 455 460

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

465 470 475 480

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

485 490 495

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

500 505 510

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520 525

<210> 626

<211> 528

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 626

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Glu Leu Val Glu Ser Gly Gly Gly Met

20 25 30

Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Thr Phe Ser Asp Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Met

50 55 60

Gly Leu Glu Trp Val Thr Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser

85 90 95

Lys Asn Thr Val Phe Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Asp Glu Val Gly Phe Val Gly Ala Phe

115 120 125

Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

145 150 155 160

Ser Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val

165 170 175

Gly Asp Arg Val Ile Ile Thr Cys Arg Ala Ser Gln Gly Ile Asn Ser

180 185 190

His Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu

195 200 205

Ile Tyr Tyr Ala Ser Thr Leu Pro Ser Gly Val Pro Ser Arg Phe Ser

210 215 220

Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Val Thr Ser Leu Gln

225 230 235 240

Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn His Tyr Pro

245 250 255

Ile Thr Phe Gly Gly Gly Thr Arg Leu Asp Ile Asn Gly Ser Gly Gly

260 265 270

Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly

275 280 285

Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly

290 295 300

Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile

305 310 315 320

Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala

325 330 335

Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr

340 345 350

Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu

355 360 365

Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile

370 375 380

Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp

385 390 395 400

Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

405 410 415

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly

420 425 430

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

435 440 445

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

450 455 460

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

465 470 475 480

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

485 490 495

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

500 505 510

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520 525

<210> 627

<211> 526

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 627

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu

20 25 30

Val Gln Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly

35 40 45

Ser Ile Ser Tyr Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys

50 55 60

Gly Leu Glu Trp Ile Gly Asn Ile Asn Tyr Met Gly Asn Thr Ile Tyr

65 70 75 80

Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys

85 90 95

Asp Gln Phe Ser Leu Lys Leu Thr Ser Val Ser Ala Ala Asp Thr Ala

100 105 110

Val Tyr Tyr Cys Val Arg Ala Glu Gly Ser Leu Asp Ala Phe Asp Phe

115 120 125

Trp Gly Glyn Gly Thr Leu Val Ala Val Ser Leu Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

