KR20160062207A - Anti-NR10 antibody and use thereof - Google Patents

Abstract

The present inventors succeeded in obtaining an anti-NR10 antibody having a neutralizing activity effective against NR10. The anti-NR10 antibodies provided by the present invention are useful, for example, as medicines for the treatment or prevention of inflammatory diseases.

Description

Anti-NR10 antibody and its use {Anti-NR10 antibody and use thereof}

The present invention relates to an anti-NR10 antibody and a pharmaceutical composition comprising an anti-NR10 antibody.

As a liquid factor involved in the proliferation, differentiation of various cells, or activation of the function of differentiated mature cells, the presence of numerous cytokines is known. In a living body, cells subjected to cytokine stimulation produce separate cytokines, and a network is formed by a plurality of cytokines. The homeostasis of the living body is maintained in a subtle balance as these networks regulate each other. It is thought that many immuno-inflammatory diseases are caused by disruption of these cytokines/networks, and anticytokine therapy using monoclonal antibodies has been attracting attention. For example, anti-TNF antibodies and anti-IL-6 receptor antibodies have shown high clinical effects. On the other hand, on the other hand, in actual conditions, the target pathway acts, and the therapeutic effect is not obtained only by blocking one cytokine such as IL-4, and there are many cases of failure.

The present inventors have succeeded in isolating a novel cytokine receptor NR10 with high homology to the signal transduction receptor gp130 of IL-6 (Patent Document 1). NR10 forms a heterodimer with the oncostatin M receptor (OSMR), and functions as a receptor for IL-31 (Non-Patent Document 1). As for IL-31, it has been reported that transgenic mice overexpressing IL-31 develop pruritic dermatitis spontaneously (Patent Document 2).

Antibodies that bind to NR10 and inhibit the binding of IL-31 and NR10 are thought to be effective in the treatment of inflammatory diseases. However, in order to use an anti-NR10 antibody in clinical practice, an antibody with low immunogenicity is required. Further, in order to exhibit a high therapeutic effect, an antibody having high binding activity or neutralizing activity to NR10 is desired.

In addition, the prior art document of this invention is shown below.

Patent Document 1: WO00/75314

Patent Document 2: WO03/060090

Non-Patent Document 1: IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis., J Allergy Clin Immunol. 2006 Feb;117(2):418-25.

The present invention has been made in view of the above-described background, and the present invention has an object to provide an anti-NR10 antibody and a pharmaceutical composition containing an anti-NR10 antibody.

The inventors of the present invention have conducted extensive research in order to solve the above problems. The present inventors have succeeded in obtaining an anti-NR10 antibody having an effective neutralizing activity against NR10. In addition, the present inventors have succeeded in humanizing the antibody while maintaining the activity of the antibody. In addition, the present inventors have succeeded in producing antibodies with improved pharmacokinetics, enhanced antigen-binding activity, improved stability, and/or reduced risk of immunogenicity. The antibody is useful as a therapeutic agent for inflammatory diseases.

The present invention relates to an anti-NR10 antibody and a pharmaceutical composition containing an anti-NR10 antibody, and more specifically, includes the inventions [1] to [15] below.

[1] An antibody that recognizes domain 1 of NR10.

[2] The antibody according to [1], which has a neutralizing activity.

[3] The antibody according to [1] or [2], which is a humanized antibody.

[4] The anti-NR10 antibody according to any one of the following (1) to (8);

(1) an antibody having a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 1, CDR2 having the amino acid sequence of SEQ ID NO: 2, and CDR3 having the amino acid sequence of SEQ ID NO: 3,

(2) an antibody having a heavy chain variable region set forth in SEQ ID NO: 4,

(3) an antibody having a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 5, CDR2 having the amino acid sequence set forth in SEQ ID NO: 6, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 7,

(4) an antibody having a light chain variable region set forth in SEQ ID NO: 8,

(5) an antibody having the heavy chain variable region of (1) and the light chain variable region of (3),

(6) an antibody having the heavy chain variable region of (2) and the light chain variable region of (4),

(7) The antibody according to any one of (1) to (6), wherein one or more amino acids are substituted, deleted, added and/or inserted in the antibody according to any one of (1) to (6). An antibody having an activity equivalent to that of,

(8) An antibody that binds to the same epitope as the epitope to which the antibody according to any one of (1) to (7) binds.

[5] The anti-NR10 antibody according to any one of the following (1) to (8);

(1) an antibody having a heavy chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO:9, CDR2 having the amino acid sequence of SEQ ID NO:10, and CDR3 having the amino acid sequence of SEQ ID NO:11,

(2) an antibody having a heavy chain variable region set forth in SEQ ID NO:12,

(3) an antibody having a light chain variable region comprising CDR1 having the amino acid sequence of SEQ ID NO: 13, CDR2 having the amino acid sequence of SEQ ID NO: 14, and CDR3 having the amino acid sequence of SEQ ID NO: 15,

(4) an antibody having a light chain variable region set forth in SEQ ID NO: 16,

(5) an antibody having the heavy chain variable region of (1) and the light chain variable region of (3),

(6) an antibody having the heavy chain variable region of (2) and the light chain variable region of (4),

(7) The antibody according to any one of (1) to (6), wherein one or more amino acids are substituted, deleted, added and/or inserted in the antibody according to any one of (1) to (6). An antibody having an activity equivalent to that of,

(8) An antibody that binds to the same epitope as the epitope to which the antibody according to any one of (1) to (7) binds.

[6] The anti-NR10 antibody according to any one of the following (1) to (8);

(1) an antibody having a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 17, CDR2 having the amino acid sequence set forth in SEQ ID NO: 18, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 19,

(2) an antibody having a heavy chain variable region set forth in SEQ ID NO:20,

(3) an antibody having a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 21, CDR2 having the amino acid sequence set forth in SEQ ID NO: 22, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 23,

(4) an antibody having a light chain variable region set forth in SEQ ID NO: 24,

(5) an antibody having the heavy chain variable region of (1) and the light chain variable region of (3),

(6) an antibody having the heavy chain variable region of (2) and the light chain variable region of (4),

(7) The antibody according to any one of (1) to (6), wherein one or more amino acids are substituted, deleted, added and/or inserted in the antibody according to any one of (1) to (6). An antibody having an activity equivalent to that of,

(8) An antibody that binds to the same epitope as the epitope to which the antibody according to any one of (1) to (7) binds.

[7] The anti-NR10 antibody according to any one of the following (1) to (8);

(1) an antibody having a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 25, CDR2 having the amino acid sequence set forth in SEQ ID NO: 26, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 27,

(2) an antibody having the heavy chain variable region set forth in SEQ ID NO: 28,

(3) an antibody having a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 29, CDR2 having the amino acid sequence set forth in SEQ ID NO: 30, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 31,

(4) an antibody having a light chain variable region set forth in SEQ ID NO: 32,

(5) an antibody having the heavy chain variable region of (1) and the light chain variable region of (3),

(6) an antibody having the heavy chain variable region of (2) and the light chain variable region of (4),

(7) The antibody according to any one of (1) to (6), wherein one or more amino acids are substituted, deleted, added and/or inserted in the antibody according to any one of (1) to (6). An antibody having an activity equivalent to that of,

(8) An antibody that binds to the same epitope as the epitope to which the antibody according to any one of (1) to (7) binds.

[8] The antibody variable region or antibody according to any one of the following (1) to (20);

(1) a heavy chain variable region (H17) comprising CDR1 of SEQ ID NO: 196, CDR2 of SEQ ID NO: 197, and CDR3 of SEQ ID NO: 11,

(2) a heavy chain variable region (H19) comprising CDR1 of SEQ ID NO: 176, CDR2 of SEQ ID NO: 197, and CDR3 of SEQ ID NO: 11,

(3) heavy chain variable regions (H28, H42) comprising CDR1 of SEQ ID NO: 196, CDR2 of SEQ ID NO: 197, and CDR3 of SEQ ID NO: 184,

(4) heavy chain variable regions (H30, H44) comprising CDR1 of SEQ ID NO:9, CDR2 of SEQ ID NO:197, and CDR3 of SEQ ID NO:184,

(5) heavy chain variable regions (H34, H46) comprising CDR1 of SEQ ID NO: 176, CDR2 of SEQ ID NO: 197, and CDR3 of SEQ ID NO: 184,

(6) heavy chain variable regions (H57, H78) comprising CDR1 of SEQ ID NO:9, CDR2 of SEQ ID NO:198, and CDR3 of SEQ ID NO:184,

(7) heavy chain variable regions (H71, H92) comprising CDR1 of SEQ ID NO: 176, CDR2 of SEQ ID NO: 198, and CDR3 of SEQ ID NO: 184,

(8) heavy chain variable regions (H97, H98) comprising CDR1 of SEQ ID NO:9, CDR2 of SEQ ID NO:199, and CDR3 of SEQ ID NO:184,

(9) a light chain variable region (L11) comprising CDR1 of SEQ ID NO: 200, CDR2 of SEQ ID NO: 170, and CDR3 of SEQ ID NO: 193,

(10) a light chain variable region (L12) comprising CDR1 of SEQ ID NO: 201, CDR2 of SEQ ID NO: 170, and CDR3 of SEQ ID NO: 193,

(11) a light chain variable region (L17) comprising CDR1 of SEQ ID NO: 202, CDR2 of SEQ ID NO: 170, and CDR3 of SEQ ID NO: 193,

(12) a light chain variable region (L50) comprising CDR1 of SEQ ID NO: 203, CDR2 of SEQ ID NO: 170, and CDR3 of SEQ ID NO: 193,

(13) an antibody comprising the heavy chain variable region of (3) and the light chain variable region of (11),

(14) an antibody comprising the heavy chain variable region of (4) and the light chain variable region of (11),

(15) an antibody comprising the heavy chain variable region of (5) and the light chain variable region of (11),

(16) an antibody comprising the heavy chain variable region of (6) and the light chain variable region of (11),

(17) an antibody comprising the heavy chain variable region of (7) and the light chain variable region of (11),

(18) an antibody comprising the heavy chain variable region of (8) and the light chain variable region of (12),

(19) The antibody according to any one of (13) to (18), wherein one or more amino acids are substituted, deleted, added and/or inserted in the antibody according to any one of (13) to (18). An antibody having an activity equivalent to that of,

(20) An antibody that binds to the same epitope as the epitope to which the antibody according to any one of (13) to (18) binds.

[9] The antibody variable region or antibody according to any one of the following (1) to (32);

(1) heavy chain variable region (H17) having the amino acid sequence set forth in SEQ ID NO: 204,

(2) heavy chain variable region (H19) having the amino acid sequence set forth in SEQ ID NO: 205,

(3) heavy chain variable region (H28) having the amino acid sequence set forth in SEQ ID NO: 206,

(4) heavy chain variable region (H30) having the amino acid sequence set forth in SEQ ID NO: 207,

(5) heavy chain variable region (H34) having the amino acid sequence set forth in SEQ ID NO: 208,

(6) heavy chain variable region (H42) having the amino acid sequence set forth in SEQ ID NO: 209,

(7) heavy chain variable region (H44) having the amino acid sequence set forth in SEQ ID NO: 210,

(8) heavy chain variable region (H46) having the amino acid sequence set forth in SEQ ID NO: 211,

(9) heavy chain variable region (H57) having the amino acid sequence set forth in SEQ ID NO: 212,

(10) heavy chain variable region (H71) having the amino acid sequence set forth in SEQ ID NO: 213,

(11) heavy chain variable region (H78) having the amino acid sequence set forth in SEQ ID NO: 214,

(12) heavy chain variable region (H92) having the amino acid sequence set forth in SEQ ID NO: 215,

(13) heavy chain variable region (H97) having the amino acid sequence set forth in SEQ ID NO: 216,

(14) heavy chain variable region (H98) having the amino acid sequence set forth in SEQ ID NO: 217,

(15) a light chain variable region (L11) having the amino acid sequence set forth in SEQ ID NO: 218,

(16) a light chain variable region (L12) having the amino acid sequence set forth in SEQ ID NO: 219,

(17) a light chain variable region (L17) having the amino acid sequence set forth in SEQ ID NO: 220,

(18) light chain variable region (L50) having the amino acid sequence set forth in SEQ ID NO: 221,

(19) an antibody (H28L17) comprising the heavy chain variable region of (3) and the light chain variable region of (17),

(20) an antibody (H30L17) comprising the heavy chain variable region of (4) and the light chain variable region of (17),

(21) an antibody (H34L17) comprising the heavy chain variable region of (5) and the light chain variable region of (17),

(22) an antibody (H42L17) comprising the heavy chain variable region of (6) and the light chain variable region of (17),

(23) an antibody (H44L17) comprising the heavy chain variable region of (7) and the light chain variable region of (17),

(24) an antibody (H46L17) comprising the heavy chain variable region of (8) and the light chain variable region of (17),

(25) an antibody (H57L17) comprising the heavy chain variable region of (9) and the light chain variable region of (17),

(26) an antibody (H71L17) comprising the heavy chain variable region of (10) and the light chain variable region of (17),

(27) an antibody (H78L17) comprising the heavy chain variable region of (11) and the light chain variable region of (17),

(28) an antibody (H92L17) comprising the heavy chain variable region of (12) and the light chain variable region of (17),

(29) an antibody (H97L50) comprising the heavy chain variable region of (13) and the light chain variable region of (18),

(30) an antibody (H98L50) comprising the heavy chain variable region of (14) and the light chain variable region of (18),

(31) The antibody according to any one of (19) to (30), wherein one or more amino acids are substituted, deleted, added and/or inserted in the antibody according to any one of (19) to (30). An antibody having an activity equivalent to that of,

(32) An antibody that binds to the same epitope as the epitope to which the antibody according to any one of (19) to (30) binds.

[10] The anti-NR10 antibody according to any one of [4] to [9], which is a humanized antibody.

[11] The antibody heavy chain, antibody light chain, or antibody of any one of the following (1) to (32);

(1) heavy chain (H17) having the amino acid sequence set forth in SEQ ID NO:222,

(2) heavy chain (H19) having the amino acid sequence set forth in SEQ ID NO:223,

(3) heavy chain (H28) having the amino acid sequence set forth in SEQ ID NO:224,

(4) heavy chain (H30) having the amino acid sequence set forth in SEQ ID NO:225,

(5) heavy chain (H34) having the amino acid sequence set forth in SEQ ID NO:226,

(6) heavy chain (H42) having the amino acid sequence set forth in SEQ ID NO:227,

(7) heavy chain (H44) having the amino acid sequence set forth in SEQ ID NO: 228,

(8) heavy chain (H46) having the amino acid sequence set forth in SEQ ID NO:229,

(9) heavy chain (H57) having the amino acid sequence set forth in SEQ ID NO: 230,

(10) heavy chain (H71) having the amino acid sequence set forth in SEQ ID NO:231,

(11) heavy chain (H78) having the amino acid sequence set forth in SEQ ID NO: 232,

(12) heavy chain (H92) having the amino acid sequence set forth in SEQ ID NO: 233,

(13) heavy chain (H97) having the amino acid sequence set forth in SEQ ID NO: 234,

(14) heavy chain (H98) having the amino acid sequence set forth in SEQ ID NO: 235,

(15) light chain (L11) having the amino acid sequence set forth in SEQ ID NO: 236,

(16) light chain (L12) having the amino acid sequence set forth in SEQ ID NO: 237,

(17) light chain (L17) having the amino acid sequence set forth in SEQ ID NO:238,

(18) light chain (L50) having the amino acid sequence set forth in SEQ ID NO:239,

(19) an antibody containing the heavy chain of (3) and the light chain of (17) (H28L17),

(20) an antibody (H30L17) comprising the heavy chain of (4) and the light chain of (17),

(21) an antibody containing the heavy chain of (5) and the light chain of (17) (H34L17),

(22) an antibody (H42L17) comprising the heavy chain of (6) and the light chain of (17),

(23) an antibody containing the heavy chain of (7) and the light chain of (17) (H44L17),

(24) an antibody containing the heavy chain of (8) and the light chain of (17) (H46L17),

(25) an antibody (H57L17) comprising the heavy chain of (9) and the light chain of (17),

(26) an antibody (H71L17) comprising the heavy chain of (10) and the light chain of (17),

(27) an antibody (H78L17) comprising the heavy chain of (11) and the light chain of (17),

(28) an antibody (H92L17) comprising the heavy chain of (12) and the light chain of (17),

(29) an antibody (H97L50) comprising the heavy chain of (13) and the light chain of (18),

(30) an antibody (H98L50) comprising the heavy chain of (14) and the light chain of (18),

(31) The antibody according to any one of (19) to (30), wherein one or more amino acids are substituted, deleted, added and/or inserted in the antibody according to any one of (19) to (30). An antibody having an activity equivalent to that of,

(32) An antibody that binds to the same epitope as the epitope to which the antibody according to any one of (19) to (30) binds.

[12] A pharmaceutical composition containing the antibody according to any one of [1] to [11].

[13] The pharmaceutical composition according to [12], which is a therapeutic agent for an inflammatory disease.

[14] A method for treating or preventing an inflammatory disease, including the step of administering the antibody according to any one of [1] to [11].

[15] Use of the antibody according to any one of [1] to [11] in the manufacture of a therapeutic agent for an inflammatory disease.

1 is a diagram showing the amino acid sequence of a heavy chain variable region of mouse antibodies NS18, NS22, NS23, NS33.
2 is a diagram showing the amino acid sequence of the light chain variable region of mouse antibodies NS18, NS22, NS23, NS33.
3 is a graph showing the inhibition of hybridoma culture supernatant on the proliferation of hNR10/hOSMR/BaF3 cells.
Fig. 4 is a graph showing the inhibition of the hybridoma culture supernatant on the proliferation of cynNR10/cynOSMR/BaF3 cells.
5 is a graph showing the activity evaluation (BaF) of chimeric NS22.
6 is a graph showing the activity evaluation (DU-145) of chimeric NS22.
7 is a graph showing the evaluation of IL-31 competitive activity of chimeric NS22.
8 is a graph showing the NR10 binding competition activity of an anti-NR10 antibody.
9 is a graph showing the IL-31 competitive activity of humanized NS22 (H0L0).
Fig. 10 is a diagram in which the influence of the humanized anti-NR10 antibody H0L0 on the heterogeneity of the constant region was evaluated by cation exchange chromatography.
Fig. 11 is a graph showing the evaluation of IL-31 competitive activity of a variant capable of lowering the isoelectric point of a variable region without significantly lowering the binding of a humanized anti-NR10 antibody to NR10.
Fig. 12 is a diagram evaluating the effect of the constant region of the anti-IL-6 receptor antibody on the heterogeneity by cation exchange chromatography.
Fig. 13 is a diagram evaluating the influence of a constant region of an anti-IL-6 receptor antibody on a denaturing peak by DSC.
Fig. 14 is a diagram in which the effect of the novel constant region M14 on the heterogeneity of the anti-IL-6 receptor antibody was evaluated by cation exchange chromatography.
Fig. 15 is a diagram evaluating the effect of the novel constant region M58 on the heterogeneity of the anti-IL-6 receptor antibody by cation exchange chromatography.
Fig. 16 is a diagram evaluating the influence of the novel constant region M58 on the denatured peak by DSC in the anti-IL-6 receptor antibody.
Fig. 17 is a diagram showing the evaluation results of plasma retention in human FcRn transgenic mice of huPM1-IgG1 and huPM1-M58.
18 is a graph showing biological activity using BaF/NR10 for each antibody.
Fig. 19 is a diagram in which a thermally accelerated product (dotted line) and an unaccelerated product (solid line) of each obtained modified antibody are analyzed by cation exchange chromatography, and the generation of decomposition products before and after thermal acceleration is compared. The arrow indicates the peak position of the basic component at which the change was confirmed.
20 is a graph showing the activity evaluation (BaF) of each variant.
Fig. 21 is a graph showing activity evaluation (BaF) of Ha401La402 and H0L0.
22 is a graph showing the activity evaluation (BaF) of H17L11 and H0L0.
23 is a graph showing the activity evaluation (BaF) of H19L12 and H0L0.
24 is a graph showing the biological activity of H0L12 and H0L17 using BaF/NR10.
25A is a graph showing the activity evaluation (BaF) of each variant.
Fig. 25B is a continuation of Fig. 25A.
Fig. 26 is a schematic diagram of human mouse wild type and chimeric NR10-ECD.
27 is a photograph of binding domains detected using Western blot. A is a photograph showing the result of detection with a humanized anti-human NR10 antibody, B is a photograph showing the result of detection with a mouse anti-human NR10 antibody, and C is a photograph showing the result of detection with an anti-Myc antibody. Depending on the anti-human NR10 antibody, binding antigens were detected only in hhh, hhm, and hmm, and binding of mmm, mmh, and mhm could not be confirmed.
28A is a diagram showing the amino acid sequence of each variant of HO (SEQ ID NO:50).
FIG. 28B is a continuation of FIG. 28A.
Fig. 28C is a continuation of Fig. 28B.
29A is a diagram showing the amino acid sequence of each variant of L0 (SEQ ID NO: 52).
Fig. 29B is a continuation of Fig. 29A.

NR10

NR10 is a protein that forms a heterodimer with the oncostatin M receptor (OSMR) and functions as a receptor for IL-31. Also known as glm-r (J Biol Chem 277, 16831-6, 2002), GPL (J Biol Chem 278, 49850-9, 2003), IL31RA (Nat Immunol 5, 752-60, 2004), etc. The NR10 of the present invention also includes a protein called such a name.

The origin of the NR10 (also referred to as IL31RA, GPL or glm-r) of the present invention is not particularly limited, and includes NR10 derived from humans, mice, monkeys, and other mammals, but preferably derived from humans, mice or monkeys. NR10, particularly preferably human-derived NR10.

As human-derived NR10, a plurality of splicing variants are known (WO00/075314). Among the splicing variants, NR10.1 is 662 amino acids, and has a cell membrane penetrating region. Further, NR10.2 is a soluble receptor-like protein that does not have a transmembrane region having a 252 amino acid sequence. On the other hand, NR10.3 and IL31RAv3 are known as NR10 splicing variants that function as a transmembrane receptor protein. Human NR10 in the present invention is not particularly limited as long as it forms a heterodimer with oncostatin M receptor (OSMR) and functions as a receptor for IL-31, but a preferable NR10 is NR10.3 (also called ILRAv4 (Nat Immunol 5, 752-60, 2004)) and IL31RAv3. NR10.3 (IL31RAv4) becomes 662 amino acids (WO00/075314, Nat Immunol 5, 752-60, 2004), and IL31RAv3 becomes 732 amino acids (GenBank ACCESSION No: NM_139017). The amino acid sequence of IL31RAv4 is shown in SEQ ID NO: 79, and the amino acid sequence of IL31RAv3 is shown in SEQ ID NO: 80. On the other hand, as NR10 derived from a mouse, for example, a protein having the amino acid sequence set forth in SEQ ID NO: 81 is exemplified. In addition, as NR10 derived from a crab monkey, for example, a protein having the amino acid sequence set forth in SEQ ID NO:66 is exemplified.

Antibody (sequence)

As a preferred embodiment of the anti-NR10 antibody of the present invention, the anti-NR10 antibody described in any one of (1) to (8) in the following (A) to (D) can be mentioned.

(A) NS18

(1) CDR1 having the amino acid sequence of SEQ ID NO: 1 (HCDR1), CDR2 having the amino acid sequence of SEQ ID NO: 2 (HCDR2), and CDR3 having the amino acid sequence of SEQ ID NO: 3 (HCDR3) Antibody with heavy chain variable region

(2) Antibody having heavy chain variable region described in SEQ ID NO: 4 (VH)

(3) CDR1 having the amino acid sequence set forth in SEQ ID NO: 5 (LCDR1), CDR2 having the amino acid sequence set forth in SEQ ID NO: 6 (LCDR2), including CDR3 having the amino acid sequence set forth in SEQ ID NO: 7 (LCDR3) Antibody with light chain variable region

(4) Antibody having the light chain variable region described in SEQ ID NO: 8 (VL)

(5) an antibody having the heavy chain variable region of (1) and the light chain variable region of (3)

(6) an antibody having the heavy chain variable region of (2) and the light chain variable region of (4)

(7) The antibody according to any one of (1) to (6), wherein one or more amino acids are substituted, deleted, added and/or inserted in the antibody according to any one of (1) to (6). Antibodies having an activity equivalent to

(8) An antibody that binds to the same epitope as the epitope to which the antibody described in any one of (1) to (7) binds

(B) NS22

(1) CDR1 having the amino acid sequence set forth in SEQ ID NO:9 (HCDR1), CDR2 having the amino acid sequence set forth in SEQ ID NO:10 (HCDR2), and CDR3 having the amino acid sequence set forth in SEQ ID NO:11 (HCDR3) Antibody with heavy chain variable region

(2) Antibody having heavy chain variable region set forth in SEQ ID NO:12 (VH)

(3) CDR1 having the amino acid sequence set forth in SEQ ID NO: 13 (LCDR1), CDR2 having the amino acid sequence set forth in SEQ ID NO: 14 (LCDR2), including CDR3 having the amino acid sequence set forth in SEQ ID NO: 15 (LCDR3) Antibody with light chain variable region

(4) Antibody having a light chain variable region set forth in SEQ ID NO: 16 (VL)

(5) an antibody having the heavy chain variable region of (1) and the light chain variable region of (3)

(6) an antibody having the heavy chain variable region of (2) and the light chain variable region of (4)

(7) The antibody according to any one of (1) to (6), wherein one or more amino acids are substituted, deleted, added and/or inserted in the antibody according to any one of (1) to (6). Antibodies having an activity equivalent to

(8) An antibody that binds to the same epitope as the epitope to which the antibody described in any one of (1) to (7) binds

Specific examples of the substitution, deletion, addition and/or insertion of one or more amino acids described above are not particularly limited, but the following modifications may be mentioned.

Substitution of the third Ile with another amino acid in the heavy chain CDR1 of SEQ ID NO:9. The amino acid after substitution is not particularly limited, but a preferred example is Val.

Substitution of the fourth Met with another amino acid in the heavy chain CDR1 of SEQ ID NO:9. The amino acid after substitution is not particularly limited, but a preferred example is Ile.

Substitution of the fourth Met with another amino acid in the heavy chain CDR1 of SEQ ID NO:9. The amino acid after substitution is not particularly limited, but a preferred example is Leu.

Substitution of the third Ile with another amino acid in the heavy chain CDR1 of SEQ ID NO:9. The amino acid after substitution is not particularly limited, but a preferred example is Ala.

Substitution of 1st Leu with another amino acid in heavy chain CDR2 of SEQ ID NO:10. The amino acid after substitution is not particularly limited, but a preferred example is Glu.

Substitution of the third Asn with another amino acid in the heavy chain CDR2 of SEQ ID NO:10. The amino acid after substitution is not particularly limited, but a preferred example is Asp.

Substitution of the 13th Gln with another amino acid in the heavy chain CDR2 of SEQ ID NO:10. The amino acid after substitution is not particularly limited, but a preferred example is Asp.

Substitution of the 14th Lys with another amino acid in the heavy chain CDR2 of SEQ ID NO:10. The amino acid after substitution is not particularly limited, but a preferred example is Gln.

Substitution of the 16th Lys with another amino acid in the heavy chain CDR2 of SEQ ID NO:10. The amino acid after substitution is not particularly limited, but a preferred example is Gln.

Substitution of the 17th Gly with another amino acid in the heavy chain CDR2 of SEQ ID NO:10. The amino acid after substitution is not particularly limited, but a preferred example is Asp.

Substitution of the 16th Lys and 17th Gly with other amino acids in the heavy chain CDR2 of SEQ ID NO:10. The amino acid after substitution is not particularly limited, but preferred examples include substitution of Gln at the 16th Lys and Gly at the 17th Asp.

Substitution of the 14th Lys, the 16th Lys, and the 17th Gly with other amino acids in the heavy chain CDR2 of SEQ ID NO:10. The amino acid after substitution is not particularly limited, but preferred examples include substitution of Gln of Lys at the 14th position, Gln of Lys at the 16th position, and Gly at the 17th position with Asp.

Substitution of the 13th Gln, 14th Lys, 16th Lys, and 17th Gly with other amino acids in the heavy chain CDR2 of SEQ ID NO:10. The amino acid after substitution is not particularly limited, but preferred examples include substitution of Asp of the 13th Gln, Gln of the 14th Lys, Gln of the 16th Lys, and Asp of the 17th Gly.

Substitution of the tenth Ser with another amino acid in the heavy chain CDR2 of SEQ ID NO:10. The amino acid after substitution is not particularly limited, but a preferred example is Asp.

Substitution of the 13th Gln with another amino acid in the heavy chain CDR2 of SEQ ID NO:10. The amino acid after substitution is not particularly limited, but a preferred example is Pro.

Substitution of the third Tyr with another amino acid in the heavy chain CDR3 of SEQ ID NO:11. The amino acid after substitution is not particularly limited, but a preferred example is Leu.

Substitution of the 10th Met with another amino acid in the heavy chain CDR3 of SEQ ID NO:11. The amino acid after substitution is not particularly limited, but a preferred example is Leu.

Substitution of the 11th Asp with another amino acid in the heavy chain CDR3 of SEQ ID NO:11. The amino acid after substitution is not particularly limited, but a preferred example is Glu.

Substitution of the 12th Tyr with another amino acid in the heavy chain CDR3 of SEQ ID NO:11. The amino acid after substitution is not particularly limited, but preferred examples include Thr or Ser.

In the heavy chain CDR3 of SEQ ID NO: 11, substitution of the 10th Met, the 11th Asp, and the 12th Tyr with other amino acids. The amino acid after substitution is not particularly limited, but preferred examples include substitution of Leu of Met at the 10th, Glu of Asp at the 11th, and Thr of Tyr at the 12th.

In the heavy chain CDR3 of SEQ ID NO: 11, Asp at the 11th position and Tyr at the 12th position are substituted with other amino acids. The amino acid after substitution is not particularly limited, but preferred examples include substitution of Asp at the 11th position with Glu and Tyr at the 12th position with Thr.

In the heavy chain CDR3 of SEQ ID NO:11, substitution of the 3rd Tyr, the 11th Asp, and the 12th Tyr with other amino acids. The amino acid after substitution is not particularly limited, but preferred examples include substitution of Leu of the 3rd Tyr, Glu of the 11th Asp, and Thr or Ser of the 12th Tyr.

Substitution of the first Arg with another amino acid in the light chain CDR1 of SEQ ID NO: 13. The amino acid after substitution is not particularly limited, but a preferred example is Gln.

Substitution of the fifth Asn with another amino acid in the light chain CDR1 of SEQ ID NO: 13. The amino acid after substitution is not particularly limited, but a preferred example is Asp.

Substitution of 1st Arg and 5th Asn with other amino acids in the light chain CDR1 of SEQ ID NO: 13. The amino acid after substitution is not particularly limited, but preferred examples include substitution of Gln of Arg at the 1st position and Asn at the 5th position with Asp.

Substitution of the 8th Ser with another amino acid in the light chain CDR1 of SEQ ID NO: 13. The amino acid after substitution is not particularly limited, but Arg is mentioned as a preferred example.

Substitution of Leu at position 10 with another amino acid in the light chain CDR1 of SEQ ID NO: 13. The amino acid after substitution is not particularly limited, but a preferred example is Val.

Substitution of 8th Ser and 10th Leu with other amino acids in the light chain CDR1 of SEQ ID NO: 13. The amino acid after substitution is not particularly limited, but preferred examples include substitution of Arg of Ser at the eighth and Val of Leu at the tenth.

Substitution of the second Thr with another amino acid in the light chain CDR1 of SEQ ID NO: 13. The amino acid after substitution is not particularly limited, but preferred examples include Ala or Ser.

Substitution of the first Asn with another amino acid in the light chain CDR2 of SEQ ID NO: 14. The amino acid after substitution is not particularly limited, but a preferred example is Asp.

Substitution of the third Lys with another amino acid in the light chain CDR2 of SEQ ID NO: 14. The amino acid after substitution is not particularly limited, but a preferred example is Gln.

Substitution of 5th Leu with another amino acid in the light chain CDR2 of SEQ ID NO: 14. The amino acid after substitution is not particularly limited, but a preferred example is Glu.

Substitution of 7th Lys with another amino acid in the light chain CDR2 of SEQ ID NO: 14. The amino acid after substitution is not particularly limited, but preferred examples include Gln or Asp.

Substitution of 3rd Lys, 5th Leu, and 7th Lys with other amino acids in the light chain CDR2 of SEQ ID NO: 14. The amino acid after substitution is not particularly limited, but preferred examples include substitution of Gln of Lys at the 3rd, Glu of Leu at the 5th, and Gln of Lys at the 7th.

Substitution of 5th Glu with another amino acid in the light chain CDR3 of SEQ ID NO:15. The amino acid after substitution is not particularly limited, but a preferred example is Asp.

Substitution of the 6th Ser with another amino acid in the light chain CDR3 of SEQ ID NO:15. The amino acid after substitution is not particularly limited, but a preferred example is Asp.

Substitution of the 9th Thr with another amino acid in the light chain CDR3 of SEQ ID NO:15. The amino acid after substitution is not particularly limited, but a preferred example is Phe.

The above-described substitution may be performed alone or a plurality of substitutions may be combined. Moreover, you may combine the substitution mentioned above and the substitution other than the above. By these substitutions, it is possible to improve the pharmacokinetics (retention in plasma) of the antibody, enhance the antigen-binding activity, improve stability, and/or reduce the risk of immunogenicity.

In the present invention, specific examples of the variable region in which the above-described substitutions are combined include a heavy chain variable region having an amino acid sequence of SEQ ID NO: 167 or a light chain variable region having an amino acid sequence of SEQ ID NO: 168. Further, as an example of an antibody incorporating the above-described substitutions, an antibody comprising a heavy chain variable region having an amino acid sequence of SEQ ID NO: 167 and a light chain variable region having an amino acid sequence of SEQ ID NO: 168 can be exemplified.

In addition, as a specific example of the heavy chain variable region or light chain variable region in which the above-described substitutions are combined, the following variable regions can be exemplified.

(a) A heavy chain variable region comprising CDR1 of SEQ ID NO: 196, CDR2 of SEQ ID NO: 197, and CDR3 of SEQ ID NO:11. (H17)

(b) A heavy chain variable region comprising CDR1 of SEQ ID NO:176, CDR2 of SEQ ID NO:197, and CDR3 of SEQ ID NO:11. (H19)

(c) A heavy chain variable region comprising CDR1 of SEQ ID NO: 196, CDR2 of SEQ ID NO: 197, and CDR3 of SEQ ID NO: 184. (H28, H42)

(d) A heavy chain variable region comprising CDR1 of SEQ ID NO:9, CDR2 of SEQ ID NO:197, and CDR3 of SEQ ID NO:184. (H30, H44)

(e) A heavy chain variable region comprising CDR1 of SEQ ID NO: 176, CDR2 of SEQ ID NO: 197, and CDR3 of SEQ ID NO: 184. (H34, H46)

(f) a heavy chain variable region comprising CDR1 of SEQ ID NO:9, CDR2 of SEQ ID NO:198, and CDR3 of SEQ ID NO:184. (H57, H78)

(g) A heavy chain variable region comprising CDR1 of SEQ ID NO: 176, CDR2 of SEQ ID NO: 198, and CDR3 of SEQ ID NO: 184. (H71, H92)

(h) A heavy chain variable region comprising CDR1 of SEQ ID NO:9, CDR2 of SEQ ID NO: 199, and CDR3 of SEQ ID NO:184. (H97, H98)

(i) A light chain variable region comprising CDR1 of SEQ ID NO: 200, CDR2 of SEQ ID NO: 170, and CDR3 of SEQ ID NO: 193. (L11)

(j) A light chain variable region comprising CDR1 of SEQ ID NO: 201, CDR2 of SEQ ID NO: 170, and CDR3 of SEQ ID NO: 193. (L12)

(k) A light chain variable region comprising CDR1 of SEQ ID NO: 202, CDR2 of SEQ ID NO: 170, and CDR3 of SEQ ID NO: 193. (L17)

(l) A light chain variable region comprising CDR1 of SEQ ID NO: 203, CDR2 of SEQ ID NO: 170, and CDR3 of SEQ ID NO: 193. (L50)

Moreover, the following antibodies are mentioned as a specific example of the antibody which combined the above-mentioned substitution.

(i) an antibody comprising the heavy chain variable region of (c) and the light chain variable region of (k)

(ii) an antibody comprising the heavy chain variable region of (d) and the light chain variable region of (k)

(iii) an antibody comprising the heavy chain variable region of (e) and the light chain variable region of (k)

(iv) an antibody comprising the heavy chain variable region of (f) and the light chain variable region of (k)

(v) an antibody comprising the heavy chain variable region of (g) and the light chain variable region of (k)

(vi) an antibody comprising the heavy chain variable region of (h) and the light chain variable region of (l)

(C) NS23

(1) CDR1 having the amino acid sequence set forth in SEQ ID NO: 17 (HCDR1), CDR2 having the amino acid sequence set forth in SEQ ID NO: 18 (HCDR2), including CDR3 having the amino acid sequence set forth in SEQ ID NO: 19 (HCDR3) Antibody with heavy chain variable region

(2) Antibody having heavy chain variable region set forth in SEQ ID NO:20 (VH)

(3) CDR1 having the amino acid sequence set forth in SEQ ID NO: 21 (LCDR1), CDR2 having the amino acid sequence set forth in SEQ ID NO: 22 (LCDR2), including CDR3 having the amino acid sequence set forth in SEQ ID NO: 23 (LCDR3) Antibody with light chain variable region

(4) Antibody having a light chain variable region described in SEQ ID NO: 24 (VL)

(5) an antibody having the heavy chain variable region of (1) and the light chain variable region of (3)

(6) an antibody having the heavy chain variable region of (2) and the light chain variable region of (4)

(7) The antibody according to any one of (1) to (6), wherein one or more amino acids are substituted, deleted, added and/or inserted in the antibody according to any one of (1) to (6). Antibodies having an activity equivalent to

(8) An antibody that binds to the same epitope as the epitope to which the antibody described in any one of (1) to (7) binds

(D) NS33

(1) CDR1 having the amino acid sequence set forth in SEQ ID NO: 25 (HCDR1), CDR2 having the amino acid sequence set forth in SEQ ID NO: 26 (HCDR2), including CDR3 having the amino acid sequence set forth in SEQ ID NO: 27 (HCDR3) Antibody with heavy chain variable region

(2) Antibody having heavy chain variable region set forth in SEQ ID NO: 28 (VH)

(3) CDR1 having the amino acid sequence set forth in SEQ ID NO: 29 (LCDR1), CDR2 having the amino acid sequence set forth in SEQ ID NO: 30 (LCDR2), including CDR3 having the amino acid sequence set forth in SEQ ID NO: 31 (LCDR3) Antibody with light chain variable region

(4) Antibody having a light chain variable region set forth in SEQ ID NO: 32 (VL)

(5) an antibody having the heavy chain variable region of (1) and the light chain variable region of (3)

(6) an antibody having the heavy chain variable region of (2) and the light chain variable region of (4)

(7) The antibody according to any one of (1) to (6), wherein one or more amino acids are substituted, deleted, added and/or inserted in the antibody according to any one of (1) to (6). Antibodies having an activity equivalent to

(8) An antibody that binds to the same epitope as the epitope to which the antibody described in any one of (1) to (7) binds

In the antibody described in (1) or (3) described above, any framework region (FR) may be used, but human-derived FRs are preferably used. In addition, in the antibodies described in (1) to (8) described above, any constant region may be used as the constant region, but it is preferable that a human-derived constant region is used. The amino acid sequence of the FR or constant region used in the antibody of the present invention may be the original FR or constant region amino acid sequence from which it is derived, or one or more amino acids are substituted, deleted, added and/or inserted. Etc. You may use it as a different amino acid sequence.

The amino acid sequence of the aforementioned NS18 heavy chain is shown in SEQ ID NO: 34, and the nucleotide sequence encoding the amino acid sequence is shown in SEQ ID NO: 33. In addition, the amino acid sequence of the light chain is shown in SEQ ID NO: 36, and the nucleotide sequence encoding the amino acid sequence is shown in SEQ ID NO: 35.

The amino acid sequence of the heavy chain of NS22 is shown in SEQ ID NO: 38, and the nucleotide sequence encoding the amino acid sequence is shown in SEQ ID NO: 37. In addition, the amino acid sequence of the light chain is shown in SEQ ID NO: 40, and the nucleotide sequence encoding the amino acid sequence is shown in SEQ ID NO: 39.

The amino acid sequence of the heavy chain of NS23 is shown in SEQ ID NO: 42, and the nucleotide sequence encoding the amino acid sequence is shown in SEQ ID NO: 41. In addition, the amino acid sequence of the light chain is shown in SEQ ID NO: 44, and the nucleotide sequence encoding the amino acid sequence is shown in SEQ ID NO: 43.

The amino acid sequence of the heavy chain of NS33 is shown in SEQ ID NO: 46, and the nucleotide sequence encoding the amino acid sequence is shown in SEQ ID NO: 45. In addition, the amino acid sequence of the light chain is shown in SEQ ID NO: 48, and the nucleotide sequence encoding the amino acid sequence is shown in SEQ ID NO: 47.

In the present invention, "the same activity as the antibody described in any one of (1) to (6)" means that the binding activity to NR10 (for example, human NR10) and/or the neutralizing activity are equivalent. In the present invention, "equivalent" does not necessarily have to be the same level of activity, and the activity may be enhanced, and as long as it has activity, the activity may be decreased. Examples of the antibody with reduced activity include antibodies having 30% or more activity, preferably 50% or more activity, and more preferably 80% or more activity compared to the original antibody.

The antibody described in any one of (1) to (6) described above is one or more in the amino acid sequence of the variable region (CDR sequence and/or FR sequence) as long as it has binding activity and/or neutralizing activity to NR10. Amino acids may be substituted, deleted, added and/or inserted. In the amino acid sequence, one or more amino acids are substituted, deleted, added and/or inserted, and as a method well known to those skilled in the art for preparing the amino acid sequence of an antibody having binding activity and/or neutralizing activity for NR10 , Methods of introducing mutations into proteins are known. For example, one of ordinary skill in the art has a site-specific mutagenesis method (Hashimoto-Gotoh, T, Mizuno, T, Ogasahara, Y, and Nakagawa, M. (1995) An oligodeoxyribonucleotide-directed dual amber method for site-directed mutagenesis. Gene 152, 271-275, Zoller, MJ, and Smith, M. (1983) Oligonucleotide-directed mutagenesis of DNA fragments cloned into M13 vectors.Methods Enzymol. 100, 468-500, Kramer, W, Drutsa, V, Jansen, HW , Kramer, B, Pflugfelder, M, and Fritz, HJ (1984) The gapped duplex DNA approach to oligonucleotide-directed mutation construction.Nucleic Acids Res. 12, 9441-9456, Kramer W, and Fritz HJ (1987) Oligonucleotide-directed construction of mutations via gapped duplex DNA Methods.Enzymol. 154, 350-367, Kunkel, TA (1985) Rapid and efficient site-specific mutagenesis without phenotypic selection.Proc Natl Acad Sci US A. 82, 488-492). Thus, by appropriately introducing a mutation into the amino acid sequence of an antibody having binding activity and/or neutralizing activity to NR10, a variant functionally equivalent to an antibody having binding activity and/or neutralizing activity to NR10 can be prepared. As described above, antibodies having one or more amino acids mutated in the variable region and having binding activity and/or neutralizing activity to NR10 are also included in the antibodies of the present invention.

In the case of altering the amino acid residue, it is preferable to change to a separate amino acid in which the nature of the amino acid side chain is preserved. For example, as the nature of the amino acid side chain, hydrophobic amino acids (A, I, L, M, F, P, W, Y, V), hydrophilic amino acids (R, D, N, C, E, Q, G, H, K, S, T), amino acids having aliphatic side chains (G, A, V, L, I, P), amino acids having hydroxyl group-containing side chains (S, T, Y), amino acids having sulfur atom-containing side chains (C, M ), amino acids having side chains containing carboxylic acids and amides (D, N, E, Q), amino acids having side chains containing bases (R, K, H), and amino acids having side chains containing aromatics (H, F, Y, W) is mentioned (all in parentheses indicate one letter of amino acid). Substitutions of amino acids within each of these groups are called conservative substitutions. It is already known that a polypeptide having an amino acid sequence modified by deletion, addition and/or substitution of one or more amino acid residues for any one amino acid sequence retains its biological activity (Mark, DF et al. ., Proc. Natl. Acad. Sci. USA (1984)81:5662-6; Zoller, MJ and Smith, M., Nucleic Acids Res. (1982) 10:6487-500; Wang, A. et al., Science (1984) 224:1431-3; Dalbadie-McFarland, G. et al., Proc. Natl. Acad. Sci. USA (1982) 79:6409-13). Such a variant is 70% or more, more preferably 75% or more, more preferably 80% or more, even more preferably with the amino acid sequence of the variable region (e.g., CDR sequence, FR sequence, and the entire variable region) of the present invention. Preferably 85% or more, even more preferably 90% or more, and most preferably 95% or more of the identity of the amino acid sequence. In the present specification, the identity of the sequence is the ratio of residues identical to the residues of the amino acid sequence of the heavy chain variable region or light chain variable region after aligning the sequence as necessary and introducing a gap appropriately so that the sequence identity is maximized Is defined as The identity of the amino acid sequence can be determined by the method described later.

In addition, in the amino acid sequence of the variable region (CDR sequence and/or FR sequence), one or more amino acids have been substituted, deleted, added and/or inserted, and thus a variable having binding activity and/or neutralizing activity to NR10 The amino acid sequence of a region can also be obtained from a nucleic acid that hybridizes under stringent conditions to a nucleic acid having a base sequence encoding the amino acid sequence of the variable region. Stringent hybridization conditions for isolating a nucleic acid that hybridizes under stringent conditions to a nucleic acid having a base sequence encoding the amino acid sequence of the variable region include 6M urea, 0.4% SDS, 0.5 x SSC , 37°C conditions or stringency hybridization conditions equivalent thereto can be exemplified. If conditions with higher stringency, for example, 6M urea, 0.4% SDS, 0.1×SSC, and 42°C are used, isolation of nucleic acids with higher homology can be expected. The sequence of the isolated nucleic acid can be determined by a known method described later. The homology of the isolated nucleic acid is at least 50% or more, more preferably 70% or more, more preferably 90% or more (e.g., 95%, 96%, 97%, 98%, 99) in the entire nucleotide sequence. % Or more) of the sequence.

