RU2803067C2 - Ligand-binding molecule with regulated ligand-binding activity - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: invention relates to the production of ligand-binding molecules, and can be used in medicine for the treatment of a disease associated with a target tissue. A ligand-binding molecule is proposed, where the ligand is a cytokine or chemokine, and the molecule is a polypeptide containing an antibody VH, an antibody VL and an IgG antibody constant region and having at least one urokinase (uPA), matriptase (MT-SP1) or metalloproteinase cleavage site. The cleavage site is located on the border between the VH of the antibody and the constant region of the antibody or on the border between the VL of the antibody and the constant region of the antibody, and the indicated VH and VL are connected to each other and this binding is eliminated by cleavage of the cleavage site by the protease, and the binding of the ligand by the molecule cleaved by at least one protease cleavage site is attenuated, the biological activity of the ligand is inhibited upon binding to an antibody whose VH and VL are bound to each other, and the ligand is released when the ligand-binding molecule is cleaved at the cleavage site.

EFFECT: obtaining a ligand-binding molecule that selectively activates a ligand in a target tissue.

17 cl, 31 dwg, 13 tbl, 15 ex

Description

Field of technology to which the invention relates

The present invention provides a ligand-binding molecule having at least one cleavage site where the binding of a ligand by a ligand-binding molecule cleaved at the cleavage site is weakened, a method for producing the ligand-binding molecule, and a pharmaceutical composition containing the ligand-binding molecule.

Prerequisites for creating the invention

Antibodies have attracted attention as drugs due to their high stability in plasma and low incidence of adverse reactions. Among them, many IgG-type antibody drugs have been marketed, and a large number of antibody drugs are currently under development (Non-Patent Documents 1 and 2).

To date, anti-CD20 Rituxan, anti-EGFR cetuximab, anti-HER2 Herceptin, etc. have been approved as anti-cancer therapeutic drugs that are antibody drugs. (Non-Patent Document 3). These antibody molecules bind to their antigens expressed on cancer cells and as a result exhibit cytotoxic activity against cancer cells through ADCC, signal inhibition, etc.

It is also known to deliver a physiologically active ligand, such as a cytokine, to solid tumors using an immunocytokine that contains a ligand fused to an antibody molecule that binds to a cancer antigen that is highly expressed on cancer cells. The cytokine delivered to solid cancer by immunocytokine activates the immune system and thereby exhibits antitumor effects. Since cytokines including IL2, IL12 and TNF are highly toxic, the local effect of these cytokines on cancer when delivered locally to cancer by an antibody is expected to enhance their effects while reducing adverse reactions (Non-Patent Documents 4, 5 and 6 ). However, all of these cytokines have not yet been approved as drugs due to problems associated with them, such as: they do not have sufficient effectiveness in clinical settings when administered systemically; their range of therapeutic effects (therapeutic window) is narrow; and they cannot be administered systemically due to severe toxicity.

This is largely because cytokines, including immunocytokines, when administered systemically, affect the entire body and therefore may be toxic when administered systemically, or the cytokines must be administered in very low doses to avoid toxicity. It is also known that the antitumor effect was not changed by the use of an immunocytokine that contained IL2 fused to an antibody that binds to a cancer antigen and an immunocytokine that contained IL2 fused to an antibody that does not bind to a cancer antigen (Non-Patent Document 7).

A method to solve the above problems is to use a molecule containing a cytokine and a cytokine receptor, which are connected by a linker that is cleaved by a protease that is characterized by a high level of expression. The cytokine is inhibited by the cytokine receptor connected to it through a linker, but the cytokine is released from the fusion with the cytokine receptor by cleavage by a protease and thereby acquires an active form. For example, a molecule containing TNF-alpha and TNF-R connected through a linker that is cleaved by uPA is described (Non-Patent Document 8), and a molecule containing IL2 and IL2R connected through a linker that is cleaved by MMP2 (Non-Patent Document 9). However, the cytokines in these molecules are active even before linker cleavage, and linker cleavage increases activity only by about 10-fold. In addition, a molecule containing IL2 linked to an anti-IL2 scFv instead of IL2R through a linker that is cleavable by MMP-2 is described (Non-Patent Document 9).