145 150 155 160

Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp

165 170 175

Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu

180 185 190

Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile Tyr

195 200 205

Lys Ala Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp

225 230 235 240

Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser Cys Thr

245 250 255

Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Ser Gly Gly Gly Gly

260 265 270

Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser

275 280 285

Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Thr

290 295 300

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

305 310 315 320

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

325 330 335

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

340 345 350

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

355 360 365

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

370 375 380

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

385 390 395 400

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

405 410 415

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn

420 425 430

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

435 440 445

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

450 455 460

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

465 470 475 480

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

485 490 495

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

500 505 510

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520 525

<210> 628

<211> 569

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 628

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glyn Val

35 40 45

Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu Thr Leu

50 55 60

Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn Ala Arg Met

65 70 75 80

Gly Val Thr Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu

85 90 95

Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser Leu Lys

100 105 110

Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Thr Gln Val Val Leu

115 120 125

Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala

130 135 140

Arg Ile Arg Asp Tyr Tyr Asp Ile Ser Ser Tyr Tyr Asp Tyr Trp Gly

145 150 155 160

Gly Gly Thr Leu Val Ser Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

165 170 175

Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro

180 185 190

Ser Ala Met Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg

195 200 205

Ala Ser Gln Asp Ile Ser Asn Tyr Leu Ala Trp Phe Gln Gln Lys Pro

210 215 220

Gly Lys Val Pro Lys Arg Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser

225 230 235 240

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr

245 250 255

Leu Thr Ile Ser Ser Leu Leu Pro Glu Asp Phe Ala Thr Tyr Tyr Cys

260 265 270

Leu Gln Leu Asn Ser Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Val

275 280 285

Glu Ile Asn Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

290 295 300

Ser Leu Cys Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr

305 310 315 320

Phe Ser Asn Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr

325 330 335

Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys Thr Thr Thr Pro Ala Pro

340 345 350

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

355 360 365

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

370 375 380

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

385 390 395 400

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

405 410 415

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

420 425 430

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

435 440 445

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

450 455 460

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

465 470 475 480

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

485 490 495

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

500 505 510

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

515 520 525

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

530 535 540

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

545 550 555 560

Leu His Met Gln Ala Leu Pro Pro Arg

565

<210> 629

<211> 579

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 629

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

35 40 45

Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu

50 55 60

Lys Ile Ser Cys Lys Gly Ser Gly Tyr Gly Phe Thr Ser Tyr Trp Ile

65 70 75 80

Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met Gly Ile

85 90 95

Ile His Pro Asp Asp Ser Asp Thr Lys Tyr Ser Pro Ser Phe Gln Gly

100 105 110

Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln

115 120 125

Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Ser

130 135 140

Ser Tyr Leu Arg Gly Leu Trp Gly Gly Tyr Phe Asp Tyr Trp Gly Gln

145 150 155 160

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

165 170 175

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Leu Gln Ser

180 185 190

Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln Arg Val

195 200 205

Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val

210 215 220

Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr

225 230 235 240

Gly Asp Tyr Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser

245 250 255

Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu

260 265 270

Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Arg Asp Asp Ser Leu Ser Gly

275 280 285

Ser Val Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu Gly Ser Gly

290 295 300

Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly

305 310 315 320

Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr

325 330 335

Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr Ser Asn

340 345 350

Pro Ser Leu Cys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

355 360 365

Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg

370 375 380

Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys

385 390 395 400

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

405 410 415

Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu

420 425 430

Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln

435 440 445

Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly

450 455 460

Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

465 470 475 480

Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

485 490 495

Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met

500 505 510

Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu

515 520 525

Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys

530 535 540

Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu

545 550 555 560

Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu

565 570 575

Pro Pro Arg

<210> 630

<211> 569

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 630

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glyn Val

35 40 45

Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu

50 55 60

Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Tyr Tyr Tyr Trp

65 70 75 80

Thr Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly His

85 90 95

Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg

100 105 110

Val Thr Ile Ser Ile Asp Thr Ser Lys Asn Leu Phe Ser Leu Lys Leu

115 120 125

Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala

130 135 140

Glu Gly Ser Leu Asp Ala Phe Asp Phe Trp Gly Gln Gly Thr Met Val

145 150 155 160

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

165 170 175

Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro

180 185 190

Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg

195 200 205

Ala Ser Gln Ser Ile Ser Thr Trp Leu Ala Trp Tyr Gln Gln Lys Pro

210 215 220

Gly Lys Ala Pro Lys Val Leu Ile Tyr Lys Ala Ser Ser Leu Glu Ser

225 230 235 240

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Ile

245 250 255

Leu Thr Ile Asn Ser Leu Gln Pro Asp Asp Phe Ala Ser Tyr Tyr Cys

260 265 270

Gln Gln Tyr Lys Ser Tyr Ser His Thr Phe Gly Gln Gly Thr Lys Leu

275 280 285

Glu Ile Lys Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

290 295 300

Ser Leu Cys Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr

305 310 315 320

Phe Ser Asn Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr

325 330 335

Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys Thr Thr Thr Pro Ala Pro

340 345 350

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

355 360 365

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

370 375 380

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

385 390 395 400

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

405 410 415

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

420 425 430

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

435 440 445

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

450 455 460

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

465 470 475 480

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

485 490 495

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

500 505 510

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

515 520 525

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

530 535 540

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

545 550 555 560

Leu His Met Gln Ala Leu Pro Pro Arg

565

<210> 631

<211> 569

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 631

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glyn Val

35 40 45

Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu

50 55 60

Ser Leu Asn Cys Thr Val Ser Gly Gly Ser Ile Ser Tyr Tyr Tyr Trp

65 70 75 80

Thr Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly His

85 90 95

Val Ile Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg

100 105 110

Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu

115 120 125

Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Val Arg Ala

130 135 140

Glu Gly Ser Leu Asp Ala Phe Asp Leu Trp Gly Gln Gly Thr Met Val

145 150 155 160

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

165 170 175

Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro

180 185 190

Ser Ile Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg

195 200 205

Ala Ser Gln Ser Val Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro

210 215 220

Gly Lys Ala Pro Lys Val Leu Ile Tyr Lys Ala Ser Ser Leu Glu Ser

225 230 235 240

Gly Val Pro Ser Arg Phe Ser Gly Thr Gly Ser Gly Thr Glu Phe Thr

245 250 255

Leu Thr Ile Ser Ser Leu Gln Ser Asp Asp Phe Ala Thr Tyr Tyr Cys

260 265 270

Gln Gln Tyr Asn Thr Tyr Ser His Thr Phe Gly Gln Gly Thr Lys Leu

275 280 285

Glu Ile Lys Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

290 295 300

Ser Leu Cys Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr

305 310 315 320

Phe Ser Asn Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr

325 330 335

Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys Thr Thr Thr Pro Ala Pro

340 345 350

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

355 360 365

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

370 375 380

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

385 390 395 400

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

405 410 415

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

420 425 430

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

435 440 445

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

450 455 460

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

465 470 475 480

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

485 490 495

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

500 505 510

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

515 520 525

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

530 535 540

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

545 550 555 560

Leu His Met Gln Ala Leu Pro Pro Arg

565

<210> 632

<211> 569

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 632

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glyn Val

35 40 45

Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Leu Gln Thr Leu

50 55 60

Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asp Gly Tyr

65 70 75 80

Tyr Trp Ser Trp Ile Arg Gln Asn Pro Gly Lys Gly Leu Glu Trp Ile

85 90 95

Gly Tyr Met Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys

100 105 110

Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu

115 120 125

Lys Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Thr

130 135 140

Arg Asp Phe Gly Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val

145 150 155 160

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

165 170 175

Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro

180 185 190

Ser Ser Leu Ser Ala Ser Val Gly Asp Ser Ile Thr Ile Thr Cys Arg

195 200 205

Ala Ser Gln Asp Ile Asp Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Thr

210 215 220

Gly Lys Val Pro Lys Val Leu Ile Tyr Ala Ala Ser Ala Leu Gln Ser

225 230 235 240

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr

245 250 255

Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys

260 265 270

Gln Asn Tyr Asn Ser Gly Pro Arg Thr Phe Gly Gln Gly Thr Lys Val

275 280 285

Glu Ile Lys Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

290 295 300

Ser Leu Cys Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr

305 310 315 320

Phe Ser Asn Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr

325 330 335

Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys Thr Thr Thr Pro Ala Pro

340 345 350

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

355 360 365

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

370 375 380

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

385 390 395 400

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

405 410 415

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

420 425 430

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

435 440 445

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

450 455 460

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

465 470 475 480

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

485 490 495

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

500 505 510

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

515 520 525

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

530 535 540

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

545 550 555 560

Leu His Met Gln Ala Leu Pro Pro Arg

565

<210> 633

<211> 569

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 633

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glyn Val

35 40 45

Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Ser Leu

50 55 60

Ser Leu Thr Cys Ser Val Ser Gly Gly Ser Val Ser Ser Asp Gly Tyr

65 70 75 80

Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp Ile

85 90 95

Gly Tyr Ile Tyr Tyr Arg Arg Ile Thr Asp Tyr Asn Pro Ser Leu Lys

100 105 110

Ser Arg Val Asn Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu

115 120 125

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

130 135 140

Arg Asp Phe Gly Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val

145 150 155 160

Ala Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

165 170 175

Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro

180 185 190

Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg

195 200 205

Ala Ser Gln Asp Ile Ser Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro

210 215 220

Gly Arg Val Pro Glu Val Leu Ile Tyr Ala Ala Ser Ala Leu Gln Ser

225 230 235 240

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr

245 250 255

Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys

260 265 270

Gln Asn Tyr Asn Ser Ala Pro Arg Thr Phe Gly Gln Gly Thr Lys Val

275 280 285

Glu Ile Lys Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

290 295 300

Ser Leu Cys Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr

305 310 315 320

Phe Ser Asn Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr

325 330 335

Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys Thr Thr Thr Pro Ala Pro

340 345 350

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

355 360 365

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

370 375 380

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

385 390 395 400

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

405 410 415

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

420 425 430

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

435 440 445

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

450 455 460

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

465 470 475 480

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

485 490 495

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

500 505 510

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

515 520 525

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

530 535 540

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

545 550 555 560

Leu His Met Gln Ala Leu Pro Pro Arg

565

<210> 634

<211> 571

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 634

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

35 40 45

Glu Leu Val Glu Ser Gly Gly Gly Met Val Gln Pro Gly Arg Ser Leu

50 55 60

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Gly Met

65 70 75 80

His Trp Val Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val Thr Val

85 90 95

Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly

100 105 110

Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Phe Leu Gln

115 120 125

Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg

130 135 140

Asp Glu Val Gly Phe Val Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr

145 150 155 160

Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

165 170 175

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln

180 185 190

Ser Pro Ser Phe Leu Ser Ala Ser Val Gly Asp Arg Val Ile Ile Thr

195 200 205

Cys Arg Ala Ser Gln Gly Ile Asn Ser His Leu Ala Trp Tyr Gln Gln

210 215 220

Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Thr Leu

225 230 235 240

Pro Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu

245 250 255

Phe Thr Leu Thr Val Thr Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr

260 265 270

Tyr Cys Gln Gln Leu Asn His Tyr Pro Ile Thr Phe Gly Gln Gly Thr

275 280 285

Arg Leu Asp Ile Asn Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser

290 295 300

Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln

305 310 315 320

Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr

325 330 335

Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys Thr Thr Thr Pro

340 345 350

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

355 360 365

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

370 375 380

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

385 390 395 400

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

405 410 415

Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

420 425 430

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

435 440 445

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser

450 455 460

Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr

465 470 475 480

Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys

485 490 495

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn

500 505 510

Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu

515 520 525

Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly

530 535 540

His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr

545 550 555 560

Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

565 570

<210> 635

<211> 569

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 635

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glyn Val

35 40 45

Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Gln Pro Ser Glu Thr Leu

50 55 60

Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Tyr Tyr Tyr Trp

65 70 75 80

Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly Asn

85 90 95

Ile Asn Tyr Met Gly Asn Thr Ile Tyr Asn Pro Ser Leu Lys Ser Arg

100 105 110

Val Thr Ile Ser Val Asp Thr Ser Lys Asp Gln Phe Ser Leu Lys Leu

115 120 125

Thr Ser Val Ser Ala Ala Asp Thr Ala Val Tyr Tyr Cys Val Arg Ala

130 135 140

Glu Gly Ser Leu Asp Ala Phe Asp Phe Trp Gly Gln Gly Thr Leu Val

145 150 155 160

Ala Val Ser Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

165 170 175

Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro

180 185 190

Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg

195 200 205

Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro

210 215 220

Gly Lys Ala Pro Lys Val Leu Ile Tyr Lys Ala Ser Asn Leu Glu Ser

225 230 235 240

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr

245 250 255

Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys

260 265 270

Gln Gln Tyr Asn Ser Tyr Ser Cys Thr Phe Gly Gln Gly Thr Lys Leu

275 280 285

Glu Ile Lys Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

290 295 300

Ser Leu Cys Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr

305 310 315 320

Phe Ser Asn Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr

325 330 335

Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys Thr Thr Thr Pro Ala Pro

340 345 350

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

355 360 365

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

370 375 380

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

385 390 395 400

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

405 410 415

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

420 425 430

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

435 440 445

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

450 455 460

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

465 470 475 480

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

485 490 495

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

500 505 510

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

515 520 525

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

530 535 540

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

545 550 555 560

Leu His Met Gln Ala Leu Pro Pro Arg

565

<210> 636

<211> 527

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 636

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Gln Val Thr Leu Lys Glu Ser Gly