Instead of using the hybridization technique, a gene amplification method using a primer synthesized based on the nucleotide sequence information encoding the amino acid sequence of the variable region, for example, a polymerase chain reaction (PCR) method, is used. Thus, it is also possible to isolate a nucleic acid that is a nucleotide sequence encoding an amino acid sequence in a variable region and a nucleic acid that hybridizes under stringent conditions.

The identity of the nucleotide sequence and the amino acid sequence can be determined by the algorithm BLAST (Proc.Natl.Acad.Sci.USA (1993)90:5873-7) by Karlin and Altschul. Based on this algorithm, a program called BLASTN or BLASTX has been developed (Altschul et al., J. Mol. Biol. (1990) 215:403-10). In the case of analyzing the base sequence by BLASTN based on BLAST, the parameters are, for example, score=100 and wordlength=12. In addition, in the case of analyzing the amino acid sequence by BLASTX based on BLAST, the parameters are, for example, score=50 and wordlength=3. When using BLAST and Gapped BLAST programs, use the default parameters of each program. The specific method of these analysis methods is known (refer to the website of BLAST (Basic Local Alignment Search Tool) of NCBI (National Center for Biotechnology Information); http://www.ncbi.nlm.nih.gov).

Further, the present invention also provides an antibody that binds to the same epitope as the epitope to which the antibody described in any one of (1) to (7) binds.

Whether one antibody recognizes the same epitope as another antibody can be confirmed by competition for both epitopes. The competition between antibodies can be evaluated by a competition binding assay, and ELISA, fluorescence energy transfer assay (FRET), fluorescence trace measurement technology (FMAT (registered trademark)) and the like can be exemplified as means. The amount of this antibody bound to the antigen is indirectly correlated with the binding ability of the candidate competitive antibody (test antibody) that competes for binding to the same epitope. That is, as the amount or affinity of the test antibody for the same epitope increases, the amount of antibody binding to the antigen decreases, and the amount of test antibody binding to the antigen increases. Specifically, with respect to the antigen, the antibody having an appropriate label and the antibody to be evaluated are simultaneously added, and the antibody bound to the antigen is detected using the label. The amount of the antibody bound to the antigen can be easily measured by labeling the antibody in advance. This label is not particularly limited, but a labeling method according to the method is selected. Specific examples of the labeling method include a fluorescent label, a radiolabel, and an enzyme label.

For example, the fluorescently-labeled antibody and the unlabeled antibody or test antibody are simultaneously added to an animal cell expressing NR10, and the labeled antibody is detected by a fluorescence trace measurement technique.

The term ``antibody that recognizes the same epitope'' herein refers to the concentration of the labeled antibody to _{reduce the amount of binding by 50% (IC 50) by binding of the unlabeled antibody.} IC ₅₀ is usually 100 times, preferably 80 times, more preferably 50 times, more preferably 30 times, more preferably 10 times At least 50% at a high concentration, reducing the binding amount of the antibody of the label. It can be an antibody.

An antibody that binds to an epitope to which the antibody described in any one of the above (1) to (7) binds is particularly useful in that it has a high neutralizing activity.

The antibody described in any one of the above (1) to (8) is not particularly limited, but it is preferably a humanized antibody.

In addition, the present invention provides a gene encoding the anti-NR10 antibody according to any one of (1) to (8) in (A) to (D) described above. The gene of the present invention may be any gene, for example, DNA or RNA.

Antibodies (humanized)

One of the preferred embodiments of the antibody in the present invention is a humanized antibody that binds to NR10. Humanized antibodies can be prepared using methods known to those skilled in the art.

The variable region of an antibody is usually composed of three complementarity determining regions (CDRs) sandwiched between four frames (FR). The CDR is a region that substantially determines the binding specificity of the antibody. The amino acid sequence of the CDRs is rich in diversity. On the other hand, the amino acid sequence constituting the FR often exhibits high homology even among antibodies having different binding specificities. Therefore, it is generally said that the binding specificity of one antibody can be grafted to another antibody by CDR grafting.

Humanized antibodies are also called reshaped human antibodies, which are obtained by grafting the CDRs of a non-human mammal, for example, a mouse antibody, into the complementarity determining region of a human antibody, and a general gene recombination technique is also known (European See Patent Application Publication No. EP 125023, WO 96/02576).

Specifically, for example, when the CDR is derived from a mouse antibody, a DNA sequence designed to connect the CDR of a mouse antibody and the framework region (FR) of a human antibody is provided in the terminal regions of both CDRs and FRs. Several oligonucleotides prepared to have overlapping portions are used as primers and synthesized by PCR method (refer to the method described in WO 98/13388). It is obtained by ligating the obtained DNA with DNA encoding the human antibody constant region, then inserting it into an expression vector, introducing it into a host, and producing it (see European Patent Application Publication No. EP 239400, International Patent Application Publication No. WO 96/02576). ).

The framework region of the human antibody linked to the CDR is selected to form an antigen-binding site having a good complementarity determining region. If necessary, amino acids in the framework region in the variable region of the antibody may be substituted, deleted, added and/or inserted so that the complementarity determining region of the reconstituted human antibody forms an appropriate antigen-binding site. For example, by applying the PCR method used for grafting mouse CDRs into human FRs, mutations in amino acid sequences can be introduced into FRs. Specifically, partial nucleotide sequence mutations can be introduced into the primers annealed to the FR. In the FR synthesized by such a primer, a nucleotide sequence mutation is introduced. A mutant FR sequence having a desired property can be selected by measuring and evaluating the antigen-binding activity of a mutant antibody substituted with an amino acid by the above method (Sato, K. etal., Cancer Res. (1993) 53, 851- 856).

For the C region of the humanized antibody, a human antibody is used.For example, in the H chain, Cγ1, Cγ2, Cγ3, Cγ4, Cμ, Cδ, Cα1, Cα2, Cε, and Cκ and Cλ can be used in the L chain. The amino acid sequence of Cκ is shown in SEQ ID NO: 58, and the nucleotide sequence encoding the amino acid sequence is shown in SEQ ID NO: 57. The amino acid sequence of Cγ1 is shown in SEQ ID NO: 60, and the nucleotide sequence encoding the amino acid sequence is shown in SEQ ID NO: 59. The amino acid sequence of Cγ2 is shown in SEQ ID NO: 62, and the nucleotide sequence encoding the amino acid sequence is shown in SEQ ID NO: 61. The amino acid sequence of Cγ4 is shown in SEQ ID NO: 64, and the nucleotide sequence encoding the amino acid sequence is shown in SEQ ID NO: 63. Further, in order to improve the stability of the antibody or its production, the human antibody C region may be modified. Examples of the modified human antibody C region include a C region described later. The human antibody used at the time of humanization may be a human antibody of any isotype such as IgG, IgM, IgA, IgE, IgD, but in the present invention, it is preferable to use IgG. As the IgG, it is possible to use IgG1, IgG2, IgG3, IgG4, or the like.

In addition, after preparing a humanized antibody, amino acids in the variable region (e.g., CDR, FR) or constant region may be substituted, deleted, added, and/or inserted with other amino acids. Humanized antibodies, such as amino acid substitutions, are also included.

The origin of the CDR in the humanized antibody is not particularly limited, and may be derived from any animal. For example, it is possible to use a sequence such as a mouse antibody, a rat antibody, a rabbit antibody, a camel antibody, etc., but it is preferably a CDR sequence of a mouse antibody.

In humanization of an antibody, it is usually difficult to humanize while maintaining the binding or neutralizing activity of the derived antibody, but in the present invention, it has the same binding activity and/or neutralizing activity as the derived mouse antibody. Acquisition of humanized antibodies was successful. Humanized antibodies are useful when administered to humans for therapeutic purposes or the like, since the immunogenicity in the human body is lowered.

Preferred examples of the humanized anti-NR10 antibody in the present invention include, for example, the antibodies described in any one of the following (a) to (e).

(a) a humanized antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 (H0-VH)

(b) a humanized antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 112 (H1-VH)

(c) a humanized antibody comprising a light chain variable region having the amino acid sequence of SEQ ID NO: 52 (L0-VL)

(d) a humanized antibody comprising a heavy chain variable region having an amino acid sequence of SEQ ID NO: 50 (H0-VH) and a light chain variable region having an amino acid sequence of SEQ ID NO: 52 (L0-VL)

(e) a human antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 112 and a light chain variable region having the amino acid sequence of SEQ ID NO: 52

In addition, a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 50 (H0-VH), a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 112, and an amino acid sequence as set forth in SEQ ID NO: 52 (L0-VL) In the light chain variable region, one or more amino acids may be substituted, deleted, added and/or inserted. Substitution, deletion, addition and/or insertion of amino acids may be performed in CDRs or FRs, or may be performed in both CDRs and FRs.

Therefore, as another preferable aspect of a humanized anti-NR10 antibody in this invention, the antibody of any one of the following (f)-(j) is mentioned, for example.

(f) an antibody comprising a heavy chain variable region having an amino acid sequence in which one or more amino acids are substituted, deleted, added and/or inserted in the amino acid sequence of SEQ ID NO: 50 (H0-VH)

(g) an antibody comprising a heavy chain variable region having an amino acid sequence in which one or more amino acids are substituted, deleted, added and/or inserted in the amino acid sequence of SEQ ID NO: 112 (H1-VH)

(h) an antibody comprising a light chain variable region having an amino acid sequence in which one or more amino acids are substituted, deleted, added and/or inserted in the amino acid sequence of SEQ ID NO: 52 (L0-VL)

(i) a heavy chain variable region having an amino acid sequence in which one or more amino acids are substituted, deleted, added and/or inserted in the amino acid sequence of SEQ ID NO: 50 (H0-VH), and SEQ ID NO: 52 (L0-VL ) Antibody comprising a light chain variable region having an amino acid sequence in which one or more amino acids are substituted, deleted, added and/or inserted in the amino acid sequence

(j) a heavy chain variable region having an amino acid sequence in which one or more amino acids are substituted, deleted, added and/or inserted in the amino acid sequence of SEQ ID NO: 112 (H1-VH), and SEQ ID NO: 52 (L0-VL ) Antibody comprising a light chain variable region having an amino acid sequence in which one or more amino acids are substituted, deleted, added and/or inserted in the amino acid sequence

Although not particularly limited, it is preferable that the antibody described in any one of (f) to (j) has the same activity as the antibody described in any one of (a) to (e).

The substitution, deletion, addition and/or insertion of amino acids are not particularly limited, but as specific examples, for example, it is possible to perform the amino acid substitution described above.

More specifically, the following amino acid substitutions are mentioned, for example.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, substitution of the third Ile of CDR1 (SEQ ID NO:9) with Val (SEQ ID NO: 173). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR1 having the amino acid sequence of SEQ ID NO:9 is substituted with CDR1 having the amino acid sequence of SEQ ID NO: 173 It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, substitution of the fourth Met in CDR1 (SEQ ID NO:9) with Ile (SEQ ID NO: 174). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR1 having the amino acid sequence of SEQ ID NO:9 is substituted with CDR1 having the amino acid sequence of SEQ ID NO: 174. It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, substitution of the fourth Met in CDR1 (SEQ ID NO:9) with Leu (SEQ ID NO: 175). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR1 having the amino acid sequence of SEQ ID NO:9 is substituted with CDR1 having the amino acid sequence of SEQ ID NO: 175 It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, substitution of the third Ile of CDR1 (SEQ ID NO:9) with Ala (SEQ ID NO: 176). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR1 having the amino acid sequence of SEQ ID NO: 9 is substituted with a CDR1 having the amino acid sequence of SEQ ID NO: 176. It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, substitution of the first Leu in CDR2 (SEQ ID NO: 10) with Glu (SEQ ID NO: 113). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR2 having the amino acid sequence of SEQ ID NO: 10 is substituted with a CDR2 having the amino acid sequence of SEQ ID NO: 113. It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, substitution of the third Asn in CDR2 (SEQ ID NO: 10) with Asp (SEQ ID NO: 114). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR2 having the amino acid sequence of SEQ ID NO: 10 is substituted with a CDR2 having the amino acid sequence of SEQ ID NO: 114 It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, substitution of the 13th Gln in CDR2 (SEQ ID NO: 10) with Asp (SEQ ID NO: 115). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR2 having the amino acid sequence of SEQ ID NO: 10 is substituted with a CDR2 having the amino acid sequence of SEQ ID NO: 115 It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, substitution of the 14th Lys of CDR2 (SEQ ID NO: 10) with Gln (SEQ ID NO: 116). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR2 having the amino acid sequence of SEQ ID NO: 10 is substituted with a CDR2 having the amino acid sequence of SEQ ID NO: 116. It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, substitution of the 16th Lys of CDR2 (SEQ ID NO: 10) with Gln (SEQ ID NO: 117). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR2 having the amino acid sequence of SEQ ID NO: 10 is substituted with a CDR2 having the amino acid sequence of SEQ ID NO: 117. It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, substitution of the 17th Gly in CDR2 (SEQ ID NO: 10) with Asp (SEQ ID NO: 118). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR2 having the amino acid sequence of SEQ ID NO: 10 is substituted with a CDR2 having the amino acid sequence of SEQ ID NO: 118. It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, the 16th Lys of CDR2 (SEQ ID NO: 10) is substituted with Gln and the 17th Gly is substituted with Asp (SEQ ID NO: 119). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR2 having the amino acid sequence of SEQ ID NO: 10 is substituted with a CDR2 having the amino acid sequence of SEQ ID NO: 119. It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, substitution of the 14th Lys with Gln of the CDR2 (SEQ ID NO:10), the substitution of the 16th Lys with Gln, and the Asp of the 17th Gly To (SEQ ID NO: 167). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR2 having the amino acid sequence of SEQ ID NO: 10 is substituted with a CDR2 having the amino acid sequence of SEQ ID NO: 167 It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, the 13th Gln of CDR2 (SEQ ID NO: 10) is substituted with Asp, the 14th Lys is substituted with Gln, and the 16th Lys is Gln. And substitution of the 17th Gly with Asp (SEQ ID NO: 172). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR2 having the amino acid sequence of SEQ ID NO: 10 is substituted with a CDR2 having the amino acid sequence of SEQ ID NO: 172. It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, substitution of the tenth Ser of CDR2 (SEQ ID NO: 10) with Asp (SEQ ID NO: 177). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR2 having the amino acid sequence of SEQ ID NO: 10 is substituted with a CDR2 having the amino acid sequence of SEQ ID NO: 177 It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, substitution of the 13th Gln in CDR2 (SEQ ID NO: 10) with Pro (SEQ ID NO: 178). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR2 having the amino acid sequence of SEQ ID NO: 10 is substituted with a CDR2 having the amino acid sequence of SEQ ID NO: 178. It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, substitution of the third Tyr of CDR3 (SEQ ID NO: 11) with Leu (SEQ ID NO: 179). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR3 having the amino acid sequence of SEQ ID NO: 11 is substituted with a CDR3 having the amino acid sequence of SEQ ID NO: 179. It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, substitution of the tenth Met of CDR3 (SEQ ID NO: 11) with Leu (SEQ ID NO: 180). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR3 having the amino acid sequence of SEQ ID NO: 11 is substituted with a CDR3 having the amino acid sequence of SEQ ID NO: 180 It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, substitution of the 11th Asp in CDR3 (SEQ ID NO: 11) with Glu (SEQ ID NO: 181). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR3 having the amino acid sequence of SEQ ID NO: 11 is substituted with a CDR3 having the amino acid sequence of SEQ ID NO: 181. It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, substitution of the 12th Tyr in CDR3 (SEQ ID NO: 11) with Thr (SEQ ID NO: 182). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR3 having the amino acid sequence of SEQ ID NO: 11 is substituted with a CDR3 having the amino acid sequence of SEQ ID NO: 182. It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, the 12th Tyr of CDR3 (SEQ ID NO: 11) is substituted with Ser (SEQ ID NO: 183). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR3 having the amino acid sequence of SEQ ID NO: 11 is substituted with a CDR3 having the amino acid sequence of SEQ ID NO: 183. It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, the 10th Met of CDR3 (SEQ ID NO: 11) is substituted with Leu, the 11th Asp is substituted with Glu, and the 12th Tyr is substituted with Thr. (SEQ ID NO:184). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR3 having the amino acid sequence of SEQ ID NO: 11 is substituted with CDR3 having the amino acid sequence of SEQ ID NO: 184. It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, the 11th Asp of CDR3 (SEQ ID NO: 11) is substituted with Glu and the 12th Tyr is substituted with Thr (SEQ ID NO: 185). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR3 having the amino acid sequence of SEQ ID NO: 11 is substituted with a CDR3 having the amino acid sequence of SEQ ID NO: 185 Provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, the 3rd Tyr of CDR3 (SEQ ID NO: 11) is substituted with Leu, the 11th Asp is substituted with Glu, and the 12th Tyr is substituted with Thr. (SEQ ID NO: 186). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR3 having the amino acid sequence of SEQ ID NO: 11 is substituted with a CDR3 having the amino acid sequence of SEQ ID NO: 186. It provides a variable region.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, the 3rd Tyr of CDR3 (SEQ ID NO: 11) is substituted with Leu, the 11th Asp is substituted with Glu, and the 12th Tyr is substituted with Ser (SEQ ID NO:187). Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein CDR3 having the amino acid sequence of SEQ ID NO: 11 is substituted with a CDR3 having the amino acid sequence of SEQ ID NO: 187. It provides a variable region.

In the light chain variable region of SEQ ID NO: 52, substitution of the first Arg of CDR1 (SEQ ID NO: 13) with Gln (SEQ ID NO: 121). Accordingly, the present invention provides a light chain variable region in which CDR1 having the amino acid sequence of SEQ ID NO: 13 is substituted with a CDR1 having the amino acid sequence of SEQ ID NO: 121 in the light chain variable region having the amino acid sequence of SEQ ID NO: 52. .

In the light chain variable region of SEQ ID NO: 52, substitution of the fifth Asn in CDR1 (SEQ ID NO: 13) with Asp (SEQ ID NO: 122). Accordingly, the present invention provides a light chain variable region in which CDR1 having the amino acid sequence of SEQ ID NO: 13 is substituted with a CDR1 having the amino acid sequence of SEQ ID NO: 122 in the light chain variable region having the amino acid sequence of SEQ ID NO: 52. .

In the light chain variable region of SEQ ID NO: 52, substitution of the 8th Ser of CDR1 (SEQ ID NO: 13) with Arg (SEQ ID NO: 188). Accordingly, the present invention provides a light chain variable region in which a CDR1 having an amino acid sequence of SEQ ID NO: 13 is substituted with a CDR1 having an amino acid sequence of SEQ ID NO: 188 in the light chain variable region having the amino acid sequence of SEQ ID NO: 52. .

In the light chain variable region of SEQ ID NO: 52, the 10th Leu of CDR1 (SEQ ID NO: 13) is substituted with Val (SEQ ID NO: 189). Accordingly, the present invention provides a light chain variable region in which a CDR1 having an amino acid sequence of SEQ ID NO: 13 is substituted with a CDR1 having an amino acid sequence of SEQ ID NO: 189 in the light chain variable region having the amino acid sequence of SEQ ID NO: 52. .

In the light chain variable region of SEQ ID NO: 52, the 8 th Ser of CDR1 (SEQ ID NO: 13) is substituted with Arg and the 10 th Leu is substituted with Val (SEQ ID NO: 190). Accordingly, the present invention provides a light chain variable region in which a CDR1 having an amino acid sequence of SEQ ID NO: 13 is substituted with a CDR1 having an amino acid sequence of SEQ ID NO: 190 in the light chain variable region having the amino acid sequence of SEQ ID NO: 52. .

In the light chain variable region of SEQ ID NO: 52, substitution of the second Thr of CDR1 (SEQ ID NO: 13) with Ala (SEQ ID NO: 191). Accordingly, the present invention provides a light chain variable region in which CDR1 having the amino acid sequence of SEQ ID NO: 13 is substituted with a CDR1 having the amino acid sequence of SEQ ID NO: 191 in the light chain variable region having the amino acid sequence of SEQ ID NO: 52. .

In the light chain variable region of SEQ ID NO: 52, substitution of the second Thr of CDR1 (SEQ ID NO: 13) with Ser (SEQ ID NO: 192). Accordingly, the present invention provides a light chain variable region in which a CDR1 having an amino acid sequence of SEQ ID NO: 13 is substituted with a CDR1 having an amino acid sequence of SEQ ID NO: 192 in the light chain variable region having the amino acid sequence of SEQ ID NO: 52. .

In the light chain variable region of SEQ ID NO: 52, substitution of the first Asn in CDR2 (SEQ ID NO: 14) with Asp (SEQ ID NO: 123). Accordingly, the present invention provides a light chain variable region in which a CDR2 having an amino acid sequence of SEQ ID NO: 14 is substituted with a CDR2 having an amino acid sequence of SEQ ID NO: 123 in the light chain variable region having the amino acid sequence of SEQ ID NO: 52. .

In the light chain variable region of SEQ ID NO: 52, substitution of the third Lys of CDR2 (SEQ ID NO: 14) with Gln (SEQ ID NO: 124). Accordingly, the present invention provides a light chain variable region in which a CDR2 having an amino acid sequence of SEQ ID NO: 14 is substituted with a CDR2 having an amino acid sequence of SEQ ID NO: 124 in the light chain variable region having the amino acid sequence of SEQ ID NO: 52. .

In the light chain variable region of SEQ ID NO: 52, substitution of 5th Leu in CDR2 (SEQ ID NO: 14) with Glu (SEQ ID NO: 125). Accordingly, the present invention provides a light chain variable region in which a CDR2 having an amino acid sequence of SEQ ID NO: 14 is substituted with a CDR2 having an amino acid sequence of SEQ ID NO: 125 in the light chain variable region having the amino acid sequence of SEQ ID NO: 52. .

In the light chain variable region of SEQ ID NO: 52, substitution of 7th Lys in CDR2 (SEQ ID NO: 14) with Gln (SEQ ID NO: 126). Accordingly, the present invention provides a light chain variable region in which the CDR2 having the amino acid sequence of SEQ ID NO: 14 is substituted with the CDR2 having the amino acid sequence of SEQ ID NO: 126 in the light chain variable region having the amino acid sequence of SEQ ID NO: 52. .

In the light chain variable region of SEQ ID NO: 52, substitution of the 7th Lys of CDR2 (SEQ ID NO: 14) with Asp (SEQ ID NO: 127). Accordingly, the present invention provides a light chain variable region in which CDR2 having the amino acid sequence of SEQ ID NO: 14 is substituted with a CDR2 having the amino acid sequence of SEQ ID NO: 127 in the light chain variable region having the amino acid sequence of SEQ ID NO: 52. .

In the light chain variable region of SEQ ID NO: 52, the first Arg of CDR1 (SEQ ID NO: 13) is substituted with Gln and the fifth Asn is substituted with Asp (SEQ ID NO: 169). Accordingly, the present invention provides a light chain variable region in which a CDR1 having an amino acid sequence of SEQ ID NO: 13 is substituted with a CDR1 having an amino acid sequence of SEQ ID NO: 169 in the light chain variable region having the amino acid sequence of SEQ ID NO: 52. .

In the light chain variable region of SEQ ID NO: 52, the 3rd Lys of CDR2 (SEQ ID NO: 14) is substituted with Gln, the 5th Leu is substituted with Glu, and the 7th Lys is substituted with Gln (SEQ ID NO: :170). Accordingly, the present invention provides a light chain variable region in which the CDR2 having the amino acid sequence of SEQ ID NO: 14 is substituted with the CDR2 having the amino acid sequence of SEQ ID NO: 170 in the light chain variable region of SEQ ID NO: 52.

In the light chain variable region of SEQ ID NO: 52, substitution of the fifth Glu of CDR3 (SEQ ID NO: 15) with Asp (SEQ ID NO: 193). Accordingly, the present invention provides a light chain variable region in which, in the light chain variable region of SEQ ID NO: 52, CDR3 having the amino acid sequence of SEQ ID NO: 15 is substituted with CDR3 having the amino acid sequence of SEQ ID NO: 193.

In the light chain variable region of SEQ ID NO: 52, substitution of the 6th Ser of CDR3 (SEQ ID NO: 15) with Asp (SEQ ID NO: 194). Accordingly, the present invention provides a light chain variable region in which, in the light chain variable region of SEQ ID NO: 52, CDR3 having the amino acid sequence of SEQ ID NO: 15 is substituted with CDR3 having the amino acid sequence of SEQ ID NO: 194.

In the light chain variable region of SEQ ID NO: 52, substitution of the 9th Thr of CDR3 (SEQ ID NO: 15) with Phe (SEQ ID NO: 195). Accordingly, the present invention provides a light chain variable region in which, in the light chain variable region of SEQ ID NO: 52, CDR3 having the amino acid sequence of SEQ ID NO: 15 is substituted with CDR3 having the amino acid sequence of SEQ ID NO: 195.

In addition, as a substitution other than the above-described amino acid, substitution of the third Arg with another amino acid in the heavy chain FR2 having the amino acid sequence of SEQ ID NO: 97 can be exemplified. The amino acid after substitution is not particularly limited, but a preferred example is Gln. In addition, when the 3rd Arg of SEQ ID NO: 97 is substituted with Gln, it is also possible to replace the 5th Ala with Ser and make FR2 a human sequence. In the amino acid sequence of SEQ ID NO: 97, the amino acid sequence obtained by substituting Gln for the third Arg and Ser for the fifth Ala is shown in SEQ ID NO: 120. Accordingly, the present invention relates to a heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, wherein FR2 having the amino acid sequence of SEQ ID NO: 97 is substituted with FR2 having the amino acid sequence of SEQ ID NO: 120 It provides a variable region.

The aforementioned amino acid substitutions may be used alone or in combination with other amino acid substitutions described above. Further, you may combine with amino acid substitutions other than those described above.

As a specific example of the antibody to which the above-described substitution has been performed, an antibody comprising a heavy chain variable region having an amino acid sequence of SEQ ID NO: 167, an antibody comprising a light chain variable region having an amino acid sequence of SEQ ID NO: 168, and SEQ ID NO: 167 And antibodies comprising a heavy chain variable region having an amino acid sequence and a light chain variable region having an amino acid sequence of SEQ ID NO: 168.

Further, as a specific example of the heavy chain variable region in which the above-described substitution has been performed, the following heavy chain variable region can be mentioned.

(1) heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 204 (H17)

(2) heavy chain variable region (H19) having the amino acid sequence set forth in SEQ ID NO: 205

(3) heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 206 (H28)

(4) heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 207 (H30)

(5) heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 208 (H34)

(6) heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 209 (H42)

(7) heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 210 (H44)

(8) heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 211 (H46)

(9) heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 212 (H57)

(10) heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:213 (H71)

(11) heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 214 (H78)

(12) heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 215 (H92)

(13) heavy chain variable region (H97) having the amino acid sequence set forth in SEQ ID NO: 216

(14) heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 217 (H98)

In addition, the following light chain variable region can be mentioned as a specific example of the light chain variable region in which the above-described substitution has been performed.

(15) light chain variable region (L11) having the amino acid sequence set forth in SEQ ID NO: 218

(16) light chain variable region (L12) having the amino acid sequence set forth in SEQ ID NO: 219

(17) light chain variable region having the amino acid sequence set forth in SEQ ID NO: 220 (L17)

(18) light chain variable region (L50) having the amino acid sequence set forth in SEQ ID NO: 221

Additionally, as specific examples of the antibody containing the heavy chain variable region and the light chain variable region described above, the following antibodies are exemplified.

(19) An antibody comprising the heavy chain variable region of (3) and the light chain variable region of (17) (H28L17)

(20) An antibody comprising the heavy chain variable region of (4) and the light chain variable region of (17) (H30L17)

(21) An antibody comprising the heavy chain variable region of (5) and the light chain variable region of (17) (H34L17)

(22) An antibody comprising the heavy chain variable region of (6) and the light chain variable region of (17) (H42L17)

(23) An antibody comprising the heavy chain variable region of (7) and the light chain variable region of (17) (H44L17)

(24) An antibody comprising the heavy chain variable region of (8) and the light chain variable region of (17) (H46L17)

(25) An antibody comprising the heavy chain variable region of (9) and the light chain variable region of (17) (H57L17)

(26) An antibody comprising the heavy chain variable region of (10) and the light chain variable region of (17) (H71L17)

(27) An antibody comprising the heavy chain variable region of (11) and the light chain variable region of (17) (H78L17)

(28) An antibody comprising the heavy chain variable region of (12) and the light chain variable region of (17) (H92L17)

(29) An antibody comprising the heavy chain variable region of (13) and the light chain variable region of (18) (H97L50)

(30) Antibody comprising the heavy chain variable region of (14) and the light chain variable region of (18) (H98L50)

The constant region used in the humanized antibody of the present invention may be any constant region derived from a human antibody. Preferred examples of the human antibody-derived constant region include an IgG1 or IgG2-derived constant region. In addition, in the constant region derived from a human antibody, one or a plurality of amino acids may be substituted, deleted, added and/or inserted into a constant region.

In the constant region derived from a human antibody, the constant region in which one or a plurality of amino acids are substituted, deleted, added and/or inserted is not particularly limited, and examples thereof include the following constant regions.

Constant region (M58) having the amino acid sequence set forth in SEQ ID NO: 128

Constant region (M14) having the amino acid sequence set forth in SEQ ID NO: 129

Constant region (SKSC) having the amino acid sequence set forth in SEQ ID NO: 62

Specific examples of the heavy chain or antibody using the above-described constant region include, for example, the following heavy chains or antibodies.

(1) heavy chain comprising a variable region having the amino acid sequence of SEQ ID NO: 167 and a constant region having the amino acid sequence of SEQ ID NO: 128

(2) In the heavy chain of (1), CDR2 having the amino acid sequence of SEQ ID NO: 171 is substituted with CDR2 having the amino acid sequence of SEQ ID NO: 172.

(3) an antibody comprising the heavy chain of (1) and a light chain having the amino acid sequence of SEQ ID NO: 152

(4) an antibody comprising the heavy chain of (2) and a light chain having the amino acid sequence of SEQ ID NO: 152

As a more specific example of the humanized anti-NR10 antibody of the present invention, for example, the antibody described in any one of the following (k) to (o) can be mentioned.

(k) Antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 54 (H0-VH + normal region)

(l) Antibody comprising a heavy chain having an amino acid sequence of SEQ ID NO: 130 (H1-VH + normal region)

(m) an antibody containing a light chain having the amino acid sequence of SEQ ID NO: 56 (L0-VL + normal region)

(n) An antibody comprising a heavy chain having an amino acid sequence of SEQ ID NO: 54 (H0-VH + normal region) and a light chain having an amino acid sequence of SEQ ID NO: 56 (L0-VL + normal region)

(o) an antibody comprising a heavy chain having an amino acid sequence of SEQ ID NO: 130 (H1-VH + normal region) and a light chain having an amino acid sequence of SEQ ID NO: 56 (L0-VL + normal region)

In addition, in the heavy chain having the amino acid sequence described in SEQ ID NO: 54 (H0-VH + normal region) and the light chain having the amino acid sequence described in SEQ ID NO: 56 (L0-VL + normal region), one or more amino acids are substituted or deleted. , May be added and/or inserted. Substitution, deletion, addition and/or insertion of amino acids may be performed in the variable region or the constant region, or may be performed in both the variable region and the constant region.

Therefore, the present invention provides the antibody according to any one of the following (p) to (t).

(p) An antibody comprising a heavy chain having an amino acid sequence in which one or more amino acids are substituted, deleted, added and/or inserted in the amino acid sequence of SEQ ID NO: 54 (H0-VH + normal region)

(q) An antibody comprising a heavy chain having an amino acid sequence in which one or more amino acids are substituted, deleted, added and/or inserted in the amino acid sequence of SEQ ID NO: 130 (H1-VH + normal region)

(r) an antibody comprising a light chain having an amino acid sequence in which one or more amino acids are substituted, deleted, added and/or inserted in the amino acid sequence of SEQ ID NO: 56 (L0-VL + normal region)

(s) a heavy chain having an amino acid sequence in which one or more amino acids are substituted, deleted, added and/or inserted in the amino acid sequence of SEQ ID NO: 54 (H0-VH + normal region), and SEQ ID NO: 56 (L0-VL + Constant region) in the amino acid sequence of one or more amino acids are substituted, deleted, added and / or inserted into the amino acid sequence of the antibody containing a light chain having an inserted amino acid sequence

(t) a heavy chain having an amino acid sequence in which one or more amino acids are substituted, deleted, added and/or inserted in the amino acid sequence of SEQ ID NO: 130 (H1-VH + normal region), and SEQ ID NO: 56 (L0-VL + Constant region) in the amino acid sequence of one or more amino acids are substituted, deleted, added and / or inserted into the amino acid sequence of the antibody containing a light chain having an inserted amino acid sequence

Although not particularly limited, it is preferable that the antibody described in any one of (p) to (t) has the same activity as the antibody described in any one of (k) to (o).

The substitution, deletion, addition and/or insertion of amino acids are not particularly limited, but as specific examples, for example, it is possible to perform the amino acid substitution described above.

In addition, the nucleotide sequence encoding the amino acid sequence (SEQ ID NO: 50) of the humanized heavy chain variable region described above is shown in SEQ ID NO: 49, and the nucleotide sequence encoding the amino acid sequence (SEQ ID NO: 52) of the humanized light chain variable region is shown in SEQ ID NO: In 51, the nucleotide sequence encoding the amino acid sequence of the humanized heavy chain (SEQ ID NO: 54) is shown in SEQ ID NO: 53, and the nucleotide sequence encoding the amino acid sequence of the humanized light chain (SEQ ID NO: 56) is shown in SEQ ID NO: 55.

Additionally, the present invention provides an antibody that recognizes the same epitope as the epitope recognized by the antibody according to any one of (a) to (t) described above. The binding to the same epitope is as previously described.

*In addition, the present invention provides the antibody according to any one of the following (u) to (w).

(u) an antibody comprising a heavy chain having the amino acid sequence set forth in SEQ ID NO: 151

(v) an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 152

(w) an antibody comprising the heavy chain of (u) and the light chain of (v)

Additionally, the present invention provides a heavy chain, a light chain, or an antibody described in any one of the following.

(1) heavy chain (H17) having the amino acid sequence set forth in SEQ ID NO:222

(2) heavy chain (H19) having the amino acid sequence set forth in SEQ ID NO:223

(3) heavy chain (H28) having the amino acid sequence set forth in SEQ ID NO:224

(4) heavy chain (H30) having the amino acid sequence set forth in SEQ ID NO:225

(5) heavy chain (H34) having the amino acid sequence set forth in SEQ ID NO:226

(6) heavy chain (H42) having the amino acid sequence set forth in SEQ ID NO:227

(7) heavy chain (H44) having the amino acid sequence set forth in SEQ ID NO:228

(8) heavy chain having the amino acid sequence set forth in SEQ ID NO:229 (H46)

(9) heavy chain (H57) having the amino acid sequence set forth in SEQ ID NO: 230

(10) heavy chain (H71) having the amino acid sequence set forth in SEQ ID NO:231

(11) heavy chain (H78) having the amino acid sequence set forth in SEQ ID NO: 232

(12) heavy chain (H92) having the amino acid sequence set forth in SEQ ID NO: 233

(13) heavy chain (H97) having the amino acid sequence set forth in SEQ ID NO:234

(14) heavy chain (H98) having the amino acid sequence set forth in SEQ ID NO: 235

(15) light chain (L11) having the amino acid sequence set forth in SEQ ID NO: 236

(16) light chain (L12) having the amino acid sequence set forth in SEQ ID NO: 237

(17) light chain having the amino acid sequence set forth in SEQ ID NO:238 (L17)

(18) light chain (L50) having the amino acid sequence set forth in SEQ ID NO:239

(19) An antibody containing the heavy chain of (3) and the light chain of (17) (H28L17)

(20) An antibody containing the heavy chain of (4) and the light chain of (17) (H30L17)

(21) An antibody containing the heavy chain of (5) and the light chain of (17) (H34L17)

(22) An antibody containing the heavy chain of (6) and the light chain of (17) (H42L17)

(23) An antibody containing the heavy chain of (7) and the light chain of (17) (H44L17)

(24) An antibody containing the heavy chain of (8) and the light chain of (17) (H46L17)

(25) An antibody containing the heavy chain of (9) and the light chain of (17) (H57L17)

(26) An antibody containing the heavy chain of (10) and the light chain of (17) (H71L17)

(27) An antibody containing the heavy chain of (11) and the light chain of (17) (H78L17)

(28) An antibody containing the heavy chain of (12) and the light chain of (17) (H92L17)

(29) An antibody containing the heavy chain of (13) and the light chain of (18) (H97L50)

(30) An antibody containing the heavy chain of (14) and the light chain of (18) (H98L50)

(31) In the heavy chain according to any one of (1) to (14), a heavy chain having an amino acid sequence in which one or more amino acids are substituted, deleted, added and/or inserted.

(32) In the light chain according to any one of (15) to (18), a light chain having an amino acid sequence in which one or more amino acids are substituted, deleted, added and/or inserted.

(33) The antibody according to any one of (19) to (30), wherein the antibody has an amino acid sequence in which one or more amino acids are substituted, deleted, added and/or inserted.

(34) An antibody that recognizes the same epitope as the epitope recognized by the antibody according to any one of (19) to (33).

Substitution, deletion, addition and/or insertion of amino acids are as described above. In addition, an antibody that recognizes the same epitope as the epitope recognized by any one antibody is as described above.

Further, the present invention provides a gene encoding the variable region of the present invention, the heavy chain of the present invention, the light chain of the present invention, or the antibody of the present invention.

In addition, the present invention provides a vector containing the aforementioned gene.

In addition, the present invention provides a host cell transformed with the above-described vector.

Further, the present invention relates to a method for producing the variable region of the present invention, the heavy chain of the present invention, the light chain of the present invention, or the antibody of the present invention, including the step of culturing the host cells described above.

The culture of the vector, host cell, and host cell is as described later.

Domain recognition antibody

As one of the preferred embodiments of the anti-NR10 antibody in the present invention, an antibody that recognizes domain 1 or an antibody that recognizes domain 2 is mentioned. In the present invention, domain 1 refers to a region from the 21st amino acid to the 120th amino acid (LPAKP to LENIA) in the state of containing the signal peptide in the amino acid sequence of human NR10 described in SEQ ID NO: 76. . In addition, in the present invention, the domain 2 is the number in the state of containing the signal peptide in the amino acid sequence of human NR10 described in SEQ ID NO: 76, and the region from the 121st amino acid to the 227th amino acid (KTEPP to EEEAP) Say.

Such an antibody is not particularly limited, but is usually an antibody having neutralizing activity, and is preferably a humanized antibody.

As an example of a preferred antibody in the present invention, an antibody that recognizes domain 1 is mentioned. Antibodies that recognize domain 1 have high neutralizing activity and are particularly useful as pharmaceuticals.

Antibody (neutralizing activity)

The present invention additionally provides an anti-NR10 antibody having neutralizing activity.

In the present invention, the neutralizing activity against NR10 is an activity that inhibits the binding of NR10 and its ligand, IL-31, and is preferably an activity that inhibits physiological activity caused by NR10.

The selection of an antibody having NR10 neutralizing activity can be performed by, for example, a method of observing the proliferation inhibitory effect of the IL-31 dependent cell line when a candidate antibody is added to an IL-31 dependent cell line. In the above method, an antibody that inhibits the proliferation of an IL-31 dependent cell line is judged to be an antibody having neutralizing activity against NR10.

Antibody (general)

The antibody of the present invention is not limited to its origin, and may be an antibody derived from any animal, such as a human antibody, a mouse antibody, or a rat antibody. Further, a recombinant antibody such as a chimeric antibody or a humanized antibody may be used. As described above, a humanized antibody can be mentioned as a preferred antibody of the present invention.

The chimeric antibody is an antibody that becomes the variable region of the heavy chain and the light chain of a non-human mammal, such as a mouse antibody, and the constant region of the heavy and light chain of a human antibody. Chimeric antibodies can be produced using known methods. For example, it is possible to clone an antibody gene from a hybridoma, insert it into an appropriate vector, and introduce it into a host (e.g., Carl, AK Borrebaeck, James, W. Larrick, THERAPEUTIC MONOCLONAL ANTIBODIES, Published in the United Kingdom by MACMILLAN PUBLISHERS LTD, 1990). Specifically, cDNA of the variable region (V region) of the antibody is synthesized from the hybridoma mRNA using reverse transcriptase. When DNA encoding the V region of the target antibody is obtained, it is ligated with DNA encoding the target human antibody constant region (region C), and this is inserted into an expression vector. Alternatively, the DNA encoding the V region of the antibody may be inserted into an expression vector containing the DNA of the human antibody C region. It is inserted into an expression vector so as to be expressed under the control of an expression control region such as an enhancer or a promoter. Next, host cells can be transformed with this expression vector to express chimeric antibodies.

In addition, methods for obtaining human antibodies are also known. For example, human lymphocytes of interest are sensitized in vitro with a target antigen or a cell expressing a target antigen, and the sensitized lymphocytes are fused with human myeloma cells, such as U266, to have antigen-binding activity. It is also possible to obtain an antibody (refer to Japanese Patent Publication No. Hei 1-59878). In addition, by immunizing a transgenic animal having all the repertoire of human antibody genes with a target antigen, a target human antibody can be obtained (International Patent Application Publication Nos. WO 93/12227, WO 92/03918, WO 94/02602, See WO 94/25585, WO 96/34096, WO 96/33735).

In addition, techniques for obtaining human antibodies by panning using a human antibody phage library are also known. For example, the variable region of a human antibody can be expressed as a single-chain antibody (scFv) on the surface of a phage by a phage display method, and a phage that binds to an antigen can be selected. By analyzing the gene of the selected phage, it is possible to determine the DNA sequence encoding the variable region of a human antibody that binds to the antigen. When the DNA sequence of the scFv that binds to the antigen is clear, a suitable expression vector having the sequence can be prepared, and a human antibody can be obtained. For these methods, reference may be made to WO 92/01047, WO 92/20791, WO 93/06213, WO 93/11236, WO 93/19172, WO 95/01438, WO 95/15388, and the like.

In the antibody of the present invention, as long as it has binding activity and/or neutralizing activity to NR10, it is possible to bind not only a divalent antibody represented by IgG, but also a monovalent antibody, or a multivalent antibody represented by IgM, or a different antigen. Bispecific antibodies are also included. The multivalent antibody of the present invention includes a multivalent antibody having all of the same antigen-binding sites, or a multivalent antibody having some or all of the different antigen-binding sites. The antibody of the present invention is not limited to the full-length molecule of the antibody, and may be a low molecular weight antibody or a plant thereof as long as it binds to the NR10 protein.

Further, the antibody in the present invention may be a low molecular weight antibody. The low molecular weight antibody is an antibody containing an antibody fragment in which a part of a full-length antibody (for example, whole IgG, etc.) is missing, and is not particularly limited as long as it has binding activity and/or neutralizing activity to NR10. In the present invention, the low molecular weight antibody is not particularly limited as long as it contains a part of the full-length antibody, but it is preferable that it contains a heavy chain variable region (VH) or a light chain variable region (VL), particularly preferably VH and VL. It is a low molecular weight antibody containing both of. Further, as another preferred example of the low molecular weight antibody of the present invention, a low molecular weight antibody containing the CDRs of the antibody is exemplified. The CDRs contained in the low molecular weight antibody may contain all six CDRs of the antibody, or may contain some of the CDRs.

The low molecular weight antibody in the present invention preferably has a molecular weight smaller than that of the full-length antibody, but for example, it may form a multimer such as a dimer, a trimer, or a tetramer, and the molecular weight may be larger than that of the full-length antibody. have.

As a specific example of an antibody fragment, Fab, Fab', F(ab')2, Fv, etc. are mentioned, for example. In addition, as a specific example of a low molecular weight antibody, for example, Fab, Fab', F(ab')2, Fv, scFv (single chain Fv), Diabody, sc(Fv)2 (single chain (Fv)2), etc. Can be mentioned. Multimers of these antibodies (for example, dimers, trimers, tetramers, and polymers) are also included in the low molecular weight antibodies of the present invention.

Antibody fragments can be obtained, for example, by treating an antibody with an enzyme to produce an antibody fragment. As an enzyme that generates an antibody fragment, for example, papain, pepsin, or plasmin are known. Alternatively, genes encoding these antibody fragments can be constructed, introduced into an expression vector, and then expressed in a suitable host cell (e.g., Co, MS et al., J. Immunol. (1994) 152, 2968-2976, Better, M. & Horwitz, AH Methods in Enzymology (1989)178, 476-496, Plueckthun, A. & Skerra, A. Methods in Enzymology (1989)178, 476-496, Lamoyi, E., Methods in Enzymology (1989) 121, 652-663, Rousseaux, J. et al., Methods in Enzymology (1989) 121, 663-669, Bird, RE et al., TIBTECH (1991)9, 132-137) .

The digestive enzyme cleaves a specific position of the antibody fragment and gives the antibody fragment having a specific structure as follows. With respect to such an enzymatically obtained antibody fragment, an arbitrary portion of the antibody can be deleted by using a genetic engineering technique.

The antibody fragment obtained when the above-described digestive enzyme is used is as follows.

Papain digestion: F(ab)2 or Fab

Pepsin digestion: F(ab')2 or Fab'

Plasmin Digestion: Facb

The low molecular weight antibody in the present invention can contain an antibody fragment in which an arbitrary region is deleted as long as it has binding activity to NR10 and/or neutralizing activity.