List of cited documents

[Non-patent documents]

[Non-Patent Document 1] Monoclonal antibody successes in the clinic. Janice M. Reichert, Clark J. Rosensweig, Laura B. Faden and Matthew C. Dewitz, Nat. Biotechnol. 23, 2005, cc. 1073-1078.

[Non-patent document 2] The therapeutic antibodies market to 2008. Pavlou A.K., Belsey M.J., Eur. J. Pharm. Biopharm. 59 (3), 2005, cc. 389-396.

[Non-Patent Document 3] Monoclonal antibodies: versatile platforms for cancer immunotherapy. Weiner L.M., Surana R., Wang S., Nat. Rev. Immunol. 10 (5), 2010, cc. 317-327.

[Non-Patent Document 4] Cyclophosphamide and tucotuzumab (huKS-IL2) following first-line chemotherapy in responding patients with extensive-disease small-cell lung cancer. Gladkov O., Ramlau R., Serwatowski P., Milanowski J., Tomeczko J., Komarnitsky P.V., Kramer D., Krzakowski M.J. Anticancer Drugs. 26(10), November 2015, p. 1061-1068.

[Non-Patent Document 5] Defining the Pharmacodynamic Profile and Therapeutic Index of NHS-IL12 Immunocytokine in Dogs with Malignant Melanoma. Paoloni M., Mazcko C., Selting K., Lana S., Barber L., Phillips J., Skorupski K., Vail D., Wilson H., Biller V., Avery A., Kiupel M., LeBlanc A. , Bernhardt A., Brunkhorst V., Tighe R., Khanna C. PLoS One. 10(6), June 19, 2015, e0129954.

[Non-Patent Document 6] Isolated limb perfusion with the tumor-targeting human monoclonal antibody-cytokine fusion protein L19-TNF plus melphalan and mild hyperthermia in patients with locally advanced extremity melanoma. Papadia F., Basso V., Patuzzo R., Maurichi A., Di Florio A., Zardi L., Ventura E., Gonzalez-Iglesias R., Lovato V., Giovannoni L., Tasciotti A., Neri D. , Santinami M., Menssen H.D., De Cian F. J Surg Oncol. 107(2), February 2013, cc. 173-179.

[Non-Patent Document 7] Antigen specificity can be irrelevant to immunocytokine efficacy and biodistribution. Tzeng A., Kwan B.H., Opel C.F., Navaratna T., Wittrup K.D. Proc Natl Acad Sci USA. 112 (11), March 17, 2015, cc. 3320-3325.

[Non-Patent Document 8] Cancer Immunol Immunother. 55(12), December 2006, cc. 1590-1600. Epub April 25, 2006 Target-selective activation of a TNF prodrug by urokinase-type plasminogen activator (uPA) mediated proteolytic processing at the cell surface. Gerspach J.L., Nemeth J., Munkel S., Wajant H., Pfizenmaier K.

[Non-Patent Document 9] Immunology. 133(2), June 2011, cc. 206-220. doi: 10.1111/j.1365-2567.2011.03428.x. Epub March 23, 2011 Development of an attenuated interleukin-2 fusion protein that can be activated by tumor-expressed proteases. Puskas J L., Skrombolas D., Sedlacek A., Lord E., Sullivan M., Frelinger J.

Summary of the invention

The problem underlying the invention

The present invention has been made taking into account the above circumstances. The present invention is based on the object of providing a ligand-binding molecule that activates a ligand, such as a cytokine or chemokine, selectively in a target tissue, a pharmaceutical composition containing the ligand-binding molecule, and methods for preparing the pharmaceutical composition and active ingredient.