35 40 45

Pro Val Leu Val Lys Pro Thr Glu Thr Leu Thr Leu Thr Cys Thr Val

50 55 60

Ser Gly Phe Ser Leu Ser Asn Ala Arg Met Gly Val Thr Trp Ile Arg

65 70 75 80

Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu Ala His Ile Phe Ser Asn

85 90 95

Asp Glu Lys Ser Tyr Ser Thr Ser Leu Lys Ser Arg Leu Thr Ile Ser

100 105 110

Lys Asp Thr Ser Lys Thr Gln Val Val Leu Thr Met Thr Asn Met Asp

115 120 125

Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala Arg Ile Arg Asp Tyr Tyr

130 135 140

Asp Ile Ser Ser Tyr Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Ser

145 150 155 160

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

165 170 175

Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ala Met Ser Ala Ser

180 185 190

Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser

195 200 205

Asn Tyr Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Val Pro Lys Arg

210 215 220

Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe

225 230 235 240

Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu

245 250 255

Leu Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Leu Asn Ser Phe

260 265 270

Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Asn Gly Gly Gly

275 280 285

Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Gly Gly Gly Gly Ser

290 295 300

Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala

305 310 315 320

Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly

325 330 335

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile

340 345 350

Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val

355 360 365

Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe

370 375 380

Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly

385 390 395 400

Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg

405 410 415

Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln

420 425 430

Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp

435 440 445

Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro

450 455 460

Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp

465 470 475 480

Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg

485 490 495

Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr

500 505 510

Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520 525

<210> 637

<211> 537

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 637

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln Ser Gly

35 40 45

Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly

50 55 60

Ser Gly Tyr Gly Phe Thr Ser Tyr Trp Ile Gly Trp Val Arg Gln Met

65 70 75 80

Pro Gly Lys Gly Leu Glu Trp Met Gly Ile Ile His Pro Asp Asp Ser

85 90 95

Asp Thr Lys Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala

100 105 110

Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala

115 120 125

Ser Asp Thr Ala Met Tyr Tyr Cys Ala Ser Ser Tyr Leu Arg Gly Leu

130 135 140

Trp Gly Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val

145 150 155 160

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

165 170 175

Ser Gly Gly Gly Gly Ser Glu Leu Gln Ser Val Leu Thr Gln Pro Pro

180 185 190

Ser Ala Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly

195 200 205

Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Asn Trp Tyr Gln Gln Leu

210 215 220

Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Gly Asp Tyr Gln Arg Pro

225 230 235 240

Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala

245 250 255

Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr

260 265 270

Cys Ala Thr Arg Asp Asp Ser Leu Ser Gly Ser Val Val Phe Gly Thr

275 280 285

Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Cys Pro Tyr Ser

290 295 300

Asn Pro Ser Leu Cys Gly Gly Gly Gly Ser Thr Thr Thr Pro Ala Pro

305 310 315 320

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

325 330 335

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

340 345 350

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

355 360 365

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

370 375 380

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

385 390 395 400

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

405 410 415

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

420 425 430

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

435 440 445

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

450 455 460

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

465 470 475 480

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

485 490 495

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

500 505 510

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

515 520 525

Leu His Met Gln Ala Leu Pro Pro Arg

530 535

<210> 638

<211> 527

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 638

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly

35 40 45

Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val

50 55 60

Ser Gly Gly Ser Ile Ser Tyr Tyr Tyr Trp Thr Trp Ile Arg Gln Pro

65 70 75 80

Pro Gly Lys Gly Leu Glu Trp Ile Gly His Ile Tyr Tyr Ser Gly Ser

85 90 95

Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Ile Asp

100 105 110

Thr Ser Lys Asn Leu Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala

115 120 125

Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala Glu Gly Ser Leu Asp Ala

130 135 140

Phe Asp Phe Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly

145 150 155 160

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

165 170 175

Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser

180 185 190

Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser

195 200 205

Thr Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val

210 215 220

Leu Ile Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe

225 230 235 240

Ser Gly Ser Gly Ser Gly Thr Glu Phe Ile Leu Thr Ile Asn Ser Leu

245 250 255

Gln Pro Asp Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Tyr Lys Ser Tyr

260 265 270

Ser His Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly

275 280 285

Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Gly Gly Gly Gly Ser

290 295 300

Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala

305 310 315 320

Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly

325 330 335

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile

340 345 350

Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val

355 360 365

Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe

370 375 380

Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly

385 390 395 400

Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg

405 410 415

Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln

420 425 430

Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp

435 440 445

Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro

450 455 460

Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp

465 470 475 480

Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg

485 490 495

Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr

500 505 510

Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520 525

<210> 639

<211> 527

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 639

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly

35 40 45

Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Asn Cys Thr Val

50 55 60

Ser Gly Gly Ser Ile Ser Tyr Tyr Tyr Trp Thr Trp Ile Arg Gln Pro

65 70 75 80

Pro Gly Lys Gly Leu Glu Trp Ile Gly His Val Ile Tyr Ser Gly Thr

85 90 95

Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp

100 105 110

Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Asn Ser Val Thr Ala Ala

115 120 125

Asp Thr Ala Val Tyr Tyr Cys Val Arg Ala Glu Gly Ser Leu Asp Ala

130 135 140

Phe Asp Leu Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly

145 150 155 160

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

165 170 175

Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ile Leu Ser Ala Ser

180 185 190

Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser

195 200 205

Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val

210 215 220

Leu Ile Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe

225 230 235 240

Ser Gly Thr Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu

245 250 255

Gln Ser Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Thr Tyr

260 265 270

Ser His Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly

275 280 285

Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Gly Gly Gly Gly Ser

290 295 300

Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala

305 310 315 320

Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly

325 330 335

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile

340 345 350

Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val

355 360 365

Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe

370 375 380

Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly

385 390 395 400

Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg

405 410 415

Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln

420 425 430

Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp

435 440 445

Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro

450 455 460

Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp

465 470 475 480

Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg

485 490 495

Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr

500 505 510

Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520 525

<210> 640

<211> 527

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 640

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly

35 40 45

Pro Gly Leu Val Lys Pro Leu Gln Thr Leu Ser Leu Thr Cys Thr Val

50 55 60

Ser Gly Gly Ser Ile Ser Ser Asp Gly Tyr Tyr Trp Ser Trp Ile Arg

65 70 75 80

Gln Asn Pro Gly Lys Gly Leu Glu Trp Ile Gly Tyr Met Tyr Tyr Ser

85 90 95

Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser

100 105 110

Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Arg Ser Val Thr

115 120 125

Ala Ala Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Phe Gly Trp Tyr

130 135 140

Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Gly Gly

145 150 155 160

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

165 170 175

Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser

180 185 190

Val Gly Asp Ser Ile Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Asp

195 200 205

Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Thr Gly Lys Val Pro Lys Val

210 215 220

Leu Ile Tyr Ala Ala Ser Ala Leu Gln Ser Gly Val Pro Ser Arg Phe

225 230 235 240

Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu

245 250 255

Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Asn Tyr Asn Ser Gly

260 265 270

Pro Arg Thr Phe Gly Glyn Gly Thr Lys Val Glu Ile Lys Gly Gly Gly

275 280 285

Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Gly Gly Gly Gly Ser

290 295 300

Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala

305 310 315 320

Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly

325 330 335

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile

340 345 350

Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val

355 360 365

Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe

370 375 380

Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly

385 390 395 400

Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg

405 410 415

Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln

420 425 430

Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp

435 440 445

Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro

450 455 460

Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp

465 470 475 480

Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg

485 490 495

Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr

500 505 510

Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520 525

<210> 641

<211> 527

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 641

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly

35 40 45

Pro Gly Leu Val Lys Pro Ser Gln Ser Leu Ser Leu Thr Cys Ser Val

50 55 60

Ser Gly Gly Ser Val Ser Ser Asp Gly Tyr Tyr Trp Ser Trp Ile Arg

65 70 75 80

Gln His Pro Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile Tyr Tyr Arg

85 90 95

Arg Ile Thr Asp Tyr Asn Pro Ser Leu Lys Ser Arg Val Asn Ile Ser

100 105 110

Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr

115 120 125

Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Phe Gly Trp Tyr

130 135 140

Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Ala Val Ser Ser Gly Gly

145 150 155 160

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

165 170 175

Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser

180 185 190

Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser

195 200 205

Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Arg Val Pro Glu Val

210 215 220

Leu Ile Tyr Ala Ala Ser Ala Leu Gln Ser Gly Val Pro Ser Arg Phe

225 230 235 240

Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu

245 250 255

Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Asn Tyr Asn Ser Ala

260 265 270

Pro Arg Thr Phe Gly Glyn Gly Thr Lys Val Glu Ile Lys Gly Gly Gly

275 280 285

Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Gly Gly Gly Gly Ser

290 295 300

Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala

305 310 315 320

Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly

325 330 335

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile

340 345 350

Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val

355 360 365

Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe

370 375 380

Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly

385 390 395 400

Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg

405 410 415

Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln

420 425 430

Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp

435 440 445

Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro

450 455 460

Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp

465 470 475 480

Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg

485 490 495

Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr

500 505 510

Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520 525

<210> 642

<211> 529

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 642

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Glu Val Glu Leu Val Glu Ser Gly

35 40 45

Gly Gly Met Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala

50 55 60

Ser Gly Phe Thr Phe Ser Asp Tyr Gly Met His Trp Val Arg Gln Ala

65 70 75 80

Pro Gly Met Gly Leu Glu Trp Val Thr Val Ile Trp Tyr Asp Gly Ser

85 90 95

Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

100 105 110

Asp Asn Ser Lys Asn Thr Val Phe Leu Gln Met Asn Ser Leu Arg Ala

115 120 125

Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Glu Val Gly Phe Val

130 135 140

Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

145 150 155 160

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

165 170 175

Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser

180 185 190

Ala Ser Val Gly Asp Arg Val Ile Ile Thr Cys Arg Ala Ser Gln Gly

195 200 205

Ile Asn Ser His Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

210 215 220

Lys Leu Leu Ile Tyr Tyr Ala Ser Thr Leu Pro Ser Gly Val Pro Ser

225 230 235 240

Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Val Thr

245 250 255

Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn

260 265 270

His Tyr Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Asp Ile Asn Gly

275 280 285

Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Gly Gly Gly

290 295 300

Gly Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

305 310 315 320

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

325 330 335

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

340 345 350

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

355 360 365

Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr

370 375 380

Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu

385 390 395 400

Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu

405 410 415

Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln

420 425 430

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu

435 440 445

Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly

450 455 460

Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln

465 470 475 480

Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu

485 490 495

Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr

500 505 510

Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro

515 520 525

Arg

<210> 643

<211> 527

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 643

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly

35 40 45

Pro Gly Leu Val Gln Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val

50 55 60

Ser Gly Gly Ser Ile Ser Tyr Tyr Tyr Trp Ser Trp Ile Arg Gln Pro

65 70 75 80

Pro Gly Lys Gly Leu Glu Trp Ile Gly Asn Ile Asn Tyr Met Gly Asn

85 90 95

Thr Ile Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp

100 105 110

Thr Ser Lys Asp Gln Phe Ser Leu Lys Leu Thr Ser Val Ser Ala Ala

115 120 125

Asp Thr Ala Val Tyr Tyr Cys Val Arg Ala Glu Gly Ser Leu Asp Ala

130 135 140

Phe Asp Phe Trp Gly Gln Gly Thr Leu Val Ala Val Ser Leu Gly Gly

145 150 155 160

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

165 170 175

Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser

180 185 190

Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser

195 200 205

Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val

210 215 220

Leu Ile Tyr Lys Ala Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe

225 230 235 240

Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu

245 250 255

Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr

260 265 270

Ser Cys Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly

275 280 285

Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Gly Gly Gly Gly Ser

290 295 300

Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala

305 310 315 320

Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly

325 330 335

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile

340 345 350

Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val

355 360 365

Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe

370 375 380

Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly

385 390 395 400

Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg

405 410 415

Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln

420 425 430

Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp

435 440 445

Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro

450 455 460

Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp

465 470 475 480

Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg

485 490 495

Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr

500 505 510

Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520 525

<210> 644

<211> 522

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 644

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Gln Val Thr Leu Lys Glu Ser Gly

