TW201028165A - Anti-NR10 antibody, and use thereof - Google Patents

Abstract

An anti-NR10 antibody having an effective neutralizing activity on NR10 is successfully produced. The anti-NR10 antibody is useful, for example, as a pharmaceutical agent for the treatment or prevention of inflammatory diseases.

Description

201028165 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to an anti-NR10 antibody and a pharmaceutical composition containing the anti-NR10 antibody. [Prior Art] • The cell function of a variety of cells that proliferate, differentiate, or differentiate into mature cells is known to have a variety of cytokines. Cells in the organism that are stimulated by cytokines produce other cytokines that form a network by a plurality of fine φβ cytokines. The constancy of the organisms is adjusted by this network to maintain a subtle balance. Most immunoinflammatory patients are thought to be caused by the flaws in these cytokines and networks, and anti-cytokine therapy with individual antibodies has attracted attention. For example, anti-TNF antibodies and antibodies against the IL-6 receptor have clinically shown high effects. On the other hand, the actual disease state causes a feedback path, blocking only one type of cytokine such as IL-4, and it is impossible to obtain a therapeutic effect. There are many examples of failure.

The present inventors succeeded in isolating the novel cytokine receptor NR10 having high identity with the IL-6 signaling receptor gp 130 (Patent Document 1). NR10 forms a heterodimer with oncostatin M receptor (OSMR) and functions as an IL-31 receptor (Non-Patent Document 1). For IL-31, it has been reported that a transgenic mouse that overexpresses IL-31 naturally develops pruritic dermatitis (Patent Document 2). It is considered that an antibody which binds to NR10 and inhibits the binding of IL-31 and NR10 is effective for the treatment of an inflammatory disease, but an anti-NR10 antibody used for clinical use must be an antibody having low immunogenicity. In order to exert a high therapeutic effect, 201028165 is expected to be an antibody having high binding activity or neutralization activity to NR 10. The prior art documents of the present invention are as follows. [Patent Document 1] WOOO/75314 [Patent Document 2] W003/06'0090 [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 [Features of the Invention] [Problems to be Solved by the Invention] The present invention has been made in view of the above circumstances, and the present invention has been made in the provision of a pharmaceutical composition containing an anti-NR1 quinone antibody. [Technical means for solving the problem] The present inventors conducted research to solve the above problems. The present inventors succeeded in obtaining an anti-NR1 〇 antibody having an effective neutralizing activity against NR10. Moreover, the inventors succeeded in humanizing antibodies that maintain the active state of the antibody. Moreover, the present inventors succeeded in producing antibodies which have increased drug motility, enhanced antigen binding activity, increased stability, and/or reduced immunogenic risk. The aforementioned antibodies are effective as therapeutic agents for inflammatory diseases. The pharmaceutical composition for anti-NR10 and anti-NR10 antibody of the present invention more specifically includes the following [1] to [15] inventions. [1] Identify antibodies to NR10 region 1 (domain 1). [2] An antibody having the neutralizing activity [1]. [3] An antibody according to [1] or [2] of a humanized antibody. 201028165 (4) The anti-NR10 antibody according to any one of (1) to (8); (1) having the CDR1 comprising the amino acid sequence having the sequence identification number: hydrazine, and the amino group having the sequence identification number: CDR2 of the acid sequence; antibody having the heavy chain variable region of CDR3 of SEQ ID NO: 3 amino acid sequence; (2) antibody having SEQ ID NO: 4 heavy chain variable region; « (3) having Including: CDR1 having the amino acid sequence of SEQ ID NO: 5, CDR2 having the amino acid sequence of SEQ ID NO: 6, and antibody loop of the light chain variable region of CDR3 having the amino acid sequence of the SEQ ID NO: (4) an antibody having a light chain variable region of SEQ ID NO: 8; (5) an antibody having a heavy chain variable region of (1) and a light chain variable region of (3); (6) having (2) An antibody of the heavy chain variable region and (4) the light chain variable region; (one of the antibodies described in any one of (1) to (6) or a plurality of amino acids are substituted or absent And an antibody which has the same activity as the antibody of any one of (1) to (6); (8) an antibody which binds to the antibody according to any one of (1) to (7); [5] An anti-NR10 antibody according to any one of the following (1) to (8); (1) comprising: an amino group having a sequence identifier: CDR1 of the acid sequence: CDR2 having the sequence identification number: amino acid sequence of 〇2, antibody having the heavy chain variable region of CDR3 of SEQ ID NO: 11 amino acid sequence; (2) having sequence identification number: An antibody of the heavy chain variable region of 12; (3) having a CDR1 comprising: an amino acid sequence having the sequence identifier: 13; a CDR2 having the amino acid sequence of SEQ ID NO: 14 having the sequence identifier: 15 An antibody to a light chain variable region of CDR3 of an amino acid sequence; 201028165 (4) an antibody having a light chain variable region of SEQ ID NO: 16; (5) having a heavy chain variable region of (1) and 3) an antibody of a light chain variable region; (6) an antibody having a heavy chain variable region of (2) and a light chain variable region of (4); (Ό is any one of (1) to (6) An antibody having one or more amino acids substituted, absent, increased, and/or inserted in the antibody, and having the antibody described in (1) to (6) (8) An antibody that binds to the same epitope as the epitope to which the antibody according to any one of (1) to (7) is attached. [6] The following (1) to (8) Any one of the anti-Nino antibodies; (1) having the CDR i comprising: the amino acid sequence having the sequence identifier: 丨7, the CDR2 having the amino acid sequence of SEQ ID NO: 18, having the sequence identifier: An antibody to the heavy chain variable region of CDR3 of the amino acid sequence of 19; (2) an antibody having a heavy chain variable region of SEQ ID NO: 20; (3) having an amino acid sequence comprising: a sequence identifier CDR1, CDR2 having the amino acid sequence of SEQ ID NO: 22, antibody having the light chain variable region of CDR3 of SEQ ID NO: 23 amino acid sequence; (4) having sequence identification number: 2 4 An antibody of a light chain variable region; (5) an antibody having a heavy chain variable region of (1) and a light chain variable region of (3); (6) a heavy chain variable region having (2) and (4) An antibody of the light chain variable region; wherein one or more of the antibodies described in any one of (1) to (6) are substituted, absent, increased, and/or inserted An antibody having the same activity as the antibody of any one of (1) to (6); (8) an antigen having the same antigenic epitope i tope as the antibody of any one of (1) to (7) Determine the binding of antibodies. [7] The anti-NR10 antibody according to any one of (1) to (8) above; (1) having CDR1 comprising: amino acid sequence having SEQ ID NO: 25; amino group having SEQ ID NO: 26 CDR2 of an acid sequence; an antibody having a heavy chain variable region of CDR3 of SEQ ID NO: 27 amino acid sequence; (2) an antibody having a heavy chain variable region of a SEQ ID NO:; CDR1 of SEQ ID NO: 29 amino acid sequence, CDR2 with amino acid sequence of SEQ ID NO: 30, with sequence recognition

No.: an antibody against a light chain variable region of CDR3 of the amino acid sequence of 31; (4) an antibody having a light chain variable region of SEQ ID NO: 32; (5) a heavy chain having (1) And (3) an antibody having a heavy chain variable region of (2) and a light chain variable region of (4); (7) being (1) to (6) An antibody having one or more amino acids substituted, absent, increased, and/or inserted, and having the same activity as the antibody of any one of (1) to (6); (8) The antibody which binds to the same epitope as the epitope (epi tope) to which the antibody according to any one of (1) to (7) is bound [8] is described in any one of (1) to (20). Antibody variable region or antibody; (1) CDR1 having the amino acid sequence of SEQ ID NO: 196, CDR2 having the amino acid sequence of SEQ ID NO: 197, amino acid sequence having SEQ ID NO: 11. CDR3 heavy chain variable region (H17); (2) CDR1 having the amino acid sequence of SEQ ID NO: 176, CDR2 having the amino acid sequence of SEQ ID NO: 197, having the sequence identification number *·11 The heavy chain variable region of CDR3 of the amino acid sequence (H19); (3) CDR1 having the amino acid sequence of SEQ ID NO: 196, having the sequence 歹, j 7 201028165 identification number: amino acid sequence of 197 CDR2, heavy chain variable region of CDR3 having amino acid sequence of sequence identification number η 84 (H28, H42); (4) CDR1 having amino acid sequence of SEQ ID NO: 9 with sequence identifier: 197 The CDR2 of the amino acid sequence, the heavy chain variable region of CDR3 having the amino acid sequence of SEQ ID NO: 184 (H30, H44); (5) CDR1 having the amino acid sequence of SEQ ID NO: 176 CDR2 having the sequence identification number: amino acid sequence of 1 97, heavy chain variable region of CDR3 having the amino acid sequence of SEQ ID NO: 184 (H34, H46); (6) having sequence identification number: 9 CDR1 of the amino acid sequence, CDR2 having the sequence identification number: amino acid sequence of 1 98, heavy chain variable region of CDR3 having the amino acid sequence of SEQ ID NO: 184 (H57, H78); (7) CDR1 having the amino acid sequence of SEQ ID NO: 176, CDR2 having the amino acid sequence of SEQ ID NO: 198, having sequence recognition No.: heavy chain variable region of CDR3 of amino acid sequence of 184 (H71, H92); (8) CDR1 having amino acid sequence of SEQ ID NO: 9 with SEQ ID NO: 1 99 amino acid CDR2 of the sequence, heavy chain variable region of CDR3 having sequence identification number: amino acid sequence of 1 84 (H97, H98); (9) CDR1 having sequence identification number: amino acid sequence of 200, having sequence recognition No.: CDR2 of the amino acid sequence of 170, light chain variable region of CDR3 having the amino acid sequence of SEQ ID NO: 193 (L11); (10) CDR1 having the amino acid sequence of SEQ ID NO: 201 CDR2 having the sequence identification number: amino acid sequence of 1 70, light chain variable region of CDR3 having sequence identification number: amino acid sequence of 1 93 (L12); (11) having sequence identification number: 202 CDIH of the amino acid sequence, CDR2 of the amino acid sequence having the sequence 201028165 identification number: 1 70, light chain variable region of the CDR3 having the amino acid sequence of SEQ ID NO: 1 93 (L17); (12) CDR2 having the amino acid sequence of SEQ ID NO: 203 having the SEQ2 of the amino acid sequence of SEQ ID NO: 170 IF: the light chain variable region of CDR3 of the amino acid sequence of 193 (L50); (13) an antibody comprising the heavy chain variable region of (3) and the light chain variable region of (11); * (14) An antibody comprising a heavy chain variable region of (4) and a 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) 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) one of the antibodies according to any one of (13) to (18) or An antibody having a plurality of amine groups substituted, absent, increased, and/or inserted, having the same activity as the antibody of any one of (13) to (18); (20) and (13) to (18) The antibody to which the antibody binds is the epitope-binding antibody of the same epitope. [9] The antibody variable region or antibody according to any one of (1) to (32) above; (1) a heavy chain variable region (H17) having an amino acid sequence of SEQ ID NO: 204; (2) a heavy chain variable region (H19) having the sequence identification number: amino acid sequence of 2〇5; (3) a heavy chain variable region (H28) having the amino acid sequence of SEQ ID NO: 206; (4) Heavy chain variable region with sequence identification number: 207 amino acid sequence 201028165 (H30); (5) heavy chain variable region (H34) having the amino acid sequence of SEQ ID NO: 208; (6) Sequence identification number: heavy chain variable region of amino acid sequence of 209 (H42); (7) heavy chain variable region (H44) having sequence identification number: amino acid sequence of 21; (8) having sequence Identification number: heavy chain variable region of amino acid sequence of 211 (H46); (9) heavy chain variable region (H57) having amino acid sequence of sequence identification number: 212; (10) having sequence identification number The heavy chain variable region of the amino acid sequence of 213 (H71); (11) the heavy chain variable region (H78) having the amino acid sequence of SEQ ID NO: 214; (12) having the sequence identifier: 215 Heavy chain variable region of amino acid sequence (H92); (13) Heavy chain variable region (H97) having the sequence identification number: amino acid sequence of 21 6; (14) heavy chain variable region having the amino acid sequence of SEQ ID NO: 217 ( H15); (15) Light chain variable region (L11) having the amino acid sequence of SEQ ID NO: 218; (16) Light chain variable region 10 having the amino acid sequence of SEQ ID NO: 21

201028165 (L12); (17) Amino acid sequence having sequence identification number: 220 (L17); (18) amino acid sequence having sequence number: 221 (L50); (19) containing the weight of (3) Chain variable region and (π) light key (H28L17); (20) comprising (4) heavy chain variable region and (17) light key (H30L17); (21) containing (5) heavy key a variable region and a light bond of (17) (H34L17); (22) a heavy chain variable region comprising (6) and a light bond (H42L17) of (17); (23) a heavy chain variable region comprising (7) And (17) the light key (H44L17); 0 (24) comprising the heavy chain variable region of (8) and (17) the light bond (H46L17); (25) comprising the heavy chain variable region of (9) (17) a light bond (H57L17); (26) a heavy chain variable region comprising (10) and a light bond (H71L17) of (17); (27) a heavy chain variable region comprising (11) and (17) a light bond (H78L17); (28) an antibody variable region of an antibody variable region comprising a heavy chain variable region of (12) and a light bond variable region variable region of (17) Antibody variable region of antibody variable region of antibody variable region of antibody variable region of antibody variable region of antibody variable region of antibody variable region of antibody 11 20102816 5 (H92L17); (29) an antibody (H97L50) comprising the heavy chain variable region of (13) and the light chain variable region of (18); (30) a heavy chain variable region comprising (14) and (is An antibody (H98L50) of the light chain variable region; (31) wherein one or more of the antibodies described in any one of (19) to (30) are substituted, absent, increased, and/or inserted An antibody having the same activity as the antibody of any one of (19) to (3), (32) having the same antigenic epitope as the antibody of any one of (19) to (30) The epitope binds to the antibody. [10] The anti-NR10 antibody according to any one of [4] to [9]. [11] The antibody heavy chain, the antibody light chain, or the antibody according to any one of (1) to (32); (1) the heavy chain (H17) having the amino acid sequence of SEQ ID NO: 222; a heavy chain (H19) having the amino acid sequence of SEQ ID NO: 223; (3) a heavy chain (H28) having the amino acid sequence of SEQ ID NO: 224; (4) having the sequence identification number: 225 The heavy chain of the amino acid sequence (H30); (5) the heavy chain (H34) having the amino acid sequence of SEQ ID NO: 226; (6) the heavy chain having the amino acid sequence of SEQ ID NO: 227 ( H42); (Ό heavy chain with sequence identification number: 228 amino acid sequence (H44); (8) heavy chain with sequence identification number: 229 amino acid sequence (H46); (9) with sequence recognition No.: heavy chain of amino acid sequence of 230 (H57); (10) heavy chain (H71) having amino acid sequence of SEQ ID NO: 231; (11) amino acid sequence having SEQ ID NO: 232 Heavy chain (H78); 12 201028165 (12) Heavy chain (H92) having the amino acid sequence of SEQ ID NO: 233 (13) Heavy chain (H97) having the amino acid sequence of SEQ ID NO: 234 ( 14) with sequence identification number: 235 Heavy chain of amino acid sequence (H98) (15) Light chain with sequence identification number: amino acid sequence of 236 (L11) (16) Light chain with sequence identification number: amino acid sequence of 237 (L12) (17) Light chain with sequence identification number: amino acid sequence of 238 (L17) (18) Light chain with sequence identification number: amino acid sequence of 239 (L50)

(19) an antibody comprising the heavy chain of (3) and the light chain of (17) (H28L1 7); (20) an antibody comprising the heavy chain of (4) and the light chain of (17) (H30L17); (21) An antibody (H34L17) comprising the heavy chain of (5) and the light chain of (17); (22) an antibody (H42L17) comprising the heavy chain of (6) and the light chain of (17); (23) comprising (7) The heavy chain and the light chain antibody of (17) (H44L17); (24) the antibody comprising the heavy chain of (8) and the light chain of (17) (H46L1 7); (25) the heavy chain comprising (9) And (17) a light chain antibody (H57L17) (26) an antibody comprising the heavy chain of (10) and the light chain of (17) (H71L17) ^ (2Ό comprising the heavy chain of (11) and (17) Chain antibody (H78L17) (28) Antibody containing (12) heavy chain and (17) light chain (H92L17) (29) Antibody containing (13) heavy chain and (18) light chain (H97L50) (30) An antibody (H98L50) comprising the heavy chain of (14) and the light chain of (18); (31) one or a plurality of amino acids of any one of (19) to (30) An antibody that is substituted, absent, increased, and/or inserted, having the same activity as the antibody of any one of (19) to (30); (32) and (1 9) to (30) An antibody that binds to the same epitope at the epitope to which the antibody binds (ep i tope). 13 201028165 [12] A pharmaceutical composition comprising the antibody according to [1] to [U]. A pharmaceutical composition according to [12], which is a therapeutic agent for inflammatory diseases. [14] A method for treating or preventing an inflammatory disease comprising the step of administering the antibody according to any one of [1] to [1丨]. 5] [1] [11] The use of the antibody according to any one of the inventions in the manufacture of a therapeutic agent for inflammatory diseases. [Embodiment] NR10 NR10 forms a heterodimer with an oncostatin M receptor (〇SMR), A protein that functions as an IL-31 receptor. Also known as glm-r (J Biol Chem 277, 1 6831-6, 2002) ^ GPL (J Biol Chem 278, 49850-9, 2003). IL31RA (Nat Immunol 5, w752-60, 2004), etc., the NR1〇 of the present invention also contains proteins of these names. The source of NR10 (also referred to as IU1RA, GpL or glmr) of the present invention is not particularly limited, and includes human, mouse, and cockroaches. NRI〇 of other mammals, but preferably NR1〇 derived from human, mouse or cockroach, especially nri〇 derived from human. NR1〇 from humans is known as a plurality of splicing variants (WO 00/075314). Among the above-described ligation mutants, NR1〇1 is composed of 662 amino acids and is characterized by having a cell membrane penetrating region. Service 2 is a soluble receptor-like protein composed of 252 amino acid sequences without a membrane penetrating region. On the other hand, NR1〇3 and IL31RAv3 are known as NR10 junction mutants which function as a cell membrane-through receptor protein. The human NR10 of the present invention forms a heterodimer with the oncostatin receptor (0SMR), and is not particularly limited as the 201028165 IL 31, but a preferred one is NR10.3C, also called ilrav4. (Nat Immunol 5, 752-60, 2004)) and IL31RAv3. NR10.3 (iL31RAv4) consists of 662 amino acids (WOOO/075314, Nat Immunol 5, 752_6〇, 2〇〇4), • IL31RAv3 consists of 732 amino acids (GenBank ACCESSI〇NN〇. NM_139017 ). The amino acid sequence of IL31RAv4 is SEQ ID NO: 79. The amino acid sequence of IL31RAv3 is shown in SEQ ID NO: 8〇. In another aspect, the NR1 0 derived from a mouse, for example, a protein consisting of the amino acid sequence described in SEQ ID NO: 81. NR1 0 from a crab eater (Macacafascicuiar; [s), for example, a protein composed of an amino acid sequence described in the sequence identification number. The antibody (sequence) of the anti-NR1 0 antibody of the present invention is the anti-nri 〇 antibody according to any one of the following items (1) to (8). (A) NS18 (1) having CDR1 comprising: an amino acid sequence having the sequence identifier: 1 (HCDR1), CDR2 having the amino acid sequence of SEQ ID NO: 2 (HCDR2) having the sequence identifier: 3 An antibody to the heavy chain variable region of CDR3 of the amino acid sequence of (HCDR3); (2) an antibody having a heavy chain variable region of SEQ ID NO: 4 (VH); (3) having an inclusion with sequence recognition No.: CDR1 of amino acid sequence of 5 (LCDR1), CDR2 of amino acid sequence having sequence identification number: 6 (LCDR2), light chain of CDR3 having amino acid sequence of sequence identification number: 7 (LCDR3) Antibody to the variable region; 15 201028165 (4) an antibody having a light chain variable region of SEQ ID NO: 8 (VL); (5) having a heavy chain variable region of (1) and (3) a light chain (6) an antibody having the heavy chain variable region of (2) and the light chain variable region of (4); (1) of the antibodies according to any one of (1) to (6) An antibody having one or more amino acids substituted, absent, increased, and/or inserted, having the same activity as the antibody of any one of (1) to (6); (8) and (1) to (7) Any one of the described antibody knots The antigen-determining site (epi tope) binds to the same epitope. (B) NS22 (1) has CDR1 comprising: amino acid sequence having sequence number: 9 (hcdri) with sequence identifier: 1 CDR2 of the amino acid sequence of 〇(HCDR2), antibody having the heavy chain variable region of CDR3 of the amino acid sequence of SEQ ID NO: 11 (HCDR3); (2) having the sequence identification number: 12 (VH) An antibody of a heavy chain variable region; (3) having a CDR1 comprising: an amino acid sequence having the sequence identifier: 13 (LCDR1), and a CDR2 having the amino acid sequence of SEQ ID NO: 14 (LCDR2) having a sequence An antibody having a light chain variable region of CDR3 of the amino acid sequence of 15 (LCDR3); (4) an antibody having a light chain variable region of SEQ ID NO: 16 (VL); (5) having (1) An antibody to the heavy chain variable region and (3) the light chain variable region; (6) an antibody having the heavy chain variable region of (2) and the light chain variable region of (4); The antibody according to any one of (1) to (6), wherein the antibody according to any one of (1) to (6), wherein the antibody is substituted, absent, increased, and/or inserted, the antibody according to any one of (1) to (6) The antibody of the same activity; 201028165 (8) The antibody which binds to the same epitope as the antigenic epitope of the antibody described in (1) to (7), and the above-mentioned enthalpy or plural amino acid is substituted, lacked, and increased. Specific examples of the insertion and/or insertion are not particularly limited, and examples thereof include the following modifications. The 'ne' of the third position in the heavy chain_ of the sequence identification number: 9 is substituted with another amino acid. The amino acid after substitution is not particularly limited, and it is preferred that, for example, the heavy bond of "B" is substituted with the Met of the fourth position in the middle to be substituted with another amino acid. The amino acid after substitution is not particularly limited. Preferably, for example, the Met of the fourth position in the heavy bond of 9 is substituted with another amino acid. The substituted amino acid is not particularly limited, and is preferably, for example, [print. Sequence identification number: 9 The substituent at position 3 of the CDR1 is substituted with another amino acid. The amino acid after substitution is not particularly limited, and is preferably, for example, Aia. Sequence identification number: 1〇 of the 2nd position of the 2nd-replacement The amino acid to be substituted is not particularly limited, and is preferably, for example, Giu. SEQ ID NO: 1 〇 heavy bond CDR 2 The third position of Asn is substituted with L 0 other amino acid. Substituted amine The base acid is not particularly limited, and is preferably, for example, Asp. Sequence identification number: Gln at position 13 in the heavy chain CDR2 of 1 被 is taken as other amino acid. The substituted amino acid is not particularly limited, and is preferably, for example.

Asp ° Sequence ID: The 14th Lys in the heavy chain CDR2 of 1〇 was substituted with other amino acids. The amino acid after substitution is not particularly limited, and preferably, for example,

Gin 序列 Sequence number: The 16th Lys in the heavy chain CDR2 of 10 is substituted with another amino acid. The amino acid after substitution is not particularly limited, and is preferably, for example, 17 201028165

Gin. Sequence identification number: G1 y at position 17 of the heavy chain CDR2 of 10 is substituted with other amino acids. The amino acid after substitution is not particularly limited, and preferably, for example, the Lys of the 16th position and the Gly of the 17th position in the heavy bond CDR2 of the Asp ° sequence identification number: 1〇 are substituted with other amino acids. The amino acid after substitution is not particularly limited. For example, Lys at the 16th position is substituted with Gin, and Gly at the 17th position is substituted with A s p. The 14th Lys, the 16th Lys, and the 17th Gly in the heavy chain CDR2 of the sequence identifier·10 are substituted with other amino acids. The amino acid after substitution is not particularly limited. For example, Lys at the 14th position is substituted with Gln, Lys at the 16th position is substituted with Gin, and Gly at the 17th position is substituted with Asp.

The sequence identification number: Gln at position 13 in the heavy chain CDR2 of 1 〇, Lys at position 14, Lys at position 16, and Giy at position 17 are substituted with other amino acids. The amino acid after substitution is not particularly limited. For example, the 13th position of Gu is substituted with Asp'. The 14th Lys is substituted with Gln, the 16th Lys is substituted with Gin, and the 17th Gly is substituted with Asp. Sequence ID: The 10th Ser in the heavy chain CDR2 of 1〇 was substituted with another amino acid. The amino acid after substitution is not particularly limited, and preferably, for example, Asg 〇 SEQ ID NO: 1 〇 The heavy bond CDR 2 at the 13th position of Gln is substituted with another amino acid. The amino acid after substitution is not particularly limited, and preferably, for example, the Tyr at position 3 in the heavy chain CDR3 of Pro 〇 SEQ ID NO: 11 is substituted with 18 201028165 other amino acids. The amino acid after substitution is not particularly limited, and is preferably, for example, Leu. The Met of the 1st position in the heavy chain CDR3 of the sequence identification number: 11 was substituted with another amino acid. The amino acid after substitution is not particularly limited, and it is preferred that, for example, the 11th Asp in the heavy chain CDR3 of Leu 序列 SEQ ID NO: 11 is substituted with another amino acid. The amino acid after substitution is not particularly limited, and is preferably, for example, G1 u. The Tyr at position 12 of the heavy chain CDR3 of the sequence identification number: 11 is substituted with ® other amino acids. The amino acid after substitution is not particularly limited, and is preferably, for example, Thr or Ser. The Met at the 1st position, the Asp at the 11th position, and the Tyr at the 12th position in the heavy chain CDR3 of the sequence identification number: 11 are substituted with other amino acids. The amino acid after substitution is not particularly limited. For example, the 10th Met is substituted with Leu, the 11th Asp is substituted with Glu, and the 12th Tyr is substituted with Thr. The 11th position Asp and the 12th place Tyr in the heavy chain CDR3 of the sequence identification number: 11 are substituted with other amino acids. The amino acid after substitution is not particularly limited. For example, the 11th Asp is substituted with G1 u, and the 12th Tyr is substituted with Thr. The Tyr at position 3, the Asp at the 11th position, and the Tyr at the 12th position in the heavy chain CDR3 of the sequence identification number: 11 are substituted with other amino acids. The substituted amino acid is not particularly limited. For example, the third Tyr is substituted with Leu, the 11th Asp is substituted with Glu, and the 12th Tyr is substituted with Thr. The Arg of the first position in the CDR1 of the sequence identification number: 13 is substituted with another amino acid. The amino acid after substitution is not particularly limited, and is preferably, for example, Gln. 19 201028165 The Asn at position 5 in the light chain CDR1 of the sequence identifier: 13 is substituted with another amino acid. The amino acid after substitution is not particularly limited, and is preferably, for example, Asp. The Arg of the 1st position and the Asn of the 5th position in the light chain CDRi of the sequence identification number: 13 are substituted with other amino acids. The amino acid after substitution is not particularly limited. For example, the first position Λα is substituted with Gln'. The fifth position Asn is substituted.

Asp. _ Sequence identification number: The 8th position in the light chain CDR1 of 13 is substituted with other amino acids. The amino acid after substitution is not particularly limited, and is preferably, for example, AU. The Uu of the first position in the light chain CDR1 of the sequence identification number: 13 is taken as 1 other amino acid. The amino acid after substitution is not particularly limited, and is preferably, for example, Val. The Ser at the 8th position and the Leu at the 1st position in the light chain CDR1 of SEQ ID NO: 3 are substituted with other amino acids. The substituted amino acid is not particularly limited. For example, the Ser at the 8th position is substituted with Arg, and the first position Uu is substituted with the residue at the 2nd position in the light chain CDR1 of the Val 〇 SEQ ID NO: 13 is substituted with another amine. Base acid. The substituted amino acid is not particularly limited, and it is preferred that, for example, Ala % or Ser ° SEQ ID NO: 14 of the light bond CDR2 in the first position of Asn is substituted with another amino acid. The amino acid after substitution is not particularly limited, and it is preferred that, for example, the Lys at position 3 of the light bond CDR2 of As = SEQ ID NO: 14 is substituted @ as another amino acid. The amino acid after substitution is not particularly limited, and it is preferred that, for example, Leu at the 5-position is substituted with a definition of "preferably, for example, Glu."

Sequence ID: 14th amino acid in the light chain CDR2. The amino acid after substitution has no particular 20 201028165. The Lys at position 7 in the light chain CDR2 of SEQ ID NO: 14 is substituted with another amino acid. The amino acid after substitution is not particularly limited, and is preferably, for example, or Asp. The Leu of position 5, the Leu of position 5, and the Lys of position 7 of the light chain CDR2 of the sequence identification number 14 are substituted with other amino acids. Substituted =. The base acid is not particularly limited. For example, the third position Lys is substituted with Gin, the fifth position Leu is substituted with G1 u, and the seventh position Ly s is substituted with G丨n. The Glu at position 5 in the light chain CDR3 of SEQ ID NO: 15 was substituted with another amino acid. The amino acid after substitution is not particularly limited, and is preferably, for example, Asp. The Ser at position 6 of the light chain CDR3 of the sequence identifier: 15 was substituted with another amino acid. The amino acid after substitution is not particularly limited, and is preferably, for example, Asp. The Thr at position 9 in the light chain CDR3 of SEQ ID NO: 15 was substituted with other amino acids. The amino acid after substitution is not particularly limited. Preferably, for example, the above-mentioned substitution may be carried out singly or in combination of plural substituents. The above substitutions and substitutions other than the above may also be combined. By the substitution described herein, the antibody drug motility (retention in plasma) can be increased to increase antigen binding activity, improve stability, and/or reduce the risk of immunogenicity. Specific examples of combining the above-mentioned substituted variable regions in the present invention include a heavy chain variable region having an amino acid sequence of SEQ ID NO: 16 7 or a light chain having an amino acid sequence of SEQ ID NO: 16 8 Variable zone. Further, the antibody which binds the above substitution includes, for example, an antibody having a heavy chain variable region having an amino acid sequence of SEQ ID NO: 67 and a light chain variable region having an amino acid sequence of SEQ ID NO: 168. Further, specific examples of the above-mentioned substituted heavy chain variable region or light chain variable region include the following variable regions. (a) SEQ ID NO: 19 6 CDR1 'SEQ ID NO: 1 197 CDR2, SEQ ID NO: CDR3 heavy chain variable region (H17) of 丨1. (b) a heavy chain variable region (H19) comprising CDR1 of SEQ ID NO: 176, SEQ ID NO: 197, SEQ ID NO: 11 CDR3. (〇 contains the CDR1 of SEQ ID: 196, SEQ ID NO: 197, SEQ ID NO: CDR3 heavy chain variable region of 184 (H28, H42). * (d) CDR1 containing SEQ ID NO: 9 , SEQ ID NO: 197, SEQ ID NO: CDR3 heavy chain variable region of 184 (H30, H44) (e) CDR comprising sequence identification number: 176, SEQ ID NO: 197 CDR2, sequence Identification number: heavy chain variable region of CDR3 of 184 (H34, H46). (f) CDR containing sequence identification number: 9, SEQ ID NO: 198, SEQ ID NO: 184 CDR3 heavy chain can be Variable region (H57, H78) (g) CDR1 containing SEQ ID NO: 176, SEQ ID NO: 198 CDR2, SEQ ID NO: CDR3 heavy chain variable region of 184 (H71, H92). CDR1 comprising SEQ ID NO: 9; SEQ ID NO: 199; CDR2, SEQ ID NO: CDR3 of 184, heavy chain variable region (Η97, Η98). (i) CDR1 comprising sequence identification number: 200 Identification number: CDR2 of 170, sequence identifier: light chain variable region of CDR3 of 193 (L11) (j) CDR1 containing sequence identification number: 201 No.: CDR2 of 170, SEQ ID NO: LR3 light chain variable region of 193 (L12) (k) CDR1 comprising SEQ ID: 202, SEQ ID NO: 170 CDR2, SEQ ID NO: 193 CDR3 Light chain variable region (L17). (1) CDR1 comprising SEQ ID NO: 203, SEQ ID NO: 22 201028165 CDR2, SEQ ID NO: 193 CDR3 light chain variable region (L50). Specific examples of the combination of the above-mentioned substituted antibodies include the following antibodies: (i) an antibody comprising the heavy bond variable region of (c) and the light chain variable region of (k) (ii) a heavy chain comprising (d) An antibody against the variable region and the light chain variable region of (k) (iii) an antibody comprising a heavy chain variable region of (e) and a light chain variable region of (k)

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

(v) an antibody comprising a heavy chain variable region of (g) and a light chain variable region of (k). (vi) an antibody comprising a heavy chain variable region of (h) and a light chain variable region of (1). (C) NS23 (1) CDR2 having the amino acid sequence 0 comprising: sequence identification number: nCHCDR1), CDR2 having the amino acid sequence of sequence identification number: 18 (HCDR2) having the sequence identifier: 19 An antibody to the heavy chain variable region of CDR3 of the amino acid sequence of (HCDR3); (2) an antibody having a heavy chain variable region of SEQ ID NO: 20 (VH); (3) having an inclusion: having a sequence identifier CDR1 of amino acid sequence of 21 (LCDR1), CDR2 of amino acid sequence having sequence identification number: 22 (LCDR2), light chain of CDR3 having amino acid sequence of SEQ ID NO: 23 (LCDR3) An antibody of a variable region; (4) an antibody having a light chain variable region of SEQ ID NO: 24 (VL); 23 201028165 (5) having a heavy chain variable region of (1) and (3) a light chain variable (6) An antibody having the heavy chain variable region of (2) and the light chain variable region of (4); (7) wherein the antibody according to any one of (1) to (6) has 1 An antibody having one or more amino acids substituted, absent, increased, and/or inserted, having the same activity as the antibody of any of (iX6); (8) and (1) to (7) Documented antibody Binding of epitopes (epitopes) to the same epitope-binding antibody. (EONS33 (1) has a CDR1 comprising: an amino acid sequence having the sequence identifier: 25 (HCDR1), a CDR2 having an amino acid sequence of SEQ ID NO: 26 (HCDR2), having a sequence identifier: 27 (HCDR3) An antibody to the heavy chain variable region of CDR3 of the amino acid sequence; (2) an antibody having a heavy chain variable region of SEQ ID NO: 28 (VH); (3) having an inclusion: having a sequence identifier: 29 CDR1 of the amino acid sequence of (LCDR1), CDR2 of the amino acid sequence having the sequence identification number: 3〇(LCDR2), and light chain of the CDR3 having the amino acid sequence of SEQ ID NO: 31 (LCDR3) (4) an antibody having a light chain variable region of sequence identification number: 32 (VL); (5) an antibody having a heavy chain variable region of (1) and a 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); (1) or a plurality of antibodies according to any one of (1) to (6) An antibody having an amino acid substituted, absent, increased, and/or inserted, having the same activity as the antibody of any one of (丨) to (6); (8) and (1) to (7) Recorded antibody binding The antigenic epitope 24 201028165 (epi tope) is an antibody that binds to the same epitope. Any of the above-described (1) or (3) antibodies may be used in any framework region (FR), but it is preferably used from a human. Further, in the antibody of the above (1) to (8), any constant region may be used for the constant region, but a constant region derived from human is preferably used. The FR of the FR or constant region used in the antibody of the present invention The acid sequence may be directly used as the amino acid sequence of the original FR or constant region, or may be a different amino acid sequence in which one or more amino acids are substituted, absent, increased and/or inserted. The heavy chain amino acid sequence is shown in SEQ ID NO: 34, and the nucleotide sequence encoding the amino acid sequence is shown in SEQ ID NO: 33. The light chain amino acid sequence of NS18 is, for example, the sequence number: 36 The nucleotide sequence encoding the amino acid sequence is shown in SEQ ID NO: 35. The heavy chain amino acid sequence of NS22 is represented by SEQ ID NO: 38, and the nucleotide sequence encoding the amino acid sequence is as a sequence. Identification number: 37. Also Μ" light chain The amino acid sequence is shown in SEQ ID NO: 4〇, and the nucleotide sequence of the amino acid sequence is as shown in SEQ ID NO: 39. The heavy chain amino acid sequence of the above NS23 is as follows: As shown, the base sequence encoding the amino acid sequence is shown in SEQ ID NO: 41. Further, the light chain amino acid sequence of NS23 is represented by SEQ ID NO: 44, and the sequence of the base acid sequence is as shown in sequence (IV). No.: 43. The heavy chain amino acid sequence of the above NS33 is shown in SEQ ID NO: 46, and the sequence encoding the amino acid sequence is shown in SEQ ID NO: 45. Further, the light chain amino acid sequence of =33 is represented by SEQ ID NO: 48, and the nucleotide sequence encoding the amino acid sequence is shown by SEQ ID NO: 47. 25 201028165 In the present invention, "the same activity as the antibody of any one of (1) to (6)" means that the binding activity and/or the neutralizing activity to NR1〇 (for example, human NR1〇) are the same as in the present invention. For a certain degree of activity, it may be a live 14 enhancer' or it may be limited to those with activity and reduced activity. The antibody having reduced activity may, for example, be an antibody having an activity of 30% or more as compared with the original antibody, preferably an antibody having an activity of 50% or more, and more preferably an antibody having an activity of 80% or more. The antibody according to any one of the above (1) to (6) is limited to having a binding activity and/or a neutralizing activity to NR1(), and the % amino acid sequence of the variable region (CDR sequence and/or FR sequence) may have One or more amino acids are substituted, absent, increased and/or inserted. Familiar with this technique in order to produce amino acid sequences in an amino acid sequence in which one or more amino acids have been substituted, lacked, increased and/or inserted and have binding activity and/or neutralizing activity to NR1 oxime. Methods known to those skilled in the art are known for methods of introducing proteins into mutations. For example, people in this technical field use site-specific mutation induction (Hashim〇t〇_G〇t〇h, 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. 1 00, 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 26 201028165 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 Kunke1, TA (1 985) Rapid and efficient site-specific mutagenesis without phenotypic selection. Proc Natl Acad Sci US A. 82,488-492 ) Alternatively, a mutant which is functionally identical to an antibody having NR10-binding activity and/or neutralizing activity can be produced by introducing an appropriate mutation to an amino acid sequence having an antibody having NR10 binding activity and/or neutralizing activity. . Therefore, an antibody having one or a plurality of amino acid mutations in the variable region and having NR10-binding activity and/or neutralizing activity is also included in the antibody of the present invention. In the case of mutating an amino acid residue, it is desirable to mutate other amino acids while preserving the nature of the amino acid side chain. For example, the nature of the amino acid side chain can be, for example, a hydrophobic amino acid (A, I, L, Μ, F, P, W, Y, V), a hydrophilic amino acid (r, d, n, c, E, q, g, h, k, s, t), an amino acid having an aliphatic side chain (G, A, V, L, I, P), an amino acid having a pendant side chain (S , T, Y), amino acids with a sulfur atomic side chain (c, M), amino acids with carbonic acid and guanamine side chains (D, N, E, Q), with base-containing side chains Amino acids (R, K, Η), and amino acids containing aromatic side chains (Η, F, Y, W) (amino acids in parentheses in parentheses). The amino acid substitutions within these groups are referred to as retention substitutions. It is known that a multi-peptide having an amino acid sequence which lacks, increases and/or is modified by other amino acid residues of one amino acid sequence of an amino acid sequence maintains its biological properties. Activity 27 201028165

(Mark, DF et a 1., Proc. Natl. Acad. Sci. USA (1984) 81: 5662-6; Zoller, MJ and Smith, M., Nucleic Acids Res. (1982) 10:6487-500; Wang, A. et a 1., Science (1984) 224: 1431-3; Dalbadie-McFarland, G. et al., Proc. Natl. Acad. Sci. USA (1982) 79: 6409-13). Such a mutant has at least 70% amino acid sequence identity of the amino acid sequence of the variable regions of the invention (e.g., CDR sequences, FR sequences, variable regions), preferably at least 75% 'better. It is at least 80%, more preferably at least 85%, even more preferably at least 90%, most preferably at least 95%. The sequence identity in this specification is defined as 'the sequence identity is maximized and the sequence is adjusted as needed. After introduction of the appropriate gap (gap), the amino acid sequence residue of the original heavy chain variable region or the light chain variable region is disabled. The same ratio of residues to the base. The identity of the amino acid sequence can be determined according to the method described later.

In the amino acid sequence of the variable region (CDR sequence and/or FR sequence), one or more amino acids have been substituted, absent, increased, and/or inserted and have binding activity and/or neutralization to NR10. The amino acid sequence of the variable region of activity can also be obtained from a nucleic acid which hybridizes under stringent conditions to a nucleic acid formed by the base sequence encoding the variable region amino acid sequence. The nucleic acid formed by isolating the nucleic acid sequence of the sequence encoding the amino acid sequence of the variable region I is hybridized under stringent conditions. The stringent hybridization conditions are as follows: 6M urea, 0.4% SDS, 0.5x SSC, 37C or This equal stringent hybridization condition. Higher stringent conditions, such as the use of 6M urea, 〇. 4% SDS, 〇·lx SSC conditions, 42. (:, separation of nucleic acids of higher identity can be expected. The determination of the isolated nucleic acid sequence is carried out by a method described later. The nucleic acid identity of the separation has at least 50% or more of the sequence identity of the entire base sequence 28 201028165, Preferably, the sequence identity is more than 7〇%, more preferably 90% or more (for example, 95%, 96%, 97%, 98%, 99% or more). The variation can be utilized to substantially synthesize the method using the above hybridization technique. A gene amplification method for introducing a primer sequence encoding a base region of a variable region amino acid sequence, for example, by using a polymerase chain reaction (PCR) method, isolating a nucleic acid formed by a base sequence encoding a variable region amino acid sequence A nucleic acid that hybridizes under stringent conditions.

The identity of the sequence and the amino acid sequence can be based on Karl in and A1tschul

The algorithm BLAST (Proc. Natl. Acad. Sci. USAC 1 993) 90 : 5873-7 ) is decided. Based on this algorithm, BLASTIN or BLASTX software was developed (Altschul et al., J. Mol. Biol. (1990) 215: 403-10). In the case of analyzing the base sequence by BLASTN on the basis of BLAST, the parameters are, for example, sc〇re = 1 〇〇, w〇rdlength = 12. Further, based on BLAST, in the case of analyzing the amino acid sequence by BLASTX, the 'parameter is, for example, score = 50, wordlength = 3. When using BLAST and gapped BLAST software, the default parameters of each software are used. The specific operation of these analytical methods is known (refer to NCBI (National Center for

Biotechnology Information ) BLAST ( Basic Local

Alignment Search Tool ) http://www.ncbi.nlm.nih.gov). The present invention also provides an antibody which binds to the same epitope as the antigenic epitope (ep i tope) of the antibody according to any one of (1) to (7). 29 201028165

Whether the antibody recognizes the same epitope as the other antibodies, and τ φ confirms the competition between the two epitopes. Competition between antibodies can be evaluated based on competitive binding assays such as ELISA, fluorescence energy transfer assay (FRET), and fluorescent microassay (FMAT (trademark)). The amount of the aforementioned antibody that binds to the antigen is indirectly related to the binding ability of the candidate competitive antibody (detected antibody) which competes for binding to the same epitope. That is, in the case where the amount and affinity of the antibody to be detected at the same epitope are increased, the amount of antigen binding to the antibody is decreased, and the amount of the antibody to the antigen to be detected is increased. Specifically, the antibody to which the antigen is simultaneously added with an appropriate marker and the antibody to be evaluated are used to detect the bound antibody. The amount of the antibody bound to the antigen can be easily determined by pre-labeling the antibody. This drum is not particularly limited, and the identification method according to the evaluation method is selected. The identification method is specifically, for example, a fluorescent marker, a radiation marker, an enzyme marker, and the like. For example, the antibody expressing the NR10 is simultaneously added with the fluorescent marker and the antibody or the antibody to be detected, and the labeled antibody is detected by a fluorescent microassay technique.

The "antibody for recognizing the same epitope" is a concentration of 5% by weight (iC5) of the binding amount of the unlabeled antibody to the labeled antibody, and the antibody to be detected is an ICs having no antibody. Usually a concentration of 1 〇〇, preferably 80 times' more preferably 5G times, even more preferably 3 () times and more preferably U times the concentration, which is a combination of at least 5% of the labeled antibody A reduced amount of antibody. The above-mentioned antigen-determining antibody ′ that binds to the antibody of any one of (1) to (7) is useful from the viewpoint of having particularly high neutralizing activity. 30. The antibody described in any one of the above (1) to (8) is preferably a non-specific antibody. Furthermore, the present invention provides a gene encoding the anti-NR10 according to any one of the above (1) to ({)) (1) gas 8). The gene of the present invention may be any gene such as MA or RNA. Antibody (humanization) One of the preferred aspects of the antibody of the present invention, such as a human that binds to 〇1〇

Typed antibodies. Humanized antibodies can be made using methods known to those skilled in the art. The variable region of the antibody is usually composed of three complementarity determining regions (CDRs) in four frameworks (FR). A CDR is a region that substantially determines the specificity of antibody binding. The amino acid sequences of the CDRs are diverse. The amino acid sequence constituting one of the FRs exhibits high identity even among antibodies having different binding specificities. Therefore, in general, the binding specificity of an antibody can be transplanted to other antibodies via CDR grafting. The humanized antibody is also known as a reshaped human antibody, and is a CDR that is transplanted to a human antibody from a mammalian CDR, and a general genetic recombination method is also known (refer to European Patent Application Publication No. Ep). 1 25023, W0 96/02576 ). Specifically, for example, in the case where the CDR is derived from a mouse antibody, a DNA sequence designed to link the framework region of the minima CDR to the human antibody (framew〇rk regi〇n; FR) is composed of the terminal regions at both the CDR and the FR. Several raised nucleotides produced by overlapping portions were used as primers and synthesized by PCR (see 31 201028165).

Test W098/13388). The resulting DNA is ligated to the j)NA encoding the human antibody, and then incorporated into the expression vector, and the vector is introduced into the host to obtain the DNA. (European Patent Application Publication No. EP 2 3 9 4 0, International Patent Application Publication No. W0 96/02576). The framework region of the human antibody linked to the CDR selects the complementarity determining region to form a good antigen binding site. As desired, the recombination-determining region of the human antibody may form an appropriate antigen-binding site, and the amino acid of the framework region in the antibody variable region may be substituted, absent, increased, and/or inserted. For example, an amino acid mutation can be introduced into FR by applying a PCR method in which a mouse CDR is transplanted into human FR. Specifically, a mutation of a partial base sequence can be introduced into a primer that is anneal to the FR. A mutation in the SEQ ID sequence is introduced into the FR synthesized by such a primer. The binding activity of the antigen of the amino acid-substituted mutant antibody is measured and evaluated by the above method, and the FR sequence having the desired property can be selected (Sato, K. et al., Cancer Res. (1993) 53, 851-856. ).

For the C region of the humanized antibody, those using human antibodies, for example, η chain can use C?M, Cr2, Cr3, Cr4, C#'C (5, Cd, Ca2, Ce, L chain can use C / c, C λ The amino acid sequence of C / c is as shown in SEQ ID NO: 58 'The sequence encoding the amino acid sequence is shown in SEQ ID NO: 57. The amino acid sequence of C 7 1 is such as the sequence identifier. The nucleotide sequence encoding the amino acid sequence is shown in SEQ ID NO: 59. The amino acid sequence of cr 2 is shown in SEQ ID NO: 6 2, and the amino acid sequence is encoded. The base sequence is shown as SEQ ID NO: 61. The amino acid sequence of C r 4 is shown in SEQ ID NO: 6 4 'The sequence encoding the amino acid sequence is shown in Sequence Identification 32 201028165: 63. Further, in order to improve the stability of the antibody or its production, the C region of the human antibody may be modified. The modified human antibody c region is, for example, the region c described later. The human antibody used in the humanization may be [gG, IgM, Any isotype of human antibodies such as igA, igE, igD, etc., but preferably used in the present invention

IgG. IgG, lgG2, IgG3, lgG4, etc. can be used for IgG. After production of a humanized antibody, the amino acid in the variable region (eg, CDR, FR) and constant region can also be substituted, absent, increased, and/or inserted with other amino acids.

Alternatively, the humanized antibody of the present invention may also comprise a humanized antibody such as such an amino acid substitution. The source of the CDR in the humanized antibody is not particularly limited and may be derived from any animal. For example, a sequence of a mouse antibody, a rat antibody, a rabbit antibody, a road wheel antibody or the like can be used, but a CDR sequence of a mouse antibody is preferred. In the humanization of an antibody, it is difficult to humanize in a state in which the binding activity and neutralizing activity of the original antibody are maintained, but in the present invention, the same binding activity and/or medium as the original mouse antibody is successfully obtained. And humanized antibodies. Humanized antibodies have reduced immunogenicity in the human body and are therefore effective for administration to humans for therapeutic purposes. In a preferred embodiment of the humanized anti-NR10 antibody of the present invention, for example, the antibody according to any one of the following (a) to (e) can be used. (a) a humanized antibody comprising a heavy chain variable region having an amino acid sequence of sequence identification number j〇(h〇-VH); (b) comprising an amine having the sequence identifier: ii2 (Hl-VH) a humanized antibody of a heavy chain variable region of a base acid sequence; (c) a humanized antibody comprising a light chain variable region of 33 201028165 comprising the amino acid sequence of SEQ ID NO: 52 (L0-VL); d) humanization of a heavy chain variable region comprising an amino acid sequence having a sequence identifier: 50 (H0-VH) and a light chain variable region having an amino acid sequence of sequence number: 52 (L0_VL) (e) a humanized antibody comprising a heavy bond variable region having the amino acid sequence of SEQ ID NO: 11 2 and a light chain variable region having the amino acid sequence of SEQ ID NO: 52. a heavy chain variable region having the amino acid sequence of sequence identification number: 50 (H0-VH), a heavy chain variable region having the amino acid sequence of sequence identification number: 112, and having the sequence identification number: 52 (L0) The light chain variable region of the amino acid sequence of -VL) may have 1 or a plurality of amino acids substituted, absent, increased and/or inserted. Substitution, deletion, addition and/or insertion of the amino acid can be carried out in the CDR or FR, or can be carried out in both the CDR and FR. Therefore, in another preferred embodiment of the humanized anti-NR1 〇 antibody of the present invention, for example, the antibody of any one of the following (f) to (j) can be used. (f) an antibody comprising a heavy bond variable region in which one or more amino acids of the amino acid sequence having the sequence identifier: 5〇 (HO-VH) are substituted, absent, increased and/or inserted; g) an antibody comprising a heavy chain variable region in which one or more amino acids of the amino acid sequence having the sequence identifier: 112 (H1-VH) are substituted, deleted, increased and/or inserted; (h) An antibody comprising a light chain variable region in which one or more amino acids of the amino acid sequence having the sequence identifier: 52 (l〇-VL) are substituted, absent, increased and/or inserted; 34 201028165 (〇 a heavy chain variable region comprising one or more amino acids having a sequence identifier of 50 (H0-V'H) substituted, lacking, increasing and/or inserted, and having a sequence identifier An antibody of a light bond variable region in which one or more amino acids of the amino acid sequence of 52 (L0-VL) are substituted, absent, increased, and/or inserted;

(j) a heavy chain variable region comprising one or more amino acids in the amino acid sequence having the sequence identifier: 112CH1-VH) substituted, deleted, added and/or inserted, and having a sequence identifier: An antibody to a light chain variable region in which one or more amino acids of the 52CL0-VL) are substituted, lacked, increased, and/or inserted. The antibody of any one of (f) to (j) preferably has the same activity as the antibody of any one of (a) to (e). The substitution, absence, addition and/or insertion of the amino acid are not particularly limited, but specifically, for example, the above-described amino acid substitution can be carried out. More specifically, for example, the following amino acid substitutions. In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, the ile of position 3 of CDR1 (SEQ ID NO: 9) is replaced by Val (sequence identification number: 73). Accordingly, the present invention provides that in the heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, CDR1 having the amino acid sequence of SEQ ID NO: 9 is replaced with sequence recognition. No.: heavy chain variable region of CDR1 of the amino acid sequence of 173. In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, the Met at position 4 of CDR1 (SEQ ID NO: 9) is substituted with I le (sequence identification number: 174). Thus, the present invention provides CDR1 in the heavy chain variable region of the amino acid sequence having the sequence identification number: 50 or the sequence 35 201028165 column identification number: 112, and the amino acid sequence of the female dandelion sequence number: The heavy chain variable region of CDR1 having the amino acid sequence of SEQ ID NO: 174 was replaced.