Diabody refers to a bivalent antibody fragment constructed by gene fusion (Holliger P et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993), EP404, 097, WO93/11161, etc.). Diabodies are dimers composed of two polypeptide chains. Usually, in the polypeptide chain constituting the dimer, VL and VH are each bonded in the same chain by a linker. The linker in the diabody is generally so short that VL and VH cannot be bonded to each other. Specifically, the number of amino acid residues constituting the linker is, for example, about 5 residues. Therefore, VL and VH encoded on the same polypeptide chain cannot form short-chain variable region fragments, thereby forming separate short-chain variable region fragments and dimers. As a result, the diabody has two antigen binding sites.

The scFv antibody is an antibody in which a heavy chain variable region ([VH]) and a light chain variable region ([VL]) are combined with a linker or the like to form a single chain polypeptide (Huston, JS et al., Proc. Natl. Acad. Sci. USA (1988) 85, 5879-5883, Plickthun ``The Pharmacology of Monoclonal Antibodies'' Vol. 113, Resenburg and Moore, Springer Verlag, New York, pp. 269-315, (1994)). The H chain V region and L chain V region in scFv may be derived from any of the antibodies described in the present specification. There is no particular limitation on the peptide linker connecting the V region. For example, any single-chain peptide having about 3 to 25 residues can be used as a linker. Specifically, for example, a peptide linker described later can be used.

The V regions of both chains can be linked by, for example, the PCR method described above. For the linking of the V region by the PCR method, first, among the following DNAs, a DNA encoding all or a desired partial amino acid sequence is used as a template.

DNA sequences encoding the H chain and H chain V regions of the antibody, and

DNA sequence encoding the L chain and L chain V region of an antibody

DNAs encoding the H chain and L chain V regions are each amplified by a PCR method using a pair of primers having sequences corresponding to the sequences at both ends of the DNA to be amplified. Next, DNA encoding the peptide linker portion is prepared. DNA encoding a peptide linker can also be synthesized using PCR. At this time, to the 5'side of the primer to be used, a nucleotide sequence that can be linked to the separately synthesized amplification product of each V region is added. Next, a PCR reaction is performed using each of the DNAs of [H chain V region DNA]-[peptide linker DNA]-[L chain V region DNA] and primers for assembly PCR.

The assembly PCR primer is a combination of a primer annealed to the 5'side of [H chain V region DNA] and a primer annealed to the 3'side of [L chain V region DNA]. That is, the primer for assembly PCR is a set of primers capable of amplifying DNA encoding the full length sequence of the scFv to be synthesized. On the other hand, a nucleotide sequence capable of linking to each V region DNA is added to [peptide linker DNA]. As a result, these DNAs are ligated, and finally, the full length of the scFv is generated as an amplification product by the primers for assembly PCR. Once the DNA encoding the scFv is produced, an expression vector containing them and a recombinant cell transformed with the expression vector can be obtained according to a conventional method. Moreover, the scFv can be obtained by culturing the resulting recombinant cells and expressing the DNA encoding the scFv.

The order of the heavy chain variable region and the light chain variable region to be bonded is not particularly limited, and may be arranged in any order, for example, the following arrangements are exemplified.

[VH]Linker[VL]

[VL] Linker [VH]

sc(Fv)2 is a low molecular weight antibody in which two VHs and two VLs are bonded to each other by a linker or the like to form a single chain (Hudson et al, J Immunol. Methods 1999;231:177-189). sc(Fv)2 can be produced, for example, by linking scFv with a linker.

In addition, two VHs and two VLs are listed in the order of VH, VL, VH, VL ([VH] linker [VL] linker [VH] linker [VL]) starting from the N-terminal side of the single-chain polypeptide. Antibodies characterized in that the present invention are preferred, but the order of the two VHs and the two VLs is not particularly limited to the above arrangement, and may be arranged in any order. For example, the following arrangements are also mentioned.

[VL]Linker[VH]Linker[VH]Linker[VL]

[VH]Linker[VL]Linker[VL]Linker[VH]

[VH]Linker[VH]Linker[VL]Linker[VL]

[VL]Linker[VL]Linker[VH]Linker[VH]

[VL]Linker[VH]Linker[VL]Linker[VH]

The amino acid sequence of the heavy chain variable region or light chain variable region in the low molecular antibody may be substituted, deleted, added and/or inserted. Further, when the heavy chain variable region and the light chain variable region are associated with each other, a part may be deleted or another polypeptide may be added as long as it has antigen-binding activity. In addition, the variable region may be chimerized or humanized.

In the present invention, the linker that binds the variable region of the antibody is any peptide linker that can be introduced by genetic engineering, or a synthetic compound linker, for example, Protein Engineering, 9(3), 299-305, 1996. Linkers disclosed in can be used.

A preferred linker in the present invention is a peptide linker. The length of the peptide linker is not particularly limited and can be appropriately selected by a person skilled in the art depending on the purpose, but usually, 1 to 100 amino acids, preferably 3 to 50 amino acids, more preferably 5 to 30 amino acids, particularly preferably 12-18 amino acids (eg, 15 amino acids).

Examples of the amino acid sequence of the peptide linker include the following sequences.

Ser

Gly Ser

Gly·Gly·Ser

Ser·Gly·Gly

Gly, Gly, Gly, Ser (SEQ ID NO:82)

Ser Gly Gly Gly (SEQ ID NO:83)

Gly, Gly, Gly, Gly, Ser (SEQ ID NO:84)

Ser Gly Gly Gly Gly (SEQ ID NO:85)

Gly, Gly, Gly, Gly, Gly, Ser (SEQ ID NO:86)

Ser·Gly·Gly·Gly·Gly·Gly (SEQ ID NO:87)

Gly, Gly, Gly, Gly, Gly, Gly, Ser (SEQ ID NO:88)

Ser Gly Gly Gly Gly Gly Gly (SEQ ID NO:89)

(Gly·Gly·Gly·Gly·Ser (SEQ ID NO:84))n

(Ser·Gly·Gly·Gly·Gly(SEQ ID NO:85))n

[n is an integer of 1 or more] and the like.

The amino acid sequence of the peptide linker can be appropriately selected by a person skilled in the art depending on the purpose. For example, n, which determines the length of the peptide linker, is usually 1 to 5, preferably 1 to 3, and more preferably 1 or 2.

Synthetic compound linkers (chemical crosslinking agents) are crosslinking agents commonly used for crosslinking peptides, such as N-hydroxysuccinimide (NHS), disuccinimidylsverate (DSS), and bis(sulfosuccinimidyl). Sverate (BS3), dithiobis (succinimidyl propionate) (DSP), dithiobis (sulfosuccinimidyl propionate) (DTSSP), ethylene glycol bis (succinimidyl succinate) (EGS), ethylene Glycol bis (sulfosuccinimidyl succinate) (sulfo-EGS), disuccinimidyl tartrate (DST), disulfosuccinimidyl tartrate (sulfo-DST), bis[2- (succinimideoxycarbonyl) Oxy)ethyl]sulfone (BSOCOES), bis[2-(sulfosuccinimideoxycarbonyloxy)ethyl]sulfone (sulfo-BSOCOES), and the like, and crosslinking agents thereof are commercially available.

In the case of binding four antibody variable regions, three linkers are usually required. The plurality of linkers may be the same or different linkers may be used.

The antibody of the present invention also includes an antibody to which one or more amino acid residues are added to the amino acid sequence of the antibody of the present invention. Also included are fusion proteins in which these antibodies and other peptides or proteins are fused. The method of producing a fusion protein is to link the polynucleotide encoding the antibody of the present invention and the polynucleotide encoding another peptide or polypeptide so that the frame is coincident, introduce it into an expression vector, and express it in a host. A known method can be used. Other peptides or polypeptides imparted to the fusion with the antibody of the present invention include, for example, FLAG (Hopp, TP et al., BioTechnology (1988) 6, 1204-1210), 6 His (histidine) residues. ×His, 10 × His, influenza agglutinin (HA), human c-myc fragment, VSV-GP fragment, p18HIV fragment, T7-tag, HSV-tag, E-tag, SV40T antigen fragment, lck tag, Known peptides such as α-tubulin fragment, B-tag, and Protein C fragment can be used. In addition, as other polypeptides imparted to the fusion with the antibody of the present invention, for example, GST (glutathione-S-transferase), HA (influenza agglutinin), immunoglobulin constant region, β-galactosidase, MBP (Maltose binding protein), etc. are mentioned. A fusion polypeptide can be prepared by fusing a polynucleotide encoding these commercially available peptides or polypeptides with a polynucleotide encoding an antibody of the present invention, and expressing the fusion polynucleotide prepared thereby.

In addition, the antibody of the present invention may be a conjugated antibody bound to various molecules such as a high molecular substance such as polyethylene glycol (PEG) or hyaluronic acid, a radioactive substance, a fluorescent substance, a luminescent substance, an enzyme, and a toxin. Such a conjugated antibody can be obtained by chemically modifying the obtained antibody. In addition, methods for modifying antibodies have already been established in this field (eg, US 5057313, US 5156840). These conjugate antibodies are also included in the "antibody" in the present invention.

Further, the antibody used in the present invention may be a bispecific antibody. The bispecific antibody refers to an antibody having a variable region that recognizes different epitopes in the same antibody molecule. In the present invention, the bispecific antibody may be a bispecific antibody that recognizes different epitopes on the NR10 molecule, and one antigen-binding site recognizes NR10 and the other antigen-binding site recognizes another substance. It is also possible to do it.

Methods for preparing bispecific antibodies are known. For example, a bispecific antibody can be produced by binding two types of antibodies having different recognition antigens. The antibody to be bound may be a half molecule each having an H chain and an L chain, or may be a 1/4 molecule consisting only of an H chain. Alternatively, hybridomas producing different monoclonal antibodies may be fused to produce bispecific antibody-producing fusion cells. In addition, bispecific antibodies can be produced by genetic engineering techniques.

The antibody of the present invention may differ in amino acid sequence, molecular weight, isoelectric point, or the presence or absence of sugar chains, or the like, depending on the cell or host or purification method for producing the antibody described later. However, as long as the obtained antibody has a function equivalent to that of the antibody of the present invention, it is included in the present invention. For example, when the antibody of the present invention is expressed in prokaryotic cells such as E. coli, a methionine residue is added to the N-terminus of the amino acid sequence of the original antibody. The antibody of the present invention also includes such an antibody.

Production of antibodies

The antibody of the present invention may be a polyclonal antibody or a monoclonal antibody. A monoclonal antibody having binding activity and/or neutralizing activity against NR10 is an anti-NR10 monoclonal antibody by a known method using NR10 or a fragment peptide thereof derived from mammals such as humans or mice as an immunogen. After preparing, it can be obtained by selecting an antibody having NR10 binding activity and/or neutralizing activity from the obtained anti-NR10 monoclonal antibody. That is, a target antigen or a cell expressing the target antigen is used as a sensitizing antigen, and this is immunized according to a conventional immunization method. It is possible to produce anti-NR10 monoclonal antibodies by fusing the obtained immune cells with known parent cells by a conventional cell fusion method and screening monoclonal antibody producing cells (hybridoma) by a conventional screening method. Do. As animals to be immunized, mammals such as mice, rats, rabbits, sheep, monkeys, goats, donkeys, cattle, horses, and pigs can be used. The antigen can be prepared using a known NR10 gene sequence and according to a known method, for example, a method using a baculovirus (WO98/46777, etc.).

The hybridoma can be prepared, for example, according to a method such as Milstein (Kohler. G. and Milstein, C., Methods Enzymol. (1981) 73: 3-46). When the antigen has low immunogenicity, it may be immunized by binding to a macromolecule having immunogenicity such as albumin.

As an embodiment of the antibody having binding and/or neutralizing activity against NR10 of the present invention, a monoclonal antibody having binding activity and/or neutralizing activity against human NR10 is exemplified. The immunogen for producing a monoclonal antibody having binding activity and/or neutralizing activity against human NR10 is not particularly limited as long as an antibody having binding activity and/or neutralizing activity against human NR10 can be produced. For example, the presence of a plurality of variants is known to human NR10, but any variant may be used as an immunogen as long as an antibody having binding activity and/or neutralizing activity to human NR10 can be produced. Alternatively, under the same conditions, an NR10 fragment peptide or a natural NR10 sequence to which an artificial mutation has been added may be used as an immunogen. Human NR10.3 is one of the preferred immunogens from the viewpoint of being able to produce an antibody having binding activity and/or neutralizing activity to NR10 of the present invention.

In addition, measurement of the binding activity and/or neutralizing activity of the antibody to NR10 can be performed, for example, by a method described in Examples, observing the proliferation inhibitory effect of the IL-31-dependent cell line.

On the other hand, monoclonal antibodies can also be obtained by DNA immunization. DNA immunity is a method of imparting immune stimulation by administering to the immunized animal a vector DNA constructed in an embodiment capable of expressing a gene encoding an antigen protein in an immunized animal, and expressing the immunizing antigen in vivo to be. Compared with general immunization methods in which protein antigens are administered, the following advantages can be expected in DNA immunization.

－Immune stimulation can be given by maintaining the structure of membrane proteins.

-No need to purify immune antigens

However, on the other hand, in DNA immunity, it is difficult to combine it with an immune stimulating means such as an adjuvant.

To obtain a monoclonal antibody by DNA immunization, first, a DNA encoding NR10 is administered to an immunized animal. DNA encoding NR10 can be synthesized by a known method such as PCR. The obtained DNA is inserted into an appropriate expression vector and administered to an immunized animal. As the expression vector, a commercially available expression vector such as pcDNA3.1 can be used. As a method of administering a vector to a living body, a generally used method can be used. For example, DNA immunization can be performed by placing gold particles adsorbed with an expression vector into cells with a gene gun. After DNA immunization, additional immunization (boost) with NR10 expressing cells is a preferred method of obtaining a monoclonal antibody.

In this way, after the mammal is immunized and an increase in the amount of the desired antibody in the serum is confirmed, immune cells are collected from the mammal and imparted to cell fusion. As a preferable immune cell, in particular, splenocytes can be used.

As the cells to be fused with the above immune cells, mammalian myeloma cells are used. It is preferable that the myeloma cells have an appropriate selection marker for screening. The selectable marker refers to a trait that can survive (or cannot) under specific culture conditions. As the selection marker, a hypoxanthine-guanine-phosphoribosyltransferase deletion (hereinafter abbreviated as HGPRT deletion), a thymidine kinase deletion (hereinafter abbreviated as TK deletion), and the like are known. Cells having a HGPRT or TK deletion have hypoxanthine-aminopterin-thymidine sensitivity (hereinafter abbreviated as HAT sensitivity). HAT-sensitive cells die because they cannot synthesize DNA in the HAT-selective medium, but when they fuse with normal cells, they can continue to synthesize DNA using the salvage circuit of the normal cells, so they proliferate even in the HAT-selective medium.

HGPRT-deficient or TK-deficient cells can be selected from a medium containing 6 thioguanine, 8 azaguanine (hereinafter abbreviated as 8AG), or 5'bromodeoxyuridine, respectively. Normal cells are killed by inserting these pyrimidine analogs into DNA, but cells lacking these enzymes can survive in a selective medium because these pyrimidine analogs cannot be inserted. In addition, a selection marker called G418 resistance confers resistance to 2-deoxystreptamine antibiotics (gentamicin analogs) by the neomycin resistance gene. Various myeloma cells suitable for cell fusion are known.

Basically, according to a known method, for example, a method such as Kohler and Milstein (Kohler. G. and Milstein, C., Methods Enzymol. (1981) 73, 3-46) of immune cells and myeloma cells. Cell fusion is carried out.

More specifically, for example, cell fusion can be performed in a normal nutrient culture medium in the presence of a cell fusion promoter. As the fusion accelerator, for example, polyethylene glycol (PEG), Sendai virus (HVJ), or the like can be used. In order to further increase the fusion efficiency, it is also possible to add an auxiliary agent such as dimethyl sulfoxide as desired.

The ratio of use of immune cells and myeloma cells can be arbitrarily set. For example, it is preferable to increase the number of immune cells to 1 to 10 times the myeloma cells. As the culture medium used for cell fusion, for example, RPMI1640 culture medium suitable for proliferation of myeloma cell lines, MEM culture medium, and other conventional culture solutions used for culturing cells of this species can be used. In addition, a serum supplement such as fetal bovine serum (FCS) can be added to the culture solution.

In cell fusion, a predetermined amount of immune cells and myeloma cells are well mixed in a culture medium, and a PEG solution warmed to about 37°C is mixed to form the target fusion cells (hybridoma). In the cell fusion method, for example, PEG having an average molecular weight of about 1000 to 6000 can be added at a concentration of usually 30 to 60% (w/v). Subsequently, an operation of sequentially adding the appropriate culture solution exemplified above and centrifuging to remove the supernatant is repeated, thereby removing a cell fusion agent that is not desirable for the growth of hybridomas.

The hybridoma obtained in this way can be selected by using a selective culture medium according to the selection marker of the myeloma used for cell fusion. For example, cells having a HGPRT or TK defect can be selected by culturing with a HAT culture solution (a culture solution containing hypoxanthine, aminopterin, and thymidine). That is, when HAT-sensitive myeloma cells are used for cell fusion, cells that have succeeded in cell fusion with normal cells can be selectively proliferated in the HAT culture medium. Cultivation using the HAT culture solution is continued for a time sufficient for the death of cells other than the target hybridoma (non-fused cells). Specifically, in general, a hybridoma of interest can be selected by culturing for several days to several weeks. Subsequently, by performing the usual limiting dilution method, hybridomas producing the target antibody can be screened and single cloned. Alternatively, an antibody that recognizes NR10 can be produced by the method described in International Publication No. WO03/104453.

Screening and single cloning of an antibody of interest can be suitably carried out by a screening method based on a known antigen-antibody reaction. For example, the antigen is bound to a carrier such as beads made of polystyrene or the like or a commercial 96-well microtiter plate, and reacted with the hybridoma culture supernatant. Subsequently, after washing the carrier, a secondary antibody or the like labeled with an enzyme is reacted. If an antibody intended to react with a sensitizing antigen is contained in the culture supernatant, the secondary antibody binds to the carrier via this antibody. Finally, by detecting the secondary antibody that binds to the carrier, it is possible to determine whether or not the target antibody is present in the culture supernatant. It becomes possible to clone a hybridoma producing an antibody of interest having antigen-binding ability by limiting dilution method or the like. At this time, as an antigen, a substantially homogeneous NR10 protein can be suitably used, including those used for immunization. For example, a cell line expressing NR10, an extracellular domain of NR10, or an oligopeptide comprising a partial amino acid sequence constituting the region can be used as an antigen.

In addition to the method of obtaining the hybridoma by immunizing an antigen of a non-human animal, it is also possible to obtain an antibody of interest by antigen-sensitizing human lymphocytes. Specifically, first, human lymphocytes are sensitized with NR10 protein in vitro. The immune sensitized lymphocytes are then fused with an appropriate fusion partner. As the fusion partner, for example, human-derived myeloma cells having permanent dividing ability can be used (refer to Japanese Patent Publication No. Hei 1-59878). The antibody obtained by this method is a human antibody having binding activity to NR10 protein.

The base sequence and amino acid sequence encoding the anti-NR10 antibody obtained by the above-described method or the like can be obtained by a method known to those skilled in the art.

Based on the sequence of the obtained anti-NR10 antibody, it is possible to produce an anti-NR10 antibody using gene recombination techniques known to those skilled in the art. Specifically, a polynucleotide encoding an antibody may be constructed based on the sequence of an antibody recognizing NR10, introduced into an expression vector, and then expressed in a suitable host cell (e.g., Co, MS et al., J. Immunol. (1994) 152, 2968-2976; Better, M. and Horwitz, AH, Methods Enzymol. (1989) 178, 476-496; Pluckthun, A. and Skerra, A., Methods Enzymol. (1989) 178, 497-515; Lamoyi, E., Methods Enzymol. (1986) 121, 652-663; Rousseaux, J. et al., Methods Enzymol. (1986) 121, 663-669; Bird, RE and Walker, BW , Trends Biotechnol. (1991) 9, 132-137).

Examples of vectors include M13 vector, pUC vector, pBR322, pBluescript, pCR-Script, and the like. Further, in the case of the purpose of subcloning or cutting cDNA, in addition to the above vector, for example, pGEM-T, pDIRECT, pT7, and the like can be mentioned. When a vector is used for the purpose of producing the antibody of the present invention, an expression vector is particularly useful. As an expression vector, for example, when the purpose is for expression in E. coli, when the vector has the above characteristics to be amplified in E. coli, and when the host is E. coli such as JM109, DH5α, HB101, XL1-Blue, etc. In E. coli, promoters that can be efficiently expressed, for example, the lacZ promoter (Ward et al., Nature (1989) 341, 544-546; FASEB J. (1992) 6, 2422-2427), araB promoter (Better et al., Science (1988) 240, 1041-1043), or it is indispensable to have a T7 promoter. As such a vector, in addition to the above vector, pGEX-5X-1 (manufactured by Pharmacia), ``QIAexpress system'' (manufactured by Qiagen), pEGFP, or pET (in this case, BL21 expressing T7 RNA polymerase as the host is preferable. ) And the like.

Further, the vector may contain a signal sequence for secretion of an antibody. As the signal sequence for antibody secretion, when produced by E. coli periplasm, a pelB signal sequence (Lei, S. P. et al., J. Bacteriol. (1987) 169, 4379) may be used. Introduction of the vector into the host cell can be performed using, for example, a calcium chloride method or an electroporation method.

In addition to Escherichia coli, for example, as a vector for producing the antibody of the present invention, a mammal-derived expression vector (for example, pcDNA3 (manufactured by Invitrogen), pEF-BOS (Nucleic Acids.Res. 1990, 18)) 17), p5322), pEF, pCDM8), insect cell-derived expression vectors (e.g., ``Bac-to-BAC baculovairus expression system'' (manufactured by Gibco BRL), pBacPAK8), plant-derived expression vectors (e.g. pMH1, pMH2), animal virus-derived expression vectors (e.g., pHSV, pMV, pAdexLcw), retrovirus-derived expression vectors (e.g. pZIPneo), yeast-derived expression vectors (e.g., ``Pichia Expression Kit" (manufactured by Invitrogen), pNV11, SP-Q01), and expression vectors derived from Bacillus Bacillus (for example, pPL608, pKTH50).

For the purpose of expression in animal cells such as CHO cells, COS cells, NIH3T3 cells, etc., promoters necessary for expression in cells, such as the SV40 promoter (Mulligan et al., Nature (1979) 277, 108), MMLV -It is indispensable to have an LTR promoter, an EF1α promoter (Mizushima et al., Nucleic Acids Res. (1990) 18, 5322), a CMV promoter, etc., and genes for selecting transformation into cells (e.g., drugs (neo It is more preferable to have a drug resistance gene that can be discriminated by mycin, G418, etc.). Examples of vectors having such characteristics include pMAM, pDR2, pBK-RSV, pBK-CMV, pOPRSV, pOP13, and the like.

In addition, in the case of stably expressing a gene and aiming to amplify the number of copies of the gene in a cell, a vector having a DHFR gene complementing it to a CHO cell lacking the nucleic acid synthesis pathway (for example, pSV2-dhfr ("Molecular Cloning 2nd edition" Cold Spring Harbor Laboratory Press, (1989)), etc.) are introduced and amplified by methotrexate (MTX). In this case, a method of transforming with a vector (pcD, etc.) having an origin of replication of SV40 using COS cells having a gene expressing the SV40 T antigen on a chromosome is exemplified. As the replication initiation point, it is also possible to use those derived from polyoma virus, adenovirus, and pyophyllosis virus (BPV). In addition, for the amplification of the gene copy number in the host cell system, the expression vector is a selection marker, an aminoglycoside transferase (APH) gene, a thymidine kinase (TK) gene, E. coli xanthine guanine phosphoribosyltransferase ( Ecogpt) gene, dihydrofolate reductase (dhfr) gene, and the like.

The antibody of the present invention thus obtained can be isolated from inside or outside of a host cell (medium, etc.) and purified as a substantially pure and homogeneous antibody. Isolation and purification of the antibody may be performed using the separation and purification methods used in ordinary antibody purification, and is not limited at all. For example, chromatography column, filter, ultrafiltration, salting out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS-polyacrylamide gel electrophoresis, isoelectric point electrophoresis, dialysis, recrystallization, etc. Can be separated and purified.

Examples of the chromatography include affinity chromatography, ion exchange chromatography, hydrophobic chromatography, gel filtration, reverse phase chromatography, and adsorption chromatography (Strategies for Protein Purification and Characterization: A Laboratory Course Manual.Ed Daniel R. Marshak et al., Cold Spring Harbor Laboratory Press, 1996). These chromatography can be performed using liquid chromatography, for example, liquid chromatography such as HPLC and FPLC. As a column used for affinity chromatography, a protein A column and a protein G column are mentioned. For example, as a column using protein A, Hyper D, POROS, Sepharose FF (GE Amersham Biosciences), etc. are mentioned. The present invention also includes highly purified antibodies using these purification methods.

The measurement of the binding activity of the obtained antibody to NR10 can be performed by a method known to those skilled in the art. For example, as a method of measuring the antigen-binding activity of an antibody, ELISA (enzyme-linked immunosorbent assay), EIA (enzyme immunoassay), RIA (radioimmunoassay), or fluorescent antibody method can be used. For example, in the case of using an enzyme immunoassay, a sample containing an antibody, for example, a culture supernatant of an antibody-producing cell or a purified antibody is added to a plate coated with an antigen. The antigen-binding activity can be evaluated by adding a secondary antibody labeled with an enzyme such as alkaline phosphatase, incubating the plate, washing, and then measuring the absorbance by adding an enzyme substrate such as p-nitrophenyl phosphate.

Pharmaceutical composition

Further, the present invention provides a pharmaceutical composition containing the above-described antibody as an active ingredient. In addition, the present invention provides a therapeutic agent for inflammatory diseases using the above-described antibody as an active ingredient.

In the present invention, an inflammatory disease is a disease accompanied by pathological findings regarding cytological and histological reactions that occur in affected blood vessels and adjacent tissues due to damage or abnormal stimulation caused by physical, chemical, or biologically active substances. (Stedman Medical Dictionary, 5th Edition, Medical Review, 2005). In general, inflammatory diseases include dermatitis (atopic dermatitis, chronic dermatitis, etc.), inflammatory bowel disease (colitis, etc.), asthma, arthritis (joint rheumatism, deformed arthrosis, etc.), bronchitis, Th-2 type autoimmune disease, systemic erythemato Death, myasthenia gravis, chronic GVHD, clonal disease, spondylitis deformed, back pain, gout, post-operative inflammation, swelling relief, neuralgia, sore throat, cystitis, hepatitis (nonalcoholic fatty hepatitis, alcoholic hepatitis, etc.), hepatitis B, C Hepatitis, arteriosclerosis, and itching.

Preferred examples of inflammatory diseases subject to the present invention include atopic dermatitis, chronic dermatitis, rheumatism, arthrosis deformed, chronic asthma, and itching.

"Containing an anti-NR10 antibody as an active ingredient" means that an anti-NR10 antibody is contained as one or more of the active ingredients, and the content rate is not limited. In addition, the therapeutic agent for an inflammatory disease of the present invention may contain, together with the anti-NR10 antibody described above, a component that promotes treatment of other inflammatory diseases.

In addition, the therapeutic agent of the present invention may be used for prophylactic purposes.

The anti-NR10 antibody of the present invention can be formulated according to a conventional method (eg, Remington's Pharmaceutical Science, latest edition, Mark Publishing Company, Easton, U.S.A). Further, if necessary, a pharmaceutically acceptable carrier and/or additive may be included together. For example, surfactants (PEG, Tween, etc.), excipients, antioxidants (ascorbic acid, etc.), coloring agents, flavoring agents, preservatives, stabilizers, buffers (phosphoric acid, citric acid, other organic acids, etc.), chelating agents (EDTA, etc.), suspension Agents, tonicity agents, binders, disintegrants, lubricants, fluidity accelerators, flavoring agents, and the like. However, the prophylactic or therapeutic agent for inflammatory diseases of the present invention is not limited to these, and other commercially available carriers may be appropriately included. Specifically, soft silicic anhydride, lactose, crystalline cellulose, mannitol, starch, carmellose calcium, carmellose sodium, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinyl acetaldiethylaminoacetate, polyvinylpyrroly Don, gelatin, medium chain fatty acid triglyceride, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethyl cellulose, corn starch, inorganic salts, etc. are mentioned. Further, other low molecular weight polypeptides, proteins such as serum albumin, gelatin, and immunoglobulins, and amino acids such as glycine, glutamine, asparagine, arginine, and lysine may be included. In the case of an aqueous solution for injection, an anti-NR10 antibody is dissolved in an isotonic solution containing, for example, physiological saline, glucose or other adjuvants. Examples of adjuvants include D-sorbitol, D-mannose, D-mannitol, and sodium chloride, and suitable solubility aids, such as alcohol (ethanol, etc.), polyalcohol (propylene glycol, PEG, etc.) , Nonionic surfactants (polysorbate 80, HCO-50), and the like may be used in combination.

In addition, if necessary, the anti-NR10 antibody is encapsulated in microcapsules (microcapsules such as hydroxymethylcellulose, gelatin, poly[methylmethacrylic acid], etc.), or colloidal drug delivery systems (liposomes, albumin microspheres, microemulsions, nanocapsules). Particles and nanocapsules, etc.) are also possible (refer to Remington's Pharmaceutical Science 16th edition &, Oslo Ed. (1980), etc.). In addition, a method of using a drug as a sustained-release drug is also known, and can be applied to an anti-NR10 antibody (Langer et al., J. Biomed. Mater. Res. (1981) 15: 167-277; Langer, Chem. Tech. (1982) 12: 98-105; U.S. Patent No. 3,773,919; European Patent Application Publication (EP) 58,481; Sidman et al., Biopolymers (1983) 22:547-56; EP 133,988).

The pharmaceutical composition of the present invention can be administered either orally or parenterally, but is preferably administered parenterally. Specifically, it is administered to a patient by injection and transdermal administration. As an example of an injection formulation, it can be administered systemically or locally by, for example, intravenous injection, intramuscular injection, or subcutaneous injection. Local injections, especially intramuscular injections, may also be employed in or around the area to be suppressed. In addition, an appropriate administration method can be selected according to the patient's age and symptoms. As the dosage, for example, it is possible to select the active ingredient per 1 kg of body weight at a time in the range of 0.0001 mg to 100 mg. In addition, for example, in the case of administration to a human patient, the active ingredient per patient can be selected in the range of 0.001 to 1000 mg/kg body weight, and the amount per dose is, for example, the antibody of the present invention. It is preferable that an amount of about 0.01-50 mg/kg·body·weight is included. However, the prophylactic or therapeutic agent of the inflammatory disease of the present invention is not limited to these dosages.

In addition, all prior art documents cited in this specification are included in this specification by reference.

Example

Hereinafter, the present invention will be specifically described using examples, but the present invention is not limited by these examples.

[Example 1] Hybridoma production

1.1. Human NR10 plasmid for DNA immunization , cynomolgus monkey Preparation of NR10 Plasmid

1.1.1. hNR10 , cynNR10 Preparation of expression vector

Human NR10 (base sequence SEQ ID NO:75, amino acid sequence SEQ ID NO:76) was inserted into a vector pMacII (WO2005/054467) expressing a protein under the control of a mouse β-actin promoter to obtain an hNR10 expression vector. Similarly, a cynNR10 expression vector was constructed from cynomolgus monkey NR10 (base sequence SEQ ID NO:65, amino acid sequence SEQ ID NO:66).

1.1.2. Fabrication of DNA cartridge

To use the hNR10 or cynNR10 expression vector prepared in 1.1.1 for DNA immunization to mice, 1 µg of DNA was immunized for each DNA using the Herios Gene Gun cartridge kit (manufactured by BIO-RAD). A capable DNA cartridge was prepared.

1.2. Anti-human NR10 Antibody production Hybridoma making

1.2.1. Human NR10 and Crab Monkey Fabrication of hybridomas using NR10 immune mice

Ten Balb/c mice (magnetic, 6 weeks old at the start of immunization, Nippon Charles River) were immunized with human NR10 or cynomolgus monkey NR10 as follows. As the initial immunization, a DNA cartridge prepared with the hNR10 expression vector was immunized using the Herios Gene Gun system (BIO-RAD). The second immunization was performed 1 week later by immunizing a DNA cartridge made with the cynNR10 expression vector with the Herios Gene Gun system. From the third time onwards, hNR10 and cynNR10 expression vectors were alternately immunized at 1-week intervals. After confirming the increase in the serum antibody titer against human NR10, human NR10 protein (extracellular region) (Reference Example 4) diluted in PBS(-) was administered intravenously at 10 µg/head as a final immunization. Four days after the final immunization, mouse splenocytes and mouse myeloma cells P3X63Ag8U.1 (referred to as P3U1, ATCC CRL-1597) were cell-fused according to a conventional method using PEG1500 (Roche Diagnostics). The fused cells, that is, hybridomas, were cultured in RPMI1640 medium containing 10% FBS (hereinafter referred to as 10% FBS/RPMI1640).

1.2.2. Hybridoma Selection

The day after the fusion, (1) the fused cells were suspended in a semi-fluid medium (StemCells), hybridomas were selectively cultured, and hybridomas were colonized.

Hybridoma colonies are picked up on the 9th or 10th day after fusion, and HAT selection medium (10% FBS/RPMI1640, 2 vol% HAT 50x concentrate (Dai Nippon Pharmaceutical), 5 vol% BM-Condimed H1 (Roche Diagnostics) ) Into a 96-well plate containing 1 colony per well. After incubation for 3 to 4 days, the culture supernatant of each well was collected, and the concentration of mouse IgG in the culture supernatant was measured. The culture supernatant from which mouse IgG could be confirmed was evaluated by neutralizing activity using a human IL-31 dependent cell line (hNR10/hOSMR/BaF3 cells; Reference Example 2), and several clones having high NR10 neutralizing activity were obtained (Fig. 3). A clone that inhibits cell proliferation induced by human IL-31 stimulation in a concentration-dependent manner, and also inhibits proliferation in a concentration-dependent manner of cells (cynNR10/cynOSMR/BaF3 cells; Reference Example 2) stimulated by Crab monkey IL-31. Was obtained (Fig. 4).

[Example 2] Preparation of chimeric antibody

chimera Construction of antibody expression vector

From hybridoma cells, total RNA was extracted using RNeasy Mini Kits (QIAGEN), and cDNA was synthesized by SMART RACE cDNA Amplification Kit (BD Biosciences). Using the 10X Universal Primer A Mix attached to the SMART RACE cDNA Amplification Kit (BD Biosciences) and the primers (H chain: mIgG1-rnot, L chain: mIgK-rnot) set for each constant region of the antibody, and PrimeSTAR HS DNA PCR was performed by polymerase (TaKaRa) to isolate the variable region gene of the antibody. The nucleotide sequence of each isolated DNA fragment is determined using the BigDye Terminator Cycle Sequencing Kit (Applied Biosystems), using a DNA sequencer ABI PRISM 3730xL DNA Sequencer or ABI PRISM 3700 DNA Sequencer (Applied Biosystems), according to the method described in the attached manual. I did. The H chain variable region of the amino acid sequence of the obtained mouse antibodies of NS18, NS22, NS23 and NS33 is shown in Fig. 1, and the L chain variable region is shown in Fig. 2.

For each of the H chain and L chain fragments obtained, PCR was performed by PrimeSTAR HS DNA Polymerase (TaKaRa) using a primer of the combination shown in Table 1, and the obtained amplified fragments were subjected to a constant region (respectively, human γ1 or γ2, human κ). ) And inserted into an animal cell expression vector. The nucleotide sequence of each DNA fragment was determined using the BigDye Terminator Cycle Sequencing Kit (Applied Biosystems), a DNA sequencer ABI PRISM 3730xL DNA Sequencer or ABI PRISM 3700 DNA Sequencer (Applied Biosystems), according to the method described in the attached manual.

chimera Preparation of antibody

HEK293H strain (Invitrogen) derived from human fetal kidney cancer cells was suspended in DMEM medium (Invitrogen) containing 10% Fetal Bovine Serum (Invitrogen), and a dish for adherent cells at a cell density of ^{6×10 5 cells/mL (10 cm in diameter)} , CORNING) in 10 mL each dish and _{cultured in a CO 2} incubator (37° C., 5% CO ₂ ) for one day, then the medium was removed by suction, and 6.9 mL of CHO-S-SFMII (Invitrogen) medium was added. I did. CHO-S-SFMII medium was added to the prepared plasmid DNA mixture (13.8 μg in total) to make 700 μL, and 20.7 μL of 1 μg/mL Polyethylenimine (Polysciences Inc.) was added, mixed, and allowed to stand for 10 minutes at room temperature. _{And incubated in a CO 2} incubator (5% CO ₂ at 37° C.) for 4 to 5 hours. Then, 6.9 mL of CHO-S-SFMII (Invitrogen) medium was added, and cultured in a _{CO 2 incubator for 3 to 4 days.} After collecting the culture supernatant, the cells were removed by centrifugation (about 2000 g, 5 minutes, room temperature), and additionally passed through a 0.22 μm filter MILLEX (registered trademark)-GV (Millipore). Each sample was stored at 4°C until use. Antibodies were purified from this supernatant using Protein G Sepharose (Amersham Biosciences). The purified antibody was concentrated using Amicon Ultra 15 (Millipore), and the solvent was additionally substituted with PBS (-) containing _{0.05% NaN 3 using PD-10 Desalting columns (Amersham Biosciences).} The absorbance of 280 nm was measured with an ND-1000 Spectrophotometer (NanoDrop), and the concentration was calculated by a method such as Pace (Protein Science (1995) 4: 2411-2423).

chimera NS22 Activity evaluation

Using the hNR10/hOSMR/BaF3 cell line that proliferates in a dose-dependent manner of hIL-31, hIL-31 neutralizing activity was evaluated as shown below.

hNR10/hOSMR/BaF3 cells were prepared to be ^{1.5×10 5} cells/mL in RPMI1640 medium (GIBCO) containing 10% FBS (MOREGATE) and 1% Penicillin-Streptomycin (Invitrogen). A part of it was taken, and hIL-31 (R&D Systems) was added to 4 ng/mL (IL-31 (+), final conc.; 2 ng/mL). The remaining cell suspension was referred to as IL-31(-). Purified NS22 was adjusted to 2 µg/mL in a medium, and additionally diluted azeotrope 3 and a total of 8 dilutions were prepared (final conc.; ≤ 1 µg/mL). Cell suspension and 50 μL of chimeric NS22 (human γ1, κ) diluted solution were seeded in each well of a 96 well flat bottom plate (CORNING), and incubated for 2 days in a _{37°C, 5% CO 2 incubator.} After the cultivation was completed, 20 μL of a solution in which an equal amount of Cell Counting Kit-8 (Dojindo) and PBS were mixed was added to each well, and absorbance (450 nm/620 nm) was measured (TECAN, SUNRISE CLASSIC). After reacting for 2 hours in a 37°C, 5% CO ₂ incubator, the absorbance was measured again. The neutralizing activity of NS22 was expressed as the inhibition rate using the value subtracting the 0 hour value from the 2 hour value. As a result, it became clear that NS22 inhibited cell proliferation by IL-31 stimulation in a concentration-dependent manner in the hNR10/hOSMR/BaF3 cell line, and it was proved that it has neutralizing activity against human IL-31 signaling (Fig. 5). ).

Using the DU145 cell line (human prostate cancer cell line) showing induction of IL-6 production by IL-31 stimulation, IL-31 neutralizing activity was evaluated as shown below.

DU145 was prepared to be ^{2.5×10 5} cells/mL in MEM medium (Invitrogen) containing 10% FBS (MOREGATE), 2 mmol/L L-glutamine (Invitrogen), and 1 mmol/L sodium pyruvate (SIGMA). Then, 200 μL was dispensed into each well of a 48 well-plate (CORNING), and cultured overnight under conditions of _{37° C. and 5% CO 2.} Purified chimeric NS22 (human γ1, κ) was diluted to 100 µg/mL in MEM medium containing 10% FBS, 2 mmol/L L-glutamine, and sodium pyruvate, and diluted azeotrope 5 with this solution. A total of 6 dilutions were prepared, each was mixed 1:1 with 100 ng/mL of human interleukin-31 (R&D systems), and 50 μL was added to each well. The concentration of IL-6 in the culture supernatant after incubation for 2 days at 37°C and 5% CO ₂ was measured using a DuoSet ELISA Development kit (R&D systems). The neutralizing activity of NS22 was evaluated as an inhibition rate (%). That is, the maximum inhibitory activity (100% inhibition) of IL-6 concentration (A) in the absence of IL-31, no inhibitory activity (0% inhibition) of IL-6 concentration (B) under the addition of IL-31 and without NS22 ), the IL-6 concentration (C) under the addition of IL-31 and the addition of NS22 was calculated by the following equation.

Inhibition rate (%) = (B-C)/(B-A)×100

As a result, it became clear that NS22 inhibited IL-6 production by IL-31 stimulation in a concentration-dependent manner in the DU145 cell line, and it was proved that it has a neutralizing activity against human IL-31 signaling (Fig. 6).

chimera term NR10 Evaluation of antibody IL-31 competitive activity

Human IL-31 (R&D Systems) was labeled by FMAT Blue Monofunctional Reactive Dye (Applied Biosystems). To 100 μL of hIL-31 prepared at 0.5 mg/mL in 50 mM sodium phosphate buffer (pH 8.0), 5.25 μL of 25 nmoles FMAT Blue dissolved in DMSO (Junsei) was added, followed by Vortex, and allowed to stand at room temperature for 15 minutes. I did. By adding 5 μL of 1 M Tris-HCl (pH 7.4) and 1.1 μL of 10% Tween20, the introduction of FMAT Blue into hIL-31 was stopped, and then Superdex 75 (GE Healthcare, 17-0771-01) was added to the column. FMAT Blue-labeled hIL-31 and unreacted FMAT Blue were separated on a 0.1% Tween20/PBS developing solution by gel filtration used as.

Using hNR10 expressing CHO cells, the IL-31/NR10 binding inhibitory activity of the antibody was evaluated as shown below.

NS22 and NA633 (each normal region is γ1, κ) diluted to an appropriate concentration using assay buffer (10 mM HEPES, 140 mM NaCl, 2.5 mM CaCl ₂ , 3 mM MgCl ₂ , 2% FBS, 0.01% NaN _{3 ).} Then, dilution azeotrope 2 and a total of 7 series of dilutions were additionally prepared and added to the plates (96-Well FMAT Plates, Applied Biosystems) at 40 μL/well. Subsequently, FMAT Blue-labeled hIL-31 was diluted 400 times with an assay buffer, and added at 20 μL/well. Finally, a cell suspension adjusted to 2.5×10 ⁵ cells/mL with an assay buffer was added at 40 μL/well (final 1×10 ⁴ cells/well). 2 hours after the cells were added, fluorescence (FL1) was measured with an 8200 Cellular Detection System (Applied Biosystems). As a result, it was shown that NS22 inhibited the binding of hIL-31/hNR10 in a dose-dependent manner, and its activity was proved to be superior to that of NA633 (Fig. 7).

[Example 3] Competition of anti-NR10 antibody against NR10

The NS22 antibody purified from the hybridoma culture supernatant was labeled with FMAT Blue (Applied Biosystems, 4328853). To 170 µL of NS22 prepared with 1 mg/ml-PBS, 17 µL 1 M NaHCO ₃ solution and 3.4 µL of 17 nmoles FMAT Blue dissolved in DMSO were added, followed by vortexing, and then allowed to stand at room temperature for 30 minutes. Gel using Superdex 75 (GE Healthcare, 17-0771-01) as a column after stopping the introduction of FMAT Blue into NS22 by adding 8 μL 1 M Tris-HCl (pH 7.4) and 1.9 μL 1% Tween20 By filtration, FMAT Blue labeled NS22 (FMAT Blue-NS22) and unreacted FMAT Blue were separated on a 0.01% Tween20/PBS developing solution.

Inhibition of the obtained FMAT Blue-NS22 against the binding of hNR10-expressing CHO cells (Reference Example 3) by various antibodies was examined using the 8200 Cellular Detection System (Applied Biosystems, 4342920). 8.8 × 10 ^-2 μg/mL FMAT Blue-NS22, 7500 cells/well, various concentrations of chimeric anti-NR10 antibodies (γ1, κ for each normal region) were added, and FMAT bound to cells after standing in the dark for 4 hours. The fluorescence signal derived from Blue was measured. The reaction was carried out in 10 mM Hepes-KOH containing _{2.5 mM CaCl 2} , 3 mM MgCl ₂ , 140 mM NaCl, 2% FBS, and 0.01% NaNO _3. The results are shown in FIG. 8. As the concentration of the NS22 and NS23 antibodies increased, the fluorescence value FL1 indicating the binding of FMAT Blue-NS22 to NR10 expressing cells decreased. On the other hand, almost no decrease in FL1 accompanying the increase in the concentration of the NA633 antibody (Reference Example 6) was observed (Fig. 8).

[Example 4] Humanization of NS22 antibody

bracket Framework Selection of a sequence

The variable region of the mouse NS22 antibody and the human germline sequence were compared. Among them, the FR sequences used at the time of humanization are summarized in Table 2. The determination of CDR and FR was performed according to Kabat numbering. As a humanized variable region, the H chain is the sequence of FR1, FR2, FR3_1, and FR4 shown in Table 2, H0-VH (SEQ ID NO: 50), the sequence of FR1, FR2, FR3_2, and FR4 is H1-VH. It was set as (SEQ ID NO:112). In addition, for the L chain, the sequence consisting of FR1, FR2, FR3, and FR4 was set to L0 (SEQ ID NO: 52).