35 40 45

Pro Val Leu Val Lys Pro Thr Glu Thr Leu Thr Leu Thr Cys Thr Val

50 55 60

Ser Gly Phe Ser Leu Ser Asn Ala Arg Met Gly Val Thr Trp Ile Arg

65 70 75 80

Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu Ala His Ile Phe Ser Asn

85 90 95

Asp Glu Lys Ser Tyr Ser Thr Ser Leu Lys Ser Arg Leu Thr Ile Ser

100 105 110

Lys Asp Thr Ser Lys Thr Gln Val Val Leu Thr Met Thr Asn Met Asp

115 120 125

Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala Arg Ile Arg Asp Tyr Tyr

130 135 140

Asp Ile Ser Ser Tyr Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Ser

145 150 155 160

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

165 170 175

Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ala Met Ser Ala Ser

180 185 190

Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser

195 200 205

Asn Tyr Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Val Pro Lys Arg

210 215 220

Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe

225 230 235 240

Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu

245 250 255

Leu Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Leu Asn Ser Phe

260 265 270

Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Asn Gly Gly Gly

275 280 285

Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Thr Thr Thr Pro Ala

290 295 300

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

305 310 315 320

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

325 330 335

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

340 345 350

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

355 360 365

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

370 375 380

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

385 390 395 400

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

405 410 415

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn

420 425 430

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

435 440 445

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

450 455 460

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

465 470 475 480

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

485 490 495

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

500 505 510

Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520

<210> 645

<211> 532

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 645

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln Ser Gly

35 40 45

Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly

50 55 60

Ser Gly Tyr Gly Phe Thr Ser Tyr Trp Ile Gly Trp Val Arg Gln Met

65 70 75 80

Pro Gly Lys Gly Leu Glu Trp Met Gly Ile Ile His Pro Asp Asp Ser

85 90 95

Asp Thr Lys Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala

100 105 110

Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala

115 120 125

Ser Asp Thr Ala Met Tyr Tyr Cys Ala Ser Ser Tyr Leu Arg Gly Leu

130 135 140

Trp Gly Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val

145 150 155 160

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

165 170 175

Ser Gly Gly Gly Gly Ser Glu Leu Gln Ser Val Leu Thr Gln Pro Pro

180 185 190

Ser Ala Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly

195 200 205

Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Asn Trp Tyr Gln Gln Leu

210 215 220

Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Gly Asp Tyr Gln Arg Pro

225 230 235 240

Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala

245 250 255

Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr

260 265 270

Cys Ala Thr Arg Asp Asp Ser Leu Ser Gly Ser Val Val Phe Gly Thr

275 280 285

Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Cys Pro Tyr Ser

290 295 300

Asn Pro Ser Leu Cys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

305 310 315 320

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

325 330 335

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

340 345 350

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

355 360 365

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys

370 375 380

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

385 390 395 400

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

405 410 415

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

420 425 430

Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

435 440 445

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

450 455 460

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

465 470 475 480

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

485 490 495

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

500 505 510

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

515 520 525

Leu Pro Pro Arg

530

<210> 646

<211> 522

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 646

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly

35 40 45

Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val

50 55 60

Ser Gly Gly Ser Ile Ser Tyr Tyr Tyr Trp Thr Trp Ile Arg Gln Pro

65 70 75 80

Pro Gly Lys Gly Leu Glu Trp Ile Gly His Ile Tyr Tyr Ser Gly Ser

85 90 95

Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Ile Asp

100 105 110

Thr Ser Lys Asn Leu Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala

115 120 125

Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala Glu Gly Ser Leu Asp Ala

130 135 140

Phe Asp Phe Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly

145 150 155 160

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

165 170 175

Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser

180 185 190

Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser

195 200 205

Thr Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val

210 215 220

Leu Ile Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe

225 230 235 240

Ser Gly Ser Gly Ser Gly Thr Glu Phe Ile Leu Thr Ile Asn Ser Leu

245 250 255

Gln Pro Asp Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Tyr Lys Ser Tyr

260 265 270

Ser His Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly

275 280 285

Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Thr Thr Thr Pro Ala

290 295 300

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

305 310 315 320

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

325 330 335

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

340 345 350

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

355 360 365

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

370 375 380

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

385 390 395 400

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

405 410 415

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn

420 425 430

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

435 440 445

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

450 455 460

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

465 470 475 480

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

485 490 495

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

500 505 510

Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520

<210> 647

<211> 522

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 647

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly

35 40 45

Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Asn Cys Thr Val

50 55 60

Ser Gly Gly Ser Ile Ser Tyr Tyr Tyr Trp Thr Trp Ile Arg Gln Pro

65 70 75 80

Pro Gly Lys Gly Leu Glu Trp Ile Gly His Val Ile Tyr Ser Gly Thr

85 90 95

Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp

100 105 110

Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Asn Ser Val Thr Ala Ala

115 120 125

Asp Thr Ala Val Tyr Tyr Cys Val Arg Ala Glu Gly Ser Leu Asp Ala

130 135 140

Phe Asp Leu Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly

145 150 155 160

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

165 170 175

Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ile Leu Ser Ala Ser

180 185 190

Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser

195 200 205

Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val

210 215 220

Leu Ile Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe

225 230 235 240

Ser Gly Thr Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu

245 250 255

Gln Ser Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Thr Tyr

260 265 270

Ser His Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly

275 280 285

Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Thr Thr Thr Pro Ala

290 295 300

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

305 310 315 320

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

325 330 335

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

340 345 350

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

355 360 365

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

370 375 380

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

385 390 395 400

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

405 410 415

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn

420 425 430

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

435 440 445

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

450 455 460

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

465 470 475 480

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

485 490 495

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

500 505 510

Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520

<210> 648

<211> 522

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 648

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly

35 40 45

Pro Gly Leu Val Lys Pro Leu Gln Thr Leu Ser Leu Thr Cys Thr Val

50 55 60

Ser Gly Gly Ser Ile Ser Ser Asp Gly Tyr Tyr Trp Ser Trp Ile Arg

65 70 75 80

Gln Asn Pro Gly Lys Gly Leu Glu Trp Ile Gly Tyr Met Tyr Tyr Ser

85 90 95

Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser

100 105 110

Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Arg Ser Val Thr

115 120 125

Ala Ala Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Phe Gly Trp Tyr

130 135 140

Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Gly Gly

145 150 155 160

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

165 170 175

Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser

180 185 190

Val Gly Asp Ser Ile Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Asp

195 200 205

Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Thr Gly Lys Val Pro Lys Val

210 215 220

Leu Ile Tyr Ala Ala Ser Ala Leu Gln Ser Gly Val Pro Ser Arg Phe

225 230 235 240

Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu

245 250 255

Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Asn Tyr Asn Ser Gly

260 265 270

Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly Gly

275 280 285

Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Thr Thr Thr Pro Ala

290 295 300

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

305 310 315 320

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

325 330 335

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

340 345 350

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

355 360 365

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

370 375 380

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

385 390 395 400

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

405 410 415

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn

420 425 430

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

435 440 445

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

450 455 460

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

465 470 475 480

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

485 490 495

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

500 505 510

Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520

<210> 649

<211> 522

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 649

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly

35 40 45

Pro Gly Leu Val Lys Pro Ser Gln Ser Leu Ser Leu Thr Cys Ser Val

50 55 60

Ser Gly Gly Ser Val Ser Ser Asp Gly Tyr Tyr Trp Ser Trp Ile Arg

65 70 75 80

Gln His Pro Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile Tyr Tyr Arg

85 90 95

Arg Ile Thr Asp Tyr Asn Pro Ser Leu Lys Ser Arg Val Asn Ile Ser

100 105 110

Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr

115 120 125

Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Phe Gly Trp Tyr

130 135 140

Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Ala Val Ser Ser Gly Gly

145 150 155 160

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

165 170 175

Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser

180 185 190

Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser

195 200 205

Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Arg Val Pro Glu Val

210 215 220

Leu Ile Tyr Ala Ala Ser Ala Leu Gln Ser Gly Val Pro Ser Arg Phe

225 230 235 240

Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu

245 250 255

Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Asn Tyr Asn Ser Ala

260 265 270

Pro Arg Thr Phe Gly Glyn Gly Thr Lys Val Glu Ile Lys Gly Gly Gly

275 280 285

Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Thr Thr Thr Pro Ala

290 295 300

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

305 310 315 320

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

325 330 335

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

340 345 350

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

355 360 365

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

370 375 380

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

385 390 395 400

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

405 410 415

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn

420 425 430

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

435 440 445

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

450 455 460

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

465 470 475 480

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

485 490 495

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

500 505 510

Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520

<210> 650

<211> 524

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 650

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Glu Val Glu Leu Val Glu Ser Gly