The solution of the problem

In making the invention, careful research was carried out to solve the problem and then a ligand-binding molecule was developed, the ligand-binding activity of which is weakened by cleavage of the cleavage site. In making the invention, it has also been found that a ligand binding molecule or a pharmaceutical composition containing a ligand binding molecule can be used to treat a disease using a ligand, and it has also been found that: a ligand binding molecule or a pharmaceutical composition can be used to treat a disease by administering a ligand binding molecule; the ligand-binding molecule can be used to prepare a drug intended to treat a disease. During the creation, a method for producing a ligand-binding molecule was also developed, which represents another object of the present invention.

The present invention is based on these data and provides specific examples of embodiments of the invention, which are described below.

(1) A ligand-binding molecule, which is a molecule having the ability to bind to a ligand, where the molecule is a polypeptide having at least one cleavage site, and the binding of the ligand by the molecule cleaved at at least one cleavage site is weakened.

(2) The ligand-binding molecule according to (1), wherein the ligand is released from the ligand-binding molecule cleaved at the cleavage site.

(3) The ligand-binding molecule of claim (1) or claim (2), wherein the cleavage site comprises a protease-cleavable sequence.

(4) The ligand-binding molecule according to (3), wherein the protease is a target tissue-specific protease.

(5) The ligand-binding molecule as set forth in (4), wherein the target tissue is a cancer tissue and the target tissue-specific protease is a cancer tissue-specific protease.

(6) The ligand-binding molecule according to claim (4), wherein the target tissue is an inflammatory tissue, and the target tissue-specific protease is an inflammatory tissue-specific protease.

(7) Ligand-binding molecule according to one of paragraphs. (3)-(6), where the protease is at least one protease selected from matriptase, urokinase (uPA) and metalloproteinase.

(8) The ligand-binding molecule according to claim (3), wherein the protease-cleavable sequence is a sequence selected from the sequences shown in SEQ ID NO: 3, 34, 66, 70, 71, 72, 73, 35, 75 , 76 and 345.

(9) Ligand-binding molecule according to one of paragraphs. (3)-(8), wherein the first flexible linker is further attached to one end of the protease cleavable sequence.

(10) The ligand-binding molecule according to claim (9), wherein the second flexible linker is further attached to the other end of the protease-cleavable sequence.

(11) The ligand-binding molecule according to claim (9), wherein the first flexible linker is a flexible linker consisting of a glycine-serine polymer.

(12) The ligand-binding molecule according to claim (10), wherein the second flexible linker is a flexible linker consisting of a glycine-serine polymer.

(13) Ligand-binding molecule according to one of paragraphs. (1)-(12), wherein the ligand binding molecule comprises an antibody VH, an antibody VL, and an antibody constant region.

(14) The ligand-binding molecule according to claim (13), wherein the cleavage site or protease-cleavable sequence and the first flexible linker or protease-cleavable sequence and the first flexible linker and the second flexible linker are located in a constant region of the antibody.

(15) The ligand-binding molecule according to claim (14), wherein the cleavage site or the protease-cleavable sequence or the protease-cleavable sequence and the first flexible linker or the protease-cleavable sequence and the first flexible linker and the second flexible linker are embedded in any a position in the sequence from amino acid position 118 (EU numbering) of the antibody heavy chain constant region to amino acid position 140 (EU numbering) of the antibody heavy chain constant region.

(16) The ligand-binding molecule according to claim (14), wherein the cleavage site or the protease-cleavable sequence or the protease-cleavable sequence and the first flexible linker or the protease-cleavable sequence and the first flexible linker and the second flexible linker are embedded in any a position in the sequence from amino acid position 108 (EU numbering) (Cabot numbering position 108) of the antibody light chain constant region to amino acid position 131 (EU numbering) (Cabot numbering position 131) of the antibody light chain constant region.

(17) The ligand-binding molecule according to claim (13), wherein the cleavage site or the protease-cleavable sequence or the protease-cleavable sequence and the first flexible linker or the protease-cleavable sequence and the first flexible linker and the second flexible linker are located in VH antibodies or VL antibodies.