Humanization NS22 H0L0 Of the variable region of

In order to construct the variable region of humanized NS22 in which the CDR region of NS22 was grafted into the FR region used for humanization, synthetic oligo DNA was designed for H chain and L chain, respectively. Each synthetic oligo DNA was mixed, and a gene encoding the variable region of humanized NS22 was produced by assembly PCR. Assembly PCR was performed using KOD-Plus (TOYOBO), and performed by the PCR method according to the following conditions. The reaction mixture consisting of the attached PCR Buffer, dNTPs, MgSO ₄ , KOD-Plus and 10 pmol of synthetic oligo DNA was heated at 94° C. for 5 minutes, followed by heating at 94° C. for 2 minutes, 55° C. for 2 minutes, and 68° C. After performing two PCR reaction cycles consisting of 2 minutes at the 5'end of the variable region, a primer with a restriction enzyme site and a Kozak sequence added, and a primer with a restriction enzyme site added at the 3'end were each 10 pmol. Then, a PCR reaction cycle consisting of 30 seconds at 94°C, 30 seconds at 55°C and 1 minute at 68°C was performed 35 times to obtain an amplified fragment. The obtained amplified fragment was cloned with TOPO TA Cloning vector (TOYOBO), and the nucleotide sequence was confirmed by the sequence. The prepared variable region and the constant region were combined, and H0-SKSC (SEQ ID NO: 54) and L0 (SEQ ID NO: 56) were prepared, and inserted into an expression vector capable of expressing the inserted gene in animal cells. The nucleotide sequence of each DNA fragment was determined using the BigDye Terminator Cycle Sequencing Kit (Applied Biosystems), a DNA sequencer ABI PRISM 3730xL DNA Sequencer or ABI PRISM 3700 DNA Sequencer (Applied Biosystems), according to the method described in the attached manual.

Humanization NS22 Fabrication of H1 variable region

Preparation of H1-SKSC (SEQ ID NO: 130) was performed by substituting lysine (K) for glutamine (E) at the 73rd kabat numbering present in FR3 of H0-SKSC (SEQ ID NO: 54). The production of the variant was carried out using a commercially available QuikChange Site-Directed Mutagenesis Kit (Stratagene), and the variant was produced according to the method of the attached manual.

IgG Expression of the transformed antibody

Expression of the antibody was performed using the following method. Human fetal renal cancer cell-derived K293H state (Invitrogen) 10% Fetal Bovine Serum (Invitrogen) were suspended in DMEM medium (Invitrogen), and containing ⁵ ~ 6 × 10 5 gae / mL of cells for adhesion at a density cells-dish (diameter: 10 cm, CORNING) each dish with 10 mL of each dish and _{cultured in a CO 2} incubator (37° C., 5% CO ₂ ) for one day, and then the medium was aspirated off, and 6.9 mL of the CHO-S-SFMII (Invitrogen) medium was added. Added. The prepared plasmid DNA mixture (total 13.8 µg) was mixed with 20.7 µL of 1 µg/mL Polyethylenimine (Polysciences Inc.) and 690 µL of CHO-S-SFMII medium, left standing at room temperature for 10 minutes, and added to the cells of each dish. -5 hours, _{incubated in a CO 2} incubator (5% CO ₂ at 37°C). Then, 6.9 mL of CHO-S-SFMII (Invitrogen) medium was added, and cultured in a _{CO 2 incubator for 3 days.} After collecting the culture supernatant, the cells were removed by centrifugation (about 2000 g, 5 minutes, room temperature), and sterilized by passing through a ^{0.22 μm filter MILLEX (R) -GV (Millipore).} Each sample was stored at 4°C until use.

IgG Purification of the purified antibody

To the obtained culture supernatant, 50 μL of rProtein A Sepharose ^™ Fast Flow (Amersham Biosciences) suspended in TBS was added, followed by conduction mixing at 4° C. for 4 hours or longer. The solution was transferred to a 0.22 µm filter cup Ultrafree (registered trademark)-MC (Millipore), washed three times with 500 µL of TBS, and then suspended in 100 µL of 50 mM sodium acetate aqueous solution, pH 3.3 in ^{rProtein A Sepharose TM resin.} After standing for 3 minutes, the antibody was eluted. Immediately, 6.7 μL of 1.5 M Tris-HCl, pH 7.8 was added to neutralize. Elution was performed twice to obtain 200 μL of purified antibody. 2 μL of a solution containing the antibody was supplied to ND-1000 Spectrophotometer (NanoDrop) (Thermo Scientific NanoDrop ^TM 1000 Spectrophotometer (Thermo Scientific)), or 50 μL was provided to a spectrophotometer DU-600 (BECKMAN), and at 280 nm. The absorbance was measured and the antibody concentration was calculated by the method of Pace et al. (Protein Science (1995) 4: 2411-2423).

FMAT Measurement of IL-31 competitive activity using

Using hNR10 expressing CHO cells, the IL-31/NR10 binding inhibitory activity of the antibody was evaluated as shown below. NS22 chimeric antibody and NS22_H0L0 (H chain H0-SKSC/SEQ ID NO:54, L chain L0/SEQ ID NO:56) assay buffer (10 mM HEPES, 140 mM NaCl, 2.5 mM CaCl ₂ , 3 mM MgCl ₂ , 2%) FBS, 0.01% NaN ₃ , pH 7.4) was used to dilute to an appropriate concentration, and additionally, diluted azeotrope 2, total 8 series of dilutions were prepared, and plated at 40 μL/well (96-Well FMAT Plates, Applied Biosystems). Added. Subsequently, FMAT Blue-labeled hIL-31 was diluted 400 times with an assay buffer, and added at 20 μL/well. Finally, a cell suspension adjusted to 2.5×10 ⁵ cells/mL with an assay buffer was added to 40 μL/well (final 1×10 ⁴ cells/well). 2 hours after the cells were added, fluorescence (FL1) was measured with an 8200 Cellular Detection System (Applied Biosystems).

As a result, humanized NS22 antibody, H0L0 (H chain H0-SKSC/SEQ ID NO:54, L chain L0/SEQ ID NO:56), H1L0 (H chain H1-SKSC/SEQ ID NO:130, L chain L0/SEQ ID NO: As shown in Fig. 9, it can be said that H0L0 and H1L0 humanized anti-IL-31 receptor antibodies show almost the same competitive activity as that of the chimeric antibody. In addition, it is considered that the FRs used for H0L0 and H1L0 can be used as FRs at the time of humanization.

Therefore, it is considered that the mutant sites for the CDRs shown in the following examples can be introduced into either H0 or H1.

[Example 5] Effect of reducing heterogeneity by novel constant regions M14 and M58 in humanized anti-IL31 receptor antibody

As shown in Reference Examples 7 to 9, in the huPM1 antibody, which is a humanized anti-IL-6 receptor antibody, by converting the constant region from IgG2 to M14 or M58, the heterogeneity derived from the hinge region of IgG2 is not reduced without reducing the stability. It was confirmed that it can be reduced. Thus, also in the humanized anti-IL-31 receptor antibody, it was examined whether or not heterogeneity could be reduced by converting the constant region from wild-type IgG2 to M14 or M58.

As H chain, IgG1 (SEQ ID NO:60), and IgG2 (SEQ ID NO:132), including M14 (SEQ ID NO:129), M58 (SEQ ID NO:128) prepared in Reference Examples 8 and 9, and Examples Executed as H0-M14, H0-M58, H0-IgG1 and H0-IgG2, L chain in which the H chain variable region H0 (H0-VH/SEQ ID NO:50) of the humanized anti-IL-31 receptor antibody produced in step 4 was combined. Using L0 (L0/SEQ ID NO:56) prepared in Example 4, H0L0-IgG1 (H chain H0-IgG1/SEQ ID NO:133, L chain L0/SEQ ID NO:56), H0L0-IgG2 (H chain H0 -IgG2/SEQ ID NO:134, L chain L0/SEQ ID NO:56), H0L0-M14 (H chain H0-M14/SEQ ID NO:135, L chain L0/SEQ ID NO:56) and H0L0-M58 (H chain H0 -M58/SEQ ID NO:136, L chain L0/SEQ ID NO:56) was prepared. Expression and purification of each antibody was performed by the method described in Example 4.

As a method for evaluating heterogeneity, evaluation by cation exchange chromatography was performed. To evaluate the heterogeneity of the produced antibody, ProPac WCX-10 (Dionex) was used as a column, 20 mM Sodium Acetate, pH 5.0 as mobile phase A, and 20 mM Sodium Acetate, 1 M NaCl, pH 5.0 as mobile phase B were used. , Using an appropriate flow rate and gradient. Fig. 10 shows the results of evaluation by cation exchange chromatography (IEC).

As shown in Fig. 10, also in the anti-IL-31 receptor antibody, heterogeneity is increased by converting the constant region from IgG1 to IgG2, and by converting the constant region to M14 or M58, the heterogeneity can be reduced in either antibody. It was confirmed that there is.

[Example 6] Effect of improving pharmacokinetics by novel constant region M58 in anti-IL-31 receptor antibody

As shown in Reference Example 9, in the huPM1 antibody, which is an anti-IL-6 receptor antibody, by converting the constant region from IgG1 to M58, binding to human FcRn is improved, and pharmacokinetics in human FcRn transgenic mice is improved. It was found to be improved. Accordingly, it was examined whether or not the pharmacokinetics could be improved by converting the constant region to M58 for the anti-IL-31 receptor antibody as well.

H0L0-IgG1 prepared in Example 4 and Example 5 (H chain H0-IgG1/SEQ ID NO:133, L chain L0/SEQ ID NO:56), H0L0-M58 (H chain H0-M58/SEQ ID NO:136, L chain L0/SEQ ID NO:56) was evaluated for binding to human FcRn by the method shown in Reference Example 9. The results are shown in Table 3.

As shown in Table 3, it was confirmed that in H0L0, an anti-IL-31 receptor antibody, by converting the constant region from IgG1 to M58, the binding property to human FcRn is improved, similar to hPM1, an anti-IL-6 receptor antibody. Became. From this, it was shown that by converting the constant region from IgG1 to M58, the pharmacokinetics of the anti-IL-31 receptor can also be improved in humans.

[Example 7] Identification of mutation sites that lower the isoelectric point

Variant making

The preparation of each variant was performed by using the method according to Example 4 or assembly PCR using PCR. The method performed using assembly PCR is to synthesize oligo DNA designed based on the sequence of the forward and reverse chains including the modified site. A straight-chain oligo DNA containing an alteration site, a back-stranded oligo DNA that binds to a vector into which the gene for modification is inserted, a back-stranded oligo DNA containing an altered site, and a forward chain that binds to a vector into which the gene for modification is inserted Each of the oligo DNAs was combined, and PCR was performed using PrimeSTAR (TAKARA) to prepare two fragments including the modified site, at the 5'end side and the 3'end side. The two fragments were ligated to each other by assembly PCR to prepare each variant. The produced mutant was inserted into an expression vector capable of expressing the inserted gene in animal cells, and the base sequence of the obtained expression vector was determined by a method known in the art. Preparation and purification of the antibody were performed according to the method of Example 4.

Sympathy of the place of mutation

In order to improve the pharmacokinetics of H0L0 (H chain H0-SKSC/SEQ ID NO:54, L chain L0/SEQ ID NO:56), an alteration site capable of lowering the isoelectric point of the variable region was examined. As a result of screening the variable region mutation sites inferred from the three-dimensional structure model, a location that lowers the isoelectric point of the variable region without significantly lowering the binding to NR10 was found, and they are summarized in Table 4 (Hp5-VH/SEQ ID NO: 137, Hp7-VH/SEQ ID NO:138, Hp8-VH/SEQ ID NO:139, Hp6-VH/SEQ ID NO:140, Hp9-VH/SEQ ID NO:141, Hp1-VH/SEQ ID NO:142, Hp13-VH /SEQ ID NO:143, Lp1-VL/SEQ ID NO:144, Lp2-VL/SEQ ID NO:145, Lp3-VL/SEQ ID NO:146, Lp4-VL/SEQ ID NO:147, Lp7-VL/SEQ ID NO:148 , Lp5-VL/SEQ ID NO:149, Lp6-VL/SEQ ID NO:150). Preparation and purification of each variant was performed by the method described in Example 4.

The hIL-31/hNR10 binding inhibitory activity of each variant was evaluated using FMAT. The method was carried out according to the method of Example 4. As shown in Fig. 11, there was no significant decrease in the competitive activity of each variant compared to that of H0L0.

* In Table 4 above is a location that has been modified although not related to the isoelectric point in order to obtain a human sequence.

Hp3Lp15 (H-chain Hp3-SKSC/SEQ ID NO:151, L-chain Lp15/SEQ ID NO:152) is an example of a humanized NS22 antibody in which the isoelectric point is decreased by combining these modifications. The affinity of Hp3Lp15 for NR10, the isoelectric point, and the plasma retention in mice were compared with HOL0.

Measure of affinity

The affinity of each antibody to NR10 was performed according to the method of Reference Example 10.

Table 5 shows the measured affinity results. It was shown that the affinity of Hp3Lp15 is almost equivalent to that of H0L0.

Isoelectric Measure

In order to evaluate the change in the isoelectric point of the full-length antibody due to amino acid alteration in the variable region, analysis by isoelectric point electrophoresis of each antibody was performed. The method of isoelectric point electrophoresis was as follows.

Using Phastsystem Cassette (manufactured by Amersham Biosciences), a Phast-Gel Dry IEF (manufactured by Amersham Biosciences) gel was swelled for about 30 minutes with the following swelling solution.

Milli Q Water 1.5 mL

Pharmalyte 5-8 for IEF (manufactured by Amersham Biosciences) 100 μL

Using the swollen gel, electrophoresis was performed with the following program by PhastSystem (manufactured by Amersham Biosciences). Samples were added to the gel in Step 2. As the pI marker, Calibration Kit for pI (manufactured by Amersham Biosciences) was used.

Step 1: 2000 V 2.5 mA 3.5 W 15℃ 75 Vh

Step 2: 200 V 2.5 mA 3.5 W 15℃ 15 Vh

Step 3: 2000 V 2.5 mA 3.5 W 15℃ 410 Vh

The gel after electrophoresis was fixed with 20% TCA, and then silver staining was performed using a Silver staining Kit, protein (manufactured by Amersham Biosciences) according to the protocol attached to the kit. After staining, the isoelectric point of the sample (full-length antibody) was calculated from the known isoelectric point of the pI marker.

As a result of measuring the isoelectric point by isoelectric point electrophoresis, the isoelectric point of H0L0 was about 7.8, and the isoelectric point of Hp3Lp15 was about 5.5, so that the isoelectric point of Hp3Lp15 decreased by about 2.3 compared to the isoelectric point of H0L0. In addition, as the theoretical isoelectric point of the variable region VH/VL was calculated by GENETYX (GENETYX CORPORATION), the theoretical isoelectric point of the variable region of H0L0 was 7.76, and the theoretical isoelectric point of the variable region of Hp3Lp15 was 4.63, and Hp3Lp15 was compared with H0L0. The theoretical isoelectric point decreased by 3.13.

Mouse Isoelectric point Degraded Evaluation of antibody pharmacokinetics

In order to evaluate the plasma retention of the modified antibody, Hp3Lp15 having lowered isoelectric point, plasma retention of H0L0 and Hp3Lp15 in normal mice was compared. H0L0 and Hp3Lp15 were administered once intravenously to mice (C57BL/6J, Nippon Charles River) at 1 mg/kg, and the change in plasma concentration was compared. The plasma concentration was measured by ELISA. A calibration curve sample and a plasma measurement sample of an appropriate concentration were dispensed into an immunoplate solidified with Anti-human IgG (Fc-specific) antibody (manufactured by Sigma) (Nunc-Immuno Plate, MaxiSorp (manufactured by Nalge nunc International)), and at room temperature. It was carried out after standing at for 1 hour. After reacting Goat Anti-Human IgG-ALP (manufactured by Sigma) for 1 hour at room temperature, a color development reaction was performed using BluePhos Microwell Phosphatase Substrates System (manufactured by Kirkegaard & Perry Laboratories) as a substrate, and absorbance of 650 nm with a microplate reader. Was measured. The concentration in plasma was calculated from the absorbance of the calibration curve using analysis software SOFTmax PRO (manufactured by Molecular Devices).

The obtained data of the change in plasma concentration was calculated using the pharmacokinetic analysis software WinNonlin (manufactured by Pharmaight Co., Ltd.) to calculate pharmacokinetic parameters (AUC, systemic clearance (CL)), and is shown in Table 6. For H0L0, the AUC after intravenous administration of Hp3Lp15 increased by about 14% and the clearance decreased by about 12%. Thus, it was found that the pharmacokinetics of Hp3Lp15 having lowered the isoelectric point of H0L0 increased.

[Example 8] Influence on biological activity by combination of variable region and constant region

In order to evaluate the effect on biological activity by using different constant regions, the following variants were prepared.

As the H chain, the constant region was prepared in Reference Examples 7 and 9 SKSC (SEQ ID NO: 62), M58 (SEQ ID NO: 128) variable region prepared in Example 7 variable region Hp3 (Hp3-VH/SEQ ID NO: 167) to prepare Hp3-M58 (SEQ ID NO:240) and Hp3-SKSC (SEQ ID NO:151). Hp3Lp15-SKSC (H chain Hp3-SKSC/SEQ ID NO:151, L chain Lp15/SEQ ID NO:152) by combining the prepared H chain and the L chain Lp15 (Lp15/SEQ ID NO:152) prepared in Example 7 and Hp3Lp15-M58 (H chain Hp3-M58/SEQ ID NO:240, L chain Lp15/SEQ ID NO:152) was prepared. Expression and purification of each antibody was performed by the method described in Example 4.

H0L0-SKSC (H chain H0-SKSC/SEQ ID NO:54, L chain L0/SEQ ID NO:56) using each antibody produced above and the constant region SKSC (SEQ ID NO:62) described in Reference Example 7, H0L0-M58 prepared in Example 5 (H chain H0-M58/SEQ ID NO:136, L chain L0/SEQ ID NO:56) and H0L0-IgG2 (H chain H0-IgG2/SEQ ID NO:134, L chain L0/ For SEQ ID NO: 56), the biological activity using BaF/NR10 was performed by the method described in Example 2, and the results are summarized in FIG. 18.

As shown in Fig. 18, no significant difference in biological activity was detected between the normal regions. Since the combination of the two variable regions H0 and Hp3 and each of the constant regions did not affect the biological activity, in the variable regions to be produced in the future, it is believed that the biological activity will not change even if they are combined with any of the constant regions.

[Example 9] Identification of mutation sites that suppress decomposition by thermal acceleration test

Antibodies used in pharmaceuticals are heterogeneous, although they are monoclonal antibodies obtained from clones derived from single antibody-producing cells. It is known that the heterogeneity of such antibodies occurs by modifications such as oxidation and deamidation, and increases during long-term storage or by exposure to stress conditions such as heat stress and light stress (Reference: Heterogeneity of Monoclonal Antibodies: Journal of pharmaceutical sciences, vol.97, No. 7,2426-2447). However, in developing antibodies as pharmaceuticals, uniformity and stability among the physical properties of the protein are very important, and it is desirable to reduce the heterogeneity of the target substance/related substance and to be a single substance as much as possible. Thus, the heterogeneity of the antibody under stress conditions was evaluated, and the following experiment was conducted in order to reduce the heterogeneity.

In order to evaluate the decomposition product, a heat-accelerated product of H0L0 (H chain H0-SKSC/SEQ ID NO:54, L chain L0/SEQ ID NO:56) was prepared by the following method. The prepared thermally accelerated product and unaccelerated product (initial) were analyzed by cation exchange chromatography in the following manner.

·Heat Accelerated Preparation method

Buffer: PBS

Antibody concentration: 0.2-1.0 mg/mL

Acceleration temperature: 60℃

Acceleration period: 1 day

·Analytical method of cation exchange chromatography

Column: ProPac WCX-10, 4 x 250 mm (Dionex)

Mobile phase: (A) 25 mmol/L MES/NaOH, pH 6.1

(B) 25 mmol/L MES/NaOH, 250 mmol/L NaCl, pH 6.1

Flow rate: 0.5 mL/min

Column temperature: 40°C

Gradient: %B 0 to 0(o-5 min)→0 to 30(5-80 min)

Detection: 280 nm

Fig. 19 shows the chromatogram results of the samples before and after the thermal acceleration of HOL0. In the sample after the thermal acceleration of HOL0, a tendency for the peak of basicity to increase was obtained.

Therefore, in order to reduce this peak, as a result of screening, Ha355, Ha356, Ha360, and Ha362 were found, and Ha355L0 (H chain Ha355-SKSC/SEQ ID NO:242 L chain L0/ SEQ ID NO:56), Ha356L0 (H chain Ha356-SKSC/SEQ ID NO:243 L chain L0/SEQ ID NO:56), Ha360L0 (H chain Ha360-SKSC/SEQ ID NO:244 L chain L0/SEQ ID NO:56), Ha362L0 (H chain Ha362-SKSC/SEQ ID NO:245 L chain L0/SEQ ID NO:56) was prepared. The sequence of each variant is summarized in Table 7.

Expression and purification of each antibody found were performed by the method described in Example 4. In the same manner as in H0L0 for each produced antibody, a thermally accelerated product was prepared and analyzed by cation exchange chromatography, and the results are shown in FIG. 19.

As a result, in the modified antibody containing the alteration in which aspartic acid at the 101st H chain was substituted with glutamic acid, generation of a basic peak that increases after heat acceleration was less than that of HOL0. These modified antibodies were subjected to biological activity using BaF/NR10 by the method described in Example 2, and the results are shown in FIG. 20. As shown in Fig. 20, the biological activity of these modifications was substantially equal to or higher than that of H0L0. From the above facts, it was found that the modification of Ha355, Ha356, Ha360, and Ha362 is effective in terms of increasing the stability of the antibody by suppressing decomposition products generated by heat acceleration.

[Example 10] Identification of mutant sites that increase affinity

In order to improve the affinity of HOL0 to NR10, a library in which mutations were introduced into the CDR sequences was prepared and examined. As a result of screening a library in which mutations were introduced into the CDRs, mutations that improve affinity to NR10 were found, and they are summarized in Table 8. Each of the H chain variants Ha101-SKSC (SEQ ID NO:246), Ha103-SKSC (SEQ ID NO:247), Ha111-SKSC (SEQ ID NO:248), Ha204-SKSC (SEQ ID NO:249), Ha219-SKSC ( SEQ ID NO:250) and L0 (L0/SEQ ID NO:56), each L chain variant La134 (SEQ ID NO:251), La130 (SEQ ID NO:252), La303 (SEQ ID NO:253), La328 (SEQ ID NO: :254) and H0 (H0-SKSC/SEQ ID NO:54) were respectively combined to prepare each antibody. Preparation and purification of each variant was performed by the method described in Example 4.

The affinity of each variant to NR10 was evaluated using Biacore, and is shown in Table 9. The method was carried out by the method described in Reference Example 10. As shown in Table 9, the KD value of each variant was found to be improved compared to that of H0L0 (H chain H0-SKSC/SEQ ID NO:54, L chain L0/SEQ ID NO:56).

As an example of combining the mutations with improved affinity and the mutations that lower the isoelectric point prepared in Example 7, Ha401La402 (H chain Ha401-SKSC/SEQ ID NO:255, L chain La402/SEQ ID NO:256), or H17L11 (H chain H17-M58/SEQ ID NO:222, L chain L11/SEQ ID NO:236) can be mentioned. Preparation and purification of each variant was performed by the method described in Example 4.

The affinity of Ha401La402 (H chain Ha401-SKSC/SEQ ID NO:255, L chain La402/SEQ ID NO:256) to NR10 and biological activity using BaF/NR10 were carried out by the methods described in Reference Examples 10 and 2. , Compared with H0L0 (H chain H0-SKSC/SEQ ID NO:54, L chain L0/SEQ ID NO:56). Table 10 shows the measured affinity results, and Fig. 21 shows the biological activity using BaF/NR10. It was found that both affinity and biological activity were improved than those of H0L0 (H chain H0-SKSC/SEQ ID NO:54, L chain L0/SEQ ID NO:56).

In addition, the affinity for NR10 of H17L11 ((H chain H17-M58/SEQ ID NO:222, L chain L11/SEQ ID NO:236) and biological activity using BaF/NR10 were described in Examples 7 and 2. And compared with H0L0 (H chain H0-M58/SEQ ID NO: 136, L chain L0/SEQ ID NO: 56) The measured affinity results are shown in Table 11, and biological activity using BaF/NR10 is shown in FIG. It was found that both affinity and biological activity were improved than those of H0L0 (H chain H0-M58/SEQ ID NO:136, L chain L0/SEQ ID NO:56).

[Example 11] Identification of mutant sites for reducing the risk of immunogenicity

H chain CDR1 Of the immunogenic Of risk Reduction

The T-cell epitope present in the H0L0 variable region sequence was analyzed using TEPITOPE (Methods. 2004 Dec; 34(4):468-75). As a result, it was predicted that the H chain CDR1 had a T-cell epitope that binds to many HLAs (there is a sequence with a high risk of immunogenicity). Therefore, in the TEPITOPE analysis, an alteration to reduce the risk of immunogenicity of H chain CDR1 was examined, and it was found that the risk of immunogenicity was greatly reduced by substituting alanine (A) for isoleucine (I) at the 33rd kabat numbering. Was found (Table 12). H19 (H19-M58/SEQ ID NO:223) added to H17 prepared in Example 10 was prepared. The prepared H19 was combined with L12 to prepare H19L12 (H chain H19-M58/SEQ ID NO:223, L chain L12/SEQ ID NO:237). Preparation and purification of each variant was performed by the method described in Example 4.

The affinity for NR10 and the bioactivity using BaF/NR10 were performed by the method described in Reference Example 10 and Example 2, and H0L0 (H chain H0-M58/SEQ ID NO:136, L chain L0/SEQ ID NO:56) Compared with. Table 13 shows the measured affinity results, and Fig. 23 shows the biological activity using BaF/NR10. It was shown that both affinity and biological activity exhibit almost the same activity as that of H0L0.

L chain CDR1 Of the immunogenic Of risk Reduction

Threonine (T) at the 25th kabat numbering in CDR1 of the L chain is alanine (A) or serine (S) in the germline sequence. Therefore, it is expected that the risk of immunogenicity is lower when the 25th threonine (T) is changed to alanine (A) or serine (S) (Table 14). Thus, L17 (SEQ ID NO:238) was prepared by adding the above modifications to L12. The prepared L17 and H0 were combined to prepare H0L17 (H chain H0-M58/SEQ ID NO:136, L chain L17/SEQ ID NO:238). Preparation and purification of the variant was performed by the method described in Example 4.

The affinity for NR10 of each variant and the biological activity using BaF/NR10 were carried out by the method described in Reference Example 10 and Example 2, and H0L0 (H chain H0-M58/SEQ ID NO:136, L chain L0/sequence Number: 56), and H0L12 (H chain H0-M58/SEQ ID NO:136, L chain L12/SEQ ID NO:237). Since L12 contains a sequence with improved affinity, it exhibits an affinity that is about twice as high as that of H0L0. Table 15 shows the measured affinity results, and Fig. 24 shows the biological activity using BaF/NR10. It was shown that both the affinity and the biological activity showed almost the same affinity and biological activity as that of H0L12.

[Example 12] Preparation of fully humanized NS22 antibody

Changes that reduce the pI found in the above examples, changes that increase affinity, changes that inhibit the degradation of the H chain, changes that reduce the risk of immunogenicity are H0 (H0-M58/SEQ ID NO:136), H1 (H1-M58/SEQ ID NO:257), or L0 (L0/SEQ ID NO:56), the variable region of the NS22 variant was prepared by combining a plurality of them, and various screenings were conducted. As a result, H28L17 (H chain H28-M58/ SEQ ID NO:224, L chain L17/SEQ ID NO:238), H30L17 (H chain H30-M58/SEQ ID NO:225, L chain L17/SEQ ID NO:238), H34L17 (H chain H34-M58/SEQ ID NO:226) , L chain L17/SEQ ID NO:238), H42L17 (H chain H42-M58/SEQ ID NO:227, L chain L17/SEQ ID NO:238), H44L17 (H chain H44-M58/SEQ ID NO:228, L chain L17 /SEQ ID NO:238), H46L17 (H chain H46-M58/SEQ ID NO:229, L chain L17/SEQ ID NO:238), H57L17 (H chain H57-M58/SEQ ID NO:230, L chain L17/SEQ ID NO: 238), H71L17 (H chain H71-M58/SEQ ID NO:231, L chain L17/SEQ ID NO:238), H78L17 (H chain H78-M58/SEQ ID NO:232, L chain L17/SEQ ID NO:238), H92L17 (H chain H92-M58/SEQ ID NO:233, L chain L17/SEQ ID NO:238), H97L50 (H chain H97-M58/SEQ ID NO:234, L chain L50/SEQ ID NO:239), H98L50 (H chain H98 -M58/SEQ ID NO:235, L chain L50/SEQ ID NO:239) was found. Preparation and purification of the variant was performed by the method described in Example 4.

The affinity for NR10 of each variant and the biological activity using BaF/NR10 were performed by the method described in Reference Example 10 and Example 2, and H0L0 (H chain H0-M58/SEQ ID NO:136, L chain L0/sequence Number: 56). The results of the measured affinity are shown in Table 16, and the biological activity using BaF/NR10 is shown in FIGS. 25-1 and 25-2. It was shown that both the affinity and the biological activity of any antibody exhibited substantially the same or higher than that of H0L0.

[Example 13] Analysis of binding domain of anti-NR10 neutralizing antibody

(1) Preparation of human/mouse wild-type and chimeric antigens

Wild-type and chimeric NR10 extracellular regions of humans and mice (hhh (SEQ ID NO:258), mmm (SEQ ID NO:259), hhm (SEQ ID NO:260), mmh (SEQ ID NO:261), hmm (SEQ ID NO:262) ), mhm (SEQ ID NO:263), mhh (SEQ ID NO:264)), the C-terminus with His tag and Myc tag (HHHHHHEQKLISEEDL/SEQ ID NO:287) attached to the animal cell expression vector, , Transient expression was made with the FreeStyle 293 Expression System (invitrogen ^{TM ).} Fig. 26 shows a schematic diagram of these human-mouse wild-type and chimeric NR10-ECDs.

Purification of human-mouse wild-type and chimeric antigens (hhh, mmm, hhm, mmh, hmm, mhm, mhh) from the culture supernatant was performed by Ni-NTA Superflow column chromatography. That is, 1 mL of Ni-NTA Superflow (QIAGEN) was charged into a Poly-Prep Empty Column (BioRad), 30 mL of each culture supernatant was added, and 150 mM sodium chloride and 20 mM imidazole After washing with D-PBS (Dulbecco's Phosphate-Buffered Salines) containing, it was eluted with D-PBS containing 150 mM sodium chloride and 250 mM imidazole. The eluted fraction was replaced with D-PBS in Amicon-Ultra (Millipore) having a molecular weight cutoff of 10 K, and then concentrated.

(2) Detection of binding antigen by Western Blot

The prepared human-mouse wild-type and chimeric antigens were electrophoresed on 3 sheets of 4-20% polyacrylamide gel (Daiichi Chemical Co., Ltd.) each equivalent to 0.5 µg/lane. In a semi-dry type blotting device, it was electrically transferred to a PVDF film (Millipore), and blocked with TBS containing 5% SkimMilk. One sheet (humanized anti-human NR10 antibody detection system) was 5 μg/mL of H44M58L17, 1 sheet (mouse anti-human NR10 antibody detection system) was 5 μg/mL of ND41, and 1 sheet (Myc tag detection system) was 5 It was reacted for 1 hour at room temperature in an anti-Myc antibody (SantaCruz, Cat.#sc-789) diluted 500 times with TBS containing% SkimMilk.

After washing three times for 3 minutes with TBS containing 0.05% Tween ^{TM 20, the secondary antibody was reacted.} Alkaline phosphatase-labeled goat anti-human IgGγ (BIOSOURCE, Cat.#AHI0305) is used in the humanized anti-human NR10 antibody detection system, and alkaline phosphatase-labeled goat anti-mouse IgG (SantaCruz, Cat.#) is used in the mouse anti-human NR10 antibody detection system. sc-2008) was reacted at room temperature for 1 hour using alkaline phosphatase-labeled goat anti-rabbit IgG (SantaCruz, Cat.#sc-2057) in the Myc tag detection system. After washing 4 times for 3 minutes with TBS containing 0.05% Tween ^TM 20, it was colored by BCIP/NBT Phosphatase substrate, 1-Component System (KPL). The TBS (Tris-Buffered Saline) used here was prepared by dissolving one TBS (Tris-Buffered-Saline) powder (TaKaRa) in 1 L of distilled water. The results are shown in Fig. 27.

When a humanized antibody or a mouse antibody was used, binding was detected only in the extracellular regions of NR10, hhh, hhm, and hmm.

[Reference Example 1] Isolation of Crab Monkey NR10, OSMR, and IL-31 Genes

For safety evaluation in the preclinical stage, the cross-linking and neutralizing activity of crab monkeys was considered important, and the isolation of the crab monkey NR10 gene and OSMR gene was attempted. Primers were designed from publicly available rhesus monkey information, and succeeded in amplifying NR10 gene and OSMR gene from cynomolgus spleen cDNA by PCR method. The gene sequences of the isolated cynomolgus monkey NR10, OSMR, and IL-31 are shown in SEQ ID NOs: 65, 69 and 67. In addition, the amino acid sequences of cynomolgus monkeys NR10, OSMR, and IL-31 are shown in SEQ ID NOs: 66, 70 and 68.

[Reference Example 2] Establishment of NR10 and OSMR-expressing Ba/F3 cell lines

Human full-length NR10 cDNA (SEQ ID NO:75) was inserted into the expression vector pCOS1 (Biochem Biophys Res Commun. 228, p838-45, 1996) to obtain pCosNR10.3. Oncostatin M receptor cDNA (OSMR, GenBank accession No. NM003999) was isolated from a human placental library by PCR, and similarly, the expression vector pCos1-hOSMR was constructed. To the cell line Ba/F3 derived from mouse IL-3 dependent pro-B cells, 10 µg of each vector was simultaneously introduced by electroporation (BioRad Gene Pulser, 960 µF, 0.33 kV). After the introduction, human IL-31 (R&D Systems) was added and cultured to obtain a cell line (hNR10/hOSMR/BaF3 cells) exhibiting proliferation in IL-31 dependence. Further, the crab monkey IL-31 gene (SEQ ID NO: 67) was inserted into an expression vector for mammalian cells, introduced into the CHO cell line DG44, and the crab monkey IL-31 was obtained as the culture supernatant. Using this culture supernatant, similarly to hNR10/hOSMR/BaF3, Crab monkey full-length NR10 and Crab monkey OSMR genes were respectively inserted into the expression vector pCOS1 and expressed in Ba/F3 cells to express the crab monkey IL-31 dependent cell line. (cynNR10/cynOSMR/BaF3 cells) were established.

[Reference Example 3] Establishment of NR10-expressing CHO cell line

The intracellular region deletion type human NR10 gene (SEQ ID NO: 73) and the intracellular region deletion type cynomolgus NR10 gene (SEQ ID NO: 71) were inserted into expression vectors for mammalian cells, respectively, and this vector was directly used as a restriction enzyme. After making a chain shape, it was introduced into the CHO cell line DG44 by electroporation (BioRad Gene Pulser, 25 μF, 1.5 kV). It was selected as a drug, and NR10-expressing cells were selected and established by FCM analysis using an anti-human NR10 antibody. In addition, the amino acid sequence encoded by the nucleotide sequence (SEQ ID NO: 73) of the intracellular region deletion type human NR10 gene was assigned to SEQ ID NO: 74 and the nucleotide sequence (SEQ ID NO: 71) of the intracellular region deletion type cynomolgus monkey NR10 gene. The amino acid sequence coded by is shown in SEQ ID NO:72.

[Reference Example 4] Preparation of NR10 protein (extracellular domain)

Using human NR10 cDNA as a template, only the extracellular region was amplified by the PCR method, and a FLAG tag sequence was added to the C-terminus and inserted into an expression vector for mammalian cells. 10 µg of this linear vector was introduced into a Chinese hamster ovary cell line DG44 by electroporation (BioRad Gene Pulser II, 25 µF, 1.5 kV) to obtain a cell line exhibiting high expression. This cell line was purified from the culture supernatant obtained by mass culturing by an anti-FLAG antibody column (manufactured by SIGMA) and a gel filtration method to obtain soluble NR10. The nucleotide sequence of the soluble NR10 is shown in SEQ ID NO: 77, and the amino acid sequence is shown in SEQ ID NO: 78.

[Reference Example 5] Preparation of anti-human NR10 antibody

Human NR10 protein (extracellular domain) (described in Reference Example 4) was immunized to mice, and hybridomas were prepared by a conventional method. The culture supernatant of these hybridomas was evaluated by neutralizing activity using the human IL-31 dependent cell line (hNR10/hOSMR/BaF3 cells) shown in Reference Example 2 to obtain NA633 having NR10 neutralizing activity.

Further, a mammalian expression vector into which a human NR10 full-length gene (SEQ ID NO: 75) was inserted was used, DNA immunization was performed using a He gas injection gene gun, and hybridomas were produced by a conventional method. The culture supernatant of these hybridomas was evaluated by neutralizing activity using the human IL-31 dependent cell line (hNR10/hOSMR/BaF3 cells) shown in Reference Example 2 to obtain ND41 having NR10 neutralizing activity.

[Reference Example 6] Preparation of human chimeric antibody

The amino acid sequence of the heavy chain variable region of NA633 is shown in SEQ ID NO: 104, and the amino acid sequence of the light chain variable region is shown in SEQ ID NO: 108. In addition, the amino acid sequence of the CDR1 of the heavy chain variable region of NA633 is in SEQ ID NO: 105, the amino acid sequence of CDR2 is in SEQ ID NO: 106, the amino acid sequence of CDR3 is in SEQ ID NO: 107, and the amino acid sequence of CDR1 in the light chain variable region is In SEQ ID NO: 109, the amino acid sequence of CDR2 is shown in SEQ ID NO: 110, and the amino acid sequence of CDR3 is shown in SEQ ID NO: 111. In addition, according to a conventional method, chimeric antibodies of these mouse variable regions and human constant regions (γ1 for H chain and κ for L chain) were prepared.

[Reference Example 7] Preparation of huPM1-SKSC with reduced heterogeneity of wild-type IgG2 without reducing stability

Since the NS22 antibody is an NR10 neutralizing antibody, when immunogenicity and side effects are considered, binding to the Fcγ receptor is considered to be undesirable. In order to reduce the binding to the Fcγ receptor, a method of selecting IgG2 or IgG4, not IgG1, as the constant region isotype (Ann Hematol. 1998 Jun;76(6):231-48.), Fcγ receptor I And from the viewpoint of retention in plasma, it was thought that IgG2 was preferable to IgG4 (Nat Biotechnol. 2007 Dec;25(12):1369-72). On the other hand, in developing antibodies as pharmaceuticals, the physical properties of the protein, especially uniformity and stability, are very important, and it has been reported that the IgG2 isotype has very many heterogeneity resulting from disulfide bonds in the hinge region (J. Biol Chem. 2008 Jun 6;283(23):16206-15.). It is not easy to manufacture in large quantities as a pharmaceutical product while maintaining the difference between the heterogeneity of the target substance/related substance derived from this, leading to an increase in cost, and it is desired to be a single substance as much as possible. Therefore, in developing an antibody of the IgG2 isotype as a pharmaceutical, it is preferable that the heterogeneity derived from disulfide bonds is reduced without reducing the stability.

In order to reduce the heterogeneity of wild-type IgG2, the cysteine at the hinge portion of IgG2 and the cysteine present in the CH1 domain were modified. As a result of examination of various variants, among wild-type IgG2 constant region sequences, EU numbering (Sequences of proteins of immunological interest, NIH Publication No.91-3242) 131st cysteine and 133th arginine present in the CH1 domain of the H chain were identified. It is possible to reduce heterogeneity without sacrificing stability by using SKSC (SEQ ID NO:62), which is a normal region that has been changed to serine and lysine, respectively, and the cysteine of the 219th EU numbering present in the upper hinge of the H chain is changed to serine. I think it's possible. On the other hand, as a method of reducing heterogeneity, a method of changing only the cysteine at the 219th EU numbering present in the upper hinge of the H chain to serine, and a method of changing only the cysteine at the 220th to serine are conceived. Accordingly, SC (SEQ ID NO: 153), which is a normal region of IgG2 whose cysteine at EU numbering 219 is changed to serine, and CS (SEQ ID NO: 154), which is a constant region of cysteine at EU numbering 220 of IgG2, which is changed to serine. Was produced.

As H chain, each of the constant regions prepared above and the variable regions of IgG1 (SEQ ID NO:60), and IgG2 (SEQ ID NO:132) and humanized anti-IL-6 receptor antibodies (H chain variable region huPM1-VH/SEQ ID NO: :155, L chain variable region huPM1-VL/SEQ ID NO:156) (Cancer Res. 1993 Feb 15;53(4):851-6.) huPM1-SC (SEQ ID NO:157), huPM1-CS (SEQ ID NO:158), huPM1-IgG1 (SEQ ID NO:159), huPM1-IgG2 (SEQ ID NO:160) and huPM1-SKSC (SEQ ID NO:161) were used, and huPM1-L (SEQ ID NO: 162) was used to prepare each antibody. Expression and purification of each antibody was performed by the method described in Example 4.

A comparison of the heterogeneity of each antibody was made. As a method for evaluating the heterogeneity of huPM1-IgG1, huPM1-IgG2, huPM1-SC, huPM1-CS, and huPM1-SKSC, evaluation by cation exchange chromatography was performed. Using ProPac WCX-10 (Dionex) as a column, 20 mM Sodium Acetate, pH 5.0 as mobile phase A, 20 mM Sodium Acetate, 1 M NaCl, pH 5.0 as mobile phase B, and using an appropriate flow rate and gradient. I did. Fig. 12 shows the results of evaluation by cation exchange chromatography.

As a result, as shown in Fig. 12, the heterogeneity increased by converting the constant region from IgG1 to IgG2, but the heterogeneity was greatly reduced by converting the constant region to SKSC. On the other hand, when the normal region is set to SC, the heterogeneity is significantly reduced as in the case of the normal area is set to SKSC, but when the normal area is set to CS, the heterogeneity is not sufficiently improved.

In general, in order to develop an antibody as a pharmaceutical, it is desirable to have low heterogeneity and high stability in order to prepare a stable formulation. Thus, as a stability evaluation method, the thermal denaturation intermediate temperature (Tm value) was evaluated by differential scanning calorimetry (DSC) (VP-DSC, manufactured by Microcal). The intermediate heat denaturation temperature (Tm value) is an index of stability, and in order to manufacture a stable formulation as a pharmaceutical, it is preferable that the intermediate heat denaturation temperature (Tm value) is high (J Pharm Sci. 2008 Apr;97(4):1414). -26). Thus, huPM1-IgG1, huPM1-IgG2, huPM1-SC, huPM1-CS, huPM1-SKSC were dialysis (EasySEP, TOMY) in a solution of 20 mM sodium acetate, 150 mM NaCl, pH 6.0, and about 0.1 mg/ At a protein concentration of mL, DSC measurement was performed from 40°C to 100°C at a heating rate of 1°C/min. The resulting DSC transformation curve is shown in Fig. 13, and the Tm value of the Fab portion is shown in Table 17 below.

Tm values of huPM1-IgG1 and huPM1-IgG2 were almost equal and were about 94°C (IgG2 was about 1°C low), whereas the Tm values of huPM1-SC and huPM1-CS were about 86°C, huPM1-IgG1 and Compared with huPM1-IgG2, the Tm value was remarkably lowered. On the other hand, the Tm value of huPM1-SKSC was about 94°C, which was almost equivalent to huPM1-IgG1 and huPM1-IgG2. Since the stability of huPM1-SC and huPM1-CS is significantly lower than that of IgG2, huPM1-SKSC in which the cysteine of the CH1 domain has also been modified with serine was considered to be preferable for development as a pharmaceutical product. As the reason why the Tm values of huPM1-SC and huPM1-CS were significantly lowered compared to that of IgG2, it was thought that huPM1-SC and huPM1-CS took a different pattern from the disulfide binding pattern of IgG2.

In addition, when comparing the DSC denaturation curves, the denaturation peaks of the Fab portions of huPM1-IgG1 and huPM1-SKSC were sharp, whereas the denaturation peaks of the Fab portions were broad compared to those of huPM1-SC and huPM1-CS. , In huPM1-IgG2, a shoulder peak was confirmed on the low-temperature side of the denatured peak of the Fab portion. The denaturation peak of DSC usually shows a sharp denaturation peak in the case of a single component, but it is considered that the denaturation peak becomes broad when a plurality of components (ie, heterogeneity) having different Tm are present. That is, a plurality of components exist in huPM1-IgG2, huPM1-SC, and huPM1-CS, and it was suggested that huPM1-SC and huPM1-CS may not sufficiently reduce the heterogeneity of native IgG2. From this fact, it is thought that the heterogeneity of the native IgG2 is not only the cysteine in the hinge region, but also the cysteine present in the CH1 domain, and in order to reduce the heterogeneity on DSC, not only the cysteine in the hinge region but also the cysteine in the CH1 domain. It was also thought that there was a need to change. Further, as described above, it is possible to have stability equivalent to that of native IgG2 only by altering the cysteine of the CH1 domain as well as the cysteine of the hinge portion.

From the above, it is considered that the constant regions in which the heterogeneity derived from the hinge region of IgG2 is reduced, and the constant regions in which only the cysteine in the hinge portion is substituted with serine, are insufficient from the viewpoint of heterogeneity and stability, and exist in the CH1 domain. It was found that only when the cysteine at the 131th EU numbering was substituted with serine, it was possible to significantly reduce heterogeneity while maintaining the stability equivalent to that of IgG2. SKSC can be mentioned as such a normal region.