35 40 45

Gly Gly Met Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala

50 55 60

Ser Gly Phe Thr Phe Ser Asp Tyr Gly Met His Trp Val Arg Gln Ala

65 70 75 80

Pro Gly Met Gly Leu Glu Trp Val Thr Val Ile Trp Tyr Asp Gly Ser

85 90 95

Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

100 105 110

Asp Asn Ser Lys Asn Thr Val Phe Leu Gln Met Asn Ser Leu Arg Ala

115 120 125

Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Glu Val Gly Phe Val

130 135 140

Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

145 150 155 160

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

165 170 175

Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser

180 185 190

Ala Ser Val Gly Asp Arg Val Ile Ile Thr Cys Arg Ala Ser Gln Gly

195 200 205

Ile Asn Ser His Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

210 215 220

Lys Leu Leu Ile Tyr Tyr Ala Ser Thr Leu Pro Ser Gly Val Pro Ser

225 230 235 240

Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Val Thr

245 250 255

Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn

260 265 270

His Tyr Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Asp Ile Asn Gly

275 280 285

Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Thr Thr Thr

290 295 300

Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro

305 310 315 320

Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val

325 330 335

His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro

340 345 350

Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu

355 360 365

Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro

370 375 380

Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys

385 390 395 400

Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe

405 410 415

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu

420 425 430

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

435 440 445

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

450 455 460

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

465 470 475 480

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

485 490 495

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

500 505 510

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520

<210> 651

<211> 522

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 651

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly

35 40 45

Pro Gly Leu Val Gln Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val

50 55 60

Ser Gly Gly Ser Ile Ser Tyr Tyr Tyr Trp Ser Trp Ile Arg Gln Pro

65 70 75 80

Pro Gly Lys Gly Leu Glu Trp Ile Gly Asn Ile Asn Tyr Met Gly Asn

85 90 95

Thr Ile Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp

100 105 110

Thr Ser Lys Asp Gln Phe Ser Leu Lys Leu Thr Ser Val Ser Ala Ala

115 120 125

Asp Thr Ala Val Tyr Tyr Cys Val Arg Ala Glu Gly Ser Leu Asp Ala

130 135 140

Phe Asp Phe Trp Gly Gln Gly Thr Leu Val Ala Val Ser Leu Gly Gly

145 150 155 160

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

165 170 175

Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser

180 185 190

Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser

195 200 205

Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val

210 215 220

Leu Ile Tyr Lys Ala Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe

225 230 235 240

Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu

245 250 255

Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr

260 265 270

Ser Cys Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly

275 280 285

Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Thr Thr Thr Pro Ala

290 295 300

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

305 310 315 320

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

325 330 335

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

340 345 350

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

355 360 365

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

370 375 380

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

385 390 395 400

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

405 410 415

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn

420 425 430

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

435 440 445

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

450 455 460

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

465 470 475 480

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

485 490 495

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

500 505 510

Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520

<210> 652

<211> 522

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 652

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu

35 40 45

Cys Gly Gly Gly Gly Ser Gln Val Thr Leu Lys Glu Ser Gly Pro Val

50 55 60

Leu Val Lys Pro Thr Glu Thr Leu Thr Leu Thr Cys Thr Val Ser Gly

65 70 75 80

Phe Ser Leu Ser Asn Ala Arg Met Gly Val Thr Trp Ile Arg Gln Pro

85 90 95

Pro Gly Lys Ala Leu Glu Trp Leu Ala His Ile Phe Ser Asn Asp Glu

100 105 110

Lys Ser Tyr Ser Thr Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp

115 120 125

Thr Ser Lys Thr Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val

130 135 140

Asp Thr Ala Thr Tyr Tyr Cys Ala Arg Ile Arg Asp Tyr Tyr Asp Ile

145 150 155 160

Ser Ser Tyr Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Ser Val Ser

165 170 175

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

180 185 190

Asp Ile Gln Met Thr Gln Ser Pro Ser Ala Met Ser Ala Ser Val Gly

195 200 205

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr

210 215 220

Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Val Pro Lys Arg Leu Ile

225 230 235 240

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

245 250 255

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Leu Pro

260 265 270

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Leu Asn Ser Phe Pro Phe

275 280 285

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Asn Thr Thr Thr Pro Ala

290 295 300

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

305 310 315 320

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

325 330 335

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

340 345 350

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

355 360 365

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

370 375 380

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

385 390 395 400

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

405 410 415

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn

420 425 430

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

435 440 445

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

450 455 460

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

465 470 475 480

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

485 490 495

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

500 505 510

Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520

<210> 653

<211> 532

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 653

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu

35 40 45

Cys Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu

50 55 60

Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly

65 70 75 80

Tyr Gly Phe Thr Ser Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly

85 90 95

Lys Gly Leu Glu Trp Met Gly Ile Ile His Pro Asp Asp Ser Asp Thr

100 105 110

Lys Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys

115 120 125

Ser Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp

130 135 140

Thr Ala Met Tyr Tyr Cys Ala Ser Ser Tyr Leu Arg Gly Leu Trp Gly

145 150 155 160

Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

165 170 175

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

180 185 190

Gly Gly Gly Ser Glu Leu Gln Ser Val Leu Thr Gln Pro Pro Ser Ala

195 200 205

Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser

210 215 220

Ser Asn Ile Gly Ser Asn Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly

225 230 235 240

Thr Ala Pro Lys Leu Leu Ile Tyr Gly Asp Tyr Gln Arg Pro Ser Gly

245 250 255

Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu

260 265 270

Ala Ile Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala

275 280 285

Thr Arg Asp Asp Ser Leu Ser Gly Ser Val Val Phe Gly Thr Gly Thr

290 295 300

Lys Leu Thr Val Leu Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

305 310 315 320

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

325 330 335

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

340 345 350

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

355 360 365

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys

370 375 380

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

385 390 395 400

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

405 410 415

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

420 425 430

Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

435 440 445

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

450 455 460

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

465 470 475 480

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

485 490 495

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

500 505 510

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

515 520 525

Leu Pro Pro Arg

530

<210> 654

<211> 522

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 654

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu

35 40 45

Cys Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly

50 55 60

Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly

65 70 75 80

Gly Ser Ile Ser Tyr Tyr Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly

85 90 95

Lys Gly Leu Glu Trp Ile Gly His Ile Tyr Tyr Ser Gly Ser Thr Asn

100 105 110

Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Ile Asp Thr Ser

115 120 125

Lys Asn Leu Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr

130 135 140

Ala Val Tyr Tyr Cys Ala Arg Ala Glu Gly Ser Leu Asp Ala Phe Asp

145 150 155 160

Phe Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly

165 170 175

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

180 185 190

Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly

195 200 205

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Thr Trp

210 215 220

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile

225 230 235 240

Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

245 250 255

Ser Gly Ser Gly Thr Glu Phe Ile Leu Thr Ile Asn Ser Leu Gln Pro

260 265 270

Asp Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Tyr Lys Ser Tyr Ser His

275 280 285

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala

290 295 300

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

305 310 315 320

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

325 330 335

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

340 345 350

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

355 360 365

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

370 375 380

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

385 390 395 400

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

405 410 415

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn

420 425 430

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

435 440 445

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

450 455 460

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

465 470 475 480

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

485 490 495

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

500 505 510

Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520

<210> 655

<211> 522

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 655

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu

35 40 45

Cys Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly

50 55 60

Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Asn Cys Thr Val Ser Gly

65 70 75 80

Gly Ser Ile Ser Tyr Tyr Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly

85 90 95

Lys Gly Leu Glu Trp Ile Gly His Val Ile Tyr Ser Gly Thr Thr Asn

100 105 110

Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser

115 120 125

Lys Asn Gln Phe Ser Leu Lys Leu Asn Ser Val Thr Ala Ala Asp Thr

130 135 140

Ala Val Tyr Tyr Cys Val Arg Ala Glu Gly Ser Leu Asp Ala Phe Asp

145 150 155 160

Leu Trp Gly Glyn Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly

165 170 175

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

180 185 190

Asp Ile Gln Met Thr Gln Ser Pro Ser Ile Leu Ser Ala Ser Val Gly

195 200 205

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Trp

210 215 220

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile

225 230 235 240

Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

245 250 255

Thr Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser

260 265 270

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Thr Tyr Ser His

275 280 285

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala

290 295 300

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

305 310 315 320

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

325 330 335

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

340 345 350

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

355 360 365

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

370 375 380

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

385 390 395 400

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

405 410 415

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn

420 425 430

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

435 440 445

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

450 455 460

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

465 470 475 480

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

485 490 495

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

500 505 510

Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520

<210> 656

<211> 522

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 656

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu

35 40 45

Cys Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly

50 55 60

Leu Val Lys Pro Leu Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly

65 70 75 80

Gly Ser Ile Ser Ser Asp Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Asn

85 90 95

Pro Gly Lys Gly Leu Glu Trp Ile Gly Tyr Met Tyr Tyr Ser Gly Ser

100 105 110

Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp

115 120 125

Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Arg Ser Val Thr Ala Ala

130 135 140

Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Phe Gly Trp Tyr Phe Asp

145 150 155 160

Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

165 170 175

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

180 185 190

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

195 200 205

Asp Ser Ile Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Asp Asn Tyr

210 215 220

Leu Ala Trp Tyr Gln Gln Lys Thr Gly Lys Val Pro Lys Val Leu Ile

225 230 235 240

Tyr Ala Ala Ser Ala Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

245 250 255

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

260 265 270

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Asn Tyr Asn Ser Gly Pro Arg

275 280 285

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala

290 295 300

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

305 310 315 320

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

325 330 335

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

340 345 350

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

355 360 365

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

370 375 380

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

385 390 395 400

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

405 410 415

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn

420 425 430

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

435 440 445

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

450 455 460

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

465 470 475 480

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

485 490 495

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

500 505 510

Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520

<210> 657

<211> 522

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 657

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu

35 40 45

Cys Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly

50 55 60

Leu Val Lys Pro Ser Gln Ser Leu Ser Leu Thr Cys Ser Val Ser Gly

65 70 75 80

Gly Ser Val Ser Ser Asp Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His

85 90 95

Pro Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile Tyr Tyr Arg Arg Ile

100 105 110

Thr Asp Tyr Asn Pro Ser Leu Lys Ser Arg Val Asn Ile Ser Leu Asp

115 120 125

Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala

130 135 140

Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Phe Gly Trp Tyr Phe Asp

145 150 155 160

Leu Trp Gly Arg Gly Thr Leu Val Ala Val Ser Ser Gly Gly Gly Gly

165 170 175

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

180 185 190

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

195 200 205

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr

210 215 220

Leu Thr Trp Tyr Gln Gln Lys Pro Gly Arg Val Pro Glu Val Leu Ile

225 230 235 240

Tyr Ala Ala Ser Ala Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

245 250 255

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

260 265 270

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Asn Tyr Asn Ser Ala Pro Arg

275 280 285

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala

290 295 300

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

305 310 315 320

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

325 330 335

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

340 345 350

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

355 360 365

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

370 375 380

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

385 390 395 400

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

405 410 415

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn

420 425 430

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

435 440 445

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

450 455 460

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

465 470 475 480

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

485 490 495

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

500 505 510

Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520

<210> 658

<211> 524

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 658

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu

35 40 45

Cys Gly Gly Gly Gly Ser Glu Val Glu Leu Val Glu Ser Gly Gly Gly

50 55 60

Met Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

65 70 75 80

Phe Thr Phe Ser Asp Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly

85 90 95

Met Gly Leu Glu Trp Val Thr Val Ile Trp Tyr Asp Gly Ser Asn Lys

100 105 110

Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

115 120 125

Ser Lys Asn Thr Val Phe Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

130 135 140

Thr Ala Val Tyr Tyr Cys Ala Arg Asp Glu Val Gly Phe Val Gly Ala

145 150 155 160

Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly

165 170 175

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

180 185 190

Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser

195 200 205

Val Gly Asp Arg Val Ile Ile Thr Cys Arg Ala Ser Gln Gly Ile Asn

210 215 220

Ser His Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu

225 230 235 240

Leu Ile Tyr Tyr Ala Ser Thr Leu Pro Ser Gly Val Pro Ser Arg Phe

245 250 255

Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Val Thr Ser Leu

260 265 270

Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn His Tyr

275 280 285

Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Asp Ile Asn Thr Thr Thr

290 295 300

Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro

305 310 315 320

Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val

325 330 335

His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro

340 345 350

Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu

355 360 365

Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro

370 375 380

Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys

385 390 395 400

Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe

405 410 415

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu

420 425 430

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

435 440 445

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

450 455 460

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

465 470 475 480

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

485 490 495

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

500 505 510

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520

<210> 659

<211> 522

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 659

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu

35 40 45

Cys Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly

50 55 60

Leu Val Gln Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly

65 70 75 80

Gly Ser Ile Ser Tyr Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly

85 90 95

Lys Gly Leu Glu Trp Ile Gly Asn Ile Asn Tyr Met Gly Asn Thr Ile

100 105 110

Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser

115 120 125

Lys Asp Gln Phe Ser Leu Lys Leu Thr Ser Val Ser Ala Ala Asp Thr

130 135 140

Ala Val Tyr Tyr Cys Val Arg Ala Glu Gly Ser Leu Asp Ala Phe Asp

145 150 155 160

Phe Trp Gly Glyn Gly Thr Leu Val Ala Val Ser Leu Gly Gly Gly Gly

165 170 175

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

180 185 190

Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly

195 200 205

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp

210 215 220

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile

225 230 235 240

Tyr Lys Ala Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

245 250 255

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

260 265 270

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser Cys

275 280 285

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala

290 295 300

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

305 310 315 320

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

325 330 335

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

340 345 350

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

355 360 365

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

370 375 380

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

385 390 395 400

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

405 410 415

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn

420 425 430

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

435 440 445

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

450 455 460

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

465 470 475 480

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

485 490 495

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

500 505 510

Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520

<210> 660

<211> 24

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 660

Asn Ser Glu Leu Leu Ser Leu Ile Asn Asp Met Pro Ile Thr Asn Asp

1.5 10 15

Gln Lys Lys Leu Met Ser Asn Asn

20

<210> 661

<211> 107

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 661

Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly

1.5 10 15

Asp Arg Val Ile Ile Thr Cys Arg Ala Ser Gln Gly Ile Asn Ser His

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Ala Ser Thr Leu Pro Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Val Thr Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn His Tyr Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 662

<211> 120

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 662

Glu Val Glu Leu Val Glu Ser Gly Gly Gly Met Val Gln Pro Gly Arg

1.5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Gly Met His Trp Val Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val

35 40 45

Thr 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 Val Phe

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 Asp Glu Val Gly Phe Val Gly Ala Phe Asp Ile Trp Gly Gln

100 105 110

Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 663

<211> 5

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 663

Asp Tyr Gly Met His

15

<210> 664

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 664

Gly Phe Thr Phe Ser Asp Tyr

15

<210> 665

<211> 10

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 665

Gly Phe Thr Phe Ser Asp Tyr Gly Met His

1.5 10

<210> 666

<211> 17

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 666

Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys

1.5 10 15

gly

<210> 667

<211> 6

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 667

Trp Tyr Asp Gly Ser Asn

15

<210> 668

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 668

Asp Glu Val Gly Phe Val Gly Ala Phe Asp Ile

1.5 10

<210> 669

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 669

Arg Ala Ser Gln Gly Ile Asn Ser His Leu Ala

1.5 10

<210> 670

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 670

Tyr Ala Ser Thr Leu Pro Ser

15

<210> 671

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

peptide

<400> 671

Gln Gln Leu Asn His Tyr Pro Ile Thr

15

<210> 672

<211> 494

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 672

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu

20 25 30

Val Lys Pro Thr Glu Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe

35 40 45

Ser Leu Ser Asn Ala Arg Met Gly Val Thr Trp Ile Arg Gln Pro Pro

50 55 60

Gly Lys Ala Leu Glu Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys

65 70 75 80

Ser Tyr Ser Thr Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr

85 90 95

Ser Lys Thr Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp

100 105 110

Thr Ala Thr Tyr Tyr Cys Ala Arg Ile Arg Asp Tyr Tyr Asp Ile Ser

115 120 125

Ser Tyr Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Ser Val Ser Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