(18) The ligand-binding molecule according to claim (17), wherein the cleavage site or the protease-cleavable sequence or the protease-cleavable sequence and the first flexible linker or the protease-cleavable sequence and the first flexible linker and the second flexible linker are embedded in any a sequence position selected from the group consisting of a sequence extending from amino acid position 7 (Cabot numbering) to amino acid position 16 (Cabot numbering), a sequence extending from amino acid position 40 (Cabot numbering) to amino acid position 47 (Cabot numbering Cabot numbering), sequence extending from amino acid position 55 (Cabot numbering) to amino acid position 69 (Cabot numbering), sequence extending from amino acid position 73 (Cabot numbering) to amino acid position 79 (Cabot numbering), sequence extending from amino acid position 83 (Cabot numbering) to amino acid position 89 (Cabot numbering), sequence extending from amino acid position 95 (Cabot numbering) to amino acid position 99 (Cabot numbering), and sequence extending from amino acid position 101 (Cabot numbering) to amino acid position 113 (Cabot numbering) in the VH of the antibody.

(19) The ligand-binding molecule according to claim (17), wherein the cleavage site or the protease-cleavable sequence or the protease-cleavable sequence and the first flexible linker or the protease-cleavable sequence and the first flexible linker and the second flexible linker are embedded in any a sequence position selected from the group consisting of a sequence extending from amino acid position 7 (Cabot numbering) to amino acid position 19 (Cabot numbering), a sequence extending from amino acid position 39 (Cabot numbering) to amino acid position 46 (Cabot numbering Cabot numbering), a sequence extending from amino acid position 49 (Cabot numbering) to amino acid position 62 (Cabot numbering), and a sequence extending from amino acid position 96 (Cabot numbering) to amino acid position 107 (Cabot numbering), in VL antibodies.

(20) The ligand-binding molecule according to claim (13), wherein the cleavage site or the protease-cleavable sequence or the protease-cleavable sequence and the first flexible linker or the protease-cleavable sequence and the first flexible linker and the second flexible linker are located near the interface between the antibody constant region and the antibody VH and/or between the antibody constant region and the antibody VL.

(21) The ligand-binding molecule according to claim (20), wherein the cleavage site or the protease-cleavable sequence or the protease-cleavable sequence and the first flexible linker or the protease-cleavable sequence and the first flexible linker and the second flexible linker are embedded in any position in the sequence from amino acid position 109 (Cabot numbering) of the antibody VH to amino acid position 122 (EU numbering) of the antibody heavy chain constant region.

(22) The ligand-binding molecule according to claim (20), wherein the cleavage site or the protease-cleavable sequence or the protease-cleavable sequence and the first flexible linker or the protease-cleavable sequence and the first flexible linker and the second flexible linker are embedded in any position in the sequence from amino acid position 104 (Cabot numbering) of the VL antibody to amino acid position 113 (EU numbering) (Cabot numbering position 113) of the antibody light chain constant region.

(23) Ligand-binding molecule according to one of paragraphs. (13)-(22), wherein the VL antibody and the VH antibody in the ligand binding molecule are in association with each other, where the association is broken by cleavage of the cleavage site or is broken by protease cleavage of the sequence cleaved by the protease.

(24) Ligand-binding molecule according to one of paragraphs. (1)-(23), where the ligand is a molecule having biological activity, and the ligand-binding molecule inhibits the biological activity of the ligand by binding to the ligand.

(25) Ligand-binding molecule according to one of paragraphs. (1)-(24), where the ligand is a cytokine or chemokine.

(26) Ligand-binding molecule according to one of paragraphs. (1)-(24), wherein the ligand is a ligand selected from interleukin, interferon, hematopoietic factor, a member of the TNF superfamily, a chemokine, a cell growth factor, and a member of the TGF-β family.