[Reference Example 8] Preparation and evaluation of optimized constant region M14 for non-binding of Fc γ receptors

In the constant region of IgG2, EU numbering of the Fcγ receptor binding site: 233, 234, 235, 236 is a non-binding type, but EU numbering of the Fcγ receptor binding site: 327, 330, 331th is a sequence different from that of non-binding IgG4. Therefore, it is necessary to change the amino acid at EU numbering: 327, 330, and 331 to the sequence of IgG4 (Eur J Immunol. 1999 Aug; G2Δa in 29(8):2613-24). However, since IgG4 EU numbering: 339 th amino acid is alanine, IgG2 is threonine, EU numbering: T that does not exist in nature only by altering the 327, 330, and 331 th amino acids into the sequence of IgG4. -A new peptide sequence of 9 amino acids that can become a cell epitope peptide appears, resulting in a risk of immunogenicity. Accordingly, it was found that it was possible to prevent the appearance of a new peptide sequence by newly changing the threonine at EU numbering:339th of IgG2 to alanine in addition to the above-described modification. In addition to these mutations, a mutation from methionine to valine at the 397th EU numbering of IgG2, which improves the stability of IgG2 under acidic conditions, was introduced. In addition, SKSC (SEQ ID NO: 62), which improves heterogeneity resulting from disulfide bonds in the hinge region prepared in Reference Example 7, is a T-cell epitope peptide that does not exist in nature due to the introduction of the 131st and 133th mutations. Since a new peptide sequence of 9 amino acids that can be used has emerged and an immunogenicity risk arises, by introducing a mutation from glutamic acid at the 137th EU numbering to glycine and a mutation from serine to glycine at the 138th position, 131 The peptide sequences in the vicinity of the 139th to the 139th were assumed to be identical to those of IgG1. A constant region sequence M14 (SEQ ID NO: 129) in which all of these mutations were introduced was prepared.

Expression and purification of huPM1-M14 using huPM1-M14 as the H chain and huPM1-L (SEQ ID NO: 162) as the L chain were performed by the method described in Reference Example 7. The heterogeneity of the produced huPM1-M14 (SEQ ID NO: 163), huPM1-IgG1, and huPM1-IgG2 was evaluated by the method described in Reference Example 7 using cation exchange chromatography.

As shown in Fig. 14, also in huPM1-M14, the heterogeneity was reduced in the same manner as in huPM1-SKSC.

[Reference Example 9] Preparation of huPM1-M58 with reduced heterogeneity at the C-terminal side of the H chain and improved pharmacokinetics

huPM1 - M58 The construction of the molecule

huPM1 is an IgG1 antibody. As the heterogeneity of the H chain C-terminal sequence of an IgG antibody, a deletion of the lysine residue of the C-terminal amino acid and amidation of the C-terminal amino group by deletion of both the C-terminal 2 amino acids glycine and lysine have been reported (Anal Biochem. 2007). Jan 1;360(1):75-83.). In huPM1 as well, its main component is a sequence in which the lysine of the C-terminal amino acid present on the nucleotide sequence is deleted by post-translational modification, but the amidation of the C-terminal amino group due to the deletion of both glycine and lysine, as well as subcomponents in which lysine remains. Subcomponents also exist as heterogeneity. It is not easy to manufacture in large quantities as a drug while maintaining the heterogeneity between the heterogeneity of the target substance/related substance, and it leads to an increase in cost, and it is desired to be a single substance as much as possible. It is desirable to be. Therefore, when developing as a pharmaceutical, it is preferable that the heterogeneity of the H chain C-terminus does not exist. In addition, in order to reduce the dose of the antibody, it is preferable to lengthen the half-life of the antibody in plasma.

Accordingly, for the purpose of producing a novel constant region in which the heterogeneity of the H chain C-terminal side is reduced, the pharmacokinetics is improved than that of huPM1-IgG1, and the heterogeneity derived from wild-type IgG2 is reduced without reducing stability, the following A change was introduced.

Specifically, for huPM1-SKSC with high stability and reduced heterogeneity of the antibody in the constant region of the IgG2 isotype, the EU numbering 137th glutamic acid was glycine, the 138th serine was glycine, and the 268th was HuPM1- which deleted glycine at position 446 and lysine at position 447 to reduce the heterogeneity of H chain C-terminus by substituting histidine for glutamine, arginine at position 355 for glutamine, and glutamine at position 419 to glutamic acid. M58 (SEQ ID NO:164) was found. Expression and purification of huPM1-M58 using huPM1-M58 as the H chain and huPM1-L (SEQ ID NO: 162) as the L chain were performed by the method described in Example 4.

The heterogeneity evaluation of the produced huPM1-M58, huPM1-IgG1, and huPM1-IgG2 was performed using cation exchange chromatography, and the stability evaluation was performed by the method described in Example 5 using DSC.

Table 18 shows the results of DSC. 13 and 16, also in huPM1-M58, similarly to huPM1-SKSC, the heterogeneity is reduced without impairing stability.

huPM1 - M58 In the plasma of Sojournability evaluation

The reason that the retention of IgG molecules in plasma is long (slow loss) is that FcRn, known as a salvage receptor for IgG molecules, is functioning (Nat Rev Immunol. 2007 Sep;7(9):715-25). The IgG molecule inserted into the endosome by pinocytosis binds to FcRn expressed in the endosome under acidic conditions in the endosome (near pH 6.0). IgG molecules that could not bind to FcRn The IgG molecule proceeds to the lysosome and is degraded to the lysosome, but the IgG molecule bound to the FcRn migrates to the cell surface, dissociates from the FcRn under neutral conditions in plasma (near pH 7.4), and returns back to the plasma.

As IgG-type antibodies, IgG1, IgG2, IgG3, and IgG4 isotypes are known, but their half-life in human plasma is about 36 days for IgG1 and IgG2, about 29 days for IgG3, and 16 days for IgG4. (Nat Biotechnol. 2007 Dec;25(12):1369-72.), it is thought that the retention of IgG1 and IgG2 in plasma is the longest. In general, the isotypes of antibody drugs are IgG1, IgG2, and IgG4, but as a method of additionally improving the pharmacokinetics of these IgG antibodies, a method of improving the binding properties to human FcRn described above by altering the sequence of the constant region of IgG. (J Biol Chem. 2007 Jan 19;282(3):1709-17, J Immunol. 2006 Jan 1;176(1):346-56).

Since there is a species difference between mouse FcRn and human FcRn (Proc Natl Acad Sci US A. 2006 Dec 5;103(49):18709-14), IgG antibodies with altered sequence of the constant region in human plasma In order to predict retention, it was considered desirable to evaluate binding to human FcRn and to evaluate retention in plasma in FcRn transgenic mice (Int Immunol. 2006 Dec; 18(12):1759-69).

human FcRn Combined evaluation into

FcRn is a complex of FcRn and β2-microglobulin. Based on the published human FcRn gene sequence (J. Exp. Med. 180 (6), 2377-2381 (1994)), oligo DNA primers were prepared. Using human cDNA (Human Placenta Marathon-Ready cDNA, Clontech) as a template, a DNA fragment encoding the full length of a gene was prepared by PCR using the prepared primers. Using the obtained DNA fragment as a template, a DNA fragment encoding an extracellular region (Met1-Leu290) containing a signal region was amplified by PCR method and inserted into an animal cell expression vector (human FcRn amino acid sequence/SEQ ID NO:165. ). Similarly, based on the published human β2-microglobulin gene sequence (Proc. Natl. Acad. Sci. U.S.A. 99(26), 16899-16903(2002)), oligo DNA primers were prepared. Using human cDNA (Hu-Placenta Marathon-Ready cDNA, CLONTECH) as a template, a DNA fragment encoding the full length of a gene was prepared by PCR using the prepared primers. Using the obtained DNA fragment as a template, a DNA fragment encoding a β2-microglobulin full length (Met1-Met119) containing a signal region was amplified by PCR and inserted into an animal cell expression vector (human β2-microglobulin amino acid sequence/sequence Number:166).

For the expression of soluble human FcRn, human fetal kidney cancer cell-derived HEK293H strain (Invitrogen) was prepared using 10% Fetal Bovine Serum (Invitrogen), and plasmids of human FcRn and human β2-microglobulin were introduced into cells by lipofection. After the obtained culture supernatant was collected, it was purified according to the method of (J Immunol. 2002 Nov 1;169(9):5171-80.) using IgG Sepharose 6 Fast Flow (Amersham Biosciences). After that, purification was performed by HiTrap Q HP (GE Healthcare).

Biacore 3000 was used for the evaluation of binding to human FcRn, and the amount of human FcRn binding when interacting with human FcRn as an analyte to an antibody bound with Protein L or rabbit anti-human IgG Kappa chain antibody immobilized on a sensor chip The affinity (KD) was calculated from. Specifically, a 50 mM Na-phosphate buffer containing 150 mM NaCl, pH 6.0 was used as a running buffer, and Protein L was immobilized on a sensor chip CM5 (BIACORE) by an amine coupling method. Thereafter, the antibody was diluted with a running buffer containing 0.02% Tween20 and injected to bind the antibody to the chip, and then human FcRn was injected to evaluate the binding property of the antibody to human FcRn.

The software, BIAevaluation, was used to calculate the affinity. From the obtained sensorgram, the amount of hFcRn binding to the antibody immediately before the completion of human FcRn injection was calculated, and this was fitted by a steady state affinity method to calculate the affinity of human FcRn to the antibody.

huPM1 - IgG1, huPM1 - predictive assessment of the residence castle in human plasma using the M58 in human FcRn

The evaluation of the binding properties of huPM1-IgG1 and huPM1-M58 to human FcRn was performed by BIAcore. As shown in Table 19, the binding property of huPM1-M58 was about 1.4 times better than that of huPM1-IgG1.

human FcRn In plasma in transgenic mice Sojournable evaluation

The evaluation of pharmacokinetics in human FcRn transgenic mice (B6.mFcRn-/-.hFcRn Tg line 276 +/+ mice, Jackson Laboratories) was performed as follows. The antibody was administered once intravenously at a dose of 1 mg/kg to mice, and blood was collected in a timely manner. The collected blood was immediately centrifuged at 4° C. and 15,000 rpm for 15 minutes to obtain plasma. The separated plasma was stored in a freezer set at -20°C or lower until measurement was performed. The plasma concentration was measured using the ELISA method.

Predictive evaluation of plasma retention in humans using human FcRn transformation of huPM1 - IgG1 and huPM1 - M58

Plasma retention in human FcRn transgenic mice of huPM1-IgG1 and huPM1-M58 was evaluated. As a result, as shown in Fig. 17, it was confirmed that huPM1-M58 improved pharmacokinetics compared to huPM1-IgG1. It was suggested that the binding to human FcRn and the plasma retention in human FcRn transgenic mice correlate.

[Reference Example 10] Affinity Measurement of Antigen Antibody Response Using Biacore

Using Biacore T100 (GE Healthcare Bioscience), a kinetic analysis of the antigen-antibody reaction was performed. Rec-Protein A (ZYMED) (hereinafter, Protein A) was immobilized on the sensor chip, and the antibody was captured by the immobilized Protein A, and the antigen was further reacted as an analyte to measure the interaction between the antibody and the antigen. For the antigen, rhNR10 prepared at various concentrations was used. From the sensorgram obtained by the measurement, the binding rate constant k _a (1/Ms), which is _{a kinetic parameter, and the dissociation rate constant k d} (1/s), are calculated, and K _D (M) is calculated based on the value. Was calculated. Biacore T100 Evaluation Software version 1.1 (GE Healthcare Bioscience) was used to calculate each parameter.

To the sensor chip Immobilization of Protein A

Protein A was immobilized on all flow cells of the sensor chip CM5 (GE Healthcare Bioscience) by the amine coupling method. HBS-EP+ (10 mM HEPES, 0.15 M NaCl, 3 mM EDTA, 0.05% v/v Surfactant P20) was used as the running buffer, and the experiment was performed at a flow rate of μL/min. In 100 μL of a 1:1 mixture of 75 mg/mL N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and 11.5 mg/mL NHS (N-hydroxysuccinimide) By activating, Protein A prepared at 50 µg/mL in 10 mM acetic acid buffer (pH 4.5) was poured therein to react. Thereafter, 100 μL of 1 M ethanolamine hydrochloride (pH 8.5) was flowed to inactivate unreacted active groups. Finally, about 4000-5000 RU was immobilized. All experiments were conducted at 25°C.

Antibodies captured by Protein A and rhNR10 Measurement of the affinity of the antigen-antibody reaction of

HBS-EP+ was used for the running buffer. Each antibody was prepared to bind 0.25 µg/mL, or about 100 RU to Protein A. RhNR10 used as an analyte was prepared at 0, 38.5, 77.0, 154 nM, or 0, 19.25, 77.01 nM using HBS-EP+. For measurement, the antibody solution was first captured by Protein A, and the analyte solution was reacted for 3 min at a flow rate of 20 μL/min, and then converted to HBS-EP+ to measure the 5 min dissociation phase. After the measurement of the dissociated phase was completed, the sensor chip was regenerated by washing with 10 mM glycine-HCl (pH 1.5). From the obtained sensorgram, kinetic analysis was performed using Biacore T100 Evaluation Software Version 1.1, which is a data analysis software exclusively for Biacore.

The anti-NR10 antibody obtained by the present inventors exhibits effective neutralizing activity against NR10, and is useful, for example, as a therapeutic agent for inflammatory diseases.