145 150 155 160

Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ala Met Ser

165 170 175

Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp

180 185 190

Ile Ser Asn Tyr Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Val Pro

195 200 205

Lys Arg Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser

210 215 220

Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser

225 230 235 240

Ser Leu Leu Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Leu Asn

245 250 255

Ser Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Asn Thr

260 265 270

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

275 280 285

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

290 295 300

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

305 310 315 320

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

325 330 335

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

340 345 350

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

355 360 365

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

370 375 380

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn

385 390 395 400

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

405 410 415

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

420 425 430

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

435 440 445

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

450 455 460

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

465 470 475 480

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 673

<211> 491

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 673

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Glu Leu Val Glu Ser Gly Gly Gly Met

20 25 30

Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Thr Phe Ser Asp Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Met

50 55 60

Gly Leu Glu Trp Val Thr Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser

85 90 95

Lys Asn Thr Val Phe Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Asp Glu Val Gly Phe Val Gly Ala Phe

115 120 125

Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

145 150 155 160

Ser Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val

165 170 175

Gly Asp Arg Val Ile Ile Thr Cys Arg Ala Ser Gln Gly Ile Asn Ser

180 185 190

His Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu

195 200 205

Ile Tyr Tyr Ala Ser Thr Leu Pro Ser Gly Val Pro Ser Arg Phe Ser

210 215 220

Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Val Thr Ser Leu Gln

225 230 235 240

Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn His Tyr Pro

245 250 255

Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Thr Thr Thr Pro

260 265 270

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

275 280 285

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

290 295 300

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

305 310 315 320

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

325 330 335

Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

340 345 350

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

355 360 365

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser

370 375 380

Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr

385 390 395 400

Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys

405 410 415

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn

420 425 430

Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu

435 440 445

Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly

450 455 460

His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr

465 470 475 480

Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 674

<211> 531

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 674

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu

20 25 30

Val Lys Pro Thr Glu Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe

35 40 45

Ser Leu Ser Asn Ala Arg Met Gly Val Thr Trp Ile Arg Gln Pro Pro

50 55 60

Gly Lys Ala Leu Glu Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys

65 70 75 80

Ser Tyr Ser Thr Ser Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr

85 90 95

Ser Lys Thr Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp

100 105 110

Thr Ala Thr Tyr Tyr Cys Ala Arg Ile Arg Asp Tyr Tyr Asp Ile Ser

115 120 125

Ser Tyr Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Ser Val Ser Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

145 150 155 160

Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ala Met Ser

165 170 175

Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp

180 185 190

Ile Ser Asn Tyr Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Val Pro

195 200 205

Lys Arg Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser

210 215 220

Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser

225 230 235 240

Ser Leu Leu Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Leu Asn

245 250 255

Ser Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Asn Gly

260 265 270

Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser

275 280 285

Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly

290 295 300

Gly Gly Gly Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

305 310 315 320

Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg

325 330 335

Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys

340 345 350

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

355 360 365

Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu

370 375 380

Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln

385 390 395 400

Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly

405 410 415

Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

420 425 430

Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

435 440 445

Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met

450 455 460

Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu

465 470 475 480

Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys

485 490 495

Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu

500 505 510

Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu

515 520 525

Pro Pro Arg

530

<210> 675

<211> 528

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 675

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Glu Val Glu Leu Val Glu Ser Gly Gly Gly Met

20 25 30

Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Thr Phe Ser Asp Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Met

50 55 60

Gly Leu Glu Trp Val Thr Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser

85 90 95

Lys Asn Thr Val Phe Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Asp Glu Val Gly Phe Val Gly Ala Phe

115 120 125

Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

145 150 155 160

Ser Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val

165 170 175

Gly Asp Arg Val Ile Ile Thr Cys Arg Ala Ser Gln Gly Ile Asn Ser

180 185 190

His Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu

195 200 205

Ile Tyr Tyr Ala Ser Thr Leu Pro Ser Gly Val Pro Ser Arg Phe Ser

210 215 220

Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Val Thr Ser Leu Gln

225 230 235 240

Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn His Tyr Pro

245 250 255

Ile Thr Phe Gly Glyn Gly Thr Arg Leu Glu Ile Lys Gly Ser Gly Gly

260 265 270

Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly

275 280 285

Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly

290 295 300

Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile

305 310 315 320

Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala

325 330 335

Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr

340 345 350

Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu

355 360 365

Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile

370 375 380

Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp

385 390 395 400

Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

405 410 415

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly

420 425 430

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

435 440 445

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

450 455 460

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

465 470 475 480

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

485 490 495

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

500 505 510

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520 525

<210> 676

<211> 574

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 676

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glyn Val

35 40 45

Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu Thr Leu

50 55 60

Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn Ala Arg Met

65 70 75 80

Gly Val Thr Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu

85 90 95

Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser Leu Lys

100 105 110

Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Thr Gln Val Val Leu

115 120 125

Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala

130 135 140

Arg Ile Arg Asp Tyr Tyr Asp Ile Ser Ser Tyr Tyr Asp Tyr Trp Gly

145 150 155 160

Gly Gly Thr Leu Val Ser Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

165 170 175

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln

180 185 190

Met Thr Gln Ser Pro Ser Ala Met Ser Ala Ser Val Gly Asp Arg Val

195 200 205

Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Ala Trp

210 215 220

Phe Gln Gln Lys Pro Gly Lys Val Pro Lys Arg Leu Ile Tyr Ala Ala

225 230 235 240

Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser

245 250 255

Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Leu Pro Glu Asp Phe

260 265 270

Ala Thr Tyr Tyr Cys Leu Gln Leu Asn Ser Phe Pro Phe Thr Phe Gly

275 280 285

Gly Gly Thr Lys Val Glu Ile Asn Gly Ser Gly Gly Gly Gly Ser Cys

290 295 300

Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Glu Leu

305 310 315 320

Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser Pro Ala

325 330 335

Lys Pro Thr Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys Thr

340 345 350

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

355 360 365

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

370 375 380

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

385 390 395 400

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

405 410 415

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

420 425 430

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

435 440 445

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

450 455 460

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn

465 470 475 480

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

485 490 495

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

500 505 510

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

515 520 525

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

530 535 540

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

545 550 555 560

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

565 570

<210> 677

<211> 571

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 677

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val

35 40 45

Glu Leu Val Glu Ser Gly Gly Gly Met Val Gln Pro Gly Arg Ser Leu

50 55 60

Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Gly Met

65 70 75 80

His Trp Val Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val Thr Val

85 90 95

Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly

100 105 110

Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Phe Leu Gln

115 120 125

Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg

130 135 140

Asp Glu Val Gly Phe Val Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr

145 150 155 160

Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

165 170 175

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln

180 185 190

Ser Pro Ser Phe Leu Ser Ala Ser Val Gly Asp Arg Val Ile Ile Thr

195 200 205

Cys Arg Ala Ser Gln Gly Ile Asn Ser His Leu Ala Trp Tyr Gln Gln

210 215 220

Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Ala Ser Thr Leu

225 230 235 240

Pro Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu

245 250 255

Phe Thr Leu Thr Val Thr Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr

260 265 270

Tyr Cys Gln Gln Leu Asn His Tyr Pro Ile Thr Phe Gly Gln Gly Thr

275 280 285

Arg Leu Glu Ile Lys Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser

290 295 300

Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln

305 310 315 320

Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr

325 330 335

Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys Thr Thr Thr Pro

340 345 350

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

355 360 365

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

370 375 380

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

385 390 395 400

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

405 410 415

Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

420 425 430

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

435 440 445

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser

450 455 460

Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr

465 470 475 480

Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys

485 490 495

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn

500 505 510

Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu

515 520 525

Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly

530 535 540

His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr

545 550 555 560

Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

565 570

<210> 678

<211> 532

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 678

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Gln Val Thr Leu Lys Glu Ser Gly

35 40 45

Pro Val Leu Val Lys Pro Thr Glu Thr Leu Thr Leu Thr Cys Thr Val

50 55 60

Ser Gly Phe Ser Leu Ser Asn Ala Arg Met Gly Val Thr Trp Ile Arg

65 70 75 80

Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu Ala His Ile Phe Ser Asn

85 90 95

Asp Glu Lys Ser Tyr Ser Thr Ser Leu Lys Ser Arg Leu Thr Ile Ser

100 105 110

Lys Asp Thr Ser Lys Thr Gln Val Val Leu Thr Met Thr Asn Met Asp

115 120 125

Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala Arg Ile Arg Asp Tyr Tyr

130 135 140

Asp Ile Ser Ser Tyr Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Ser

145 150 155 160

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

165 170 175

Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser

180 185 190

Ala Met Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala

195 200 205

Ser Gln Asp Ile Ser Asn Tyr Leu Ala Trp Phe Gln Gln Lys Pro Gly

210 215 220

Lys Val Pro Lys Arg Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly

225 230 235 240

Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu

245 250 255

Thr Ile Ser Ser Leu Leu Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu

260 265 270

Gln Leu Asn Ser Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu

275 280 285

Ile Asn Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys

290 295 300

Gly Gly Gly Gly Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

305 310 315 320

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

325 330 335

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

340 345 350

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

355 360 365

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys

370 375 380

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

385 390 395 400

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

405 410 415

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

420 425 430

Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

435 440 445

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

450 455 460

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

465 470 475 480

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

485 490 495

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

500 505 510

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

515 520 525

Leu Pro Pro Arg

530

<210> 679

<211> 529

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 679

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Glu Val Glu Leu Val Glu Ser Gly