The Met of position 4 of CDR1 (SEQ ID NO: 9) in the variable region of sequence identification number: 50 or sequence identification number: 112 is substituted with Leu (sequence identification number: 1 75). Accordingly, the present invention provides that in the heavy chain variable region having the amino acid sequence of SEQ ID NO: 5 〇 or SEQ ID NO: 112, the CDR1 having the amino acid sequence of SEQ ID NO: 9 is replaced with Sequence ID: heavy chain variable region of CDR1 of the amino acid sequence of 175. In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, the lie of position 3 of CDR1 (SEQ ID NO: 9) is replaced with AU (sequence identification number: 176). Accordingly, the present invention provides that in the heavy chain variable region having the amino acid sequence of sequence identifier: 5〇 or sequence identifier: 112, the CDR1 having the amino acid sequence of SEQ ID NO: 9 is replaced with a sequence. Identification number: heavy chain variable region of CDR1 of the amino acid sequence of 176.

In the heavy chain variable region of the sequence identifier No. 50 or the sequence identifier: 112, the Leu of the first position of the CDR2 (SEQ ID NO: 1〇) is substituted with Glu (SEQ ID NO: 113). Thus, the present invention provides that in the heavy chain variable region having the amino acid sequence of SEQ ID NO: 5 〇 or SEQ ID NO: 112, the CDR2 having the amino acid sequence of SEQ ID NO: 1 被 is replaced with Sequence ID: heavy chain variable region of CDR2 of the amino acid sequence of 113. In the heavy chain variable region of sequence identification number: 50 or sequence identification number: 11 2, the Asn of position 3 of the CDR2C sequence identification number: 1〇) is substituted with Asp (SEQ ID NO: 114). Thus, the present invention provides that in the heavy chain variable region having the amino acid sequence of sequence identification number: 5 〇 or 36 201028165 SEQ ID NO: 112, the CDR2 having the amino acid sequence of SEQ ID NO: 1 被 is replaced Is the heavy chain variable region of CDR2 having the amino acid sequence of SEQ ID NO: 114. In the heavy chain variable region of sequence identification number: 50 or sequence identification number: 112, the Gin of position 13 of the CDR2C sequence identifier: 1〇) is substituted with Asp (SEQ ID NO: 115). Therefore, the present invention provides that the CDR2 having the amino acid sequence of SEQ ID NO: 10 is substituted with the heavy chain variable region having the amino acid sequence of SEQ ID NO. 5 〇 or SEQ ID NO: 112. The heavy chain variable region of CDR2 having the amino acid sequence of the sequence identification reference number: 115. In the heavy chain variable region of sequence identification number: 50 or sequence identification number: 112, the 14th position of the CDR2C sequence identification number: 1〇) is substituted with Gln (sequence identification number: 116). Thus, the present invention provides that in the heavy chain variable region having the amino acid sequence of SEQ ID NO: 5〇 or SEQ ID NO: 112, the CDR2 having the amino acid sequence of SEQ ID NO: 1 被 is replaced with Sequence ID: heavy chain variable region of CDR2 of the amino acid sequence of 116.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, the 16th Lys of CDR2C SEQ ID NO: 10) is substituted with Gln (SEQ ID NO: 117). Accordingly, the present invention provides that in the heavy chain variable region having the amino acid sequence of sequence identifier: 5〇 or SEQ ID NO: 112, the CDR2 having the amino acid sequence of SEQ ID NO: 1 被 is replaced with Sequence ID: heavy chain variable region of CDR2 of the amino acid sequence of 117. In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, the Gly at position 17 of CDR2 (SEQ ID NO: 10) was replaced with Asp (SEQ ID NO: 118). Thus, the present invention provides that in the heavy chain variable region having the amino acid sequence of SEQ ID NO: 5〇 or 37 201028165 SEQ ID NO: 112, the CDR2 having the amino acid sequence of SEQ ID NO: 10 is replaced with The heavy chain variable region of CDR2 having the amino acid sequence of SEQ ID NO: 118. In the heavy chain variable region of sequence identification number: 50 or sequence identifier: 112, the 16th Ly s of CDR2 (sequence ID: 10) is replaced by g 1 η and the 1st 7th G1 y is Substituted as Asp (sequence identification number: 119). Accordingly, the present invention provides that in the heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, the CDR2 having the amino acid sequence of SEQ ID NO: 10 is replaced with a sequence. Identification number: heavy chain variable region of CDR2 of the amino acid sequence of 119. In the heavy chain variable region of sequence identification number: 50 or sequence identification number: 112, Lys of position 14 of CDR2 (sequence identification number: 10) is substituted with G1 η, and Lys of position 16 is substituted with Gin, And the 17th Gly was replaced by Asp (preface)

Column identification number: 167). Accordingly, the present invention provides that in the heavy chain variable region having the amino acid sequence of SEQ ID NO: 50 or SEQ ID NO: 112, the CDR2 having the amino acid sequence of SEQ ID NO: 10 is replaced with sequence recognition. No.: heavy chain variable region of CDR2 of the amino acid sequence of 171. In the heavy chain variable region of sequence identification number: 50 or sequence identification number: 112, Gin at position 13 of CDR2C sequence identification number: 10) is substituted with Asp, and Lys at position 14 is replaced with Gin, 16th. The Lys of the position is substituted with Gin, and the Gly of the 17th position is substituted with Asp (SEQ ID NO: 172). Accordingly, the present invention provides that the CDR2 having the amino acid sequence of SEQ ID NO: 1 被 is substituted with a CDR2 having a SEQ ID NO: 1 胺 or amino acid sequence of SEQ ID NO: 112 Sequence ID: heavy chain variable region of CDR2 of 胺72 amino acid sequence 38 201028165. In the heavy chain variable region of sequence identification number: 50 or sequence identifier: 112, the 10th Ser of CDR2 (SEQ ID NO: 1〇) is substituted with Asp (SEQ ID NO: 1 77). Thus, the present invention provides that in the heavy chain variable region having the amino acid sequence of SEQ ID NO: 5〇 or SEQ ID NO: 112, the CDR2 having the amino acid sequence of SEQ ID NO: 1 被 is replaced with Sequence ID: heavy chain variable region of CDR2 of the amino acid sequence of 177.

In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 12, Gin at position 13 of CDR2 (SEQ ID NO: 1 〇) is substituted with pro (SEQ ID NO: 1 7 8 ). Accordingly, the present invention provides that in the heavy chain variable region having the amino acid sequence of sequence identification number: 5 〇 or SEQ ID NO: 11 2, the CDR2 having the amino acid sequence of SEQ ID NO: 10 is substituted with Sequence ID: heavy chain variable region of CDR2 of the amino acid sequence of 178. In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, the Tyr at position 3 of CDR3 (SEQ ID NO: 11) is substituted with Leu (SEQ ID NO: 17 9 ). Thus, the present invention provides that in the heavy bond variable region of the amino acid sequence having the sequence identifier: 5 〇 or SEQ ID NO: 112, the CDR3 having the amino acid sequence of SEQ ID NO: 11 is replaced with a sequence. Identification number: heavy chain variable region of CDR3 of the amino acid sequence of 179. In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, the Met of the first CDR of CDR3 (SEQ ID NO: 11) is substituted with Leu (SEQ ID NO: 180). Thus, the present invention provides that in the heavy chain variable region having the amino acid sequence of SEQ ID NO: 5 〇 or SEQ ID NO: 112, the CDR3 having the amino acid sequence of SEQ ID NO: 11 is replaced with a sequence. The heavy chain variable region of CDR3 of the amino acid sequence of 180 is identified in 39 201028165. In the heavy chain variable region of sequence identification number: 50 or sequence identifier: 112, the 11th Asp of CDR3 (SEQ ID NO: 11) is substituted with Glu (SEQ ID NO: 181). Accordingly, the present invention provides that in the heavy chain variable region having the amino acid sequence of sequence identifier: 5 〇 or SEQ ID NO: 112, the CDR3 having the amino acid sequence of SEQ ID NO: 11 is replaced with a sequence. Identification number: heavy chain variable region of CDR3 of the amino acid sequence of 181. In the variable region of the sequence identification number: 50 or the sequence identifier: 112, the Tyr of the 12th position of the CDR3 (SEQ ID NO: 11) is substituted with Thr (SEQ ID NO: 182). Accordingly, the present invention provides that in the heavy chain variable region having the amino acid sequence of sequence identifier: 5〇 or SEQ ID NO: 112, the CDR3 having the amino acid sequence of SEQ ID NO: 11 is replaced with a sequence. Identification number: heavy chain variable region of CDR3 of the amino acid sequence of 182. In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, the Tyr of position 12 of CDR3 (SEQ ID NO: 11) is substituted with Ser (SEQ ID NO: 183). Accordingly, the present invention provides that in the heavy chain variable region having the amino acid sequence of sequence identifier: 5〇 or SEQ ID NO: 112, the CDR3 having the amino acid sequence of SEQ ID NO: 11 is replaced with a sequence. Identification number: The heavy bond variable region of CDR3 of the amino acid sequence of 183. In the variable region of sequence identification number: 50 or sequence identification number: 112, the Met of the 10th position of the CDR3C sequence identification number: 11) is replaced by Leu, and the Asp of the 11th position is replaced by Glu and the 12th place. Tyr was replaced by Thr (SEQ ID NO: 184). Accordingly, the present invention provides that in the heavy chain variable region having the amino acid sequence of sequence identifier: 5〇 or SEQ ID NO: 112, the CDR3 having the amino acid sequence of the sequence 201028165, the identification number: 11 is replaced with The heavy bond variable region of CDR3 having the amino acid sequence of SEQ ID NO: 184. In the heavy chain variable region of sequence identification number: 50 or sequence identifier: 112, the 11th position of the CDR3C sequence identification number: 11) is substituted with Glu and the Tyr of position 12 is substituted with Thr (sequence identification number). :185). Thus, the present invention provides an amino acid sequence having the sequence identifier: 11 in the heavy chain variable region of the amino acid sequence having the sequence identifier: 50 or the sequence identifier: 11 2

The CDR3 was replaced with a heavy chain variable region having the sequence identifier: 185 CDR3. In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 112, the third position Tyr of CDR3 (SEQ ID NO: 11) is substituted with Leu, and the 11th Asp is The Tyr substituted with Glu and the 12th position was substituted with Thr (SEQ ID NO: 18 6). Accordingly, the present invention provides that in the heavy chain variable region having the amino acid sequence of sequence identifier: 5 〇 or SEQ ID NO: 112, the CDR3 having the amino acid sequence of SEQ ID NO: 11 is replaced with a sequence. Identification

No.: heavy chain variable region of CDR3 of the amino acid sequence of 186. In the heavy chain variable region of SEQ ID NO: 50 or SEQ ID NO: 11 2, Tyr at position 3 of CDR3 (SEQ ID NO: 11) is substituted with Leu, and Asp at position 11 is replaced with Glu and The Tyr of position 12 was replaced by Ser (sequence number: 187). Accordingly, the present invention provides that in the heavy chain variable region having the amino acid sequence of sequence identifier: 5〇 or SEQ ID NO: 112, the CDR3 having the amino acid sequence of SEQ ID NO: 11 is replaced with a sequence. Identification number: heavy chain variable region of CDR3 of the amino acid sequence of 187. SEQ ID NO: CDR1 (SEQ ID NO: 13) 41 in the light-chain variable region of DD 2 The Arg at position 1 of 201028165 was replaced with Gln (SEQ ID NO: 121). Accordingly, the present invention provides that the CDR1 having the amino acid sequence of SEQ ID NO: 13 is substituted with an amino group having the SEQ ID NO: 121 in the light chain variable region having the amino acid sequence of SEQ ID NO: 52. The light chain variable region of the CDR1 of the acid sequence is 0. In the light chain variable region of 52, the Asn at position 5 of CDR1 (SEQ ID NO: 13) is substituted with Asp (SEQ ID NO: 122). Accordingly, the present invention provides that the CDR1 having the amino acid sequence of SEQ ID NO: 13 is substituted with an amine having the SEQ ID NO: 122 in the light chain variable region having the amino acid sequence of SEQ ID NO: 52. The light chain variable region of CDR1 of the base acid sequence. In the light chain variable region of sequence identification number: 52, the Ser of the 8th position of CDR1 (SEQ ID NO: 13) was substituted with Arg (SEQ ID NO: 188). Accordingly, the present invention provides that the CDR1 having the amino acid sequence of SEQ ID NO: 13 is substituted with an amino group having the SEQ ID NO: 188 in the light chain variable region having the amino acid sequence of SEQ ID NO: 52. The light chain variable region of CDR1 of the acid sequence. In the light chain variable region of sequence identification number: 52, the Leu at position 10 of the CDRK sequence identifier: 13) is substituted with Val (SEQ ID NO: 189). Accordingly, the present invention provides that in the light chain variable region having the amino acid sequence of SEQ ID NO: 52, the CDR1 having the amino acid sequence of SEQ ID NO: 13 is substituted with an amino group having the sequence number: 189. The light chain variable region of CDR1 of the acid sequence. SEQ ID NO: 52 in the light chain variable region, CDR1 (SEQ ID NO: 13) The Ser at position 8 of 201028165 is substituted with Arg and Leu at position 1 Replaced by Va 1 (sequence identification number: 1 90). Accordingly, the present invention provides that in the light chain variable region having the amino acid sequence of SEQ ID NO: 5 2, CDR1 having the amino acid sequence of SEQ ID NO: 13 is replaced with a sequence identifier: 1 9 〇 The light bond variable region of CDR1 of the amino acid sequence. In the light chain variable region of SEQ ID NO: 52, Thr of the second position of CDR1 (SEQ ID NO: 13) was replaced with A1 a (SEQ ID NO: 191). therefore,

The present invention provides that the CDR1 having the amino acid sequence of SEQ ID NO: 13 is substituted with an amine having the SEQ ID NO: 1 91 in the light bond variable region having the amino acid sequence of SEQ ID NO: 5 2 The light chain of CDR1 of the acid sequence is variable. The sequence identification number: 52 in the light bond variable region, the second bit of CDR 1 (SEQ ID NO: 13) is replaced by Ser (sequence identification number: 192 ). Accordingly, the present invention provides that in the light chain variable region having the amino acid sequence of SEQ ID NO: 52, the CDR1 having the amino acid sequence of SEQ ID NO: 13 is substituted with an amino group having the sequence identifier: 192. In the light chain variable region of CDR1 of the acid sequence: in the light chain variable region of 52, the Asn at position 1 of CDR2 (SEQ ID NO: 14) is substituted with Asp (SEQ ID NO: 123). Accordingly, the present invention provides that in the light chain variable region having the amino acid sequence of SEQ ID NO: 52, the CDR2 having the amino acid sequence of SEQ ID NO: 14 is substituted with an amino group having the SEQ ID NO: 123 The light chain of the CDR2 of the acid sequence is variable (3⁄4 〇 SEQ ID NO: 52 in the light chain variable region, CDR2 (SEQ ID NO: 14) 43 The 3rd Lys of 201028165 is substituted with Gin (SEQ ID NO: 124). Accordingly, the present invention provides that in the light chain variable region having the amino acid sequence of SEQ ID NO: 52, the CDR2 having the amino acid sequence of SEQ ID NO: 14 is replaced with the sequence identifier: 124 The light chain variable region of CDR2 of the amino acid sequence. Sequence identification number: 52 in the light chain variable region, CDR2 (SEQ ID NO: 14) · The 5th Leu is substituted with Glu (SEQ ID NO: :125). Accordingly, the present invention provides that in the light chain variable region having the amino acid sequence of SEQ ID NO: 52, the CDR2 having the amino acid sequence of SEQ ID NO: 14 is replaced with a sequence identifier: Light chain variable region 0 of CDR2 of the amino acid sequence of 125. Sequence ID: 52 In the light chain variable region, the Lys at position 7 of CDR2 (SEQ ID NO: 14) is substituted with Gin (SEQ ID NO: 126). Thus, the present invention provides an amino acid having the sequence identifier: 52. In the light chain variable region of the sequence, the CDR2 having the amino acid sequence of SEQ ID NO: 14 is replaced

Is the light chain variable region 0 of the CDR2 having the sequence identification number: 1 26 amino acid sequence: the light chain variable region of 52: the Lys of the 7th position of the CDR2 (SEQ ID NO: 14) is Substituted as Asp (SEQ ID NO: 127). Accordingly, the present invention provides that in the light chain variable region of the amino acid sequence having the sequence identification number: 52, the CDR2 having the amino acid sequence of SEQ ID NO: 14 is replaced with the sequence identifier: 1 27 Light chain variable region of CDR2 of amino acid sequence SEQ ID NO: 52 light chain variable region, CDR1 (SEQ ID NO: 13) 44 201028165 The first position of Arg is replaced by Gin and the 5th position Asn is replaced by Asp (SEQ ID NO: 169). Accordingly, the present invention provides that in the light chain variable region having the amino acid sequence of SEQ ID NO: 52, the CDR1 having the amino acid sequence of SEQ ID NO: i 3 is replaced with the sequence identifier: 丨69 The light chain variable region of CDR1 of the amino acid sequence. In the light chain variable region of sequence identification number: 52, the Lys of position 3 of CDR2 (SEQ ID NO: 14) _ is substituted with Gln, the Leu of position 5 is substituted with Glu, and the Lys of position 7 is substituted. Is Gln (sequence identification number: 170). Thus, the present invention provides that the CDR2 having the amino acid sequence of SEQ ID NO: 14 is substituted with an amine having the SEQ ID NO: 170 in the light chain variable region having the amino acid sequence of SEQ ID NO: 52. The light chain variable region of CDR2 of the basal acid sequence. In the light chain variable region of sequence identification number: 52, the Glu at position 5 of CDR3 (SEQ ID NO: 15) was substituted with Asp (SEQ ID NO: 193). Accordingly, the present invention provides that in the light chain variable region having the amino acid sequence of SEQ ID NO: 52, the CDR3 having the amino acid sequence of SEQ ID NO: 丨5 is substituted with an amine having the SEQ ID NO: 193. The light chain variable region of CDR3 of the base acid sequence. In the light chain variable region of sequence identification number: 52, the Ser of position 6 of CDR3 (SEQ ID NO: 15) was replaced with Asp (SEQ ID NO: 194). Accordingly, the present invention provides that in the light chain variable region having the amino acid sequence of SEQ ID NO: 52, the CDR3 having the amino acid sequence of SEQ ID NO: 丨5 is substituted with the SEQ ID NO: 194 amine Light chain variable region of CDR3 of the base acid sequence 0 45 201028165 Sequence identification number: In the light chain variable region of 5 2, Thr at position 9 of CDR3 (SEQ ID NO: 15) is substituted with Phe (SEQ ID NO: :195). Accordingly, the present invention provides that in the light chain variable region having the amino acid sequence of SEQ ID NO: 52, the CDR3 having the amino acid sequence of SEQ ID NO: 15 is replaced with an amine having the SEQ ID NO: 1 95 The light chain variable region of CDR3 of the base acid sequence. Further, the substitution other than the above amino acid substitution may be, for example, the third Arg in the heavy chain FR2 having the amino acid sequence of the sequence identification number: 97 substituted with another amino acid. The amino acid after substitution is not particularly limited, but may preferably be, for example, Gin. Further, it is also possible that the third Arg of the sequence identification number: 97 is substituted with Gin, the fifth Ala is replaced by Ser, and the FR2 is a human sequence. In the amino acid sequence of sequence identification number: 97, the Arg at position 3 is substituted with Gin, and the Ala at position 5 is substituted with the amino acid sequence of Ser, as shown in SEQ ID NO: 126. Accordingly, the present invention provides that in the heavy chain variable region having the amino acid sequence of sequence identifier: 50 or sequence identifier: 11 2, FR2 having the amino acid sequence of SEQ ID NO: 97 can be replaced with Heavy chain variable region of FR2 having the sequence identification number: amino acid sequence of 1-20. The above amino acid substitution may be used singly or in combination with the other amino acid described above. It may also be combined with an amino acid substitution other than the above. Specific examples of the antibody subjected to the above substitution may, for example, be an antibody comprising a heavy chain variable region having an amino acid sequence of SEQ ID NO: 167, and a light chain variable region comprising an amino acid sequence having SEQ ID NO: 168. An antibody, a heavy chain variable region comprising the amino acid sequence having the sequence identification number: 167, and an antibody having a light chain variable region having the amino acid sequence of the sequence 46 201028165, No. 168. Further, specific examples of the above-described substituted heavy chain variable region include the following double bond variable regions. (1) The heavy chain variable region (H17) having the sequence identification number: amino acid sequence of 2〇4; (2) the heavy chain variable region having the amino acid sequence of SEQ ID NO: 205 - (H19) (3) Heavy chain variable region with sequence identification number: amino acid sequence of 2〇6•❿(H28); (4) Heavy chain with sequence identification number: amino acid sequence of 2〇7 Region (H30); (5) heavy chain variable region (H34) having the amino acid sequence of SEQ ID NO: 208; (6) heavy chain variable having the amino acid sequence of SEQ ID NO: 209 District (H42);

(7) a heavy chain variable region (H44) having the amino acid sequence of sequence identification number: 210; (8) a heavy chain variable region (H46) having the amino acid sequence of SEQ ID NO: 211; a heavy chain variable region (H57) having the amino acid sequence of sequence identification number: 212; (10) a heavy chain variable region (H71) having the amino acid sequence of SEQ ID NO: 213; (11) SEQ ID NO: 47 heavy chain variable region of the amino acid sequence of 214 201028165 (H78); (12) heavy chain variable region (H92) having the amino acid sequence of SEQ ID NO: 215; (13) Sequence identification number: heavy chain variable region of the amino acid sequence of 216 (H97); (14) Heavy chain variable region (H98) having the amino acid sequence of SEQ ID NO: 217. Further, specific examples of the light chain variable region in which the above substitution is carried out include the following light chain variable regions. (15) a light chain variable region (L11) having the amino acid sequence of SEQ ID NO: 218; (16) a light bond variable region (L12) having the amino acid sequence of SEQ ID NO: 219; a light chain variable region (L17) having the amino acid sequence of sequence identification number: 220; (18) a light chain (L50) having the amino acid sequence of SEQ ID NO: 221. <Resistance of the specific chain variable region of the antibody The above-mentioned heavy chain variable region and light chain variable region are exemplified by the following antibodies. (19) a heavy chain variable region comprising (3) and a light body (H28L17) of (17); < an anti-light chain variable region of the light chain variable region (20) comprising (4) a chain variable region and (17) (H30L17); (21) a heavy chain variable region comprising (5) and (17) 201028165 (H34L17); (22) a heavy chain variable region comprising (6) (17) an antibody to a light chain variable region (H42L17); (23) an antibody comprising a heavy bond variable region of (7) and (a light chain variable region of 1 ( (H44L17); (24) comprising (8) The heavy chain variable region and the anti-body of the light chain variable region of UO (H46L17); (25) the heavy bond variable region comprising (9) and (the light chain variable region of 1 (H57L17); (26) an antibody comprising a heavy bond variable region of (10) and (a light chain variable region of 1 ( (H71L17); (27) a heavy chain variable region comprising (11) and a light chain variable of (17) a region antibody (H78L17); (28) an antibody (H29L17) 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) comprising the heavy chain variable region of (14) and the light chain of (18) Transformer antibody (H98L50). The constant region used in the humanized antibody of the present invention is not particularly limited, and any constant region derived from a human antibody can be used. Any constant region from a human antibody is preferably, for example, from a genomic region of IgGl or igG2. It is also possible to use a constant region in which one or more amino acids are substituted, absent, increased, and/or inserted in the value region of the human antibody. 49 201028165 A region derived from the substitution, absence, addition, and/or insertion of one or a plurality of amino acids in the constant region of a human antibody is not particularly limited, but may be, for example, the following constant region. Constant region with amino acid sequence of sequence identification number: 128 (M58); constant region with amino acid sequence of sequence identification number: 12 9 (Μ14); constant with amino acid sequence of sequence identification number: 62 District (SKSC). Specific examples of the heavy chain or antibody using the above constant region include the following heavy chains or antibodies. (1) a variable region comprising the amino acid sequence having the sequence identifier: 167 and a sequence identifier: a heavy chain of the deuterated region of the amino acid sequence of 1 2 8; (2) in the (1) heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 171 is substituted with the heavy chain of CDR2 having the amino acid sequence of SEQ ID NO: 1 72; (3) comprising (1) a heavy chain and having a sequence identifier: An antibody to the light chain of the amino acid sequence of 1 5 2;

(4) An antibody comprising (2) a heavy chain and a light chain having the amino acid sequence of SEQ ID NO: 152. More specific examples of the humanized anti-NR10 antibody of the present invention include the antibodies of any one of (k) to (o). (k) an antibody comprising a heavy chain having an amino acid sequence of sequence identification number: 54 (H0-VH + constant region); (1) comprising a sequence identification number: 130 (H1-VH+'|·亘定区) An antibody to the heavy chain of the amino acid sequence; (m) an antibody comprising a light chain of the amino acid 50 201028165 sequence having the sequence identifier: 56CL0-VL + constant region; (η) comprising the sequence identification number: 54CH0 -VH + constant region) the heavy chain of the amino acid sequence and the antibody having the light chain of the amino acid sequence of sequence identification number: 56 (L0-VL + constant region); (〇) contains the sequence identification number: 130CH1- The heavy chain of the amino acid sequence of the VH+ constant region) and the antibody having the light chain of the amino acid sequence of SEQ ID NO: 56 (L0-VL+ constant region). Furthermore, the heavy chain of the amino acid sequence having the sequence identifier: 54CH0-VH + constant region) and the light chain having the amino acid sequence of the sequence identifier: 56 (LD-m region) may have one Or a plurality of amino acids are substituted, absent, increased, and/or inserted. The substitution, absence, addition and/or insertion of the amino acid can be carried out in the variable or constant region' and can also be carried out 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 amino acid having one or more amino acids substituted, absent, increased, and/or inserted in an amino acid sequence of sequence identification number: 54 (H0-VH + strange region) An antibody to the heavy chain of the sequence; (q) having one or more amino acids substituted, absent, increased, and/or inserted in the amino acid sequence of SEQ ID NO: 130 (H1-VH+ constant region) An antibody to the heavy chain of an amino acid sequence; (r) one or more amino acids contained in the amino acid sequence of SEQ ID NO: 56 (L0-VL + constant region) are substituted, absent, increased, and / or an antibody to the light chain of the inserted amino acid sequence; (s) one or more amino acids substituted or absent in the amino acid sequence comprising the sequence number: 54 (H0-VH + constant region) , adding and/or inserting the heavy chain of the amino acid sequence of 51 201028165, and having one or more amino acids in the amino acid sequence of sequence identification number: 56 (L0-VL + constant region) An antibody lacking, increasing, and/or inserting the light chain of the amino acid sequence; (t) an amino acid sequence comprising the sequence identifier: 130 (H1-VH+ constant region) a heavy chain having an amino acid sequence in which one or more amino acids are substituted, absent, increased, and/or inserted, and an amino acid sequence in sequence number: 56 (L0-VL + constant region) An antibody having a light chain of one or more amino acids that are substituted, deleted, added, and/or inserted into an amino acid sequence. The antibody of any one of (P) to (t) preferably has the same activity as the antibody of any one of (k) to (〇). The substitution, absence, addition, and/or insertion of the amino acid are not particularly limited, but specific examples thereof may be carried out, for example, by the above-described amino acid substitution.

Further, the base sequence encoding the amino acid sequence of the above humanized heavy chain variable region (SEQ ID NO: 50) is represented by SEQ ID NO: 49, and the amine encoding the above humanized light chain variable region The base sequence of the base acid sequence (SEQ ID NO: 52) is as shown in SEQ ID NO: 51: the nucleotide sequence encoding the amino acid sequence of the above humanized heavy chain (SEQ ID NO: 5 4 ), such as sequence recognition No.: 5, the base sequence encoding the amino acid sequence of the above humanized light chain (SEQ ID NO: 56) is shown as SEQ ID NO: 55. Furthermore, the present invention provides an antibody which recognizes an epitope having the same epitope as that of the above-described (a) to (t), and which has been described for binding to the same epitope. The present invention further provides the antibody according to any one of the following (u) to (w). (U) 52 201028165 antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 151; (V) an antibody comprising a light chain having the amino acid sequence of SEQ ID NO: 1 52; (W) comprising ( U) antibodies to the heavy chain and (V) light chain. The present invention further provides a heavy bond, a light chain, or an antibody as described in any one of the following. (1) Heavy chain (H17) having the amino acid sequence of SEQ ID NO: 222 (2) Heavy chain having the amino acid sequence of SEQ ID NO: J23 (H19)

(3) Heavy chain with sequence identification number: amino acid sequence of 224 (H28) (4) Heavy chain with sequence identification number: amino acid sequence of 225 (H30) (5) with sequence identification number: 226 The heavy chain of the amino acid sequence (H34) (6) has the heavy chain of the amino acid sequence of SEQ ID NO: 227 (H42) (7) Heavy chain with the amino acid sequence of SEQ ID NO: 228 (H44) (8) Heavy chain with sequence identification number: 229 amino acid sequence (H46) (9) Heavy chain with sequence identification number: amino acid sequence of 230 (H57) (10) with sequence identifier: 231 The heavy chain of the amino acid sequence (H71) (11) has the heavy chain of the amino acid sequence of sequence identification number: 232 (H78) (12) heavy chain with the amino acid sequence of sequence identification number: 233 (H92) (13) Heavy chain with sequence identification number: amino acid sequence of 234 (H97) (14) Heavy chain with sequence identification number: amino acid sequence of 235 (H98) (15) with sequence identifier: 236 The light chain of the amino acid sequence (L11) (16) has the light chain (L1 2) of the amino acid sequence of SEQ ID NO: 237 (1 轻 light chain with the amino acid sequence of SEQ ID NO: 238 (L17) (1 8) Light chain (L50) 09 having the sequence identification number: amino acid sequence of 239 ()) (3) heavy chain and (17) light chain antibody (H28L17); 53 201028165 (20) containing (4) heavy chain And (π) light chain antibody (H30L17); (21) an antibody comprising (5) a heavy chain and (17) a light chain (H34L17); (22) an antibody comprising (6) a heavy chain and (17) a light chain (H42L17); (23) an antibody comprising (7) a heavy chain and (17) a light chain (H44L17); (24) an antibody comprising (8) a heavy chain and (17) a light chain (H46L17); (25) comprising (9) heavy chain and (17) light chain antibody (H57L17); (26) antibody containing (10) heavy chain and (π) light chain (H71L17); (27) containing (11) heavy chain and (17) a light chain antibody (H78L17); (28) an antibody comprising (12) a heavy chain and (17) a light chain (H92L17); (29) an antibody comprising (13) a heavy chain and (18) a light chain (H97L50) (30) An antibody (H98L50) comprising (14) a heavy chain and (18) a light chain; (31) having one or a plurality of amine groups in the heavy chain according to any one of (1) to (14) a heavy chain of an amino acid sequence in which the acid is substituted, absent, increased, and/or inserted; (32) In the light chain of any one of (15) to (18), one or A light bond in which the amino acid is substituted, absent, increased, and/or inserted into the amino acid sequence; (33) In the antibody of any one of (19M30), one or more amino acids are substituted An antibody that lacks, increases, and/or inserts an amino acid sequence; (34) an antibody that recognizes an epitope corresponding to the epitope determined by the antibody of any of (19M33). Substitution, deficiency, addition and/or insertion of amino acids are as described above. An antibody that recognizes the same epitope as the antigenic epitope of the antibody as described above. 54 201028165 0 The invention further provides a variable region encoding the invention, a heavy chain of the invention, a light chain of the invention or an antibody encoding the invention Gene. The present invention further provides a vector comprising the above gene. • The invention further provides host cells transformed with the vectors described above. The invention further relates to a method of producing a variable region of the invention, a heavy chain of the invention, a light chain of the invention, or an antibody of the invention, comprising the step of culturing said host cell. The culture of the vector, the host cell, and the host cell is as follows. Domain identification antibody One of the preferred aspects of the anti-NR 10 antibody of the present invention, for example, an antibody of domain 1 or an antibody of recognition region (d〇fflain) 2. In the present invention, 'region 1 is the amino acid of the 2nd position in the state containing the message peptide (si gna 1 pept i de ) in the amino acid sequence of the human nri〇 of the sequence identification number: 76 to the 120th position The region of the amino acid (lpakP~LENIA). In the present invention, the 'region 2 is the amino acid of the 121st position of the amino acid sequence of the NR10 sequence of the human NR10 described in the sequence identification number: 76, and the amino acid of the 227th position in the state of the signal peptide. (KTEPP~EEEAP). The antibody is not particularly limited, but is usually an antibody having neutralizing activity, preferably a humanized antibody. Examples of preferred antibodies in the present invention include antibodies recognizing the region 1. The antibody of the recognition region 1 has high neutralizing activity and is particularly useful as a pharmaceutical. Antibody (neutralizing activity) 55 201028165 The present invention further provides an antibody having neutralizing activity against NR1 〇. The neutralizing activity against NR1〇 in the present invention is an activity of inhibiting the binding of NR1〇 to its ligand (1 igand) IL-31, and is preferably an activity of inhibiting the physiological activity based on NR1 〇.

The classification of the antibody having the NR10-neutralizing activity can be carried out, for example, by observing the growth inhibitory effect of the il_3i-dependent cell line when a candidate antibody is added to the IL-31-dependent cell line. The antibody which inhibits the proliferation of the IL-31-dependent cell line in the above method is judged to be an antibody having neutralizing activity against NR1. Antibody (General) The antibody of the present invention is not limited, and may be any animal-derived antibody such as a human antibody, a mouse antibody, or a rat antibody. A recombinant antibody such as a chimera antibody or a humanized antibody may also be used. As described above, preferred antibodies of the invention may, for example, be humanized antibodies.

The antibody to death is an antibody composed of a 0i milk animal other than human, for example, a variable region of a heavy chain or a light chain of a mouse antibody, and a constant region of a heavy chain or a light chain of a human antibody. Chimeric antibodies can be made using known methods. For example, it can be carried out by cloning an antibody gene from a hybridoma, incorporating an appropriate vector, and introducing the vector into a host (for example, Carl, A. K.

Borrebaeck, James, W. Larrick, THERAPEUTIC MONOCLONAL ANTIBODIES, Published in the United

Kingdom by MACMILLAN PUBLISHERS LTD, 1 990). Specifically, cDNA of an antibody variable region (v region) is synthesized from the mRNA of the fusion tumor using reverse transcriptase. The DNA of the V region encoding the antibody of interest is ligated to the DNA encoding the human antibody constant region (C region) of the desired 56 201028165, and this is incorporated into the expression vector. Alternatively, the DNA encoding the V region of the antibody may be incorporated into a expression vector containing DNA of the human antibody c region. The expression control region, such as the form of the original control expression of the enhancer and the promoter, is incorporated into the expression vector. Secondly, the vector is transformed into the host cell via the expression vector, and the posterior antibody is expressed. Furthermore, the method of obtaining human antibodies has also been known. For example, in vitro (eg, by sputum) with the desired antigen or cells expressing the desired antigen, the human lymphocytes are immunized, and the immunized lymphocytes are fused with human myeloma cells such as U266. A desired human antibody having an antigen-binding activity can also be obtained (see U.S. Patent 1-57987). Further, a transgenic animal having a full-length human antibody gene is resuscitably immunized with a desired antigen to obtain a desired human antibody (refer to w〇93/12227, W0 92/03918, W0 94/). 02602, W0 94/25585, W0 96/34096, WO 96/33735). Further, a technique of obtaining a human antibody by a panning method using a human antibody phage 1 ibrary is also known. For example, the human antibody variable region is made into a single-chain antibody (scFv), and is expressed on the surface of the bacillus by a phage display, and a phage which binds to the antigen can be selected. Analysis of the selected phage gene determines the DNA sequence encoding the variable region of the human antibody that binds to the antigen. If the DNA sequence of the scFv that binds to the antigen is clearly ', an appropriate expression vector having the sequence can be made to obtain a human antibody. Such a method is well known, and can be referred to W0 92/01047, W0 92/20791, W0 93/06213, W0 93/11236, W0 93/19172, W0 95/01438, 57 201028165 WO 95/15388, and the like. The antibody of the present invention is limited to those having a binding activity and/or a neutralizing activity of NR1〇, and includes not only a divalent antibody represented by IgG but also a monovalent antibody, or a multivalent antibody represented by IgM. A bispecific antibody that binds to different antigens. The multivalent antibody of the present invention comprises a multivalent antibody having all of the same antigen binding sites, or a multivalent antibody having a part or all of different antigen binding sites. The antibody of the present invention is not limited

The full-length molecule 'antibody' may be a small-densified antibody or a modification thereof as long as it binds to the NR1 〇 protein. The antibody of the present invention may also be a small molecule antibody. The small-molecule antibody is an antibody having an antibody fragment partially deficient in a full-length antibody (such as a full-length IgG), and is not particularly limited to having a binding activity to NR1〇 and/or a neutralizing activity. The small molecule antibody of the present invention is not particularly limited except for the full-length portion, but preferably includes a heavy chain variable region (VH) or a light chain variable region (VL), particularly including and

The small molecule antibody is preferred. Further, as another preferred example of the small molecule antibody of the present invention, a small molecule antibody containing an antibody CDR can be mentioned. The CDRs contained in the small molecule antibody may comprise all of the six CDRs of the antibody, and may also comprise a portion of the CDRs. The small-molecule antibody of the present invention preferably has a molecular weight longer than a full-length antibody, such as a dimer, a triffler, a tetramer, or the like. The antibody is larger. Specific examples of antibody fragments, such as Fab, Fab, F(ab,) 2, Fv, and the like. 58 201028165 Specific examples of small molecule antibodies, such as Fab, Fab, FUb, w, π, scFv (single-chain Fv), bifunctional antibody (diab〇dy), sc (f〇2 (single-chain chain scare 2 A multimer (for example, a binary, a ternary, a quaternary, or a polymer) of the antibody described herein is also included in the small molecule antibody of the present invention. The antibody fragment can be obtained, for example, from an enzyme. The antibody is processed to form an antibody sheet. An enzyme that forms an antibody fragment, such as papain, pepsin, or plasmin (in), is known. Alternatively, a gene encoding the antibody fragment can be constructed. After introduction of the expression vector, it is expressed in a suitable host cell (for example, Co' M.S_ et al,, lmmunol·(1 994) 152, 2968 2976 > Better, M. & Horwitz, AH Methods in Enzymology (1989) 178 , 476_496 , piueckthun, A· &

Skerra, A. Methods in Enzymology (1989) 178, 497 515, Lamoyi, E., Methods in Enzymology (1989) 121' 652 663 Rousseaux, J. et al., Methods in Enzyraology (1989) 121, 663-66 > Bird, RE et al., TIBTECH (1991) 9, 132-137.). The digestive enzyme cleaves the specific position of the antibody fragment, and an antibody fragment of a specific structure as described below is administered. Antibody fragments obtained from such enzymes can be deficient in any part of the antibody by genetic engineering. The antibody fragment obtained when the above digestive enzyme was used is shown below. Papaya enzyme: F(ab)2 or Fab pepsin: F(ab,)2 or Fab, plasmin: Facb 59 201028165 The small molecule antibody of the present invention is limited to having binding activity to NR1 〇 And/or neutralizing activity, which may comprise antibody fragments lacking any region. A diabody is a bivalent antibody fragment constructed by gene fusion (Holliger p 0t al,

Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993), EP404, 097, W093/11161, etc.). A bifunctional antibody (diab〇dy) is a dimer composed of two multi-peptide bonds. In general, the multi-peptide linkers constituting the binary each bind VL to VH as a linker (1 inker) in the same chemical bond. The linker (1 inker) in a diabody is usually shorter than where VL and VH cannot bind to each other. Specifically, the amino acid residue constituting the linker is, for example, about 5 residues. Thus, VL and VH encoded on the same multi-peptide chain cannot form single-stranded variable region fragments, but form other single-stranded variable region fragments and dimers. This result makes the bifunctional antibody (d i abody) a site having two antigen binding sites. The scFv antibody is an antibody that binds to the heavy chain variable region ([VH]) and the light chain variable region ([VL]) as a single-chain polypeptide by a linker (Π nker) or the like (Huston, JS et al., Proc Natl. Acad. Sci. USA (1 988) 85, 5879-5883, Pluckthun "The Pharmacology of Monoclonal Antibodies" Vol. 113, edited by Resenburg and Moore, Springer Verlag, New York, pp. 269-31 5, (1 994)) = The H chain V region and the L chain V region of scFv may also be derived from any of the antibodies described in the present specification. The peptide linker (li nker) linked to the V region is not particularly limited. For example, any single-stranded peptide formed from about 3 to 25 residues can be used as a linker 201028165 (linker). Specifically, for example, a peptide linker or the like described below can be used. The V-chain of the two strands can be linked using, for example, the above PCR method. In order to link the V region by PCR, first, DNA encoding the entire amino acid sequence or the desired partial amino acid sequence is used as a template in the following DNA. A DNA sequence encoding an antibody Η chain or Η chain V region, and a DNA sequence encoding an antibody L bond or L chain V region. Each of the DNAs encoding the V region of the Η bond and the L chain is amplified by a pair of 'PCR-based' primers having a sequence corresponding to the sequence of the both ends of the DNA to be amplified. Next, prepare a continent A that encodes a partial peptide linker (1丨nker). The DNA encoding the peptide linker was synthesized by PCR. At the 5' end of the primer used at this time, the base sequence which can be ligated to the respective amplified V region amplification products has been added. Next, a PCR reaction was carried out using [H chain v region DNA] _ [peptide peptide DNA] - [L chain V region DNA] DNA and primer for assembly PCR.

Φ The primer for assembly pCR is composed of an primer which is connected to the 5' end of the DNA of the V region and an primer which is anal to the end of the [L chain v region MA] 3 . That is, the primer for the aggregation (assemMy) pCR is a primer set which can amplify the DNA encoding the full length sequence of the scFv to be synthesized. On the other hand, a base sequence which can be linked to each v region dna is added to [peptide peptide DNA]. As a result, the DNA described herein was linked, and the amplification product of the full-length scFv was finally produced by the primer for polymerization PCR. Once the DNA encoding the scFv is produced, the expression vector containing the aforementioned DNA, and the recombinant cell transformed from the expression vector can be obtained by following the usual method. Further, the scFv can be obtained by expressing the recombinant cell obtained by the cultivation of the result of the scFv. The order of the bound heavy chain variable region and the light chain variable region is not particularly limited, and may be arranged in any order, for example, in the following order. [VH] linker [VL] [VL] linker [VH] . sc(FV)2 is 2 VH and 2 single-stranded small molecule antibodies bound by a linker (Hudson et al, j Immun〇 1. Meth〇ds 1 999; 231 M77-189). For example, sc(Fv)2 can combine scFv with a linker to make 0. Although 2 VH and 2 VL are preferably based on the N-terminus of the single-stranded multi-peptide, according to VH, VL, VH, VL ([VH] The order of the linker [VL] linker [VH] linker [VL]) is linked to a characteristic antibody, but the order of 2 vh and 2 VL is not particularly limited to the above configuration, and may be connected in any order. For example, the following sequence can be used.

[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] heavy chain variable region in small molecule antibody The amino acid sequence of the light chain variable region can also be substituted, deleted, added, and/or inserted. Further, in the case of combining a heavy chain variable region and a light chain variable region, it is limited to having antigen-binding activity, and partial deletion or addition of other multi-peptides may be caused. The variable region can also be embedded 62 201028165 chimera or humanized. In the present invention, a linker (1 i nker ) that binds to an antibody variable region can use any peptide linker that has been genetically engineered, or a linker of a synthetic compound, such as Protein Engineering, 9(3), 299-305, 1996. Reveal the connection. A preferred linker in the present invention is a peptide linker. The length of the peptide linker is not particularly limited and may be appropriately selected by those skilled in the art for the purpose, but is usually 1 to 1 amino acid, preferably 3 to 50 amino acids, more preferably 5 to 30. The amino acid is particularly preferably 12 to 18 amino acids (for example, 15 amino acids). The amino acid sequence of the peptide linker can be exemplified by the following sequence.