SEQUENCE LISTING <110> CHUGAI SEIYAKU KABUSHIKI KAISHA <120> Anti-NR10 antibodies, and their use <130> C1-A0712Y1P <150> JP 2007-315143 <151> 2007-12-05 <150> JP 2008-247425 <151> 2008-09-26 <160> 287 <170> PatentIn version 3.4 <210> 1 <211> 5 <212> PRT <213> Mus musculus <400> 1 Gly Tyr Ile Met Asn 1 5 <210> 2 <211> 17 <212> PRT <213> Mus musculus <400> 2 Leu Ile Asn Pro Tyr Asn Gly Asp Thr Asn Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <210> 3 <211> 12 <212> PRT <213> Mus musculus <400> 3 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr 1 5 10 <210> 4 <211> 121 <212> PRT <213> Mus musculus <400> 4 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Ile Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Ile 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Asp Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 5 <211> 11 <212> PRT <213> Mus musculus <400> 5 Arg Ala Ser Glu Asn Ile Tyr Ser Phe Leu Ala 1 5 10 <210> 6 <211> 7 <212> PRT <213> Mus musculus <400> 6 Asn Ala Lys Thr Leu Ala Lys 1 5 <210> 7 <211> 9 <212> PRT <213> Mus musculus <400> 7 Gln His His Tyr Glu Ser Pro Leu Thr 1 5 <210> 8 <211> 107 <212> PRT <213> Mus musculus <400> 8 Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro His Leu Leu Val 35 40 45 Tyr Asn Ala Lys Thr Leu Ala Lys Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Glu Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 9 <211> 5 <212> PRT <213> Mus musculus <400> 9 Gly Tyr Ile Met Asn 1 5 <210> 10 <211> 17 <212> PRT <213> Mus musculus <400> 10 Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <210> 11 <211> 12 <212> PRT <213> Mus musculus <400> 11 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr 1 5 10 <210> 12 <211> 121 <212> PRT <213> Mus musculus <400> 12 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Ile Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Ile 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 13 <211> 11 <212> PRT <213> Mus musculus <400> 13 Arg Thr Ser Glu Asn Ile Tyr Ser Phe Leu Ala 1 5 10 <210> 14 <211> 7 <212> PRT <213> Mus musculus <400> 14 Asn Ala Lys Thr Leu Ala Lys 1 5 <210> 15 <211> 9 <212> PRT <213> Mus musculus <400> 15 Gln His His Tyr Glu Ser Pro Leu Thr 1 5 <210> 16 <211> 107 <212> PRT <213> Mus musculus <400> 16 Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Glu Thr Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Ile Tyr Ser Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro His Leu Leu Val 35 40 45 Tyr Asn Ala Lys Thr Leu Ala Lys Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Gly Ser Tyr Phe Cys Gln His His Tyr Glu Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 17 <211> 5 <212> PRT <213> Mus musculus <400> 17 Gly Tyr Ile Met Asn 1 5 <210> 18 <211> 17 <212> PRT <213> Mus musculus <400> 18 Leu Ile Asn Pro Tyr Asn Gly Gly Ala Glu Tyr Asn Gln Lys Phe Lys 1 5 10 15 Asp <210> 19 <211> 12 <212> PRT <213> Mus musculus <400> 19 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr 1 5 10 <210> 20 <211> 121 <212> PRT <213> Mus musculus <400> 20 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Thr 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Ile Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Ile 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Ala Glu Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Phe Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 21 <211> 11 <212> PRT <213> Mus musculus <400> 21 Arg Ala Asn Glu Asn Ile Tyr Ser Tyr Leu Ala 1 5 10 <210> 22 <211> 7 <212> PRT <213> Mus musculus <400> 22 Asn Ala Lys Thr Leu Ala Glu 1 5 <210> 23 <211> 9 <212> PRT <213> Mus musculus <400> 23 Gln His His Tyr Gly Thr Pro Pro Thr 1 5 <210> 24 <211> 107 <212> PRT <213> Mus musculus <400> 24 Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Glu Thr Val Thr Phe Thr Cys Arg Ala Asn Glu Asn Ile Tyr Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val 35 40 45 Tyr Asn Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Pro 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 25 <211> 5 <212> PRT <213> Mus musculus <400> 25 Asn Tyr Trp Met His 1 5 <210> 26 <211> 17 <212> PRT <213> Mus musculus <400> 26 Ala Ile Tyr Pro Gly Asn Ser Asp Thr Asp Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <210> 27 <211> 8 <212> PRT <213> Mus musculus <400> 27 Asp Gly Tyr Asp Asp Phe Asp His 1 5 <210> 28 <211> 116 <212> PRT <213> Mus musculus <400> 28 Glu Val Gln Leu Gln Gln Ser Gly Thr Val Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Ser Asp Thr Asp Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Lys Leu Thr Ala Val Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Thr Asn Glu Asp Ser Ala Val Phe Phe Cys 85 90 95 Thr Thr Gly Tyr Asp Asp Phe Asp His Trp Gly Gln Gly Thr Thr Leu 100 105 110 Thr Val Ser Ser 115 <210> 29 <211> 12 <212> PRT <213> Mus musculus <400> 29 Arg Ala Ser Ser Ser Val Ser Ser Ser Tyr Leu His 1 5 10 <210> 30 <211> 7 <212> PRT <213> Mus musculus <400> 30 Ser Thr Ser Asn Leu Ala Ser 1 5 <210> 31 <211> 9 <212> PRT <213> Mus musculus <400> 31 Gln Gln Tyr Ser Gly Tyr Pro Leu Thr 1 5 <210> 32 <211> 108 <212> PRT <213> Mus musculus <400> 32 Glu Asn Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Ser Ser 20 25 30 Tyr Leu His Trp Tyr Gln Gln Lys Ser Gly Ala Ser Pro Lys Leu Trp 35 40 45 Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Ser Tyr Tyr Phe Thr Ile Ser Ser Val Glu 65 70 75 80 Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Gly Tyr Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 33 <211> 1406 <212> DNA <213> Mus musculus <400> 33 atgggatgga gctggatctt tctcttcctc ctgtcaggaa ctgcaggtgt ccactctgag 60 gtccagctgc aacagtctgg acctgagctg gtgaagcctg gagcttcaat gaagatctcc 120 tgcaaggctt ctggttactc attcactggc tacatcatga actgggtgaa gcagagccat 180 ggaaagaacc ttgagtggat tggacttatt aatccttaca atggtgatac taactacaac 240 cagaagttca agggcaaggc cacattaact gtagacaagt catccagcac agcctacatg 300 gaactcctca gtctgacatc agaggactct gcagtctatt actgtgcaag ggatggttac 360 gacgacggac cctatactat ggactactgg ggtcaaggaa cctcagtcac cgtctcctca 420 gccaaaacga cacccccatc tgtctatcca ctggcccctg gatctgctgc ccaaactaac 480 tccatggtga ccctgggatg cctggtcaag ggctatttcc ctgagccagt gacagtgacc 540 tggaactctg gatccctgtc cagcggtgtg cacaccttcc cagctgtcct gcagtctgac 600 ctctacactc tgagcagctc agtgactgtc ccctccagca cctggcccag cgagaccgtc 660 acctgcaacg ttgcccaccc ggccagcagc accaaggtgg acaagaaaat tgtgcccagg 720 gattgtggtt gtaagccttg catatgtaca gtcccagaag tatcatctgt cttcatcttc 780 cccccaaagc ccaaggatgt gctcaccatt actctgactc ctaaggtcac gtgtgttgtg 840 gtagacatca gcaaggatga tcccgaggtc cagttcagct ggtttgtaga tgatgtggag 900 gtgcacacag ctcagacgca accccgggag gagcagttca acagcacttt ccgctcagtc 960 agtgaacttc ccatcatgca ccaggactgg ctcaatggca aggagttcaa atgcagggtc 1020 aacagtgcag ctttccctgc ccccatcgag aaaaccatct ccaaaaccaa aggcagaccg 1080 aaggctccac aggtgtacac cattccacct cccaaggagc agatggccaa ggataaagtc 1140 agtctgacct gcatgataac agacttcttc cctgaagaca ttactgtgga gtggcagtgg 1200 aatgggcagc cagcggagaa ctacaagaac actcagccca tcatggacac agatggctct 1260 tacttcgtct acagcaagct caatgtgcag aagagcaact gggaggcagg aaatactttc 1320 acctgctctg tgttacatga gggcctgcac aaccaccata ctgagaagag cctctcccac 1380 tctcctggta aataatgagc ggccgc 1406 <210> 34 <211> 445 <212> PRT <213> Mus musculus <400> 34 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Ile Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Ile 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Asp Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser 115 120 125 Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val 130 135 140 Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro 180 185 190 Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro 195 200 205 Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly 210 215 220 Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys 245 250 255 Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln 260 265 270 Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu 290 295 300 Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg 305 310 315 320 Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro 340 345 350 Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr 355 360 365 Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln 370 375 380 Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly 385 390 395 400 Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu 405 410 415 Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn 420 425 430 His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 435 440 445 <210> 35 <211> 716 <212> DNA <213> Mus musculus <400> 35 atgagtgtgc ccactcaggt cctggggttg ctgctgctgt ggcttacagg tgccagatgt 60 gacatccaga tgactcagtc tccagcctcc ctatctgcat ctgtgggaga aactgtcacc 120 atcacatgtc gagcaagtga gaatatttac agttttttag catggtatca gcagaaacag 180 ggaaaatctc ctcacctcct ggtctataat gcaaaaacct tagcaaaagg tgtgccatca 240 aggttcagtg gcagtggatc tggcacacag ttttctctga agatcaacag cctgcagcct 300 gaagattttg ggagttatta ctgtcaacat cattatgaga gtcctctgac gttcggtgga 360 ggcaccaagc tggaaatcaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 420 tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 480 cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 540 aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 600 ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 660 tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttaatgagc ggccgc 716 <210> 36 <211> 214 <212> PRT <213> Mus musculus <400> 36 Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro His Leu Leu Val 35 40 45 Tyr Asn Ala Lys Thr Leu Ala Lys Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Glu Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala 100 105 110 Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly 115 120 125 Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile 130 135 140 Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu 145 150 155 160 Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser 165 170 175 Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr 180 185 190 Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser 195 200 205 Phe Asn Arg Asn Glu Cys 210 <210> 37 <211> 1406 <212> DNA <213> Mus musculus <400> 37 atgggatgga gctggatctt tctcttcctc ctgtcaggaa ctgcaggtgt ccactctgag 60 gtccagctgc aacagtctgg acctgagctg gtgaagcctg gagcttcaat gaagatctcc 120 tgcaaggctt ctggttactc attcactggc tacatcatga actgggtgaa gcagagccat 180 ggaaagaacc ttgagtggat tggacttatt aatccttaca atggtggtac tagctacaac 240 cagaagttca agggcaaggc cacattaact gtagacaagt catccagtac agcctacatg 300 gaactcctca gtctgacatc agaggactct gcagtctatt actgtgcaag ggatggttac 360 gacgacggac cctatactat ggactactgg ggtcaaggaa cctcagtcac cgtctcctca 420 gccaaaacga cacccccatc tgtctatcca ctggcccctg gatctgctgc ccaaactaac 480 tccatggtga ccctgggatg cctggtcaag ggctatttcc ctgagccagt gacagtgacc 540 tggaactctg gatccctgtc cagcggtgtg cacaccttcc cagctgtcct gcagtctgac 600 ctctacactc tgagcagctc agtgactgtc ccctccagca cctggcccag cgagaccgtc 660 acctgcaacg ttgcccaccc ggccagcagc accaaggtgg acaagaaaat tgtgcccagg 720 gattgtggtt gtaagccttg catatgtaca gtcccagaag tatcatctgt cttcatcttc 780 cccccaaagc ccaaggatgt gctcaccatt actctgactc ctaaggtcac gtgtgttgtg 840 gtagacatca gcaaggatga tcccgaggtc cagttcagct ggtttgtaga tgatgtggag 900 gtgcacacag ctcagacgca accccgggag gagcagttca acagcacttt ccgctcagtc 960 agtgaacttc ccatcatgca ccaggactgg ctcaatggca aggagttcaa atgcagggtc 1020 aacagtgcag ctttccctgc ccccatcgag aaaaccatct ccaaaaccaa aggcagaccg 1080 aaggctccac aggtgtacac cattccacct cccaaggagc agatggccaa ggataaagtc 1140 agtctgacct gcatgataac agacttcttc cctgaagaca ttactgtgga gtggcagtgg 1200 aatgggcagc cagcggagaa ctacaagaac actcagccca tcatggacac agatggctct 1260 tacttcgtct acagcaagct caatgtgcag aagagcaact gggaggcagg aaatactttc 1320 acctgctctg tgttacatga gggcctgcac aaccaccata ctgagaagag cctctcccac 1380 tctcctggta aataatgagc ggccgc 1406 <210> 38 <211> 445 <212> PRT <213> Mus musculus <400> 38 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Ile Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Ile 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser 115 120 125 Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val 130 135 140 Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro 180 185 190 Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro 195 200 205 Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly 210 215 220 Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys 245 250 255 Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln 260 265 270 Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu 290 295 300 Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg 305 310 315 320 Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro 340 345 350 Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr 355 360 365 Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln 370 375 380 Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly 385 390 395 400 Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu 405 410 415 Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn 420 425 430 His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 435 440 445 <210> 39 <211> 716 <212> DNA <213> Mus musculus <400> 39 atgagtgtgc ccactcaggt cctggggttg ctgctgctgt ggcttacagg tgccagatgt 60 gacatccaga tgactcagtc tccagcctcc ctatctgcat ctgtgggaga aactgtcacc 120 atcacatgtc gaacaagtga gaatatttac agttttttag catggtatca gcagaaacag 180 ggaaaatctc ctcacctcct ggtctataat gcaaaaacct tagcaaaagg tgtgccatca 240 aggttcagtg gcagtggatc tggcacacag ttttctctga agatcaacag cctgcagcct 300 gaagattttg ggagttattt ctgtcaacat cattatgaga gtcctctgac gttcggtgga 360 ggcaccaagc tggaaatcaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 420 tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 480 cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 540 aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 600 ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 660 tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttaatgagc ggccgc 716 <210> 40 <211> 214 <212> PRT <213> Mus musculus <400> 40 Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Glu Thr Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Ile Tyr Ser Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro His Leu Leu Val 35 40 45 Tyr Asn Ala Lys Thr Leu Ala Lys Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Gly Ser Tyr Phe Cys Gln His His Tyr Glu Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala 100 105 110 Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly 115 120 125 Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile 130 135 140 Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu 145 150 155 160 Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser 165 170 175 Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr 180 185 190 Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser 195 200 205 Phe Asn Arg Asn Glu Cys 210 <210> 41 <211> 1406 <212> DNA <213> Mus musculus <400> 41 atgggatgga gctggatctt tctcttcctc ctgtcaggaa ctgcaggtgt ccactctgag 60 gtccagctgc aacagtctgg acctgagctg gtgaagcctg gaacttcaat gaagatatcc 120 tgcaaggctt ctggttactc attcactggc tacatcatga actgggtgaa gcagagccat 180 ggaaagaacc ttgagtggat tggacttatt aatccttaca atggtggtgc tgagtacaac 240 cagaagttca aggacaaggc cacattcact gtagacaagt catccagcac agcctacatg 300 gagctcctca gtctgacatc tgaagactct gcagtctatt actgtgcaag ggatggttac 360 gacgacggac cctatactat ggactactgg ggtcaaggaa cctcagtcac cgtctcctca 420 gccaaaacga cacccccatc tgtctatcca ctggcccctg gatctgctgc ccaaactaac 480 tccatggtga ccctgggatg cctggtcaag ggctatttcc ctgagccagt gacagtgacc 540 tggaactctg gatccctgtc cagcggtgtg cacaccttcc cagctgtcct gcagtctgac 600 ctctacactc tgagcagctc agtgactgtc ccctccagca cctggcccag cgagaccgtc 660 acctgcaacg ttgcccaccc ggccagcagc accaaggtgg acaagaaaat tgtgcccagg 720 gattgtggtt gtaagccttg catatgtaca gtcccagaag tatcatctgt cttcatcttc 780 cccccaaagc ccaaggatgt gctcaccatt actctgactc ctaaggtcac gtgtgttgtg 840 gtagacatca gcaaggatga tcccgaggtc cagttcagct ggtttgtaga tgatgtggag 900 gtgcacacag ctcagacgca accccgggag gagcagttca acagcacttt ccgctcagtc 960 agtgaacttc ccatcatgca ccaggactgg ctcaatggca aggagttcaa atgcagggtc 1020 aacagtgcag ctttccctgc ccccatcgag aaaaccatct ccaaaaccaa aggcagaccg 1080 aaggctccac aggtgtacac cattccacct cccaaggagc agatggccaa ggataaagtc 1140 agtctgacct gcatgataac agacttcttc cctgaagaca ttactgtgga gtggcagtgg 1200 aatgggcagc cagcggagaa ctacaagaac actcagccca tcatggacac agatggctct 1260 tacttcgtct acagcaagct caatgtgcag aagagcaact gggaggcagg aaatactttc 1320 acctgctctg tgttacatga gggcctgcac aaccaccata ctgagaagag cctctcccac 1380 tctcctggta aataatgagc ggccgc 1406 <210> 42 <211> 445 <212> PRT <213> Mus musculus <400> 42 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Thr 1 5 10 15 Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Ile Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Ile 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Ala Glu Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Phe Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser 115 120 125 Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val 130 135 140 Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro 180 185 190 Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro 195 200 205 Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly 210 215 220 Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys 245 250 255 Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln 260 265 270 Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu 290 295 300 Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg 305 310 315 320 Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro 340 345 350 Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr 355 360 365 Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln 370 375 380 Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly 385 390 395 400 Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu 405 410 415 Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn 420 425 430 His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 435 440 445 <210> 43 <211> 716 <212> DNA <213> Mus musculus <400> 43 atgagtgtgc ccactcaggt cctggggttg ctgctgctgt ggcttacagg tgccagatgt 60 gacatccaga tgactcagtc tccagcctcc ctatctgcat ctgtgggaga aactgtcacc 120 ttcacatgtc gagcaaatga gaatatttac agttatttag catggtatca gcagaaacag 180 ggaaaatctc ctcagctcct ggtctataat gcaaaaacct tagcagaagg tgtgccatca 240 aggttcagtg gcagtggatc aggcacacag ttttctctga agatcaacag cctgcagcct 300 gaagattttg ggagttatta ctgtcaacat cattatggaa ctcctccgac gttcggtgga 360 ggcaccaagc tggaaatcaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 420 tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 480 cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 540 aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 600 ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 660 tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttaatgagc ggccgc 716 <210> 44 <211> 214 <212> PRT <213> Mus musculus <400> 44 Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Glu Thr Val Thr Phe Thr Cys Arg Ala Asn Glu Asn Ile Tyr Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val 35 40 45 Tyr Asn Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Pro 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala 100 105 110 Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly 115 120 125 Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile 130 135 140 Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu 145 150 155 160 Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser 165 170 175 Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr 180 185 190 Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser 195 200 205 Phe Asn Arg Asn Glu Cys 210 <210> 45 <211> 1391 <212> DNA <213> Mus musculus <400> 45 atggaatgta actggatact tccttttatt ctgtcggtaa tttcaggggt ctactcagag 60 gttcagctcc agcagtctgg gactgtgctg gcaaggcctg gggcttccgt gaagatgtcc 120 tgcaaggctt ctggctacac ctttaccaac tactggatgc actgggtaaa acagaggcct 180 ggacagggtc tagaatggat tggtgctatt tatcctggaa atagtgatac tgactacaac 240 cagaagttca agggcaaggc caaactgact gcagtcacat ccgccagcac tgcctacatg 300 gaactcagca gcctgacaaa tgaggactct gcggtctttt tctgtaccac tggttacgac 360 gacttcgacc actggggcca aggcaccact ctcacagtct cctcagccaa aacgacaccc 420 ccatctgtct atccactggc ccctggatct gctgcccaaa ctaactccat ggtgaccctg 480 ggatgcctgg tcaagggcta tttccctgag ccagtgacag tgacctggaa ctctggatcc 540 ctgtccagcg gtgtgcacac cttcccagct gtcctgcagt ctgacctcta cactctgagc 600 agctcagtga ctgtcccctc cagcacctgg cccagcgaga ccgtcacctg caacgttgcc 660 cacccggcca gcagcaccaa ggtggacaag aaaattgtgc ccagggattg tggttgtaag 720 ccttgcatat gtacagtccc agaagtatca tctgtcttca tcttcccccc aaagcccaag 780 gatgtgctca ccattactct gactcctaag gtcacgtgtg ttgtggtaga catcagcaag 840 gatgatcccg aggtccagtt cagctggttt gtagatgatg tggaggtgca cacagctcag 900 acgcaacccc gggaggagca gttcaacagc actttccgct cagtcagtga acttcccatc 960 atgcaccagg actggctcaa tggcaaggag ttcaaatgca gggtcaacag tgcagctttc 1020 cctgccccca tcgagaaaac catctccaaa accaaaggca gaccgaaggc tccacaggtg 1080 tacaccattc cacctcccaa ggagcagatg gccaaggata aagtcagtct gacctgcatg 1140 ataacagact tcttccctga agacattact gtggagtggc agtggaatgg gcagccagcg 1200 gagaactaca agaacactca gcccatcatg gacacagatg gctcttactt cgtctacagc 1260 aagctcaatg tgcagaagag caactgggag gcaggaaata ctttcacctg ctctgtgtta 1320 catgagggcc tgcacaacca ccatactgag aagagcctct cccactctcc tggtaaataa 1380 tgagcggccg c 1391 <210> 46 <211> 440 <212> PRT <213> Mus musculus <400> 46 Glu Val Gln Leu Gln Gln Ser Gly Thr Val Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Ser Asp Thr Asp Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Lys Leu Thr Ala Val Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Thr Asn Glu Asp Ser Ala Val Phe Phe Cys 85 90 95 Thr Thr Gly Tyr Asp Asp Phe Asp His Trp Gly Gln Gly Thr Thr Leu 100 105 110 Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala 115 120 125 Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu 130 135 140 Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly 145 150 155 160 Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp 165 170 175 Leu Tyr Thr Leu Ser Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro 180 185 190 Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys 195 200 205 Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile 210 215 220 Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro 225 230 235 240 Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val 245 250 255 Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val 260 265 270 Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln 275 280 285 Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln 290 295 300 Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala 305 310 315 320 Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro 325 330 335 Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala 340 345 350 Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu 355 360 365 Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr 370 375 380 Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr 385 390 395 400 Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe 405 410 415 Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu Lys 420 425 430 Ser Leu Ser His Ser Pro Gly Lys 435 440 <210> 47 <211> 725 <212> DNA <213> Mus musculus <400> 47 atggattttc tggtgcagat tttcagcttc ttgctaatca gtgcctcagt tgcaatgtcc 60 agaggagaaa atgtgctcac ccagtctcca gcaatcatgt ctgcatctcc aggggaaaag 120 gtcaccatga cctgcagggc cagctcaagt gtaagttcca gttacttgca ctggtaccag 180 cagaagtcag gtgcctcccc caaactctgg atttatagca cttccaactt ggcttctgga 240 gtccctgctc gcttcagtgg cagtgggtct gggacctctt actatttcac aatcagcagt 300 gtggaggctg aagatgctgc cacttattac tgccagcaat acagtggtta cccactcacg 360 ttcggagggg ggaccaagct ggaaataaaa cgggctgatg ctgcaccaac tgtatccatc 420 ttcccaccat ccagtgagca gttaacatct ggaggtgcct cagtcgtgtg cttcttgaac 480 aacttctacc ccaaagacat caatgtcaag tggaagattg atggcagtga acgacaaaat 540 ggcgtcctga acagttggac tgatcaggac agcaaagaca gcacctacag catgagcagc 600 accctcacgt tgaccaagga cgagtatgaa cgacataaca gctatacctg tgaggccact 660 cacaagacat caacttcacc cattgtcaag agcttcaaca ggaatgagtg ttaatgagcg 720 gccgc 725 <210> 48 <211> 215 <212> PRT <213> Mus musculus <400> 48 Glu Asn Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Ser Ser 20 25 30 Tyr Leu His Trp Tyr Gln Gln Lys Ser Gly Ala Ser Pro Lys Leu Trp 35 40 45 Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Ser Tyr Tyr Phe Thr Ile Ser Ser Val Glu 65 70 75 80 Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Gly Tyr Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala 100 105 110 Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser 115 120 125 Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp 130 135 140 Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val 145 150 155 160 Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met 165 170 175 Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser 180 185 190 Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys 195 200 205 Ser Phe Asn Arg Asn Glu Cys 210 215 <210> 49 <211> 425 <212> DNA <213> Artificial <220> <223> an artificially synthesized sequence <400> 49 ccaccatgga ctggacctgg agggtcttct gcttgctggc tgtagctcca ggtgctcact 60 cccaggtgca gctggtgcag tctggggctg aggtgaagaa gcctggggcc tcagtgaagg 120 tttcctgcaa ggcatctgga tacaccttca ccggctacat catgaactgg gtgcgacagg 180 cccctggaca agggcttgag tggatgggac ttattaatcc ttacaatggt ggtactagct 240 acaaccagaa gttcaagggc agagtcacga ttaccgcgga cgaatccacg agcacagcct 300 acatggagct gagcagcctg agatctgagg acacggccgt gtattactgt gcgagagatg 360 gttacgacga cggaccctat actatggact actggggcca gggcaccctc gtcacagtct 420 cctca 425 <210> 50 <211> 121 <212> PRT <213> Artificial <220> <223> an artificially synthesized sequence <400> 50 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 51 <211> 398 <212> DNA <213> Artificial <220> <223> an artificially synthesized sequence <400> 51 ccaccatgga catgagggtc cccgctcagc tcctggggct cctgctactc tggctccgag 60 gtgccagatg tgacatccag atgacccagt ctccatcctc cctgtctgca tctgtaggag 120 acagagtcac catcacttgc cgaacaagtg agaatattta cagtttttta gcatggtatc 180 agcagaaacc agggaaagcc cctaagctcc tgatctataa tgcaaaaacc ttagcaaaag 240 gggtcccatc aaggttcagt ggcagtggat ctgggacaga tttcactctc accatcagca 300 gtctgcaacc tgaagatttt gcaacttact actgtcaaca tcattatgag agtcctctga 360 cgttcggcgg agggaccaag gtggagatca aacgtacg 398 <210> 52 <211> 107 <212> PRT <213> Artificial <220> <223> an artificially synthesized sequence <400> 52 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 Thr Ser Glu Asn Ile Tyr Ser Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Lys Thr Leu Ala Lys 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 His His Tyr Glu Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 53 <211> 1422 <212> DNA <213> Artificial <220> <223> an artificially synthesized sequence <400> 53 gaattccacc atggactgga cctggagggt cttctgcttg ctggctgtag ctccaggtgc 60 tcactcccag gtgcagctgg tgcagtctgg ggctgaggtg aagaagcctg gggcctcagt 120 gaaggtttcc tgcaaggcat ctggatacac cttcaccggc tacatcatga actgggtgcg 180 acaggcccct ggacaagggc ttgagtggat gggacttatt aatccttaca atggtggtac 240 tagctacaac cagaagttca agggcagagt cacgattacc gcggacgaat ccacgagcac 300 agcctacatg gagctgagca gcctgagatc tgaggacacg gccgtgtatt actgtgcgag 360 agatggttac gacgacggac cctatactat ggactactgg ggccagggca ccctcgtcac 420 agtctcctca gctagcacca agggcccatc ggtcttcccc ctggcgccct cctccaagag 480 cacctccgag agcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt 540 gacggtgtcg tggaactcag gcgctctgac cagcggcgtg cacaccttcc cggctgtcct 600 acagtcctca ggactctact ccctcagcag cgtggtgacc gtgccctcca gcaacttcgg 660 cacccagacc tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagac 720 agttgagcgc aaatcttgtg tcgagtgccc accgtgccca gcaccacctg tggcaggacc 780 gtcagtcttc ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga 840 ggtcacgtgc gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta 900 cgtggacggc gtggaggtgc ataatgccaa gacaaagcca cgggaggagc agttcaacag 960 cacgttccgt gtggtcagcg tcctcaccgt cgtgcaccag gactggctga acggcaagga 1020 gtacaagtgc aaggtctcca acaaaggcct cccagccccc atcgagaaaa ccatctccaa 1080 aaccaaaggg cagccccgag aaccacaggt gtacaccctg cccccatccc gggaggagat 1140 gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc 1200 cgtggagtgg gagagcaatg ggcagccgga gaacaactac aagaccacac ctcccatgct 1260 ggactccgac ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca 1320 gcaggggaac gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacaca 1380 gaagagcctc tccctgtctc cgggtaaatg ataagcggcc gc 1422 <210> 54 <211> 447 <212> PRT <213> Artificial <220> <223> an artificially synthesized sequence <400> 54 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 55 <211> 719 <212> DNA <213> Artificial <220> <223> an artificially synthesized sequence <400> 55 ccaccatgga catgagggtc cccgctcagc tcctggggct cctgctactc tggctccgag 60 gtgccagatg tgacatccag atgacccagt ctccatcctc cctgtctgca tctgtaggag 120 acagagtcac catcacttgc cgaacaagtg agaatattta cagtttttta gcatggtatc 180 agcagaaacc agggaaagcc cctaagctcc tgatctataa tgcaaaaacc ttagcaaaag 240 gggtcccatc aaggttcagt ggcagtggat ctgggacaga tttcactctc accatcagca 300 gtctgcaacc tgaagatttt gcaacttact actgtcaaca tcattatgag agtcctctga 360 cgttcggcgg agggaccaag gtggagatca aacgtacggt ggctgcacca tctgtcttca 420 tcttcccgcc atctgatgag cagttgaaat ctggaactgc ctctgttgtg tgcctgctga 480 ataacttcta tcccagagag gccaaagtac agtggaaggt ggataacgcc ctccaatcgg 540 gtaactccca ggagagtgtc acagagcagg acagcaagga cagcacctac agcctcagca 600 gcaccctgac gctgagcaaa gcagactacg agaaacacaa agtctacgcc tgcgaagtca 660 cccatcaggg cctgagctcg cccgtcacaa agagcttcaa caggggagag tgttgataa 719 <210> 56 <211> 214 <212> PRT <213> Artificial <220> <223> an artificially synthesized sequence <400> 56 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 Thr Ser Glu Asn Ile Tyr Ser Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Lys Thr Leu Ala Lys 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 His His Tyr Glu Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 57 <211> 327 <212> DNA <213> Homo sapiens <400> 57 cgtacggtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct 60 ggaactgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag 120 tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac 180 agcaaggaca gcacctacag cctcagcagc accctgacgc tgagcaaagc agactacgag 240 aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag 300 agcttcaaca ggggagagtg ttgataa 327 <210> 58 <211> 107 <212> PRT <213> Homo sapiens <400> 58 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 59 <211> 990 <212> DNA <213> Homo sapiens <400> 59 gctagcacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240 tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 300 aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 720 ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840 ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960 cagaagagcc tctccctgtc tccgggtaaa 990 <210> 60 <211> 330 <212> PRT <213> Homo sapiens <400> 60 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <210> 61 <211> 984 <212> DNA <213> Homo sapiens <400> 61 gctagcacca agggcccatc ggtcttcccc ctggcgccct cctccaagag cacctccgag 60 agcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120 tggaactcag gcgctctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcaacttcgg cacccagacc 240 tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagac agttgagcgc 300 aaatcttgtg tcgagtgccc accgtgccca gcaccacctg tggcaggacc gtcagtcttc 360 ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacgtgc 420 gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta cgtggacggc 480 gtggaggtgc ataatgccaa gacaaagcca cgggaggagc agttcaacag cacgttccgt 540 gtggtcagcg tcctcaccgt cgtgcaccag gactggctga acggcaagga gtacaagtgc 600 aaggtctcca acaaaggcct cccagccccc atcgagaaaa ccatctccaa aaccaaaggg 660 cagccccgag aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac 720 caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg 780 gagagcaatg ggcagccgga gaacaactac aagaccacac ctcccatgct ggactccgac 840 ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 900 gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacaca gaagagcctc 960 tccctgtctc cgggtaaatg ataa 984 <210> 62 <211> 326 <212> PRT <213> Homo sapiens <400> 62 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Thr Val Glu Arg Lys Ser Cys Val Glu Cys Pro Pro Cys Pro Ala Pro 100 105 110 Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 115 120 125 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 130 135 140 Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 145 150 155 160 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 165 170 175 Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp 180 185 190 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 195 200 205 Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu 210 215 220 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 225 230 235 240 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 245 250 255 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 260 265 270 Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 275 280 285 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 290 295 300 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 305 310 315 320 Ser Leu Ser Pro Gly Lys 325 <210> 63 <211> 995 <212> DNA <213> Homo sapiens <400> 63 gctagcacca agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 60 agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 240 tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 300 aaatatggtc ccccatgccc accatgccca gcacctgagt tcctgggggg accatcagtc 360 ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 420 tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 480 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 540 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 600 tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 660 gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 720 aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 780 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 840 gacggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg 900 aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 960 ctctccctgt ctctgggtta atgataagcg gccgc 995 <210> 64 <211> 326 <212> PRT <213> Homo sapiens <400> 64 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 100 105 110 Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 145 150 155 160 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 165 170 175 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys 225 230 235 240 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 260 265 270 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 305 310 315 320 Leu Ser Leu Ser Leu Gly 325 <210> 65 <211> 2208 <212> DNA <213> Macaca fascicularis <400> 65 atgatgtgga cctgggcact gtggatgttc cctttactct gcaaattcgg cctggcagct 60 ctgccagcta agcctgagaa catttcctgt gtctactact ataggaaaaa tttaacctgc 120 acttggagtc caggaaagga aactagttat acccagtaca cagctaagag aacttacgct 180 tttggaaaaa aacatgataa ttgtacaacc agtagttcta caagtgaaaa tcgtgcttcg 240 tgctcttttt tccttccaag aataacgatc ccagataatt ataccattga ggtggaagct 300 gaaaatggag atggtgtaat taaatctgat atgacatgtt ggagattaga ggacatagcg 360 aaaactgaac cacctgagat tttcagtgtg aaaccagttt tgggcatcaa acgaatgatt 420 cggattgaat ggataaagcc tgagttggca cctgtttcat ctgatttaaa atatgcactt 480 cgattcagga cagtcaatag taccagctgg atggaagtca acttcgctaa gaaccgtaaa 540 gatacaaacc aaacctacaa ccttatgggg ctgcaggctt ttacagagta tgtcgtagct 600 ctgcgatgtg cggtcaagga gtcaaagttc tggagtgact ggagccaaga aaaaatggga 660 atgactgagg aagaagctcc atgtggcctg gaactgtgga gagtcctgaa accaactgag 720 gtggatggaa gaaggccagt gcggttgtta tggaagaagg caagaggagc cccagtccta 780 gagaaaacac ttggctacaa catatggtac tttccagaaa acaacactaa cctcacagag 840 acagtgaaca ccactaacca gcagcttgaa ctgcatctgg gaggcgagag ctattgggtg 900 tctatgattt cttataattc tcttgggaag tctccagtga ccaccctgag gattccagcc 960 attcaggaaa agtcatttcg gtgcattgag gtcatgcagg cctgccttgc tgaggaccag 1020 ctagtggtga agtggcaaag ctctgctcta gacgtgaaca cttggatgat tgaatggttt 1080 ccggacatgg actcagagca ccccactctt tcctgggaat ctgtgtctca ggccacgaac 1140 tggacaatcc agcaagataa attaaaacct ttctggtgct ataacatctc tgtgtatcca 1200 atgttgcacg acaaagttgg cgagccatat tccatccagg cttatgccaa agaaggcatt 1260 ccatcaaaag gtcctgagac caaggtggag aacattggcg tgaagacggt cacgatcaca 1320 tggaaagaga ttcccaagag tgagagaaag ggtatcatct gcaactacac catcttttac 1380 caagctgaag gtggaaaagg attctccaag acagtcaact ccagcatctt gcagtatggc 1440 ctggagtccc tgaaacgaaa gacctcttac actgttcggg tcatggccag caccagtgct 1500 gggggaatca acgggaccag cataaatttc aagacattgt cattcagtgt ttttgagatt 1560 atccttataa cttctctgat tggtggaggc cttcttattc tcattatcct gacggtggca 1620 tatggtctca aaaaacccaa caaattgact cacctgtgtt ggcccagtgt tcccaaccct 1680 gctgaaagta gtatagccac atggcgtgga gatgatttca aggataagct aaacctgaag 1740 gagtctgatg actctgtgaa cacagaagac aggatcttaa aaccatgttc cacccccagt 1800 gacaagttgg ttattgacaa gtcggtggtg aactttggga atgttctgca agaaatgttc 1860 acagatgaag ccagaacggg tcaggaaaac aatttaggag gggaaaagaa tgagtatgtg 1920 acccacccct tcagggctga ctgtcccctg gggaaaagtt ttgaggagct cccagtttca 1980 cctgagattc ctcccagaaa atcccaatac ctacgttcga ggatgccaga agggacctgc 2040 ctagaagccg aagagcagct tctcgtttct ggtcaaagtc tagaaagtct agcaccagac 2100 catgtgcggg aggcagcggc cccaaatccg tatttgaaaa attcagtgac aaccagggaa 2160 tttcttgtgt ctcaaaaact tccagagcac accaaaggag aagtctaa 2208 <210> 66 <211> 735 <212> PRT <213> Macaca fascicularis <400> 66 Met Met Trp Thr Trp Ala Leu Trp Met Phe Pro Leu Leu Cys Lys Phe 1 5 10 15 Gly Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn Ile Ser Cys Val Tyr 20 25 30 Tyr Tyr Arg Lys Asn Leu Thr Cys Thr Trp Ser Pro Gly Lys Glu Thr 35 40 45 Ser Tyr Thr Gln Tyr Thr Ala Lys Arg Thr Tyr Ala Phe Gly Lys Lys 50 55 60 His Asp Asn Cys Thr Thr Ser Ser Ser Thr Ser Glu Asn Arg Ala Ser 65 70 75 80 Cys Ser Phe Phe Leu Pro Arg Ile Thr Ile Pro Asp Asn Tyr Thr Ile 85 90 95 Glu Val Glu Ala Glu Asn Gly Asp Gly Val Ile Lys Ser Asp Met Thr 100 105 110 Cys Trp Arg Leu Glu Asp Ile Ala Lys Thr Glu Pro Pro Glu Ile Phe 115 120 125 Ser Val Lys Pro Val Leu Gly Ile Lys Arg Met Ile Arg Ile Glu Trp 130 135 140 Ile Lys Pro Glu Leu Ala Pro Val Ser Ser Asp Leu Lys Tyr Ala Leu 145 150 155 160 Arg Phe Arg Thr Val Asn Ser Thr Ser Trp Met Glu Val Asn Phe Ala 165 170 175 Lys Asn Arg Lys Asp Thr Asn Gln Thr Tyr Asn Leu Met Gly Leu Gln 180 185 190 Ala Phe Thr Glu Tyr Val Val Ala Leu Arg Cys Ala Val Lys Glu Ser 195 200 205 Lys Phe Trp Ser Asp Trp Ser Gln Glu Lys Met Gly Met Thr Glu Glu 210 215 220 Glu Ala Pro Cys Gly Leu Glu Leu Trp Arg Val Leu Lys Pro Thr Glu 225 230 235 240 Val Asp Gly Arg Arg Pro Val Arg Leu Leu Trp Lys Lys Ala Arg Gly 245 250 255 Ala Pro Val Leu Glu Lys Thr Leu Gly Tyr Asn Ile Trp Tyr Phe Pro 260 265 270 Glu Asn Asn Thr Asn Leu Thr Glu Thr Val Asn Thr Thr Asn Gln Gln 275 280 285 Leu Glu Leu His Leu Gly Gly Glu Ser Tyr Trp Val Ser Met Ile Ser 290 295 300 Tyr Asn Ser Leu Gly Lys Ser Pro Val Thr Thr Leu Arg Ile Pro Ala 305 310 315 320 Ile Gln Glu Lys Ser Phe Arg Cys Ile Glu Val Met Gln Ala Cys Leu 325 330 335 Ala Glu Asp Gln Leu Val Val Lys Trp Gln Ser Ser Ala Leu Asp Val 340 345 350 Asn Thr Trp Met Ile Glu Trp Phe Pro Asp Met Asp Ser Glu His Pro 355 360 365 Thr Leu Ser Trp Glu Ser Val Ser Gln Ala Thr Asn Trp Thr Ile Gln 370 375 380 Gln Asp Lys Leu Lys Pro Phe Trp Cys Tyr Asn Ile Ser Val Tyr Pro 385 390 395 400 Met Leu His Asp Lys Val Gly Glu Pro Tyr Ser Ile Gln Ala Tyr Ala 405 410 415 Lys Glu Gly Ile Pro Ser Lys Gly Pro Glu Thr Lys Val Glu Asn Ile 420 425 430 Gly Val Lys Thr Val Thr Ile Thr Trp Lys Glu Ile Pro Lys Ser Glu 435 440 445 Arg Lys Gly Ile Ile Cys Asn Tyr Thr Ile Phe Tyr Gln Ala Glu Gly 450 455 460 Gly Lys Gly Phe Ser Lys Thr Val Asn Ser Ser Ile Leu Gln Tyr Gly 465 470 475 480 Leu Glu Ser Leu Lys Arg Lys Thr Ser Tyr Thr Val Arg Val Met Ala 485 490 495 Ser Thr Ser Ala Gly Gly Ile Asn Gly Thr Ser Ile Asn Phe Lys Thr 500 505 510 Leu Ser Phe Ser Val Phe Glu Ile Ile Leu Ile Thr Ser Leu Ile Gly 515 520 525 Gly Gly Leu Leu Ile Leu Ile Ile Leu Thr Val Ala Tyr Gly Leu Lys 530 535 540 Lys Pro Asn Lys Leu Thr His Leu Cys Trp Pro Ser Val Pro Asn Pro 545 550 555 560 Ala Glu Ser Ser Ile Ala Thr Trp Arg Gly Asp Asp Phe Lys Asp Lys 565 570 575 Leu Asn Leu Lys Glu Ser Asp Asp Ser Val Asn Thr Glu Asp Arg Ile 580 585 590 Leu Lys Pro Cys Ser Thr Pro Ser Asp Lys Leu Val Ile Asp Lys Ser 595 600 605 Val Val Asn Phe Gly Asn Val Leu Gln Glu Met Phe Thr Asp Glu Ala 610 615 620 Arg Thr Gly Gln Glu Asn Asn Leu Gly Gly Glu Lys Asn Glu Tyr Val 625 630 635 640 Thr His Pro Phe Arg Ala Asp Cys Pro Leu Gly Lys Ser Phe Glu Glu 645 650 655 Leu Pro Val Ser Pro Glu Ile Pro Pro Arg Lys Ser Gln Tyr Leu Arg 660 665 670 Ser Arg Met Pro Glu Gly Thr Cys Leu Glu Ala Glu Glu Gln Leu Leu 675 680 685 Val Ser Gly Gln Ser Leu Glu Ser Leu Ala Pro Asp His Val Arg Glu 690 695 700 Ala Ala Ala Pro Asn Pro Tyr Leu Lys Asn Ser Val Thr Thr Arg Glu 705 710 715 720 Phe Leu Val Ser Gln Lys Leu Pro Glu His Thr Lys Gly Glu Val 725 730 735 <210> 67 <211> 495 <212> DNA <213> Macaca fascicularis <400> 67 atggcctctc actcagcagg ccccgcgacg tccgtgctgt ttctgctctg ctgcctggga 60 ggctggctga cctcccacac gttgcccgtc catttcctac aaccaagtga tatacagaaa 120 atagtcgagg aattacagtc cctctcgaag atgcttttga aagatgtgaa ggaagacaag 180 ggggtgctcg tgtcccagaa ttacacgctg ccgtgtctca cccctgacgc ccagccgcca 240 aacatcatcc acagcccagc catccgggca tatctcaaga caatcagaca gttagacaac 300 aaatctgtta ttgatgagat catagagcac ctcgacaaac tcatatttca agatgcacca 360 gaaacaaaca tttctgtgcc aacagacacc catgaatgta aacgcttcat cctgactatt 420 tctcaacagt tttcagagtg catggacctt gcattaaaat cgttgacttc tggagcccag 480 caggccacca cttaa 495 <210> 68 <211> 164 <212> PRT <213> Macaca fascicularis <400> 68 Met Ala Ser His Ser Ala Gly Pro Ala Thr Ser Val Leu Phe Leu Leu 1 5 10 15 Cys Cys Leu Gly Gly Trp Leu Thr Ser His Thr Leu Pro Val His Phe 20 25 30 Leu Gln Pro Ser Asp Ile Gln Lys Ile Val Glu Glu Leu Gln Ser Leu 35 40 45 Ser Lys Met Leu Leu Lys Asp Val Lys Glu Asp Lys Gly Val Leu Val 50 55 60 Ser Gln Asn Tyr Thr Leu Pro Cys Leu Thr Pro Asp Ala Gln Pro Pro 65 70 75 80 Asn Ile Ile His Ser Pro Ala Ile Arg Ala Tyr Leu Lys Thr Ile Arg 85 90 95 Gln Leu Asp Asn Lys Ser Val Ile Asp Glu Ile Ile Glu His Leu Asp 100 105 110 Lys Leu Ile Phe Gln Asp Ala Pro Glu Thr Asn Ile Ser Val Pro Thr 115 120 125 Asp Thr His Glu Cys Lys Arg Phe Ile Leu Thr Ile Ser Gln Gln Phe 130 135 140 Ser Glu Cys Met Asp Leu Ala Leu Lys Ser Leu Thr Ser Gly Ala Gln 145 150 155 160 Gln Ala Thr Thr <210> 69 <211> 2934 <212> DNA <213> Macaca fascicularis <400> 69 atggctctat ttgtagtctt tcagacaaca ttcttcttaa cattgctgtc cttgaggact 60 taccagagtg aagtcttggc tgaacgttta ccattgactc ctgtgtcact taaagtttcc 120 accaattcta tacatcagag tttgcattta caatggactg tccacaacct tccttatcat 180 caggaattga aaatggtatt tcagatccag atcagtagga ttgaaacatc caatgtcgtc 240 tgggtgggga attacagcac cactgtgaag tggaaccagg ttctgcattg gagctgggaa 300 tcggaactcc ctttggaatg tgccacacac tttgtaagaa tcaagagtgt gatagacgat 360 gccagtttcc ctgagccaaa tttctggagc aactggagtt cctgggagga agtcagtgta 420 caagattatc ttggacgggg cactttgttc gttttcccta aagataagct ggtggaagaa 480 ggctccaatg ttaccatttg ttatgtttct aggaacattc aaaataatgt atcctgttat 540 ttggaaggga aacagattca cggagaacaa cttgatccac atgtaactgc attcaacttg 600 aatagtgtgc ctttcattag gaatagaggg acaaatatct attgtgaggc gagtcaagga 660 aatgtcagta aaggcataga aggcatcgtt ctctttgtct caaaagtact tgaggagccc 720 aaggactttt cttgtgaatc ccaggacttc aacactttgc actgtacttg ggatcctggg 780 acggacactg ccttggggtg gtctaaacaa ccttcccaaa gctacacttt atttgaatca 840 ttttctgggg aaaagaaact ttgtacgcac aaaaactggt gtaattggca aataactcaa 900 gactcacaag aaatgtataa cttcacactc atagctgaaa attacttaag gaagagaagt 960 gtcaatatcc tttttaacct gactcatcga gtttatttaa tgaatccttt tagtgtcaac 1020 tttgaaaatg taaatgccac aaatgccatc atgacctgga aggtgcactc catgaggaat 1080 aatttcacat atttgtgtca gattgaactc catggtgaag gaaaaatgat gcaatacgat 1140 gtttctatca acgtgaacgg tgagtacttc ttaagtgaac tggaacctgc cacagaatat 1200 atggcccgag tacgctgtgc tgatgccagc cacttctgga aatggactga atggagtggt 1260 cagaacttca ccacacttga agctgctccg tcagaggccc ctgatgtctg gagaagtgtg 1320 aactcagagc caggaaatca tactgtgacc ttattctgga agccattatc aaaactgcat 1380 gccaatggaa agatcctgtt ctataatgta gttgtagaaa acctagacaa accgtccagg 1440 tcagagctcc gttccattcc ggcaccagcc aacagcacaa aactaatcct cgacaggtgt 1500 tcctaccaaa tctgcgtcac agctaacaac agtgtgggcg cttctcctgc ttctataata 1560 gtcatctctg cggaccctga aaacaaagag gttgaggaag aaagaattgc aggcacagag 1620 ggtggattct ctctgtcttg gaaaccccag cctggagatg ttataggcta tgttgtggac 1680 tggtgtgacc atccccagga tgtgctccag tggaagaatg taggtcccaa taccacaagc 1740 acagtcatta gcacagatgc ttttaggcca ggagttcgat acgacttcag aatctatggg 1800 ttatctacaa aaaggattgc ttgtttatta gagaaaaaaa caggatactc tcaggaactg 1860 gctccttcag acaaccctca cgtgctggta gatatgttga catcccactc cttcactctg 1920 agttggaaag attactctac tgaatctcaa cctggtttta tacaagggta ccatgtctat 1980 ctgaaatcca aggcgaggca gtgccaccca cgatttcaaa aggcagttct ttcagatggt 2040 tcagaatgtt gcaaatacaa aattgacaac ccagaagaaa aggcattgat tgtggacaac 2100 ctaaagccag aatccttcta tgagtttttc gttactccat tcactagtgc tggcgagggc 2160 cccaatgcta cgttcacgaa ggtcacgact ccggatgaac actcctccat gttgattcgt 2220 atcctactgc ccatggtttt ctgcgtcttg ctcatcatga tcgtgtgcta cttgaaaagt 2280 cagtggatca aggagacgtg ttatcctgac atccctgacc cttacaagag cagcatcctg 2340 tcgttaataa aattcaagga gaaccctcac ctaacaataa tgaatgtcag tgactgtatc 2400 ccagatgcta ttgaagttgt cagcaagcca gaagggacaa agatacagct cctaggcact 2460 aggaagtcac tcacagaaac tgagttaact aagcctaact acctttatct ccttccaaca 2520 gaaaagaatc actctggccc tggcccctgc atctgttttg agaactttac ctacaaccag 2580 gcagcttctg acgctggctc ttgtggccat gttccagtac cccccaaagc cccaccaagt 2640 atgctaggac taatgacctc acctgaaaat gtactaaagg cgctagaaaa aaactacatg 2700 aactccctgg gagaagtccc agctggagaa acaagtttga attatgtgtc ccagttggct 2760 tcacccatgt ctggagacaa ggacagtctc ccaacaaacc cagtggagcc accacactgt 2820 tcagagtata aaatgcaaat ggcagtcccc ctgcgtcttg ccctgcctcc cccgaccgag 2880 aatagcagcc tttcctcaat taccctttta gatccaggtg aacactaccg ctaa 2934 <210> 70 <211> 977 <212> PRT <213> Macaca fascicularis <400> 70 Met Ala Leu Phe Val Val Phe Gln Thr Thr Phe Phe Leu Thr Leu Leu 1 5 10 15 Ser Leu Arg Thr Tyr Gln Ser Glu Val Leu Ala Glu Arg Leu Pro Leu 20 25 30 Thr Pro Val Ser Leu Lys Val Ser Thr Asn Ser Ile His Gln Ser Leu 35 40 45 His Leu Gln Trp Thr Val His Asn Leu Pro Tyr His Gln Glu Leu Lys 50 55 60 Met Val Phe Gln Ile Gln Ile Ser Arg Ile Glu Thr Ser Asn Val Val 65 70 75 80 Trp Val Gly Asn Tyr Ser Thr Thr Val Lys Trp Asn Gln Val Leu His 85 90 95 Trp Ser Trp Glu Ser Glu Leu Pro Leu Glu Cys Ala Thr His Phe Val 100 105 110 Arg Ile Lys Ser Val Ile Asp Asp Ala Ser Phe Pro Glu Pro Asn Phe 115 120 125 Trp Ser Asn Trp Ser Ser Trp Glu Glu Val Ser Val Gln Asp Tyr Leu 130 135 140 Gly Arg Gly Thr Leu Phe Val Phe Pro Lys Asp Lys Leu Val Glu Glu 145 150 155 160 Gly Ser Asn Val Thr Ile Cys Tyr Val Ser Arg Asn Ile Gln Asn Asn 165 170 175 Val Ser Cys Tyr Leu Glu Gly Lys Gln Ile His Gly Glu Gln Leu Asp 180 185 190 Pro His Val Thr Ala Phe Asn Leu Asn Ser Val Pro Phe Ile Arg Asn 195 200 205 Arg Gly Thr Asn Ile Tyr Cys Glu Ala Ser Gln Gly Asn Val Ser Lys 210 215 220 Gly Ile Glu Gly Ile Val Leu Phe Val Ser Lys Val Leu Glu Glu Pro 225 230 235 240 Lys Asp Phe Ser Cys Glu Ser Gln Asp Phe Asn Thr Leu His Cys Thr 245 250 255 Trp Asp Pro Gly Thr Asp Thr Ala Leu Gly Trp Ser Lys Gln Pro Ser 260 265 270 Gln Ser Tyr Thr Leu Phe Glu Ser Phe Ser Gly Glu Lys Lys Leu Cys 275 280 285 Thr His Lys Asn Trp Cys Asn Trp Gln Ile Thr Gln Asp Ser Gln Glu 290 295 300 Met Tyr Asn Phe Thr Leu Ile Ala Glu Asn Tyr Leu Arg Lys Arg Ser 305 310 315 320 Val Asn Ile Leu Phe Asn Leu Thr His Arg Val Tyr Leu Met Asn Pro 325 330 335 Phe Ser Val Asn Phe Glu Asn Val Asn Ala Thr Asn Ala Ile Met Thr 340 345 350 Trp Lys Val His Ser Met Arg Asn Asn Phe Thr Tyr Leu Cys Gln Ile 355 360 365 Glu Leu His Gly Glu Gly Lys Met Met Gln Tyr Asp Val Ser Ile Asn 370 375 380 Val Asn Gly Glu Tyr Phe Leu Ser Glu Leu Glu Pro Ala Thr Glu Tyr 385 390 395 400 Met Ala Arg Val Arg Cys Ala Asp Ala Ser His Phe Trp Lys Trp Thr 405 410 415 Glu Trp Ser Gly Gln Asn Phe Thr Thr Leu Glu Ala Ala Pro Ser Glu 420 425 430 Ala Pro Asp Val Trp Arg Ser Val Asn Ser Glu Pro Gly Asn His Thr 435 440 445 Val Thr Leu Phe Trp Lys Pro Leu Ser Lys Leu His Ala Asn Gly Lys 450 455 460 Ile Leu Phe Tyr Asn Val Val Val Glu Asn Leu Asp Lys Pro Ser Arg 465 470 475 480 Ser Glu Leu Arg Ser Ile Pro Ala Pro Ala Asn Ser Thr Lys Leu Ile 485 490 495 Leu Asp Arg Cys Ser Tyr Gln Ile Cys Val Thr Ala Asn Asn Ser Val 500 505 510 Gly Ala Ser Pro Ala Ser Ile Ile Val Ile Ser Ala Asp Pro Glu Asn 515 520 525 Lys Glu Val Glu Glu Glu Arg Ile Ala Gly Thr Glu Gly Gly Phe Ser 530 535 540 Leu Ser Trp Lys Pro Gln Pro Gly Asp Val Ile Gly Tyr Val Val Asp 545 550 555 560 Trp Cys Asp His Pro Gln Asp Val Leu Gln Trp Lys Asn Val Gly Pro 565 570 575 Asn Thr Thr Ser Thr Val Ile Ser Thr Asp Ala Phe Arg Pro Gly Val 580 585 590 Arg Tyr Asp Phe Arg Ile Tyr Gly Leu Ser Thr Lys Arg Ile Ala Cys 595 600 605 Leu Leu Glu Lys Lys Thr Gly Tyr Ser Gln Glu Leu Ala Pro Ser Asp 610 615 620 Asn Pro His Val Leu Val Asp Met Leu Thr Ser His Ser Phe Thr Leu 625 630 635 640 Ser Trp Lys Asp Tyr Ser Thr Glu Ser Gln Pro Gly Phe Ile Gln Gly 645 650 655 Tyr His Val Tyr Leu Lys Ser Lys Ala Arg Gln Cys His Pro Arg Phe 660 665 670 Gln Lys Ala Val Leu Ser Asp Gly Ser Glu Cys Cys Lys Tyr Lys Ile 675 680 685 Asp Asn Pro Glu Glu Lys Ala Leu Ile Val Asp Asn Leu Lys Pro Glu 690 695 700 Ser Phe Tyr Glu Phe Phe Val Thr Pro Phe Thr Ser Ala Gly Glu Gly 705 710 715 720 Pro Asn Ala Thr Phe Thr Lys Val Thr Thr Pro Asp Glu His Ser Ser 725 730 735 Met Leu Ile Arg Ile Leu Leu Pro Met Val Phe Cys Val Leu Leu Ile 740 745 750 Met Ile Val Cys Tyr Leu Lys Ser Gln Trp Ile Lys Glu Thr Cys Tyr 755 760 765 Pro Asp Ile Pro Asp Pro Tyr Lys Ser Ser Ile Leu Ser Leu Ile Lys 770 775 780 Phe Lys Glu Asn Pro His Leu Thr Ile Met Asn Val Ser Asp Cys Ile 785 790 795 800 Pro Asp Ala Ile Glu Val Val Ser Lys Pro Glu Gly Thr Lys Ile Gln 805 810 815 Leu Leu Gly Thr Arg Lys Ser Leu Thr Glu Thr Glu Leu Thr Lys Pro 820 825 830 Asn Tyr Leu Tyr Leu Leu Pro Thr Glu Lys Asn His Ser Gly Pro Gly 835 840 845 Pro Cys Ile Cys Phe Glu Asn Phe Thr Tyr Asn Gln Ala Ala Ser Asp 850 855 860 Ala Gly Ser Cys Gly His Val Pro Val Pro Pro Lys Ala Pro Pro Ser 865 870 875 880 Met Leu Gly Leu Met Thr Ser Pro Glu Asn Val Leu Lys Ala Leu Glu 885 890 895 Lys Asn Tyr Met Asn Ser Leu Gly Glu Val Pro Ala Gly Glu Thr Ser 900 905 910 Leu Asn Tyr Val Ser Gln Leu Ala Ser Pro Met Ser Gly Asp Lys Asp 915 920 925 Ser Leu Pro Thr Asn Pro Val Glu Pro Pro His Cys Ser Glu Tyr Lys 930 935 940 Met Gln Met Ala Val Pro Leu Arg Leu Ala Leu Pro Pro Pro Thr Glu 945 950 955 960 Asn Ser Ser Leu Ser Ser Ile Thr Leu Leu Asp Pro Gly Glu His Tyr 965 970 975 Arg <210> 71 <211> 1665 <212> DNA <213> Macaca fascicularis <400> 71 atgatgtgga cctgggcact gtggatgttc cctttactct gcaaattcgg cctggcagct 60 ctgccagcta agcctgagaa catttcctgt gtctactact ataggaaaaa tttaacctgc 120 acttggagtc caggaaagga aactagttat acccagtaca cagctaagag aacttacgct 180 tttggaaaaa aacatgataa ttgtacaacc agtagttcta caagtgaaaa tcgtgcttcg 240 tgctcttttt tccttccaag aataacgatc ccagataatt ataccattga ggtggaagct 300 gaaaatggag atggtgtaat taaatctgat atgacatgtt ggagattaga ggacatagcg 360 aaaactgaac cacctgagat tttcagtgtg aaaccagttt tgggcatcaa acgaatgatt 420 cggattgaat ggataaagcc tgagttggca cctgtttcat ctgatttaaa atatgcactt 480 cgattcagga cagtcaatag taccagctgg atggaagtca acttcgctaa gaaccgtaaa 540 gatacaaacc aaacctacaa ccttatgggg ctgcaggctt ttacagagta tgtcgtagct 600 ctgcgatgtg cggtcaagga gtcaaagttc tggagtgact ggagccaaga aaaaatggga 660 atgactgagg aagaagctcc atgtggcctg gaactgtgga gagtcctgaa accaactgag 720 gtggatggaa gaaggccagt gcggttgtta tggaagaagg caagaggagc cccagtccta 780 gagaaaacac ttggctacaa catatggtac tttccagaaa acaacactaa cctcacagag 840 acagtgaaca ccactaacca gcagcttgaa ctgcatctgg gaggcgagag ctattgggtg 900 tctatgattt cttataattc tcttgggaag tctccagtga ccaccctgag gattccagcc 960 attcaggaaa agtcatttcg gtgcattgag gtcatgcagg cctgccttgc tgaggaccag 1020 ctagtggtga agtggcaaag ctctgctcta gacgtgaaca cttggatgat tgaatggttt 1080 ccggacatgg actcagagca ccccactctt tcctgggaat ctgtgtctca ggccacgaac 1140 tggacaatcc agcaagataa attaaaacct ttctggtgct ataacatctc tgtgtatcca 1200 atgttgcacg acaaagttgg cgagccatat tccatccagg cttatgccaa agaaggcatt 1260 ccatcaaaag gtcctgagac caaggtggag aacattggcg tgaagacggt cacgatcaca 1320 tggaaagaga ttcccaagag tgagagaaag ggtatcatct gcaactacac catcttttac 1380 caagctgaag gtggaaaagg attctccaag acagtcaact ccagcatctt gcagtatggc 1440 ctggagtccc tgaaacgaaa gacctcttac actgttcggg tcatggccag caccagtgct 1500 gggggaatca acgggaccag cataaatttc aagacattgt cattcagtgt ttttgagatt 1560 atccttataa cttctctgat tggtggaggc cttcttattc tcattatcct gacggtggca 1620 tatggtctca aaaaacccaa caaattgact cacctgtgtt aatga 1665 <210> 72 <211> 553 <212> PRT <213> Macaca fascicularis <400> 72 Met Met Trp Thr Trp Ala Leu Trp Met Phe Pro Leu Leu Cys Lys Phe 1 5 10 15 Gly Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn Ile Ser Cys Val Tyr 20 25 30 Tyr Tyr Arg Lys Asn Leu Thr Cys Thr Trp Ser Pro Gly Lys Glu Thr 35 40 45 Ser Tyr Thr Gln Tyr Thr Ala Lys Arg Thr Tyr Ala Phe Gly Lys Lys 50 55 60 His Asp Asn Cys Thr Thr Ser Ser Ser Thr Ser Glu Asn Arg Ala Ser 65 70 75 80 Cys Ser Phe Phe Leu Pro Arg Ile Thr Ile Pro Asp Asn Tyr Thr Ile 85 90 95 Glu Val Glu Ala Glu Asn Gly Asp Gly Val Ile Lys Ser Asp Met Thr 100 105 110 Cys Trp Arg Leu Glu Asp Ile Ala Lys Thr Glu Pro Pro Glu Ile Phe 115 120 125 Ser Val Lys Pro Val Leu Gly Ile Lys Arg Met Ile Arg Ile Glu Trp 130 135 140 Ile Lys Pro Glu Leu Ala Pro Val Ser Ser Asp Leu Lys Tyr Ala Leu 145 150 155 160 Arg Phe Arg Thr Val Asn Ser Thr Ser Trp Met Glu Val Asn Phe Ala 165 170 175 Lys Asn Arg Lys Asp Thr Asn Gln Thr Tyr Asn Leu Met Gly Leu Gln 180 185 190 Ala Phe Thr Glu Tyr Val Val Ala Leu Arg Cys Ala Val Lys Glu Ser 195 200 205 Lys Phe Trp Ser Asp Trp Ser Gln Glu Lys Met Gly Met Thr Glu Glu 210 215 220 Glu Ala Pro Cys Gly Leu Glu Leu Trp Arg Val Leu Lys Pro Thr Glu 225 230 235 240 Val Asp Gly Arg Arg Pro Val Arg Leu Leu Trp Lys Lys Ala Arg Gly 245 250 255 Ala Pro Val Leu Glu Lys Thr Leu Gly Tyr Asn Ile Trp Tyr Phe Pro 260 265 270 Glu Asn Asn Thr Asn Leu Thr Glu Thr Val Asn Thr Thr Asn Gln Gln 275 280 285 Leu Glu Leu His Leu Gly Gly Glu Ser Tyr Trp Val Ser Met Ile Ser 290 295 300 Tyr Asn Ser Leu Gly Lys Ser Pro Val Thr Thr Leu Arg Ile Pro Ala 305 310 315 320 Ile Gln Glu Lys Ser Phe Arg Cys Ile Glu Val Met Gln Ala Cys Leu 325 330 335 Ala Glu Asp Gln Leu Val Val Lys Trp Gln Ser Ser Ala Leu Asp Val 340 345 350 Asn Thr Trp Met Ile Glu Trp Phe Pro Asp Met Asp Ser Glu His Pro 355 360 365 Thr Leu Ser Trp Glu Ser Val Ser Gln Ala Thr Asn Trp Thr Ile Gln 370 375 380 Gln Asp Lys Leu Lys Pro Phe Trp Cys Tyr Asn Ile Ser Val Tyr Pro 385 390 395 400 Met Leu His Asp Lys Val Gly Glu Pro Tyr Ser Ile Gln Ala Tyr Ala 405 410 415 Lys Glu Gly Ile Pro Ser Lys Gly Pro Glu Thr Lys Val Glu Asn Ile 420 425 430 Gly Val Lys Thr Val Thr Ile Thr Trp Lys Glu Ile Pro Lys Ser Glu 435 440 445 Arg Lys Gly Ile Ile Cys Asn Tyr Thr Ile Phe Tyr Gln Ala Glu Gly 450 455 460 Gly Lys Gly Phe Ser Lys Thr Val Asn Ser Ser Ile Leu Gln Tyr Gly 465 470 475 480 Leu Glu Ser Leu Lys Arg Lys Thr Ser Tyr Thr Val Arg Val Met Ala 485 490 495 Ser Thr Ser Ala Gly Gly Ile Asn Gly Thr Ser Ile Asn Phe Lys Thr 500 505 510 Leu Ser Phe Ser Val Phe Glu Ile Ile Leu Ile Thr Ser Leu Ile Gly 515 520 525 Gly Gly Leu Leu Ile Leu Ile Ile Leu Thr Val Ala Tyr Gly Leu Lys 530 535 540 Lys Pro Asn Lys Leu Thr His Leu Cys 545 550 <210> 73 <211> 1665 <212> DNA <213> Homo sapiens <400> 73 atgatgtgga cctgggcact gtggatgctc ccctcactct gcaaattcag cctggcagct 60 ctgccagcta agcctgagaa catttcctgt gtctactact ataggaaaaa tttaacctgc 120 acttggagtc caggaaagga aaccagttat acccagtaca cagttaagag aacttacgct 180 tttggagaaa aacatgataa ttgtacaacc aatagttcta caagtgaaaa tcgtgcttcg 240 tgctcttttt tccttccaag aataacgatc ccagataatt ataccattga ggtggaagct 300 gaaaatggag atggtgtaat taaatctcat atgacatact ggagattaga gaacatagcg 360 aaaactgaac cacctaagat tttccgtgtg aaaccagttt tgggcatcaa acgaatgatt 420 caaattgaat ggataaagcc tgagttggcg cctgtttcat ctgatttaaa atacacactt 480 cgattcagga cagtcaacag taccagctgg atggaagtca acttcgctaa gaaccgtaag 540 gataaaaacc aaacgtacaa cctcacgggg ctgcagcctt ttacagaata tgtcatagct 600 ctgcgatgtg cggtcaagga gtcaaagttc tggagtgact ggagccaaga aaaaatggga 660 atgactgagg aagaagctcc atgtggcctg gaactgtgga gagtcctgaa accagctgag 720 gcggatggaa gaaggccagt gcggttgtta tggaagaagg caagaggagc cccagtccta 780 gagaaaacac ttggctacaa catatggtac tatccagaaa gcaacactaa cctcacagaa 840 acaatgaaca ctactaacca gcagcttgaa ctgcatctgg gaggcgagag cttttgggtg 900 tctatgattt cttataattc tcttgggaag tctccagtgg ccaccctgag gattccagct 960 attcaagaaa aatcgtttca gtgcattgag gtcatgcagg cctgcgttgc tgaggaccag 1020 ctagtggtga agtggcaaag ctctgctcta gacgtgaaca cttggatgat tgaatggttt 1080 ccggatgtgg actcagagcc caccaccctt tcctgggaat ctgtgtctca ggccacgaac 1140 tggacgatcc agcaagataa attaaaacct ttctggtgct ataacatctc tgtgtatcca 1200 atgttgcatg acaaagttgg cgagccatat tccatccagg cttatgccaa agaaggcgtt 1260 ccatcagaag gtcctgagac caaggtggag aacattggcg tgaagacggt cacgatcaca 1320 tggaaagaga ttcccaagag tgagagaaag ggtatcatct gcaactacac catcttttac 1380 caagctgaag gtggaaaagg attctccaag acagtcaatt ccagcatctt gcagtacggc 1440 ctggagtccc tgaaacgaaa gacctcttac attgttcagg tcatggccag caccagtgct 1500 gggggaacca acgggaccag cataaatttc aagacattgt cattcagtgt ctttgagatt 1560 atcctcataa cttctctgat tggtggaggc cttcttattc tcattatcct gacagtggca 1620 tatggtctca aaaaacccaa caaattgact catctgtgtt aatga 1665 <210> 74 <211> 553 <212> PRT <213> Homo sapiens <400> 74 Met Met Trp Thr Trp Ala Leu Trp Met Leu Pro Ser Leu Cys Lys Phe 1 5 10 15 Ser Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn Ile Ser Cys Val Tyr 20 25 30 Tyr Tyr Arg Lys Asn Leu Thr Cys Thr Trp Ser Pro Gly Lys Glu Thr 35 40 45 Ser Tyr Thr Gln Tyr Thr Val Lys Arg Thr Tyr Ala Phe Gly Glu Lys 50 55 60 His Asp Asn Cys Thr Thr Asn Ser Ser Thr Ser Glu Asn Arg Ala Ser 65 70 75 80 Cys Ser Phe Phe Leu Pro Arg Ile Thr Ile Pro Asp Asn Tyr Thr Ile 85 90 95 Glu Val Glu Ala Glu Asn Gly Asp Gly Val Ile Lys Ser His Met Thr 100 105 110 Tyr Trp Arg Leu Glu Asn Ile Ala Lys Thr Glu Pro Pro Lys Ile Phe 115 120 125 Arg Val Lys Pro Val Leu Gly Ile Lys Arg Met Ile Gln Ile Glu Trp 130 135 140 Ile Lys Pro Glu Leu Ala Pro Val Ser Ser Asp Leu Lys Tyr Thr Leu 145 150 155 160 Arg Phe Arg Thr Val Asn Ser Thr Ser Trp Met Glu Val Asn Phe Ala 165 170 175 Lys Asn Arg Lys Asp Lys Asn Gln Thr Tyr Asn Leu Thr Gly Leu Gln 180 185 190 Pro Phe Thr Glu Tyr Val Ile Ala Leu Arg Cys Ala Val Lys Glu Ser 195 200 205 Lys Phe Trp Ser Asp Trp Ser Gln Glu Lys Met Gly Met Thr Glu Glu 210 215 220 Glu Ala Pro Cys Gly Leu Glu Leu Trp Arg Val Leu Lys Pro Ala Glu 225 230 235 240 Ala Asp Gly Arg Arg Pro Val Arg Leu Leu Trp Lys Lys Ala Arg Gly 245 250 255 Ala Pro Val Leu Glu Lys Thr Leu Gly Tyr Asn Ile Trp Tyr Tyr Pro 260 265 270 Glu Ser Asn Thr Asn Leu Thr Glu Thr Met Asn Thr Thr Asn Gln Gln 275 280 285 Leu Glu Leu His Leu Gly Gly Glu Ser Phe Trp Val Ser Met Ile Ser 290 295 300 Tyr Asn Ser Leu Gly Lys Ser Pro Val Ala Thr Leu Arg Ile Pro Ala 305 310 315 320 Ile Gln Glu Lys Ser Phe Gln Cys Ile Glu Val Met Gln Ala Cys Val 325 330 335 Ala Glu Asp Gln Leu Val Val Lys Trp Gln Ser Ser Ala Leu Asp Val 340 345 350 Asn Thr Trp Met Ile Glu Trp Phe Pro Asp Val Asp Ser Glu Pro Thr 355 360 365 Thr Leu Ser Trp Glu Ser Val Ser Gln Ala Thr Asn Trp Thr Ile Gln 370 375 380 Gln Asp Lys Leu Lys Pro Phe Trp Cys Tyr Asn Ile Ser Val Tyr Pro 385 390 395 400 Met Leu His Asp Lys Val Gly Glu Pro Tyr Ser Ile Gln Ala Tyr Ala 405 410 415 Lys Glu Gly Val Pro Ser Glu Gly Pro Glu Thr Lys Val Glu Asn Ile 420 425 430 Gly Val Lys Thr Val Thr Ile Thr Trp Lys Glu Ile Pro Lys Ser Glu 435 440 445 Arg Lys Gly Ile Ile Cys Asn Tyr Thr Ile Phe Tyr Gln Ala Glu Gly 450 455 460 Gly Lys Gly Phe Ser Lys Thr Val Asn Ser Ser Ile Leu Gln Tyr Gly 465 470 475 480 Leu Glu Ser Leu Lys Arg Lys Thr Ser Tyr Ile Val Gln Val Met Ala 485 490 495 Ser Thr Ser Ala Gly Gly Thr Asn Gly Thr Ser Ile Asn Phe Lys Thr 500 505 510 Leu Ser Phe Ser Val Phe Glu Ile Ile Leu Ile Thr Ser Leu Ile Gly 515 520 525 Gly Gly Leu Leu Ile Leu Ile Ile Leu Thr Val Ala Tyr Gly Leu Lys 530 535 540 Lys Pro Asn Lys Leu Thr His Leu Cys 545 550 <210> 75 <211> 2199 <212> DNA <213> Homo sapiens <400> 75 atgatgtgga cctgggcact gtggatgctc ccctcactct gcaaattcag cctggcagct 60 ctgccagcta agcctgagaa catttcctgt gtctactact ataggaaaaa tttaacctgc 120 acttggagtc caggaaagga aaccagttat acccagtaca cagttaagag aacttacgct 180 tttggagaaa aacatgataa ttgtacaacc aatagttcta caagtgaaaa tcgtgcttcg 240 tgctcttttt tccttccaag aataacgatc ccagataatt ataccattga ggtggaagct 300 gaaaatggag atggtgtaat taaatctcat atgacatact ggagattaga gaacatagcg 360 aaaactgaac cacctaagat tttccgtgtg aaaccagttt tgggcatcaa acgaatgatt 420 caaattgaat ggataaagcc tgagttggcg cctgtttcat ctgatttaaa atacacactt 480 cgattcagga cagtcaacag taccagctgg atggaagtca acttcgctaa gaaccgtaag 540 gataaaaacc aaacgtacaa cctcacgggg ctgcagcctt ttacagaata tgtcatagct 600 ctgcgatgtg cggtcaagga gtcaaagttc tggagtgact ggagccaaga aaaaatggga 660 atgactgagg aagaagctcc atgtggcctg gaactgtgga gagtcctgaa accagctgag 720 gcggatggaa gaaggccagt gcggttgtta tggaagaagg caagaggagc cccagtccta 780 gagaaaacac ttggctacaa catatggtac tatccagaaa gcaacactaa cctcacagaa 840 acaatgaaca ctactaacca gcagcttgaa ctgcatctgg gaggcgagag cttttgggtg 900 tctatgattt cttataattc tcttgggaag tctccagtgg ccaccctgag gattccagct 960 attcaagaaa aatcgtttca gtgcattgag gtcatgcagg cctgcgttgc tgaggaccag 1020 ctagtggtga agtggcaaag ctctgctcta gacgtgaaca cttggatgat tgaatggttt 1080 ccggatgtgg actcagagcc caccaccctt tcctgggaat ctgtgtctca ggccacgaac 1140 tggacgatcc agcaagataa attaaaacct ttctggtgct ataacatctc tgtgtatcca 1200 atgttgcatg acaaagttgg cgagccatat tccatccagg cttatgccaa agaaggcgtt 1260 ccatcagaag gtcctgagac caaggtggag aacattggcg tgaagacggt cacgatcaca 1320 tggaaagaga ttcccaagag tgagagaaag ggtatcatct gcaactacac catcttttac 1380 caagctgaag gtggaaaagg attctccaag acagtcaatt ccagcatctt gcagtacggc 1440 ctggagtccc tgaaacgaaa gacctcttac attgttcagg tcatggccag caccagtgct 1500 gggggaacca acgggaccag cataaatttc aagacattgt cattcagtgt ctttgagatt 1560 atcctcataa cttctctgat tggtggaggc cttcttattc tcattatcct gacagtggca 1620 tatggtctca aaaaacccaa caaattgact catctgtgtt ggcccaccgt tcccaaccct 1680 gctgaaagta gtatagccac atggcatgga gatgatttca aggataagct aaacctgaag 1740 gagtctgatg actctgtgaa cacagaagac aggatcttaa aaccatgttc cacccccagt 1800 gacaagttgg tgattgacaa gttggtggtg aactttggga atgttctgca agaaattttc 1860 acagatgaag ccagaacggg tcaggaaaac aatttaggag gggaaaagaa tgggtatgtg 1920 acctgcccct tcaggcctga ttgtcccctg gggaaaagtt ttgaggagct cccagtttca 1980 cctgagattc cgcccagaaa atcccaatac ctacgttcga ggatgccaga ggggacccgc 2040 ccagaagcca aagagcagct tctcttttct ggtcaaagtt tagtaccaga tcatctgtgt 2100 gaggaaggag ccccaaatcc atatttgaaa aattcagtga cagccaggga atttcttgtg 2160 tctgaaaaac ttccagagca caccaaggga gaagtctaa 2199 <210> 76 <211> 732 <212> PRT <213> Homo sapiens <400> 76 Met Met Trp Thr Trp Ala Leu Trp Met Leu Pro Ser Leu Cys Lys Phe 1 5 10 15 Ser Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn Ile Ser Cys Val Tyr 20 25 30 Tyr Tyr Arg Lys Asn Leu Thr Cys Thr Trp Ser Pro Gly Lys Glu Thr 35 40 45 Ser Tyr Thr Gln Tyr Thr Val Lys Arg Thr Tyr Ala Phe Gly Glu Lys 50 55 60 His Asp Asn Cys Thr Thr Asn Ser Ser Thr Ser Glu Asn Arg Ala Ser 65 70 75 80 Cys Ser Phe Phe Leu Pro Arg Ile Thr Ile Pro Asp Asn Tyr Thr Ile 85 90 95 Glu Val Glu Ala Glu Asn Gly Asp Gly Val Ile Lys Ser His Met Thr 100 105 110 Tyr Trp Arg Leu Glu Asn Ile Ala Lys Thr Glu Pro Pro Lys Ile Phe 115 120 125 Arg Val Lys Pro Val Leu Gly Ile Lys Arg Met Ile Gln Ile Glu Trp 130 135 140 Ile Lys Pro Glu Leu Ala Pro Val Ser Ser Asp Leu Lys Tyr Thr Leu 145 150 155 160 Arg Phe Arg Thr Val Asn Ser Thr Ser Trp Met Glu Val Asn Phe Ala 165 170 175 Lys Asn Arg Lys Asp Lys Asn Gln Thr Tyr Asn Leu Thr Gly Leu Gln 180 185 190 Pro Phe Thr Glu Tyr Val Ile Ala Leu Arg Cys Ala Val Lys Glu Ser 195 200 205 Lys Phe Trp Ser Asp Trp Ser Gln Glu Lys Met Gly Met Thr Glu Glu 210 215 220 Glu Ala Pro Cys Gly Leu Glu Leu Trp Arg Val Leu Lys Pro Ala Glu 225 230 235 240 Ala Asp Gly Arg Arg Pro Val Arg Leu Leu Trp Lys Lys Ala Arg Gly 245 250 255 Ala Pro Val Leu Glu Lys Thr Leu Gly Tyr Asn Ile Trp Tyr Tyr Pro 260 265 270 Glu Ser Asn Thr Asn Leu Thr Glu Thr Met Asn Thr Thr Asn Gln Gln 275 280 285 Leu Glu Leu His Leu Gly Gly Glu Ser Phe Trp Val Ser Met Ile Ser 290 295 300 Tyr Asn Ser Leu Gly Lys Ser Pro Val Ala Thr Leu Arg Ile Pro Ala 305 310 315 320 Ile Gln Glu Lys Ser Phe Gln Cys Ile Glu Val Met Gln Ala Cys Val 325 330 335 Ala Glu Asp Gln Leu Val Val Lys Trp Gln Ser Ser Ala Leu Asp Val 340 345 350 Asn Thr Trp Met Ile Glu Trp Phe Pro Asp Val Asp Ser Glu Pro Thr 355 360 365 Thr Leu Ser Trp Glu Ser Val Ser Gln Ala Thr Asn Trp Thr Ile Gln 370 375 380 Gln Asp Lys Leu Lys Pro Phe Trp Cys Tyr Asn Ile Ser Val Tyr Pro 385 390 395 400 Met Leu His Asp Lys Val Gly Glu Pro Tyr Ser Ile Gln Ala Tyr Ala 405 410 415 Lys Glu Gly Val Pro Ser Glu Gly Pro Glu Thr Lys Val Glu Asn Ile 420 425 430 Gly Val Lys Thr Val Thr Ile Thr Trp Lys Glu Ile Pro Lys Ser Glu 435 440 445 Arg Lys Gly Ile Ile Cys Asn Tyr Thr Ile Phe Tyr Gln Ala Glu Gly 450 455 460 Gly Lys Gly Phe Ser Lys Thr Val Asn Ser Ser Ile Leu Gln Tyr Gly 465 470 475 480 Leu Glu Ser Leu Lys Arg Lys Thr Ser Tyr Ile Val Gln Val Met Ala 485 490 495 Ser Thr Ser Ala Gly Gly Thr Asn Gly Thr Ser Ile Asn Phe Lys Thr 500 505 510 Leu Ser Phe Ser Val Phe Glu Ile Ile Leu Ile Thr Ser Leu Ile Gly 515 520 525 Gly Gly Leu Leu Ile Leu Ile Ile Leu Thr Val Ala Tyr Gly Leu Lys 530 535 540 Lys Pro Asn Lys Leu Thr His Leu Cys Trp Pro Thr Val Pro Asn Pro 545 550 555 560 Ala Glu Ser Ser Ile Ala Thr Trp His Gly Asp Asp Phe Lys Asp Lys 565 570 575 Leu Asn Leu Lys Glu Ser Asp Asp Ser Val Asn Thr Glu Asp Arg Ile 580 585 590 Leu Lys Pro Cys Ser Thr Pro Ser Asp Lys Leu Val Ile Asp Lys Leu 595 600 605 Val Val Asn Phe Gly Asn Val Leu Gln Glu Ile Phe Thr Asp Glu Ala 610 615 620 Arg Thr Gly Gln Glu Asn Asn Leu Gly Gly Glu Lys Asn Gly Tyr Val 625 630 635 640 Thr Cys Pro Phe Arg Pro Asp Cys Pro Leu Gly Lys Ser Phe Glu Glu 645 650 655 Leu Pro Val Ser Pro Glu Ile Pro Pro Arg Lys Ser Gln Tyr Leu Arg 660 665 670 Ser Arg Met Pro Glu Gly Thr Arg Pro Glu Ala Lys Glu Gln Leu Leu 675 680 685 Phe Ser Gly Gln Ser Leu Val Pro Asp His Leu Cys Glu Glu Gly Ala 690 695 700 Pro Asn Pro Tyr Leu Lys Asn Ser Val Thr Ala Arg Glu Phe Leu Val 705 710 715 720 Ser Glu Lys Leu Pro Glu His Thr Lys Gly Glu Val 725 730 <210> 77 <211> 1542 <212> DNA <213> Homo sapiens <400> 77 atgatgtgga cctgggcact gtggatgctc ccttcactct gcaaattcag cctggcagct 60 ctgccagcta agcctgagaa catttcctgt gtctactact ataggaaaaa tttaacctgc 120 acttggagtc caggaaagga aaccagttat acccagtaca cagttaagag aacttacgct 180 tttggagaaa aacatgataa ttgtacaacc aatagttcta caagtgaaaa tcgtgcttcg 240 tgctcttttt tccttccaag aataacgatc ccagataatt ataccattga ggtggaagct 300 gaaaatggag atggtgtaat taaatctcat atgacatact ggagattaga gaacatagcg 360 aaaactgaac cacctaagat tttccgtgtg aaaccagttt tgggcatcaa acgaatgatt 420 caaattgaat ggataaagcc tgagttggcg cctgtttcat ctgatttaaa atacacactt 480 cgattcagga cagtcaacag taccagctgg atggaagtca acttcgctaa gaaccgtaag 540 gataaaaacc aaacgtacaa cctcacgggg ctgcagcctt ttacagaata tgtcatagct 600 ctgcgatgtg cggtcaagga gtcaaagttc tggagtgact ggagccaaga aaaaatggga 660 atgactgagg aagaagctcc atgtggcctg gaactgtgga gagtcctgaa accagctgag 720 gcggatggaa gaaggccagt gcggttgtta tggaagaagg caagaggagc cccagtccta 780 gagaaaacac ttggctacaa catatggtac tatccagaaa gcaacactaa cctcacagaa 840 acaatgaaca ctactaacca gcagcttgaa ctgcatctgg gaggcgagag cttttgggtg 900 tctatgattt cttataattc tcttgggaag tctccagtgg ccaccctgag gattccagct 960 attcaagaaa aatcgtttca gtgcattgag gtcatgcagg cctgcgttgc tgaggaccag 1020 ctagtggtga agtggcaaag ctctgctcta gacgtgaaca cttggatgat tgaatggttt 1080 ccggatgtgg actcagagcc caccaccctt tcctgggaat ctgtgtctca ggccacgaac 1140 tggacgatcc agcaagataa attaaaacct ttctggtgct ataacatctc tgtgtatcca 1200 atgttgcatg acaaagttgg cgagccatat tccatccagg cttatgccaa agaaggcgtt 1260 ccatcagaag gtcctgagac caaggtggag aacattggcg tgaagacggt cacgatcaca 1320 tggaaagaga ttcccaagag tgagagaaag ggtatcatct gcaactacac catcttttac 1380 caagctgaag gtggaaaagg attctccaag acagtcaatt ccagcatctt gcagtacggc 1440 ctggagtccc tgaaacgaaa gacctcttac attgttcagg tcatggccag caccagtgct 1500 gggggaacca acgggaccag cataaatttc aagacattgt ca 1542 <210> 78 <211> 514 <212> PRT <213> Homo sapiens <400> 78 Met Met Trp Thr Trp Ala Leu Trp Met Leu Pro Ser Leu Cys Lys Phe 1 5 10 15 Ser Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn Ile Ser Cys Val Tyr 20 25 30 Tyr Tyr Arg Lys Asn Leu Thr Cys Thr Trp Ser Pro Gly Lys Glu Thr 35 40 45 Ser Tyr Thr Gln Tyr Thr Val Lys Arg Thr Tyr Ala Phe Gly Glu Lys 50 55 60 His Asp Asn Cys Thr Thr Asn Ser Ser Thr Ser Glu Asn Arg Ala Ser 65 70 75 80 Cys Ser Phe Phe Leu Pro Arg Ile Thr Ile Pro Asp Asn Tyr Thr Ile 85 90 95 Glu Val Glu Ala Glu Asn Gly Asp Gly Val Ile Lys Ser His Met Thr 100 105 110 Tyr Trp Arg Leu Glu Asn Ile Ala Lys Thr Glu Pro Pro Lys Ile Phe 115 120 125 Arg Val Lys Pro Val Leu Gly Ile Lys Arg Met Ile Gln Ile Glu Trp 130 135 140 Ile Lys Pro Glu Leu Ala Pro Val Ser Ser Asp Leu Lys Tyr Thr Leu 145 150 155 160 Arg Phe Arg Thr Val Asn Ser Thr Ser Trp Met Glu Val Asn Phe Ala 165 170 175 Lys Asn Arg Lys Asp Lys Asn Gln Thr Tyr Asn Leu Thr Gly Leu Gln 180 185 190 Pro Phe Thr Glu Tyr Val Ile Ala Leu Arg Cys Ala Val Lys Glu Ser 195 200 205 Lys Phe Trp Ser Asp Trp Ser Gln Glu Lys Met Gly Met Thr Glu Glu 210 215 220 Glu Ala Pro Cys Gly Leu Glu Leu Trp Arg Val Leu Lys Pro Ala Glu 225 230 235 240 Ala Asp Gly Arg Arg Pro Val Arg Leu Leu Trp Lys Lys Ala Arg Gly 245 250 255 Ala Pro Val Leu Glu Lys Thr Leu Gly Tyr Asn Ile Trp Tyr Tyr Pro 260 265 270 Glu Ser Asn Thr Asn Leu Thr Glu Thr Met Asn Thr Thr Asn Gln Gln 275 280 285 Leu Glu Leu His Leu Gly Gly Glu Ser Phe Trp Val Ser Met Ile Ser 290 295 300 Tyr Asn Ser Leu Gly Lys Ser Pro Val Ala Thr Leu Arg Ile Pro Ala 305 310 315 320 Ile Gln Glu Lys Ser Phe Gln Cys Ile Glu Val Met Gln Ala Cys Val 325 330 335 Ala Glu Asp Gln Leu Val Val Lys Trp Gln Ser Ser Ala Leu Asp Val 340 345 350 Asn Thr Trp Met Ile Glu Trp Phe Pro Asp Val Asp Ser Glu Pro Thr 355 360 365 Thr Leu Ser Trp Glu Ser Val Ser Gln Ala Thr Asn Trp Thr Ile Gln 370 375 380 Gln Asp Lys Leu Lys Pro Phe Trp Cys Tyr Asn Ile Ser Val Tyr Pro 385 390 395 400 Met Leu His Asp Lys Val Gly Glu Pro Tyr Ser Ile Gln Ala Tyr Ala 405 410 415 Lys Glu Gly Val Pro Ser Glu Gly Pro Glu Thr Lys Val Glu Asn Ile 420 425 430 Gly Val Lys Thr Val Thr Ile Thr Trp Lys Glu Ile Pro Lys Ser Glu 435 440 445 Arg Lys Gly Ile Ile Cys Asn Tyr Thr Ile Phe Tyr Gln Ala Glu Gly 450 455 460 Gly Lys Gly Phe Ser Lys Thr Val Asn Ser Ser Ile Leu Gln Tyr Gly 465 470 475 480 Leu Glu Ser Leu Lys Arg Lys Thr Ser Tyr Ile Val Gln Val Met Ala 485 490 495 Ser Thr Ser Ala Gly Gly Thr Asn Gly Thr Ser Ile Asn Phe Lys Thr 500 505 510 Leu Ser <210> 79 <211> 662 <212> PRT <213> Homo sapiens <400> 79 Met Lys Leu Ser Pro Gln Pro Ser Cys Val Asn Leu Gly Met Met Trp 1 5 10 15 Thr Trp Ala Leu Trp Met Leu Pro Ser Leu Cys Lys Phe Ser Leu Ala 20 25 30 Ala Leu Pro Ala Lys Pro Glu Asn Ile Ser Cys Val Tyr Tyr Tyr Arg 35 40 45 Lys Asn Leu Thr Cys Thr Trp Ser Pro Gly Lys Glu Thr Ser Tyr Thr 50 55 60 Gln Tyr Thr Val Lys Arg Thr Tyr Ala Phe Gly Glu Lys His Asp Asn 65 70 75 80 Cys Thr Thr Asn Ser Ser Thr Ser Glu Asn Arg Ala Ser Cys Ser Phe 85 90 95 Phe Leu Pro Arg Ile Thr Ile Pro Asp Asn Tyr Thr Ile Glu Val Glu 100 105 110 Ala Glu Asn Gly Asp Gly Val Ile Lys Ser His Met Thr Tyr Trp Arg 115 120 125 Leu Glu Asn Ile Ala Lys Thr Glu Pro Pro Lys Ile Phe Arg Val Lys 130 135 140 Pro Val Leu Gly Ile Lys Arg Met Ile Gln Ile Glu Trp Ile Lys Pro 145 150 155 160 Glu Leu Ala Pro Val Ser Ser Asp Leu Lys Tyr Thr Leu Arg Phe Arg 165 170 175 Thr Val Asn Ser Thr Ser Trp Met Glu Val Asn Phe Ala Lys Asn Arg 180 185 190 Lys Asp Lys Asn Gln Thr Tyr Asn Leu Thr Gly Leu Gln Pro Phe Thr 195 200 205 Glu Tyr Val Ile Ala Leu Arg Cys Ala Val Lys Glu Ser Lys Phe Trp 210 215 220 Ser Asp Trp Ser Gln Glu Lys Met Gly Met Thr Glu Glu Glu Ala Pro 225 230 235 240 Cys Gly Leu Glu Leu Trp Arg Val Leu Lys Pro Ala Glu Ala Asp Gly 245 250 255 Arg Arg Pro Val Arg Leu Leu Trp Lys Lys Ala Arg Gly Ala Pro Val 260 265 270 Leu Glu Lys Thr Leu Gly Tyr Asn Ile Trp Tyr Tyr Pro Glu Ser Asn 275 280 285 Thr Asn Leu Thr Glu Thr Met Asn Thr Thr Asn Gln Gln Leu Glu Leu 290 295 300 His Leu Gly Gly Glu Ser Phe Trp Val Ser Met Ile Ser Tyr Asn Ser 305 310 315 320 Leu Gly Lys Ser Pro Val Ala Thr Leu Arg Ile Pro Ala Ile Gln Glu 325 330 335 Lys Ser Phe Gln Cys Ile Glu Val Met Gln Ala Cys Val Ala Glu Asp 340 345 350 Gln Leu Val Val Lys Trp Gln Ser Ser Ala Leu Asp Val Asn Thr Trp 355 360 365 Met Ile Glu Trp Phe Pro Asp Val Asp Ser Glu Pro Thr Thr Leu Ser 370 375 380 Trp Glu Ser Val Ser Gln Ala Thr Asn Trp Thr Ile Gln Gln Asp Lys 385 390 395 400 Leu Lys Pro Phe Trp Cys Tyr Asn Ile Ser Val Tyr Pro Met Leu His 405 410 415 Asp Lys Val Gly Glu Pro Tyr Ser Ile Gln Ala Tyr Ala Lys Glu Gly 420 425 430 Val Pro Ser Glu Gly Pro Glu Thr Lys Val Glu Asn Ile Gly Val Lys 435 440 445 Thr Val Thr Ile Thr Trp Lys Glu Ile Pro Lys Ser Glu Arg Lys Gly 450 455 460 Ile Ile Cys Asn Tyr Thr Ile Phe Tyr Gln Ala Glu Gly Gly Lys Gly 465 470 475 480 Phe Ser Lys Thr Val Asn Ser Ser Ile Leu Gln Tyr Gly Leu Glu Ser 485 490 495 Leu Lys Arg Lys Thr Ser Tyr Ile Val Gln Val Met Ala Ser Thr Ser 500 505 510 Ala Gly Gly Thr Asn Gly Thr Ser Ile Asn Phe Lys Thr Leu Ser Phe 515 520 525 Ser Val Phe Glu Ile Ile Leu Ile Thr Ser Leu Ile Gly Gly Gly Leu 530 535 540 Leu Ile Leu Ile Ile Leu Thr Val Ala Tyr Gly Leu Lys Lys Pro Asn 545 550 555 560 Lys Leu Thr His Leu Cys Trp Pro Thr Val Pro Asn Pro Ala Glu Ser 565 570 575 Ser Ile Ala Thr Trp His Gly Asp Asp Phe Lys Asp Lys Leu Asn Leu 580 585 590 Lys Glu Ser Asp Asp Ser Val Asn Thr Glu Asp Arg Ile Leu Lys Pro 595 600 605 Cys Ser Thr Pro Ser Asp Lys Leu Val Ile Asp Lys Leu Val Val Asn 610 615 620 Phe Gly Asn Val Leu Gln Glu Ile Phe Thr Asp Glu Ala Arg Thr Gly 625 630 635 640 Gln Glu Asn Asn Leu Gly Gly Glu Lys Asn Gly Thr Arg Ile Leu Ser 645 650 655 Ser Cys Pro Thr Ser Ile 660 <210> 80 <211> 732 <212> PRT <213> Homo sapiens <220> <221> SIGNAL <222> (1)..