35 40 45

Gly Gly Met Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala

50 55 60

Ser Gly Phe Thr Phe Ser Asp Tyr Gly Met His Trp Val Arg Gln Ala

65 70 75 80

Pro Gly Met Gly Leu Glu Trp Val Thr Val Ile Trp Tyr Asp Gly Ser

85 90 95

Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

100 105 110

Asp Asn Ser Lys Asn Thr Val Phe Leu Gln Met Asn Ser Leu Arg Ala

115 120 125

Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Glu Val Gly Phe Val

130 135 140

Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

145 150 155 160

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

165 170 175

Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser

180 185 190

Ala Ser Val Gly Asp Arg Val Ile Ile Thr Cys Arg Ala Ser Gln Gly

195 200 205

Ile Asn Ser His Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

210 215 220

Lys Leu Leu Ile Tyr Tyr Ala Ser Thr Leu Pro Ser Gly Val Pro Ser

225 230 235 240

Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Val Thr

245 250 255

Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn

260 265 270

His Tyr Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Gly

275 280 285

Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Gly Gly Gly

290 295 300

Gly Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

305 310 315 320

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

325 330 335

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

340 345 350

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

355 360 365

Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr

370 375 380

Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu

385 390 395 400

Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu

405 410 415

Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln

420 425 430

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu

435 440 445

Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly

450 455 460

Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln

465 470 475 480

Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu

485 490 495

Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr

500 505 510

Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro

515 520 525

Arg

<210> 680

<211> 527

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 680

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Gln Val Thr Leu Lys Glu Ser Gly

35 40 45

Pro Val Leu Val Lys Pro Thr Glu Thr Leu Thr Leu Thr Cys Thr Val

50 55 60

Ser Gly Phe Ser Leu Ser Asn Ala Arg Met Gly Val Thr Trp Ile Arg

65 70 75 80

Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu Ala His Ile Phe Ser Asn

85 90 95

Asp Glu Lys Ser Tyr Ser Thr Ser Leu Lys Ser Arg Leu Thr Ile Ser

100 105 110

Lys Asp Thr Ser Lys Thr Gln Val Val Leu Thr Met Thr Asn Met Asp

115 120 125

Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala Arg Ile Arg Asp Tyr Tyr

130 135 140

Asp Ile Ser Ser Tyr Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Ser

145 150 155 160

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

165 170 175

Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser

180 185 190

Ala Met Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala

195 200 205

Ser Gln Asp Ile Ser Asn Tyr Leu Ala Trp Phe Gln Gln Lys Pro Gly

210 215 220

Lys Val Pro Lys Arg Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly

225 230 235 240

Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu

245 250 255

Thr Ile Ser Ser Leu Leu Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu

260 265 270

Gln Leu Asn Ser Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu

275 280 285

Ile Asn Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys

290 295 300

Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala

305 310 315 320

Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly

325 330 335

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile

340 345 350

Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val

355 360 365

Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe

370 375 380

Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly

385 390 395 400

Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg

405 410 415

Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln

420 425 430

Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp

435 440 445

Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro

450 455 460

Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp

465 470 475 480

Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg

485 490 495

Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr

500 505 510

Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520 525

<210> 681

<211> 524

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic

polypeptide

<400> 681

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1.5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gly Gly Gly Ser Glu Val Glu Leu Val Glu Ser Gly

35 40 45

Gly Gly Met Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala

50 55 60

Ser Gly Phe Thr Phe Ser Asp Tyr Gly Met His Trp Val Arg Gln Ala

65 70 75 80

Pro Gly Met Gly Leu Glu Trp Val Thr Val Ile Trp Tyr Asp Gly Ser

85 90 95

Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

100 105 110

Asp Asn Ser Lys Asn Thr Val Phe Leu Gln Met Asn Ser Leu Arg Ala

115 120 125

Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Glu Val Gly Phe Val

130 135 140

Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

145 150 155 160

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

165 170 175

Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser

180 185 190

Ala Ser Val Gly Asp Arg Val Ile Ile Thr Cys Arg Ala Ser Gln Gly

195 200 205

Ile Asn Ser His Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

210 215 220

Lys Leu Leu Ile Tyr Tyr Ala Ser Thr Leu Pro Ser Gly Val Pro Ser

225 230 235 240

Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Val Thr

245 250 255

Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn

260 265 270

His Tyr Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Gly

275 280 285

Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Thr Thr Thr

290 295 300

Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro

305 310 315 320

Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val

325 330 335

His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro

340 345 350

Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu

355 360 365

Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro

370 375 380

Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys

385 390 395 400

Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe

405 410 415

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu

420 425 430

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

435 440 445

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

450 455 460

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

465 470 475 480

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

485 490 495

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

500 505 510

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520

<210> 682

<211> 40

<212> PROTEIN

<213> Homo sapiens

<400> 682

Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro

1.5 10 15

Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu

20 25 30

Glu Glu Glu Gly Gly Cys Glu Leu

35 40

<210> 683

<211> 112

<212> PROTEIN

<213> Homo sapiens

<400> 683

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly

1.5 10 15

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

20 25 30

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

35 40 45

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

50 55 60

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

65 70 75 80

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

85 90 95

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

100 105 110

<---

Claims (160)