Ser G1y · Ser Gly · Gly · Ser

Ser · Gly · Gly p Gly· Gly· Gly· Ser (sequence ID::82)

Ser · Gly · Gly · Gly (sequence ID::83) G1 y · G1 y · G1 y . G1 y · Ser (sequence ID::84)

Ser · Gly · Gly · Gly . Gly (sequence ID::85)

Gly· Gly· Gly. Gly· Gly· Ser (sequence ID::86)

Ser· Gly· Gly· Gly· Gly· Gly (sequence ID::87)

Gly · Gly · Gly · Gly · Gly · Gly · Ser (sequence ID::88)

Ser · Gly . Gly · Gly · Gly · Gly · Gly (sequence identification number · 89 : (Gly · Gly · Gly · Gly · Ser (serial identification number:: 84) ) n 63 201028165 (Ser · Gly · Gly · Gly · Gly (sequence identification number::85) )n [η is an integer of 1 or more]. The amino acid sequence of the phenotype linker can be suitably selected by those skilled in the art for the purpose. For example, η which determines the length of the above-mentioned peptide linker is usually 丨_5, preferably 1-3' or more preferably 1 or 2. The linker of the synthetic compound (chemical cross-linking agent) is a commonly used cross-linking agent for cross-linking of peptides, such as hydrazine-hydroxysuccinimide (NHS), diammonium sulfoximine. Diacid vinegar (DSS), Bis(sulfosuccinimide) suberate (BS3), disulfide bis(succinimide propionate) (DSP), disulfide bis(sulfosuccinimide) Acid ester) (DTSSP), ethylene glycol bis(succinimide, succinic acid S) (EGS), ethylene glycol bis(sulfosuccinimide succinate sulfo-EGS), diammonium醯imino-based tartrate (DST), disulfosuccinimide-based tartrate (sulfo-DST), bis[2-(succinimide oxycarbonyloxy)ethyl] sulfone (BS0C0ES) And bis[2-(sulfoarylideneimidooxycarbonyloxy)ethyl]-((-)-----------

In the case of binding 4 antibody variable regions, it is usually necessary to have 3 linkers. Multiple connectors may use the same or different connectors. The antibody of the present invention also comprises an antibody having one or more amino acid residues added to the amino acid sequence of the antibody of the present invention. The antibody described herein also contains a fusion protein with other peptides or proteins. Preferably, the fusion protein is prepared by linking a polynucleotide encoding the antibody of the present invention to a polynucleotide encoding another peptide or a multi-peptide, and introducing the same into a expression vector, which is expressed in the injured host. A method known to those skilled in the art can be used. Other peptides or polypeptides fused to the antibodies of the invention may be used, for example, by flag 64 201028165 (Hopp, T. Ρ. et al., BioTechnology (1988) 6, 1204-1210), 6 His (histidine) residues 6xHis, 10xHis, influenza agglutinin (HA), human c-myc fragment, VSV-GP fragment, P18 HIV fragment, T7-tag, HSV-tag, E-tag, SV40T antigen fragment, lck tag, α - a known peptide such as a tubul in fragment, a B-tag, or a protein C fragment. Further multi-peptides fused to the antibodies of the invention, such as GST (glutathione-S-transferase), HA (influenza lectin), immunoglobulin constant region,/5-galactosidase , MBP (maltose binding protein) and the like. A commercially available polynucleotide encoding the aforementioned peptide or polypeptide is fused to a polynucleotide encoding the antibody of the present invention to thereby modulate the fusion polynucleic acid, and a fusion polypeptide can be produced. The antibody of the present invention may be a conjugate antibody which binds to various molecules such as a polyethylene glycol (PEG) or hyaluronic acid, a radioactive substance, a fluorescent substance, a luminescent substance, an enzyme, and a toxin. The binding antibody described herein can be obtained by chemically modifying the obtained antibody. antibody

A modification method of US has been established in this technical field (for example, US 5057313 5156840). The "antibody" in the present invention also includes the conjugate antibody described herein. Moreover, the antibody used in the present invention may also be a bispecific antibody. A bispecific antibody is an antibody having variable regions that recognize different epitopes within the same antibody molecule. In the present invention, the bispecific antibody may be a bispecific antibody that recognizes different epitopes on the NR1〇 molecule, one antigen binding site recognizes NR1 0, and the other antigen binding site recognizes a bispecific anti-65 201028165 body of another substance. For example, a method for identifying an antigen and a bispecific antibody is known to be a combination of different antibodies, and Sword & φ & j m is used as a bispecific antibody. The bound antibodies may each be a 1/2 molecule having an 胄Η chain and an L chain, or may be a 1/4 molecule having only the H chain. Alternatively, 'a fusion cell producing a different monoclonal antibody (hybrid) can be used to produce a fusion cell that produces a bispecific antibody. A bispecific antibody can be produced by a genetic engineering method. The antibody of the present invention is produced after the production. Antibody cell and host or pure

The method can be different in the amino acid sequence, molecular weight, isoelectric point or presence or absence of a sugar chain or type. However, the obtained antibody is included in the present invention as long as it has the same function as the antibody of the present invention. For example, in the case where the antibody of the present invention is expressed by a prokaryotic cell (e.g., Escherichia coli), the thiosamine is added to the N-terminus of the amino acid sequence of the antibody itself to "(10) 匕 ... residue. Antibodies of the invention also include such antibodies. Antibody production

The antibody of the present invention may be a plurality of antibodies or a monoclonal antibody. A monoclonal antibody having binding activity and/or neutralizing activity to NR 1 可 can be obtained, for example, by forming an immunogen with NR1 〇 or a fragment thereof from a mammal such as a human or a mouse, and producing an anti-NR10 by a known method. After the monoclonal antibody, an antibody having NR1 〇 binding activity and/or neutralizing activity is classified from the obtained anti-NR10 monoclonal antibody. That is, a desired antigen or a cell expressing a desired antigen is used as an antigen for generating immunity, and a general immunization method is performed to generate an immunity. The obtained immune cells are fused with a known parental cell by a general cell fusion method to screen antibody-producing cells 66 201028165 (hybrid〇ma) of a single antibody by a general screening method, and can produce an anti-NR1 〇. Individual antibodies. The immunized animal can use mammals such as mice, rats, rabbits, sheep, donkeys, goats, magnets, cows, horses, pigs and the like. The production of the antigen can be carried out by a known method using a known NR1 〇 gene sequence, for example, using a baculvirus (WO 98/46777, etc.). Method of waiting

The fabrication of fusion tumors can be based, for example, on Milstein (Kohler, G. and Milstein, c.

hZym〇1· (1 981 ) 73:3-46) and so on. The immunogenicity of the antigen is also low in combination with immunogenic macromolecules such as albumin. One of the antibodies having binding activity and/or neutralizing activity to NR1〇 of the present invention, for example, a monoclonal antibody having binding activity and/or neutralizing activity to human NR1 〇. An immunogen for producing a monoclonal antibody having binding activity and/or neutralizing activity to human NR1〇 is limited to the production of an antibody having binding activity and/or neutralizing activity to human NR1〇, and is not particularly limited. For example, human 0 NR10 is known to have a plurality of variants, but is limited to antibodies having binding activity and/or neutralizing activity to human NR10, and any variant can be used as an immunogen. Alternatively, under the same conditions, the peptide fragment of NR1〇 and the natural NR10 sequence may be added as an immunogen. Among the antibodies having the binding activity and/or neutralizing activity to the NR10 of the present invention, 'human NR10. 3' is one of the preferred immunogens. The measurement of the binding activity and/or the neutralizing activity of the antibody NR10 can be carried out, for example, by the method of observing the proliferation-inhibiting effect of the IL-31-dependent cell line as described in Example A. 67 201028165

DNA immunization (DNA, on the other hand, monoclonal antibodies can also be obtained via immunization). The DNA immunization is a vector DNA constructed by expressing a gene encoding an antigenic protein in an immunized animal, and the immunized animal is administered with an immunostimulating antigen in the immunized animal to give an immunostimulatory method. DNA immunization can be expected to have advantages as described below in comparison with general immunization methods for administering protein antigens. - It can maintain the structure of membrane proteins and give immune stimulation. - No need to purify immune antigens. However, on the other hand, in DNA immunization, it is difficult to combine with immunostimulatory means such as adjuvants. In the case of obtaining a monoclonal antibody by DNA immunization, the dna encoding nr1() is first administered to an immunized animal. The DNA encoding NR10 can be synthesized by a known method such as PCR. The resulting DNA is inserted into an appropriate expression vector and administered to an immunized animal. The expression vector can be, for example, a commercially available expression vector such as pCDNA3.1. The method of administering the vector to the living body can also be carried out by a method generally used. For example will

The gold particles adsorbing the expression vector are driven into the cells by gene gUm to perform DNA immunization. After DNA immunization, a booster cell is expressed by NR10, and a method for obtaining a monoclonal antibody is preferred. In the mammal thus immunized, after confirming that the amount of the antibody desired in the serum is increased, the immune cells are collected from the mammal to perform cell fusion. Preferred immune cells are particularly spleen cells. The cells fused with the above immune cells use mammalian myeloma cells. The myeloma cells are preferably screened with appropriate screening markers. A marker refers to a characteristic that can survive (or not) survive under specific culture conditions. In the marker, the hypoxanthine guanine phosphoribosyltransferase defect (hereinafter referred to as HGPRT defect) or the thymidine kinase defect (hereinafter referred to as TK defect), etc. It is known. Cells with HGPRT and TK defects have hypoxanthine-Aminopterin-Thymidine sensitivity (hereinafter referred to as HAT sensitivity). HAT-sensitive cells in the HAT screening medium will not die without DNA synthesis, but fusion with normal cells can continue the synthesis of j) na using the salvage pathway of normal cells' so even in HAT screening It can also proliferate in the medium. HGPRT-deficient and TK-deficient cells can be deoxyurized by containing 6-thioguanine, 8-azaguanine (hereinafter referred to as 8AG), or 5,-brominated deoxyuridine, respectively. The medium of (5,-bromodeoxyuridine) was selected. Normal cells are killed by taking the pyrimidine analogue into the DNA, but cells lacking such enzymes can survive in the screening medium because they do not take such pyrimidine analogs. Other screening markers called G418 tolerance are resistant to 2-deoxystreptamine antibiotics (gentamycin analogs) due to the neomycin tolerance gene. Receptive. A variety of myeloma cells suitable for cell fusion are well known. The cells of # are basically performed by a known method such as the method of Kohler and Milstein et al. (Kohler, G. and Milstein, C., Methods Enzymol. 69 201028165 (1 981 ) 73, 3-46.). Fusion. The sputum "cell and bone tumor cells are more specific, for example, cell fusion can be carried out in the same culture medium as in the case of cell fusion. The fusion promotes the use of the drug. PEG), Sendai virus (HVJ), etc. In order to - recombine the efficiency, you can also add dimethyl M (Dimethyl sulfQxide) and other (four) auxiliaries. The ratio of the use of immune cells and myeloma cells can be arbitrarily set. For example, In the case of myeloma cells, the culture medium used for the combination of the immune cells and the Φφ can be used, for example, a lip of a good cell, a culture solution, a lip of a surface culture, and other general cultures for such cell culture. In addition, the medium τ clear replenisher. The serum ((10) and other blood cell fusion system mixes the specific amount of immune cells and bone tumor cells in the liquid well, and pre-twisted by mixing..., the main PEG solution of about 37 C To form a fusion cell of interest (fusion tumor). In a fine fat sputum, for example, ppp + with an average molecular weight of about 1000 to about 6000.

After the PEG of U is usually added at a concentration of 30% (w/v), the appropriate culture solution as listed above is added, and the supernatant is removed by centrifugation, and the operation is repeated to remove the tumor growth. Cell fusion agent. The fusion tumor thus obtained can be smothered and smeared by using the screening marker of the sputum of the bone tumor used for cell fusion. For example, cells with HGPRT and sputum defects can be slowed down by η AT + iL 益 4 HAT medium (culture medium containing hypoxanthine, amino guanidine and thymidine). That is, the HAT-sensitive salty myeloma cells are used for the cell-incorporated sputum, ^, in the case of hydration, in the HAT culture solution, the cells successfully merged with the normal cells and the cells of the sigma σ are selectively selected. proliferation. Since the cells other than the tumor (non-fused cells) died, there is sufficient time to continue the culture using the above HAT medium. Specifically, it is usually possible to screen for the fusion tumor of interest after several days to several weeks. Therefore, screening and single cloning of fusion tumors producing the antibody of interest can be carried out by performing a general limiting dilution method. Alternatively, an antibody recognizing NR10 is produced according to the method described in 03/1〇4453. Screening and single selection of the antibody of interest can be suitably carried out based on a well-known antigen-antibody reaction. A carrier such as polystyrene or a commercially available 96-well microtiter plate is reacted with the antigen and reacted with the culture supernatant of the fusion tumor. Next, after washing the carrier, the enzyme-labeled secondary antibody or the like is reacted. In the case where the culture supernatant contains an antibody of interest which reacts with an antigen which produces an immunity, the secondary antibody binds to the carrier via the antibody. Finally, the detection of the secondary antibody bound to the carrier determines whether or not the antibody of interest is present in the culture supernatant. A fusion tumor which produces a desired antibody having an ability to bind antigen can be screened by a limiting dilution method or the like. In this case, the antigen is a starter, and an NR1 〇 protein having substantially the same properties can be suitably used. For example, a cell line expressing NR 1 、, a domain other than cells of NR 10 or a nucleotide sequence composed of an amino acid sequence constituting the region can be used as an antigen. In addition to the method of immunizing animal antigens other than humans to obtain the above-mentioned fusion tumors, it is also possible to produce antigen-sensitive rain from human lymphocytes to obtain an antibody of interest. Specifically, first in vitro (immunization of human lymphocytes with NR1 〇 protein. Secondly, the lymphocytes that have been immunized are fused with appropriate partner partners. The fusion partner can utilize, for example, humans with permanent 71 201028165 knife-cracking ability The antibody obtained by the method is a human antibody having an activity of binding to NR10 protein. The base sequence encoding the anti-NR1 0 antibody obtained by the above method or the like, and an amino group. The acid sequence can be obtained by a person skilled in the art by a known method. Moreover, the amino acid contained in the amino acid sequence described in the present invention can also be a case where G is decorated after translation (for example, the N-terminal giutamine is The pyrophthalic acid modification of pyroglutamine is a modification known to those skilled in the art. However, such an amino acid is included in the amino acid sequence described in the present invention even in the case of post-translational modification. Based on the obtained anti-NR10 antibody sequence, one skilled in the art can make anti-NR1 〇 antibodies using well-known genetic recombination techniques. Specifically, based on the antibody sequence recognizing NR10, constructing an oligonucleotide encoding the antibody, and introducing it into a expression vector, it is preferable to perform an appropriate prime cell (for example, C〇, MS et al., J. Immunol). (1994) 152, 2968-297; Better, M. and

Horwitz, A. H., Methods Enzymol. (1989) 178, 476-496; Pluckthun, A. and Skerra, A., Methods

Enzymol. (1989) 178, 497-515; Lamoyi, E., Mehtods

Enzymol. (1986) 121, 652-663; RRousseaux, J. et al.,

Mehtods Enzymol. (1986) 121, 663-669; Bird, R. E. and Walker, B. W., Trends Biotechnol. (1991) 9, 132-137.). Examples of the vector include, for example, an M13-based vector, a pUC-based vector, pBR322, pBluescript, pCR-Script, and the like. Further, in the case of subcloning and screening for cDNA, in addition to the above vectors, 72 201028165 , pT7 and the like. In production. In producing the antibody of the invention

In addition, for example, in the case of pGEM-Τ, pDIRECT, and in the purpose, the carrier is used in the case of a carrier, for example, by a membrane control; "; Table. (Ward et al., Nature (1989) 341, 544-546; FASEBJ. (1992) 6, 2422-2427), 240, 1041-1043) araB promoter (Better et al, Science (1988), or T7 promoter. Such vectors are in addition to the above vectors, such as pGEX-5X-1 (manufactured by Pharmacy), "QiAexpress system" (manufactured by Qiagen), pEGFP, or pET (in this case, the host is preferably BL21 which expresses T7 RNA polymerase). The vector may also contain a signal sequence for antibody secretion. The sequence of signals, in the case of the production of cytoplasmic (periplasma) of E. coli, can be used in the peiB message sequence (Lei, SP _ et al J. Bacteriol. (1 987) 169, 4379). Carrier introduction can be performed using, for example, calcium chloride method, electroporation

In addition to E. coli, a vector for producing an antibody of the present invention is, for example, a mammalian expression vector (for example, pcDNA3 (manufactured by Invitrogen) or pEF-BOS (Nucleic Acids. Res. 1990, 18(17), p5322) 'pEF, pCDM8), Expression vector derived from insects (for example, "Bac-to-BAC baculovirus expression system" (manufactured by GIBCO BRL), pBacPAK8), plant-derived expression vector (for example, pMH1, pMH2), expression vector from 73 201028165 virus (eg, pHSV, pMV, pAdexLcw), expression vector from retrovirus (eg PZI Pneo), expression vector from yeast (eg, "Pichia Expression Kit" (Invitrogen), PNV11 SP - Q01), from Bacillus subtilis For the performance vector (eg, pPL608, PKTH50), for the purpose of expressing animal cells such as CH0 cells, c〇s cells, and NIH3T3 cells, the vector expressing the plastid must have intracellular expression. • The necessary promoters such as sv4 〇 promoter (Mul丨igan et al, I (丨 979) 277, 108), MMLV_LTR & mover, EFla promoter (Mizushima% et al, Nucleic Acids Res. (1990) 18, 532 2) The 'CMV promoter or the like' is more preferably a gene for screening for cell transformation (e.g., a drug tolerance gene discriminating from a drug (neomycin, G418, etc.)). Vectors having such characteristics are, for example, PMAM, pDR2, pBK-RSV, pBK-CMV, pOPRSV, pOP13 and the like.

Further, in the case of stably expressing a gene and expanding the number of copies of a gene in a cell, for example, in a cell lacking a nucleic acid synthesis pathway, V is inserted into a vector having a DHFR gene complementary thereto (for example, psv2-dhfr ("Molecular Cloning 2nd edition"Cold Spring Harbor

Laboratory Press, (1989)), etc., in the case of amplification by methyl hydrazine (Methotrexate; MTX), or in the case of temporary gene expression, for example, a gene having an SV4〇τ antigen on a chromosome is used. The COS cells 'transformed as a vector having a SV40 origin of replication (pcD, etc.). The starting point of replication can be used from polyomavirus, adenovirus, bovine papilloma virus (BPV) 74 201028165 and the like. Moreover, in order to amplify the gene replication number by the host cell line, the expression vector may include an amino glycosyltransferase (APH) gene, a thymidine kinase (τκ) gene, and Escherichia coli A ribotransferase (Ecogpt) gene, a dihydrofolate reductase (dhfr) gene, or the like is used as a marker. Thus, the present invention provides a method for producing a encoded multi-peptide using the multi-peptide of the present invention or a gene encoding the multi-peptide of the present invention, comprising a host for culturing a vector into which a polynucleotide encoding a multi-peptide of the present invention is encoded. The steps of the cells. More specifically, a method of producing a multi-peptide of the present invention comprising the following steps is provided. (a) a step of cultivating a host cell comprising a vector into which a gene encoding a polypeptide of the present invention is introduced; (b) a step of obtaining a encoded multi-peptide by the gene. The antibody of the present invention thus obtained can be purified by cleavage from a host cell or an extracellular (culture medium or the like) to a substantially homogeneous antibody. For the separation and purification of the antibody, the separation and purification methods used for the usual antibody purification can be used without any limitation. For example, appropriate selection or combination of chromatography, filtration, restriction filtration, salting out, solvent precipitation, solvent extraction, distillation, Immunoprecipitation, sds-polyacrylamide gel electrophoresis, isoelectric point electrophoresis, dialysis, recrystallization, etc., can be used to separate and purify antibodies. Chromatography such as affinity chromatography, ion exchange chromatography, hydrophobic chromatography, gel filtration, reverse phase chromatography, adsorption chromatography, etc. (Strategies)

Protein Purification and Characterization: A Laboratory Course Manual. Ed Daniel R. Marshak et al. 75 201028165 c〇ld Spring Harbor T a 〇rat〇ry PreSS, 1996 ). The method described herein can be carried out by liquid chromatography using liquid chromatography such as HpLc or FpLc. A column used for affinity chromatography is, for example, a protein A column or a protein G column. For example, using protein A, you 丨 & u

Hyper D, P0R0S, Sepharose FF (GE Amersham Bi〇Sr; ..., ences) and the like. The present invention also encompasses the use of purified human* highly purified antibodies as described herein. The measurement of the binding activity of the obtained antibody to the NR1 〇 receptor can be carried out by a method known to those skilled in the art. For example, an ELISA (Enzyme-Linked Immunosorbent Assay), EIA (Enzyme-Free Immunoassay), RIA (Radioimmunoassay) or fluorescent antibody method can be used as a method for measuring the antigen-binding activity of an antibody. For example, when an enzyme immunoassay is used, a sample containing an antibody, for example, a culture supernatant of antibody-producing cells or a purified antibody, is added to an antigen-coated disk. A secondary antibody labeled with an enzyme such as phytase was added, and the plate was cultured, and after washing, an enzyme substrate such as p-nitrophenyl phosphate was added thereto, and the absorbance was measured to evaluate the antigen-binding activity. Pharmaceutical Composition The present invention provides a pharmaceutical composition containing the above antibody as an active ingredient. The present invention further provides a therapeutic agent for an inflammatory disease comprising the above antibody as an active ingredient. The inflammatory disease of the present invention is a blood vessel affected by a physical or chemical, or biologically acting substance, and an abnormal stimuli. The cytological and histological responses caused by adjacent tissues are accompanied by pathologically seen diseases (STEDMAN'S MEDICAL DICTIONARY, 5th ed., MEDICAL VIEW CO., LTD., 2005.). In general, inflammatory disease 76 201028165 diseases such as dermatitis (atopic dermatitis, chronic dermatitis, etc.), inflammatory bowel disease (colitis, etc.), asthma, arthritis (rheumatoid arthritis, deformed arthritis) Etc.), bronchitis, type 12 autoimmune disease, systemic lupus erythematosus, myasthenia gravis, chronic GVHD, Crohn's disease, osteoarthritis, low back pain, gout, inflammation after surgery, relief of swelling, nerve Pain, pharynx, laryngitis, cystitis, hepatitis (nonalcoholic steatohepatitis, alcoholic hepatitis, etc.), hepatitis B, hepatitis C, arteriosclerosis, itching, etc. Preferred examples of the inflammatory diseases of the subject of the present invention include atopic dermatitis, chronic dermatitis, rheumatoid arthritis, osteoarthritis, chronic pruritus and the like. The phrase "containing an anti-leg 0 antibody as an active ingredient" means at least one type containing an anti-Xie 抗体 antibody as an active ingredient, and the content rate is not limited. The therapeutic agent for an inflammatory disease of the present invention may also comprise other components which are combined with the above anti-rigid antibodies to promote the treatment of inflammatory diseases. Moreover, the therapeutic agents of the invention may also be used for prophylactic purposes. The anti-deletion antibody of the present invention can be formulated conventionally (e.g., -ngton^s Pharfflaceutical = PubushingC (10) pany, East 〇n, u s a). Moreover, it is also possible to include a pharmaceutically active agent (PEG τ竣^ additive. For example, it may include an interface with a sputum agent, an antioxidant (ascorbic acid, etc.), a material, a preservative, a stabilizer, a buffer (phosphoric acid, a lemon) An acid, a drug, a suspension agent, an isotonic agent, a combination of a cleaning agent, a lubricant, a prophylactic agent for promoting an inflammatory disease of the invention, and the like. However, the topping agent and/or a therapeutic agent are not limited thereto. As mentioned, it can also be applied to 77 201028165 when it contains other commonly used lactose, crystalline fiber sounds specifically 'for example, light anhydrous arsenoic acid, methyl cellulose nano: _ propyl = alcohol, temple powder, base cellulose about, slow : base cellulose, propyl methacrylate, polyethylene ethyl ethanoacetate, polyethylene ..., gelatin, medium-chain fatty acid diglycerin brewing, polyoxyethyl hydrazine hardening Tibetan hemp; from 6 〇, white sugar, Carboxymethyl fiber, only inorganic salts, etc. It may also contain other low molecular weight polypeptides, serum albumin, proteins such as gelatin and immunoglobulin, and amino acids. Anti-NR10 antibody is dissolved in the case containing physiological saline, Portuguese In an isotonic solution of sugar or other auxiliary drugs. The auxiliary drug may also be used, for example, D-sorbitol, d-mannose, D_mannitol, sodium chloride, etc., and a suitable dissolution aid such as an alcohol (ethanol) may be used in combination. Etc.), polyol (propylene glycol, PEG, etc.), nonionic surfactant (polysorbate 8〇, HCO-50), etc. Anti-NR10 antibody can be encapsulated in microcapsules (hydroxymethylcellulose, gelatin, poly Microcapsules such as [methyl methacrylate] can also be used as colloidal drug delivery systems (such as liposome, albumin microparticles, microemulsions, nanoparticles, and nanocapsules) (Ref. Remington, s Pharmaceutical ^

Science 16th edition &, Oslo Ed. (1980), etc.). Further, a method of preparing a pharmaceutical agent as a radioactive agent is also known, and is applicable to an anti-NR 1 〇 antibody (Langer et al., J. Biomed. Mater. Res. (1981) 15: 167-277; Langer, Chem. Tech· (1982) 12: 98-105; U.S. Patent No. 3,773,91 9; European Patent Application Publication (EP) No. 58, 481; Sidman et al., Biopolymers (1983) 22:547-56; EP 133, No. 988). 78 201028165 The pharmaceutical composition of the present invention can be administered parenterally. And the body is "\ non-mouth injection, but it is better: main injection ... and transdermal administration to the patient. The injection dosage form can be, for example, intravenous injection, intramuscular injection, subcutaneous or other systemic or local measures. + , one 'h, and again. It can also be used to inhibit the site of inflammation or its surrounding area...', and it is better to use intramuscular injection. The appropriate prescription, prescription, and prescription can be selected according to the patient's age and symptoms. The dosage can be selected, for example, that the active ingredient per #1 kg body weight is in the range of u001 mg g. Alternatively, for example, when a human patient is administered, each patient can be administered a range of U〇H()_g/kg body weight' The amount of the parent-human administration is preferably, for example, an amount of the antibody of the present invention. The amount of the anti-inflammatory agent for the inflammatory disease of the present invention is not limited to the administration amount described herein. All of the prior art references cited are incorporated into the present specification. [Example 1] Preparation of fusion tumors 1.1. Preparation of human NR10 plastids for MA immunization, Macaca fascicularis NR10 plastids 1.1.1. Production of hNRIO and cynNRIO expression vectors will be human NR10 (base sequence identification) Alias: 75, amino acid sequence sequence ID: 76) The vector pMacII (w〇20 05/) that is expressed under the control of the promoter of mouse wan-actin (/5_ac1; in). 054467) 'The hNRIO expression vector was produced. In the same way, the cynNRIO expression vector was constructed from Crab 猿1010 (base sequence SEQ ID NO: 65, amino acid sequence SEQ ID NO: 66). 1.1.2. DNA card c c c 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 H H H H H H Make a DNA card that can be immunized with 1 g of DNA at a time! £1.2•Production of fusion tumors producing anti-human NR10 antibody 1.2.1. Preparation of fusion tumors using human NR10 and crab NR10 mice for 10 Ba 1 b/c mouse (female '6 weeks old at the start of immunization, Charles River, Japan) was immunized with human NR10 or crab sputum NR10 as follows. The first immunization was performed using a Herios gene gun system (manufactured by BI0-RAD) The DNA card produced by the ®9 hNRIO expression vector produces immunity. The second immunization is 1 week later. Herios with gene gun system (BI0-RAD Inc.) administering cynNRl 0 expression vector a DNA cassette produced. After the third immunization at one week interval and interaction of immune hNRl 0 cynNRl 0 expression vector. After confirming that the serum antibody price of human NR1 上升 was increased, the final immunization was intravenous administration of 10# g/only human NR10 protein diluted in PBS(-) (extracellular region) (Reference example)

4). Four days after the final immunization, mouse spleen cells and mouse myeloma cells P3X63Ag8U.1 (referred to as P3U1, ATCC CRL-1 597) cells were fused using PEG1500 (Roche Diagnostics). The fused cells, i.e., the fusion tumor, were cultured in RPMI 1640 medium (hereinafter referred to as 10% FBS/RPMI 1640) containing 10% FBS. 1.2.2. Screening of fusion tumors On the next day of fusion, (1) The fusion cells were suspended in semi-flowing medium (StemCel Is), and the fusion tumors were screened and cultured and colonized (colony) was performed. 80 201028165 On the 9th or 10th day after fusion, a colony-incorporated colony (colony) was used, and 1 community per well was sown in FBS/RPMI 1640 supplemented with MT screening medium, 2 vol% HAT 50x concentration (Dainippon Pharmaceutical Co., Ltd.). 96 vol% BM-Condimed Hl (R〇che Diagnostics) 96-well plate. After culturing 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. For the culture supernatant of mouse IgG, the neutralization activity of human IL-31-dependent cell line (hNR1〇/h〇SMR/BaF3 cells; ^Reference Example 2) was evaluated to obtain high NR10 neutralizing activity. A few colonies (Fig. 3). A concentration-dependent inhibition of cell proliferation stimulated by human IL-31, and concentration-dependent inhibition of cells stimulated by crab chyme IL-31 (cynNR1〇/cyn〇SMR/BaF3 cells; Reference Example 2) proliferation The selected strain (Fig. 4). [Example 2] Preparation of chimeric antibody Production of chimeric antibody expression vector All RNA was extracted from fusion tumor cells using RNeasy Mini Kit (QIAGEN). cDNA was synthesized using SMART RACE cDNA amplification kit (BD Biosciences). Use the 1 〇χ universal primer a mixture attached to the SMART RACE cDNA Amplification Kit (BD Biosciences) (Universal

Primer A Mix) and an initiator set to each constant region of the antibody (H chain: mlgGl-rnot, L chain: mlgK-rnot), PCR was carried out with PrimeSTAR HS DNA polymerase (TaKaRa) to isolate the variable region gene of the antibody. Use the BigDye Terminator Cycle Sequencing Kit (Applied Biosystems) in the DNA sequencer ABI PRISM 3730xL DNA sequencer or ABI PRISM 3700 DNA to determine the order of the 2010 2010 165 Bios (Appl i ed Biosystems), according to The method described in the attached specification determines the base sequence of each of the separated DNA fragments. The Η chain variable region of the amino acid sequence of the mouse antibodies of NS18, NS22, NS23 and NS33 obtained is shown in Fig. 1, and the L chain variable region is shown in Fig. 2. Using the combination primers shown in Table 1 for each of the obtained Η chain and L chain fragments, PCR was carried out by PrimeSTAR HS DNA polymerase (TaKaRa) to obtain the amplified fragment and the constant region (human T 1 or T 2, respectively). Human/c) binding, expression vector for insertion into animal cells. The B i gDye terminator cycle sequencing kit (Applied Biosystems) was used to determine the DNA sequencer ABI PRISM 3730X1 DNA sequencer or ABI PRISM 3700 DNA sequencer (Applied Biosysterns) according to the method described in the attached manual. The base sequence of each DNA fragment. [Table 1] Sequence (5 '^) sequence cesium alias mlgGI-rnot TMTAGCG ^ OGCTMTTAmmGGA ^ GTGGGAGAG 90 mtgK-rnot TAATAeceecCQCTCATTAACACTCAncCTGTT6MecT 9 1 mNS18H-feco GACaAATTCCACCATGGSATGGMCTiaATCTT 9 2 mNS18L-feco GACi ^ TTCGACCATGAfiTGTGCCCACTCAGGT S 3 mNS33H-feco CAGQAAnCGACQATGGAATGTAACTGQATACT 9 4 mNS33L -feco GACGAATTCCACCATGGATTTTCTGGTGCAGAT 9 5 顺 句 句 NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS -rnot NS23 Η 钡ir«S18H-feco mlGI-rnot NS23 L镔ir«S18L-feco mlGK-rnot NS33 Η lock mNS33H-feco mlGI-rnot 啦 3 L-locked raNS33L-feoo tn[IS(-rnot chimeric antibody HEK293H strain (Invitrogen) from human fetal kidney cancer cells was prepared and suspended in DMEM medium 82 201028165 (Invitrogen) containing 10% fetal calf serum (Invitrogen), and the cell fixation plate was fixed at a cell concentration of 6×10 5 cells/mL ( Dish) (diameter 10cm, CORNING) i〇mL per dish, cultured in C〇2 incubator (37 °C, 5% C〇2) for one night The medium was aspirated, and 6.9 mL of CHO-S-SFMII (Invitrogen) medium was added. The prepared plastid DNA mixture (total 13.8" g) was added to CH0-S-SFMII medium to form 700//L, and 20.7 was added. //L 1" g/mL polyethylenimine (Polysciences Inc.) mixed, allowed to stand at room temperature for 10 minutes, put into the cells of each plate, in C〇2 incubator (37 ° C, 5% C〇2) culture for 4 to 5 hours. Then, 6.9 mL of (^0-8-8? 11 (111 ¥11:1'〇舀611) medium was added, and cultured in a (:2 incubator for 3 to 4 days. After recovering the culture supernatant) , centrifugation (about 2000g, 5 minutes, room temperature), remove the cells 're-input 0.22 μ m filter MILLEX (business

Mark) _GV (Millip〇re). Each sample was stored at 4 until use. (: The antibody was purified from the supernatant using Protein G Sepharose (Amersham Biosciences). The purified antibody was concentrated using Am icon Ultra 15 (M illi pore), and the solvent was replaced with a PD-10 desalting column (Amersham Biosciences). PBS(-) containing 0.05% NaN〇3. The absorbance at 280 nm was measured with a ND-1 000 spectrophotometer (NanoDrop), and the concentration was calculated according to the method of Pace et al. (Protein Science (1995) 4:241 Bu 2423). Activity evaluation of chimeric NS22 hNR10/hOSMR/BaF3 cell line was used in a dose-dependent proliferation, and the neutralizing activity of hIL-31 was evaluated as follows. hNR10/hOSMR/BaF3 cells were contained in 10% FBS (MOREGATE), 1% Penicillin-streptomycin 83 201028165 (Streptomycin) (Invitrogen) RPMI 1640 medium (GIBCO) was prepared to 1.5xl05 cells/mL. Part of it was added with hIL-31 (R&D Systems) ' 4 ng/mL (IL-31(+), final concentration 2 ng/mL). The remaining cell suspension was labeled as IL_31(-). The purified NS22 was adjusted to 2 μg/mL in the medium, and the dilution ratio was adjusted. 3. A total of 8 series dilutions (final concentration S 1 β g/mL). Each well of the chassis (CORNING) was mixed with cell suspension and chimeric NS22 (human 7*1, /c) diluted solution -50 / L, and cultured at 37 ° C, 5% C 〇 2 incubator for 2 days After the end of the culture, add a cell count set of -8 (Dojindo) and PBS in an equal amount of solution 20 /z L ' to determine the absorbance (450 nm / 620 nm) (TECAN, SUNRISE CLASSIC). 37 ° C, 5% C After 2 hours of reaction in the 培养2 incubator, the absorbance was measured again. The NS22 neutralizing activity was subtracted from the value of 〇 hours by the value of 2 hours, indicating the inhibition rate. Results NS22 significantly inhibited concentration-dependent IL in hNR10/hOSMR/BaF3 cells. -31 stimulated cell proliferation, demonstrating neutralizing activity against human Il-31 signaling (si gna 1 i ng ) (Fig. 5).

The DU145 cell strain (human prostate cancer cell line) which induced IL-6 production by stimulation with IL-31 was used to evaluate the neutralizing activity of IL-31 as follows. DU145 was prepared into 2.5xl05cells/ in MEM medium (Invitrogen) containing 10% FBS (MOREGATE), 2 mmol/L L-face glutamine (Invitrogen), 1 mmol/L sodium pyruvate (SIGMA). The mL' was incubated for one night in each well of a 48-well plate (CORNING) by injecting 200 # L ' 37 ° C and 5% C 〇 2 . The purified chimeric ns22 (human 7 1 , /c ) was diluted to 84 201028165 1 MEM in MEM medium containing 10% FBS, 2 mmol/L L-faced tyrosine (Invitrogen), sodium pyruvate (SIGMA). Μ, use this solution to prepare a diluted dilution ratio of 5, a total of 6 series of dilutions" Do not mix with 1 ng / mL of human interleukin-31 (R & D Systems) λ 1 , add 50 to each well L. The IL-6 concentration in the culture supernatant after culture at 3 TC and 5% C 〇 2 was measured by the DuoSet ELISA Development Kit (R&D Systems). The neutralizing activity of NS22 was evaluated as the inhibition rate (%). That is, in the absence of IL-31 # IL_6 concentration (A) is the maximum inhibitory activity I* (100/D inhibition), IL_31 is added and il_6 concentration without ns22 is added (B) is no inhibitory activity (〇% inhibition) , add α_3ι and add Μ. The lower IL-6 concentration (〇 is calculated as follows. Inhibition rate (%) = (BC)/(BA)xlOO Results NS22 significantly inhibited IL-6-producing IL-6 production in DU145 cells, demonstrating Human IL_31 message delivery has neutralizing activity (Fig. 6). Evaluation of il-31 competitive activity of chimeric anti-NR10 antibody FMI Blue Monofunctional Reactive DyeKAppl stained for human IL-31 (R&D Systems) by FMAT Blue Monofunctional Reactive DyeKAppl Ied Biosystems) was labeled with 50 Mm sodium phosphate buffer (pH 8.0) to 0.5 mg/mL of hIL-31, taken at 100//L, and added to 25 nmole FMAT blue 5.25/L dissolved in DMSO (Junsei). After shaking (vortex), let stand for 15 minutes at room temperature. Add 1M Tris-HCl (pH 7.4) 5//L and 1% Tween20 1 · 1 " L to stop the FMAT blue for hIL-31. After the introduction reaction, the gel was filtered using Superdex 75 (GE Healthcare, 17-0771-01) as a column, and FMAT blue-labeled hIL-31 and unreacted FMAT blue were separated on a 0.1% Tween20/PBS developing solution. 85 201028165 Using CH0 cells expressing hNR10, the IL-31/NR10 binding inhibitory activity of the antibody was evaluated as follows. NS22 and NA 633 (the ambiguous region is γΐ, with analysis buffer (10 mM HEPES' 140 mM NaCl, 2.5 mM CaCl2, 3 mM

MgCh ' 2% FBS ' 0. 01% of NaNO was diluted to the appropriate concentration, and then diluted to a dilution ratio of 2, a total of 7 series of dilutions, added to each tray of 4 〇 yl 'yield (96-well FMAT disk, Appl Ied Biosystems). Continue, FMAT Blue. " 'The standard hIL_31 diluted 400 times with the analysis buffer, adding 20 / / L per well. Finally, the cell suspension was adjusted to 2.5 x 105 / mL with assay buffer plus 40/zL/well per well (final concentration 1 x l04/we 11 per well). 2200 Cellular Detection System (Applied) after 2 hours of cell addition

Biosystems) measures fluorescence (FL1). The results showed that NS22 dose-dependently inhibited the binding of hIL-31/hNR10, demonstrating that its activity is better than that of NA633 (Fig. 7).

[Example 3] Competition of NR10 against NR10 antibody

The more purified NS22 antibody from the fusion tumor culture supernatant was labeled with FMAT Blue (Applied Biosystems, 4328853). Add 170 mg/zL of NS22 prepared in lmg/ml-PBS, add 1M dissolved in 17#L

NaHC〇3 solution and DMS0 17nmole FMAT blue 3.4yL, after shaking (vortex), let stand for 30 minutes at room temperature. Add 8M L of 1M 1 [1*15-team 1 (卩117.4) and 1.9//1 of 1% Ding ¥661120 to stop the introduction of the \822 FMAT blue, and then take Superdex 75 (GE Healthcare, 17 -077Bu 01) Used as a column for gel filtration, at 〇 _ 〇ι% of 86 201028165

FMAT blue-labeled NS22 (FMAT Blue-NS22) and unreacted FMAT Blue were separated on Tween20/PBS developing solution. The binding of the obtained FNR blue-NS22 expressing hNRIO CH0 cells (Reference Example 3) was inhibited by various antibodies and was examined by an 8200 cell culture system (Applied Biosystems, 4342920). Add various concentrations of chimeric anti-NR10 antibody (constant region γ 1 , /〇) to 8·8xl (T2// g/mL FMAT blue-NS22, 7500 cells/we 11 per well), and opt in the dark After 4 hours, the fluorescent signal from FMAT blue bound to the cells was measured. The reaction was carried out in a 10 mM Hepes-containing 2.5 mM CaCl 2 , 3 mM MgCl 2 , 140 mM NaCl, 2% FBS, 0.01% NaN〇3. The results were as shown in Fig. 8. The increase in the concentration of the NS22 and NS23 antibodies indicates that the fluorescence value pi of the binding of NR10 expressing cells to FMAT blue-NS22 is decreased. On the other hand, F1 is hardly considered to be accompanied by NA633. The antibody (Reference Example 6) was decreased in concentration (Fig. 8). [Example 4] Humanization of NS22 antibody Selection of each framework sequence Comparison of variable regions of mouse NS22 antibody and human germ cells (germi Ine) sequence. The FR sequence used for humanization is shown in Table 2. The confirmation of CDR and FR was carried out according to Kabat number. The humanized variable region, η chain is fri, fR2 as shown in Table 2. FR3_1, FR4 consists of the sequence H0-VH (sequence identification number: 50); FR1, FR2, FR3-2, FR4 The sequence is HI VH (sequence identification number: 11 2). The L chain is composed of FR1, FR2, FR3, and FR4, and the sequence is L0 (sequence identification number: 52). Production of variable region of humanized NS22 H0L0 87 201028165 In order to create a humanized NS22 variable region in which the CDR region of NS22 was transplanted into the FR region used for humanization, the synthetic DNA strands and L· linkages were designed, and the synthesized oligo DNA was mixed. The gene encoding the humanized NS22 variable region was produced by polymerizing pCR. Polymerase PCR was carried out using K〇D_pius (T〇Y〇B〇). The PCR method was carried out according to the following conditions. The attached PCR buffer, dNTPs, MgS〇4, The synthesis of KOD-Plus and lOpmol raises the opposite of dna formation

The mixture was heated at 94 ° C for 5 minutes and then at 94 ° C for 2 minutes, 55. (: 2 minutes, 68 ° C 2 minutes PCR reaction cycle, after 2 cycles, 'in the variable region 5' end increased restriction enzyme position and Kozac sequence primer, and the 3' end increased restriction enzyme position primer,丨〇pm〇1 was separately added, and a PCR reaction cycle consisting of 94° C. for 30 seconds, 55 t: 30 seconds, and 68° C. for 1 minute was performed for 35 cycles to obtain an amplified fragment. The obtained amplified fragment was τ〇ρ〇ta. Colonization vector (Τ0Υ0Β0) cloning 'sequence confirmation sequence. Combine the variable and constant regions, make H〇_SKSC (sequence identification number: 54), L0 (sequence identification number: 56) ), which is incorporated into a expression vector capable of displaying an inserted gene in an animal cell. The base sequence of each DNA fragment is used in Big])ye terminator cycle sequencing set (Applied Bi〇systems) in DNA sequencer ABI PRISM The 3730xL DNA sequencer or the ABI PRISM 37〇〇DNA sequencer (Applied Biosystems) was confirmed according to the method described in the attached manual. Production of the variable region of humanized NS22 H1 Production of H1-SKSC (SEQ ID NO: 130) via the bat 3 of the FR3 present in H0-SKSC (SEQ ID NO: 54), position 73, branide (E) ) is substituted with lysine (K). The mutant was produced using the QuikChang site-Directed Muagenesis Kit (Stratagene) sold at City 88 201028165, and mutants were prepared according to the attached instructions.

Expression of IgGylated antibodies The performance of antibodies was carried out as follows. The HEK293H strain (Invitrogen) from human fetal kidney cancer cells was suspended in DMEM medium (Invitrogen) containing 10% fetal bovine serum (Invitrogen), and seeded in a cell fixing plate at a cell concentration of 5 to 6×10 5 /mL ( Diameter 1 〇cin, CORNING), 10 mL per sowing ' After culturing overnight in a C〇2 incubator (37Ό, 5% C〇2), aspirate the medium and add 6.9 mL of CHO-S_SFMII (Invitrogen) medium. . Modulated plastid DNA mixture (total §13.8/zg) and 20.7//L of 1/zg/mL polyethyleneimine

(polyethylenimine) (Polysciences Inc.) and CHO-S-SFMII medium 690/zL mixed 'room at room temperature for 1 minute, put into the cells of each plate, in C〇2 incubator (37 ° C, 5% C〇2 ) culture for 4 to 5 hours. Thereafter, 6.9 mL of CHO-S-SFMII (Invi trogen) medium was added and cultured in a C〇2 incubator for 3 days. After recovering the culture supernatant, centrifuge (about 20,000 g, 5 minutes, room temperature), remove the cells and re-admit the 〇. 2 2 μ m filter MILLEX®-GV (Mi 11 ipore), sterilize. Each sample was stored at 4 °C until use.

Purification of IgGylated antibodies

Adding rPotein A suspended in TBS to the obtained culture supernatant

Sepharose Fast F low (Amersham Biosciences), mixed at 4 ° C for up to 4 hours. Move this solution to 〇· 22 " m filter cup 89 201028165 1111:^^66 (trademark)-1110 (PCT 1111?〇犷6), wash it with 500 of 500"1 3 times, and suspend it at 100 /z L of 50 mM sodium acetate aqueous solution pH 3.3 in rPote in A SepharoseTM resin, allowed to stand for 3 minutes, eluting the antibody. Further, 6.7 #L of 1.5 M Tris-HCl, pH 7.0 was neutralized. Two times of dissolution was carried out to obtain a purified antibody of 200 "L. The antibody-containing solution 2//L is supplied to an ND-100 spectroscopy spectrometer (N a η 〇D r ο p company) (Thermo Scientific NanoDropTM 1000 Spectrophotometer (Thermo Scientific)), or a solution containing the antibody 50 #L Provided in Spectrophotometer DU-600 (BECKMAN) 'Measure the absorbance at 280 nm, and calculate the antibody concentration according to the method of Pace et al. (Protein Science (1995) 4:2411-2423). Measurement of IL-31 competitive activity using FMAT Using CH0 cells expressing hNRIO, the IL-31/NR10 binding inhibitory activity of the antibody was evaluated as follows. NS22 chimeric antibody and NS22_H0L0 (H chain H0-SKSC/SEQ ID NO: 54, L chain L0/SEQ ID NO: 56) in assay buffer (1 mM HEPES, 140 mM NaCl, 2. 5 mM CaCl2) '3mM MgCl2, 2% FBS, 0. 0U NaN3, pH 7.4) was diluted to the appropriate concentration and then diluted to a dilution ratio of 2, a total of 8 series of dilutions, 40 / L / wel per well Added to the disk (96-well FMAT disk,

Applied Biosystems). Continuing, the FMAT blue-labeled hIL-31 was diluted 400-fold with knife resolution buffer and 20//L/we 11 was added to the parent well. Finally, the cell suspension was adjusted to 2. 5xl〇5/mL with an analysis buffer, and 40 " L/wel 1 (final concentration of lxi〇4/wel丨 per well) was added to each well. Two hours after the addition of the cells, fluorescence (FL1) was measured using an 8200 cell detection system (Applied Bi〇systems) 201028165. The results showed that the humanized NS22 antibody H0L0 (H chain H0-SKSC/SEQ ID NO: 54, L chain L0/SEQ ID NO: 56), H1L0 (H chain SKSKSC/ SEQ ID NO: 130, L chain L0/ Sequence identification number: 56) As shown in Fig. 9, the competitive activity is almost the same as that of the chimeric antibody, and therefore it is called H0L0, H1L0 human type-anti-IL-31 receptor antibody. The FR of H0L0 and H1L0 is considered to be acceptable. • It is used as FR when it is humanized. Therefore, the position of the mutation of the CDR shown in the following examples can be considered, and any of HO and Η1 can also be introduced. [Table 2 ]

H0 germ cell series human FR sequence pair FR1 Gerral ine: hVH_1_46 (Accession No.) (92343) QVQLVOSGAEVKKPGASVKVSCKASGYTFT (Preface "R96" FR2 Germ丨ine: hVH_1_46 (Accession No. X92343) WVRQAPGOGLEWMG (Sequence FR3J (5erniline: hVHJ_69 {Accession No.L2258Z) RVT1TADESTSTAYHELSSLRSEDTAVYYCAR (order FR3.2 6ernline:hVIL1J9 {Accession N〇.Z27506) RVT1TADKSTSTAYHELSSLRSEDTAVYYCAR FR4 0srmline:JH1 WGQGTLVTVSS L0 Germ cell series human F_R order pair FR1 Germline:hVKJ_39 {Accession No.X59315) D10MT0SPSSLSASV6DRVT1TC C卓月ΛΚ100) FR2 Gernline:hVKJ_39 (Accession No.X59315) WYQQKPGKAPKLLIY (preface jmsuoi) FR3 Gernline:hVLL39 (Accession No.X59315) GVPSRFSGSGSGTDFTLT1SSLQPEDFATYYC (Preface "*射号102" FR4 Germline:ilK4 FGGGTKVEIK (Preface Knowledge; MR103)

[Example 5] The heterogeneity reduction effect of the novel constant regions Μ14 and Μ58 in the humanized anti-IL-31 receptor antibody is shown in Reference Examples 7 to 9, in the humanized anti-IL-6 receptor. In the antibody huPM1 antibody, the constant region was converted from IgG2 to M14 or M58, confirming that the stability was not lowered, but the heterogeneity from the IgG2柩 region was reduced. Here, it is reviewed whether the conversion of the wild-type IgG2 to M14 or M58 in the constant region of human 91 201028165-type anti-IL31 receptor antibody can reduce heterogeneity. The Η chain uses IgG1 (SEQ ID NO: 6〇) and IgG2 (SEQ ID NO: 132) containing M14 (SEQ ID NO: 129) and M58 (SEQ ID NO: 128) prepared in Reference Examples 8 and 9, and Examples and Examples 4 The humanized anti-IL-31 receptor antibody has the Η chain variable region H0CH0-VH/SEQ ID NO: 5〇) combined Η0-Μ14, Η0-Μ58, HO-IgG1 and H0-IgG2, L chain H0L0-IgG1 (H-chain H0-IgG1/SEQ ID NO: 133, L-chain L0/SEQ ID NO: 56), ©3 was produced using L0 (L0/SEQ ID NO: 56) prepared in Example 4;

H0L0-IgG2 (H chain H0-IgG2/SEQ ID NO: 134, L chain L0/SEQ ID NO: 56), H0L0-M14 (H-key HO-M14/SEQ ID NO: 134, L-chain L0/SEQ ID NO: :56), and H0L0-M58 (H chain H0-M58/sequence identification number: 136, L chain L0/sequence identification number: 56). The expression and purification of each antibody were carried out by the method described in Example 4. The heterogeneity evaluation method was evaluated by cation exchange chromatography. The heterogeneity of the prepared antibody was evaluated using Pr〇Pac wcx-1〇(Di〇nex) as the column, mobile phase A was 20 mM sodium acetate, pH 5. 〇, mobile phase b was 20 mM ^ sodium acetate, 1 M NaCl, pH 5.0, was carried out at the appropriate flow rate and gradient. The results of the evaluation of the cation exchange chromatography (IEC) are shown in Figure 1. As shown in Fig. 10, in the anti-IL-3 purinoceptor antibody, the constant region was changed from igGi to IgG2, the heterogeneity was increased, and the value was changed to Mu & the heterogeneity of both antibodies was reduced. [Example 6] Drug motility-improving effect of novel constant region M58 in anti-IL31 receptor antibody 92 201028165 As shown in Reference Example 9, in the anti-IL-6 receptor antibody huPM1 antibody, the ambiguity region was changed from IgG1 to M58. The binding to human FcRn was increased, and in human FcRri transgenic mice, drug motility was found to be elevated. Here, it is reviewed whether the drug power of the anti-IL-31 receptor antibody is increased in the conversion of the constant region to M58. H0L0-IgG1 (H chain HO-IgG1/SEQ ID NO: 133, L bond L0/SEQ ID NO: 56) and h〇LO-M58 (H bond H0-M58/sequence identification number) prepared in Examples 4 and 5: 136. L chain L0/SEQ ID NO: 56) The method of Reference Example 9 was used to evaluate the binding to human FcRn. The results are shown in Table 3. [Table 3] _KD(/iM) H0L0-IgG1 Γ〇7~ H0L0-M58 0.91 As shown in Table 3, the anti-IL-31 receptor antibody H0L0 is converted from igGi to M58, and anti-IL-6. The receptor antibody hPM1 was identical, and the binding to human FcRn was confirmed to be improved. This shows that the constant region is transformed from ig (u converted to the 'anti-IL-31 receptor may also increase the drug motility in the human body. [Example 7] Confirmation of mutation positions at which the isoelectric point is lowered The preparation was carried out according to the method of Example 4 or the polymerization of pcR using PCR. The oligo DNA was synthesized by the method of polymerization PCR based on the sequence of the forward and reverse strands containing the mutation site. The cis-chain containing the mutation site The oligo DNA is ligated with a vector inserted into the vector of the mutated gene, and the oligo DNA containing the reverse strand of the mutated portion is ligated with the ligated DNA of the gene inserted into the mutated gene, and each is combined. PCR was carried out using PrimeSTAR (TAKARA) to prepare two 5' ends and 3' ends of the fragment containing the mutation site. These two fragments were combined by PCR to prepare each mutant. The inserted mutants may be expressed in animal cells. The expression vector of the inserted gene is inserted, and the sequence of the obtained expression vector is confirmed by a method known in the art. The preparation and purification of the antibody are carried out as in the method of Example 4. It was confirmed that in order to improve the drug kinetics of HOLO (H chain HO-SKSC/SEQ ID NO: 54, L chain L0/SEQ ID NO: 56), a mutation position at which the isoelectric point of the variable region was lowered was examined. As a result of the predicted mutation position of the variable region in the structural model, it was found that the position of the variable region was lowered without significantly reducing the binding of NR1 ,, as shown 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: 14〇, Hp9-VH/SEQ ID NO: 141 'Hp Bu VH/Sequence ID: 142, Hpl3-VH/SEQ ID NO: 143, Lpl-VL/SEQ ID NO: 丨44, Lp2-VL/SEQ ID NO: 145 'Lp3-VL/SEQ ID NO: 146, Lp4-VL/Sequence Identification Number : 147, Lp7-VL/SEQ ID NO: 148, Lp5_VL/SEQ ID NO: 149, Lp6-VL/SEQ ID NO: 15〇) The preparation and purification of each mutant were carried out as described in Example 4. The hIL-31/hNR1〇 binding inhibitory activity of the mutant was evaluated by FMAT. The method was carried out as in Example 4. As shown in the figure, each Variable 94 201028165 The competitive activity of the body was not significantly reduced compared with HOLO [Table 4] The name of the defibrillation HO sequence to the mutation position H0 mutation after the mutation sequence (kabat Ho.) sequence pair «基鼸Hp5 FR2 WVRQAPGOGLEWMQ 38 RQ WVQ0GQQLEWNG (Ordering Alfe :9ί) 40 ※8 S (sequence identification 鼍:丨20) Hp7 CDR2 LINPYN6GTSYNQKFKG 50 LE EINPYNGGTSYNQKFKG (Sequence 33⁄4) iSE :10) (Sequence: 113) Hp8 CDR2 LINPYNQGTSYNQKFKG 52 ND LIDPYNGGTSYNQKFKG (Preface "JWR: 10" (Preface "Identify me: 丨14" Hp6 CDR2 LINPYNGGTSYNQKFKG 61 QD LINPYNGGTSYNDKFKG (Serial identification: l〇) C-sequence identification: 丨15) Hp9 CDR2 LINPYNGGTSYNQKFKQ 62 KQ LINPYNGGTSYMQQFKG (Preface For sensitization*: 10) (Serial identification: 116) Hp1 CDR2 LINPYNGGTSYNQKFKG 64 KQ LINPYNGGTSYNQKFQG (Sequence recognition; MR: 10) (Sequence W identification K: 117) Hp13 CDR2 LINPYNGGTSYNQKFKG 64 KQ LINPYNGGTSYNQKFQD (Order against JMK: 10) 65 GD (Order W identification*: 丨19) The name is divided into ififi LO order! ! The mutation position L0 is mutated after the mutation pair (kabat No.} «Base acid Lp1 CDR1 RTSENIYSFLA 24 RQ QTSENIYSFLA (sequence recognition: 13) (sequence pair sensitization * : 121) Lp2 CDR1 RTSENIYSFLA 28 ND RTSEDIYSFLA (Preface "Identification": 13) C-sequence "谶: 122" Lp3 CDR2 " NAKTIAK 50 ND DAKTLAK (Order pair identification « : 14) (Order "Identification S : 丨 23" Lp4 CDR2 NAKTLAK (Order JSiK : 14) 52 KQ NAQTLAK (Order "Received Gold: 124" Lp7 CDR2 NAKTLAK 54 LE NAKTEAK (preface ;; M*: 14) (Order: 125) Lp5 CDR2 NAKTLAK 56 KQ NAKTLA0 (4 蚵 £ : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : "Identification number: u" (r«sr«r* ii27) The * symbol in the above list 4 indicates the position of the mutation irrespective of the isoelectric point used to form the human sequence. A humanized NS22 antibody which reduces the isoelectric point of the mutant combination described above, for example, Hp3-Lpl5 (H chain Hp3-SKSC/SEQ ID NO: 151, L chain Lpl5/SEQ ID NO: 152). The affinity for Hr3-Lpl5 NR10, the isoelectric point, and the retention in mouse plasma were compared with H0L0. Measurement of affinity The affinity of each antibody for NR10 was carried out as in the method of Reference Example 10. 95 201028165 The affinity results determined are shown in Table 5. The affinity of Hp3Lpl 5 showed almost the same affinity as H0L0. [Table 5] ka (1/Ms) kd (1/s) KD (M) H0L0 Hd3Ld15 3.7E+05 4.2E+05 1.2E-03 1 _6E - 03 3.3E - 09 3.9E-09 Isoelectric point Measurement> In order to evaluate the change in the isoelectric point of the full-length antibody due to the change of the amino acid in the variable region, the isoelectric point electrophoresis analysis of each antibody was carried out. The method of isoelectric point electrophoresis is as follows. Phast_Gel Dry IEF (Amersham Biosciences) gel was swelled using a Phastsystem Cassette (manufactured by Amersham Biosciences) for about 30 minutes with the following swelling solution.