(20) <220> <221> TRANSMEM <222> (520)..(543) <400> 80 Met Met Trp Thr Trp Ala Leu Trp Met Leu Pro Ser Leu Cys Lys Phe 1 5 10 15 Ser Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn Ile Ser Cys Val Tyr 20 25 30 Tyr Tyr Arg Lys Asn Leu Thr Cys Thr Trp Ser Pro Gly Lys Glu Thr 35 40 45 Ser Tyr Thr Gln Tyr Thr Val Lys Arg Thr Tyr Ala Phe Gly Glu Lys 50 55 60 His Asp Asn Cys Thr Thr Asn Ser Ser Thr Ser Glu Asn Arg Ala Ser 65 70 75 80 Cys Ser Phe Phe Leu Pro Arg Ile Thr Ile Pro Asp Asn Tyr Thr Ile 85 90 95 Glu Val Glu Ala Glu Asn Gly Asp Gly Val Ile Lys Ser His Met Thr 100 105 110 Tyr Trp Arg Leu Glu Asn Ile Ala Lys Thr Glu Pro Pro Lys Ile Phe 115 120 125 Arg Val Lys Pro Val Leu Gly Ile Lys Arg Met Ile Gln Ile Glu Trp 130 135 140 Ile Lys Pro Glu Leu Ala Pro Val Ser Ser Asp Leu Lys Tyr Thr Leu 145 150 155 160 Arg Phe Arg Thr Val Asn Ser Thr Ser Trp Met Glu Val Asn Phe Ala 165 170 175 Lys Asn Arg Lys Asp Lys Asn Gln Thr Tyr Asn Leu Thr Gly Leu Gln 180 185 190 Pro Phe Thr Glu Tyr Val Ile Ala Leu Arg Cys Ala Val Lys Glu Ser 195 200 205 Lys Phe Trp Ser Asp Trp Ser Gln Glu Lys Met Gly Met Thr Glu Glu 210 215 220 Glu Ala Pro Cys Gly Leu Glu Leu Trp Arg Val Leu Lys Pro Ala Glu 225 230 235 240 Ala Asp Gly Arg Arg Pro Val Arg Leu Leu Trp Lys Lys Ala Arg Gly 245 250 255 Ala Pro Val Leu Glu Lys Thr Leu Gly Tyr Asn Ile Trp Tyr Tyr Pro 260 265 270 Glu Ser Asn Thr Asn Leu Thr Glu Thr Met Asn Thr Thr Asn Gln Gln 275 280 285 Leu Glu Leu His Leu Gly Gly Glu Ser Phe Trp Val Ser Met Ile Ser 290 295 300 Tyr Asn Ser Leu Gly Lys Ser Pro Val Ala Thr Leu Arg Ile Pro Ala 305 310 315 320 Ile Gln Glu Lys Ser Phe Gln Cys Ile Glu Val Met Gln Ala Cys Val 325 330 335 Ala Glu Asp Gln Leu Val Val Lys Trp Gln Ser Ser Ala Leu Asp Val 340 345 350 Asn Thr Trp Met Ile Glu Trp Phe Pro Asp Val Asp Ser Glu Pro Thr 355 360 365 Thr Leu Ser Trp Glu Ser Val Ser Gln Ala Thr Asn Trp Thr Ile Gln 370 375 380 Gln Asp Lys Leu Lys Pro Phe Trp Cys Tyr Asn Ile Ser Val Tyr Pro 385 390 395 400 Met Leu His Asp Lys Val Gly Glu Pro Tyr Ser Ile Gln Ala Tyr Ala 405 410 415 Lys Glu Gly Val Pro Ser Glu Gly Pro Glu Thr Lys Val Glu Asn Ile 420 425 430 Gly Val Lys Thr Val Thr Ile Thr Trp Lys Glu Ile Pro Lys Ser Glu 435 440 445 Arg Lys Gly Ile Ile Cys Asn Tyr Thr Ile Phe Tyr Gln Ala Glu Gly 450 455 460 Gly Lys Gly Phe Ser Lys Thr Val Asn Ser Ser Ile Leu Gln Tyr Gly 465 470 475 480 Leu Glu Ser Leu Lys Arg Lys Thr Ser Tyr Ile Val Gln Val Met Ala 485 490 495 Ser Thr Ser Ala Gly Gly Thr Asn Gly Thr Ser Ile Asn Phe Lys Thr 500 505 510 Leu Ser Phe Ser Val Phe Glu Ile Ile Leu Ile Thr Ser Leu Ile Gly 515 520 525 Gly Gly Leu Leu Ile Leu Ile Ile Leu Thr Val Ala Tyr Gly Leu Lys 530 535 540 Lys Pro Asn Lys Leu Thr His Leu Cys Trp Pro Thr Val Pro Asn Pro 545 550 555 560 Ala Glu Ser Ser Ile Ala Thr Trp His Gly Asp Asp Phe Lys Asp Lys 565 570 575 Leu Asn Leu Lys Glu Ser Asp Asp Ser Val Asn Thr Glu Asp Arg Ile 580 585 590 Leu Lys Pro Cys Ser Thr Pro Ser Asp Lys Leu Val Ile Asp Lys Leu 595 600 605 Val Val Asn Phe Gly Asn Val Leu Gln Glu Ile Phe Thr Asp Glu Ala 610 615 620 Arg Thr Gly Gln Glu Asn Asn Leu Gly Gly Glu Lys Asn Gly Tyr Val 625 630 635 640 Thr Cys Pro Phe Arg Pro Asp Cys Pro Leu Gly Lys Ser Phe Glu Glu 645 650 655 Leu Pro Val Ser Pro Glu Ile Pro Pro Arg Lys Ser Gln Tyr Leu Arg 660 665 670 Ser Arg Met Pro Glu Gly Thr Arg Pro Glu Ala Lys Glu Gln Leu Leu 675 680 685 Phe Ser Gly Gln Ser Leu Val Pro Asp His Leu Cys Glu Glu Gly Ala 690 695 700 Pro Asn Pro Tyr Leu Lys Asn Ser Val Thr Ala Arg Glu Phe Leu Val 705 710 715 720 Ser Glu Lys Leu Pro Glu His Thr Lys Gly Glu Val 725 730 <210> 81 <211> 716 <212> PRT <213> Mus musculus <400> 81 Met Trp Thr Leu Ala Leu Trp Ala Phe Ser Phe Leu Cys Lys Phe Ser 1 5 10 15 Leu Ala Val Leu Pro Thr Lys Pro Glu Asn Ile Ser Cys Val Phe Tyr 20 25 30 Phe Asp Arg Asn Leu Thr Cys Thr Trp Arg Pro Glu Lys Glu Thr Asn 35 40 45 Asp Thr Ser Tyr Ile Val Thr Leu Thr Tyr Ser Tyr Gly Lys Ser Asn 50 55 60 Tyr Ser Asp Asn Ala Thr Glu Ala Ser Tyr Ser Phe Pro Arg Ser Cys 65 70 75 80 Ala Met Pro Pro Asp Ile Cys Ser Val Glu Val Gln Ala Gln Asn Gly 85 90 95 Asp Gly Lys Val Lys Ser Asp Ile Thr Tyr Trp His Leu Ile Ser Ile 100 105 110 Ala Lys Thr Glu Pro Pro Ile Ile Leu Ser Val Asn Pro Ile Cys Asn 115 120 125 Arg Met Phe Gln Ile Gln Trp Lys Pro Arg Glu Lys Thr Arg Gly Phe 130 135 140 Pro Leu Val Cys Met Leu Arg Phe Arg Thr Val Asn Ser Ser Arg Trp 145 150 155 160 Thr Glu Val Asn Phe Glu Asn Cys Lys Gln Val Cys Asn Leu Thr Gly 165 170 175 Leu Gln Ala Phe Thr Glu Tyr Val Leu Ala Leu Arg Phe Arg Phe Asn 180 185 190 Asp Ser Arg Tyr Trp Ser Lys Trp Ser Lys Glu Glu Thr Arg Val Thr 195 200 205 Met Glu Glu Val Pro His Val Leu Asp Leu Trp Arg Ile Leu Glu Pro 210 215 220 Ala Asp Met Asn Gly Asp Arg Lys Val Arg Leu Leu Trp Lys Lys Ala 225 230 235 240 Arg Gly Ala Pro Val Leu Glu Lys Thr Phe Gly Tyr His Ile Gln Tyr 245 250 255 Phe Ala Glu Asn Ser Thr Asn Leu Thr Glu Ile Asn Asn Ile Thr Thr 260 265 270 Gln Gln Tyr Glu Leu Leu Leu Met Ser Gln Ala His Ser Val Ser Val 275 280 285 Thr Ser Phe Asn Ser Leu Gly Lys Ser Gln Glu Ala Ile Leu Arg Ile 290 295 300 Pro Asp Val His Glu Lys Thr Phe Gln Tyr Ile Lys Ser Met Lys Ala 305 310 315 320 Tyr Ile Ala Glu Pro Leu Leu Val Val Asn Trp Gln Ser Ser Ile Pro 325 330 335 Ala Val Asp Thr Trp Ile Val Glu Trp Leu Pro Glu Ala Ala Met Ser 340 345 350 Lys Phe Pro Ala Leu Ser Trp Glu Ser Val Ser Gln Val Thr Asn Trp 355 360 365 Thr Ile Glu Gln Asp Lys Leu Lys Pro Phe Thr Cys Tyr Asn Ile Ser 370 375 380 Val Tyr Pro Val Leu Gly His Arg Val Gly Glu Pro Tyr Ser Ile Gln 385 390 395 400 Ala Tyr Ala Lys Glu Gly Thr Pro Leu Lys Gly Pro Glu Thr Arg Val 405 410 415 Glu Asn Ile Gly Leu Arg Thr Ala Thr Ile Thr Trp Lys Glu Ile Pro 420 425 430 Lys Ser Ala Arg Asn Gly Phe Ile Asn Asn Tyr Thr Val Phe Tyr Gln 435 440 445 Ala Glu Gly Gly Lys Glu Leu Ser Lys Thr Val Asn Ser His Ala Leu 450 455 460 Gln Cys Asp Leu Glu Ser Leu Thr Arg Arg Thr Ser Tyr Thr Val Trp 465 470 475 480 Val Met Ala Ser Thr Arg Ala Gly Gly Thr Asn Gly Val Arg Ile Asn 485 490 495 Phe Lys Thr Leu Ser Ile Ser Val Phe Glu Ile Val Leu Leu Thr Ser 500 505 510 Leu Val Gly Gly Gly Leu Leu Leu Leu Ser Ile Lys Thr Val Thr Phe 515 520 525 Gly Leu Arg Lys Pro Asn Arg Leu Thr Pro Leu Cys Cys Pro Asp Val 530 535 540 Pro Asn Pro Ala Glu Ser Ser Leu Ala Thr Trp Leu Gly Asp Gly Phe 545 550 555 560 Lys Lys Ser Asn Met Lys Glu Thr Gly Asn Ser Gly Asp Thr Glu Asp 565 570 575 Val Val Leu Lys Pro Cys Pro Val Pro Ala Asp Leu Ile Asp Lys Leu 580 585 590 Val Val Asn Phe Glu Asn Phe Leu Glu Val Val Leu Thr Glu Glu Ala 595 600 605 Gly Lys Gly Gln Ala Ser Ile Leu Gly Gly Glu Ala Asn Glu Tyr Val 610 615 620 Thr Ser Pro Ser Arg Pro Asp Gly Pro Pro Gly Lys Ser Phe Lys Glu 625 630 635 640 Pro Ser Val Leu Thr Glu Val Ala Ser Glu Asp Ser His Ser Thr Cys 645 650 655 Ser Arg Met Ala Asp Glu Ala Tyr Ser Glu Leu Ala Arg Gln Pro Ser 660 665 670 Ser Ser Cys Gln Ser Pro Gly Leu Ser Pro Pro Arg Glu Asp Gln Ala 675 680 685 Gln Asn Pro Tyr Leu Lys Asn Ser Val Thr Thr Arg Glu Phe Leu Val 690 695 700 His Glu Asn Ile Pro Glu His Ser Lys Gly Glu Val 705 710 715 <210> 82 <211> 4 <212> PRT <213> Artificial <220> <223> an artificially synthesized peptide sequence <400> 82 Gly Gly Gly Ser One <210> 83 <211> 4 <212> PRT <213> Artificial <220> <223> an artificially synthesized peptide sequence <400> 83 Ser Gly Gly Gly One <210> 84 <211> 5 <212> PRT <213> Artificial <220> <223> an artificially synthesized peptide sequence <400> 84 Gly Gly Gly Gly Ser 1 5 <210> 85 <211> 5 <212> PRT <213> Artificial <220> <223> an artificially synthesized peptide sequence <400> 85 Ser Gly Gly Gly Gly 1 5 <210> 86 <211> 6 <212> PRT <213> Artificial <220> <223> an artificially synthesized peptide sequence <400> 86 Gly Gly Gly Gly Gly Ser 1 5 <210> 87 <211> 6 <212> PRT <213> Artificial <220> <223> an artificially synthesized peptide sequence <400> 87 Ser Gly Gly Gly Gly Gly 1 5 <210> 88 <211> 7 <212> PRT <213> Artificial <220> <223> an artificially synthesized peptide sequence <400> 88 Gly Gly Gly Gly Gly Gly Ser 1 5 <210> 89 <211> 7 <212> PRT <213> Artificial <220> <223> an artificially synthesized peptide sequence <400> 89 Ser Gly Gly Gly Gly Gly Gly 1 5 <210> 90 <211> 40 <212> DNA <213> Artificial <220> <223> an artificially synthesized primer sequence <400> 90 taatagcggc cgctcattat ttaccaggag agtgggagag 40 <210> 91 <211> 40 <212> DNA <213> Artificial <220> <223> an artificially synthesized primer sequence <400> 91 taatagcggc cgctcattaa cactcattcc tgttgaagct 40 <210> 92 <211> 33 <212> DNA <213> Artificial <220> <223> an artificially synthesized primer sequence <400> 92 gacgaattcc accatgggat ggagctggat ctt 33 <210> 93 <211> 33 <212> DNA <213> Artificial <220> <223> an artificially synthesized primer sequence <400> 93 gacgaattcc accatgagtg tgcccactca ggt 33 <210> 94 <211> 33 <212> DNA <213> Artificial <220> <223> an artificially synthesized primer sequence <400> 94 gacgaattcc accatggaat gtaactggat act 33 <210> 95 <211> 33 <212> DNA <213> Artificial <220> <223> an artificially synthesized primer sequence <400> 95 gacgaattcc accatggatt ttctggtgca gat 33 <210> 96 <211> 30 <212> PRT <213> Homo sapiens <400> 96 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 20 25 30 <210> 97 <211> 14 <212> PRT <213> Homo sapiens <400> 97 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly 1 5 10 <210> 98 <211> 32 <212> PRT <213> Homo sapiens <400> 98 Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr Met Glu 1 5 10 15 Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 99 <211> 11 <212> PRT <213> Homo sapiens <400> 99 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> 100 <211> 23 <212> PRT <213> Homo sapiens <400> 100 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 20 <210> 101 <211> 15 <212> PRT <213> Homo sapiens <400> 101 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> 102 <211> 32 <212> PRT <213> Homo sapiens <400> 102 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 20 25 30 <210> 103 <211> 10 <212> PRT <213> Homo sapiens <400> 103 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 1 5 10 <210> 104 <211> 119 <212> PRT <213> Mus musculus <400> 104 Asp Val Gln Leu Arg Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp 20 25 30 Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp 35 40 45 Met Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe 65 70 75 80 Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95 Ala Pro Met Ile Thr Thr Asp Trp Phe Phe Asp Val Trp Gly Ala Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <210> 105 <211> 6 <212> PRT <213> Mus musculus <400> 105 Ser Asp Tyr Ala Trp Asn 1 5 <210> 106 <211> 15 <212> PRT <213> Mus musculus <400> 106 Tyr Ile Ser Tyr Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu Lys 1 5 10 15 <210> 107 <211> 10 <212> PRT <213> Mus musculus <400> 107 Met Ile Thr Thr Asp Trp Phe Phe Asp Val 1 5 10 <210> 108 <211> 107 <212> PRT <213> Mus musculus <400> 108 Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly 1 5 10 15 Asp Arg Val Ser Leu Ser Cys Arg Ala Ser His Asp Ile Ser Asp Phe 20 25 30 Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile 35 40 45 Lys Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Ser Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Pro 65 70 75 80 Glu Asp Val Gly Val Tyr Tyr Cys Gln Asn Gly His Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 109 <211> 11 <212> PRT <213> Mus musculus <400> 109 Arg Ala Ser His Asp Ile Ser Asp Phe Leu His 1 5 10 <210> 110 <211> 7 <212> PRT <213> Mus musculus <400> 110 Tyr Ala Ser Gln Ser Ile Ser 1 5 <210> 111 <211> 9 <212> PRT <213> Mus musculus <400> 111 Gln Asn Gly His Ser Phe Pro Trp Thr 1 5 <210> 112 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 112 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 113 <211> 17 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 113 Glu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <210> 114 <211> 17 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 114 Leu Ile Asp Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <210> 115 <211> 17 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 115 Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Asp Lys Phe Lys 1 5 10 15 Gly <210> 116 <211> 17 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 116 Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Gln Phe Lys 1 5 10 15 Gly <210> 117 <211> 17 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 117 Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe Gln 1 5 10 15 Gly <210> 118 <211> 17 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 118 Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe Lys 1 5 10 15 Asp <210> 119 <211> 17 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 119 Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe Gln 1 5 10 15 Asp <210> 120 <211> 14 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 120 Trp Val Gln Gln Ser Pro Gly Gln Gly Leu Glu Trp Met Gly 1 5 10 <210> 121 <211> 11 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 121 Gln Thr Ser Glu Asn Ile Tyr Ser Phe Leu Ala 1 5 10 <210> 122 <211> 11 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 122 Arg Thr Ser Glu Asp Ile Tyr Ser Phe Leu Ala 1 5 10 <210> 123 <211> 7 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 123 Asp Ala Lys Thr Leu Ala Lys 1 5 <210> 124 <211> 7 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 124 Asn Ala Gln Thr Leu Ala Lys 1 5 <210> 125 <211> 7 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 125 Asn Ala Lys Thr Glu Ala Lys 1 5 <210> 126 <211> 7 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 126 Asn Ala Lys Thr Leu Ala Gln 1 5 <210> 127 <211> 7 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 127 Asn Ala Lys Thr Leu Ala Asp 1 5 <210> 128 <211> 324 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 128 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Thr Val Glu Arg Lys Ser Cys Val Glu Cys Pro Pro Cys Pro Ala Pro 100 105 110 Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 115 120 125 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 130 135 140 Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 145 150 155 160 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 165 170 175 Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp 180 185 190 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 195 200 205 Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu 210 215 220 Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn 225 230 235 240 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 245 250 255 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 260 265 270 Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 275 280 285 Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys 290 295 300 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 305 310 315 320 Ser Leu Ser Pro <210> 129 <211> 326 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 129 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Thr Val Glu Arg Lys Ser Cys Val Glu Cys Pro Pro Cys Pro Ala Pro 100 105 110 Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 115 120 125 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 130 135 140 Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 145 150 155 160 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 165 170 175 Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp 180 185 190 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 195 200 205 Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 210 215 220 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 225 230 235 240 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 245 250 255 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 260 265 270 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 275 280 285 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 290 295 300 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 305 310 315 320 Ser Leu Ser Pro Gly Lys 325 <210> 130 <211> 447 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 130 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 131 <211> 32 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 131 Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu 1 5 10 15 Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 132 <211> 326 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 132 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro 100 105 110 Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 115 120 125 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 130 135 140 Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 145 150 155 160 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 165 170 175 Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp 180 185 190 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 195 200 205 Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu 210 215 220 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 225 230 235 240 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 245 250 255 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 260 265 270 Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 275 280 285 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 290 295 300 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 305 310 315 320 Ser Leu Ser Pro Gly Lys 325 <210> 133 <211> 451 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 133 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 <210> 134 <211> 447 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 134 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 135 <211> 447 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 135 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 136 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 136 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 <210> 137 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 137 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 Ile Met Asn Trp Val Gln Gln Ser Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 138 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 138 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Glu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 139 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 139 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asp Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 140 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 140 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Asp Lys Phe 50 55 60 Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 141 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 141 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Gln Phe 50 55 60 Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 142 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 142 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 143 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 143 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Gln Asp 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 144 <211> 107 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 144 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 Thr Ser Glu Asn Ile Tyr Ser Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Lys Thr Leu Ala Lys 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 His His Tyr Glu Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 145 <211> 107 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 145 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 Thr Ser Glu Asp Ile Tyr Ser Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Lys Thr Leu Ala Lys 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 His His Tyr Glu Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 146 <211> 107 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 146 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 Thr Ser Glu Asn Ile Tyr Ser Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Lys Thr Leu Ala Lys 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 His His Tyr Glu Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 147 <211> 107 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 147 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Ile Tyr Ser Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Gln Thr Leu Ala Lys 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 His His Tyr Glu Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 148 <211> 107 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 148 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 Thr Ser Glu Asn Ile Tyr Ser Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Lys Thr Glu Ala Lys 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 His His Tyr Glu Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 149 <211> 107 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 149 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 Thr Ser Glu Asn Ile Tyr Ser Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Lys Thr Leu Ala Gln 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 His His Tyr Glu Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 150 <211> 107 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 150 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 Thr Ser Glu Asn Ile Tyr Ser Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Lys Thr Leu Ala Asp 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 His His Tyr Glu Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 151 <211> 447 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 151 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Gln Phe 50 55 60 Gln Asp 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 152 <211> 214 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 152 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 Thr Ser Glu Asp Ile Tyr Ser Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Gln Thr Glu Ala Gln 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 His His Tyr Glu Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 153 <211> 326 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 153 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Thr Val Glu Arg Lys Ser Cys Val Glu Cys Pro Pro Cys Pro Ala Pro 100 105 110 Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 115 120 125 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 130 135 140 Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 145 150 155 160 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 165 170 175 Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp 180 185 190 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 195 200 205 Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu 210 215 220 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 225 230 235 240 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 245 250 255 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 260 265 270 Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 275 280 285 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 290 295 300 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 305 310 315 320 Ser Leu Ser Pro Gly Lys 325 <210> 154 <211> 326 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 154 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Thr Val Glu Arg Lys Cys Ser Val Glu Cys Pro Pro Cys Pro Ala Pro 100 105 110 Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 115 120 125 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 130 135 140 Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly 145 150 155 160 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn 165 170 175 Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp 180 185 190 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 195 200 205 Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu 210 215 220 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 225 230 235 240 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 245 250 255 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 260 265 270 Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 275 280 285 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 290 295 300 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 305 310 315 320 Ser Leu Ser Pro Gly Lys 325 <210> 155 <211> 119 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 155 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp 20 25 30 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp 35 40 45 Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Ser Leu Val Thr Val Ser Ser 115 <210> 156 <211> 107 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 156 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 Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser 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 Gly Asn Thr Leu Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 157 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 157 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp 20 25 30 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp 35 40 45 Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys Val Glu 210 215 220 Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 290 295 300 Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 158 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 158 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp 20 25 30 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp 35 40 45 Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Ser Val Glu 210 215 220 Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 290 295 300 Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 159 <211> 449 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 159 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp 20 25 30 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp 35 40 45 Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210> 160 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 160 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp 20 25 30 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp 35 40 45 Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu 210 215 220 Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 290 295 300 Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 161 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 161 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp 20 25 30 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp 35 40 45 Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys Val Glu 210 215 220 Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 290 295 300 Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 162 <211> 214 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 162 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 Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser 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 Gly Asn Thr Leu Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 163 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 163 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp 20 25 30 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp 35 40 45 Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys Val Glu 210 215 220 Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 290 295 300 Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys 325 330 335 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 164 <211> 443 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 164 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp 20 25 30 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp 35 40 45 Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys Val Glu 210 215 220 Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 290 295 300 Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 <210> 165 <211> 267 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 165 Ala Glu Ser His Leu Ser Leu Leu Tyr His Leu Thr Ala Val Ser Ser 1 5 10 15 Pro Ala Pro Gly Thr Pro Ala Phe Trp Val Ser Gly Trp Leu Gly Pro 20 25 30 Gln Gln Tyr Leu Ser Tyr Asn Ser Leu Arg Gly Glu Ala Glu Pro Cys 35 40 45 Gly Ala Trp Val Trp Glu Asn Gln Val Ser Trp Tyr Trp Glu Lys Glu 50 55 60 Thr Thr Asp Leu Arg Ile Lys Glu Lys Leu Phe Leu Glu Ala Phe Lys 65 70 75 80 Ala Leu Gly Gly Lys Gly Pro Tyr Thr Leu Gln Gly Leu Leu Gly Cys 85 90 95 Glu Leu Gly Pro Asp Asn Thr Ser Val Pro Thr Ala Lys Phe Ala Leu 100 105 110 Asn Gly Glu Glu Phe Met Asn Phe Asp Leu Lys Gln Gly Thr Trp Gly 115 120 125 Gly Asp Trp Pro Glu Ala Leu Ala Ile Ser Gln Arg Trp Gln Gln Gln 130 135 140 Asp Lys Ala Ala Asn Lys Glu Leu Thr Phe Leu Leu Phe Ser Cys Pro 145 150 155 160 His Arg Leu Arg Glu His Leu Glu Arg Gly Arg Gly Asn Leu Glu Trp 165 170 175 Lys Glu Pro Pro Ser Met Arg Leu Lys Ala Arg Pro Ser Ser Pro Gly 180 185 190 Phe Ser Val Leu Thr Cys Ser Ala Phe Ser Phe Tyr Pro Pro Glu Leu 195 200 205 Gln Leu Arg Phe Leu Arg Asn Gly Leu Ala Ala Gly Thr Gly Gln Gly 210 215 220 Asp Phe Gly Pro Asn Ser Asp Gly Ser Phe His Ala Ser Ser Ser Leu 225 230 235 240 Thr Val Lys Ser Gly Asp Glu His His Tyr Cys Cys Ile Val Gln His 245 250 255 Ala Gly Leu Ala Gln Pro Leu Arg Val Glu Leu 260 265 <210> 166 <211> 99 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 166 Ile Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Arg His Pro Ala Glu 1 5 10 15 Asn Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro 20 25 30 Ser Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys 35 40 45 Val Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu 50 55 60 Leu Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys 65 70 75 80 Arg Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp 85 90 95 Arg Asp Met <210> 167 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 167 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Gln Phe 50 55 60 Gln Asp 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 168 <211> 107 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 168 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 Thr Ser Glu Asp Ile Tyr Ser Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Gln Thr Glu Ala Gln 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 His His Tyr Glu Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 169 <211> 11 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 169 Gln Thr Ser Glu Asp Ile Tyr Ser Phe Leu Ala 1 5 10 <210> 170 <211> 8 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 170 Asn Ala Gln Thr Glu Ala Gln 1 5 <210> 171 <211> 17 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 171 Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Gln Phe Gln 1 5 10 15 Asp <210> 172 <211> 17 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 172 Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Asp Gln Phe Gln 1 5 10 15 Asp <210> 173 <211> 5 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 173 Gly Tyr Val Met Asn 1 5 <210> 174 <211> 5 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 174 Gly Tyr Ile Ile Asn 1 5 <210> 175 <211> 5 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 175 Gly Tyr Ile Leu Asn 1 5 <210> 176 <211> 5 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 176 Gly Tyr Ala Met Asn 1 5 <210> 177 <211> 17 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 177 Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <210> 178 <211> 17 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 178 Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Pro Lys Phe Lys 1 5 10 15 Gly <210> 179 <211> 12 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 179 Asp Gly Leu Asp Asp Gly Pro Tyr Thr Met Asp Tyr 1 5 10 <210> 180 <211> 12 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 180 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Asp Tyr 1 5 10 <210> 181 <211> 12 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 181 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Glu Tyr 1 5 10 <210> 182 <211> 12 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 182 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Thr 1 5 10 <210> 183 <211> 12 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 183 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Ser 1 5 10 <210> 184 <211> 12 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 184 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr 1 5 10 <210> 185 <211> 12 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 185 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Glu Thr 1 5 10 <210> 186 <211> 12 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 186 Asp Gly Leu Asp Asp Gly Pro Tyr Thr Met Glu Thr 1 5 10 <210> 187 <211> 12 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 187 Asp Gly Leu Asp Asp Gly Pro Tyr Thr Met Glu Ser 1 5 10 <210> 188 <211> 11 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 188 Arg Thr Ser Glu Asn Ile Tyr Arg Phe Leu Ala 1 5 10 <210> 189 <211> 11 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 189 Arg Thr Ser Glu Asn Ile Tyr Ser Phe Val Ala 1 5 10 <210> 190 <211> 11 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 190 Arg Thr Ser Glu Asn Ile Tyr Arg Phe Val Ala 1 5 10 <210> 191 <211> 11 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 191 Arg Ala Ser Glu Asn Ile Tyr Ser Phe Leu Ala 1 5 10 <210> 192 <211> 11 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 192 Arg Ser Ser Glu Asn Ile Tyr Ser Phe Leu Ala 1 5 10 <210> 193 <211> 9 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 193 Gln His His Tyr Asp Ser Pro Leu Thr 1 5 <210> 194 <211> 9 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 194 Gln His His Tyr Glu Asp Pro Leu Thr 1 5 <210> 195 <211> 9 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 195 Gln His His Tyr Glu Ser Pro Leu Phe 1 5 <210> 196 <211> 5 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 196 Gly Tyr Val Leu Asn 1 5 <210> 197 <211> 17 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 197 Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe Gln 1 5 10 15 Asp <210> 198 <211> 17 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 198 Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe Gln 1 5 10 15 Gly <210> 199 <211> 17 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 199 Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Gln Phe Gln 1 5 10 15 Asp <210> 200 <211> 11 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 200 Gln Thr Ser Glu Asp Ile Tyr Arg Phe Val Ala 1 5 10 <210> 201 <211> 11 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 201 Gln Thr Ser Glu Asp Ile Tyr Ser Phe Val Ala 1 5 10 <210> 202 <211> 11 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 202 Gln Ala Ser Glu Asp Ile Tyr Ser Phe Val Ala 1 5 10 <210> 203 <211> 11 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 203 Gln Ala Ser Glu Asp Ile Tyr Ser Phe Leu Ala 1 5 10 <210> 204 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 204 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 Val Leu Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe 50 55 60 Gln Asp 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 205 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 205 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 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe 50 55 60 Gln Asp 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 206 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 206 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 Val Leu Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe 50 55 60 Gln Asp 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 207 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 207 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe 50 55 60 Gln Asp 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 208 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 208 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 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe 50 55 60 Gln Asp 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 209 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 209 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 Val Leu Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe 50 55 60 Gln Asp Arg Val Thr Ile Thr Ala Asp Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 210 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 210 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe 50 55 60 Gln Asp Arg Val Thr Ile Thr Ala Asp Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 211 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 211 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 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe 50 55 60 Gln Asp Arg Val Thr Ile Thr Ala Asp Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 212 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 212 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 213 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 213 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 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 214 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 214 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 215 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 215 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 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 216 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 216 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Gln Phe 50 55 60 Gln Asp 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 217 <211> 121 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 217 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Gln Phe 50 55 60 Gln Asp Arg Val Thr Ile Thr Ala Asp Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 218 <211> 107 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 218 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 Thr Ser Glu Asp Ile Tyr Arg Phe 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Gln Thr Glu Ala Gln 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 His His Tyr Asp Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 219 <211> 107 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 219 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 Thr Ser Glu Asp Ile Tyr Ser Phe 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Gln Thr Glu Ala Gln 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 His His Tyr Asp Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 220 <211> 107 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 220 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 Glu Asp Ile Tyr Ser Phe 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Gln Thr Glu Ala Gln 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 His His Tyr Asp Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 221 <211> 107 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 221 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 Glu Asp Ile Tyr Ser Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Gln Thr Glu Ala Gln 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 His His Tyr Asp Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 222 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 222 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 Val Leu Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe 50 55 60 Gln Asp 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 <210> 223 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 223 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 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe 50 55 60 Gln Asp 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 <210> 224 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 224 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 Val Leu Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe 50 55 60 Gln Asp 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 <210> 225 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 225 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe 50 55 60 Gln Asp 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 <210> 226 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 226 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 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe 50 55 60 Gln Asp 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 <210> 227 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 227 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 Val Leu Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe 50 55 60 Gln Asp Arg Val Thr Ile Thr Ala Asp Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 <210> 228 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 228 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe 50 55 60 Gln Asp Arg Val Thr Ile Thr Ala Asp Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 <210> 229 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 229 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 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe 50 55 60 Gln Asp Arg Val Thr Ile Thr Ala Asp Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 <210> 230 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 230 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 <210> 231 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 231 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 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 <210> 232 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 232 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 <210> 233 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 233 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 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gln Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 <210> 234 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 234 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Gln Phe 50 55 60 Gln Asp 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 <210> 235 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 235 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Gln Phe 50 55 60 Gln Asp Arg Val Thr Ile Thr Ala Asp Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 <210> 236 <211> 214 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 236 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 Thr Ser Glu Asp Ile Tyr Arg Phe 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Gln Thr Glu Ala Gln 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 His His Tyr Asp Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 237 <211> 214 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 237 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 Thr Ser Glu Asp Ile Tyr Ser Phe 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Gln Thr Glu Ala Gln 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 His His Tyr Asp Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 238 <211> 214 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 238 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 Glu Asp Ile Tyr Ser Phe 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Gln Thr Glu Ala Gln 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 His His Tyr Asp Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 239 <211> 214 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 239 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 Glu Asp Ile Tyr Ser Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Gln Thr Glu Ala Gln 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 His His Tyr Asp Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 240 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 240 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Gln Phe 50 55 60 Gln Asp 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 <210> 241 <211> 447 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 241 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Gln Phe 50 55 60 Gln Asp 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 242 <211> 447 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 242 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 243 <211> 447 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 243 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 244 <211> 447 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 244 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys 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 Asp Gly Leu Asp Asp Gly Pro Tyr Thr Met Glu Thr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 245 <211> 447 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 245 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys 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 Asp Gly Leu Asp Asp Gly Pro Tyr Thr Met Glu Ser Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 246 <211> 447 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 246 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 Val Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 247 <211> 447 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 247 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 Ile Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 248 <211> 447 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 248 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 Ile Leu Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 249 <211> 447 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 249 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Gln Lys Phe 50 55 60 Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 250 <211> 447 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 250 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Pro Lys Phe 50 55 60 Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 251 <211> 214 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 251 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 Thr Ser Glu Asn Ile Tyr Arg Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Lys Thr Leu Ala Lys 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 His His Tyr Glu Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 252 <211> 214 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 252 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 Thr Ser Glu Asn Ile Tyr Arg Phe 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Lys Thr Leu Ala Lys 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 His His Tyr Glu Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 253 <211> 214 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 253 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 Thr Ser Glu Asn Ile Tyr Ser Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Lys Thr Leu Ala Lys 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 His His Tyr Asp Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 254 <211> 214 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 254 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 Thr Ser Glu Asn Ile Tyr Ser Phe 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Lys Thr Leu Ala Lys 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 His His Tyr Glu Asp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 255 <211> 447 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 255 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 Val Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Gln Lys Phe 50 55 60 Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 256 <211> 214 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 256 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 Thr Ser Glu Asn Ile Tyr Arg Phe 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asn Ala Lys Thr Leu Ala Lys 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 His His Tyr Asp Ser Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 257 <211> 445 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 257 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 Ile Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys 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 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Ser Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 <210> 258 <211> 530 <212> PRT <213> Homo sapiens <400> 258 Met Met Trp Thr Trp Ala Leu Trp Met Leu Pro Ser Leu Cys Lys Phe 1 5 10 15 Ser Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn Ile Ser Cys Val Tyr 20 25 30 Tyr Tyr Arg Lys Asn Leu Thr Cys Thr Trp Ser Pro Gly Lys Glu Thr 35 40 45 Ser Tyr Thr Gln Tyr Thr Val Lys Arg Thr Tyr Ala Phe Gly Glu Lys 50 55 60 His Asp Asn Cys Thr Thr Asn Ser Ser Thr Ser Glu Asn Arg Ala Ser 65 70 75 80 Cys Ser Phe Phe Leu Pro Arg Ile Thr Ile Pro Asp Asn Tyr Thr Ile 85 90 95 Glu Val Glu Ala Glu Asn Gly Asp Gly Val Ile Lys Ser His Met Thr 100 105 110 Tyr Trp Arg Leu Glu Asn Ile Ala Lys Thr Glu Pro Pro Lys Ile Phe 115 120 125 Arg Val Lys Pro Val Leu Gly Ile Lys Arg Met Ile Gln Ile Glu Trp 130 135 140 Ile Lys Pro Glu Leu Ala Pro Val Ser Ser Asp Leu Lys Tyr Thr Leu 145 150 155 160 Arg Phe Arg Thr Val Asn Ser Thr Ser Trp Met Glu Val Asn Phe Ala 165 170 175 Lys Asn Arg Lys Asp Lys Asn Gln Thr Tyr Asn Leu Thr Gly Leu Gln 180 185 190 Pro Phe Thr Glu Tyr Val Ile Ala Leu Arg Cys Ala Val Lys Glu Ser 195 200 205 Lys Phe Trp Ser Asp Trp Ser Gln Glu Lys Met Gly Met Thr Glu Glu 210 215 220 Glu Ala Pro Cys Gly Leu Glu Leu Trp Arg Val Leu Lys Pro Ala Glu 225 230 235 240 Ala Asp Gly Arg Arg Pro Val Arg Leu Leu Trp Lys Lys Ala Arg Gly 245 250 255 Ala Pro Val Leu Glu Lys Thr Leu Gly Tyr Asn Ile Trp Tyr Tyr Pro 260 265 270 Glu Ser Asn Thr Asn Leu Thr Glu Thr Met Asn Thr Thr Asn Gln Gln 275 280 285 Leu Glu Leu His Leu Gly Gly Glu Ser Phe Trp Val Ser Met Ile Ser 290 295 300 Tyr Asn Ser Leu Gly Lys Ser Pro Val Ala Thr Leu Arg Ile Pro Ala 305 310 315 320 Ile Gln Glu Lys Ser Phe Gln Cys Ile Glu Val Met Gln Ala Cys Val 325 330 335 Ala Glu Asp Gln Leu Val Val Lys Trp Gln Ser Ser Ala Leu Asp Val 340 345 350 Asn Thr Trp Met Ile Glu Trp Phe Pro Asp Val Asp Ser Glu Pro Thr 355 360 365 Thr Leu Ser Trp Glu Ser Val Ser Gln Ala Thr Asn Trp Thr Ile Gln 370 375 380 Gln Asp Lys Leu Lys Pro Phe Trp Cys Tyr Asn Ile Ser Val Tyr Pro 385 390 395 400 Met Leu His Asp Lys Val Gly Glu Pro Tyr Ser Ile Gln Ala Tyr Ala 405 410 415 Lys Glu Gly Val Pro Ser Glu Gly Pro Glu Thr Lys Val Glu Asn Ile 420 425 430 Gly Val Lys Thr Val Thr Ile Thr Trp Lys Glu Ile Pro Lys Ser Glu 435 440 445 Arg Lys Gly Ile Ile Cys Asn Tyr Thr Ile Phe Tyr Gln Ala Glu Gly 450 455 460 Gly Lys Gly Phe Ser Lys Thr Val Asn Ser Ser Ile Leu Gln Tyr Gly 465 470 475 480 Leu Glu Ser Leu Lys Arg Lys Thr Ser Tyr Ile Val Gln Val Met Ala 485 490 495 Ser Thr Ser Ala Gly Gly Thr Asn Gly Thr Ser Ile Asn Phe Lys Thr 500 505 510 Leu Ser His His His His His His Glu Gln Lys Leu Ile Ser Glu Glu 515 520 525 Asp Leu 530 <210> 259 <211> 517 <212> PRT <213> Mus musculus <400> 259 Met Trp Thr Leu Ala Leu Trp Ala Phe Ser Phe Leu Cys Lys Phe Ser 1 5 10 15 Leu Ala Val Leu Pro Thr Lys Pro Glu Asn Ile Ser Cys Val Phe Tyr 20 25 30 Phe Asp Arg Asn Leu Thr Cys Thr Trp Arg Pro Glu Lys Glu Thr Asn 35 40 45 Asp Thr Ser Tyr Ile Val Thr Leu Thr Tyr Ser Tyr Gly Lys Ser Asn 50 55 60 Tyr Ser Asp Asn Ala Thr Glu Ala Ser Tyr Ser Phe Pro Arg Ser Cys 65 70 75 80 Ala Met Pro Pro Asp Ile Cys Ser Val Glu Val Gln Ala Gln Asn Gly 85 90 95 Asp Gly Lys Val Lys Ser Asp Ile Thr Tyr Trp His Leu Ile Ser Ile 100 105 110 Ala Lys Thr Glu Pro Pro Ile Ile Leu Ser Val Asn Pro Ile Cys Asn 115 120 125 Arg Met Phe Gln Ile Gln Trp Lys Pro Arg Glu Lys Thr Arg Gly Phe 130 135 140 Pro Leu Val Cys Met Leu Arg Phe Arg Thr Val Asn Ser Ser Arg Trp 145 150 155 160 Thr Glu Val Asn Phe Glu Asn Cys Lys Gln Val Cys Asn Leu Thr Gly 165 170 175 Leu Gln Ala Phe Thr Glu Tyr Val Leu Ala Leu Arg Phe Arg Phe Asn 180 185 190 Asp Ser Arg Tyr Trp Ser Lys Trp Ser Lys Glu Glu Thr Arg Val Thr 195 200 205 Met Glu Glu Val Pro His Val Leu Asp Leu Trp Arg Ile Leu Glu Pro 210 215 220 Ala Asp Met Asn Gly Asp Arg Lys Val Arg Leu Leu Trp Lys Lys Ala 225 230 235 240 Arg Gly Ala Pro Val Leu Glu Lys Thr Phe Gly Tyr His Ile Gln Tyr 245 250 255 Phe Ala Glu Asn Ser Thr Asn Leu Thr Glu Ile Asn Asn Ile Thr Thr 260 265 270 Gln Gln Tyr Glu Leu Leu Leu Met Ser Gln Ala His Ser Val Ser Val 275 280 285 Thr Ser Phe Asn Ser Leu Gly Lys Ser Gln Glu Thr Ile Leu Arg Ile 290 295 300 Pro Asp Val His Glu Lys Thr Phe Gln Tyr Ile Lys Ser Met Gln Ala 305 310 315 320 Tyr Ile Ala Glu Pro Leu Leu Val Val Asn Trp Gln Ser Ser Ile Pro 325 330 335 Ala Val Asp Thr Trp Ile Val Glu Trp Leu Pro Glu Ala Ala Met Ser 340 345 350 Lys Phe Pro Ala Leu Ser Trp Glu Ser Val Ser Gln Val Thr Asn Trp 355 360 365 Thr Ile Glu Gln Asp Lys Leu Lys Pro Phe Thr Cys Tyr Asn Ile Ser 370 375 380 Val Tyr Pro Val Leu Gly His Arg Val Gly Glu Pro Tyr Ser Ile Gln 385 390 395 400 Ala Tyr Ala Lys Glu Gly Thr Pro Leu Lys Gly Pro Glu Thr Arg Val 405 410 415 Glu Asn Ile Gly Leu Arg Thr Ala Thr Ile Thr Trp Lys Glu Ile Pro 420 425 430 Lys Ser Ala Arg Asn Gly Phe Ile Asn Asn Tyr Thr Val Phe Tyr Gln 435 440 445 Ala Glu Gly Gly Lys Glu Leu Ser Lys Thr Val Asn Ser His Ala Leu 450 455 460 Gln Cys Asp Leu Glu Ser Leu Thr Arg Arg Thr Ser Tyr Thr Val Trp 465 470 475 480 Val Met Ala Ser Thr Arg Ala Gly Gly Thr Asn Gly Val Arg Ile Asn 485 490 495 Phe Lys Thr Leu Ser His His His His His His Glu Gln Lys Leu Ile 500 505 510 Ser Glu Glu Asp Leu 515 <210> 260 <211> 531 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 260 Met Met Trp Thr Trp Ala Leu Trp Met Leu Pro Ser Leu Cys Lys Phe 1 5 10 15 Ser Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn Ile Ser Cys Val Tyr 20 25 30 Tyr Tyr Arg Lys Asn Leu Thr Cys Thr Trp Ser Pro Gly Lys Glu Thr 35 40 45 Ser Tyr Thr Gln Tyr Thr Val Lys Arg Thr Tyr Ala Phe Gly Glu Lys 50 55 60 His Asp Asn Cys Thr Thr Asn Ser Ser Thr Ser Glu Asn Arg Ala Ser 65 70 75 80 Cys Ser Phe Phe Leu Pro Arg Ile Thr Ile Pro Asp Asn Tyr Thr Ile 85 90 95 Glu Val Glu Ala Glu Asn Gly Asp Gly Val Ile Lys Ser His Met Thr 100 105 110 Tyr Trp Arg Leu Glu Asn Ile Ala Lys Thr Glu Pro Pro Lys Ile Phe 115 120 125 Arg Val Lys Pro Val Leu Gly Ile Lys Arg Met Ile Gln Ile Glu Trp 130 135 140 Ile Lys Pro Glu Leu Ala Pro Val Ser Ser Asp Leu Lys Tyr Thr Leu 145 150 155 160 Arg Phe Arg Thr Val Asn Ser Thr Ser Trp Met Glu Val Asn Phe Ala 165 170 175 Lys Asn Arg Lys Asp Lys Asn Gln Thr Tyr Asn Leu Thr Gly Leu Gln 180 185 190 Pro Phe Thr Glu Tyr Val Ile Ala Leu Arg Cys Ala Val Lys Glu Ser 195 200 205 Lys Phe Trp Ser Asp Trp Ser Gln Glu Lys Met Gly Met Thr Glu Glu 210 215 220 Glu Ala Pro His Val Leu Asp Leu Trp Arg Ile Leu Glu Pro Ala Asp 225 230 235 240 Met Asn Gly Asp Arg Lys Val Arg Leu Leu Trp Lys Lys Ala Arg Gly 245 250 255 Ala Pro Val Leu Glu Lys Thr Phe Gly Tyr His Ile Gln Tyr Phe Ala 260 265 270 Glu Asn Ser Thr Asn Leu Thr Glu Ile Asn Asn Ile Thr Thr Gln Gln 275 280 285 Tyr Glu Leu Leu Leu Met Ser Gln Ala His Ser Val Ser Val Thr Ser 290 295 300 Phe Asn Ser Leu Gly Lys Ser Gln Glu Thr Ile Leu Arg Ile Pro Asp 305 310 315 320 Val His Glu Lys Thr Phe Gln Tyr Ile Lys Ser Met Gln Ala Tyr Ile 325 330 335 Ala Glu Pro Leu Leu Val Val Asn Trp Gln Ser Ser Ile Pro Ala Val 340 345 350 Asp Thr Trp Ile Val Glu Trp Leu Pro Glu Ala Ala Met Ser Lys Phe 355 360 365 Pro Ala Leu Ser Trp Glu Ser Val Ser Gln Val Thr Asn Trp Thr Ile 370 375 380 Glu Gln Asp Lys Leu Lys Pro Phe Thr Cys Tyr Asn Ile Ser Val Tyr 385 390 395 400 Pro Val Leu Gly His Arg Val Gly Glu Pro Tyr Ser Ile Gln Ala Tyr 405 410 415 Ala Lys Glu Gly Thr Pro Leu Lys Gly Pro Glu Thr Arg Val Glu Asn 420 425 430 Ile Gly Leu Arg Thr Ala Thr Ile Thr Trp Lys Glu Ile Pro Lys Ser 435 440 445 Ala Arg Asn Gly Phe Ile Asn Asn Tyr Thr Val Phe Tyr Gln Ala Glu 450 455 460 Gly Gly Lys Glu Leu Ser Lys Thr Val Asn Ser His Ala Leu Gln Cys 465 470 475 480 Asp Leu Glu Ser Leu Thr Arg Arg Thr Ser Tyr Thr Val Trp Val Met 485 490 495 Ala Ser Thr Arg Ala Gly Gly Thr Asn Gly Val Arg Ile Asn Phe Lys 500 505 510 Thr Leu Ser His His His His His His Glu Gln Lys Leu Ile Ser Glu 515 520 525 Glu Asp Leu 530 <210> 261 <211> 516 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 261 Met Trp Thr Leu Ala Leu Trp Ala Phe Ser Phe Leu Cys Lys Phe Ser 1 5 10 15 Leu Ala Val Leu Pro Thr Lys Pro Glu Asn Ile Ser Cys Val Phe Tyr 20 25 30 Phe Asp Arg Asn Leu Thr Cys Thr Trp Arg Pro Glu Lys Glu Thr Asn 35 40 45 Asp Thr Ser Tyr Ile Val Thr Leu Thr Tyr Ser Tyr Gly Lys Ser Asn 50 55 60 Tyr Ser Asp Asn Ala Thr Glu Ala Ser Tyr Ser Phe Pro Arg Ser Cys 65 70 75 80 Ala Met Pro Pro Asp Ile Cys Ser Val Glu Val Gln Ala Gln Asn Gly 85 90 95 Asp Gly Lys Val Lys Ser Asp Ile Thr Tyr Trp His Leu Ile Ser Ile 100 105 110 Ala Lys Thr Glu Pro Pro Ile Ile Leu Ser Val Asn Pro Ile Cys Asn 115 120 125 Arg Met Phe Gln Ile Gln Trp Lys Pro Arg Glu Lys Thr Arg Gly Phe 130 135 140 Pro Leu Val Cys Met Leu Arg Phe Arg Thr Val Asn Ser Ser Arg Trp 145 150 155 160 Thr Glu Val Asn Phe Glu Asn Cys Lys Gln Val Cys Asn Leu Thr Gly 165 170 175 Leu Gln Ala Phe Thr Glu Tyr Val Leu Ala Leu Arg Phe Arg Phe Asn 180 185 190 Asp Ser Arg Tyr Trp Ser Lys Trp Ser Lys Glu Glu Thr Arg Val Thr 195 200 205 Met Glu Glu Val Pro Cys Gly Leu Glu Leu Trp Arg Val Leu Lys Pro 210 215 220 Ala Glu Ala Asp Gly Arg Arg Pro Val Arg Leu Leu Trp Lys Lys Ala 225 230 235 240 Arg Gly Ala Pro Val Leu Glu Lys Thr Leu Gly Tyr Asn Ile Trp Tyr 245 250 255 Tyr Pro Glu Ser Asn Thr Asn Leu Thr Glu Thr Met Asn Thr Thr Asn 260 265 270 Gln Gln Leu Glu Leu His Leu Gly Gly Glu Ser Phe Trp Val Ser Met 275 280 285 Ile Ser Tyr Asn Ser Leu Gly Lys Ser Pro Val Ala Thr Leu Arg Ile 290 295 300 Pro Ala Ile Gln Glu Lys Ser Phe Gln Cys Ile Glu Val Met Gln Ala 305 310 315 320 Cys Val Ala Glu Asp Gln Leu Val Val Lys Trp Gln Ser Ser Ala Leu 325 330 335 Asp Val Asn Thr Trp Met Ile Glu Trp Phe Pro Asp Val Asp Ser Glu 340 345 350 Pro Thr Thr Leu Ser Trp Glu Ser Val Ser Gln Ala Thr Asn Trp Thr 355 360 365 Ile Gln Gln Asp Lys Leu Lys Pro Phe Trp Cys Tyr Asn Ile Ser Val 370 375 380 Tyr Pro Met Leu His Asp Lys Val Gly Glu Pro Tyr Ser Ile Gln Ala 385 390 395 400 Tyr Ala Lys Glu Gly Val Pro Ser Glu Gly Pro Glu Thr Lys Val Glu 405 410 415 Asn Ile Gly Val Lys Thr Val Thr Ile Thr Trp Lys Glu Ile Pro Lys 420 425 430 Ser Glu Arg Lys Gly Ile Ile Cys Asn Tyr Thr Ile Phe Tyr Gln Ala 435 440 445 Glu Gly Gly Lys Gly Phe Ser Lys Thr Val Asn Ser Ser Ile Leu Gln 450 455 460 Tyr Gly Leu Glu Ser Leu Lys Arg Lys Thr Ser Tyr Ile Val Gln Val 465 470 475 480 Met Ala Ser Thr Ser Ala Gly Gly Thr Asn Gly Thr Ser Ile Asn Phe 485 490 495 Lys Thr Leu Ser His His His His His His Glu Gln Lys Leu Ile Ser 500 505 510 Glu Glu Asp Leu 515 <210> 262 <211> 524 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 262 Met Met Trp Thr Trp Ala Leu Trp Met Leu Pro Ser Leu Cys Lys Phe 1 5 10 15 Ser Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn Ile Ser Cys Val Tyr 20 25 30 Tyr Tyr Arg Lys Asn Leu Thr Cys Thr Trp Ser Pro Gly Lys Glu Thr 35 40 45 Ser Tyr Thr Gln Tyr Thr Val Lys Arg Thr Tyr Ala Phe Gly Glu Lys 50 55 60 His Asp Asn Cys Thr Thr Asn Ser Ser Thr Ser Glu Asn Arg Ala Ser 65 70 75 80 Cys Ser Phe Phe Leu Pro Arg Ile Thr Ile Pro Asp Asn Tyr Thr Ile 85 90 95 Glu Val Glu Ala Glu Asn Gly Asp Gly Val Ile Lys Ser His Met Thr 100 105 110 Tyr Trp Arg Leu Glu Asn Ile Ala Lys Thr Glu Pro Pro Ile Ile Leu 115 120 125 Ser Val Asn Pro Ile Cys Asn Arg Met Phe Gln Ile Gln Trp Lys Pro 130 135 140 Arg Glu Lys Thr Arg Gly Phe Pro Leu Val Cys Met Leu Arg Phe Arg 145 150 155 160 Thr Val Asn Ser Ser Arg Trp Thr Glu Val Asn Phe Glu Asn Cys Lys 165 170 175 Gln Val Cys Asn Leu Thr Gly Leu Gln Ala Phe Thr Glu Tyr Val Leu 180 185 190 Ala Leu Arg Phe Arg Phe Asn Asp Ser Arg Tyr Trp Ser Lys Trp Ser 195 200 205 Lys Glu Glu Thr Arg Val Thr Met Glu Glu Val Pro His Val Leu Asp 210 215 220 Leu Trp Arg Ile Leu Glu Pro Ala Asp Met Asn Gly Asp Arg Lys Val 225 230 235 240 Arg Leu Leu Trp Lys Lys Ala Arg Gly Ala Pro Val Leu Glu Lys Thr 245 250 255 Phe Gly Tyr His Ile Gln Tyr Phe Ala Glu Asn Ser Thr Asn Leu Thr 260 265 270 Glu Ile Asn Asn Ile Thr Thr Gln Gln Tyr Glu Leu Leu Leu Met Ser 275 280 285 Gln Ala His Ser Val Ser Val Thr Ser Phe Asn Ser Leu Gly Lys Ser 290 295 300 Gln Glu Thr Ile Leu Arg Ile Pro Asp Val His Glu Lys Thr Phe Gln 305 310 315 320 Tyr Ile Lys Ser Met Gln Ala Tyr Ile Ala Glu Pro Leu Leu Val Val 325 330 335 Asn Trp Gln Ser Ser Ile Pro Ala Val Asp Thr Trp Ile Val Glu Trp 340 345 350 Leu Pro Glu Ala Ala Met Ser Lys Phe Pro Ala Leu Ser Trp Glu Ser 355 360 365 Val Ser Gln Val Thr Asn Trp Thr Ile Glu Gln Asp Lys Leu Lys Pro 370 375 380 Phe Thr Cys Tyr Asn Ile Ser Val Tyr Pro Val Leu Gly His Arg Val 385 390 395 400 Gly Glu Pro Tyr Ser Ile Gln Ala Tyr Ala Lys Glu Gly Thr Pro Leu 405 410 415 Lys Gly Pro Glu Thr Arg Val Glu Asn Ile Gly Leu Arg Thr Ala Thr 420 425 430 Ile Thr Trp Lys Glu Ile Pro Lys Ser Ala Arg Asn Gly Phe Ile Asn 435 440 445 Asn Tyr Thr Val Phe Tyr Gln Ala Glu Gly Gly Lys Glu Leu Ser Lys 450 455 460 Thr Val Asn Ser His Ala Leu Gln Cys Asp Leu Glu Ser Leu Thr Arg 465 470 475 480 Arg Thr Ser Tyr Thr Val Trp Val Met Ala Ser Thr Arg Ala Gly Gly 485 490 495 Thr Asn Gly Val Arg Ile Asn Phe Lys Thr Leu Ser His His His His 500 505 510 His His Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu 515 520 <210> 263 <211> 524 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 263 Met Trp Thr Leu Ala Leu Trp Ala Phe Ser Phe Leu Cys Lys Phe Ser 1 5 10 15 Leu Ala Val Leu Pro Thr Lys Pro Glu Asn Ile Ser Cys Val Phe Tyr 20 25 30 Phe Asp Arg Asn Leu Thr Cys Thr Trp Arg Pro Glu Lys Glu Thr Asn 35 40 45 Asp Thr Ser Tyr Ile Val Thr Leu Thr Tyr Ser Tyr Gly Lys Ser Asn 50 55 60 Tyr Ser Asp Asn Ala Thr Glu Ala Ser Tyr Ser Phe Pro Arg Ser Cys 65 70 75 80 Ala Met Pro Pro Asp Ile Cys Ser Val Glu Val Gln Ala Gln Asn Gly 85 90 95 Asp Gly Lys Val Lys Ser Asp Ile Thr Tyr Trp His Leu Ile Ser Ile 100 105 110 Ala Lys Thr Glu Pro Pro Lys Ile Phe Arg Val Lys Pro Val Leu Gly 115 120 125 Ile Lys Arg Met Ile Gln Ile Glu Trp Ile Lys Pro Glu Leu Ala Pro 130 135 140 Val Ser Ser Asp Leu Lys Tyr Thr Leu Arg Phe Arg Thr Val Asn Ser 145 150 155 160 Thr Ser Trp Met Glu Val Asn Phe Ala Lys Asn Arg Lys Asp Lys Asn 165 170 175 Gln Thr Tyr Asn Leu Thr Gly Leu Gln Pro Phe Thr Glu Tyr Val Ile 180 185 190 Ala Leu Arg Cys Ala Val Lys Glu Ser Lys Phe Trp Ser Asp Trp Ser 195 200 205 Gln Glu Lys Met Gly Met Thr Glu Glu Glu Ala Pro His Val Leu Asp 210 215 220 Leu Trp Arg Ile Leu Glu Pro Ala Asp Met Asn Gly Asp Arg Lys Val 225 230 235 240 Arg Leu Leu Trp Lys Lys Ala Arg Gly Ala Pro Val Leu Glu Lys Thr 245 250 255 Phe Gly Tyr His Ile Gln Tyr Phe Ala Glu Asn Ser Thr Asn Leu Thr 260 265 270 Glu Ile Asn Asn Ile Thr Thr Gln Gln Tyr Glu Leu Leu Leu Met Ser 275 280 285 Gln Ala His Ser Val Ser Val Thr Ser Phe Asn Ser Leu Gly Lys Ser 290 295 300 Gln Glu Thr Ile Leu Arg Ile Pro Asp Val His Glu Lys Thr Phe Gln 305 310 315 320 Tyr Ile Lys Ser Met Gln Ala Tyr Ile Ala Glu Pro Leu Leu Val Val 325 330 335 Asn Trp Gln Ser Ser Ile Pro Ala Val Asp Thr Trp Ile Val Glu Trp 340 345 350 Leu Pro Glu Ala Ala Met Ser Lys Phe Pro Ala Leu Ser Trp Glu Ser 355 360 365 Val Ser Gln Val Thr Asn Trp Thr Ile Glu Gln Asp Lys Leu Lys Pro 370 375 380 Phe Thr Cys Tyr Asn Ile Ser Val Tyr Pro Val Leu Gly His Arg Val 385 390 395 400 Gly Glu Pro Tyr Ser Ile Gln Ala Tyr Ala Lys Glu Gly Thr Pro Leu 405 410 415 Lys Gly Pro Glu Thr Arg Val Glu Asn Ile Gly Leu Arg Thr Ala Thr 420 425 430 Ile Thr Trp Lys Glu Ile Pro Lys Ser Ala Arg Asn Gly Phe Ile Asn 435 440 445 Asn Tyr Thr Val Phe Tyr Gln Ala Glu Gly Gly Lys Glu Leu Ser Lys 450 455 460 Thr Val Asn Ser His Ala Leu Gln Cys Asp Leu Glu Ser Leu Thr Arg 465 470 475 480 Arg Thr Ser Tyr Thr Val Trp Val Met Ala Ser Thr Arg Ala Gly Gly 485 490 495 Thr Asn Gly Val Arg Ile Asn Phe Lys Thr Leu Ser His His His His 500 505 510 His His Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu 515 520 <210> 264 <211> 523 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 264 Met Trp Thr Leu Ala Leu Trp Ala Phe Ser Phe Leu Cys Lys Phe Ser 1 5 10 15 Leu Ala Val Leu Pro Thr Lys Pro Glu Asn Ile Ser Cys Val Phe Tyr 20 25 30 Phe Asp Arg Asn Leu Thr Cys Thr Trp Arg Pro Glu Lys Glu Thr Asn 35 40 45 Asp Thr Ser Tyr Ile Val Thr Leu Thr Tyr Ser Tyr Gly Lys Ser Asn 50 55 60 Tyr Ser Asp Asn Ala Thr Glu Ala Ser Tyr Ser Phe Pro Arg Ser Cys 65 70 75 80 Ala Met Pro Pro Asp Ile Cys Ser Val Glu Val Gln Ala Gln Asn Gly 85 90 95 Asp Gly Lys Val Lys Ser Asp Ile Thr Tyr Trp His Leu Ile Ser Ile 100 105 110 Ala Lys Thr Glu Pro Pro Lys Ile Phe Arg Val Lys Pro Val Leu Gly 115 120 125 Ile Lys Arg Met Ile Gln Ile Glu Trp Ile Lys Pro Glu Leu Ala Pro 130 135 140 Val Ser Ser Asp Leu Lys Tyr Thr Leu Arg Phe Arg Thr Val Asn Ser 145 150 155 160 Thr Ser Trp Met Glu Val Asn Phe Ala Lys Asn Arg Lys Asp Lys Asn 165 170 175 Gln Thr Tyr Asn Leu Thr Gly Leu Gln Pro Phe Thr Glu Tyr Val Ile 180 185 190 Ala Leu Arg Cys Ala Val Lys Glu Ser Lys Phe Trp Ser Asp Trp Ser 195 200 205 Gln Glu Lys Met Gly Met Thr Glu Glu Glu Ala Pro Cys Gly Leu Glu 210 215 220 Leu Trp Arg Val Leu Lys Pro Ala Glu Ala Asp Gly Arg Arg Pro Val 225 230 235 240 Arg Leu Leu Trp Lys Lys Ala Arg Gly Ala Pro Val Leu Glu Lys Thr 245 250 255 Leu Gly Tyr Asn Ile Trp Tyr Tyr Pro Glu Ser Asn Thr Asn Leu Thr 260 265 270 Glu Thr Met Asn Thr Thr Asn Gln Gln Leu Glu Leu His Leu Gly Gly 275 280 285 Glu Ser Phe Trp Val Ser Met Ile Ser Tyr Asn Ser Leu Gly Lys Ser 290 295 300 Pro Val Ala Thr Leu Arg Ile Pro Ala Ile Gln Glu Lys Ser Phe Gln 305 310 315 320 Cys Ile Glu Val Met Gln Ala Cys Val Ala Glu Asp Gln Leu Val Val 325 330 335 Lys Trp Gln Ser Ser Ala Leu Asp Val Asn Thr Trp Met Ile Glu Trp 340 345 350 Phe Pro Asp Val Asp Ser Glu Pro Thr Thr Leu Ser Trp Glu Ser Val 355 360 365 Ser Gln Ala Thr Asn Trp Thr Ile Gln Gln Asp Lys Leu Lys Pro Phe 370 375 380 Trp Cys Tyr Asn Ile Ser Val Tyr Pro Met Leu His Asp Lys Val Gly 385 390 395 400 Glu Pro Tyr Ser Ile Gln Ala Tyr Ala Lys Glu Gly Val Pro Ser Glu 405 410 415 Gly Pro Glu Thr Lys Val Glu Asn Ile Gly Val Lys Thr Val Thr Ile 420 425 430 Thr Trp Lys Glu Ile Pro Lys Ser Glu Arg Lys Gly Ile Ile Cys Asn 435 440 445 Tyr Thr Ile Phe Tyr Gln Ala Glu Gly Gly Lys Gly Phe Ser Lys Thr 450 455 460 Val Asn Ser Ser Ile Leu Gln Tyr Gly Leu Glu Ser Leu Lys Arg Lys 465 470 475 480 Thr Ser Tyr Ile Val Gln Val Met Ala Ser Thr Ser Ala Gly Gly Thr 485 490 495 Asn Gly Thr Ser Ile Asn Phe Lys Thr Leu Ser His His His His His 500 505 510 His Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu 515 520 <210> 265 <211> 12 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 265 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr 1 5 10 <210> 266 <211> 12 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 266 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr 1 5 10 <210> 267 <211> 12 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 267 Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Glu Thr 1 5 10 <210> 268 <211> 12 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 268 Asp Gly Leu Asp Asp Gly Pro Tyr Thr Met Glu Thr 1 5 10 <210> 269 <211> 12 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 269 Asp Gly Leu Asp Asp Gly Pro Tyr Thr Met Glu Ser 1 5 10 <210> 270 <211> 5 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 270 Gly Tyr Ile Met Asn 1 5 <210> 271 <211> 17 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 271 Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <210> 272 <211> 5 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 272 Gly Tyr Val Met Asn 1 5 <210> 273 <211> 5 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 273 Gly Tyr Ile Ile Asn 1 5 <210> 274 <211> 5 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 274 Gly Tyr Ile Leu Asn 1 5 <210> 275 <211> 17 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 275 Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <210> 276 <211> 17 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 276 Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Pro Lys Phe Lys 1 5 10 15 Gly <210> 277 <211> 11 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 277 Arg Thr Ser Glu Asn Ile Tyr Ser Phe Leu Ala 1 5 10 <210> 278 <211> 9 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 278 Gln His His Tyr Glu Ser Pro Leu Thr 1 5 <210> 279 <211> 11 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 279 Arg Thr Ser Glu Asn Ile Tyr Arg Phe Leu Ala 1 5 10 <210> 280 <211> 11 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 280 Arg Thr Ser Glu Asn Ile Tyr Arg Phe Val Ala 1 5 10 <210> 281 <211> 9 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 281 Gln His His Tyr Asp Ser Pro Leu Thr 1 5 <210> 282 <211> 9 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 282 Gln His His Tyr Glu Asp Pro Leu Thr 1 5 <210> 283 <211> 9 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 283 Gln His His Thr Glu Ser Pro Leu Phe 1 5 <210> 284 <211> 5 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 284 Gly Tyr Ala Met Asn 1 5 <210> 285 <211> 11 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 285 Arg Ala Ser Glu Asn Ile Tyr Ser Phe Leu Ala 1 5 10 <210> 286 <211> 11 <212> PRT <213> Artificial <220> <223> An artificially synthesized peptide sequence <400> 286 Arg Ser Ser Glu Asn Ile Tyr Ser Phe Leu Ala 1 5 10 <210> 287 <211> 16 <212> PRT <213> Artificial <220> <223> An artificially synthesized sequence <400> 287 His His His His His His Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu 1 5 10 15