1. Chimeric antigen receptor (CAR) specific for cluster of differentiation 70 (CD70) containing an extracellular ligand-binding domain, a first transmembrane domain and an intracellular signaling domain, where the extracellular domain contains a single-chain Fv fragment (scFv) that binds to the extracellular domain of CD70 where scFv contains the amino acid sequences CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3, respectively, selected from one of SEQ ID NO: a) 97-99, 100-101, 102, 217, 218, 219; b) 478-480, 481-482, 483, 562, 563, 564; c) 49-51, 52-53, 54, 193, 194, 195; d) 55-57, 58-59, 60, 196, 197, 198; e) 61-63, 64-65, 66, 199, 200, 201; f) 67-69, 70-71, 72, 202, 203, 204; g) 73-75, 76-77, 78, 205, 206, 207; h) 79-81, 82-83, 84, 208, 209, 210; i) 85-87, 88-89, 90, 211, 212, 213; j) 91-93, 94-95, 96, 214, 215, 216; k) 103-105, 106-107, 108, 220, 221, 222; l) 109-111, 112-113, 114, 223, 224, 225; m) 115-117, 118-119, 120, 226, 227, 228; n) 121-123, 124-125, 126, 229, 230, 231; o) 127-129, 130-131, 132, 232, 233, 234; p) 133-135, 136-137, 138, 235, 236, 237; q) 139-141, 142-143, 144, 238, 239, 240; r) 145-147, 148-149, 150, 241, 242, 243; s) 151-153, 154-155, 156, 244, 245, 246; t) 157-159, 160-161, 162, 247, 248, 249; u) 163-165, 166-167, 168, 250, 251, 252; v) 169-171, 172-173, 174, 253, 254, 255; w) 175-177, 178-179, 180, 256, 257, 258; x) 181-183, 184-185, 186, 259, 260, 261; y) 187-189, 190-191, 192, 262, 263, 264; z) 382-384, 385-386, 387, 514, 515, 516; aa) 388-390, 391-392, 393, 517, 518, 519; bb) 394-396, 397-398, 399, 520, 521, 522; cc) 400-402, 403-404, 405, 523, 524, 525; dd) 406-408, 409-410, 411, 526, 527, 528; ee) 412-414, 415-416, 417, 529, 530, 531; ff) 418-420, 421-422, 423, 532, 533, 534; gg) 424-426, 427-428, 429, 535, 536, 537; hh) 430-432, 433-434, 435, 538, 539, 540; ii) 436-438, 439-440, 441, 541, 542, 543; jj) 442-444, 445-446, 447, 544, 545, 546; kk) 448-450, 451-452, 453, 547, 548, 549; ll) 454-456, 457-458, 459, 550, 551, 552; mm) 460-462, 463-464, 465, 553, 554, 555; nn) 466-468, 469-470, 471, 556, 557, 558; oo) 472-474, 475-476, 477, 559, 560, 561; pp) 484-486, 487-488, 489, 565, 566, 567; qq) 490-492, 493-494, 495, 568, 569, 570; rr) 496-498, 499-500, 501, 571, 572, 573; ss) 502-504, 505-506, 507, 574, 575, 576; tt) 508-510, 511-512, 513, 577, 578, 579; And uu) 663-665, 666-667, 668, 669, 670, 671. 2. CAR specific to CD70, according to claim 1, where the scFv contains a CDRH1 containing the amino acid sequence shown under SEQ ID NO: 97, 98 or 99; CDRH2 containing the amino acid sequence shown under SEQ ID NO: 100 or 101; and CDRH3 containing the amino acid sequence shown under SEQ ID NO: 102; CDRL1 containing the amino acid sequence shown under SEQ ID NO: 217; CDRL2 containing the amino acid sequence shown under SEQ ID NO: 218; and CDRL3 containing the amino acid sequence shown under SEQ ID NO: 219. 3. The CD70-specific CAR according to claim 1, wherein the scFv contains a VH region that contains the amino acid sequence shown under SEQ ID NO: 18 and a VL region that contains the amino acid sequence shown under SEQ ID NO: 17. 4. CAR specific to CD70, according to claim 1, where scFv contains CDRH1 containing the amino acid sequence presented under SEQ ID NO: 478, 479 or 480; CDRH2 containing the amino acid sequence shown under SEQ ID NO: 481 or 482; and CDRH3 containing the amino acid sequence shown under SEQ ID NO: 483; CDRL1 containing the amino acid sequence shown under SEQ ID NO: 562; CDRL2 containing the amino acid sequence shown under SEQ ID NO: 563; and CDRL3 containing the amino acid sequence shown under SEQ ID NO: 564. 5. A CD70-specific CAR according to claim 1, wherein the scFv contains a VH region that contains the amino acid sequence shown under SEQ ID NO: 371 and a VL region that contains the amino acid sequence shown under SEQ ID NO: 370. 6. CAR specific to CD70, according to any one of paragraphs. 1-5, where the intracellular signaling domain includes the CD3ζ signaling domain or the 4-1BB domain. 7. CAR, specific to CD70, according to any one of paragraphs. 1-6 containing a second intracellular signaling domain. 8. The CD70-specific CAR of claim 7, wherein the CAR contains the CD3ζ intracellular signaling domain and the 4-1BB intracellular signaling domain. 9. CAR, specific to CD70, according to any one of paragraphs. 1-8 containing a hinge domain between the extracellular ligand-binding domain and the first transmembrane domain. 10. The CD70-specific CAR of claim 9, wherein the hinge is selected from the group consisting of a human CD8α hinge, an IgG1 hinge, and a FcγRIIIα hinge. 11. CAR, specific to CD70, according to any one of paragraphs. 1-10 containing the CD20 epitope. 12. A CD70-specific CAR according to claim 11, wherein the CD20 epitope contains the amino acid sequence shown under SEQ ID NO: 293 or SEQ ID NO: 294 or SEQ ID NO: 609. 13. CAR, specific to CD70, according to any one of paragraphs. 1-12, where the first transmembrane domain provides for the transmembrane domain of the CD8α chain. 14. CAR, specific to CD70, according to any one of paragraphs. 1-13 containing another extracellular ligand-binding domain that is not specific for CD70. 15. CAR, specific to CD70, according to any one of paragraphs. 1-14, where the extracellular (extracellular) ligand-binding (ligand-binding) domain (domains), the first transmembrane domain and intracellular (intracellular) signaling domain (s) are located in the same polypeptide. 16. CAR, specific to CD70, according to any one of paragraphs. 1-15, containing a second transmembrane domain, where the first transmembrane domain and the extracellular (extracellular) ligand-binding (ligand-binding) domain (domains) are located in the first polypeptide and where the second transmembrane domain and intracellular (intracellular) signal (signal) domain ( domains) are located in the second polypeptide. 17. A CD70-specific CAR according to claim 16, comprising a third polypeptide comprising a third transmembrane domain fused to an intracellular signaling domain from a costimulatory molecule. 18. The CD70-specific CAR of claim 1, wherein the CD70-specific CAR comprises the amino acid sequence shown under SEQ ID NOs: 311-334. 19. The CD70-specific CAR of claim 1, wherein the CD70-specific CAR comprises the amino acid sequence shown under SEQ ID NO: 319 or 596. 20. A CD70-specific CAR according to claim 1, wherein the CD70-specific CAR comprises the amino acid sequence shown under SEQ ID NOs: 596, 619, 620, 627, 628, 635, 636, 643, 644, 651, 672, 674, 676, 678 or 680. 21. The CD70-specific CAR of claim 1, wherein the CD70-specific CAR comprises the amino acid sequence shown under SEQ ID NOs: 580-601. 22. Nucleic acid encoding a CAR specific to CD70, containing a nucleic acid sequence encoding a CAR specific to CD70, according to any one of paragraphs. 18-21. 23. Nucleic acid according to claim 22, containing the nucleic acid sequence shown under SEQ ID NO: 336 or 337, or a nucleic acid sequence that encodes the amino acid sequence of SEQ ID NO: 319 or SEQ ID NO: 596. 24. An expression vector containing a nucleic acid according to any one of paragraphs. 22 or 23. 25. An engineered immune cell that expresses on its outer cell membrane a CAR specific for CD70 encoded by a nucleic acid according to any one of paragraphs. 22-23 or an expression vector according to claim 24, where the engineered immune cell is a natural killer (NK) cell or a T cell, where the T cell is a T cell selected from the group consisting of inflammatory T lymphocytes, cytotoxic T lymphocytes and helper T lymphocytes, or the T cell is derived from the group consisting of CD4+ T lymphocytes and CD8+ T lymphocytes. 26. The engineered immune cell of claim 25, further comprising a polynucleotide encoding a "suicidal" polypeptide comprising an amino acid sequence according to any of SEQ ID NOs: 291, 292, 293, 295, 603-611, 660. 27. The engineered immune cell of claim 26, wherein the "suicidal" polypeptide has the amino acid sequence of SEQ ID NO: 291. 28. Constructed immune cell according to any one of paragraphs. 25-27, further characterized by disruption of one or more endogenous genes, wherein the endogenous gene encodes TCRα, TCRβ, CD52, glucocorticoid receptor (GR), deoxycytidine kinase (dCK), CD70, or an immune response checkpoint protein such as, for example, programmed death protein -1 (PD-1). 29. Constructed immune cell according to any one of paragraphs. 25-27, further characterized by destruction of TCRα and CD52 or TCRα, CD52 and CD70. 30. Constructed immune cell according to any one of paragraphs. 25-29, where the immune cell is obtained from a healthy donor. 31. Constructed immune cell according to any one of paragraphs. 25-29 where the immune cell is obtained from a patient. 32. Constructed immune cell according to any one of paragraphs. 25-31 for use as a drug. 33. The engineered immune cell of claim 32, wherein the drug is for use in the treatment of cancer. 34. The engineered immune cell of claim 33, wherein the cancer is selected from the group consisting of renal cell carcinoma, glioblastoma, glioma such as low grade glioma, non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD), Waldenström's macroglobulinemia, acute myeloid leukemia, multiple myeloma, diffuse large cell lymphoma, follicular lymphoma, and non-small cell lung cancer. 35. The population of engineered immune cells according to any one of paragraphs. 25-34, where a) said cell population contains a percentage of memory stem cells and central memory cells greater than 20%, 30% or 40%, and/or b) said cell population achieves a percentage lysis of CD70-expressing cells by day 6 greater than 10%, 20%, 30%, or 40% for recursive CD70-expressing cells, as measured using an appropriate stress-based screening assay -test. 36. The immune engineered cell population of claim 35, wherein said cell population achieves a percent lysis of CD70-expressing cells by day 6 greater than 20% in the case of recursive CD70-expressing cells, as measured using an appropriate screening assay based on stress test. 37. A method for constructing an immune cell expressing a CAR specific for CD70 encoded by a polynucleotide according to any one of paragraphs. 22, 23 or an expression vector according to claim 24, providing: a) providing an immune cell, wherein the immune cell is a T cell, dendritic cell, killer dendritic cell, mast cell, NK cell, B cell, or T cell selected from the group consisting of inflammatory T lymphocytes, cytotoxic T -lymphocytes, regulatory T-lymphocytes and helper T-lymphocytes, or derived from stem cells, progenitor cells, induced pluripotent stem cells, totipotent stem cells or hematopoietic stem cells; b) introducing into the cell at least one polynucleotide according to paragraph 22 or 23 or an expression vector according to paragraph 24; And c) allowing expression of said polynucleotide or vector in an immune cell. 38. A method for treating a condition associated with malignant cells expressing CD70 in a subject in need thereof, comprising: a) providing an effective amount of engineered immune cells according to any one of paragraphs. 25-34 or populations of engineered immune cells according to claim 35 or 36; And b) administering said immune cells or said population of engineered immune cells to said patient. 39. Pharmaceutical composition for the treatment of a condition associated with malignant cells expressing CD70, containing an effective amount of engineered immune cells according to any one of paragraphs. 25-34 or an effective amount of the engineered immune cell population according to claims 35, 36. 40. A method of treating a condition associated with malignant cells expressing CD70 in a subject, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 39. 41. The method of claim 40 wherein the condition is cancer. 42. The method of claim 41 wherein the cancer is selected from the group consisting of renal cell carcinoma, glioblastoma, glioma such as low grade glioma, non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD), Waldenström's macroglobulinemia, acute myeloid leukemia , multiple myeloma, diffuse large cell lymphoma, follicular lymphoma, and non-small cell lung cancer. 43. A method for suppressing tumor growth or progression in a subject that has CD70-expressing cancer cells, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 39. 44. A method for inhibiting metastasis of malignant cells expressing CD70 in a subject, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 39. 45. A method for inducing tumor regression in a subject that has malignant cells expressing CD70, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 39. 46. The CD70-specific CAR of claim 1, wherein the scFv comprises the amino acid sequences of a light chain variable domain and a heavy chain variable domain, respectively, selected from one of SEQ ID NOs: a) 17 and 18; b) 370 and 371; c) 1 and 2; d) 3 and 4; e) 5 and 6; f) 7 and 8; g) 9 and 10; h) 11 and 12; i) 13 and 14; j) 15 and 16; k) 19 and 20; l) 21 and 22; m) 23 and 24; n) 25 and 26; o) 27 and 28; p) 29 and 30; q) 31 and 32; r) 33 and 34; s) 35 and 36; t) 37 and 38; u) 39 and 40; v) 41 and 42; w) 43 and 44; x) 45 and 46; y) 47 and 48; z) 338 and 339; aa) 340 and 341; bb) 342 and 343; cc) 344 and 345; dd) 346 and 347; ee) 348 and 349; ff) 350 and 351; gg) 352 and 353; hh) 354 and 355; ii) 356 and 357; jj) 358 and 359; kk) 360 and 361; ll) 362 and 363; mm) 364 and 365; nn) 366 and 367; oo) 368 and 369; pp) 372 and 373; qq) 374 and 375; rr) 376 and 377; ss) 378 and 379; tt) 380 and 381; And uu) 661 and 662; or the antigen-binding molecule competes for binding to CD70 with an antigen-binding molecule at any of (a)-(uu). 47. The CD70-specific CAR of claim 46, wherein the intracellular signaling domain comprises a CD3ζ signaling domain or a 4-1BB domain. 48. CAR, specific to CD70, according to any one of paragraphs. 46, 47 containing a second intracellular signaling domain. 49. The CD70-specific CAR of claim 48, wherein the CAR contains the CD3ζ intracellular signaling domain and the 4-1BB intracellular signaling domain. 50. CAR, specific to CD70, according to any one of paragraphs. 46-49 containing a hinge domain between the extracellular ligand-binding domain and the first transmembrane domain. 51. The CD70-specific CAR of claim 50, wherein the hinge domain is selected from the group consisting of a human CD8α hinge, an IgG1 hinge, and a FcγRIIIα hinge. 52. CAR, specific to CD70, according to any one of paragraphs. 46-50, additionally containing the CD20 epitope. 53. The CD70-specific CAR of claim 53, wherein the CD20 epitope contains the amino acid sequence shown under SEQ ID NO: 293 or SEQ ID NO: 294 or SEQ ID NO: 609. 54. CAR, specific to CD70, according to any one of paragraphs. 46-53, where the first transmembrane domain provides for the transmembrane domain of the CD8α chain. 55. CAR, specific to CD70, according to any one of paragraphs. 46-54 containing another extracellular ligand-binding domain that is not specific to CD70. 56. CAR, specific to CD70, according to any one of paragraphs. 46-55, wherein the extracellular(s) ligand-binding(s) domain(s), the first transmembrane domain(s), and the intracellular(s) signal(s) domain(s) are located in the same polypeptide. 57. CAR, specific to CD70, according to any one of paragraphs. 46-56, containing a second transmembrane domain, where the first transmembrane domain and the extracellular (extracellular) ligand-binding (ligand-binding) domain (domains) are located in the first polypeptide and where the second transmembrane domain and intracellular (intracellular) signal (signal) domain ( domains) are located in the second polypeptide. 58. A CD70-specific CAR according to claim 57, comprising a third polypeptide containing a third transmembrane domain fused to an intracellular signaling domain from a costimulatory molecule.

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