Milli —Q Water L5 mL

Pharmalyte 5-8 100 "L for IEF

(manufactured by Amersham Biosciences Co., Ltd.) Electrophoresis was carried out by using the swelled gel' by PhastSystem (manufactured by Amersham Bioscences Co., Ltd.). The sample was added to the gel at step 2. A calibration kit for pl (manufactured by Amersham Blosciences Co., Ltd.) was used for the Pi marker. Step 1: 2000 V 2.[ j mA 3. 5 W 15°C 75 Vh Step 2: 200 V 2. 5 • mA 3. 5 W 15°C 15 Vh Step 3: 2000 V 2. 5 丨mA 3. 5 ff 15 °C 410 Vh After the electrophoresis of the gel was fixed at 2% TCA, the sample was calculated using the silver dyeing kit and the protein 96 201028165 (manufactured by Amersham Bi〇sciences), according to the method of the kit. Silver dyeing. After staining, the isoelectric point of the known isoelectric (full-length antibody) of the Pi marker was measured by isoelectric point electrophoresis. The isoelectric point of H〇L〇 was about 7.8, and the isoelectric point of HP3LP15. It is about 5. 5, so the isoelectric point of Hp3Lpi5 is about 2.3 lower than the isoelectric point of H0L0. The theoretical isoelectric point of the variable region vh/vl is calculated by genetyx (genetyxcorporati〇n). The theoretical isoelectric point of h〇l〇 is about 7.76, and the theoretical isoelectric point of Hp3Lpl5 is about 4 63. The theoretical isoelectric point of this Hp3Lpl5 is about 313 lower than the theoretical isoelectric point of H〇L〇. Evaluation of Antibody Drug Motivation Using Isoelectric Point of Mice In order to evaluate the plasma retention of the mutant antibody Hp3Lpl5 which lowers the isoelectric point, the plasma retention of H0L0 and HP3LP15 in normal mice was compared. H0L0 and Hp3Lpl 5 were intravenously administered to mice (C57BL/6J, Charles River, Japan) at a dose of 1 mg/kg, and the changes in plasma concentrations were compared. The plasma concentration was determined by ELISA. An appropriate concentration test sample and a plasma test sample were dispensed into an immunoplate (Nunc_Immun〇) immobilized with an anti-human IgG (Fc-specific) antibody (manufactured by Sigma).

Plate, MaxiSorp (manufactured by Nalge Nunc International)), and allowed to stand at room temperature for 1 hour. After the goat anti-human IgG-ALP (manufactured by Sigma) was reacted at room temperature for 1 hour, it was used as a substrate by BluePhos Microporase Matrix System (Kirkegaard & Perry Laboratories) for color development. The reaction was measured for absorbance at 650 nm on a micropiate reader. From the absorbance of the test line, the software SOFTmax PRO (manufactured by Molecular Devices) was used to calculate the concentration of the blood in the 97 201028165. The obtained blood plasma concentration change data was calculated by the pharmacokinetic analysis software WinNcmlir KPharsight Co., Ltd. for the pharmacokinetic parameters (Auc, systemic clearance (CL)), as shown in Table 6. The AUC increased by about 14% after intravenous administration relative to HOLO' Hp3Lpl5, and the clearance rate was reduced by about 12%. It can be seen that Hp3Lpl5, which lowers the isoelectric point of H〇L〇, has an improved drug power. [Table 6] AUC (pgBd/kg) CL (ml/d/kg) Average SD Average SD HOLO 281.8 13.1 3.6 0.2 Hp3Lp15 321.1 26.1 3.1 0.3 [Example 8] Effect of combination of variable region and constant region on biological activity In order to evaluate the effects of different strange regions on biological activity, a mutant of the jaw was prepared. The Η chain is 'SKSC (SEQ ID NO: 62), Μ 58 (SEQ ID NO: 1 28) produced in Combination Reference Examples 7 and 9 is a constant region, and the variable region Hp3 (Hp3-VH/sequence) produced in Example 7 Identification number: 167) is a variable region, and Hp3-M58 (sequence identification number: 240) and Hp3-SKSC (sequence identification number: 151) were produced. The Η chain produced in combination and the L chain Lpl 5 (Lpl 5/SEQ ID NO: 152) produced in Example 7 were used to prepare Hp3Lpl5-SKSC (H chain Hp3-SKSC/SEQ ID NO: 151, L chain Lpl5/SEQ ID NO: : 152) and Hp3Lpl5-M58 (H-chain 458 3458/SEQ ID NO: 240, [chain 1^15/SEQ ID NO: 152). The expression and purification of each antibody were carried out as in Example 4. For each of the antibodies produced above and H0L0-SKSC (H chain H0-SKSC/SEQ ID NO: 54 'L chain L0/SEQ ID NO:: using the constant 98 201028165 region SKSC (SEQ ID NO: 62) described in Reference Example 7: 56), H0L0-M58CH chain Ή0-Μ58/SEQ ID NO: 136 'L chain L0/SEQ ID NO: 56) and H0L0-IgG2 (H-bond H〇-IgG2/SEQ ID NO: 134, produced in Example 5, L-L0/SEQ ID NO: 56), the biological activity of BaF/NR1〇 was carried out by the method described in Example 2, and the results are shown in Fig. 18. As shown in Figure 18, there is no significant difference in biological activity between the identified regions. The combination of the two variable regions HO, Hp3 and each constant region also does not affect the activity of the mash, so it is considered that the combination of the variable region produced in the future and any constant region does not change the biological activity. [Example 9] Identification of a mutation site for inhibiting decomposition by thermal acceleration test An antibody used in a pharmaceutical product, even a monoclonal antibody obtained from a clone of a single antibody-producing cell, has heterogeneity. . The heterogeneity of such antibodies is known to be caused by modifications such as oxidation, de-amidation, etc., or by exposure to prolonged storage and under pressure conditions such as heat and krypton beta (Reference: Heterogeneity of Monoclonal Antibodies: Journal) Of pharmaceutical sciences, vo 1·97, Νο·7, 2426-2447). However, when an antibody is developed into a pharmaceutical product, the physical properties of the protein, particularly homogeneity and stability, are extremely important, and it is desirable to reduce the heterogeneity of the target substance/related substance as much as possible. Here, the heterogeneity of the antibody under stress conditions was evaluated, and the following experiment was conducted to reduce the heterogeneity. For the evaluation of the decomposition product, a heat-accelerated product of H〇L〇 (H chain H〇_SKSC/SEQ ID NO: 54, L chain L0/SEQ ID NO: 56) was produced in the following manner. The heat-accelerated and unaccelerated products manufactured by 99 201028165 were analyzed by cation exchange resin in the following manner.

• Preparation method of thermal acceleration product Buffer: PBS Antibody concentration: 0. 2-1· 〇mg/mL Accelerated temperature: 60°c Acceleration period: 1 day • Analytical method of cationic parent-exchange chromatography Column: ProPac WCX- 10,4x250 with (Di_x) 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: 0 to 0 (0-5 min) - 〇 to 3 〇 (5_8 〇 min) Detection: Sample chromatographic results before and after thermal acceleration of 280 nm H0L0 The figure shows. In the sample before and after the thermal acceleration of H0L0, a basic peak ({^31^increasing inclination. Here, in order to reduce the peak], the result was found to be Ha355,

Ha356, Ha360, Ha362, Ha355L0 (H chain Ha355-SKSC/SEQ ID NO: 242, L chain L0/SEQ ID NO: 56) and Ha356L0 (H chain Ha356-SKSC/sequence) combining the η chain mutant and L0 Identification number: 243, L key L0/sequence identification number: 56), Ha360L0 (H chain Ha360-SKSC/sequence 100 201028165 ID: 244, L chain L0/sequence identification number: 56), Ha362L0 (H chain Ha362-SKSC / sequence identification number: 245, L chain L0 / sequence identification number: 56). The sequences of the respective mutants are shown in Table 7. [Table 7] Names _ B0 Λ 突变 突变 银 1 1 1 1 1 1 ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke ke

Ha3ss cdr3 mmmmi (Preface "Taking 鳌: 26S"

Ha356 CDR3 MWGPYTW (Preface Hall: Remuneration) Ha360 CDR3 MYDD6PYT鲰 (Preface to Xie Wei: 2) 012 12 ο ο ο ο ο 11111

Mm CS VI

Ha362 CDR3 W delete PYT break (Humble "Dai Si餮JSS" 712 712 900 900 11 11 E OSYDOSPYTMET T (Special shot: 2) L DeU^aPYTMET E (Preface Xiao Xiaolian: Π 8)

The expression and purification of each of the above YDY antibodies were carried out as in Example 4. Each of the produced antibodies was prepared in the same manner as H0L0, and was analyzed by cation exchange chromatography. The results are shown in Fig. 19. As a result, a mutant antibody comprising a mutant of aspartic acid at position 101 of the oxime chain substituted with glutamic acid was used, and the increase in the alkaline peak after thermal acceleration was less than that of H0L0. The mutant antibody described above was subjected to the biological activity of BaF/NRIO by the method described in Example 2, and the results are shown in Fig. 20. As shown in Fig. 20, the biological activity of the aforementioned mutation is almost the same as or higher than H0L0 as compared with H0L0. From the above, the mutation inhibition of Ha355, Ha356, Ha360, and Ha362 generates a decomposition product of ΙΟΙ201028165 due to thermal acceleration, and is effective in improving the stability of the antibody. [Example 1 〇 ] Determination of mutation position at which affinity was increased In order to increase the affinity of H0L0 for NR10, a gene library into which a mutation was introduced in the CDR sequence was prepared and reviewed. As a result of screening a gene library in which a mutation was introduced in the CDR sequence, it was found that the mutation which has an increased affinity for NR10 is shown in Table 8. The η chain mutant HalOl-SKSC (sequence. column identification number: 246), Hal03-SKSC (sequence identification number: 247),

Halil-SKSC (sequence identification number: 248), Ha204-SKSC (sequence identification number: 249), Ha219-SKSC (sequence identification number: 25 〇) combined with L0 (L0/sequence identification number: 56), and respectively L Chain mutant U134 (SEQ ID NO: 251), Lal30 (SEQ ID NO: 252), U3〇3 (SEQ ID NO: 253), La328 (SEQ ID NO: 254) and H〇 (H〇_SKSC/sequence Identification number: 54) Combine 'produce various antibodies. The preparation and purification of each mutant were carried out as described in Example 4. The deductive, secret, and v-affinity of each mutant against NR10 was evaluated by Biacore as shown in Table 9. The method was carried out as described in Reference Example 10. As shown in Table 9, the KD value of each mutant was significantly higher than that of H0L0 (H chain HO SKSC/SEQ ID NO: 54, [key L〇/SEQ ID NO: 102. 2010 2010165 [Table 8]分· 蕊钇鸠伙 III·录(10)

Ha101 CDR1 m\m i4mmmm.: 2iGy 33 IV (Order "*鬅 mold: 272) Ha103 CDR1 aYlHN (library > f Wei period: no) 34 MI (Preface "讥期鳖:2Τ3) Ha111 CDR1 m\m (Preorder crocodile shooting: 270) 34 ML, GYiLN (preface) identification number: 27« Ha204 CDR2 ϋ, job TSY dirty ugly SS < order Xiaoyang SD UNPVNQGTDYNQKRCS (preface: 275) Ha219 CDR2 UW *YP»GTSYra(FKG <Preface "Daishou Wei: 2Π" 61 0 Ψ UBPyNOQTSYWKFKe (Preface "谶"甏:2?β) 名ϋ分· 咖 ("奶 U Ilf·刚咖La134 CDR1 BTSENIYSFU (Preface Ι«:2Τ0 31 s R IISENIYRFIA (Order to mine "戮H8" La130 COR1 _ENIYSFU (溥厅识"Ε:2Π) 31 33 s LV (来尔尔霪:280) Ls303 COR3 QHHYESPIT 93 E 0 OHHYDSFIT (痔财漉射龟:2»> L^28 CDR3 QHHYESPIT (Ordering the soil; im:2?8> 94 SD 0ΗΗΥΕ 眺T (痔辨瀵颴: Wei xiao La326 COR3 QHHYESPiT (Special for 瀛*tm: 278" 97 TF ^ 0HHYESRFe <Preorder" 耄钃 mold: 283) [Table 9] Name ka{1/Wls) kd(1/s) K_) H0L0 1 QP4.ni; 6.2E-04 3.2E-09 Ha101L0 2.0E+05 3.1E-D4 1 5E-09 Ha103L0 2.2E+05 5.3E*04 2.4E-09 HalULO 2.6E+05 5.6E-04 2.1E-09 Ha204LO 3.7E+05 4.8E-04 1.3E-09 Ha219LO 3.2E+05 98E-04 3.0E-09 103 201028165

Name ka(1/Ms) kd(1/s) KD(M) H0L0 1·5Ε+05 7.4E-04 5.1E-09 H0La134 2.5E+0S 4.4E-04 18E-09 H0La13O 2.6E+05 4.0E -04 1.5E-09 H0La303 2.2E+0S 4.6E-CNI 2.1E-09 H0La328 1.8E+05 5.2E-04 2.9E-D9 H0La326 1.4h+05 5.2E-04 d· / t-uy Combination Examples of mutations that increase affinity and mutations that reduce the isoelectric point produced in Example 7, such as Ha401La402 (H-chain Ha401-SKSC/SEQ ID NO: 255, L-chain La402/SEQ ID NO: 256) or H17L1UH Chain H17-M58/SEQ ID NO: 222, L-chain LI 1 / Sequence ID: 236). The preparation and purification of each mutant were carried out in the same manner as described in Example 4.

Ha401La402 (H-chain Ha4 (H-SKSC/SEQ ID NO: 255, L-chain La402/SEQ ID NO: 256) affinity for NR10 and biological activity of BaF/NRIO, as described in Reference Example 10 and Example 2 The comparison was performed with H0L0 (Η chain H0-SKSC/SEQ ID NO: 54, L chain L0/SEQ ID NO: 56). The affinity results determined are shown in Table 10, and the biological activity of BaF/NR 10 is as follows. As shown in Fig. 21, both affinity and biological activity are higher than Η 0 L 0 (Η chain H0-SKSC/SEQ ID NO: 54, L chain L0/SEQ ID NO: 56). ] ka(1/Ms) kd(1/s) KD(M) H0L0 2.9E+05 9.1E-04 3.2E-09 Ha401La402 5.8E+05 2.9E-04 5.0E-10 104 201028165 Then to HnLll(H) Chain H17-M58/SEQ ID NO: 222, L chain L11/SEQ ID NO: 236) Affinity for NR10 and biological activity of BaF/NR10, as described in Example 7 and Example 2, with HOLO ( The H chain H0-M58/SEQ ID NO: 136, L chain L0/SEQ ID NO: 56) were compared. The affinity results of the assay are shown in Table 11, and the biological activity of BaF/NR10 is shown in Fig. 22. Whether it is affinity or biological activity, it is better than h〇 LO (H chain H0-M58/sequence identification number: 136, L chain L0/sequence identification number: 56) is high. [Table 11] ka(1/Ms) kd(1/s) KD(M) H0L0 H17L11 1.4 E+05 4.3E+05 6.9E-04 2.6E-04 4.8E-09 6.2E-10

[Example 11] Confirmation of mutation position for reducing the risk of immunogenicity Reduction of immunogenicity risk of Η chain CDR1 The Τ cell epitope (epi tope) in the H0L0 variable sequence was determined by TEPITOPE (Methods. 2004 Dec; 34(4): 468-75) for analysis. As a result, it was predicted that there were more T cell epitopes (sequences with a higher risk of immunogenicity) which bind to HLA which has more Η chain CDR1. Here, in the TEPITOPE analysis, when reviewing the change in the risk of reducing the immunogenicity of the CDR1 of the Η chain, it was found that when the kabat number 33th isolinic acid (is) replaced with alanine (a 1 an i At ne) (A), the risk of immunogenicity was greatly reduced, indicating the change (Table 12). This mutation was added to H17 produced in Example 1 to prepare Η19 (Η19-Μ58/SEQ ID NO: 223). The prepared H19 and L12 were combined to form H19L12CH chain 19-Μ58/sequence identification number: 223, L chain L12/sequence identification number··237). The preparation and purification of each mutant were carried out as described in Example 4, in the method of 105 201028165. The affinity for NR10 and the biological activity of BaF/NR1〇 are as described in Reference Example ι and Example 2, with h〇LO (H chain H0-M58/SEQ ID NO: 1 36, L chain L0/sequence Identification number: 56) compared. The measured affinity results are shown in Table 13, and the biological activity of BaF/NR1 〇 is shown in Fig. 23. Both affinity and biological activity showed almost the same activity as H〇L〇. [Table 12] Name classification flO order pair mutation value B0 (kabat No·) of the 蚵-mutation 爹k change after the sequence Θ~ "base acid H19 CDR1 GYIMN (order pair to thin: 270) 33 | A GYAMN (Order pair identification: 284) [Table 13] ka(1/Ms) kd(1/s) KD(M) H0L0 1.8E+05 8.7E-04 4.8E-09 H19L12 2.3E+05 1.2E- 03 5.1E-09 L-chain CDR1 reduction in immunogenicity risk

The threonine (T) of kabat number No. 25 in the L chain CDR1 is alanine (A) or serine (S) in the sequence of the germ cell series. It is expected that the change of the threonine (T) at position 25 to alanine (A) or serine (S) will reduce the risk of immunogenicity (Table 14). Here, the above mutation was added to L12 to prepare L17 (SEQ ID NO: 238). The produced L17 is combined with H0 to form a H0L17CH chain H0-M58/SEQ ID NO: 136 'L chain L17/SEQ ID NO: 238). The preparation and purification of each mutant were carried out as described in Example 4. 06 201028165 The affinity of each mutant for NR10 and the biological activity of BaF/NRIO were carried out according to the methods described in Reference Example 10 and Example 2, and H0L0 was compared (H-chain HO-M58/SEQ ID NO: 136, L-chain L0/) Sequence identification number: 56) and H0L12CH chain H0-M58/sequence identification number: 136, L chain L12/sequence identification number: 237). Since L12 contains a sequence which increases affinity, it exhibits about 2 times higher affinity than H0L0. The affinity results of the assay are shown in Table 15. The biological activity of BaF/NRIO is shown in Figure 24. Affinity and biological activity showed almost the same affinity and biological activity as Η 0 L1 2 .

[Table 14] Name classification L0 sequence variation position (kabat No) L0 sequence after mutation of amino acid 1 mutated Ld-1 CDR1 msmnmA (SEQ ID NO: 25 TA RA® iIYSFLA (sequence identification number: 2 fat) CDR1 RTSENIYSRA "sequence identification number: 2?7" 25 TS mmirwik (sequence identification number: 28 volumes) [Table 15] ka(1/Ms) kd(1/s) KD(M) H0L0 1.6E+05 7.8E- 04 4.8E-09 H0L12 3.8E+05 7.4E-04 2.0E-09 H0L17 3.9E+05 8.1E-04 2.1E-09 [Example 12] Preparation of fully humanized NS22 antibody was found in the above examples. Mutations that reduce pi, mutations that increase affinity, mutations that inhibit Η chain decomposition, mutations that reduce the risk of immunogenicity, H0CH0-M58/SEQ ID NO: 136), ΗΚΗ1-Μ58/SEQ ID: 257), or L0 (L0/SEQ ID NO: 56) as a plurality of combinations, 107 201028165 The variable region of the NS22 mutant was produced, and various screening results were performed, and H2 8L17 (H chain H28-M58/SEQ ID: 224, L chain L17/SEQ ID NO: 238), H3 0L17CH Chain H30-M58/SEQ ID NO: 225, L chain L17/ SEQ ID NO: 238), H34L17CH chain H34-M58/ ID NO: 226, L chain, L17 / SEQ ID NO: 238), H42L17CH chain H42-M58 /

Sequence ID: 227, L chain L17/SEQ ID NO: 238), H44L17 (H chain H44-M58/SEQ ID NO: 228 'L chain L17/SEQ ID NO: 238), H46L17CH chain H46-M58/sequence recognition No.: 229, L chain L17/sequence identification number: 238), H57L17CH chain H57-M58/sequence identification number: 230, L lock L17/ sequence identification number: 238), H71L17CH chain H7 Bu M58/sequence identification number: 23 L chain L17/SEQ ID NO: 238), H78L17CH 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), H9 7L50CH 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 /

Sequence ID: 239). The preparation and purification of each mutant were carried out as described in Example 4. The affinity of each mutant for NR10 and the biological activity of BaF/NR10 were as described in Reference Example 10 and Example 2, and compared with /SEQ ID NO: 136, L chain L0/SEQ ID NO: 56). The affinity results of the assay are shown in Table 16, and the biological activity of BaF/NR1〇 is as shown in Figures 25-2. Affinity and biological activity were shown to be almost the same as or higher than H0L0. 108 201028165

[Table 16] Sample ka(1/Ms) kd(1/s) KD(M) H0L0 2.1E+05 8.8E-04 4.2E-09 H28L17 6.4E+05 3.3E-04 5.2E-10 H30L17 6.8E +05 5.7E-04 8.3E-10 H34L17 3.4E+05 1 2E-03 3.6E-09 H42L17 5.7E+05 3.7E-04 6.5E-10 H44L17 6.1E+05 7.2E-04 1.2E-09 H46L17 2.9E+05 1.3E-03 4.6E-09 B H57L17 7.1E+05 55E-04 7.7E-10 'H71L17 3.7E+05 1.2E-03 3.3E-09 H78L17 6.1E+05 7.0E-04 1.1E -09 H92L17 3.1E+05 1.3E-03 4.1E-09 H97L50 3.6E+05 1.3E-03 3.5E-09 H98L50 2.9E+05 1.3E-03 4.6E-09 [Example 13] Anti-NR10 Neutralization Analysis of the binding domain of the antibody (1) Preparation of human-mouse wild-type antigen and chimera antigen The wild-type and chimeric NR10 extracellular region encoding human and mouse (hhh (sequence recognition) No.: 258), mmm (sequence identification number: 259), hhm (sequence identification number: 260), mmh (sequence identification number: 261), hmm (sequence identification number: 262), mhm (sequence identification number: 263), Mhh (SEQ ID NO: 264)) gene, add His tag and Myc tag (HHHHHHEQKLISEEDL/SEQ ID NO: 287) at the C-terminus, insert the animal cell expression vector into FreeStyle 293 performance system (invi trogenTM) - secondary performance. A schematic diagram of the human/mouse wild type and chimeric NR10-ECD is shown in Fig. 26. Purification of human-mouse wild-type and chimeric antigens (hhh, 109 201028165 mmm, hhm, occupation 11, 11111111, 11111! 11, 111] 111) from the culture supernatant to 1^-1^8叩 641 (^ column chromatography), that is, 1 mL of Ni-NTA Superilow (QIAGEN) was filled in a previously prepared empty column (BioRad), and each 30 mL of the culture supernatant was added to contain 15 mM of chlorine. After washing with sodium and 20 mM of imidazole D-PBS (I) ulbecco's phosphate buffered saline, it was eluted with D-PBS containing 150 mM sodium chloride and 250 mM sodium sulphate. The fraction of the strip which was eluted was replaced with D-PBS by a layered molecular weight of 10K Amicon-Ultra (Millipore). (2) Detection of bound antigen by Western Blot

The human and mouse wild-type and chimeric antigens prepared as described above were electrophoresed by adding three 4-20% polypropylene sulphate gums (first chemistry) in each of 5 /5 g/g. The semidry type spot device was electrically transferred to the PVDF film (Millip0re) to terminate with TBS containing 5% skim milk. One (humanized anti-human NR10 antibody detection system) was lg41 with 5 g/mL of H44M58L17 and 1 (mouse anti-human NR1 0 antibody detection system) of 5 // g/mL, 1 (Myc The tag detection system was an anti-Myc antibody (Santa Cruz, Cat. #sc-789) diluted 500-fold with TBS containing 5% skim milk, and reacted at room temperature for 1 hour. The TBS containing 0. 05% TweenTM20 was washed 3 times in 3 minutes to react with the secondary antibody. The humanized anti-human NR10 antibody detection system was reacted with alkaline phosphatase-labeled goat anti-human IgG r (BIOSOURCE, Cat·#AHI0305) for 1 hour at room temperature, and the mouse anti-human NR10 antibody detection system and alkaline phosphoric acid were used. The enzyme-labeled goat anti-mouse IgG (Santa Cruz, Cat. #sc-2008) was reacted for 1 hour at room temperature, and the Myc tag was detected with the ELISA-labeled goat anti-rabbit IgG (Santa Cruz, Cat·#sc- 2057) Reaction at room temperature for 1 hour. With 110 201028165 0. 05% TweenTM20 TBS in 3 minutes, go! After the door was washed 4 times, the color was developed by BCIP/NBT phosphatase substrate and Bu composition system (KPL). The TBS (Tris-buffered physiological saline) used herein was prepared by dissolving TBs (Tris_buffered physiological saline) powder (TaKaRa) in 1 L of distilled water. The result is shown in Figure 27. In the case of using a humanized antibody or a mouse antibody, it was detected that it only binds to the NR1〇 extracellular region hhh, hhm, hmm. [Reference Example 1] Isolation of NR10, OSMR, and IL-31 genes in crab eater A. The safety evaluation of the pre-clinical stage was considered. It is important to consider the cross-over and neutralizing activity of crab chyme. NR1〇 gene, 〇SMR gene. From the published information of the rhesus monkey genome, the primers were designed, and the NR10 gene and the 〇SMr gene were successfully propagated from the crab chyme cDNA by the PCR method. The isolated crab eateries NR10, OSMR, and IL-31 gene sequences are shown as sequence identification numbers: 65, 69, and 67. The amino acid sequences of NR10, OSMR, and IL-31 of the crab eater are shown in sequence identification numbers: 66, 70, and 68. [Reference Example 2] Establishment of Ba/F3 cell line expressing NR10 and OSMR The human full-length cDNA of NR10 (SEQ ID NO: 75) was incorporated into the expression vector pCOS1 (Biochem Biophys Res Commun. 228, p838-45, 1996). , making pCosNRIO. 3. The oligostatin M receptor cDNA (0SMR, GenBank accession No. NM003999) was isolated from the human placental gene pool by PCR, and the expression vector pC〇sl-hOSMR was constructed in the same manner. Each l〇#g vector was simultaneously introduced into the cell line Ba/F3 derived from mouse IL-31-dependent pro-B cells by electroporation (BioRad).

Gene Pulser, 960 " F, 0.33 kV). Add people after importing 111 201028165

System] cultured to obtain a cell line with IL-31-dependent proliferation (hNR10/hOSMR/BaF3 cells). Further, the crab 猿il-31 gene (SEQ ID NO: 67) was placed in a mammalian expression vector, and introduced into a culture supernatant of CH0 cell line DG44' to obtain a crab-to-vegetation ratio _31. Using this culture supernatant, the hSR10/hOSMR/BaF3 gene was inserted into the expression vector pC〇si, and the Ba/F3 cells were expressed in the same manner as the hNR10/hOSMR/BaF3, and the IL-31 dependence of the crab eater was established. Sex cell line (cynNR10/cynOSMR/BaF3 cells). [Reference Example 3] Establishment of CH0 cell line expressing NR10

The intracellular region lacks the human NR10 gene (SEQ ID NO: 73) and the intracellular region-deficient crab NR10 gene (SEQ ID NO: 71) are inserted into the mammalian expression vector, respectively. C-0 cell line DG44 (BioRad Gene Pulser, 25 to F, 1.5 Kv) was introduced by electroporation. After screening with the drug, anti-human NR1 〇 antibody was used, and the NR10 expression cells were analyzed and screened by FCM. Further, the amino acid sequence encoded by the base sequence of the human NR10 gene (SEQ ID NO: 73) lacking the intracellular region has the sequence identification number: 7 4 indicating that the 'intracellular region lacks the type of crab 猿 NR 1 0 gene. The amino acid sequence encoded by the sequence (SEQ ID NO: 71) is represented by SEQ ID NO: 7 2 . [Reference Example 4] Preparation of NR 10 protein (extracellular region) Using the human NR10 cDNA as a template, only the extracellular region was proliferated by PCR, and the FLAG tag sequence was added to the C-terminus to form a expression vector for mammalian cells. A linear vector ΙΟ/zg was formed and introduced into a Chinese hamster cell line DG44 (BioRad Gene Pul ser 11, 25 ^ F 1 5 112 201028165 kV) by electroporation to obtain a highly expressed cell line. This cell strain was cultured in a large amount, and the culture supernatant was purified by an anti-FLAG antibody column (manufactured by SIGMA) and a gel filtration method to obtain a soluble NR 1 〇. The base sequence of the soluble NR 1 〇 is represented by SEQ ID NO: 77. The amino acid is represented by the sequence SEQ ID NO: 78. [Reference Example 5] Preparation of anti-human NR1 〇 antibody A human NR1 prion protein (extracellular region) [as described in Reference Example 4] was used to immunize mice to produce a fusion tumor (hybr丨d〇ma) by a general method. The fusion culture supernatant of the present invention was evaluated by the neutralizing activity of the human IL_31-dependent cell strain (hNR10/hOSMR/BaF3 cells) described in Reference Example 2, and N A 6 3 3 having NR1 〇 neutralizing activity was obtained. The expression vector for mammals inserted into the full-length gene (SEQ ID NO: 75) of human NR10 was used, and DNA immunization was carried out using a hernia emission gene to obtain a fusion tumor by a general method. The fusion culture supernatant of the present invention was evaluated by the neutralizing activity of the human R_3]-dependent cell strain (hNR10/hOSMR/BaF3 cells) described in Reference Example 2, and ND41 having NR1〇 neutralizing activity was obtained. [Reference Example 6] Preparation of human chimeric antibody The amino acid sequence of the heavy bond variable region of ΝΑ633 is as shown in SEQ ID NO: 4, and the amino acid sequence of the light chain variable region is, for example, a sequence identifier: 1〇8 is shown. The amino acid sequence of CDR1 of the heavy chain variable region of NA633 is shown in SEQ ID NO: 105, and the amino acid sequence of CDR2 is as shown in SEQ ID NO: 1〇6. The amino acid sequence of CDR3 is, for example, a sequence identifier. :1〇7, the amino acid sequence of CDR1 of the light chain variable region is shown in SEQ ID NO: 1〇9, and the amino acid sequence of CDR2 is shown in SEQ ID NO: 110, the amino acid of CDR3 The sequence is as in Sequence 113 201028165. The mice described herein can be used to produce a fungic antibody. The identification of the heterogeneity of IgG2 is shown by 111. Moreover, according to the general method, the variable region and the human constant region (H chain is r 1, L chain is [Reference Example 7] stability is not reduced but the production of wild type huPMl-SKSC is reduced. Since the NS22 antibody is a neutralizing antibody, the immune is considered. In the case of both primordial and side effects, consider the possibility of poor binding to the FcT receptor. To reduce binding to the Fc τ receptor, the isotype of the constant region does not use IgG1, consider IgG2 or igG4 (Ann

Hematol. 1 998 Jun;76(6):231-48.), from the point of view of Fc7 receptor sputum and blood retention, igG2 is considered to be more desirable than IgG4 (Nat

Biotechnol. 2007 Dec;25(12):1369-72). In addition, when antibodies are developed as pharmaceuticals, the physical properties of proteins, especially homogeneity and stability, are very important. It is known that IgG2 isotypes have a large number of disulfide from the hinge domain. Heterogeneity of the bond (J Bi〇1

Chem. 2008 Jun 6; 283(23): 16206-15·). It is not easy to maintain the mass-produced difference in the heterogeneity of the substances/related substances from these substances and to manufacture them as a pharmaceutical product. Therefore, it is desirable to be a single substance as much as possible. Therefore, in the development of an antibody having an IgG2 isoform as a pharmaceutical product, it is desirable that the stability does not decrease but the heterogeneity from the disulfide bond is reduced. In order to reduce the heterogeneity of wild-type IgG2, the disulfide bond of the hinge portion of igG2 and the change of the disulfide bond of the CH1 domain were carried out. The results of various mutants were reviewed. The wild type IgG2 constant region sequence has the EU number in the CH1 region of the Η chain (Sequences of Proteins of immunological interest, NIH Publication 114 201028165

No.91-3242) The cysteine at position 131 (in this case) and the arginine at position 133 were changed to serine and lysine, respectively.

(lysine), the cysteine of the EU number 219 where the upper hinge of the Η chain is present is changed to the SKSC of the constant region of serine (sequence identification number: 62), It may not reduce stability but reduce heterogeneity. On the other hand, in the method of reducing the heterogeneity, it is considered that only the method of changing the cysteine (CySteine) of EU No. 219 in which the upper hub of the Η bond is present to serine, and only the 220th A method in which cysteine is changed to serine. Here, the cysteine of EU No. 219 for making IgG2 was changed to the constant region SC of serine (sequence number: 153), and the cysteamine of EU No. 220 of IgG2. The cysteine is changed to the constant region CS of serine (sequence identification number: 154). The Η chain is used to combine the above-described constant regions and igG1 (SEQ ID NO: 60) and IgG2 (SEQ ID NO: 132) and humanized anti-IL-6 receptor _ antibody variable region (H chain variable _, / SEQ ID NO: 155 吖 key variable region huPMl-VL / SEQ ID NO: 156) (Cancer Res. 1993 Feb 15; 53 (4): 85 Bu 6.) huPMl-SC (sequence identification number :157), huPMl-CS (sequence identification number: 158), huPMl-IgGl (sequence identification number: 159), huPM IgG2 (sequence identification number: 160), and huPM SBSKSC (sequence identification number: 161), L chain Each antibody was produced using huPM Bu L (SEQ ID NO: 162). The expression and purification of each antibody were carried out as described in Example 4. A heterogeneity comparison of each antibody was performed. The method for evaluating the heterogeneity of huPM1-IgG1, huPM1-IgG2, 115 201028165 huPM1-SC, huPMl_cs, huPM1_SKSC was evaluated by cation exchange chromatography. The column is such that wcx_i〇 (Dl〇neX), mobile phase A uses 20 mM sodium acetate, pH 5. 〇; mobile phase B is carried out using 20 (10) sodium acetate, upper M Nan, pH 5 q, _"^ gradient. The results of the evaluation are shown in Fig. 12. In Fig. 12, although the constant region is converted from IgG1 to ig (j2, the heterogeneity of the constant region conversion to SKSC is greatly reduced as the first heterogeneity is low. In the aspect of 'the strange area is sc and the strange area is not sinking

The shape is the same, the heterogeneity is greatly reduced, but the heterogeneity is not sufficiently improved when the constant region is CS. In order to develop antibodies as pharmaceuticals, the heart is expected to have low heterogeneity and high stability for use in preparations. Here, the evaluation of the purity; the method was evaluated by the thermal denaturation intermediate temperature (τ m) of the differential scanning calorimeter (D S C) (VP-DSC, manufactured by Microcai Co., Ltd.). The heat-denatured intermediate temperature (Tm) is a stable property. It is expected to be a heat-denatured intermediate temperature (Tm value) in a custom formulation for pharmaceuticals (J pharm (10)

ApnMU): 1414-26.). Here, a solution of 2 mM sodium acetate, 15 turbid NaCl, ΡΗ6·0 (EasySEp, τ〇Μγ) was used for dialysis of 匕(四)卜(四)卜huPMl-IgG2, huPMl-SC, huPMl-CS, huPMl-SKSC. ,, 』0. 1 mg / mL of protein is affected, 1.匸/m丨n heating rate from 4 〇乞 to 1 G0 °C ’ for DSC measurement. The obtained denaturation curve is shown in the figure, and the Tm value of the Fab portion is shown in Table 17. 116 201028165 [Table π] Name Tm/X: huPMl-IgGl 94.8 huPMl-IgG2 93.9 huPMl-SC 86. 7 huPMl-CS 86.4 huPMl-SKSC 93.7 huPM IgGl and huPM IgG2 have almost the same Tm value, about 94 ° C (IgG2 is low about rc), and the Tm 値 of huPM Bu and huPMl-CS is about 86 C ', and the Tm value is significantly lower than that of huPM1-IgG1 and huPM1-IgG2. In addition, the Tm値 of huPM1-SKSC is about 94t, which is almost the same as huPMl-IgGl and huPM IgG2. The stability of huPM Bu and huPM Bu CS is significantly lower than that of IgG2. Therefore, as a pharmaceutical development, it is preferable to change the cysteine (cysteine) in the cm region to the huPMhSKSC of serine. The reason why the Tm 値 of huPMl-SC and huPMl-CS is significantly lower than that of IgG2 is considered to be because the disulfide bond mode of huPMl-SC and huPMl-CS and IgG2 is different. Comparing the DSC denaturing curve, compared with huP] (the denaturation peak of the Fab part of a_IgG1 and huPMl-SKSC is steep, the huPM1_sc and huPMl-CS are flat, and the peak of the Fab is flat. The peak of the Fab portion of hUPM1-IgG2 is a short peak on the low temperature side. The denatured peak of DSC exhibits a generally steep (sharp) denaturation peak when it is a single component, but there is In the case where different plural species are present in the presence of 117 201028165 (ie heterogeneity), the denaturation peak of Tm is considered to be flat. That is, there are multiple components in huPMl-IgG2, huPMl-SC and huPMl-CS, and darkness does not exist. huPMl-SC and huPMl-CS cannot fully reduce the heterogeneity of natural UG2. Therefore, it is judged that the heterogeneity of natural IgG2 is related not only to the central part of cysteine but also to the presence of cysteine in the region. In order to reduce the heterogeneity on the DSC, it is considered that not only the cysteine in the hinge part but also the cysteine in the CH1 region must be changed. As described above, the cysteine and CH1 regions of the hinge portion are changed. Cysteamine can be The same stability as the original native IgG2. From the above-mentioned constant region of reducing heterogeneity from the IgG2 pivot region, it is considered that only the central portion of the cysteine is replaced by the constant region SC and CS of serine, in heterogeneity The viewpoint of sex and stability is not sufficient. However, it has been found that the substitution of the cysteine of the 131st position of the EU number in the CH1 region with the serine acid can maintain the same stability as the original IgG2 and greatly reduce the heterogeneity. This constant region is for example SKSC.

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

Among the constant region Fcr receptor binding sites of IgG2, EU numbers: 233, 24, 235, and 26 are unbound, but among the Fct receptor binding sites, EU number: positions 327, 330, and 331 are unbound IgG4. Sequences with different sequences' therefore must change the EU number: amino acid at positions 327, 330, 331 to the sequence for IgG4 (Eur J Immunol. 1999 Aug; G(A) in 29(8): 2613-24) . However, the amino acid at position 339 of the EU number in IgG4 is arginine, and IgG2 is sulphate 118 201028165 (threonine), so only the amino acid: amino acid at positions 327, 330, and 331 is changed. The sequence of IgG4 forms a non-naturally occurring tau cell epitope, and a new peptide sequence of 9 amino acids occurs, posing an immunogenic risk. Here, it was found that the addition of a new IgG number eu number to the above change, threonine at position 339, to arginine can prevent the appearance of a new peptide sequence. In the mutation described here, the meth 〇 meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth meth Further, SKSC (SEQ ID NO: 62) with improved heterogeneity from the pivotal disulfide bond prepared in Reference Example 7 was introduced as a non-naturally occurring T cell epitope peptide derived from the 131st and 133th mutations. The new peptide sequence of the nine amino acids formed has an increased risk of immunogenicity, and therefore, the glutamic acid at position 137 of the EU number is changed to glycine, 138th. The serine of the position was changed to a mutation introduction of glycine, and the peptide sequence near the 131st to 139th position was identical to that of the IgG1. A strange sequence M14 (sequence identification number: 129) for introducing all of the mutations described above was produced. The huPM1-M14 in which the Η chain is huPMl-M14 and the L chain is huPM1-L (SEQ ID NO: 162) was expressed and purified as described in Reference Example 7. The heterogeneity evaluation of the produced huPM1-M14 (SEQ ID NO: 163) and hupM1_IgG1, huPM IgG2 was carried out by the method described in Reference Example 7 by cation exchange chromatography. As shown in Fig. 14, huPM Bu M14 is also the same as huPMbSKSC to reduce heterogeneity. 119 201028165 [Reference Example 9] Preparation of huPMl-M58 which reduces the heterogeneity of the C-terminal side of the Η chain and the drug motility huPMl-M58 molecule preparation huPMl is an IgG1 antibody. The heterogeneity of the C chain C-terminal sequence of the IgG1 antibody is known to be absent from the lysine residue of the C-terminal amino acid and (the 2 amino acid glycine and the lysine) Lack of the resulting C-terminal amino acid amide (Anal Biochem. 2007 Jan 1; 360(1): 75-83.). In huPMl, although its main component is the base sequence

The presence of the C-terminal amino acid lysine (iysine) is post-translationally modified to lack the sequence, but the remaining sub-components of lysine and lysine are lacking due to glycine and lysine. The resulting sub-component of the c-terminal amine group amide is also heterogeneous. It is difficult to maintain the heterogeneity of the test substance/related substance and it is not easy to be produced as a large amount of pharmaceuticals. It is expected to be a single substance as much as possible, and it is desirable to reduce these heterogeneities in the development of antibodies as pharmaceuticals. Therefore, it is hoped that there is no (4) c-end heterogeneity in the development of medical drugs. Further, in order to reduce the amount of antibody administered, it is desirable to prolong the plasma half-life of the antibody. Here, the heterogeneity of the C-end of the Η chain is reduced, and it is changed from hupjn igGl. For the purpose of drug motility and a novel constant region which reduces heterogeneity from wild type 1 Qi 2 without reducing stability, a mutation as described below was introduced. Specifically, for the above-mentioned heterogeneity, which has high stability and is associated with antibodies to the IgG2 isoform assay region, it was found that the EU numbered miis acid (glutaffiic deduction (4) was changed to glycine g Υ The serine at position 138 is changed to glycine 120 201028165 (glycine), the histidine at position 268 is changed to glutamine, arginine at position 355 ( Arginine) changed to glutamine, glutamine at position 419 changed to glutamic acid' plus 446th in order to reduce the heterogeneity of the C-terminus of the Η chain Glycine (glyCine) and 447th lysine (173丨1^) 1111 elbow 1458 (SEQ ID NO: 164). 11 chain is huPM Bu M58, L chain is huPM Bu L (sequence identification number: 162) huPM Bu M58

The performance and purification were carried out as described in Example 4. The heterogeneity of the produced huPMl-M58 and huPMl-IgG huPMl-IgG2 was evaluated by cation exchange chromatography, and the stability evaluation was carried out by the method described in Example 5 using DSC. The results of the DSC are shown in Table 18. As shown in Figures 13 and 16, huPMl-M58 is also the same as huPM BUSC, reducing heterogeneity under lossless stability. [Table 18] ^ Name Tm/t huPMl-IgGl 94.8 huPMl-IgG2 93,9 huPMl-SKSC 93.7 huPMl-M58 93.7 huPM1-M58 blood retention retention IgG molecule has long retention in plasma (slow disappearance) This is because of the known FcRn function as a salvage receptor for IgG molecules (Nat Rev Immunol. 2007 Sep; 7(9): 715-25). Transplanted cells 121 201028165 IgG molecules that enter the endocytic sac (end〇s〇me) with (pinocytosis), bind to FCRn expressed in the inner capsule under acidic conditions (near PH6_0) in the inner capsule. The igG molecule that does not bind to FcRn enters the lysosome where it is broken down 'but the IgG molecule that binds to FcRn moves to the cell surface' under neutral conditions in plasma (near pH 4. 〇), by FcRn Dissociate and return to the plasma.

The IgG type antibody is known to have isoforms of igG1, IgG2, IgG3, and igG4. However, the half-life in human plasma is about 36 days for IgG1 and IgG2, and about 30 days for IgG3 for IgG4 for 16 days (Nat Biotechnol. 2007).

Dec; 25( 1 2) :1369-72.) ' I gGl and I gG2 have the most retention in plasma

long. In general, the antibody of the antibody is IgG1, IgG2, and IgG4. However, a method for improving the drug kinetics of these IgG antibodies is known, and it is known to improve the binding property to human FcRn by changing the sequence of the IgG-determining region (J).

Biol Chem. 2007 Jan 19;282(3):1709-17 'J Immunol. 2006 Jan l;176(l):346-56).

Mouse FcRn has a poor species relationship with human FcRn (Pr〇c Nati Acad

Sci US A. 2006 Dec 5;103(49):18709-14), therefore, in order to predict the retention of IgG antibodies in the human body by changing the constant region sequence, consideration is given to the evaluation and evaluation of binding to human FcRn in human FcRi1 Retention in plasma in transgenic mice (Int I_n〇1. 2006 Dec; 18(12): 1759-69). Evaluation of binding to human FcRn

FcRn is FcRn and Θ2-microglobulin. A DNA primer was prepared according to the published human FcRn gene sequence (j· Εχρ. Med. 18〇 (6), 122 201028165 2377-2381 (1 994)). By human cDNACHunmn

Placenta Marathon-Ready cDNA, Clontech) was used as a template to prepare a DNA fragment encoding the full-length gene by PCR using the primers prepared above. Using the obtained DNA fragment as a template, a DNA fragment encoding an extracellular region (Metl-Leu290) containing a message region was amplified by PCR and inserted into an animal cell expression vector (human FcRn amino acid sequence/SEQ ID NO: 165 ). Similarly, an oligo DNA primer was prepared according to the published human cold 2-microglobulin gene sequence (Proc. Natl. Acad. Sci. U.S.A. 99 (26), Θ 1 6899-1 6903 (2002)). Using the cDNACHu-Placenta Marathon-Ready cDNA, CLONTECH) as a template, the DNA fragment encoding the full-length gene was prepared by PCR using the primers prepared above. Using the obtained DNA fragment as a template, a DNA fragment encoding the full length of the /3 2-microglobulin (Metl-Metll9) containing the message region was amplified by PCR and inserted into an animal cell expression vector (human cold 2-microglobulin amine) Acid sequence/sequence identification number: 1 6 6 ).

The expression of soluble human FcRn was introduced into human fetal kidney cancer cells by lipofection (1 ipofection) using the above-prepared human FcRn and human/92-microglobulin plastids using 1% fetal bovine serum (Invitrogen). HEK293H strain (Invi trogen). After the resulting culture supernatant was recovered, IgG Sepharose 6 Fast Flow (Amersham) was used.