Claims (10)

Recognizes a region from the 21st amino acid to the 120th amino acid in the amino acid sequence of human NR10 described in SEQ ID NO: 76,
As the anti-NR10 antibody having neutralizing activity against human NR10 and crab-like monkey NR10,
An anti-NR10 antibody according to any one of the following:
(1) a CDR1 having the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 10, a heavy chain variable region comprising the CDR3 having the amino acid sequence set forth in SEQ ID NO: 11, An antibody having a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 14, CDR2 having the amino acid sequence set forth in SEQ ID NO: 14, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 15;
(2) an antibody having the heavy chain variable region according to SEQ ID NO: 12 and the light chain variable region according to SEQ ID NO: 16;
(3) a heavy chain variable region encoded by a nucleic acid hybridizing under stringent conditions to a nucleic acid encoding a heavy chain variable region as set forth in SEQ ID NO: 12,
An antibody having a light chain variable region encoded by a nucleic acid hybridizing under stringent conditions to the nucleic acid encoding the light chain variable region of SEQ ID NO: 16 and having an activity equivalent to that of the antibody described in (2); And
(4) An antibody that binds to the same epitope as the epitope to which the antibody described in (1) or (2) binds. Recognizes a region from the 21st amino acid to the 120th amino acid in the amino acid sequence of human NR10 described in SEQ ID NO: 76,
As the anti-NR10 antibody having neutralizing activity against human NR10 and crab-like monkey NR10,
An anti-NR10 antibody according to any one of the following:
(1) a CDR1 having the amino acid sequence of SEQ ID NO: 1, a CDR2 having the amino acid sequence of SEQ ID NO: 2, a CDR3 having the amino acid sequence of SEQ ID NO: 3, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: An antibody having a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 6, CDR2 having the amino acid sequence set forth in SEQ ID NO: 6, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 7;
(2) an antibody having the heavy chain variable region according to SEQ ID NO: 4 and the light chain variable region according to SEQ ID NO: 8;
(3) a heavy chain variable region encoded by a nucleic acid that hybridizes under stringent conditions to a nucleic acid encoding the heavy chain variable region of SEQ ID NO: 4,
An antibody having a light chain variable region encoded by a nucleic acid hybridizing under stringent conditions to a nucleic acid encoding the light chain variable region of SEQ ID NO: 8 and having an activity equivalent to that of the antibody described in (2);
(4) a heavy chain variable region having 90% or more identity with the sequence of SEQ ID NO: 4,
An antibody having a light chain variable region having 90% or more identity with the sequence of SEQ ID NO: 8 and having an activity equivalent to that of the antibody described in (2);
(5) a heavy chain variable region having 95% or more identity with the sequence of SEQ ID NO: 4,
An antibody having a light chain variable region having an identity of 95% or more with the sequence of SEQ ID NO: 8 and having an activity equivalent to that of the antibody described in (2); And
(6) An antibody that binds to the same epitope as the epitope to which the antibody described in any one of (1), (2), (4) and (5) binds. Recognizes a region from the 21st amino acid to the 120th amino acid in the amino acid sequence of human NR10 described in SEQ ID NO: 76,
As the anti-NR10 antibody having neutralizing activity against human NR10 and crab-like monkey NR10,
An anti-NR10 antibody according to any one of the following:
(1) a CDR1 having the amino acid sequence set forth in SEQ ID NO: 17, a CDR2 having the amino acid sequence set forth in SEQ ID NO: 18, a heavy chain variable region comprising the CDR3 having the amino acid sequence set forth in SEQ ID NO: 19, An antibody having a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 23, CDR2 having the amino acid sequence set forth in SEQ ID NO: 22, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 23;
(2) an antibody having the heavy chain variable region according to SEQ ID NO: 20 and the light chain variable region according to SEQ ID NO: 24;
(3) a heavy chain variable region encoded by a nucleic acid hybridizing under stringent conditions to the nucleic acid encoding the heavy chain variable region of SEQ ID NO: 20,
An antibody having a light chain variable region encoded by a nucleic acid hybridizing under stringent conditions to a nucleic acid encoding the light chain variable region of SEQ ID NO: 24 and having an activity equivalent to that of the antibody described in (2); And
(4) An antibody that binds to the same epitope as the epitope to which the antibody described in (1) or (2) binds.
Recognizes a region from the 21st amino acid to the 120th amino acid in the amino acid sequence of human NR10 described in SEQ ID NO: 76,
As the anti-NR10 antibody having neutralizing activity against human NR10 and crab-like monkey NR10,
An anti-NR10 antibody according to any one of the following:
(1) an antibody having a heavy chain variable region as set forth in SEQ ID NO: 50 and a light chain variable region as set forth in SEQ ID NO: 52;
(2) a heavy chain variable region encoded by a nucleic acid hybridizing under stringent conditions to a nucleic acid encoding a heavy chain variable region as set forth in SEQ ID NO: 50,
An antibody having a light chain variable region encoded by a nucleic acid hybridizing under stringent conditions to a nucleic acid encoding a light chain variable region of SEQ ID NO: 52 and having an activity equivalent to that of the antibody described in (1); And
(3) a heavy chain variable region having 90% or more identity with the sequence of SEQ ID NO: 50,
An antibody having a neutralizing activity against human NR10 and crab monkey NR10, which has a light chain variable region having 90% or more identity with the sequence of SEQ ID NO: 52 and is equivalent to the antibody described in (1).
Recognizes a region from the 21st amino acid to the 120th amino acid in the amino acid sequence of human NR10 described in SEQ ID NO: 76,
As the anti-NR10 antibody having neutralizing activity against human NR10 and crab-like monkey NR10,
An anti-NR10 antibody according to any one of the following:
(1) an antibody having the light chain of SEQ ID NO: 130 and the light chain of SEQ ID NO: 56;
(2) having a heavy chain encoded by a nucleic acid hybridizing under stringent conditions to a nucleic acid encoding the heavy chain of SEQ ID NO: 130,
An antibody having a light chain encoded by a nucleic acid hybridizing under stringent conditions to a nucleic acid encoding the light chain of SEQ ID NO: 56 and having an activity equivalent to that of the antibody described in (1); And
(3) a heavy chain having 90% or more identity with the sequence of SEQ ID NO: 130,
An antibody having a light chain having 90% or more identity with the sequence of SEQ ID NO: 56, and having neutralizing activity against human NR10 and gecko monkey NR10 equivalent to the antibody described in (1). 6. The method according to any one of claims 1 to 5,
An anti-NR10 antibody that is a humanized antibody. 7. The method according to any one of claims 1 to 6,
An anti-NR10 antibody that is a recombinant antibody. A pharmaceutical composition comprising an antibody according to any one of claims 1 to 7. 9. The method of claim 8,
A pharmaceutical composition for the treatment of inflammatory diseases. Use of the antibody of any one of claims 1 to 7 in the manufacture of a medicament for the treatment of inflammatory diseases.

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