Biosciences) according to (j lmmun〇l. 2002 Nov

1 ; 169 (9): 517 Bu 80.) Method purification. Then with HiTrap Q HP (GE

Healthcare) purification. Evaluation of binding to human FcRn using Biacore 3000, an antibody that binds to on-chip immobilized protein L or rabbit anti-human IgG/c chain antibody, which is an analyte, as an analyte, the amount of binding to FcRn when interacting with human FcRn, Calculate the affinity (KD). Specifically, the running buffer was immobilized on the sensing wafer CM5 by an amine coupling method using a 50 mM Na-packing buffer containing 150 mM NaCl at pH 6.0. On BIAC0RE). Thereafter, the antibody was diluted with a running buffer containing 0.02% Tween20, injected, and the antibody was bound to the crystal plate, and then human FcRn was injected to evaluate the binding of the antibody to human FcRn. The calculation of affinity uses the software BIAevaluation. The amount of hFcRn binding to the antibody at the end of the human FcRn injection was determined from the obtained sensergram. This binding amount was determined by the steady state affinity (stea (jy state affinity) method, and the human FcRn was calculated for the antibody. Affinity. Prediction of human blood cell retention in human FcRn using huPM1-IgG1, huPM1-M58. The binding of huPM IgG1 and huPM1-M58 to human FcRn was evaluated by f BIAcore. As shown in Table 19, huPMl- The binding of M58 is about 1.4 times higher than that of huPM IgGl. [Table 19]

ΚΟ(μΜ) huPMl-IgGl huPMl*~M58 1.62 1.17

Evaluation of plasma retention in human FcRn transgenic mice 124 201028165 Evaluation of drug motility in human FcRπ transgenic mouse (B6-inFcRn_/-.hFcRn Tg line 276 + /+murine 'Jackson Laboratories) was performed as follows . The antibody was administered to the mice in a single intravenous dose at a dose of 1 mg/kg. The collected blood was centrifuged at 15 ° C for 15 minutes at 4 ° C to obtain plasma. The separated plasma is stored in a cold bundle bank set below -2 〇〇c until the measurement is performed. Plasma concentrations were determined by ELISA. ▲Evaluation of plasma retention in human FcRn transgenic mice with huPM1-IgG1 and huPM1-M58 using huPM1-IgG1 and huPM1-M58 human FcRn transgenic mice to predict blood retention in humans . As a result, as shown in Fig. 17, it was confirmed that huPM1-M58 was improved in drug power compared to huPM1-IgG1. It is suggested that binding to human FcRn is associated with plasma retention in human FcRn transgenic mice. [Reference Example 10] Affinity measurement using antigen-antibody reaction of β i a cor e The velocity analysis of the antigen-antibody reaction was carried out using Biacore T100 (GE Healthcare BioSciene). Recombinant protein A (ZYMED) (hereinafter referred to as protein a) is immobilized on the sensor wafer, and the immobilized protein a captures the antibody' and the antigen acts as an analyte to determine the interaction of the antibody with the antigen. The antigen was prepared into various concentrations of rhNR10. From the measured sensergram, the combined velocity coefficient ka (1/Ms) of the kinetics parameter and the dissociation velocity coefficient kd (1/s)' are calculated from this value to calculate KD(M). The calculation of each parameter was performed using Biac〇re T100 evaluation software version 1. i (( Healthcare Bi〇Sciene). Immobilization of protein A on the induction wafer 125 201028165 Immobilization of protein A by amine coupling (amine coup 1 ing) method All the flow cells of the sensing chip CM5 (GE Healthcare BioSciene). The running buffer used HBS-EP+ (l〇mM HEPES, 0.15 M NaCl, 3 mM EDTA, 0.05% v/v interface) The active agent P20) was tested at a flow rate of 10 #L/inin. The carboxyl group of carboxymethy 1 dextran on the induction wafer was subjected to 1 〇〇# L of 75 mg/mL EDC (N- Ethyl-N*-(3-dimethylaminopropy1) · carbodi imide hydrochloride was activated with a 1:1 mixture of 11.5 mg/mL NHS (N-hydroxysuccinimide), and the inflow was formulated with 10 1 〇 elbow acetate buffer (91!4.5). The protein of 50//8/1111^ was reacted. After that, 10 〇 of 1 Μ of ethanolamine hydrochloride (ρΗ8·5) was flowed in, and the unreacted active group was not activated. Finally, about 4000-5000 RU was immobilized. The whole experiment was carried out at 25 ° C. The antigen captured by protein A and the antigen resistance of rhNR10 Affinity assay reactions

The running buffer used HBS-EP+. Each antibody was formulated to 0. 25 # g/mL, or formulated in combination with protein A of about 100 RU. The rhNRIO used as the analyte was formulated to 0, 38.5, 77·0, 154 nM, or 0, 19.25, 77. 01 nM using HBS-EP+. The measurement method was such that the first protein A capture antibody solution, and the analyte solution was reacted for 3 minutes at a flow rate of 20 #L/min, and then switched to HBS-EP + 5 minutes to measure the dissociation phase. After the measurement of the dissociation phase was completed, it was washed with 10 mM glycine-HCl (pH 1.5) to regenerate the induction wafer. From the obtained sensorgram (sensergram), use Biacore's dedicated data analysis software 126 201028165

The Biacore T100 evaluated the _, 4, & software version 1.1 for speed theory analysis. [Industrial Applicability] The anti-NR1G antibody obtained by the present invention exhibits an effective neutralizing activity against NR10, and is effective as, for example, a therapeutic agent for inflammatory diseases. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a view showing the amino acid sequence of the heavy ‘chain variable region of the mouse antibodies NS18, NS22, NS23, and NS33. Fig. 2 is a diagram showing the amino acid sequence of the light chain variable region of the mouse antibodies NS!8, NS22, NS23, and NS33. Figure 3 is a graph showing the inhibition of proliferation of hNR10/hOSMR/BaF3 cells by the supernatant of the fusion culture. Fig. 4 is a graph showing the inhibition of proliferation of cynNR1 〇/cynOSMR/BaF3 cells by the culture supernatant of the fusion tumor. Figure 5 is a graph showing the activity evaluation (BaF) of chimeric NS22. Fig. 6 is a graph showing the evaluation of the activity of the chimera NS22 (DU-145). Figure 7 is a graph showing the evaluation of IL-31 competition activity of chimeric NS22. Figure 8 is a graph showing the nri〇 binding competitive activity against the NR10 antibody. Figure 9 is a graph showing IL-31 competition activity against humanized NS22 (h〇l〇). Figure 10 is a graph showing the effect of humanized anti-Nrio anti- 127 201028165 body HOL0 constant·definite region on heterogeneity by cation exchange chromatography. Fig. 11 is a graph showing the evaluation of the IL_31 competition activity of a mutant which can reduce the isoelectric point of the variable region without significantly reducing the binding of the NR1 〇 of the humanized anti-NR10 antibody. Figure 12 is a graph showing the effect of constant region of anti-IL-6 receptor antibody on heterogeneity by cation exchange chromatography. Figure 13 is a graph showing the effect of the constant region of the anti-IL-6 receptor antibody on the denaturation peak by DSC. Figure 14 is a graph showing the effect of a new constant region M14 on heterogeneity in an anti-receptor antibody as assessed by cation exchange chromatography. Figure 15 is a graph showing the effect of the new constant region M58 on heterogeneity in the anti-il_6 receptor antibody as assessed by cation exchange chromatography. Figure 16 is a graph showing the effect of a new constant region M58 on the denaturation peak in the anti-u_6 receptor antibody as assessed by DSC. Figure 17 shows the transfer of huPM1_IgG1 and hupMi-M58

A graph showing the results of evaluation of plasma retention in a murine gene mouse. Figure 18 is a graph showing the biological activity of BaF/NR1〇 for each antibody. Fig. 19 is a graph showing the thermal acceleration w (broken line) and the unaccelerated product (solid line) of each mutant antibody obtained by cation exchange chromatography, and comparing the generation of decomposition products before and after thermal acceleration. The peak position of the base component confirming the change is displayed at the arrow. Figure 20 is a graph showing the activity of each mutant (Fig. 21 is a graph showing the activity evaluation of Ha4〇1La4〇2, H〇L〇 128 201028165. Figure 22 is a graph showing H17L11 The graph of activity evaluation (BaF) of H0L0. Fig. 23 is a graph showing the activity evaluation (BaF) of H19L12 and H0L0. Fig. 24 is a graph showing the bioactivity of BaF/NRIO of H0L12 and H0L17. .

Figure 25-1 is a graph showing the activity evaluation (BaF) of each mutant. Figure 25-2 continues with Figure 25-1. Figure 26 is a schematic diagram of human and mouse wild type and chimeric NR10_ecd. Fig. 27 is a photograph showing the binding region (d〇main) using the Western dot collapse method. Fig. 27A is a photograph showing the results of detection by humanized anti-human NR1 〇 antibody. Figure 27B is a photograph showing the results of detection by mouse anti-human NR10 antibody. Figure 27C is a photograph showing the results of detection by anti-Myc antibody. Only the binding antigens of hhh, hhm and hmm were detected by anti-human NR1 0 antibody, and the binding of mmm, mmh and mhm could not be confirmed. Figure 28-1 is a diagram showing the amino acid sequence of each mutant of ho (SEQ ID NO: 5〇). Figure 28-2 continues with Figure 28-1. Figure 28-3 continues with Figure 28-2. Figure 29-1 is a diagram showing the amine 129 201028165 basal acid sequence of each mutant of l〇 (SEQ ID NO: 52). Figure 29-2 continues with Figure 29-1. [Main component symbol description] None

130 201028165 Sequence Listing <11〇> GHUGAI SEIYAKU KABUSHIKI KAISHA &lt;120>Anti-NR10 Antibody and Its Use

&lt;130&gt; C1-A0712Y1PPP &lt;150&gt; PCT/JP2008/072152 &lt;151> 2008-12-05 &lt;150> PCT/JP2009/054941 &lt;151> 2009-03-13

&lt;160&gt; 287 &lt;170&gt; Patent In version 3. 4

&lt;210&gt; 1 &lt;211&gt; 5 &lt;212> PRT &lt;213&gt; Mus musculus <400> 1 Gly Tyr lie Met Asn 1 5 &lt;210> 2 <211> 17 &lt;212> PRT <213> Mus Musculus <400> 2 Leu lie Asn Pro Tyr 1 5 Gly &lt;210> 3 &lt;211&gt; 12 <212> PRT 1 15 201028165 &lt;213&gt; Mus musculus &lt;400〉 3

Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr 1 5 10 &lt;210&gt; 4 &lt;211&gt; 121 &lt;212> PRT &lt;213> Mus musculus <400> 4

Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15

Ser Met Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Lys Gin Ser His Gly Lys Asn Leu Glu Trp lie 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Asp Thr Asn Tyr Asn Gin 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

Gin Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 5 &lt;211> 11 &lt;212&gt; PRT &lt;213> Mus musculus <400> 5 201028165

Arg Ala Ser Glu Asn lie Tyr Ser Phe Leu Ala 1 5 10 &lt;210〉 6 &lt;211〉 7

&lt;212&gt; PRT &lt;213&gt; Mus musculus &lt;400&gt; 6

Asn Ala Lys Thr Leu Ala Lys 1 5

&lt;210&gt; 7 &lt;211&gt; 9 <212> PRT &lt;213> Mus musculus &lt;400&gt; 7

Gin His His Tyr Glu Ser Pro Leu Thr 1 5 &lt;210〉 &lt;211&gt;&lt;212〉&lt;213〉

&lt;400〉 8 107 PRT Mus musculus 8

Asp lie Gin Met Thr Gin Ser Pro Ala Ser Leu Ser Ala Ser Val Gly 15 10 15

Glu Thr Val Thr lie Thr Cys Arg Ala Ser Glu Asn lie Tyr Ser Phe 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Gin 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 Gin Phe Ser Leu Lys lie Asn Ser Leu Gin Pro 3 201028165 65 70 75 80

Glu Asp Phe Gly Ser Tyr Tyr Cys Gin His His Tyr 6lu Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys 100 105 &lt;210&gt; 9 &lt;211> 5 <212> PRT <213> Mus musculus &lt;400&gt; 9

Gly Tyr lie Met Asn 1 5 <210> 10 &lt;211〉 17

&lt;212> PRT &lt;213&gt; Mus musculus <400> 10

Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe Lys 15 10 15

Gly &lt;210&gt; 11 <211> 12 &lt;212&gt; PRT &lt;213&gt; Mus musculus <400> 11

Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr 1 5 10

&lt;210&gt; 12 <211> 121 &lt;212> PRT 4 201028165 &lt;213&gt; Mus musculus <400> 12

Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro 6ly Ala 15 10 15

Ser Met Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Lys Gin Ser His Gly Lys Asn Leu Glu Trp lie . 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn 6ln 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

Gin Gly Thr Ser Val Thr Val Ser Ser 115 120 &lt;210> <211> &lt;212> <213>

13 11 PRT &lt;400〉

Mus musculus 13

Arg Thr Ser Glu Asn lie Tyr Ser Phe Leu Ala 1 5 10 &lt;210> 14 <211> 7

&lt;212> PRT &lt;213&gt; Mus musculus &lt;400> 14 5 201028165

Asn Ala Lys Thr Leu Ala Lys 1 5 &lt;210> 15 <211> 9

&lt;212> PRT &lt;213&gt; Mus musculus <400> 15

Gin His His Tyr Glu Ser Pro Leu Thr 1 5 &lt;210〉 16

<211> 107

&lt;212> PRT &lt;213&gt; Mus musculus <400> 16

Asp lie Gin Met Thr Gin Ser Pro Ala Ser Leu Ser Ala Ser Val Gly 15 10 15

Glu Thr Val Thr lie Thr Cys Arg Thr Ser Glu Asn lie Tyr Ser Phe 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Gin 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 Gin Phe Ser Leu Lys lie Asn Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Gly Ser Tyr Phe Cys Gin His His Tyr Glu Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys 100 105

&lt;210&gt; 17 &lt;211&gt; 5 <212> PRT 6 201028165 &lt;213&gt; Mus musculus &lt;400> 17

Gly Tyr lie Met Asn 1 5 &lt;210〉 18 &lt;211&gt; 17

&lt;212&gt; PRT &lt;213&gt; Mus musculus <400> 18

Leu lie Asn Pro Tyr Asn Gly Gly Ala Glu Tyr Asn Gin Lys Phe Lys 15 10 15

Asp &lt;210> 19 &lt;211〉 12

&lt;212〉 PRT &lt;213&gt; Mus musculus &lt;400> 19

Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr 15 10 <210> 20 &lt;211&gt; 121

&lt;212&gt; PRT &lt;213&gt; Mus musculus &lt;400&gt; 20

Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Thr 15 10 15

Ser Met Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Lys Gin Ser His Gly Lys Asn Leu Glu Trp lie 7 201028165 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Ala Glu Tyr Asn Gin 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

Gin Gly Thr Ser Val Thr Val Ser Ser 115 120 &lt;210〉 21 &lt;211〉 11

<212> PRT &lt;213&gt; Mus musculus <400> 21

Arg Ala Asn Glu Asn lie Tyr Ser Tyr Leu Ala 1 5 10

&lt;210> 22 <211> 7 <212> PRT &lt;213> Mus musculus &lt;400> 22

Asn Ala Lys Thr Leu Ala Glu 1 5 &lt;210> 23 <211> 9

&lt;212> PRT &lt;213&gt; Mus musculus &lt;400> 23 8 201028165

Gin His His Tyr Gly Thr Pro Pro Thr 1 5 &lt;210> 24 &lt;211> 107 <212> PRT &lt;213&gt; Mus musculus &lt;400> 24

Asp lie Gin Met Thr Gin Ser Pro Ala Ser Leu Ser Ala Ser Val Gly 15 10 15

Glu Thr Val Thr Phe Thr Cys Arg Ala Asn 6lu Asn lie Tyr Ser Tyr 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Gin Gly Lys Ser Pro Gin 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 Gin Phe Ser Leu Lys lie Asn Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Gly Ser Tyr Tyr Cys Gin His His Tyr Gly Thr Pro Pro 85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys 100 105 <210> 25 <211> 5 <212> PRT <213> Mus musculus <400> 25

Asn Tyr Trp Met His 1 5

&lt;210&gt; 26 &lt;211> 17 <212> PRT 9 201028165 &lt;213&gt; Mus musculus &lt;400&gt; 26

Ala lie Tyr Pro Gly Asn Ser Asp Thr Asp Tyr Asn Gin Lys Phe Lys 15 10 15

Gly &lt;210> 27 <211> 8

&lt;212&gt; PRT &lt;213> Mus musculus <400> 27

Asp Gly Tyr Asp Asp Phe Asp His 1 5 &lt;210> 28 <211> 116

&lt;212> PRT &lt;213&gt; Mus musculus <400> 28

Glu Val Gin Leu Gin Gin Ser Gly Thr Val Leu Ala Arg Pro Gly Ala 15 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 Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45

Gly Ala lie Tyr Pro Gly Asn Ser Asp Thr Asp Tyr Asn Gin 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 10 201028165

Thr Thr Gly Tyr Asp Asp Phe Asp His Trp Gly Gin 6ly Thr Thr Leu 100 105 110

Thr Val Ser Ser 115 &lt;210&gt; 29 &lt;211&gt; 12 <212> PRT <213> Mus musculus <400> 29

Arg Ala Ser Ser Ser Ser Ser Ser Tyr Leu His 1 5 10 &lt;210> 30 &lt;211&gt; 7

&lt;212&gt; PRT &lt;213&gt; Mus musculus &lt;400&gt; 30

Ser Thr Ser Asn Leu Ala Ser 1 5 &lt;210〉 31 &lt;211〉 9

<212> PRT &lt;213&gt; Mus musculus <400> 31

Gin Gin Tyr Ser Gly Tyr Pro Leu Thr 1 5 &lt;210〉 32 &lt;211〉 108

&lt;212&gt; PRT &lt;213&gt; Mus musculus <400> 32 11 201028165

Glu Asn Val Leu Thr 6ln Ser Pro Ala lie Met Ser Ala Ser Pro Gly 15 10 15

Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Ser Ser Ser 20 25 30

Tyr Leu His Trp Tyr Gin Gin Lys Ser Gly Ala Ser Pro Lys Leu Trp 35 40 45 lie 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 lie Ser Ser Val Glu 65 70 75 80

Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Gly Tyr Pro 85 90 95

Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys 100 105 &lt;210&gt; 33 &lt;211&gt; 1406 &lt;212&gt; DNA <213> Mus musculus &lt;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 12 600 600

201028165 tggaactctg gatccctgtc cagcggtgtg cacaccttcc cagctgtcct gcagtctgac ctctacactc tgagcagctc agtgactgtc ccctccagca cctggcccag cgagaccgtc acctgcaacg ttgcccaccc ggccagcagc accaaggtgg acaagaaaat tgtgcccagg gattgtggtt gtaagccttg catatgtaca gtcccagaag tatcatctgt cttcatcttc cccccaaagc ccaaggatgt gctcaccatt actctgactc ctaaggtcac gtgtgttgtg gtagacatca gcaaggatga tcccgaggtc cagttcagct ggtttgtaga tgatgtggag gtgcacacag ctcagacgca accccgggag gagcagttca acagcacttt ccgctcagtc agtgaacttc ccatcatgca ccaggactgg ctcaatggca aggagttcaa atgcagggtc aacagtgcag ctttccctgc ccccatcgag aaaaccatct ccaaaaccaa aggcagaccg aaggctccac aggtgtacac cattccacct cccaaggagc agatggccaa ggataaagtc agtctgacct gcatgataac agacttcttc cctgaagaca ttactgtgga gtggcagtgg aatgggcagc cagcggagaa ctacaagaac actcagccca tcatggacac agatggctct tacttcgtct acagcaagct caatgtgcag aagagcaact gggaggcagg aaatactttc acctgctctg tgttacatga gggcctgcac aaccaccata ctgagaagag cctctcccac tctcctggta aataatgagc ggccgc &lt; 210> 34 <211> 445

&lt;212> PRT &lt;213&gt; Mus musculus &lt;400> 34

Glu Val Gin Leu Gin Gin Ser Gly Pro 6lu Leu Val Lys Pro 6ly Ala 15 10 15

Ser Met Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1406 13 201028165 lie Met Asn Trp Val Lys Gin Ser His Gly Lys Asn Leu 6lu Trp Lie 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Asp Thr Asn Tyr Asn Gin 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

Gin 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 Gin 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 Gin 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 lie Val Pro Arg Asp Cys Gly 210 215 220

Cys Lys Pro Cys lie Cys Thr Val Pro Glu Val Ser Ser Val Phe lie 225 230 235 240

Phe Pro Pro Lys Pro Lys Asp Val Leu Thr lie Thr Leu Thr Pro Lys 245 250 255

Val Thr Cys Val Val Val Asp lie Ser Lys Asp Asp Pro Glu Val Gin 260 265 270 14 201028165

Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gin Thr Gin 275 280 285

Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu 290 295 300

Pro lie Met His Gin Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg 305 310 315 320

Val Asn Ser Ala Ala Phe Pro Ala Pro lie Glu Lys Thr lie Ser Lys 325 330 335

Thr Lys Gly Arg Pro Lys Ala Pro Gin Val Tyr Thr lie Pro Pro Pro 340 345 350

Lys Glu Gin Met AI a Lys Asp Lys VaI Ser Leu Thr Cys Met 11e Thr 355 360 365

Asp Phe Phe Pro Glu Asp lie Thr Val Glu Trp Gin Trp Asn Gly Gin 370 375 380

Pro Ala Glu Asn Tyr Lys Asn Thr Gin Pro lie Met Asp Thr Asp Gly 385 390 395 400

Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val 61n Lys Ser Asn Trp Gtu 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 &lt;210> 35 &lt;211> 716

&Lt; 212> DNA &lt; 213 &gt; Mus musculus &lt; 400 &gt; 35 60 120 atgagtgtgc ccactcaggt cctggggttg ctgctgctgt ggcttacagg tgccagatgt gacatccaga tgactcagtc tccagcctcc ctatctgcat ctgtgggaga aactgtcacc 15 201028165 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

&lt;212&gt; PRT &lt;213&gt; Mus musculus &lt;400> 36

Asp lie Gin Met Thr Gin Ser Pro Ala Ser Leu Ser Ala Ser Val Gly 15 10 15

Glu Thr Val Thr lie Thr Cys Arg Ala Ser Glu Asn lie Tyr Ser Phe 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Gin 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 Gin Phe Ser Leu Lys lie Asn Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Gly Ser Tyr Tyr Cys Gin His His Tyr Glu Ser Pro Leu 85 90 95 16 201028165

Thr Phe Gly 6ly Gly Thr Lys Leu 6lu lie Lys Arg Ala Asp Ala Ala 100 105 110

Pro Thr Val Ser lie Phe Pro Pro Ser Ser Glu Gin Leu Thr Ser Gly 115 120 125

Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp lie 130 135 140

Asn Val Lys Trp Lys lie Asp Gly Ser Glu Arg Gin Asn Gly Val Leu . 145 150 155 160

Asn Ser Trp Thr Asp Gtn 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 lie Val Lys Ser 195 200 205

Phe Asn Arg Asn Glu Cys 210

&Lt; 210 &gt; 37 &lt; 211> 1406 &lt; 212> DNA &lt; 213 &gt; Mus musculus <400> 37 60 120 180 240 300 360 atgggatgga gctggatctt tctcttcctc ctgtcaggaa ctgcaggtgt ccactctgag gtccagctgc aacagtctgg acctgagctg gtgaagcctg gagcttcaat gaagatctcc tgcaaggctt ctggttactc attcactggc tacatcatga actgggtgaa gcagagccat ggaaagaacc ttgagtggat tggacttatt aatccttaca atggtggtac tagctacaac cagaagttca agggcaaggc cacattaact gtagacaagt catccagtac agcctacatg gaactcctca gtctgacatc agaggactct gcagtctatt actgtgcaag ggatggttac gacgacggac cctatactat ggactactgg ggtcaaggaa cctcagtcac cgtctcctca 17 420 201028165 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 cttcatctt c 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 &lt;210&gt; 38 &lt;211&gt;

<212> PRT &lt;213&gt; Mus musculus <400> 38

Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 15 10 15 18 201028165

Ser Met Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Lys Gin Ser His Gly Lys Asn Leu Glu Trp lie 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin 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

Gin 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 Gin 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 Gin 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 lie Val Pro Arg Asp Gys Gly 210 215 220

Cys Lys Pro Cys lie Cys Thr Val Pro Glu Val Ser Ser Val Phe lie 225 230 235 240

Phe Pro Pro Lys Pro Lys Asp Val Leu Thr lie Thr Leu Thr Pro Lys 19 201028165 245 250 255

Val Thr Gys Val Val Val Asp Me Ser Lys Asp Asp Pro Glu Val Gin 260 265 270

Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gin Thr Gin 275 280 285

Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu 290 295 300

Pro lie Met His Gin Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg 305 310 315 320

Val Asn Ser Ala Ala Phe Pro Ala Pro lie Glu Lys Thr lie Ser Lys 325 330 335

Thr Lys Gly Arg Pro Lys Ala Pro Gin Val Tyr Thr Ile Pro Pro Pro 340 345 350

Lys Glu Gin Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met lie Thr 355 360 365

Asp Phe Phe Pro Glu Asp lie Thr Val Glu Trp Gin Trp Asn Gly Gin 370 375 380

Pro Ala Glu Asn Tyr Lys Asn Thr Gin Pro lie Met Asp Thr Asp Gly 385 390 395 400

Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gin 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 &lt;211> 716 &lt;212&gt; DNA &lt;213&gt; Mus musculus &lt;400> 39 20 60 60 201028165 atgagtgtgc ccactcaggt gacatccaga tgactcagtc atcacatgtc Gaacaagtga ggaaaatctc ctcacctcct aggttcagtg gcagtggatc gaagattttg ggagttattt ggcaccaagc tggaaatcaa tccagtgagc agttaacatc cccaaagaca tcaatgtcaa aacagttgga ctgatcagga ttgaccaagg acgagtatga tcaacttcac ccattgtcaa

cctggggttg ctgctgctgt ggcttacagg tgccagatgt tccagcctcc ctatctgcat ctgtgggaga aactgtcacc gaatatttac agttttttag catggtatca gcagaaacag ggtctataat gcaaaaacct tagcaaaagg tgtgccatca tggcacacag ttttctctga agatcaacag cctgcagcct ctgtcaacat cattatgaga gtcctctgac gttcggtgga acgggctgat gctgcaccaa ctgtatccat cttcccacca tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg cagcaaagac agcacctaca gcatgagcag caccctcacg acgacataac agctatacct gtgaggccac tcacaagaca gagcttcaac aggaatgagt gttaatgagc ggccgc 120 180 240 300 360 420 480 540 600 660 716 <210> 40 <211> 214

&lt;212〉 PRT &lt;213&gt; Mus musculus

&lt;400&gt; 40

Asp lie Gin Met Thr Gin Ser Pro Ala Ser Leu Ser Ala Ser Val Gly 15 10 15

Glu Thr Val Thr lie Thr Cys Arg Thr Ser Glu Asn lie Tyr Ser Phe 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Gin 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 Gin Phe Ser Leu Lys lie Asn Ser Leu Gin Pro 21 201028165 65 70 75 80 6lu Asp Phe 6ly Ser Tyr Phe Cys 6ln His His Tyr 6lu Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Ala Asp Ala Ala 100 105 110

Pro Thr Val Ser lie Phe Pro Pro Ser Ser Glu Gin Leu Thr Ser Gly 115 120 125

Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp lie 130 135 140

Asn Val Lys Trp Lys lie Asp Gly Ser Glu Arg Gin Asn Gly Val Leu 145 150 155 160

Asn Ser Trp Thr Asp Gin 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 lie Val Lys Ser 195 200 205

Phe Asn Arg Asn Glu Cys 210 &lt;210> 41 &lt;211&gt; 1406

&Lt; 212 &gt; DNA &lt; 213 &gt; Mus musculus &lt; 400> 41 60 120 180 240 atgggatgga gctggatctt tctcttcctc ctgtcaggaa ctgcaggtgt ccactctgag .gtccagctgc aacagtctgg acctgagctg gtgaagcctg gaacttcaat gaagatatcc tgcaaggctt ctggttactc attcactggc tacatcatga actgggtgaa gcagagccat ggaaagaacc ttgagtggat tggacttatt aatccttaca atggtggtgc tgagtacaac cagaagttca aggacaaggc cacattcact gtagacaagt catccagcac Agcctacatg 22 300 360 360

201028165 gagctcctca gtctgacatc tgaagactct gcagtctatt actgtgcaag ggatggttac gacgacggac cctatactat ggactactgg ggtcaaggaa cctcagtcac cgtctcctca gccaaaacga cacccccatc tgtctatcca ctggcccctg gatctgctgc ccaaactaac tccatggtga ccctgggatg cctggtcaag ggctatttcc ctgagccagt gacagtgacc tggaactctg gatccctgtc cagcggtgtg cacaccttcc cagctgtcct gcagtctgac ctctacactc tgagcagctc agtgactgtc ccctccagca cctggcccag cgagaccgtc acctgcaacg ttgcccaccc ggccagcagc accaaggtgg acaagaaaat tgtgcccagg gattgtggtt gtaagccttg catatgtaca gtcccagaag tatcatctgt cttcatcttc cccccaaagc ccaaggatgt gctcaccatt actctgactc ctaaggtcac gtgtgttgtg gtagacatca gcaaggatga tcccgaggtc cagttcagct ggtttgtaga tgatgtggag gtgcacacag ctcagacgca accccgggag gagcagttca acagcacttt ccgctcagtc agtgaacttc ccatcatgca ccaggactgg ctcaatggca aggagttcaa atgcagggtc aacagtgcag ctttccctgc ccccatcgag aaaaccatct ccaaaaccaa aggcagaccg aaggctccac aggtgtacac cattccacct cccaaggagc agatggccaa ggataaagtc agtctgacct gcatgataac agacttcttc cctgaagaca ttactgtgga gtggcagtgg Aatgggcagc cagcggagaa ctacaagaac actcagccca tcatggacac agatggctct tacttcgtct acagcaagct caatgtgcag aagagcaaot gggaggcagg aaatactttc acctgctctg tgttacatga gggcctgcac aaccaccata ctgagaagag cctctcccac tctcctggta aataatgagc ggccgc &lt;210> 42 &lt;211&gt;

&lt;212&gt; PRT &lt;213&gt; Mus musculus 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 23 1406 201028165 &lt;400&gt;

Glu Val Gin Leu Gin Gin Ser Gly Pro Glu Leu Val Lys Pro Gly Thr 15 10 15

Ser Met Lys lie Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Lys Gin Ser His Gly Lys Asn Leu Glu Trp lie 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Ala Glu Tyr Asn Gin 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

Gin 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 Gin 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 Gin 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 lie Val Pro Arg Asp Cys Gly 210 215 220 24 201028165

Cys Lys Pro Cys lie Cys Thr Val Pro Glu Val Ser Ser Val Phe lie 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 lie Ser Lys Asp Asp Pro Glu Val Gin 260 265 270

Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gin Thr Gin 275 280 285

Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu 290 295 300

Pro lie Met His Gin Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg 305 310 315 320

Val Asn Ser Ala Ala Phe Pro Ala Pro lie Glu Lys Thr lie Ser Lys 325 330 335

Thr Lys Gly Arg Pro Lys Ala Pro Gin Val Tyr Thr lie Pro Pro Pro 340 345 350

Lys Glu Gin Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met lie Thr 355 360 365

Asp Phe Phe Pro Glu Asp lie Thr Val Glu Trp Gin Trp Asn Gly Gin 370 375 380

Pro Ala Glu Asn Tyr Lys Asn Thr Gin Pro lie Met Asp Thr Asp Gly 385 390 395 400

Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gin 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 &lt;210> 43 <211> 716 25 60 201028165

&Lt; 212 &gt; DNA &lt; 213 &gt; Mus musculus &lt; 400 &gt; 43 atgagtgtgc ccactcaggt cctggggttg ctgctgctgt ggcttacagg tgccagatgt gacatccaga tgactcagtc tccagcctcc ctatctgcat ctgtgggaga aactgtcacc ttcacatgtc gagcaaatga gaatatttac agttatttag catggtatca gcagaaacag ggaaaatctc ctcagctcct ggtctataat gcaaaaacct tagcagaagg tgtgccatca aggttcagtg gcagtggatc aggcacacag ttttctctga agatcaacag cctgcagcct gaagattttg ggagttatta ctgtcaacat cattatggaa ctcctccgac gttcggtgga ggcaccaagc tggaaatcaa acgggctgat gctgcaccaa ctgtatccat cttcccacca tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttaatgagc ggccgc &lt; 210> 44 &lt; 211 &gt; 214

<212> PRT &lt;213&gt; Mus musculus &lt;400&gt; 44

Asp lie Gin Met Thr 6ln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly 15 10 15 6lu Thr Val Thr Phe Thr Cys Arg Ala Asn Glu Asn Ile Tyr Ser Tyr 20 25 30

Leu Ala Trp Tyr Gin 6ln Lys Gin Gly Lys Ser Pro Gin Leu Leu Val 35 40 45 120 180 240 300 360 420 480 540 600 660 716

26 201028165

Tyr Asn Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr 6ln Phe Ser Leu Lys Ile Asn Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Gly Ser Tyr Tyr Cys Gin His His Tyr Gly Thr Pro Pro 85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Ala Asp Ala Ala 100 105 110

Pro Thr Val Ser lie Phe Pro Pro Ser Ser Glu 6ln Leu Thr Ser Gly 115 120 125

Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp lie 130 135 140

Asn Val Lys Trp Lys lie Asp Gly Ser Glu Arg 6ln Asn Gly Val Leu 145 150 155 160

Asn Ser Trp Thr Asp 6ln 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 Gys Glu Ala Thr His Lys Thr Ser Thr Ser Pro lie Val Lys Ser 195 200 205

Phe Asn Arg Asn Glu Cys 210 &lt;210> 45 &lt;211> 1391

&Lt; 212> DNA &lt; 213 &gt; Mus musculus &lt; 400 &gt; 45 60 120 180 atggaatgta actggatact tccttttatt ctgtcggtaa tttcaggggt ctactcagag gttcagctcc agcagtctgg gactgtgctg gcaaggcctg gggcttccgt gaagatgtcc tgcaaggctt ctggctacac ctttaccaac tactggatgc actgggtaaa acagaggcct 27 201028165 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 g actcctaag 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 &lt;210&gt; 46 28 201028165 &lt;211> 440 &lt;212&gt; PRT <213> Mus musculus &lt;400> 46

Glu Val Gin Leu Gin Gin Ser Gly Thr Val Leu Ala Arg Pro Gly Ala 15 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 Gin Arg Pro Gly Gin Gly Leu Glu Trp lie 35 40 45

Giy Ala lie Tyr Pro Gly Asn Ser Asp Thr Asp Tyr Asn Gin 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 Gin 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 Gin 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 Gin Ser Asp 165 170 175

Leu Tyr Thr Leu 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 29 201028165

Val Asp Lys Lys lie Val Pro Arg Asp Cys Gly Cys Lys Pro Cys lie 210 215 220

Cys Thr Val Pro Glu Val Ser Ser Val Phe lie Phe Pro Pro Lys Pro 225 230 235 240

Lys Asp Val Leu Thr lie Thr Leu Thr Pro Lys Val Thr Cys Val Val 245 250 255

Val Asp lie Ser Lys Asp Asp Pro Glu Val Gin Phe Ser Trp Phe Val 260 265 270

Asp Asp Val Glu Val His Thr Ala Gin Thr Gin Pro Arg Glu Glu Gin 275 280 285

Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro lie Met His Gin 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 lie Glu Lys Thr lie Ser Lys Thr Lys Gly Arg Pro 325 330 335

Lys Ala Pro Gin Val Tyr Thr lie Pro Pro Pro Lys Glu 6ln Met Ala 340 345 350

Lys Asp Lys Val Ser Leu Thr Cys Met lie Thr Asp Phe Phe Pro Glu 355 360 365

Asp lie Thr Val Glu Trp 6ln Trp Asn Gly Gin Pro Ala Glu Asn Tyr 370 375 380

Lys Asn Thr Gin Pro lie Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr 385 390 395 400

Ser Lys Leu Asn Val Gin Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe 405 410 415

Thr Cys Ser Val Leu His Glu Gly Leu His As His His Thr Glu Lys 420 425 430

Ser Leu Ser His Ser Pro Gly Lys 30

201028165 435 440 &lt; 210> 47 &lt; 211> 725 &lt; 212> DNA &lt; 213 &gt; Mus musculus &lt; 400> 47 atggattttc tggtgcagat tttcagcttc ttgctaatca gtgcctcagt tgcaatgtcc agaggagaaa atgtgctcac ccagtctcca gcaatcatgt ctgcatctcc aggggaaaag gtcaccatga cctgcagggc cagctcaagt gtaagttcca gttacttgca ctggtaccag cagaagtcag gtgcctcccc caaactctgg atttatagca cttccaactt ggcttctgga gtccctgctc gcttcagtgg cagtgggtct gggacctctt actatttcac aatcagcagt gtggaggctg aagatgctgc cacttattac tgccagcaat acagtggtta cccactcacg ttcggagggg ggaccaagct ggaaataaaa cgggctgatg ctgcaccaac tgtatccatc ttcccaccat ccagtgagca gttaacatct ggaggtgcct cagtcgtgtg cttcttgaac aacttctacc ccaaagacat caatgtcaag tggaagattg atggcagtga acgacaaaat ggcgtcctga acagttggac tgatcaggac agcaaagaca gcacctacag catgagcagc accctcacgt tgaccaagga cgagtatgaa cgacataaca gctatacctg tgaggccact cacaagacat caacttcacc cattgtcaag agcttcaaca ggaatgagtg Ttaatgagcg gccgc &lt;210> 48 &lt;211&gt; 2t5 &lt;212&gt; PRT &lt;213> Mus musculus &lt;400> 48

Glu Asn Val Leu Thr Gin Ser Pro Ala lie Met Ser Ala Ser Pro Gly 15 10 15 60 120 180 240 300 360 420 480 540 600 660 720 725 31 201028165

Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Ser Ser Ser 20 25 30

Tyr Leu His Trp Tyr Gin Gin Lys Ser Gly Ala Ser Pro Lys Leu Trp 35 40 45 lie 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 lie Ser Ser Val Glu 65 70 75 80

Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gin Gin Tyr Ser Gly Tyr Pro 85 90 95

Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg Ala Asp Ala 100 105 110

Ala Pro Thr Val Ser lie Phe Pro Pro Ser Ser Glu Gin 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 lie Asn Val Lys Trp Lys lie Asp Gly Ser Glu Arg Gin Asn Gly Val 145 150 155 160

Leu Asn Ser Trp Thr Asp Gin 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 lie Val Lys 195 200 205

Ser Phe Asn Arg Asn Glu Cys 210 215 &lt;210&gt; 49 <211> 425 &lt;212&gt; DNA &lt;213&gt; Artificial sequence 32 60 201028165 &lt;220> <223> Synthetic sequence &lt;400> 49 ccaccatgga ctggacctgg egggtcttct gcttgctggc igtagctcca ggtgctcact cccaggtgca gctggtgcag tctggggctg aggtgaagaa gcctggggcc tcagtgaagg tttcctgcaa ggcatctgga tacaccttca ccggctacat catgaactgg gtgcgacagg cocctggaca agggcttgag tggatgggac ttattaatcc ttacaatggt ggtactagct acaaccagaa gttcaagggc agagtcacga ttaccgcgga cgaatccacg agcacagcct

120 180 240 300 360 420 425 acatggagct gagcagcctg agatctgagg acacggccgt gtattactgt gcgagagatg gttacgacga cggaccctat actatggact actggggcca gggcaccctc gtcacagtct cctca &lt;210> 50 &lt;211> 121 &lt;212> PRT &lt;213>AX sequence &lt;220> &lt;223>AX Synthetic sequence φ &lt;4〇〇&gt; 5〇6ln Val Gin Leu Val Gin Ser Gly Ala 6lu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe 50 55 60

Lys Gly Arg Val Thr Me Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 33 201028165

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

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120

&lt;210&gt; 51 &lt;211> 398 &lt;212&gt; DNA &lt;213>Artificial sequence&lt;220&gt;&lt;223&gt;AX synthesis sequence&lt;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

&lt;210&gt; 52 &lt;211> 107 &lt;212> PRT &lt; 213 &gt; 213 &gt; artificial sequence &lt;220 &lt; 223 &gt; 223 &gt; artificial synthesis sequence &lt;400 &gt; 52

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 34 201028165 5 10 15

Asp Arg Val Thr lie Thr Cys Arg Thr Ser Glu Asn Me Tyr Ser Phe 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 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 lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Glu Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105

&lt;210> 53 <211> 1422 &lt;212&gt; DNA <213>Artificial sequence&lt;220> &lt;223>synthetic sequence&lt;400&gt; 53 60 120 180 240 300 360 420 gaattccacc atggactgga cctggagggt cttctgcttg ctggctgtag ctccaggtgc tcactcccag gtgcagctgg tgcagtctgg ggctgaggtg aagaagcctg gggcctcagt gaaggtttcc tgcaaggcat ctggatacac cttcaccggc tacatcatga actgggtgcg acaggcccct ggacaagggc ttgagtggat gggacttatt aatccttaca atggtggtac tagctacaac cagaagttca agggcagagt cacgattacc gcggacgaat ccacgagcac agcctacatg gagctgagca gcctgagatc tgaggacacg gccgtgtatt actgtgcgag agatggttac gacgacggac cctatactat ggactactgg ggccagggca ccctcgtcac agtctcctca gctagcacca agggcccatc ggtcttcccc ctggcgccct cctccaagag 35 480 201028165 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 tcg Agtgocc 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 &lt;211&gt; 447 &lt;212&gt; PRT &lt;213>Artificial sequence &lt;220> <223>AX synthesis sequence &lt;400&gt;

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Ly Gly Ala 36 201028165 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe . 50 55 60 , Lys Gly Arg Val Thr lie 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

Gin 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 Gys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 37 201028165

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie 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 6ln Phe Asn Trp Tyr Val Asp 6ly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445

&lt;210&gt; 55 &lt;211&gt; 719 &lt;212&gt; DNA &lt;213&gt; artificial sequence 38 60 60

201028165 &lt; 220 &gt; &lt; 223> artificially synthesized sequence &lt; 400> 55 ccaccatgga catgagggtc cccgctcagc tcctggggct cctgctactc tggctccgag gtgccagatg tgacatccag atgacccagt ctccatcctc cctgtctgca tctgtaggag acagagtcac catcacttgc cgaacaagtg agaatattta cagtttttta gcatggtatc agcagaaacc agggaaagcc cctaagctcc tgatctataa tgcaaaaacc ttagcaaaag gggtcccatc aaggttcagt ggcagtggat ctgggacaga tttcactctc accatcagca gtctgcaacc tgaagatttt gcaacttact actgtcaaca tcattatgag agtcctctga cgttcggcgg agggaccaag gtggagatca aacgtacggt ggctgcacca tctgtcttca tcttcccgcc atctgatgag cagttgaaat ctggaactgc ctctgttgtg tgcctgctga ataacttcta tcccagagag gccaaagtac agtggaaggt ggataacgcc ctccaatcgg gtaactccca ggagagtgtc acagagcagg acagcaagga cagcacctac agcctcagca gcaccctgac gctgagcaaa gcagactacg agaaacacaa agtctacgcc tgcgaagtca cccatcaggg cctgagctcg cccgtcacaa agagcttcaa caggggagag tgttgataa <210> 56 &lt; 211 &gt; 214 &lt; 212> PRT &lt; 213 > Artificial Sequence &lt; 220 &gt; 220 &lt; 223 &gt; Synthetic Sequence &lt; 400 > 56

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Thr Ser Glu Asn lie Tyr Ser Phe 20 25 30 120 180 240 300 420 480 540 600 660 719 39 201028165

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 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 lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Glu Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 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 Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 &lt;210> 57 <211> 327

&Lt; 212 &gt; DNA &lt; 213 &gt; Homo sapiens &lt; 400> 57 cgtacggtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct 40 60 120 201028165 ggaactgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag a agcttcaaca ggggagagtg ttgataa ' &lt;210&gt; 58 &lt;211> 107 &lt;212> PRT &lt;213> Homo sapiens • 参&lt;400>58

Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu 1 5 10 15

Gin 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 Gin Trp Lys Val Asp Asn Ala Leu Gin 35 40 45

Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 50 55 60

180 240 300 327

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 Gin Gly Leu Ser Ser 85 90 95

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 &lt;210〉 59 &lt;211〉 990

&Lt; 212 &gt; DNA &lt; 213 &gt; Homo sapiens &lt; 400 &gt; 59 41 201028165 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 &lt; 210 &gt; 60 &lt; 211> 330 <212> PRT &lt; 213 &gt; Homo sapiens <400> 60

Ala Ser Thr Lys 6ly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 42 201028165

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 Gin Ser Ser Gly Leu Tyr Ser 50 55 60 *

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr ' 65 70 75 80

Tyr lie 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 lie 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 Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190

His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205

Lys Ala Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys Ala Lys Gly 210 215 220

Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240

Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 43 201028165

Pro Ser Asp lie Ala Val 6lu Trp Glu Ser Asn Gly Gin 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 Gin Gin 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

Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 &lt;210> 61 &lt;211&gt; 984

&Lt; 212 &gt; DNA &lt; 213 &gt; Homo sapiens &lt; 400> 61 gctagcacca agggcccatc ggtcttcccc ctggcgccct cctccaagag cacctccgag agcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg tggaactcag gcgctctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca ggactctact ccctcagcag cgtggtgacc gtgccctcca gcaacttcgg cacccagacc tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagac agttgagcgc aaatcttgtg tcgagtgccc accgtgocca gcaccacctg tggcaggacc gtcagtcttc ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacgtgc gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagcca cgggaggagc agttcaacag cacgttccgt gtggtcagcg tcctcaccgt cgtgcaccag gactggctga acggcaagga gtacaagtgc aaggtctcca acaaaggcct cccagccccc atcgagaaaa ccatctccaa aaccaaaggg 60 120 180 240 300 360 420 480 540 600 44 660 720 201028165 cagccccgag aaccacaggt gtacaccctg cccccatccc Gggaggagat gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaaca Actac aagaccacac ctcccatgct ggactccgac ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacaca gaagagcctc tccctgtctc cgggtaaatg ataa &lt;210&gt; 62 &lt;211&gt; 326

780 840 900 960 984

<212> PRT &lt;213&gt; Homo sapiens &lt;400> 62

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 15 10 15

Ser Thr Ser GIu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30

Phe Pro GIu 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 Gin Ser Ser Gly Leu Tyr Ser 50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gin 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 GIu Arg Lys Ser Cys Val GIu 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 lie Ser Arg Thr Pro GIu Val Thr Cys Val Val Val Asp 45 201028165 130 135 140

Val Ser His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly 145 150 155 160

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn 165 170 175

Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gin 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 lie Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu 210 215 220

Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 225 230 235 240

Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie 245 250 255

Ala Val Glu Trp Glu Ser Asn Gly Gin 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 Gin Gin Gly Asn Val Phe Ser Cys 290 295 300

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu 305 310 315 320

Ser Leu Ser Pro Gly Lys 325 &lt;210> 63 <211> 995

&Lt; 212 &gt; DNA &lt; 213 &gt; Homo sapiens &lt; 400> 63 46 60 201028165 gctagcacca agggcccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc »tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc aaatatggtc ccccatgccc accatgccca gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc Ggagaacaac tacaagacca cgcctcccgt gctggactcc ga Cggctcct tcttcctcta cagcaggcta accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtta atgataagcg gccgc &lt;210&gt; 64 &lt;211&gt; 326 &lt;212> PRT &lt;213&gt; Homo sapiens <400> 64

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 15 10 15 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 995 47 201028165

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 Gin 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 lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140

Asp Val Ser Gin Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp 145 150 155 160

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe 165 170 175

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin 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 lie Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg 210 215 220

Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Gin Glu Glu Met Thr Lys 225 230 235 240

Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 48

201028165 lie Ala Val Glu Trp Glu Ser Asn Gly Gin 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 61n Glu Gly Asn Val Phe Ser * 290 295 300 * Cys Ser Val Met His Glu Ala Leu His As His Hisr Thr Gin Lys Ser 305 310 315 320

Leu Ser Leu Ser Leu Gly 325

agtagttcta caagtgaaaa 65 atgatgtgga cctgggcact gtggatgttc cctttactct gcaaattcgg cctggcagct ctgccagcta agcctgagaa catttcctgt gtctactact ataggaaaaa tttaacctgc acttggagtc caggaaagga aactagttat acccagtaca cagctaagag aacttacgct tttggaaaaa aacatgataa ttgtacaacc; &lt; 210> 65 &lt; 211 &gt; 2208 &lt; 212> DNA &lt; 213 &gt; Macaca fascicular is &lt; 400 & gt tcgtgcttcg tgctcttttt tccttccaag aataacgatc ccagataatt ataccattga ggtggaagct gaaaatggag atggtgtaat taaatctgat atgacatgtt ggagattaga ggacatagcg aaaactgaac cacctgagat tttcagtgtg aaaccagttt tgggcatcaa acgaatgatt cggattgaat ggataaagcc tgagttggca cctgtttcat ctgatttaaa atatgcactt cgattcagga cagtcaatag taccagctgg atggaagtca acttcgctaa gaaccgtaaa gatacaaacc aaacctacaa ccttatgggg ctgcaggctt ttacagagta tgtcgtagct ctgcgatgtg cggtcaagga gtcaaagttc tggagtgact ggagccaaga aaaaatggga 60 120 180 240 300 360 420 480 540 600 49 660 201028165 atgactgagg aagaagctcc atgtggcctg gtggatggaa gaaggccagt gcggttgtta gagaaaacac ttggctacaa catatggtac acagtgaaca ccactaacca gca gcttgaa tctatgattt cttataattc tcttgggaag attcaggaaa agtcatttcg gtgcattgag ctagtggtga agtggcaaag ctctgctcta ccggacatgg actcagagca ccccactctt tggacaatcc agcaagataa attaaaacct atgttgcacg acaaagttgg cgagccatat ccatcaaaag gtcctgagac caaggtggag tggaaagaga ttcccaagag tgagagaaag caagctgaag gtggaaaagg attctccaag ctggagtccc tgaaacgaaa acgggaccag gacctcttac gggggaatca cacagaagac gacaagttgg ttattgacaa cataaatttc atccttataa cttctctgat tggtggaggc tatggtctca aaaaacccaa caaattgact gctgaaagta gtatagccac atggcgtgga gagtctgatg actctgtgaa gtcggtggtg acagatgaag ccagaacggg tcaggaaaac acccacccct tcagggctga ctgtcccctg gaactgtgga gagtcctgaa accaactgag 720 tggaagaagg caagaggagc cccagtccta 780 tttccagaaa acaacactaa cctcacagag 840 ctgcatctgg gaggcgagag ctattgggtg 900 tctccagtga ccaccctgag gattccagcc 960 gtcatgcagg cctgccttgc tgaggaccag 1020 gacgtgaaca cttggatgat tgaatggttt 1080 tcctgggaat ctgtgtctca ggccacgaac 1140 ttctggtgct ataacatctc tgtgtatcca 1200 tccatccagg cttatgccaa agaaggcatt 1260 aacattggcg tgaagacggt c acgatcaca 1320 ggtatcatct gcaactacac catcttttac 1380 acagtcaact ccagcatctt gcagtatggc 1440 actgttcggg tcatggccag caccagtgct 1500 aagacattgt cattcagtgt ttttgagatt 1560 cttcttattc tcattatcct gacggtggca 1620 cacctgtgtt ggcccagtgt tcccaaccct 1680 gatgatttca aggataagct aaacctgaag 1740 aggatcttaa aaccatgttc cacccccagt 1800 aactttggga atgttctgca agaaatgttc 1860 aatttaggag gggaaaagaa tgagtatgtg 1920 gggaaaagtt ttgaggagct cccagtttca 1980 50 201028165 cctgagattc ctcccagaaa Atcccaatac ctacgttcga ggatgccaga agggacctgc ctagaagccg aagagcagct tctcgtttct ggtcaaagtc tagaaagtct agcaccagac catgtgcggg aggcagcggc cccaaatccg tatttgaaaa attcagtgac aaccagggaa tttcttgtgt ctcaaaaact tccagagcac accaaaggag aagtctaa

'&lt;210&gt; 66 &lt;211> 735 &lt;212> PRT &lt;213&gt; Macaca fascicular is &lt;400> 66

Met Met Trp Thr Trp Ala Leu Trp Met Phe Pro Leu Leu Cys Lys Phe 15 10 15

Gly Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn lie 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 Gin Tyr Thr Ala Lys Arg Thr Tyr Ala Phe Gly Lys Lys 50 55 60

His Asp Asn Cys Thr Thr Ser Ser Ser Ser Ser Glu Asn Arg Ala Ser

2040 2100 2160 2208 65 70 75 80

Cys Ser Phe Phe Leu Pro Arg Me Thr lie Pro Asp Asn Tyr Thr Ile 85 90 95

Glu Val Glu Ala Glu Asn Gly Asp Gly Val lie Lys Ser Asp Met Thr 100 105 110

Cys Trp Arg Leu Glu Asp lie Ala Lys Thr Glu Pro Pro Glu lie Phe 115 120 125

Ser Val Lys Pro Val Leu Gly lie Lys Arg Met lie Arg Me Glu Trp 130 135 140 lie Lys Pro Glu Leu Ala Pro Val Ser Ser Asp Leu Lys Tyr Ala Leu 145 150 155 160 51 201028165

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 Gin Thr Tyr Asn Leu Met Gly Leu Gin 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 Gin 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 lie Trp Tyr Phe Pro 260 265 270

Glu Asn Asn Thr Asn Leu Thr Glu Thr Val Asn Thr Thr Asn Gin Gin 275 280 285

Leu Glu Leu His Leu Gly Gly Glu Ser Tyr Trp Val Ser Met lie Ser 290 295 300

Tyr Asn Ser Leu Gly Lys Ser Pro Val Thr Thr Leu Arg lie Pro Ala 305 310 315 320 lie Gin Glu Lys Ser Phe Arg Cys lie Glu Val Met Gin Ala Cys Leu 325 330 335

Ala Glu Asp Gin Leu Val Val Lys Trp Gin Ser Ser Ala Leu Asp Val 340 345 350

Asn Thr Trp Met lie Glu Trp Phe Pro Asp Met Asp Ser Glu His Pro 355 360 365

Thr Leu Ser Trp Glu Ser Val Ser Gin Ala Thr Asn Trp Thr lie Gin 370 375 380

Gin Asp Lys Leu Lys Pro Phe Trp Cys Tyr Asn lie Ser Val Tyr Pro 52 201028165 385 390 395 400

Met Leu His Asp Lys Val Gly Glu Pro Tyr Ser lie Gin Ala Tyr Ala 405 410 415

Lys Glu Gly lie Pro Ser Lys Gly Pro Glu Thr Lys Val Glu Asn lie 420 425 430

Gly Val Lys Thr Val Thr lie Thr Trp Lys Glu lie Pro Lys Ser Glu 435 440 445

Arg Lys Gly lie lie Cys Asn Tyr Thr lie Phe Tyr Gin Ala Glu Gly 450 455 460

Gly Lys Gly Phe Ser Lys Thr Val Asn Ser Ser lie Leu Gin Tyr Gly β© 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 lie Asn Gly Thr Ser lie Asn Phe Lys Thr 500 505 510

Leu Ser Phe Ser Val Phe Glu lie Ile Leu lie Thr Ser Leu lie Gly 515 520 525

Gly Gly Leu Leu lie Leu lie lie 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 lie 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 lie 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 Gin Glu Met Phe Thr Asp Glu Ala 610 615 620 53 201028165

Arg Thr Gly Gin 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 lie Pro Pro Arg Lys Ser Gin Tyr Leu Arg 660 665 670

Ser Arg Met Pro Glu Gly Thr Cys Leu Glu Ala Glu Glu Gin Leu Leu 675 680 685

Val Ser Gly Gin 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 Gin Lys Leu Pro Glu His Thr Lys Gly Glu Val 725 730 735

&lt;210> 67 &lt;211&gt; 495 &lt;212> DNA &lt;213&gt; Macaca fascicular is &lt;400> 67 60 120 180 240 300 360 420 480 atggcctctc actcagcagg ccccgcgacg tccgtgctgt ttctgctctg ctgcctggga ggctggctga cctcccacac gttgcccgtc catttcctac aaccaagtga tatacagaaa atagtcgagg aattacagtc cctctcgaag atgcttttga aagatgtgaa ggaagacaag ggggtgctcg tgtcccagaa ttacacgctg ccgtgtctca cccctgacgc ccagccgcca aacatcatcc acagcccagc catccgggca tatctcaaga caatcagaca gttagacaac aaatctgtta ttgatgagat catagagcac ctcgacaaac tcatatttca agatgcacca gaaacaaaca tttctgtgcc aacagacacc catgaatgta aacgcttcat cctgactatt tctcaacagt tttcagagtg catggacctt gcattaaaat cgttgacttc tggagcccag caggccacca cttaa 54 495 201028165

&lt;210> 68 &lt;211&gt; 164 &lt;212> PRT &lt;213&gt; Macaca fascicular is &lt;400> 68

Met Ala Ser His Ser Ala Gly Pro Ala Thr Ser Val Leu Phe Leu Leu 15 10 15

Cys Cys Leu Gly Gly Trp Leu Thr Ser His Thr Leu Pro Val His Phe 20 25 30

Leu Gin Pro Ser Asp lie Gin Lys lie Val Glu Glu Leu Gin 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 Gin Asn Tyr Thr Leu Pro Cys Leu Thr Pro Asp Ala Gin Pro Pro 65 70 75 80

Asn lie lie His Ser Pro Ala Ile Arg Ala Tyr Leu Lys Thr Ile Arg 85 90 95

Gin Leu Asp Asn Lys Ser Val lie Asp Glu lie lie Glu His Leu Asp 100 105 110

Lys Leu lie Phe Gin Asp Ala Pro Glu Thr Asn lie Ser Val Pro Thr 115 120 125

Asp Thr His Glu Cys Lys Arg Phe lie Leu Thr lie Ser Gin Gin Phe 130 135 140

Ser Glu Cys Met Asp Leu Ala Leu Lys Ser Leu Thr Ser Gly Ala Gin 145 150 155 160

Gin Ala Thr Thr

<210> 69 &lt; 211 &gt; 2934 &lt; 212> DNA 55 201028165 &lt; 213 &gt; Macaca fascicular is &lt; 400 &gt; 69 atggctctat ttgtagtctt tcagacaaca ttcttcttaa cattgctgtc cttgaggact taccagagtg aagtcttggc tgaacgttta ccattgactc ctgtgtcact taaagtttcc accaattcta tacatcagag caatggactg tccacaacct caggaattga aaatggtatt tcagatccag atcagtagga tttgcattta tccttatcat ttgaaacatc caatgtcgtc tgggtgggga attacagcac cactgtgaag tggaaccagg ttctgcattg gagctgggaa tcggaactcc ctttggaatg tgccacacac tttgtaagaa tcaagagtgt gatagacgat gccagtttcc ctgagccaaa tttctggagc aactggagtt cctgggagga agtcagtgta caagattatc ttggacgggg cactttgttc gttttcccta aagataagct ggtggaagaa ggctccaatg ttaccatttg ttatgtttct aggaacattc aaaataatgt atcctgttat ttggaaggga aacagattca cggagaacaa cttgatccac atgtaactgc attcaacttg aatagtgtgc ctttcattag gaatagaggg acaaatatct attgtgaggc gagtcaagga aatgtcagta aggcatcgtt ctctttgtct caaaagtact aaggcataga tgaggagccc Aaggactttt cttgtgaatc ccaggacttc aacactttgc actgtacttg ggatcctggg acggacactg ccttggggtg gtctaaacaa cct tcccaaa gctacacttt atttgaatca ttttctgggg aaaagaaact ttgtacgcac aaaaactggt gtaattggca aataactcaa gactcacaag aaatgtataa cttcacactc atagctgaaa attacttaag gaagagaagt gtcaatatcc tttttaacct gactcatcga gtttatttaa tgaatccttt tagtgtcaac tttgaaaatg taaatgccac aaatgccatc atgacctgga aggtgcactc catgaggaat aatttcacat atttgtgtca gattgaactc catggtgaag gaaaaatgat gcaatacgat gtttctatca acgtgaacgg tgagtacttc ttaagtgaac tggaacctgc cacagaatat atggcccgag tacgctgtgc tgatgccagc cacttctgga aatggactga atggagtggt 201028165

cagaacttca aactcagagc gccaatggaa tcagagctcc tcctaccaaa gtcatctctg ggtggattct tggtgtgacc acagtcatta ttatctacaa gctccttcag agttggaaag ctgaaatcca tcagaatgtt ctaaagccag cccaatgcta atcctactgc cagtggatca tcgttaataa ccagatgcta ccacacttga caggaaatca agatcctgtt gttccattcc tctgcgtcac cggaccctga ctctgtcttg atccccagga gcacagatgc aaaggattgc acaaccctca attactctac aggcgaggca gcaaatacaa aatccttcta cgttcacgaa ccatggtttt aggagacgtg aattcaagga ttgaagttgt agctgctccg tactgtgacc ctataatgta ggcaccagcc agctaacaac aaacaaagag gaaaccccag tgtgctccag ttttaggcca ttgtttatta cgtgctggta tgaatctcaa gtgccaccca aattgacaac tgagtttttc ggtcacgact ctgcgtcttg ttatcctgac gaaccctcac cagcaagcca tcagaggccc ttattctgga gttgtagaaa aacagcacaa agtgtgggcg gttgaggaag cctggagatg tggaagaatg ggagttcgat gagaaaaaaa gatatgttga cctggtttta cgatttcaaa ccagaagaaa gttactccat ccggatgaac ctcatcatga atccctgacc ctaacaataa gaagggacaa ctgatgtctg agccattatc acctagacaa aactaatcct cttctcctgc aaagaattgc ttataggcta taggtcccaa acgacttcag caggatactc catcccactc tacaagggta aggcagttct aggcattgat tcactagtgc actcctccat tcgtgtgcta cttacaagag tgaatgtcag agatacagct gagaagtgtg aaaactgcat accgtccagg cgacaggtgt ttctataata aggcacagag tgttgtggac taccacaagc aatctatggg tcaggaactg cttcactctg ccatgtctat ttcagatggt tgtggacaac tggcgagggc gttgattcgt cttgaaaagt cagcatcctg tgactgtatc cctaggcact aggaagtcac tcacagaaac tgagttaact aagcctaact acctttatct ccttccaaca gaaaagaatc actctggccc tggcccctgc atctgttttg agaactttac ctacaaccag 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 57 201028165 2640 2700 2760 2820 2880 2934 gcagcttctg acgctggctc ttgtggccat gttccagtac cccccaaagc cccaccaagt atgctaggac taatgacctc acctgaaaat gtactaaagg cgctagaaaa aaactacatg aactccctgg gagaagtccc agctggagaa acaagtttga attatgtgtc ccagttggct tcacccatgt ctggagacaa ggacagtctc ccaacaaacc cagtggagcc accacactgt tcagagtata aaatgcaaat ggcagtcccc ctgcgtcttg ccctgcctcc Cccgaccgag aatagcagcc tttcctcaat taccctttta gatccaggtg aacactaccg ctaa

&lt;210> 70 &lt;211&gt; 977 <212> PRT &lt;213&gt; Macaca fascicular is &lt;400> 70

Met Ala Leu Phe Val Val Phe Gin Thr Thr Phe Phe Leu Thr Leu Leu 15 10 15

Ser Leu Arg Thr Tyr Gin Ser Glu Val Leu Ala Glu Arg Leu Pro Leu 20 25 30

Thr Pro Val Ser Leu Lys Val Ser Thr Asn Ser lie His Gin Ser Leu 35 40 45

His Leu Gin Trp Thr Val His Asn Leu Pro Tyr His Gin Glu Leu Lys 50 55 60

Met Val Phe Gin lie Gin lie Ser Arg lie Glu Thr Ser Asn Val Val 65 70 75 80

Trp Val Gly Asn Tyr Ser Thr Thr Val Lys Trp Asn Gin 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 lie Lys Ser Val lie Asp Asp Ala Ser Phe Pro Glu Pro Asn Phe 115 120 125 58 201028165

Trp Ser Asn Trp Ser Ser Trp Glu Glu Val Ser Val Gin 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 lie Cys Tyr Val Ser Arg Asn lie Gin Asn Asn 165 170 175

Val Ser Gys Tyr Leu Glu Gly Lys Gin lie His Gly Glu 6ln Leu Asp ' 180 185 190

Pro His Val Thr Ala Phe Asn Leu Asn Ser Val Pro Phe lie Arg Asn 195 200 205 ginseng Arg Gly Thr Asn lie Tyr Cys Glu Ala Ser Gin Gly Asn Val Ser Lys 210 215 220

Gly lie Glu Gly lie Val Leu Phe Val Ser Lys Val Leu Glu Glu Pro 225 230 235 240

Lys Asp Phe Ser Cys Glu Ser Gin Asp Phe Asn Thr Leu His Cys Thr 245 250 255

Trp Asp Pro Gly Thr Asp Thr Ala Leu Gly Trp Ser Lys Gin Pro Ser 260 265 270

Gin 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 Gin lie Thr Gin Asp Ser Gin Glu 290 295 300

Met Tyr Asn Phe Thr Leu lie Ala Glu Asn Tyr Leu Arg Lys Arg Ser 305 310 315 320

Val Asn lie 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 lie Met Thr 340 345 350

Trp Lys Val His Ser Met Arg Asn Asn Phe Thr Tyr Leu Cys Gin lie 355 360 365 59 201028165

Glu Leu His Gly Glu Gly Lys Met Met Gin Tyr Asp Val Ser lie 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 Gin 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 Giy 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 lie Leu Phe Tyr Asn Val Val Val Glu Asn Leu Asp Lys Pro Ser Arg 465 470 475 480

Ser Glu Leu Arg Ser lie Pro Ala Pro Ala Asn Ser Thr Lys Leu lie 485 490 495

Leu Asp Arg Cys Ser Tyr Gin lie Cys Val Thr Ala Asn Asn Ser Val 500 505 510

Gly Ala Ser Pro Ala Ser lie lie Val lie Ser Ala Asp Pro Glu Asn 515 520 525

Lys Glu Val Glu Glu Glu Arg lie Ala Gly Thr Glu Gly Gly Phe Ser 530 535 540

Leu Ser Trp Lys Pro Gin Pro Gly Asp Val lie Gly Tyr Val Val Asp 545 550 555 560

Trp Cys Asp His Pro Gin Asp Val Leu Gin Trp Lys Asn Val Gly Pro 565 570 575

Asn Thr Thr Ser Thr Val lie Ser Thr Asp Ala Phe Arg Pro Gly Val 580 585 590

Arg Tyr Asp Phe Arg lie Tyr Gly Leu Ser Thr Lys Arg Me Ala Cys 60 201028165 595 600 605

Leu Leu Glu Lys Lys Thr Gly Tyr Ser Gin 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 Gin Pro Gly Phe lie Gin Gly 645 650 655

Tyr His Val Tyr Leu Lys Ser Lys Ala Arg Gin Cys His Pro Arg Phe 660 665 670

Gin Lys Ala Val Leu Ser Asp Gly Ser Glu Cys Cys Lys Tyr Lys lie 675 680 685

Asp Asn Pro Glu Glu Lys Ala Leu lie 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 lie Arg lie Leu Leu Pro Met Val Phe Cys Val Leu Leu lie 740 745 750

Met lie Val Cys Tyr Leu Lys Ser Gin Trp lie Lys Glu Thr Cys Tyr 755 760 765

Pro Asp He Pro Asp Pro Tyr Lys Ser Ser lie Leu Ser Leu lie Lys 770 775 780

Phe Lys Glu Asn Pro His Leu Thr lie Met Asn Val Ser Asp Cys lie 785 790 795 800

Pro Asp Ala lie Glu Val Val Ser Lys Pro Glu Gly Thr Lys lie Gin 805 810 815

Leu Leu Gly Thr Arg Lys Ser Leu Thr Glu Thr Glu Leu Thr Lys Pro 820 825 830 61 201028165

Asn Tyr Leu Tyr Leu Leu Pro Thr Glu Lys Asn His Ser Gly Pro Gly 835 840 845

Pro Cys lie Cys Phe Glu Asn Phe Thr Tyr Asn Gin 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 Gin 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 Gin Met Ala Val Pro Leu Arg Leu Ala Leu Pro Pro Pro Thr Glu 945 950 955 960

Asn Ser Ser Leu Ser Ser lie Thr Leu Leu Asp Pro Gly Glu His Tyr 965 970 975

Arg

&Lt; 210 &gt; 71 &lt; 211 &gt; 1665 &lt; 212> DNA &lt; 213 &gt; Macaca fascicular is &lt; 400 &gt; 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 62 300 300

201028165 tgctcttttt tccttccaag aataacgatc ccagataatt ataccattga ggtggaagct gaaaatggag atggtgtaat taaatctgat atgacatgtt ggagattaga ggacatagcg aaaactgaac cacctgagat tttcagtgtg aaaccagttt tgggcatcaa acgaatgatt cggattgaat ggataaagcc tgagttggca cctgtttcat ctgatttaaa atatgcactt cgattcagga cagtcaatag taccagctgg atggaagtca acttcgctaa gaaccgtaaa gatacaaacc aaacctacaa ccttatgggg ctgcaggctt ttacagagta tgtcgtagct ctgcgatgtg cggtcaagga gtcaaagttc tggagtgact ggagccaaga aaaaatggga atgactgagg aagaagctcc atgtggcctg gaactgtgga gagtcctgaa accaactgag gtggatggaa gaaggccagt gcggttgtta tggaagaagg caagaggagc cccagtccta gagaaaacac ttggctacaa catatggtac tttccagaaa acaacactaa cctcacagag acagtgaaca ccactaacca gcagcttgaa ctgcatctgg gaggcgagag ctattgggtg tctatgattt cttataattc tcttgggaag tctccagtga ccaccctgag gattccagcc attcaggaaa agtcatttcg gtgcattgag gtcatgcagg cctgccttgc tgaggaccag ctagtggtga agtggcaaag ctctgctcta gacgtgaaca cttggatgat tgaatggttt ccggacatgg actcagagca ccccactctt tcctgggaat ctgtgtctca ggccacgaac tggacaatcc agcaagataa attaaaacct ttctggtgct ataacatctc tgtgtatcca atgttgcacg acaaagttgg cgagccatat tccatccagg cttatgccaa agaaggcatt ccatcaaaag gtcctgagac caaggtggag aacattggcg tgaagacggt cacgatcaca tggaaagaga ttcccaagag tgagagaaag ggtatcatct gcaactacac catcttttac caagctgaag gtggaaaagg attctccaag acagtcaact ccagcatctt gcagtatggc ctggagtccc tgaaacgaaa gacctcttac actgttcggg tcatggccag caccagtgct gggggaatca acgggaccag cataaatttc aagacattgt cattcagtgt ttttgagatt 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 63 201028165 1620 1665 atccttataa cttctctgat tggtggaggc cttcttattc tcattatcct gacggtggca tatggtctca aaaaacccaa caaattgact cacctgtgtt aatga

&lt;210> 72 &lt;211&gt; 553 &lt;212> PRT &lt;213&gt; Macaca fascicular is &lt;400&gt; 72

Met Met Trp Thr Trp Ala Leu Trp Met Phe Pro Leu Leu Cys Lys Phe 15 10 15

Gly Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn lie 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 Gin Tyr Thr Ala Lys Arg Thr Tyr Ala Phe Gly Lys Lys 50 55 60

His Asp Asn Cys Thr Thr Ser Ser Ser Ser Ser Glu Asn Arg Ala Ser 65 70 75 80

Cys Ser Phe Phe Leu Pro Arg ile Thr lie Pro Asp Asn Tyr Thr lie 85 90 95

Glu Val Glu Ala Glu Asn Gly Asp Gly Val lie Lys Ser Asp Met Thr 100 105 110

Cys Trp Arg Leu Glu Asp lie Ala Lys Thr Glu Pro Pro Glu lie Phe 115 120 125

Ser Val Lys Pro Val Leu Gly lie Lys Arg Met lie Arg lie Glu Trp 130 135 140 lie 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 64 201028165

Lys Asn Arg Lys Asp Thr Asn Gin Thr Tyr Asn Leu Met 61y Leu Gin 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 Gin 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 ❿ ❿ Ala Pro Val Leu Glu Lys Thr Leu Gly Tyr Asn lie Trp Tyr Phe Pro 260 265 270

Glu Asn Asn Thr Asn Leu Thr Glu Thr Val Asn Thr Thr Asn Gin Gin 275 280 285

Leu Glu Leu His Leu Gly Gly Glu Ser Tyr Trp Val Ser Met lie Ser 290 295 300

Tyr Asn Ser Leu Gly Lys Ser Pro Val Thr Thr Leu Arg lie Pro Ala 305 310 315 320 lie Gin Glu Lys Ser Phe Arg Cys lie Glu Val Met Gin Ala Cys Leu

325 330 335

Ala Glu Asp Gin Leu Val Val Lys Trp Gin Ser Ser Ala Leu Asp Val 340 345 350

Asn Thr Trp Met lie Glu Trp Phe Pro Asp Met Asp Ser Glu His Pro 355 360 365

Thr Leu Ser Trp Glu Ser Val Ser Gin Ala Thr Asn Trp Thr lie Gin 370 375 380

Gin Asp Lys Leu Lys Pro Phe Trp Cys Tyr Asn lie Ser Va! Tyr Pro 385 390 395 400

Met Leu His Asp Lys Val Gly Glu Pro Tyr Ser lie Gin Ala Tyr Ala 405 410 415 65 201028165

Lys Glu Gly lie Pro Ser Lys Gly Pro Glu Thr Lys Val Glu Asn lie 420 425 430

Gly Val Lys Thr Val Thr lie Thr Trp Lys Glu lie Pro Lys Ser Glu 435 440 445

Arg Lys Gly lie lie Cys Asn Tyr Thr lie Phe Tyr Gin Ala Glu Gly 450 455 460

Gly Lys Gly Phe Ser Lys Thr Val Asn Ser Ser lie Leu Gin 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 lie Asn Gly Thr Ser lie Asn Phe Lys Thr 500 505 510

Leu Ser Phe Ser Val Phe Glu lie lie Leu lie Thr Ser Leu lie Gly 515 520 525

Gly Gly Leu Leu lie Leu lie lie Leu Thr Val Ala Tyr Gly Leu Lys 530 535 540

Lys Pro Asn Lys Leu Thr His Leu Cys 545 550 &lt;210> 73 &lt;211> 1665 &lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 73 60 120 180 240 atgatgtgga cctgggcact gtggatgctc ccctcactct gcaaattcag cctggcagct ctgccagcta agcctgagaa catttcctgt Gtctactact ataggaaaaa tttaacctgc acttggagtc caggaaagga aaccagttat acccagtaca cagttaagag aacttacgct tttggagaaa aacatgataa ttgtacaacc aatagttcta caagtgaaaa tcgtgcttcg tgctcttttt tccttccaag aataacgatc ccagataatt ataccattga ggtggaagct 66 300 360 360

201028165 gaaaatggag atggtgtaat taaatctcat atgacatact ggagattaga gaacatagcg aaaactgaac cacctaagat tttccgtgtg aaaccagttt tgggcatcaa acgaatgatt caaattgaat ggataaagcc tgagttggcg cctgtttcat ctgatttaaa atacacactt cgattcagga cagtcaacag taccagctgg atggaagtca acttcgctaa gaaccgtaag gataaaaacc aaacgtacaa cctcacgggg ctgcagcctt ttacagaata tgtcatagct ctgcgatgtg cggtcaagga gtcaaagttc tggagtgact ggagccaaga aaaaatggga atgactgagg aagaagctcc atgtggcctg gaactgtgga gagtcctgaa accagctgag gcggatggaa gaaggccagt gcggttgtta tggaagaagg caagaggagc cccagtccta gagaaaacac ttggctacaa catatggtac tatccagaaa gcaacactaa cctcacagaa acaatgaaca ctactaacca gcagcttgaa ctgcatctgg gaggcgagag cttttgggtg tctatgattt cttataattc tcttgggaag tctccagtgg ccaccctgag gattccagct attcaagaaa aatcgtttca gtgcattgag gtcatgcagg cctgcgttgc tgaggaccag ctagtggtga agtggcaaag ctctgctcta gacgtgaaca cttggatgat tgaatggttt ccggatgtgg actcagagcc caccaccctt ctgtgtctca ggccacgaac tggacgatcc agcaagataa attaaaacct ttctggtgct ataacatctc tgtgtatcca tcctgggaat atgttgcatg acaaagttgg cgagccatat tccatccagg cttatgccaa agaaggcgtt ccatcagaag gtcctgagac caaggtggag aacattggcg tgaagacggt cacgatcaca tggaaagaga ttcccaagag tgagagaaag ggtatcatct gcaactacac catcttttac caagctgaag gtggaaaagg attctccaag acagtcaatt ccagcatctt gcagtacggc ctggagtccc tgaaacgaaa gacctcttac attgttcagg tcatggccag caccagtgct gggggaacca acgggaccag cataaatttc aagacattgt cattcagtgt ctttgagatt atcctcataa cttctctgat tggtggaggc cttcttattc tcattatcct gacagtggca 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 67 201028165 1665 tatggtctca aaaaacccaa caaattgact catctgtgtt aatga &lt;210> 74 &lt;211&gt; 553 &lt;212> PRT &lt;213&gt; Homo sapiens &lt;400> 74

Met Met Trp Thr Trp Ala Leu Trp Met Leu Pro Ser Leu Cys Lys Phe 15 10 15

Ser Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn lie 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 Gin 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 lie Pro Asp Asn Tyr Thr lie 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 lie Ala Lys Thr Glu Pro Pro Lys lie Phe 115 120 125

Arg Val Lys Pro Val Leu Gly lie Lys Arg Met lie Gin lie Glu Trp 130 135 140 lie 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 Gin Thr Tyr Asn Leu Thr Gly Leu Gin 180 185 190 68 201028165

Pro Phe Thr Glu Tyr Val lie Ala Leu Arg Cys Ala Val Lys Glu Ser 195 200 205

Lys Phe Trp Ser Asp Trp Ser Gin 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 lie Trp Tyr Tyr Pro 260 265 270

Glu Ser Asn Thr Asn Leu Thr Glu Thr Met Asn Thr Thr Asn Gin Gin 275 280 285

Leu Glu Leu His Leu Gly Gly Glu Ser Phe Trp Val Ser Met lie Ser 290 295 300

Tyr Asn Ser Leu Gly Lys Ser Pro Val Ala Thr Leu Arg lie Pro Ala 305 310 315 320 lie Gin Glu Lys Ser Phe Gin Cys lie Glu Val Met Gin Ala Cys Val 325 330 335

Ala Glu Asp Gin Leu Val Val Lys Trp Gin Ser Ser Ala Leu Asp Val 340 345 350

Asn Thr Trp Met lie Glu Trp Phe Pro Asp Val Asp Ser Glu Pro Thr 355 360 365

Thr Leu Ser Trp Glu Ser Val Ser Gin Ala Thr Asn Trp Thr lie Gin 370 375 380

Gin Asp Lys Leu Lys Pro Phe Trp Cys Tyr Asn lie Ser Val Tyr Pro 385 390 395 400

Met Leu His Asp Lys Val Gly Glu Pro Tyr Ser lie Gin Ala Tyr Ala 405 410 415

Lys Glu Gly Val Pro Ser Glu Gly Pro Glu Thr Lys Val Glu Asn lie 69 201028165 430 425 420

Gly Val Lys Thr Val Thr lie Thr Trp Lys Glu lie Pro Lys Ser Glu 435 440 445

Arg Lys Gly lie Me Cys Asn Tyr Thr lie Phe Tyr Gin Ala Glu Gly 450 455 460

Gly Lys Gly Phe Ser Lys Thr Val Asn Ser Ser lie Leu Gin Tyr Gly 465 470 475 480

Leu Glu Ser Leu Lys Arg Lys Thr Ser Tyr lie Val Gin Val Met Ala 485 490 495

Ser Thr Ser Ala Gly Gly Thr Asn Gly Thr Ser lie Asn Phe Lys Thr 500 505 510

Leu Ser Phe Ser Val Phe Glu lie lie Leu lie Thr Ser Leu lie Gly 515 520 525

Gly Gly Leu Leu lie Leu lie lie Leu Thr Val Ala Tyr Gly Leu Lys 530 535 540

Lys Pro Asn Lys Leu Thr His Leu Cys 545 550 &lt;210&gt; 75 &lt;211〉 2199

ataccattga ggtggaagct Hano sapiens <400> 75 60 120 180 240 300 atgatgtgga cctgggcact gtggatgctc ccctcactct gcaaattcag cctggcagct ctgccagcta agcctgagaa catttcctgt gtctactact ataggaaaaa tttaacctgc acttggagtc caggaaagga aaccagttat acccagtaca cagttaagag aacttacgct tttggagaaa aacatgataa ttgtacaacc aatagttcta caagtgaaaa tcgtgcttcg tgctcttttt tccttccaag aataacgatc ccagataatt; &lt; 212 &gt; DNA &lt; 213 & gt Gaaaatggag atggtgtaat taaatctcat atgacatact ggagattaga gaacatagcg 70 360 420 420

201028165 aaaactgaac cacctaagat tttccgtgtg aaaccagttt tgggcatcaa acgaatgatt caaattgaat ggataaagcc tgagttggcg cctgtttcat ctgatttaaa atacacactt cgattcagga cagtcaacag taccagctgg atggaagtca acttcgctaa gaaccgtaag gataaaaacc aaacgtacaa cctcacgggg ctgcagcctt ttacagaata tgtcatagct ctgcgatgtg cggtcaagga gtcaaagttc tggagtgact ggagccaaga aaaaatggga atgactgagg aagaagctcc atgtggcctg gaactgtgga gagtcctgaa accagctgag gcggatggaa gaaggccagt gcggttgtta tggaagaagg caagaggagc cccagtccta gagaaaacac ttggctacaa catatggtac tatccagaaa gcaacactaa cctcacagaa acaatgaaca ctactaacca gcagcttgaa ctgcatctgg gaggcgagag cttttgggtg tctatgattt cttataattc tcttgggaag tctccagtgg ccaccctgag gattccagct attcaagaaa aatcgtttca gtgcattgag gtcatgcagg cctgcgttgc tgaggaccag ctagtggtga agtggcaaag ctctgctcta gacgtgaaca cttggatgat tgaatggttt ccggatgtgg actcagagcc caccaccctt tcctgggaat ctgtgtctca ggccacgaac tggacgatcc agcaagataa attaaaacct ttctggtgct ataacatctc tgtgtatcca atgttgcatg acaaagttgg cgagccatat tccatccagg cttatgccaa agaaggcgtt ccatcagaag gtcctgagac caaggtggag aacattggcg tgaagacggt cacgatcaca tggaaagaga ttcccaagag tgagagaaag ggtatcatct gcaactacac catcttttac caagctgaag gtggaaaagg attctccaag acagtcaatt ccagcatctt gcagtacggc ctggagtccc tgaaacgaaa gacctcttac attgttcagg tcatggccag caccagtgct gggggaacca acgggaccag cataaatttc aagacattgt cattcagtgt ctttgagatt atcctcataa cttctctgat tggtggaggc cttcttattc tcattatcct gacagtggca tatggtctca aaaaacccaa caaattgact catctgtgtt ggcccaccgt tcccaaccct 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 71 201028165 gctgaaagta gtatagccac atggcatgga gatgatttca aggataagct aaacctgaag gagtctgatg actctgtgaa cacagaagac aggatcttaa aaccatgttc cacccccagt gacaagttgg tgattgacaa gttggtggtg aactttggga atgttctgca agaaattttc acagatgaag ccagaacggg tcaggaaaac aatttaggag gggaaaagaa tgggtatgtg acctgcccct tcaggcctga ttgtcccctg gggaaaagtt ttgaggagct cccagtttca cctgagattc cgcccagaaa atcccaatac ctacgttcga ggatgccaga Ggggacccgc ccagaagcca aagagcagct tctcttttct Ggtcaaagtt tagtaccaga tcatctgtgt gaggaaggag ccccaaatcc atatttgaaa aattcagtga cagccaggga atttcttgtg tctgaaaaac ttccagagca caccaaggga gaagtctaa &lt;210〉 76 &lt;211〉 732

<212> PRT &lt;213&gt; Homo sapiens &lt;400〉 76

Met Met Trp Thr Trp Ala Leu Trp Met Leu Pro Ser Leu Cys Lys Phe 15 10 15

Ser Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn lie 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 Gin 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 lie Thr lie Pro Asp Asn Tyr Thr lie 85 90 95

Glu Val Glu Ala Glu Asn Gly Asp Gly Val lie Lys Ser His Met Thr 1740 1800 i860 1920 1980 2040 2100 2160 2199 72 201028165 100 105 110

Tyr Trp Arg Leu Glu Asn lie Ala Lys Thr Glu Pro Pro Lys lie Phe 115 120 125

Arg Val Lys Pro Val Leu Gly lie Lys Arg Met lie Gin lie Glu Trp 130 135 140 lie 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 Gin Thr Tyr Asn Leu Thr Gly Leu Gin 180 185 190

Pro Phe Thr Glu Tyr Val lie Ala Leu Arg Cys Ala Val Lys Glu Ser 195 200 205

Lys Phe Trp Ser Asp Trp Ser Gin 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 lie Trp Tyr Tyr Pro 260 265 270

Glu Ser Asn Thr Asn Leu Thr Glu Thr Met Asn Thr Thr Asn Gin Gin 275 280 285

Leu Glu Leu His Leu Gly Gly Glu Ser Phe Trp Val Ser Met lie Ser 290 295 300

Tyr Asn Ser Leu Gly Lys Ser Pro Val Ala Thr Leu Arg lie Pro Ala 305 310 315 320

Me Gin Glu Lys Ser Phe Gin Cys lie Glu Val Met Gin Ala Cys Val 325 330 335 73 201028165

Ala Glu Asp Gin Leu Val Vat Lys Trp Gin Ser Ser Ala Leu Asp Val 340 345 350

Asn Thr Trp Met lie Glu Trp Phe Pro Asp Val Asp Ser Glu Pro Thr 355 360 365

Thr Leu Ser Trp Glu Ser Val Ser Gin Ala Thr Asn Trp Thr lie Gin 370 375 380

Gin Asp Lys Leu Lys Pro Phe Trp Cys Tyr Asn lie Ser Val Tyr Pro 385 390 395 400

Met Leu His Asp Lys Val Gly Glu Pro Tyr Ser lie Gin Ala Tyr Ala 405 410 415

Lys Glu Gly Val Pro Ser Glu Gly Pro Glu Thr Lys Val Glu Asn lie 420 425 430

Gly Val Lys Thr Val Thr lie Thr Trp Lys Glu Me Pro Lys Ser Glu 435 440 445

Arg Lys Gly lie lie Cys Asn Tyr Thr lie Phe Tyr Gin Ala Glu Gly 450 455 460

Gly Lys Gly Phe Ser Lys Thr Val Asn Ser Ser lie Leu Gin Tyr Gly 465 470 475 480

Leu Glu Ser Leu Lys Arg Lys Thr Ser Tyr lie Val Gin Val Met Ala 485 490 495

Ser Thr Ser Ala Gly Gly Thr Asn Gly Thr Ser lie Asn Phe Lys Thr 500 505 510

Leu Ser Phe Ser Val Phe Glu lie lie Leu lie Thr Ser Leu lie Gly 515 520 525

Gly Gly Leu Leu lie Leu lie lie 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 lie Ala Thr Trp His Gly Asp Asp Phe Lys Asp Lys 565 570 575 74 201028165

Leu Asn Leu Lys Glu Ser Asp Asp Ser Val Asn Thr Glu Asp Arg lie 580 585 590

Leu Lys Pro Cys Ser Thr Pro Ser Asp Lys Leu VaI lie Asp Lys Leu 595 600 605

Val Val Asn Phe Gly Asn Val Leu Gin Glu lie Phe Thr Asp Glu Ala 610 615 620

Arg Thr Gly Gin 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 lie Pro Pro Arg Lys Ser Gin Tyr Leu Arg 660 665 670

Ser Arg Met Pro Glu Gly Thr Arg Pro Glu Ala Lys Glu Gin Leu Leu 675 680 685

Phe Ser Gly Gin 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 &lt;211&gt; 1542

&Lt; 212> DNA &lt; 213 &gt; Homo sapiens &lt; 400 &gt; 77 60 120 180 atgatgtgga cctgggcact gtggatgctc ccttcactct gcaaattcag cctggcagct ctgccagcta agcctgagaa catttcctgt gtctactact ataggaaaaa tttaacctgc acttggagtc caggaaagga aaccagttat acccagtaca cagttaagag aacttacgct tttggagaaa aacatgataa ttgtacaacc aatagttcta caagtgaaaa tcgtgcttcg 75 240 ccagataatt ataccattga ggtggaagct 300 atgacatact ggagattaga gaacatagcg 360 aaaccagttt tgggcatcaa acgaatgatt 420 cctgtttcat ctgatttaaa atacacactt 480 atggaagtca acttcgctaa gaaccgtaag 540 ctgcagcctt ttacagaata tgtcatagct 600 tggagtgact ggagccaaga aaaaatggga 660 gaactgtgga gagtcctgaa accagctgag 720 tggaagaagg caagaggagc cccagtccta 780 tatccagaaa gcaacactaa cctcacagaa 840 ctgcatctgg gaggcgagag cttttgggtg 900 tctccagtgg ccaccctgag gattccagct 960 gtcatgcagg cctgcgttgc tgaggaccag 1020 gacgtgaaca cttggatgat tgaatggttt 1080 tcctgggaat ctgtgtctca ggccacgaac 1140 ttctggtgct ataacatctc tgtgtatcca 1200 tccatccagg cttatgccaa agaaggcgtt 1260 aacattggcg tgaagacggt cacgatc aca 1320 ggtatcatct gcaactacac catcttttac 1380 acagtcaatt ccagcatctt gcagtacggc 1440 attgttcagg tcatggccag caccagtgct 1500 aagacattgt ca 1542 201028165 tgctcttttt tccttccaag aataacgatc gaaaatggag atggtgtaat taaatctcat aaaactgaac cacctaagat tttccgtgtg caaattgaat ggataaagcc tgagttggcg cgattcagga cagtcaacag taccagctgg gataaaaacc aaacgtacaa cctcacgggg ctgcgatgtg cggtcaagga gtcaaagttc atgactgagg aagaagctcc atgtggcctg gcggatggaa gaaggccagt gcggttgtta gagaaaacac ttggctacaa catatggtac acaatgaaca ctactaacca gcagcttgaa tctatgattt cttataattc tcttgggaag attcaagaaa aatcgtttca gtgcattgag ctagtggtga agtggcaaag ctctgctcta ccggatgtgg actcagagcc caccaccctt tggacgatcc agcaagataa attaaaacct atgttgcatg acaaagttgg cgagccatat ccatcagaag gtcctgagac caaggtggag tggaaagaga ttcccaagag tgagagaaag caagctgaag gtggaaaagg attctccaag ctggagtccc tgaaacgaaa gacctcttac gggggaacca acgggaccag cataaatttc 76 201028165 &lt; 210> 78 <211 &gt; 514 &lt; 212> PRT &lt;213〉 Homo sapiens <400> 78

Met Met Trp Thr Trp Ala Leu Trp Met Leu Pro Ser Leu Cys Lys Phe 15 10 15

Ser Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn lie 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 Gin Tyr Thr Val Lys Arg Thr Tyr Ala Phe Gly Glu Lys 50 55 60

His Asp Asn Gys Thr Thr Asn Ser Ser Thr Ser Glu Asn Arg Ala Ser 65 70 75 80

Cys Ser Phe Phe Leu Pro Arg lie Thr lie Pro Asp Asn Tyr Thr lie 85 90 95

Glu Val Glu Ala Glu Asn Gly Asp Gly Val lie Lys Ser His Met Thr 100 105 110

Tyr Trp Arg Leu Glu Asn lie Ala Lys Thr Glu Pro Pro Lys lie Phe 115 120 125

Arg Val Lys Pro Val Leu Gly lie Lys Arg Met lie Gin lie Glu Trp 130 135 140 lie 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 Gin Thr Tyr Asn Leu Thr Gly Leu Gin 180 185 190 77 201028165

Pro Phe Thr Glu Tyr Val Me Ala Leu Arg Cys Ala Val Lys Glu Ser 195 200 205

Lys Phe Trp Ser Asp Trp Ser Gin 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 lie Trp Tyr Tyr Pro 260 265 270

Glu Ser Asn Thr Asn Leu Thr Glu Thr Met Asn Thr Thr Asn Gin Gin 275 280 285

Leu Glu Leu His Leu Gly Gly Glu Ser Phe Trp Val Ser Met lie Ser 290 295 300

Tyr Asn Ser Leu Gly Lys Ser Pro Val Ala Thr Leu Arg lie Pro Ala 305 310 315 320 lie Gin Glu Lys Ser Phe 6ln Cys lie Glu Val Met Gin Ala Cys Val 325 330 335

Ala Glu Asp Gin Leu Val Val Lys Trp Gin Ser Ser Ala Leu Asp Val 340 345 350

Asn Thr Trp Met lie Glu Trp Phe Pro Asp Val Asp Ser Glu Pro Thr 355 360 365

Thr Leu Ser Trp Glu Ser Val Ser 6ln Ala Thr Asn Trp Thr lie Gin 370 375 380

Gin Asp Lys Leu Lys Pro Phe Trp Cys Tyr Asn lie Ser Val Tyr Pro 385 390 395 400

Met Leu His Asp Lys Val Gly Glu Pro Tyr Ser lie Gin Ala Tyr Ala 405 410 415

Lys Glu Gly Val Pro Ser Glu Gly Pro Glu Thr Lys Val Glu Asn lie 420 425 430 78 201028165

Gly Val Lys Thr Val Thr Ile Thr Trp Lys Glu lie Pro Lys Ser Glu 435 440 445

Arg Lys Gly lie lie Cys Asn Tyr Thr lie Phe Tyr Gin Ala Glu Gly 450 455 460

Gly Lys Gly Phe Ser Lys Thr Val Asn Ser Ser Me Leu Gin Tyr Gly 465 470 475 480

Leu Glu Ser Leu Lys Arg Lys Thr Ser Tyr lie Val Gin Val Met Ala 485 490 495

Ser Thr Ser Ala Gly Gly Thr Asn Gly Thr Ser lie Asn Phe Lys Thr 500 505 510

Leu Ser &lt;210> 79 <211> 662 &lt;212> PRT &lt;213&gt; Homo sapiens <400> 79

Met Lys Leu Ser Pro Gin Pro Ser Cys Val Asn Leu Gly Met Met Trp 15 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

Gin 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 79 201028165

Phe Leu Pro Arg lie Thr lie Pro Asp Asn Tyr Thr lie Glu Val Glu 100 105 110

Ala Glu Asn Gly Asp Gly Val lie Lys Ser His Met Thr Tyr Trp Arg 115 120 125

Leu Glu Asn lie Ala Lys Thr Glu Pro Pro Lys lie Phe Arg Val Lys 130 135 140

Pro Val Leu Gly lie Lys Arg Met lie Gin lie Glu Trp lie 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 Gin Thr Tyr Asn Leu Thr Gly Leu Gin Pro Phe Thr 195 200 205

Glu Tyr Val lie Ala Leu Arg Cys Ala Val Lys Glu Ser Lys Phe Trp 210 215 220

Ser Asp Trp Ser Gin 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 lie Trp Tyr Tyr Pro Glu Ser Asn 275 280 285

Thr Asn Leu Thr Glu Thr Met Asn Thr Thr Asn Gin Gin Leu Glu Leu 290 295 300

His Leu Gly Gly Glu Ser Phe Trp Val Ser Met lie Ser Tyr Asn Ser 305 310 315 320

Leu Gly Lys Ser Pro Val Ala Thr Leu Arg lie Pro Ala lie Gin Glu 325 330 335 80 201028165

Lys Ser Phe Gin Cys lie Glu Val Met Gin Ala Cys Val Ala Glu Asp 340 345 350

Gin Leu Val Val Lys Trp Gin Ser Ser Ala Leu Asp Val Asn Thr Trp 355 360 365

Met lie Glu Trp Phe Pro Asp Val Asp Ser Glu Pro Thr Thr Leu Ser 370 375 380

Trp Glu Ser Val Ser Gin Ala Thr Asn Trp Thr lie Gin Gin Asp Lys 385 390 395 400

Leu Lys Pro Phe Trp Cys Tyr Asn lie Ser Val Tyr Pro Met Leu His 405 410 415

Asp Lys Val Gly Glu Pro Tyr Ser lie Gin Ala Tyr Ala Lys Glu Gly 420 425 430

Val Pro Ser Glu Gly Pro Glu Thr Lys Val Glu Asn lie Gly Val Lys 435 440 445

Thr Val Thr lie Thr Trp Lys Glu lie Pro Lys Ser Glu Arg Lys Gly 450 455 460 lie lie Cys Asn Tyr Thr lie Phe Tyr Gin Ala Glu Gly Gly Lys Gly 465 470 475 480

Phe Ser Lys Thr Val Asn Ser Ser Ile Leu Gin Tyr Gly Leu Glu Ser 485 490 495

Leu Lys Arg Lys Thr Ser Tyr lie Val Gin Val Met Ala Ser Thr Ser 500 505 510

Ala Gly Gly Thr Asn Gly Thr Ser lie Asn Phe Lys Thr Leu Ser Phe 515 520 525

Ser Val Phe Glu lie lie Leu lie Thr Ser Leu lie Gly Gly Gly Leu 530 535 540

Leu lie Leu lie lie 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 81 201028165 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 lie Leu Lys Pro 595 600 605

Cys Ser Thr Pro Ser Asp Lys Leu Val lie Asp Lys Leu Val Val Asn 610 615 620

Phe Gly Asn Val Leu Gin Glu lie Phe Thr Asp Glu Ala Arg Thr Gly 625 630 635 640

Gin Glu Asn Asn Leu Gly Gly Glu Lys Asn Gly Thr Arg lie Leu Ser 645 650 655

Ser Cys Pro Thr Ser lie 660 &lt;210&gt; 80 &lt;211〉 732

&lt;212> PRT &lt;213&gt; Homo sapiens <220> &lt;221&gt; SIGNAL &lt;222>(1)..(20) &lt;220> &lt;221&gt; TRANSMEM &lt;222> (520)__ (543 ) <400> 80

Met Met Trp Thr Trp Ala Leu Trp Met Leu Pro Ser Leu Cys Lys Phe 15 10 15

Ser Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn lie 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 82 201028165

Ser Tyr Thr Gin 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 lie Lys Ser His Met Thr 100 105 110

Tyr Trp Arg Leu Glu Asn lie Ala Lys Thr Glu Pro Pro Lys lie Phe 115 120 125

Arg Val Lys Pro Val Leu Gly lie Lys Arg Met lie Gin lie Glu Trp 130 135 140 lie 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 Gin Thr Tyr Asn Leu Thr Gly Leu Gin 180 185 190

Pro Phe Thr Glu Tyr Val lie Ala Leu Arg Cys Ala Val Lys Glu Ser 195 200 205

Lys Phe Trp Ser Asp Trp Ser Gin 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 lie Trp Tyr Tyr Pro 260 265 270

Glu Ser Asn Thr Asn Leu Thr Glu Thr Met Asn Thr Thr Asn Gin Gin 275 280 285 83 201028165

Leu Glu Leu His Leu Gly Gly Glu Ser Phe Trp Val Ser Met lie Ser 290 295 300

Tyr Asn Ser Leu Gly Lys Ser Pro Val Ala Thr Leu Arg lie Pro Ala 305 310 315 320 lie Gin Glu Lys Ser Phe Gin Cys lie Glu Val Met Gin Ala Cys Val 325 330 335

Ala Glu Asp Gin Leu Val Val Lys Trp Gin Ser Ser Ala Leu Asp Val 340 345 350

Asn Thr Trp Met lie Glu Trp Phe Pro Asp Val Asp Ser Glu Pro Thr 355 360 365

Thr Leu Ser Trp Glu Ser Val Ser Gin Ala Thr Asn Trp Thr lie Gin 370 375 380

Gin Asp Lys Leu Lys Pro Phe Trp Cys Tyr Asn lie Ser Val Tyr Pro 385 390 395 400

Met Leu His Asp Lys Val Gly Glu Pro Tyr Ser lie Gin Ala Tyr Ala 405 410 415

Lys Glu Gly Val Pro Ser Glu Gly Pro Glu Thr Lys Val Glu Asn lie 420 425 430

Gly Val Lys Thr Val Thr lie Thr Trp Lys Glu lie Pro Lys Ser Glu 435 440 445

Arg Lys Gly lie lie Cys Asn Tyr Thr lie Phe Tyr Gin Ala Glu Gly 450 455 460

Gly Lys Gly Phe Ser Lys Thr Val Asn Ser Ser Ile Leu Gin Tyr Gly 465 470 475 480

Leu Glu Ser Leu Lys Arg Lys Thr Ser Tyr lie Val Gin Val Met Ala 485 490 495

Ser Thr Ser Ala Gly Gly Thr Asn Gly Thr Ser lie Asn Phe Lys Thr 500 505 510

Leu Ser Phe Ser Val Phe Glu lie lie Leu lie Thr Ser Leu lie Gly 84 201028165 515 520 525

Gly Gly Leu Leu lie Leu lie lie 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 lie 580 585 590 _ Leu Lys Pro Cys Ser Thr Pro Ser Asp Lys Leu Val lie Asp Lys Leu 595 600 605

Val Val Asn Phe Gly Asn Val Leu Gin Glu lie Phe Thr Asp Glu Ala 610 615 620

Arg Thr Gly Gin 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 lie Pro Pro Arg Lys Ser Gin Tyr Leu Arg 660 665 670

Ser Arg Met Pro Glu Gly Thr Arg Pro Glu Ala Lys Glu Gin Leu Leu 675 680 685

Phe Ser Gly Gin 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

&lt;210> 81 <211> 716 &lt;212> PRT 85 201028165 &lt;213&gt; Mus musculus &lt;400&gt; 81

Met Trp Thr Leu Ala Leu Trp Ala Phe Ser Phe Leu Cys Lys Phe Ser 15 10 15

Leu Ala Val Leu Pro Thr Lys Pro Glu Asn lie Ser Cys Val Phe Tyr 20 25 30

Phe Asp Arg Asn Leu Thr Gys Thr Trp Arg Pro Glu Lys Glu Thr Asn 35 40 45

Asp Thr Ser Tyr lie 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 lie Cys Ser Val Glu Val Gin Ala Gin Asn Gly 85 90 95

Asp Gly Lys Val Lys Ser Asp Me Thr Tyr Trp His Leu lie Ser lie 100 105 110

Ala Lys Thr Glu Pro Pro lie lie Leu Ser Val Asn Pro lie Cys Asn 115 120 125

Arg Met Phe Gin lie Gin 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 Gin Val Cys Asn Leu Thr Gly 165 170 175

Leu Gin 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 lie Leu Glu Pro 86 201028165 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 lie Gin Tyr 245 250 255

Phe Ala Glu Asn Ser Thr Asn Leu Thr Glu lie Asn Asn lie Thr Thr 260 265 270

Gin Gin Tyr Glu Leu Leu Leu Met Ser Gin Ala His Ser Val Ser Val 275 280 285

Thr Ser Phe Asn Ser Leu Gly Lys Ser Gin Glu Ala lie Leu Arg lie 290 295 300

Pro Asp Val His Glu Lys Thr Phe Gin Tyr lie Lys Ser Met Lys Ala 305 310 315 320

Tyr lie Ala Glu Pro Leu Leu Val Val Asn Trp Gin Ser Ser lie Pro 325 330 335

Ala Val Asp Thr Trp lie Val Glu Trp Leu Pro Glu Ala Ala Met Ser 340 345 350

Lys Phe Pro Ala Leu Ser Trp Glu Ser Val Ser Gin Val Thr Asn Trp 355 360 365

Thr lie Glu Gin Asp Lys Leu Lys Pro Phe Thr Cys Tyr Asn lie Ser 370 375 380

Val Tyr Pro Val Leu Gly His Arg Val Gly Glu Pro Tyr Ser lie Gin 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 lie Gly Leu Arg Thr Ala Thr lie Thr Trp Lys Glu lie Pro 420 425 430

Lys Ser Ala Arg Asn Gly Phe lie Asn Asn Tyr Thr Val Phe Tyr Gin 435 440 445 87 201028165

Ala Glu Gly Gly Lys Glu Leu Ser Lys Thr Val Asn Ser His Ala Leu 450 455 460

Gin 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 lie Asn 485 490 495

Phe Lys Thr Leu Ser lie Ser Val Phe Glu Me Val Leu Leu Thr Ser 500 505 510

Leu Val Gly Gly Gly Leu Leu Leu Leu Ser lie 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 lie 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 Gin Ala Ser lie 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 Gin Pro Ser 660 665 670

Ser Ser Cys Gin Ser Pro Gly Leu Ser Pro Pro Arg Glu Asp Gin Ala 675 680 685 88 201028165

Gin Asn Pro Tyr Leu Lys Asn Ser Val Thr Thr Arg Glu Phe Leu Val 690 695 700

His Glu Asn lie Pro Glu His Ser Lys 6ly Glu Val 705 710 715 <210> 82 <211> 4 &lt;212&gt; PRT <213>Artificial sequence &lt;220> <223> Manufactured peptide sequence <400> 82

Gly Gly Gly Ser &lt;210&gt; 83 &lt;211&gt; 4 &lt;212&gt; PRT &lt; 213 &gt; 213 &gt; artificial sequence &lt;220 &lt; 223 &gt; 223 &gt; synthetic peptide sequence

&lt;400〉 83

Ser Gly Gly Gly 1 &lt;210〉 84 &lt;211> 5 &lt;212> PRT &lt;213>Artificial sequence &lt;220&gt;&lt;223>Synthetic peptide sequence &lt;400> 84

Gly Gly Gly Gly Ser 89 201028165 1 5 &lt;210&gt; 85 &lt;211&gt; 5 &lt;212&gt; PRT <213>Artificial sequence <220> &lt;223> Synthetic peptide sequence &lt;400> 85

Ser Gly Gly Gly Gly 1 5

&lt;210&gt; 86 <211> 6 <212> PRT &lt;213>Artificial sequence &lt;220> <223> Synthetic peptide sequence &lt;400&gt; 86

Gly GlyGly Gly Gly Ser 1 5

&lt;210> 87 <211> 6 &lt;212&gt; PRT &lt;213>Artificial sequence &lt;220> &lt;223>Synthetic peptide sequence &lt;400> 87

Ser Gly Gly Gly Gly Gly 1 5

&lt;210&gt; 88 <211> 7 &lt;212> PRT 90 201028165 &lt;213>Artificial sequence &lt;220&gt;&lt;223>Artificial winning sequence &lt;400&gt; 88

Gly Gly Gly Gly Gly Gly Ser '1 5 ' <210> 89 &lt;211> 7 &lt;212> PRT <213> Artificial sequence <22〇&gt;&lt;223> Synthetic peptide sequence &lt;400&gt; 89

Ser Gly Gly Gly Gly Gly Gly 1 5

&lt;210> 90 <211> 40 &lt;212> DMA <213> artificial sequence

&lt;220> <223> Synthetic primer sequence &lt;400> 90 40 taatagcggc cgctcattat ttaccaggag agtgggagag &lt;210> 91 &lt;211&gt; 40 &lt;212&gt; DNA <213>Artificial sequence &lt;220> &lt;223>Artificial Synthetic primer sequence &lt;400&gt; 91 taatagcggc cgctcattaa cactcattcc tgttgaagct 91 40 201028165 &lt;210> 92 &lt;211> 33 &lt;212&gt; DNA &lt;213>Artificial sequence &lt;220> &lt;223> Synthetic primer sequence &lt; 400> 92 gacgaattcc accatgggat ggagctggat ctt 33 &lt;210&gt; 93 &lt;211> 33 &lt;212&gt; DNA &lt;213>artificial sequence &lt;220&gt;&lt;223&gt;&gt;&gt;&gt; artificial synthesis primer sequence &lt;400&gt; 93 gacgaattcc accatgagtg tgcccactca ggt

33 <210> 94 &lt;211> 33 &lt;212> DNA <213> artificial sequence &lt;220&gt;&lt;223>synthetic synthesis primer sequence &lt;400> 94 gacgaattcc accatggaat gtaactggat act

33 &lt;210&gt; 95 &lt;211&gt; 33 &lt;212> DNA <213> artificial sequence &lt;220> <223> Synthetic primer sequence &lt;400> 95 gacgaattcc accatggatt ttctggtgca gat 92 33 201028165 &lt;210&gt; 96 &lt;;211&gt; 30

&lt;212> PRT &lt;213&gt; Homo sapiens &lt;400> 96

Gin Val Gin Leu Val Gin Ser Gly Ala 6lu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 20 25 30 &lt;210> 97 &lt;211&gt; 14

&lt;212&gt; PRT &lt;213&gt; Homo sapiens <400> 97

Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met Gly 1 5 10 <210> 98 &lt;211&gt; 32 &lt;212> PRT <213> Homo sapiens

&lt;400> 98

Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr Met Glu 15 10 15

Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 &lt;210> 99 <211> 11 &lt;212&gt; PRT &lt;213&gt; Homo sapiens <400> 99 93 201028165

Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> 100 &lt;211> 23 <212> PRT &lt;213&gt; Homo sapiens <400> 100

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys 20 &lt;210&gt; 101 &lt;211&gt; 15

&lt;212&gt; PRT &lt;213&gt; Homo sapiens <400> 101

Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr 15 10 15

&lt;210> 102 <211> 32 &lt;212> PRT <213> Homo sapiens &lt;400> 102

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15

Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Gys 20 25 30 &lt;210> 103 &lt;211> 10

<212> PRT &lt;213&gt; Homo sapiens 94 201028165 &lt;400&gt; 103

Phe Gly Gly Gly Thr Lys Val Glu lie Lys 1 5 10 <210> 104 &lt;211> 119 <212> PRT &lt;213&gt; Mus musculus &lt;400&gt; 104

Asp Val Gin Leu Arg Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser lie Thr Ser Asp 20 25 30

Tyr Ala Trp Asn Trp lie Arg Gin Phe Pro Gly Asn Lys Leu Glu Trp 35 40 45

Met Gly Tyr lie Ser Tyr Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu 50 55 60

Lys Ser Arg Val Ser lie Thr Arg Asp Thr Ser Lys Asn 6ln Phe Phe 65 70 75 80

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

85 90 95

Ala Pro Met lie 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 &lt;213&gt; Mus musculus &lt;400&gt; 105

Ser Asp Tyr Ala Trp Asn 95 201028165 1 5 &lt;210&gt; 106 &lt;211> 15 &lt;212> PRT &lt;213> Mus musculus &lt;400&gt; 106

Tyr lie Ser Tyr Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu Lys 15 10 15 &lt;210> 107 &lt;211> 10 <212> PRT &lt;213&gt; Mus musculus &lt;400&gt; 107

Met lie Thr Thr Asp Trp Phe Phe Asp Val 1 5 10 &lt;210&gt; 108 <211> 107 <212> PRT <213> Mus musculus &lt;400> 108

Asp lie Val Met Thr Gin Ser Pro Ala Thr Leu Ser Val Thr Pro Gly 15 10 15

Asp Arg Val Ser Leu Ser Cys Arg Ala Ser His Asp lie Ser Asp Phe 20 25 30

Leu His Trp Tyr Gin Gin Lys Ser His Glu Ser Pro Arg Leu Leu lie 35 40 45

Lys Tyr Ala Ser Gin Ser lie Ser Gly lie Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Ser Asp Phe Thr Leu Ser lie Asn Ser Va! Glu Pro 65 70 75 80 96 201028165

Glu Asp Val 6ly Val Tyr Tyr Cys Gin Asn Gly His Ser Phe Pro Trp 85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys 100 105 <210> 109 <211> ' &lt;212> &lt;213> 11 PRT Mus musculus &lt;400&gt; 109

Arg Ala Ser His Asp lie Ser Asp Phe Leu His 5 10 <210> <211> 110 7 &lt;212> PRT &lt;213&gt; Mus musculus <400> 110

Tyr Ala Ser 6ln Ser lie Ser 1 5 &lt;210&gt; 111 &lt;211> 9 <212> ^ &lt;213&gt; PRT Mus musculus <400> 111

Gin Asn Gly His Ser Phe Pro Trp Thr 1 5 <210> 112 &lt;211> &lt;212> &lt;213> 121 PRT Artificial Sequence &lt;220> &lt;223&gt; Synthetic peptide sequence 97 201028165 &lt;400〉 112

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro 6ly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe 50 55 60

Lys Gly Arg Val Thr lie 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

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 &lt;210&gt; 113 &lt;211&gt; 17 &lt;212> PRT &lt;213>Artificial Sequence &lt;220> <223> Artificial Synthetic Sequence &lt;400&gt; 113

Glu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe Lys 15 10 15

Gly &lt;210> 114 <211> 17 98 201028165 &lt;212&gt; PRT &lt;213>Artificial sequence <220> <223> Synthetic peptide sequence &lt;400&gt;

Leu lie Asp Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe Lys 1 5 10 15

Gly &lt;210&gt; 115 &lt;211&gt; 17 &lt;212> PRT &lt; 213 > artificial sequence &lt;220&gt; <223> artificial synthetic sequence <400> 115

Leu He Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Asp Lys Phe Lys 15 10 15

Gly

&lt;210&gt; 116 <211> 17 &lt;212> PRT &lt; 213 > artificial sequence &lt; 220 &lt; 223 &gt; 223 > artificial synthetic sequence &lt;400 &gt; 116

Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Gin Phe Lys 15 10 15

Gly 99 201028165 &lt;210&gt; 117 &lt;211> 17 &lt;212> PRT <213> artificial sequence &lt;220> &lt;223>synthetic peptide sequence &lt;400&gt;

Leu lie Asn Pro Tyr Asn Gly 6ly Thr Ser Tyr Asn Gin Lys Phe Gin 15 10 15

Gly &lt;210&gt; 118 &lt;211&gt; 17 &lt;212&gt; PRT &lt;213&gt; Artificial sequence <220> &lt;223> Synthetic peptide sequence &lt;400&gt;

Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe Lys 15 10 15

Asp

<210> 119 &lt;211> 17 &lt;212> PRT <213> artificial sequence &lt;220> <223> artificially synthesized peptide sequence &lt;400&gt; 119 100 201028165

Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe Gin 15 10 15

Asp <210> 120 &lt;211&gt; 14 &lt;212> PRT &lt;213>Artificial sequence &lt;220&gt; <223>Synthetic peptide sequence

&lt;400&gt; 120

Trp Val 6ln Gin Ser Pro Gly Gin Gly Leu Glu Trp Met Gly 1 5 10 &lt;210> 121 &lt;211> 11 <212> PRT &lt;213>Artificial Sequence &lt;220> &lt;223> Synthetic peptide sequence &lt;400> 121

Gin Thr Ser Glu Asn lie Tyr Ser Phe Leu Ala 1 5 10 <210> 122 &lt;211&gt; 11 &lt;212> PRT &lt; 213 &gt; 213 &gt; artificial sequence &lt; 220 &gt; 220 &lt; 223 &gt; artificial synthetic sequence &lt;400&gt; 122

Arg Thr Ser Glu Asp lie Tyr Ser Phe Leu Ala 1 5 10 101 201028165 &lt;210&gt; 123 &lt;211> 7 &lt;212> PRT &lt;213>Artificial sequence &lt;220&gt;&lt;223&gt;&lt;400〉 123

Asp Ala Lys Thr Leu Ala Lys 1 5 &lt;210> 124 &lt;211&gt; <212> &lt;213&gt; 7 PRT artificial sequence &lt;220> &lt;223> Synthetic peptide sequence &lt;400&gt; 124

Asn Ala Gin Thr Leu Ala Lys 1 5 &lt;210> &lt;211> &lt;212&gt;&lt;213&gt; 125 7 PRT artificial sequence &lt;220&gt;&lt;223> Synthetic peptide sequence <400> 125

Asn Ala Lys Thr Glu Ala Lys 1 5 &lt;210&gt; 126 &lt;211> 7 &lt;212> PRT &lt;213>Artificial sequence 201028165 &lt;220〉 &lt;223>Synthetic peptide sequence &lt;400&gt;

Asn Ala Lys Thr Leu Ala Gin 1 5 &lt;210&gt; 127 &lt;211> 7 &lt;212> PRT &lt;213>Artificial Sequence &lt;220&gt; • Xin &lt;223> Synthetic Hall Sequence &lt;400&gt;

Asn Ala Lys Thr Leu Ala Asp 1 5 &lt;210&gt; 128 &lt;211> 324 &lt;212&gt; PRT &lt; 213 &gt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; 223 Synthetic peptide sequence &lt;400&gt;

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 15 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 Gin Ser Ser Gly Leu Tyr Ser 50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr 103 201028165 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 6lu 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 lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 130 135 140

Val Ser Gin Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly 145 150 155 160

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn 165 170 175

Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gin 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 lie Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu 210 215 220

Pro Gin Val Tyr Thr Leu Pro Pro Ser Gin Glu Glu Met Thr Lys Asn 225 230 235 240

Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie 245 250 255

Ala Val Glu Trp Glu Ser Asn Gly Gin 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 Gin Glu Gly Asn Val Phe Ser Cys 290 295 300 104 201028165

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu 305 310 315 320

Ser Leu Ser Pro <210> 129 <211> 326 &lt;212> PRT <213> Artificial Sequence &lt;220〉

<223> Synthetic peptide sequence &lt;400> 129

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 15 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 Gin Ser Ser Gly Leu Tyr Ser 50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr 6ln 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 lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 130 135 140

Val Ser His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly 105 201028165 145 150 155 160

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn 165 170 175

Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gin 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 lie Glu Lys Thr lie Ser Lys Ala Lys Gly 6ln Pro Arg Glu 210 215 220

Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 225 230 235 240

Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie 245 250 255

Ala Val Glu Trp Glu Ser Asn Gly Gin 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 Gin Gin Gly Asn Val Phe Ser Cys 290 295 300

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu 305 310 315 320

Ser Leu Ser Pro Gly Lys 325 <210> 130 &lt;211> 447 &lt;212> PRT <213> Artificial Sequence &lt;220> &lt;223> Synthetic Peptide Sequence &lt;400> 130 106 201028165

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe 50 55 60

Lys Gly Arg Val Thr lie 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

Gin 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 107 201028165 225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie 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 Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445

<210> 131 &lt;211&gt; 32 &lt;212> PRT 108 201028165 <213> Artificial sequence &lt;220> &lt;223> Synthetic peptide sequence &lt;400&gt; 131

Arg Val Thr lie Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu ' 15 10 15

Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30

&lt;210> 132 <211> 326 <212> PRT <213> artificial sequence &lt;220> <223> Synthetic peptide sequence &lt;400&gt; 132

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 15 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 Gin Ser Ser Gly Leu Tyr Ser 50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gin 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 100 105 110 109 201028165

Pro Val Ala 6ly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 115 120 125

Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 130 135 140

Val Ser His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly 145 150 155 160

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn 165 170 175

Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gin 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 lie Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu 210 215 220

Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 225 230 235 240

Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie 245 250 255

Ala Val Glu Trp Glu Ser Asn Gly Gin 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 Gin Gin Gly Asn Val Phe Ser Cys 290 295 300

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu 305 310 315 320

Ser Leu Ser Pro Gly Lys 325 &lt;210&gt; 133 <211> 451 no 201028165 &lt;212&gt; PRT <213> Artificial sequence &lt;220> &lt;223> Synthetic peptide sequence &lt;400&gt;

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 ‘ lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe 50 55 60

Lys Gly Arg Val Thr lie 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

Gin 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 Gys 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 111 201028165

Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie 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 lie 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 6ln Tyr Asn Ser Thr Tyr 290 295 300

Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly 305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie 325 330 335

Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val 340 345 350

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val Ser 355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu 370 375 380

Trp Glu Ser Asn Gly Gin 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 Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 112 201028165

His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser 435 440 445

Pro Gly Lys 450 <210> 134 _ 〈211〉 447

&lt;212〉 PRT ' <213> artificial sequence &lt;220&gt; <223> artificial synthetic peptide sequence &lt;400>134

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe 50 55 60

Lys Gly Arg Val Thr lie 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

Gin 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 130 135 140 113 201028165

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 6ln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 Gys 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 lie 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 Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380 114 201028165

Gly Gin 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 Gin 6ln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu ' 420 425 430 ' His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 &lt;210> 135 Flat · &lt;211〉 447 &lt;212&gt; PRT &lt; 213 &gt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; artificial synthetic peptide sequence &lt;400&gt;

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30

Lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe 50 55 60

Lys Gly Arg Val Thr lie 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 100 105 110 115 201028165

Gin 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 lie 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 Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His 6ln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser lie Glu Lys Thr lie 325 330 335

Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350 116 201028165

Pro Ser Arg 6lu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 &lt;210> 136 &lt;211&gt; 445 &lt;212&gt; PRT <213>Artificial Sequence &lt;220> &lt;223> Synthetic peptide Sequence &lt;400&gt; 136 U Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe 50 55 60

Lys Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 117 201028165

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

Gin 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 lie Ser Arg Thr 245 250 255

Pro Glu Val Thr Gys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu 260 265 270

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 118 201028165

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445 &lt;210&gt; 137 &lt;211&gt; 121 &lt;212>PRT &lt;213>Artificial Sequence&lt;220&gt;&lt;220&gt; Synthetic peptide sequence&lt;;400> 137

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 119 201028165 lie Met Asn Trp Val Gin Gin Ser Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe 50 55 60

Lys Gly Arg Val Thr lie 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 Gys 85 90 95

Ala Arg Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 &lt;210> 138 &lt;211&gt; 121 &lt;212> PRT <213>Artificial Sequence &lt;220> <223> Artificial Synthetic Sequence &lt;400> 138

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Glu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe 50 55 60 120 201028165

Lys Gly Arg Val Thr lie 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 A!a Arg Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly ' 100 105 110 ' Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 &lt;210&gt; 139 Win-Win &lt;211>121 &lt;212&gt; PRT <213>Artificial Sequence&lt;220> <223>Artificial Synthetic Sequence of Sequences&lt;400> 139

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Gys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30

Lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asp Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe 50 55 60

Lys Gly Arg Val Thr lie 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 100 105 110 121 201028165

Gin 6ly Thr Leu Val Thr Val Ser Ser 115 120 &lt;210> 140 &lt;211&gt; 121 &lt;212> PRT <213>Artificial sequence &lt;220&gt;&lt;223>Synthetic peptide sequence &lt;400&gt; 140

Gin Val Gin Leu Val 6ln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Asp Lys Phe 50 55 60

Lys Gly Arg Val Thr lie 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

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 &lt;210&gt; 141 &lt;211> 121 <212> PRT &lt; 213 > Artificial Sequence &lt;220&gt;&lt;223&gt; 223 Synthetic Victory Sequence 122 201028165 &lt;400&gt; 141

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met * 35 40 45

Gly Leu Me Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Gin Phe 50 55 60

Lys Gly Arg Val Thr lie 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

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 €3 &lt;210> 142 <211> 121 &lt;212> PRT &lt;213>Artificial sequence &lt;220&gt; <223> Synthetic peptide sequence &lt;400> 142

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 123 201028165 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe 50 55 60

Gin Gly Arg Val Thr lie 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

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 &lt;210> 143 &lt;211&gt; 121 &lt;212&gt; PRT <213> Artificial Sequence &lt;220> <223> Synthetic peptide sequence &lt;400> 143

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe 50 55 60

Gin Asp Arg Val Thr lie 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 95 124 201028165

Ala Arg Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 144 &lt;211&gt; 107 &lt;212> PRT <213>Artificial sequence &lt;220> &lt;223> Synthetic peptide sequence &lt;400>144

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Gin Thr Ser Glu Asn lie Tyr Ser Phe 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 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 lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Glu Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105 <210> 145 &lt;211&gt; 107 &lt;212&gt; PRT <213> Artificial sequence 125 &lt;220&gt; 201028165 <223> Synthetic peptide sequence &lt;400&gt; 145

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Thr Ser Glu Asp lie Tyr Ser Phe 20 25 30

Leu Ala Trp Tyr 6ln Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 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 lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Glu Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105

<210> 146 &lt;211> 107 &lt;212&gt; PRT &lt;213>Artificial sequence &lt;220&gt;<223&gt; Synthetic peptide sequence &lt;400&gt;

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Thr Ser Glu Asn lie Tyr Ser Phe 20 25 30

Leu Ala Trp Tyr Gin Gtn Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45 126 201028165

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 lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Glu Ser Pro Leu &gt; 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys '100 105 &lt;210&gt; 147 <211> 107 &lt;212>PRT &lt;213>Artificial Sequence &lt;220> <223> Synthetic peptide sequence &lt;400&gt; 147

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Thr Ser Glu Asn lie Tyr Ser Phe 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asn Ala Gin 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 lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys 6ln His His Tyr Glu Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105 &lt;210&gt; 148 127 201028165 &lt;211> 107 &lt;212&gt; PRT &lt;213>Artificial Sequence &lt;220> &lt;223>Artificial Synthetic Sequence &lt;223&gt;;400> 148

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Thr Ser Glu Asn lie Tyr Ser Phe 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 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 lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Glu Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105

&lt;210> 149 &lt;211&gt; 107 &lt;212> PRT &lt; 213 &gt; artificial sequence &lt;220 &lt; 220 &gt; 223 &gt; artificially synthesized peptide sequence &lt;400&gt;

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Thr Ser Glu Asn lie Tyr Ser Phe 128 201028165 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asn Ala Lys Thr Leu Ala Gin Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Glu Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105

&lt;210> 150 &lt;211&gt; 107 &lt;212> PRT &lt; 213 &gt; artificial sequence &lt;220&gt;<223&gt; Synthetic peptide sequence &lt;400&gt;

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly ^ 1 5 10 15

Asp Arg Val Thr lie Thr Cys Arg Thr Ser Glu Asn lie Tyr Ser Phe 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 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 lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Glu Ser Pro Leu 85 90 95 129 201028165

Thr Phe Gly Gly Gly Thr Lys Val Glu He Lys 100 105 &lt;210> 151 <211> 447 <212> PRT <213> Artificial Sequence &lt;220&gt;&lt;223> Synthetic Peptide Sequence &lt;400> 151

6ln Val Gin Leu Val Gin Ser 6iy Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Gin Phe 50 55 60

Gin Asp Arg Val Thr lie 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

Gin 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 145 150 155 160 130 201028165

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175

Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr 6ln 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 lie 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 Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 131 201028165

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415

Trp Gin Gin Gly Asn Val Phe Ser Gys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr 6ln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 &lt;210> 152 <211> 214 <212> PRT &lt;213> Artificial Sequence

&lt;220&gt;&lt;223&gt; synthetic peptide sequence &lt;400&gt; 152

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Gin Thr Ser Glu Asp lie Tyr Ser Phe 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asn Ala Gin Thr Glu Ala Gin Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Glu Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125 132 201028165

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr ' 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 &lt;210> 153 <211> 326 <212> PRT <213> Artificial Sequence &lt;220> <223> Artificial Synthetic Peptide Sequence &lt;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 6ln Ser Ser Gly Leu Tyr Ser 50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr 65 70 75 80

Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 133 201028165 85 90 95

Thr Val Glu Arg Lys Ser Cys Val 6lu 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 lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 130 135 140

Val Ser His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly 145 150 155 160

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn 165 170 175

Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gin 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 lie Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu 210 215 220

Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 225 230 235 240

Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie 245 250 255

Ala Val Glu Trp Glu Ser Asn Gly Gin 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 Gin Gin Gly Asn Val Phe Ser Cys 290 295 300

Ser Val Met His Glu Ala Leu His Ass His Tyr Thr Gin Lys Ser Leu 305 310 315 320 134 201028165

Ser Leu Ser Pro Gly Lys 325 <210> 154 &lt;211> 326 &lt;212&gt; PRT &lt;213>Artificial sequence &lt;220&gt; <223>Artificial peptide sequence &lt;400&gt;

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg

Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Gys 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 Gin Ser Ser Gly Leu Tyr Ser 50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr 65 70 75 80

Tyr Thr Gys 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 lie Ser Arg Thr Pro Glu Val Thr Gys Val Val Val Asp 130 135 140

Val Ser His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly 145 150 155 160

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn 135 201028165 165 170 175

Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gin 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 lie Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu 210 215 220

Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 225 230 235 240

Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie 245 250 255

Ala Val Glu Trp Glu Ser Asn Gly Gin 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 Gin Gin Gly Asn Val Phe Ser Cys 290 295 300

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu 305 310 315 320

Ser Leu Ser Pro Gly Lys 325 &lt;210&gt; 155 <211> 119 <212> PRT &lt;213>Artificial Sequence &lt;220> <223> Synthetic Peptide Sequence &lt;400&gt; 155

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gin 15 10 15 136 201028165

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser lie Thr Ser Asp 20 25 30

His Ala Trp Ser Trp Val Arg Gin Pro Pro Gly Arg Gly Leu Glu Trp 35 40 45 lie Gly Tyr lie Ser Tyr Ser Gly lie Thr Thr Tyr Asn Pro Ser Leu 50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gin 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 Gin Gly 100 105 110

Ser Leu Val Thr Val Ser Ser 115 &lt;210> 156 &lt;211> 107 <212> PRT &lt;213>Artificial Sequence &lt;220> &lt;223>Synthetic Peptide Sequence &lt;400> 156

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp lie Ser Ser Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin 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 60 137 201028165

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp lie Ala Thr Tyr Tyr Cys Gin Gin Gly Asn Thr Leu Pro Tyr 85 90 95

Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 100 105

&lt;210> 157 <211> 445 <212> PRT <213> artificial sequence &lt;220&gt;<223&gt; Synthetic peptide sequence &lt;400&gt; 157

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Gys Thr Val Ser Gly Tyr Ser lie Thr Ser Asp 20 25 30

His Ala Trp Ser Trp Val Arg Gin Pro Pro Gly Arg Giy Leu Glu Trp 35 40 45 lie Gly Tyr lie Ser Tyr Ser Gly lie Thr Thr Tyr Asn Pro Ser Leu 50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gin 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 Gin 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 138 201028165 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

Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190

Ser Asn Phe Gly Thr Gin 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 lie Ser Arg Thr Pro Glu 245 250 255

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin 260 265 270

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Coffee 1’ Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 290 295 300

Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320

Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys 325 330 335

Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 340 345 350

Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 355 360 365 139 201028165

Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin 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 Gin 405 410 415

Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430

His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 158 &lt;211> 445 &lt;212&gt; PRT &lt;213>Artificial Sequence &lt;220> <223> Synthetic peptide sequence &lt; 400> 158

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser lie Thr Ser Asp 20 25 30

His Ala Trp Ser Trp Val Arg Gin Pro Pro Gly Arg Gly Leu Glu Trp 35 40 45 lie Gly Tyr lie Ser Tyr Ser Gly lie Thr Thr Tyr Asn Pro Ser Leu 50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gin 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 Gin Gly 140 201028165 105 110 100

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 G(y 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

Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190

Ser Asn Phe Gly Thr Gin 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 lie Ser Arg Thr Pro Glu 245 250 255 Cao' Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin 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 Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 290 295 300

Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320

Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys 325 330 335 141 201028165

Thr Lys 6ly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 340 345 350

Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 355 360 365

Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin 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 Gin 405 410 415

Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430

His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 &lt;210&gt; 159 <211> 449 &lt;212&gt; PRT <213>Artificial Sequence &lt;220> <223> Synthetic peptide sequence &lt;400 〉 159

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser lie Thr Ser Asp 20 25 30

His Ala Trp Ser Trp Val Arg Gin Pro Pro Gly Arg Gly Leu Glu Trp 35 40 45 lie Gly Tyr lie Ser Tyr Ser Gly lie Thr Thr Tyr Asn Pro Ser Leu 50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gin Phe Ser 142 201028165 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 Gin 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 Gys 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

Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190

Ser Ser Leu Gly Thr Gin Thr Tyr lie 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 lie 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 Gin Tyr Asn Ser Thr Tyr Arg Val 290 295 300 143 201028165

Val Ser Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu 305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys 325 330 335

Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 340 345 350

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr 355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu 370 375 380

Ser Asn Gly Gin 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 Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430

Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445

Lys &lt;210> 160 &lt;211&gt; 445 &lt;212> PRT <213>&gt; artificial sequence &lt;220> &lt;223>synthetic peptide sequence &lt;400&gt; 160

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser lie Thr Ser Asp 144 201028165 20 25 30

His Ala Trp Ser Trp Val Arg 6ln Pro Pro Gly Arg 6ly Leu 6lu Trp 35 40 45 lie Gly Tyr lie Ser Tyr Ser Gly lie Thr Thr Tyr Asn Pro Ser Leu 50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gin 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 Gin 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

Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190

Ser Asn Phe Gly Thr Gin 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 lie Ser Arg Thr Pro Glu 245 250 255 145 201028165

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin 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 Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 290 295 300

Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320

Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys 325 330 335

Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 340 345 350

Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 355 360 365

Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin 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 Gin

405 410 415

Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430

His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 &lt;210> 161 <211> 445 &lt;212&gt; PRT <213> Artificial Sequence &lt;220> <223> Synthetic peptide sequence 146 201028165 &lt;lt;;400> 161

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser lie Thr Ser Asp 20 25 30

His Ala Trp Ser Trp Val Arg Gin Pro Pro Gly Arg Gly Leu Glu Trp 35 40 45 lie Gly Tyr lie Ser Tyr Ser Gly lie Thr Thr Tyr Asn Pro Ser Leu 50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gin 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 6ln 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

Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190

Ser Asn Phe Gly Thr Gin 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 210 215 220 147 201028165

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 lie Ser Arg Thr Pro Glu 245 250 255

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin 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 Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 290 295 300

Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320

Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys 325 330 335

Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 340 345 350

Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 355 360 365

Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin 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 Gin 405 410 415

Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430

His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 &lt;210> 162 <211> 214 148 201028165 &lt;212&gt; PRT &lt;213>Artificial Sequence &lt;220&gt;&lt;223&gt; Sequence &lt;400&gt; 162

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp lie Ser Ser Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Aia Pro Lys Leu Leu lie 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 lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp lie Ala Thr Tyr Tyr Cys Gin Gin Gly Asn Thr Leu Pro Tyr 85 90 95

Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 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 Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin 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 180 185 190 149 201028165

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Gys 210

&lt;210&gt; 163 &lt;211> 445 <212> PRT <213> artificial sequence &lt;220> <223> artificial synthetic peptide sequence &lt;400&gt; 163

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser lie Thr Ser Asp 20 25 30

His Ala Trp Ser Trp Val Arg Gin Pro Pro Gly Arg Gly Leu Glu Trp 35 40 45 lie Gly Tyr lie Ser Tyr Ser Gly lie Thr Thr Tyr Asn Pro Ser Leu 50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gin 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 Gin 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 150 201028165 145 150 155 160

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175

Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190

Ser Asn Phe Gly Thr Gin 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 6lu 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 lie Ser Arg Thr Pro Glu 245 250 255

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin 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 Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 290 295 300

Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320

Val Ser Asn Lys Gly Leu Pro Ser Ser lie Glu Lys Thr lie Ser Lys 325 330 335

Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 340 345 350

Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 355 360 365

Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin 370 375 380 151 201028165

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 6ly 385 390 395 400

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin 405 410 415

Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430

His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 &lt;210> 164 &lt;211> 443 &lt;212> PRT &lt; 213 > Artificial Sequence &lt; 220 &lt; 223 &gt; 223 > Synthetic peptide sequence &lt;400&gt; 164

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser lie Thr Ser Asp 20 25 30

His Ala Trp Ser Trp Val Arg Gin Pro Pro Gly Arg Gly Leu Glu Trp 35 40 45

He Gly Tyr lie Ser Tyr Ser Gly lie Thr Thr Tyr Asn Pro Ser Leu 50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gin 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 Gin Gly 100 105 110

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 152 201028165 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

Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190

Ser Asn Phe Gly Thr Gin 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 lie Ser Arg Thr Pro Glu 245 250 255

Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu Val Gin 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 Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 290 295 300

Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320

Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys 325 330 335

Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 340 345 350 153 201028165

Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 355 360 365

Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin 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 Gin 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 Gin Lys Ser Leu Ser Leu Ser Pro 435 440 <210> 165 &lt;211&gt; 267 &lt;212> PRT &lt;213>Artificial sequence <220> <223> Synthetic peptide sequence &lt;400> 165

Ala Glu Ser His Leu Ser Leu Leu Tyr His Leu Thr Ala Val Ser Ser 15 10 15

Pro Ala Pro Gly Thr Pro Ala Phe Trp Val Ser Gly Trp Leu Gly Pro 20 25 30

Gin Gin Tyr Leu Ser Tyr Asn Ser Leu Arg Gly Glu Ala Glu Pro Cys 35 40 45

Gly Ala Trp Val Trp Glu Asn Gin Val Ser Trp Tyr Trp Glu Lys Glu 50 55 60

Thr Thr Asp Leu Arg lie Lys Glu Lys Leu Phe Leu Glu Ala Phe Lys 65 70 75 80

Ala Leu Gly Gly Lys Gly Pro Tyr Thr Leu Gin Gly Leu Leu Gly Cys 154 201028165 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 Gin Gly Thr Trp Gly 115 120 125

Gly Asp Trp Pro Glu Ala Leu Ala lie Ser Gin Arg Trp Gin Gin Gin 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

Gin Leu Arg Phe Leu Arg Asn Gly Leu Ala Ala Gly Thr Gly Gin 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 lie Val Gin His 245 250 255

Ala Gly Leu Ala Gin Pro Leu Arg Val Glu Leu 260 265 <210> 166 &lt;211&gt; 99 &lt;212> PRT <213>Artificial sequence &lt;220&gt;&lt;223> Synthetic peptide sequence &lt;400> 166 155 201028165 lie Gin Arg Thr Pro Lys lie Gin Val Tyr Ser Arg His Pro Ala Glu 15 10 15

Asn Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro 20 25 30

Ser Asp lie Glu Val Asp Leu Leu Lys Asn Gly Glu Arg lie 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 Gin Pro Lys lie Val Lys Trp Asp 85 90 95

Arg Asp Met &lt;210> 167 <211> 121 &lt;212&gt; PRT <213> Artificial Sequence &lt;220&gt;

<223> Synthetic peptide sequence &lt;400&gt; 167

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Gin Phe 50 55 60 156 201028165

Gin Asp Arg Val Thr lie 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

Aia Arg Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp 6ly 100 105 110

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120

<210> 168 &lt;211&gt; 107 <212> PRT <213> Artificial sequence &lt;220> <223> Synthetic peptide sequence &lt;400> 168

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gfy 15 10 15

Asp Arg Val Thr lie Thr Cys Gin Thr Ser Glu Asp lie Tyr Ser Phe 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asn Ala Gin Thr Glu Ala Gin Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Glu Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105 157 201028165 &lt;210&gt; 169 &lt;211> 11 &lt;212&gt; PRT &lt;213>Artificial sequence <220&gt;<223&gt; Synthetic peptide sequence &lt;400 〉 169

Gin Thr Ser Glu Asp lie Tyr Ser Phe Leu Ala 1 5 10

<210> 170 &lt;211> 7 <212> PRT &lt;213>Artificial sequence &lt;220&gt;&lt;223>Synthetic peptide sequence &lt;400> 170

Asn Ala Gin Thr Glu Ala Gin 1 5

&lt;210&gt; 171 &lt;211&gt; 17 &lt;212> PRT &lt;213>Artificial sequence <220> <223> Synthetic peptide sequence &lt;400> 171

Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Gin Phe Gin 15 10 15

Asp 158 201028165 &lt;210&gt; 172 &lt;211> 17 <212> PRT &lt;213&gt; Artificial sequence &lt;220> <223> Synthetic peptide sequence &lt;400> 172

Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Asp Gin Phe Gin 15 10 15

Asp <210> 173 <211> 5 <212> PRT &lt;213>Artificial sequence &lt;220&gt;&lt;223>Synthetic peptide sequence &lt;400> 173

Gly Tyr Val Met Asn <210> 174 &lt;211&gt; 5 &lt;212> PRT &lt; 213 &gt; 213 &gt; artificial sequence &lt;220 &gt; 220 &gt; artificial synthetic peptide sequence &lt;400&gt;

Gly Tyr He lie Asn 1 5 159 201028165 &lt;210> 175 &lt;211&gt; 5 &lt;212> PRT &lt;213>Artificial sequence &lt;220> <223> Synthetic peptide sequence &lt;400> 175

Gly Tyr Ile Leu Asn 1 5

<210> 176 &lt;211> 5 &lt;212> PRT &lt;213>Artificial sequence &lt;220> &lt;223>Synthetic peptide sequence &lt;400> 176

Gly Tyr Ala Met Asn 1 5

&lt;210> 177 &lt;211> 17 <212> PRT &lt;213>Artificial sequence &lt;220> <223> Synthetic peptide sequence &lt;400> 177

Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Gin Lys Phe Lys 15 10 15

Gly 160 201028165 &lt;210&gt; 178 &lt;211> 17 &lt;212&gt; PRT &lt; 213 &gt; 213 &gt; artificial sequence &lt; 220 &gt; 220 &gt; artificial synthetic peptide sequence <400> 178

Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Pro Lys Phe Lys 1 5 Gly &lt;210> 179 &lt;211> 12 <212> PRT &lt;213> Artificial Sequence &lt;220> <223> Synthetic peptide Sequence <400> 179

Asp Gly Leu Asp Asp Gly Pro Tyr Thr Met Asp Tyr 1 5 10 &lt;210&gt; 180 &lt;211> 12 &lt;212&gt; PRT &lt;213> Artificial Sequence &lt;220> <223> Synthetic peptide sequence <400 〉 180 161 201028165

Asp Gly Tyr Asp Asp Gly Fro Tyr Thr Leu Asp Tyr 1 5 10 <210> 181 &lt;211> 12 &lt;212&gt; PRT &lt;213>Artificial Sequence &lt;220> <223> Synthetic peptide sequence &lt;400&gt;; 181

Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Glu Tyr 1 5 10 &lt;210> 182 &lt;211> 12 &lt;212> PRT <213> Artificial Sequence &lt;220> &lt;223> Synthetic peptide sequence &lt;400&gt; 182

Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Thr 1 5 10 &lt;210&gt; 183 &lt;211> 12 &lt;212> PRT <213>Artificial sequence &lt;220> &lt;223> Synthetic peptide sequence &lt;400&gt; 183

Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Ser 162 201028165 1 5 10 <210> 184 &lt;211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptide sequence &lt;400&gt; 184

Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr 1 5 10 <210> 185 &lt;211> 12 &lt;212> PRT <213> Artificial sequence &lt;220&gt; <223> Synthetic peptide sequence &lt;400&gt; 185

Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Glu Thr 1 5 10 &lt;210> 186 &lt;211&gt; 12 &lt;212> PRT &lt; 213 &gt; 213 &gt; Artificial Sequence &lt; 220 &gt; 220 &lt; 223 &gt; Synthetic peptide sequence &lt; 400> 186

Asp Gly Leu Asp Asp Gly Pro Tyr Thr Met Glu Thr 1 5 10 163 201028165 &lt;210> 187 &lt;211&gt; 12 &lt;212&gt; PRT &lt;213>Artificial Sequence&lt;220&gt;<223&gt; Synthetic peptide sequence &lt;400&gt; 187

Asp Gly Leu Asp Asp Gly Pro Tyr Thr Met Glu Ser 1 5 10 &lt;210> 188 &lt;211> 11 &lt;212> PRT <213>Artificial sequence &lt;220&gt; <223> Synthetic peptide sequence &lt;400 〉 188

Arg Thr Ser Glu Asn lie Tyr Arg Phe Leu Ala 1 5 10 <210> 189 &lt;211&gt; 11 &lt;212> PRT &lt;213>Artificial sequence &lt;220&gt;&lt;223> Synthetic peptide sequence &lt;400&gt;; 189

Arg Thr Ser Glu Asn lie Tyr Ser Phe Val Ala 1 5 10 &lt;210> 190 164 201028165

&lt;211&gt; 11 &lt;212&gt; PRT <213> Artificial sequence &lt;220> &lt;223> Synthetic peptide sequence &lt;400&gt; 190 Arg Thr Ser Glu Asn lie Tyr Arg Phe Val Ala 1 5 10 &lt;210&gt 191 &lt;211> 11 &lt;212> PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide sequence &lt;400&gt; 191 Arg Ala Ser Glu Asn lie Tyr Ser Phe Leu Ala 1 5 10 &lt;210> 192 <211> 11 &lt;212> PRT &lt;213&gt; Artificial sequence &lt;220> &lt;223> Synthetic peptide sequence &lt;400&gt; 192 Arg Ser Ser Glu Asn lie Tyr Ser Phe Leu Ala 1 5 10 &lt;210> 193 &lt;211&gt; 9 <212> PRT 165 201028165 <213>Artificial sequence &lt;220> &lt;223> Synthetic peptide sequence &lt;400> 193

Gin His His Tyr Asp Ser Pro Leu Thr 1 5 <210> 194 &lt;211> 9 <212> PRT <213> Artificial Sequence &lt;220> &lt;223> Synthetic peptide sequence &lt;400> 194

Gin His His Tyr Glu Asp Pro Leu Thr 1 5 &lt;210> 195 &lt;211&gt; 9 &lt;212> PRT &lt;213>Artificial sequence &lt;220> <223> Synthetic peptide sequence &lt;400> 195

Gin His His Tyr Glu Ser Pro Leu Phe 1 <210> 196 &lt;211> 5 <212> PRT <213> Artificial sequence 201028165 &lt;220&gt; <223> Synthetic peptide sequence &lt;400&gt; 196 6ly Tyr Val Leu Asn 1 5 &lt;210> 197 &lt;211&gt; 17 <212> PRT &lt;213> artificial sequence • in &lt;220&gt;<223&gt; Synthetic surface sequence &lt;400&gt;

Leu lie Asn Pro Tyr Asn 6ly Gly Thr Asp Tyr Asn Pro Gin Phe Gin 15 10 15

Asp

&lt;210> 198 &lt;211> 17 <212> PRT &lt; 213 > artificial sequence &lt;220&gt;&lt;223&gt; artificial synthetic peptide sequence &lt;400&gt;

Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe Gin 15 10 15

Gly 167 201028165 &lt;210&gt; 199 &lt;211&gt; 17 &lt;212&gt; PRT &lt; 213 &gt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt;&gt;223 synthetic peptide sequence &lt;400> 199

Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Gin Phe Gin 15 10 15

Asp &lt;210> 200 &lt;211> 11 <212> PRT &lt;213>Artificial sequence &lt;220> &lt;223>Synthetic peptide sequence &lt;400> 200

Gin Thr Ser Glu Asp lie Tyr Arg Phe Val Ala 1 5 10 &lt;210&gt; 201 &lt;211&gt; 11 &lt;212&gt; PRT &lt;213>Artificial Sequence &lt;220&gt;&lt;223&gt;&gt;223 Synthetic peptide sequence&lt;400&gt; 201

Gin Thr Ser Glu Asp lie Tyr Ser Phe Val Ala 168 201028165 1 5 10

&lt;210> 202 &lt;211> 11 &lt;212> PRT &lt;213>Artificial sequence &lt;220&gt; <223>Synthetic peptide sequence <400> 202

Gin Ala Ser Glu Asp lie Tyr Ser Phe Val Ala 1 5 10 &lt;210> 203 &lt;211&gt; 11 <212> PRT &lt; 213 > Artificial Sequence &lt;220&gt; s <223> Artificial Synthetic Sequence ' &lt;400&gt; 203

Gin Ala Ser Glu Asp lie Tyr Ser Phe Leu Ala ^ 1 5 10 &lt;210&gt; 204 <211> 121 <212> PRT &lt;213>Artificial Sequence &lt;220> &lt;223> Synthetic peptide sequence &lt;400&gt;; 204

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15 169 201028165

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 Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Asp Arg Val Thr lie 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

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120

&lt;210&gt; 205 &lt;211&gt; 121 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;<223&gt; Synthetic peptide sequence &lt;400&gt;

Gin Val 6ln Leu Val 6ln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 170 201028165 20 25 30

Ala Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Asp Arg Val Thr lie 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

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 &lt;210> 206 &lt;211> 121 &lt;212> PRT &lt;213>Artificial Sequence &lt;220> &lt;223>Artificial Synthetic Sequence &lt;400&gt; 206

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 171 201028165

Val Leu Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Asp Arg Val Thr lie 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

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120

&lt;210> 207 <211> 121 &lt;212> PRT <213> artificial sequence &lt;220> &lt;223>synthetic peptide sequence &lt;400> 207

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 172 201028165 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Asp Arg Val Thr lie 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

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 208 &lt;211&gt; 121 <212> PRT &lt;213>Artificial Sequence <22〇> &lt;223>Artificial Synthetic Peptide Sequence &lt;400&gt; 208

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 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 Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45 173 201028165

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Asp Arg Val Thr lie 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

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 &lt;210&gt; 209 &lt;211&gt; 121 &lt;212&gt; PRT <213>Artificial Sequence &lt;220> &lt;223>Synthetic Peptide Sequence &lt;400> 209

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 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 Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 174 201028165 50 55 60

Gin Asp Arg Val Thr lie 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

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 &lt;210&gt; 210 &lt;211&gt; 121 <212> PRT &lt;213>Artificial sequence &lt;220&gt;<223&gt; Synthetic peptide sequence &lt;400&gt;

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60 175 201028165

Gin Asp Arg Val Thr lie Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser 6lu Asp Thr Ala Vai 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

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 &lt;210&gt; 211 &lt;211&gt; 121 &lt;212&gt; PRT <213>Artificial Sequence &lt;220&gt;&lt;223>Artificial Synthesis Peptide Sequence &lt;400&gt;

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Gys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30

Ala Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Asp Arg Val Thr lie Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 176 201028165 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

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 &lt;210>212 &lt;211&gt; 121 <212> PRT <213>Artificial sequence &lt;220&gt; <223> Synthetic peptide sequence &lt;400> 212 6ln Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Gly Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 177 201028165

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

Gin &lt;212&gt;211&gt ; 213

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 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 Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Gly Arg Val Thr lie 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 178 201028165 85 90 95

Ala Arg Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120

<210> 214 &lt;211&gt; 121 <212> PRT <213> artificial sequence &lt;220> <223> artificial synthetic sequence &lt;400&gt; 214

Gin Val 6ln Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Gly Arg Val Thr lie 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 95 179 201028165

Ala Arg Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu 6lu Thr Trp Gly 100 105 110

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 &lt;210&gt; 215 <211> 121 &lt;212> PRT &lt;213>Artificial sequence &lt;220&gt;<223&gt; Synthetic peptide sequence &lt;400&gt;

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 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 Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Gly Arg Val Thr lie 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 180 201028165 100 105 110

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 216 &lt;211&gt; 121 &lt;212> PRT, &lt;213>Artificial Sequence &lt;220> &lt;223>Synthetic Peptide Sequence &lt;400&gt;

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu I le Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Gin Phe 50 55 60

Gin Asp Arg Val Thr lie 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 100 105 110 181 201028165

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 217 &lt;211> 121 <212> PRT &lt;213>Artificial Sequence &lt;220> &lt;223>Artificial Synthetic Sequence &lt;400&gt; 217

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Gin Phe 50 55 60

Gin Asp Arg Val Thr lie 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

Gin Gly Thr Leu Val Thr Val Ser Ser 182 201028165 115 120

&lt;210> 218 &lt;211&gt; 107 &lt;212&gt; PRT <213> artificial sequence • &lt;220> <223> artificial synthetic peptide sequence &lt;400&gt;

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

Asp Arg Val Thr lie Thr Cys Gin Thr Ser Glu Asp Me Tyr Arg Phe 20 25 30

Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asn Ala Gin Thr Glu Ala Gin Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Asp Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105

&lt;210&gt; 219 <211> 107 &lt;212> PRT 183 201028165 <&gt;13&gt; Artificial sequence <220> &lt;223> Synthetic peptide sequence &lt;400&gt; 219

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 t5

Asp Arg Val Thr lie Thr Cys Gin Thr Ser Glu Asp lie Tyr Ser Phe 20 25 30

Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asn Ala Gin Thr Glu Ala Gin Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu 6ln Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Asp Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105 &lt;210> 220 &lt;211> 107 &lt;212> PRT &lt; 213 &gt; 213 &gt; artificial sequence &lt; 220 &lt; 223 &gt; 223 &gt; synthetic peptide sequence &lt;400&gt;; 220 184 201028165

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Gin Ala Ser Glu Asp lie Tyr Ser Phe 20 25 30

Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asn Ala Gin Thr Glu Ala Gin Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Asp Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105

<210> 221 <211> 107 <212> PRT &lt;213>Artificial sequence &lt;220&gt;&lt;223>Synthetic peptide sequence &lt;400&gt; 221

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Gin Ala Ser Glu Asp lie Tyr Ser Phe 185 201028165 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asn Ala Gin Thr Glu Ala Gin Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Asp Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105 &lt;210> 222 &lt;211&gt; 445 &lt;212> PRT <213> Artificial Sequence

&lt;220〉 &lt;223>synthetic peptide sequence &lt;400> 222

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 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 Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45 186 201028165

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Asp Arg Val Thr lie 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

Gin 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 210 215 220 187 201028165

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 lie Ser Arg Thr 245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser 6ln Glu Asp Pro Glu 260 265 270 .

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 ©3

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Gin Glu Glu Met Thr Lys Asn 6ln Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 188 201028165

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415

Trp Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445 &lt;210> 223 &lt;211> 445 &lt;212&gt; PRT &lt;213>Artificial Sequence &lt;220&gt;<223&gt; Synthetic Peptide Sequence &lt;;400> 223

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 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 Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Asp Arg Val Thr lie 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 189 201028165 85 90 95

Ala Arg Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110

Gin 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 lie Ser Arg Thr 245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu 190 201028165 260 265 270

Val Gin Phe Asn Trp Tyr Vai Asp Gly Vai Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu 6ln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 191 201028165 435 440 445 &lt;210> 224 &lt;211> 445 &lt;212&gt; PRT &lt;213>Artificial Sequence &lt;220&gt; <223> Synthetic peptide Sequence &lt;400&gt; 224

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 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 Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Asp Arg Val Thr lie 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

Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 192 201028165

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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 lie Ser Arg Thr 245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu 260 265 270

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 193 201028165

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Vai Glu Trp Glu Ser Asn 370 375 380

Gly 6ln 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 Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445 &lt;210&gt; 225 <211> 445 &lt;212> PRT &lt;213>Artificial Sequence &lt;220&gt; <223> Synthetic peptide sequence 194 201028165 &lt;400&gt; 225

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Asp Arg Val Thr lie 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

Gin 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 195 201028165 165 170 175

Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 Gin Glu Asp Pro Glu 260 265 270

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 196 201028165 340 345 350

Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445 &lt;210&gt; 226 <211> 445 &lt;212&gt; PRT &lt;213>Artificial Sequence &lt;220> <223> Artificial Synthetic Sequence <400> ; 226

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 197 201028165

Ala Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Asp Arg Val Thr lie 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

Gin 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His 195 200 205 198 201028165

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 lie Ser Arg Thr 245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu 260 265 270

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380 199 201028165 61y Gin Pro 6lu 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 Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445

&lt;210> 227 <211> 445 <212> PRT <213> artificial sequence &lt;220&gt; <223> artificial synthetic sequence &lt;400&gt; 227

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 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 Gin Ala Pro Gly 6ln Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Asp Arg Val Thr lie Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 200 201028165 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

Gin 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 lie Ser Arg Thr 201 201028165 245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser 6ln Glu Asp Pro Glu 260 265 270

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 202 201028165 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445 <210> 228 - <211> 445 &lt;212> PRT -&lt;213>Artificial Sequence&lt;220&gt;<223&gt; Synthetic peptide sequence Xin <400> 228

Gin Val Gin Leu Val Gin 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 lie Met Asn Trp Val Arg Gin Ala Pro Gly 6ln Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Asp Arg Val Thr lie 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 100 105 110 203 201028165

Gin 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 lie Ser Arg Thr 245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu 260 265 270

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 204 201028165

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His 6ln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445

&lt;210&gt; 229 &lt;211&gt; 445 &lt;212> PRT 205 201028165 <213> Artificial sequence &lt;220> &lt;223> Synthetic peptide sequence &lt;400&gt;

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 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 Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Asp Arg Val Thr lie 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

Gin 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 206 201028165 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 lie Ser Arg Thr 245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu 260 265 270

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Me Glu Lys Thr lie 207 201028165 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445 &lt;210> 230 &lt;211&gt; 445 &lt;212&gt; PRT <213>Artificial Sequence &lt;220&gt;&lt;223> Synthetic peptide sequence &lt;223&gt;;400&gt; 230

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15 208 201028165

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Gly Arg Val Thr lie 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

Gin 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 209 201028165

Pro Ser Ser Asn Phe Gly Thr Gin 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 lie Ser Arg Thr 245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu 260 265 270

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365 210 201028165

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly 6In 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 6ln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445 <210> 231 <211> 445 &lt;212> PRT <213> Artificial Sequence &lt;220&gt; <223> Synthetic peptide sequence &lt;400&gt; 231

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 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 Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 211 201028165 50 55 60

Gin Gly Arg Val Thr lie 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

6ln 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 212 201028165 225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr 245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu 260 265 270

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 213 201028165 405 410 415

Trp Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445

<210> 232 &lt;211> 445 <212> PRT &lt;213>Artificial sequence &lt;220&gt;&lt;223>Synthetic peptide sequence &lt;400> 232

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30

Lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Gly Arg Val Thr lie 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 95 214 201028165

Ala Arg Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110

Gin 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 lie Ser Arg Thr 245 250 255

Pro Glu Val Thr Gys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu 260 265 270 215 201028165

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445 216 201028165 &lt;210&gt; 233 &lt;211> 445 &lt;212> PRT &lt;213>Artificial Sequence &lt;220&gt; <223> Synthetic peptide Sequence &lt;400> 233

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 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 Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Pro Gin Phe 50 55 60

Gin Gly Arg Val Thr lie 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

Gin 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 217 201028165 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 lie Ser Arg Thr 245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu 260 265 270

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 218 201028165 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445 &lt;210> 234 <211> 445 <212> PRT <213> Artificial Sequence &lt;220> &lt;223> Synthetic Peptide Sequence &lt;400&gt ; 234 219 201028165

Gin Val 61n Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Gin Phe 50 55 60

Gin Asp Arg Val Thr lie 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

Gin 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 165 170 175 220 201028165

Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 lie Ser Arg Thr 245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu 260 265 270

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350 221 201028165

Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly 61n 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 Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445 &lt;210> 235 &lt;211&gt; 445 &lt;212> PRT &lt;213>Artificial Sequence &lt;220&gt; <223>Artificial Synthetic Sequence &lt;;400&gt; 235

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 222 201028165 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Gin Phe 50 55 60

Gin Asp Arg Val Thr lie 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 Gys 85 90 95

Ala Arg Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr Trp Gly 100 105 110

Gin 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 223 201028165 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 lie Ser Arg Thr 245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu 260 265 270

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 224 201028165 385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415

Trp Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445

&lt;210&gt; 236 <211> 214 &lt;212> PRT &lt;213>Artificial sequence &lt;220&gt;<223&gt; Synthetic peptide sequence &lt;400> 236

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Gin Thr Ser Glu Asp lie Tyr Arg Phe 20 25 30

Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asn Ala Gin Thr Glu Ala Gin Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 225 201028165

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Asp Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 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 Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 &lt;210> 237 &lt;211&gt; 214 &lt;212> PRT &lt; 213 &gt; 213 &gt; artificial sequence &lt;220 &lt; 223 &gt; 223 &gt; artificially synthesized peptide sequence 226 201028165 &lt;400> 237

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Gin Thr Ser Glu Asp lie Tyr Ser Phe 20 25 30

Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asn Ala Gin Thr Glu Ala Gin Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Asp Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu 6ln Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ata 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 227 201028165 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 6ln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210

&lt;210> 238 &lt;211&gt; 214 &lt;212&gt; PRT <213> artificial sequence &lt;220&gt;&lt;223&gt; artificial synthetic peptide sequence &lt;400> 238

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Gin Ala Ser Glu Asp lie Tyr Ser Phe 20 25 30

Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asn Ala Gin Thr Glu Ala Gin Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 228 201028165

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Asp Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 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 Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 &lt;210&gt; 239 <211> 214 <212> PRT &lt;213>Artificial sequence &lt;220&gt;<223&gt; Synthetic peptide sequence 229 201028165 &lt;400&gt;

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Gin Ala Ser Glu Asp lie Tyr Ser Phe 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asn Ala Gin Thr Glu Ala Gin Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Asp Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 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 Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 230 201028165 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 6lu Lys His Lys Val Tyr 180 185 190

Ala Gys Glu Val Thr His Gin 6ly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210

&lt;210> 240 <211> 445 &lt;212> PRT <213> Artificial sequence &lt;220> <223> Synthetic peptide sequence &lt;400> 240

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Gin Phe 50 55 60

Gin Asp Arg Val Thr lie Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 231 201028165

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

Gin 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 Gys 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 lie Ser Arg Thr 245 250 255 232 201028165

Pro 6lu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu 260 265 270

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 233 201028165

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445 &lt;210> 241 &lt;211&gt; 447 <212> PRT <213> Artificial Sequence &lt;220> <223> Synthetic peptide sequence <400> 241

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Aia Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Gin Phe 50 55 60

Gin Asp Arg Val Thr lie 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

Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 234 201028165 115 120 125

Val Phe Pro Leu Ala Pro Gys 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 lie 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 Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu 6ln Phe Asn Ser Thr Phe Arg Val Val Ser 235 201028165 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn 6ly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 242 &lt;211&gt; 447 <212> PRT <213> Artificial Sequence 236 201028165 &lt;220&gt;&lt;223> Synthetic peptide Sequence &lt;400> 242 6ln Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly 6In Gly Leu Glu Trp Met

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe 50 55 60

Lys Gly Arg Val Thr lie 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

Gin 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 145 150 155 160 237 201028165

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175

Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 lie 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 Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335 238 201028165

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 &lt;210&gt; 243 <211> 447 &lt;212> PRT <213>Artificial Sequence &lt;220> &lt;223> Synthetic peptide sequence &lt;400&gt; 243

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 239 201028165 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe 50 55 60

Lys Gly Arg Val Thr lie 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

Gin 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His 240 201028165 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 lie 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 Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Gys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 241 201028165 370 375 380

Gly Gin 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 Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 244 &lt;211&gt; 447 <212> PRT <213> Artificial Sequence &lt;220&gt;&lt;223> Synthetic peptide sequence &lt;223&gt;;400> 244

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu Ile Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe 50 55 60 242 201028165

Lys Gly Arg Val Thr lie 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

Gin 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 225 230 235 240 243 201028165

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie 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 Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 405 410 415 244 201028165

Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His 61u Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 &lt;210&gt; 245 • &lt;211> 447 <212> PRT &lt;213>Artificial Sequence &lt;220> <223> Artificial Estrogen Sequence &lt;400&gt; 245

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30

Lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe 50 55 60

Lys Gly Arg Val Thr lie 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 245 201028165 100 105 110

Gin 6ly 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

Vat Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 lie 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 Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 246 201028165 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 〈210> 246 247 201028165 &lt;211&gt; 447 &lt;212&gt; PRT <213>Artificial Sequence &lt;220&gt;&lt;223&gt; Peptide sequence &lt;400&gt; 246

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 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 Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe 50 55 60

Lys Gly Arg Val Thr lie 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

Gin 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 130 135 140 248 201028165

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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 lie 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 Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu 6ln Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 249 201028165

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly 6ln Pro Arg Glu Pro 6ln Val Tyr Thr Leu Pro 340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr 6ln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 &lt;210&gt; 247 &lt;211&gt; 447 &lt;212> PRT &lt; 213 &gt; 213 &gt; Artificial Sequence &lt; 220 &gt; 220 &lt; 223 &gt; Synthetic peptide Sequence &lt;400> 247

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 250 201028165 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie lie Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe 50 55 60

Lys Gly Arg Val Thr lie 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

Gin 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 251 201028165 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 lie 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 Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 252 201028165 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 &lt;210> 248 &lt;211&gt; 447 <212> PRT <213> Artificial Sequence &lt;220&gt;&lt;223> Synthetic peptide sequence &lt;400&gt; 248

Gin Val Gin Leu Val Gin Ser Gly Ala Giu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Leu Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45 253 201028165

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe 50 55 60

Lys Gly Arg Val Thr lie 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

Gin 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 210 215 220 254 201028165

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 lie 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 Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335 Vigilant Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 255 201028165

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415

Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His 6lu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445

&lt;210&gt; 249 &lt;211> 447 <212> PRT &lt; 213 > artificial sequence &lt;220&gt; <223> artificial synthetic sequence &lt;400&gt; 249

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly 6ln Gly Leu Glu Trp Met 35 40 45

Gly Leu Me Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Gin Lys Phe 50 55 60

Lys Gly Arg Val Thr lie 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 256 201028165 85 90 95

Ala Arg Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr Trp Gly 100 105 110

Gin 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 lie Ser Arg Thr 245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 257 201028165 260 265 270

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 258 201028165 435 440 445 &lt;210&gt; 250 &lt;211&gt; 447 &lt;212> PRT &lt; 213 > Artificial Sequence &lt; 220 &lt; 223 &gt; Synthetic peptide sequence &lt;400> 250

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Pro Lys Phe 50 55 60

Lys Gly Arg Val Thr lie 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

Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 259 201028165

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Glu Ser Thr Ala 130 135 140

Ala Leu Giy 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 lie 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 Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 260 201028165

Val Leu Thr Val Val His Gin Asp Trp Leu Asn 6ly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 &lt;210&gt; 251 &lt;211> 214 &lt;212&gt; PRT <213>Artificial Sequence&lt;220> <223> Synthetic peptide sequence 261 201028165 &lt;400&gt; 251

Asp Me Gin Met Thr 6ln Ser Pro Ser Ser Leu Ser Ala Ser Val 6ly 15 10 15

Asp Arg Val Thr lie Thr Gys Arg Thr Ser Glu Asn lie Tyr Arg Phe 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 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 lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Glu Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 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 Gin Trp Lys Val Asp Asn Ala Leu 6ln Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 262 201028165 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210

<210> 252 &lt;211&gt; 214 &lt;212> PRT <213> artificial sequence &lt;220&gt;<223&gt; Synthetic peptide sequence &lt;400&gt; 252

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Thr Ser Glu Asn lie Tyr Arg Phe 20 25 30

Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 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 Gin Pro 65 70 75 80 263 201028165

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Glu Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 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 Gin Trp Lys Val Asp Asn Ala Leu 6ln Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 <210> 253 &lt;211> 214 &lt;212&gt; PRT <213>Artificial sequence &lt;220> <223> Synthetic peptide sequence 264 201028165 &lt;400&gt; 253

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Thr Ser Glu Asn lie Tyr Ser Phe 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 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 lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Asp Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 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 Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 265 201028165 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210

<210> 254 <211> 214 &lt;212> PRT &lt;213>Artificial sequence &lt;220&gt;&lt;223>Synthetic peptide sequence &lt;400&gt; 254

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Thr Ser Glu Asn lie Tyr Ser Phe 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 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 lie Ser Ser Leu Gin Pro 65 70 75 80 266 201028165

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Glu Asp Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 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 Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 &lt;210> 255 <211> 447 <212> PRT &lt;213>Artificial sequence &lt;220> <223> Synthetic peptide sequence 267 201028165 &lt;400&gt; 255

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30

Val lie Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Gin Lys Phe 50 55 60

Lys Gly Arg Val Thr lie 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

Gin 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 268 201028165 165 170 175

Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 lie 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 Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 269 201028165 340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445

<210> 256 &lt;211> 214 <212> PRT &lt;213>Artificial sequence &lt;220&gt; <223> Synthetic peptide sequence &lt;400&gt; 256

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Gin Thr Ser Glu Asn lie Tyr Arg Phe 20 25 30 270 201028165

Val Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 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 lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin His His Tyr Asp Ser Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 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 Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin 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 Vai Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 271 201028165

Phe Asn Arg Gly Glu Cys 210 &lt;210&gt; 257 <211> 445 <212> PRT &lt;213>Artificial Sequence &lt;220&gt;&lt;223>Synthetic Peptide Sequence &lt;400&gt;

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 lie Met Asn Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe 50 55 60

Lys Gly Arg Val Thr lie 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

Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 272 201028165 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 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin 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 lie Ser Arg Thr 245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gin Glu Asp Pro Glu 260 265 270

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 273 201028165 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn 6ly Lys 6lu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Gin Glu Glu Met Thr Lys Asn Gin Vai Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Vai Glu Trp Glu Ser Asn 370 375 380

Gly Gin 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 Gin Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr 6ln Lys Ser Leu Ser Leu Ser Pro 435 440 445 &lt;210> 258 <211> 530 &lt;212&gt; PRT &lt;213&gt; Homo sapiens 274 201028165 &lt;400&gt;

Met Met Trp Thr Trp Ala Leu Trp Met Leu Pro Ser Leu Cys Lys Phe 15 10 15

Ser Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn lie Ser Gys 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 Gin Tyr Thr Val Lys Arg Thr Tyr Ala Phe Gly Glu Lys

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 lie Thr lie Pro Asp Asn Tyr Thr lie 85 90 95

Glu Val Glu Ala Glu Asn Gly Asp Gly Val lie 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 lie Lys Arg Met lie Gin lie Glu Trp 130 135 140 lie Lys Pro Glu Leu Ala Pro Val Ser Ser Asp Leu Lys Tyr Thr Leu 145 彳50 155 160

Arg Phe Arg Thr Val Asn Ser Thr Ser Trp Met Glu Val Asn Phe Ala 165 170 175 275 201028165

Lys Asn Arg Lys Asp Lys Asn Gin Thr Tyr Asn Leu Thr Gly Leu Gin 180 185 190

Pro Phe Thr Glu Tyr Val lie Ala Leu Arg Cys Ala Val Lys Glu Ser 195 200 205

Lys Phe Trp Ser Asp Trp Ser Gin 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 lie Trp Tyr Tyr Pro 260 265 270

Glu Ser Asn Thr Asn Leu Thr Glu Thr Met Asn Thr Thr Asn Gin Gin 275 280 285 〇

Leu Glu Leu His Leu Gly Gly Glu Ser Phe Trp Val Ser Met lie Ser 290 295 300

Tyr Asn Ser Leu Gly Lys Ser Pro Val Ala Thr Leu Arg lie Pro Ala 305 310 315 320 lie Gin Glu Lys Ser Phe Gin Cys lie Glu Val Met Gin Ala Gys Val 325 330 335

Ala Glu Asp Gin Leu Val Val Lys Trp Gin Ser Ser Ala Leu Asp Val 340 345 350 276 201028165

Asn Thr Trp Met lie 61u Trp Phe Pro Asp Val Asp Ser Glu Pro Thr 355 360 365

Thr Leu Ser Trp Glu Ser Val Ser Gin Ala Thr Asn Trp Thr lie Gin 370 375 380

Gin Asp Lys Leu Lys Pro Phe Trp Cys Tyr Asn lie Ser Val Tyr Pro 385 390 395 400

Met Leu His Asp Lys Val G!y Glu Pro Tyr Ser lie Gin Ala Tyr Ala 405 410 415

Lys Glu Gly Val Pro Ser Glu Gly Pro Glu Thr Lys Val Glu Asn lie 420 425 430

Gly Val Lys Thr Val Thr lie Thr Trp Lys Glu lie Pro Lys Ser Glu 435 440 445

Arg Lys Gly lie lie Gys Asn Tyr Thr lie Phe Tyr 6ln Ala Glu Gly 450 455 460

Gly Lys Gly Phe Ser Lys Thr Val Asn Ser Ser lie Leu Gin Tyr Gly 465 470 475 480

Leu Glu Ser Leu Lys Arg Lys Thr Ser Tyr Ile Val Gin Val Met Ala 485 490 495

Ser Thr Ser Ala Gly Gly Thr Asn Gly Thr Ser lie Asn Phe Lys Thr 500 505 510

Leu Ser His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His

Asp Leu 530 &lt;210> 259 &lt;211&gt; 517 &lt;212> PRT &lt;213&gt; Mus musculus &lt;400&gt; 259

Met Trp Thr Leu Ala Leu Trp Ala Phe Ser Phe Leu Cys Lys Phe Ser 15 10 15

Leu Ala Val Leu Pro Thr Lys Pro Glu Asn lie 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 lie 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 lie Cys Ser Val Glu Vai Gin Ala Gin Asn Gly 85 90 95

Asp Gly Lys Val Lys Ser Asp lie Thr Tyr Trp His Leu lie Ser lie 100 105 110

Ala Lys Thr Glu Pro Pro lie Leu Ser Val Asn Pro lie Cys Asn 115 120 125 278 201028165

Arg Met Phe 61n lie Gin 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 Gin Val Cys Asn Leu Thr Gly 165 170 175

Leu Gin 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 lie Gin Tyr 245 250 255

Phe Ala Glu Asn Ser Thr Asn Leu Thr Glu lie Asn Asn lie Thr Thr 260 265 270

Gin Gin Tyr Glu Leu Leu Leu Met Ser Gin Ala His Ser Val Ser Val 275 280 285

Thr Ser Phe Asn Ser Leu Gly Lys Ser Gin Glu Thr lie Leu Arg lie 290 295 300 279 201028165

Pro Asp Val His Glu Lys Thr Phe Gin Tyr lie Lys Ser Met Gin Ala 305 310 315 320

Tyr lie Ala Glu Pro Leu Leu Val Val Asn Trp Gin Ser Ser lie Pro 325 330 335

Ala Val Asp Thr Trp lie Val Glu Trp Leu Pro Glu Ala Ala Met Ser 340 345 350

Lys Phe Pro Ala Leu Ser Trp Glu Ser Val Ser Gin Val Thr Asn Trp 355 360 365

Thr lie Glu Gin Asp Lys Leu Lys Pro Phe Thr Gys Tyr Asn lie Ser 370 375 380

Val Tyr Pro Val Leu Gly His Arg Val Gly Glu Pro Tyr Ser lie Gin 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 Me Gly Leu Arg Thr Ala Thr lie Thr Trp Lys Glu lie Pro 420 425 430

Lys Ser Ala Arg Asn Gly Phe lie Asn Asn Tyr Thr Val Phe Tyr Gin 435 440 445

Ala Glu Gly Gly Lys Glu Leu Ser Lys Thr Val Asn Ser His Ala Leu 450 455 460

Gin Cys Asp Leu Glu Ser Leu Thr Arg Arg Thr Ser Tyr Thr Val Trp 465 470 475 480 280 201028165

Val Met Ala Ser Thr Arg Ala Gly Gly Thr Asn Gly Val Arg lie Asn 485 490 495

Phe Lys Thr Leu Ser His His His His His His His His Glu Lys Leu lie 500 505 510

Ser Glu Glu Asp Leu 515

&lt;210&gt; 260 &lt;211> 531 &lt;212> PRT <213> artificial sequence &lt;220> &lt;223>synthetic peptide sequence &lt;400&gt; 260

Met Met Trp Thr Trp Ala Leu Trp Met Leu Pro Ser Leu Cys Lys Phe 15 10 15

Ser Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn lie 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 Gin 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 lie Thr lie Pro Asp Asn Tyr Thr lie 281 201028165 85 90 95

Glu Val Glu Ala Glu Asn Gly Asp Gly Val lie Lys Ser His Met Thr 100 105 110

Tyr Trp Arg Leu Glu Asn lie Ala Lys Thr Glu Pro Pro Lys lie Phe 115 120 125

Arg Val Lys Pro Val Leu Gly lie Lys Arg Met lie Gin lie Glu Trp 130 135 140 lie 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 Gin Thr Tyr Asn Leu Thr Gly Leu Gin 180 185 190

Pro Phe Thr Glu Tyr Val lie Ala Leu Arg Cys Ala Val Lys Glu Ser 195 200 205

Lys Phe Trp Ser Asp Trp Ser Gin Glu Lys Met Gly Met Thr Glu Glu 210 215 220

Glu Ala Pro His Val Leu Asp Leu Trp Arg lie 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 lie Gin Tyr Phe Ala 282 201028165 260 265 270

Glu Asn Ser Thr Asn Leu Thr Glu lie Asn Asn lie Thr Thr Gin Gin 275 280 285

Tyr Glu Leu Leu Leu Met Ser Gin Ala His Ser Val Ser Val Thr Ser 290 295 300

Phe Asn Ser Leu Gly Lys Ser 6ln Glu Thr lie Leu Arg lie Pro Asp 305 310 315 320

Val His Glu Lys Thr Phe Gin Tyr lie Lys Ser Met Gin Ala Tyr lie 325 330 335

Ala Glu Pro Leu Leu Val Val Asn Trp Gin Ser Ser lie Pro Ala Val 340 345 350

Asp Thr Trp lie Val Glu Trp Leu Pro Glu Ala Ala Met Ser Lys Phe 355 360 365

Pro Ala Leu Ser Trp Glu Ser Val Ser Gin Val Thr Asn Trp Thr lie 370 375 380

Glu Gin Asp Lys Leu Lys Pro Phe Thr Cys Tyr Asn lie Ser Val Tyr 385 390 395 400

Pro Val Leu Gly His Arg Val Gly Glu Pro Tyr Ser lie Gin Ala Tyr 405 410 415

Ala Lys Glu Gly Thr Pro Leu Lys Gly Pro Glu Thr Arg Val Glu Asn 420 425 430 lie Gly Leu Arg Thr Ala Thr lie Thr Trp Lys Glu lie Pro Lys Ser 283 201028165 435 440 445

Ala Arg Asn Gly Phe lie Asn Asn Tyr Thr Val Phe Tyr Gin Ala Glu 450 455 460

Gly Gly Lys Glu Leu Ser Lys Thr Val Asn Ser His Ala Leu Gin 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 lie Asn Phe Lys 500 505 510

Thr Leu Ser His His His His His His His His G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G

Glu Asp Leu 530

<210> 261 &lt;211> 516 &lt;212> PRT <213> Artificial sequence &lt;220&gt; <223> Synthetic peptide sequence &lt;400> 261

Met Trp Thr Leu Ala Leu Trp Ala Phe Ser Phe Leu Cys Lys Phe Ser 15 10 15

Leu Ala Val Leu Pro Thr Lys Pro Glu Asn lie Ser Cys Val Phe Tyr 20 25 30 284 201028165

Phe Asp Arg Asn Leu Thr Cys Thr Trp Arg Pro Glu Lys Glu Thr Asn 35 40 45

Asp Thr Ser Tyr lie 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 lie Cys Ser Val Glu Val Gin Ala Gin Asn Gly 85 90 95

Asp Gly Lys Val Lys Ser Asp I le Thr Tyr Trp His Leu lie Ser lie 100 105 110

Ala Lys Thr Glu Pro Pro lie lie Leu Ser Val Asn Pro lie Cys Asn 115 120 125

Arg Met Phe Gin lie 6ln 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 Gin Val Cys Asn Leu Thr Gly 165 170 175

Leu Gin 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 195 200 205 285 201028165

Met Glu Glu Val Pro Cys Gly Leu 6lu 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 lie Trp Tyr 245 250 255

Tyr Pro Glu Ser Asn Thr Asn Leu Thr Glu Thr Met Asn Thr Thr Asn 260 265 270

Gin Gin Leu Glu Leu His Leu Gly Gly Glu Ser Phe Trp Val Ser Met 275 280 285 lie Ser Tyr Asn Ser Leu Gly Lys Ser Pro Val Ala Thr Leu Arg lie 290 295 300

Pro Ala lie Gin Glu Lys Ser Phe Gin Cys lie Glu Val Met Gin Ala 305 310 315 320

Cys Val Ala Glu Asp Gin Leu Val Val Lys Trp Gin Ser Ser Ala Leu 325 330 335

Asp Val Asn Thr Trp Met lie Glu Trp Phe Pro Asp Val Asp Ser Glu 340 345 350

Pro Thr Thr Leu Ser Trp Glu Ser Val Ser Gin Ala Thr Asn Trp Thr 355 360 365 lie Gin Gin Asp Lys Leu Lys Pro Phe Trp Cys Tyr Asn lie Ser Val 370 375 380 286 201028165

Tyr Pro Met Leu His Asp Lys Val Gly Glu Pro Tyr Ser lie Gin 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 lie Gly Val Lys Thr Val Thr lie Thr Trp Lys Glu lie Pro Lys 420 425 430

Ser Glu Arg Lys Gly lie lie Cys Asn Tyr Thr lie Phe Tyr Gin Ala 435 440 445

Glu Gly Gly Lys Gly Phe Ser Lys Thr Val Asn Ser Ser Me Leu Gin 450 455 460

Tyr Gly Leu Glu Ser Leu Lys Arg Lys Thr Ser Tyr lie Val 6ln Val 465 470 475 480

Met Ala Ser Thr Ser Ala Gly Gly Thr Asn Gly Thr Ser lie Asn Phe 485 490 495

Lys Thr Leu Ser His His His His His His His His G G G G G G G G G G G G G G G G G G G G G G

Glu Glu Asp Leu 515 <210> 262 &lt;211> 524 <212> PRT &lt;213>Artificial sequence &lt;220&gt;&lt;223>Synthetic peptide sequence 287 201028165 &lt;400> 262

Met Met Trp Thr Trp Ala Leu Trp Met Leu Pro Ser Leu Cys Lys Phe 15 10 15

Ser Leu Ala Ala Leu Pro Ala Lys Pro Glu Asn lie 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 Gin 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 lie Thr lie Pro Asp Asn Tyr Thr lie 85 90 95

Glu Val Glu Ala Glu Asn Gly Asp Gly Val lie Lys Ser His Met Thr 100 105 110

Tyr Trp Arg Leu Glu Asn lie Ala Lys Thr Glu Pro Pro lie lie Leu 115 120 125

Ser Val Asn Pro lie Cys Asn Arg Met Phe 6ln lie Gin 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 288 201028165 165 170 175

Gin Val Cys Asn Leu Thr Gly Leu Gin 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 lie Gin Tyr Phe Ala Glu Asn Ser Thr Asn Leu Thr 260 265 270

Glu lie Asn Asn lie Thr Thr Gin Gin Tyr Glu Leu Leu Leu Met Ser 275 280 285

Gin Ala His Ser Val Ser Val Thr Ser Phe Asn Ser Leu Gly Lys Ser 290 295 300

Gin Glu Thr lie Leu Arg lie Pro Asp Val His Glu Lys Thr Phe Gin 305 310 315 320

Tyr lie Lys Ser Met Gin Ala Tyr lie Ala Glu Pro Leu Leu Val Val 325 330 335

Asn Trp Gin Ser Ser lie Pro Ala Val Asp Thr Trp lie Val Glu Trp 289 201028165 340 345 350

Leu Pro Glu Ala Ala Met Ser Lys Phe Pro Ala Leu Ser Trp Glu Ser 355 360 365

Val Ser Gin VaI Thr Asn Trp Thr lie Glu Gin Asp Lys Leu Lys Pro 370 375 380

Phe Thr Cys Tyr Asn lie Ser Val Tyr Pro Val Leu Gly His Arg Val 385 390 395 400

Gly Glu Pro Tyr Ser lie Gin Ala Tyr Ala Lys Glu Gly Thr Pro Leu 405 410 415

Lys Gly Pro Glu Thr Arg Val Glu Asn lie Gly Leu Arg Thr Ala Thr 420 425 430 lie Thr Trp Lys Glu lie Pro Lys Ser Ala Arg Asn Gly Phe lie Asn 435 440 445

Asn Tyr Thr Val Phe Tyr Gin Ala Glu Gly Gly Lys Glu Leu Ser Lys 450 455 460

Thr Val Asn Ser His Ala Leu Gin 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 lie Asn Phe Lys Thr Leu Ser His His His His 500 505 510

His His Glu Gin Lys Leu lie Ser Glu Glu Asp Leu 290 201028165 515 520 &lt;210&gt; 263 &lt;211&gt; 524 <212> PRT <213> Artificial Sequence &lt;220&gt;&lt;223> Synthetic peptide sequence &lt; 400> 263

Met Trp Thr Leu Ala Leu Trp Ala Phe Ser Phe Leu Cys Lys Phe Ser

Leu Ala Val Leu Pro Thr Lys Pro Glu Asn lie Ser Gys 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 lie 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 lie Cys Ser Val Glu Val Gin Ala 6ln Asn Gly 85 90 95

Asp Gly Lys Val Lys Ser Asp lie Thr Tyr Trp His Leu lie Ser lie 100 105 110

Ala Lys Thr Glu Pro Pro Lys lie Phe Arg Val Lys Pro Val Leu Gly 115 120 125 291 201028165 lie Lys Arg Met lie Gin lie Glu Trp lie Lys Pro Giu 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

Gin Thr Tyr Asn Leu Thr Gly Leu Gin Pro Phe Thr Glu Tyr Val lie 180 185 190

Ala Leu Arg Cys Ala Val Lys Glu Ser Lys Phe Trp Ser Asp Trp Ser 195 200 205

Gin Glu Lys Met Gly Met Thr Glu Glu Glu Ala Pro His Val Leu Asp 210 215 220

Leu Trp Arg lie 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 lie Gin Tyr Phe Ala Glu Asn Ser Thr Asn Leu Thr 260 265 270

Glu lie Asn Asn lie Thr Thr Gin Gin Tyr Glu Leu Leu Leu Met Ser 275 280 285

Gin Ala His Ser Val Ser Val Thr Ser Phe Asn Ser Leu Gly Lys Ser 290 295 300 292 201028165

Gin Glu Thr lie Leu Arg lie Pro Asp Val His Glu Lys Thr Phe Gin 305 310 315 320

Tyr lie Lys Ser Met Gin Ala Tyr lie Ala Glu Pro Leu Leu Val Val 325 330 335

Asn Trp Gin Ser Ser lie Pro Ala Val Asp Thr Trp lie 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 Gin Val Thr Asn Trp Thr lie Glu 6ln Asp Lys Leu Lys Pro 370 375 380

Phe Thr Cys Tyr Asn lie Ser Val Tyr Pro Val Leu Gly His Arg Val 385 390 395 400

Gly Glu Pro Tyr Ser lie Gin Ala Tyr Ala Lys Glu Gly Thr Pro Leu 405 410 415

Lys Gly Pro Glu Thr Arg Val Glu Asn lie Gly Leu Arg Thr Ala Thr 420 425 430

Ile Thr Trp Lys Glu Ile Pro Lys Ser Ala Arg Asn Gly Phe Me Asn 435 440 445

Asn Tyr Thr Val Phe Tyr Gin Ala Glu Gly Gly Lys Glu Leu Ser Lys 450 455 460

Thr Val Asn Ser His Ala Leu Gin Cys Asp Leu Glu Ser Leu Thr Arg 465 470 475 480 293 201028165

Arg Thr Ser Tyr Thr Val Trp Val Met Ala Ser Thr Arg Ala Gly Gly 485 490 495

Thr Asn Gly Val Arg lie Asn Phe Lys Thr Leu Ser His His His His 500 505 510

His His Glu Gin Lys Leu lie Ser Glu Glu Asp Leu 515 520 &lt;210> 264 <211> 523 &lt;212> PRT <213> Artificial Sequence &lt;220> &lt;223> Synthetic Peptide Sequence &lt;400&gt; 264

Met Trp Thr Leu Ala Leu Trp Ala Phe Ser Phe Leu Cys Lys Phe Ser 15 10 15

Leu Ala Val Leu Pro Thr Lys Pro Glu Asn lie 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 lie 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 lie Cys Ser Val Glu Val Gin Ala Gin Asn Gly 294 201028165 85 90 95

Asp Gly Lys Val Lys Ser Asp lie Thr Tyr Trp His Leu lie Ser lie 100 105 110

Ala Lys Thr Glu Pro Pro Lys lie Phe Arg Val Lys Pro Val Leu Gly 115 120 125 lie Lys Arg Met lie Gin lie Glu Trp lie 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

Gin Thr Tyr Asn Leu Thr Gly Leu Gin Pro Phe Thr Glu Tyr Val lie 180 185 190

Ala Leu Arg Cys Ala Val Lys Glu Ser Lys Phe Trp Ser Asp Trp Ser 195 200 205

Gin 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 lie Trp Tyr Tyr Pro Glu Ser Asn Thr Asn Leu Thr 295 201028165 260 265 270

Glu Thr Met Asn Thr Thr Asn Gin Gin 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 lie Pro Ala lie Gin Glu Lys Ser Phe Gin 305 310 315 320

Cys lie Glu Val Met Gin Ala Cys Val Ala Glu Asp Gin Leu Val Val 325 330 335

Lys Trp Gin Ser Ser Ala Leu Asp Val Asn Thr Trp Met lie 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 Gin Ala Thr Asn Trp Thr lie Gin Gin Asp Lys Leu Lys Pro Phe 370 375 380

Trp Cys Tyr Asn lie Ser Val Tyr Pro Met Leu His Asp Lys Val Gly 385 390 395 400

Glu Pro Tyr Ser Me Gin Ala Tyr Ala Lys Glu Gly Val Pro Ser Glu 405 410 415

Gly Pro Glu Thr Lys Val Glu Asn lie Gly Val Lys Thr Val Thr lie 420 425 430

Thr Trp Lys Glu lie Pro Lys Ser Glu Arg Lys Gly lie lie Cys Asn 296 201028165 435 440 445

Tyr Thr lie Phe Tyr Gin Ala Glu Gly Gly Lys Gly Phe Ser Lys Thr 450 455 460

Val Asn Ser Ser lie Leu Gin Tyr Gly Leu Glu Ser Leu Lys Arg Lys 465 470 475 480

Thr Ser Tyr lie Val Gin Val Met Ala Ser Thr Ser Ala Gly Gly Thr 485 490 495

Asn Gly Thr Ser lie Asn Phe Lys Thr Leu Ser His His His His His 500 505 510

His Glu 61n Lys Leu Me Ser Glu Glu Asp Leu 515 520 <210> 265 &lt;211&gt; 12 &lt;212> PRT <213> Artificial Sequence <220> <223> Artificial Synthetic Peptide Sequence &lt;400&gt;

Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Asp Tyr 1 5 10 &lt;210&gt; 266 &lt;211> 12 <212> PRT <213> Artificial Sequence &lt;220> <223> Synthetic peptide sequence 297 201028165 &lt;400&gt; 266

Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Leu Glu Thr 1 5 10 &lt;210> 267 <211> 12 &lt;212> PRT &lt;213>Artificial sequence <220> &lt;223> Synthetic peptide sequence &lt;400 〉 267

Asp Gly Tyr Asp Asp Gly Pro Tyr Thr Met Glu Thr 1 5 10 <210> 268 &lt;211> 12 <212> PRT &lt;213>Artificial Sequence &lt;220&gt;&lt;223>Artificial Synthesis Peptide Sequence <400> 268

Asp Gly Leu Asp Asp Gly Pro Tyr Thr Met Glu Thr 1 5 10 &lt;210&gt; 269 &lt;211> 12 <212> PRT &lt;213>Artificial Sequence &lt;220> <223> Synthetic peptide sequence &lt;400 〉 269 298 201028165

Asp Gly Leu Asp Asp Gly Pro Tyr Thr Met Glu Ser 1 5 10 <210> 270 <211> 5 <212> PRT <213> Artificial Sequence &lt;220> <223> Synthetic peptide sequence &lt;400> 270

Gly Tyr lie Met Asn 1 5 &lt;210&gt; 271 &lt;211> 17 &lt;212> PRT &lt; 213 &gt; 213 &gt; artificial sequence &lt;220 &lt; 223 &gt; 223 &gt; artificially synthesized peptide sequence &lt;400&gt;

Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Gin Lys Phe Lys 15 10 15

Gly <210> 272 &lt;211> 5 <212> PRT &lt;213>Artificial sequence <220> &lt;223> Synthetic peptide sequence 299 201028165 &lt;400> 272

Gly Tyr Val Met Asn 1 5 &lt;210> 273 &lt;211> 5 &lt;212&gt; PRT <213>Artificial sequence &lt;220> &lt;223>Synthetic peptide sequence

&lt;400&gt; 273

Gly Tyr lie lie Asn 1 5 &lt;210&gt; 274 &lt;211> 5 &lt;212> PRT &lt;213&gt; Artificial sequence <220> &lt;223&gt; Synthetic winning sequence &lt;400&gt;

Gly Tyr lie Leu Asn 1 5 &lt;210&gt; 275 <211> 17 &lt;212> PRT <213>Artificial sequence &lt;220&gt;&lt;223> Synthetic peptide sequence &lt;400&gt; 275 300 201028165

Leu lie Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Gin Lys Phe Lys 15 10 15

Gly &lt;210> 276 &lt;211> 17 <212> PRT <213> artificial sequence &lt;220&gt;&lt;223>synthetic peptide sequence

&lt;400&gt; 276

Leu lie Asn Pro Tyr Asn Gly Gly Thr Ser Tyr Asn Pro Lys Phe Lys 15 10 15

Gly &lt;210> 277 &lt;211&gt; 11 &lt;212> PRT &lt;213>Artificial sequence ◎<220> &lt;223>Synthetic peptide sequence &lt;400&gt; 277

Arg Thr Ser Glu Asn lie Tyr Ser Phe Leu Ala 1 5 10 &lt;210> 278 &lt;211> 9 &lt;212> PRT &lt;213>Artificial Sequence 301 &lt;220> 201028165 <223&gt;400&gt; 278

Gin His His Tyr Glu Ser Pro Leu Thr 1 5 &lt;210&gt; 279 <211> 11 <212> PRT &lt;213>Artificial Sequence &lt;220&gt;

<223> Synthetic peptide sequence &lt;400&gt; 279

Arg Thr Ser Glu Asn lie Tyr Arg Phe Leu Ala 1 5 10 &lt;210> 280 &lt;211> 11 <212> PRT &lt;213>Artificial Sequence &lt;220〉

&lt;223&gt; Synthetic peptide sequence &lt;400&gt; 280

Arg Thr Ser Glu Asn lie Tyr Arg Phe Val Ala 1 5 10 &lt;210> 281 &lt;211&gt; 9 <212> PRT &lt;213&gt; Artificial sequence <220> &lt;223> Synthetic peptide sequence &lt;400> 281 302 201028165

Gin His His Tyr Asp Ser Pro Leu Thr 1 5 &lt;210&gt; 282 <211> 9 &lt;212> PRT <213> Artificial Sequence &lt;220> <223> Artificial Synthetic Peptide Sequence &lt;400&gt; 282

Gin His His Tyr Glu Asp Pro Leu Thr 1 5 &lt;210&gt; 283 &lt;211> 9 &lt;212> PRT <213>Artificial Sequence &lt;220> &lt;223>Synthetic Peptide Sequence &lt;400> 283

Gin His His Thr Glu Ser Pro Leu Phe 1 5 &lt;210> 284 <211> 5 &lt;212&gt; PRT &lt;213>Artificial sequence &lt;220&gt;<223&gt; Synthetic peptide sequence <400> 284

Gly Tyr Ala Met Asn 303 201028165 1 5 &lt;210〉 &lt;211> &lt;212> &lt;213> 285 11 PRT artificial sequence <220> <223> Synthetic peptide sequence &lt;400&gt;

Arg Ala Ser Glu Asn lie Tyr Ser Phe Leu Ala 1 5 10 &lt;210&gt; 286 <211> &lt;212> &lt;213&gt; 11 PRT artificial sequence &lt;220> &lt;223> Synthetic peptide sequence &lt;400&gt;; 286

Arg Ser Ser Glu Asn lie Tyr Ser Phe Leu Ala 1 5 10 &lt;210> 287 &lt;211> &lt;212> &lt;213&gt; 16 PRT artificial sequence &lt;220> &lt;223> Artificial synthetic sequence&lt;400&gt; 287

His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His His

Claims (1)

201028165 VII. Patent application scope: 1. An antibody variable region or anti-OA body as described in any one of the following (1) to (20). (1) CDR1 containing the sequence identification number: 196, sequence identification number: 197. CDR2, SEQ ID NO: 1 CDR3 heavy chain variable region (Η1Ό; (2) SEQ ID NO: 176 CDR1, SEQ ID NO: 197 CDR2, SEQ ID NO: 11 CDR3 Chain variable region (H19); (3) CDR1 comprising SEQ ID: 196, SEQ ID NO: 197, SEQ ID NO: CDR3 heavy chain variable region (H28, H42); (4) CDR1 comprising SEQ ID NO: 9; SEQ ID NO: 197, SEQ ID NO: CDR3 heavy chain variable region (H30, H44); (5) CDR1 comprising SEQ ID: 176, sequence recognition No.: 197 CDR2, SEQ ID NO: 184 CDR3 heavy chain variable region (H34, H46); (6) SEQ ID NO: 9 CDR1, SEQ ID NO: 198 CDR2, SEQ ID NO: 184 CDR3 heavy chain variable region (H57, H78); (7) SEQ ID NO: 176, SEQ ID NO: 198 CDR2, sequence The CDR3 heavy chain variable region of 184 (H7 and H92); (8) The CDR containing SEQ ID NO: 9 SEQ ID NO: 199 CDR2, SEQ ID NO: 184 CDR3 heavy chain variable Region (H97, H98); (9) SEQ ID NO: 200 CDR1, SEQ ID NO: 170 CDR2, SEQ ID NO: 193 CDR3 light chain variable region (L11); (10) Include sequence recognition No.: CDR1 of 201, SEQ ID NO: 170 CDR2, SEQ ID NO: CDR3 of light chain variable region (L12); (11) CDR containing sequence identification number: 202, sequence identification number: 170 I 201028165 CDR2, sequence identifier: light chain variable region of CDR3 of 193 (L17); (12) CDR1 comprising SEQ ID: 203, SEQ ID NO: 17 CDR2, SEQ ID NO: 193 CDR3 a light chain variable region (L50); (13) an antibody comprising a heavy chain variable region of (3) and a light chain variable region of (11); (14) a heavy chain variable region comprising (4) and 11) an antibody to a light chain variable region; (15) an antibody comprising a heavy chain variable region of (5) and a light chain variable region of (11); (16) a heavy chain variable region comprising (6) And (11) An antibody to a variable region of a chain; (1) an antibody comprising a heavy chain variable region of (7) and a light chain variable region of (11); (18) a heavy chain variable region comprising (8) and (12) The antibody of the light chain variable region; (19) The antibody according to any one of (13) to (18), wherein one or more of the amino acids are substituted, absent, increased, and/or inserted, having (13) to (18) an antibody having the same activity as the antibody of 5; (20) the same epitope as the epitope of the antibody of any one of (13) to (18) Binding antibodies. 2. An antibody variable region or antibody according to any one of the following (1) to (32): (1) a heavy chain variable region having a SEQ ID NO: 2〇4 amino acid sequence (H17) (2) Heavy chain variable region (H19) having the sequence identification number: amino acid sequence of 205; (3) heavy chain variable region having sequence identification number: amino acid sequence of 2〇6 (H28) (4) Heavy chain variable region (H30) having the sequence identification number: amino acid sequence of 2〇7; 201028165 (5) Heavy chain variable region having the amino acid sequence of SEQ ID NO: 208 (H34) (6) The heavy chain variable region (H42) having the amino acid sequence of SEQ ID NO: 209; (7) The heavy chain variable region having the amino acid sequence of SEQ ID NO: 210. (8) a heavy chain variable region (H46) having the amino acid sequence of SEQ ID NO: 211; (9) a heavy chain variable region (H57) having the amino acid sequence of SEQ ID NO: 212; (10) a heavy chain variable region (H71) having the amino acid sequence of SEQ ID NO: 213; (11) a heavy chain variable region (H78) having the amino acid sequence of SEQ ID NO: 214; ) with sequence identification number: 215 Heavy chain variable region of amino acid sequence ^13⁄4 (H92) * (13) heavy chain variable region (H97) having the amino acid sequence of SEQ ID NO: 216; (14) having sequence identifier: 217 The heavy chain variable region of the amino acid sequence (H98); (15) the light chain variable region (L11) having the amino acid sequence of SEQ ID NO: 218; (16) the amino group having the sequence identifier: 219 Light chain variable region of acid sequence (L12); 3 201028165 (17) Light chain variable region (L17) having sequence identification number: amino acid sequence of 220; (18) having sequence identifier: 221 a light bond variable region of the amino acid sequence (L50); (19) an antibody comprising the heavy chain variable region of (3) and the light chain variable region of (17) (H28L17); comprising the heavy chain of (4) The variable region and the antibody of the light chain variable region of (17) - (H30L17); (21) the heavy chain variable region comprising (5) and the gate 7) Xi 4 gin, the light chain variable region of Ai Antibody (H34L17); (22) an antibody (H42L17) comprising the heavy chain of (6), which can be used to detect the light chain variable region of s 1 ton &amp; and (17); (23) Heavy-chain variable f β broad ± variable &amp; and (17) light chain variable region Antibody (H44L17); (24) Antibody comprising the heavy chain variable p·n of (8) and the light chain variable region of (17) (H46L17); antibody of the antibody variable region of the antibody variable region of the variable region The variable region antibody (25) comprises the heavy chain variable region of (8) and the light chain of (17) (H57L17); (26) the heavy chain variable region comprising (10) and ((7) the light chain (H71L17) (27) a heavy chain variable region comprising (11) and ((7) a light chain (H78L17); (28) a heavy chain variable region comprising (12) and ((7) a light chain (H92L17); 4 The antibody (29) of the light chain variable region of 201028165 comprises the heavy chain variable region of (13) and (18) (H97L50); (30) the heavy chain variable region comprising (14) and (18^ ± ± ^ An antibody (H98L50) of the light chain variable region of the long-term U8); (31) one or more amino acids of the (19) to (30)-any of the antibody are substituted, absent, increased, and And an antibody to be inserted, which has the same activity as the antibody of any one of (19) (3); (32) An antibody which binds to the same epitope as the epitope (epi tope) to which the antibody according to any one of (19) to (30) is bound. 3_ The anti-NR1 〇 antibody according to claim 1 or 2, which is a humanized antibody. 4. An antibody heavy chain, an antibody light chain or an antibody according to any one of the following (1) to (32): (1) a heavy chain (H17) having an amino acid sequence of SEQ ID NO: 222; a heavy chain (H19) having the amino acid sequence of SEQ ID NO: 223; ^ (3) a heavy chain (H28) having the amino acid sequence of SEQ ID NO: 224; (4) having the sequence identifier: 225 The heavy chain of the amino acid sequence (H30); (5) the heavy chain (H34) having the amino acid sequence of SEQ ID NO: 226; (6) the heavy chain having the amino acid sequence of SEQ ID NO: 227 (H42); (7) heavy chain (H44) having the amino acid sequence of SEQ ID NO: 228; (8) heavy chain (H46) having the amino acid sequence of SEQ ID NO: 229; (9) SEQ ID NO: 230 heavy chain of amino acid sequence (H57); (10) heavy chain (H71) having the amino acid sequence of SEQ ID NO: 231; (11) Amino group having SEQ ID NO: 232 The heavy chain of the acid sequence (H78); 5 201028165 (12) the heavy chain (H92) having the amino acid sequence of SEQ ID NO: 233; (13) the heavy chain having the amino acid sequence of SEQ ID NO: 234 ( H97); (14) a heavy chain (H98) having the amino acid sequence of SEQ ID NO: 235; (15) a light chain (L11) having the amino acid sequence of SEQ ID NO: 236; (16) an amine having the sequence number: 237 Light chain of the acid sequence (L12); (17) Light chain (L17) having the amino acid sequence of SEQ ID NO: 238; (18) Light chain having the amino acid sequence of SEQ ID NO: 239 (L50) (19) an antibody comprising the heavy chain of (3) and the light chain of (17) (H28L17); (20) an antibody comprising the heavy chain of (4) and the light chain of (17) (H30L17); An antibody (H34L1 7) comprising a heavy chain of (5) and a light chain of (17); (22) an antibody (H42L17) comprising a heavy chain of (6) and a light chain of (17); (23) comprising ( 7) a heavy chain and (17) a light chain antibody (H44L17); (24) an antibody comprising the heavy chain of (8) and the light chain of (17) (H46L17); (25) comprising the weight of (9) The antibody of the chain and the light chain of (17) (H57L17); (26) the antibody comprising the heavy chain of (10) and the light chain of (17) (H71L17); (27) the heavy chain comprising (11) and (17) a light chain antibody (H78L1 7); (28) an antibody comprising the heavy chain of (12) and the light chain of (17) (H92L17); (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) (19) The antibody according to any one of (19) to (30), wherein one or more of the antibodies described in any one of the above-mentioned antibodies are substituted, absent, increased, and/or inserted. (32) An antibody that binds to the same epitope as the epitope to which the antibody of any one of (19) to (30) is bound. 201028165 5. A pharmaceutical composition comprising the antibody of any one of the claims. 6. The pharmaceutical composition according to claim 5, which is a therapeutic agent for an inflammatory disease. 7