(27) Ligand-binding molecule according to one of paragraphs. (1)-(24), where the ligand is CXCL10, IL12, PD1 or IL6R.

(28) The ligand binding molecule according to claim (27), wherein the ligand is CXCL10, and the ligand binding molecule comprises a VH antibody and a VL antibody, wherein the ligand binding molecule has:

(a) VH, which contains H-CDR1 presented in SEQ ID NO: 374, H-CDR2 presented in SEQ ID NO: 375, and H-CDR3 presented in SEQ ID NO: 376, and antibody VL, which contains L-CDR1, presented in SEQ ID NO: 377, L-CDR2, presented in SEQ ID NO: 378, and L-CDR3, presented in SEQ ID NO: 379;

(b) a VH of an antibody that contains H-CDR1 shown in SEQ ID NO: 380, an H-CDR2 shown in SEQ ID NO: 381, and an H-CDR3 shown in SEQ ID NO: 382, and a VL of an antibody that contains L-CDR1 presented in SEQ ID NO: 383, L-CDR2 presented in SEQ ID NO: 384, and L-CDR3 presented in SEQ ID NO: 385;

(c) VH antibodies and VL antibodies that compete with the VH antibodies and VL antibodies described in subparagraph (a) or (b); or

(d) VH antibodies and VL antibodies that bind to the same epitope as the VH antibodies and VL antibodies described in subparagraph (a) or (b).

(29) The ligand-binding molecule according to claim (28), wherein the ligand-binding molecule is an antibody that contains an antibody heavy chain selected from the sequences set forth in SEQ ID NO: 4-14, 23-27, 33, 59, 60, 356 and 367, or an antibody light chain selected from the sequences presented in SEQ ID NO: 15-22.

(30) The ligand binding molecule according to claim (27), wherein the ligand is IL12, and the ligand binding molecule comprises a VH antibody and a VL antibody, wherein the ligand binding molecule has:

(a) a VH of an antibody that contains H-CDR1 shown in SEQ ID NO: 386, H-CDR2 shown in SEQ ID NO: 387, and H-CDR3 shown in SEQ ID NO: 388, and a VL of an antibody that contains L-CDR1 presented in SEQ ID NO: 389, L-CDR2 presented in SEQ ID NO: 390, and L-CDR3 presented in SEQ ID NO: 391;

(b) VH antibodies and VL antibodies that compete with the VH antibodies and VL antibodies described in subparagraph (a); or

(c) VH antibodies and VL antibodies that bind to the same epitope as the VH antibodies and VL antibodies described in subparagraph (a).

(31) The ligand-binding molecule according to claim (30), wherein the ligand-binding molecule is an antibody comprising an antibody heavy chain as set forth in SEQ ID NO: 146.

(32) The ligand binding molecule according to claim (27), wherein the ligand is PD1, and the ligand binding molecule comprises a VH antibody and a VL antibody, wherein the ligand binding molecule has:

(a) a VH of an antibody that contains H-CDR1 shown in SEQ ID NO: 392, H-CDR2 shown in SEQ ID NO: 393, and H-CDR3 shown in SEQ ID NO: 394, and a VL of an antibody that contains L-CDR1 presented in SEQ ID NO: 395, L-CDR2 presented in SEQ ID NO: 396, and L-CDR3 presented in SEQ ID NO: 397;

(b) VH antibodies and VL antibodies that compete with the VH antibodies and VL antibodies described in subparagraph (a); or

(c) VH antibodies and VL antibodies that bind to the same epitope as the VH antibodies and VL antibodies described in subparagraph (a).

(33) The ligand-binding molecule according to claim (32), wherein the ligand-binding molecule is an antibody that contains an antibody heavy chain selected from the sequences presented in SEQ ID NOs: 304 and 305, or an antibody light chain selected from the sequences presented in SEQ ID NO: 306-315 and 322.

(34) The ligand binding molecule according to claim (27), wherein the ligand is IL-6R (IL-6 receptor), and the ligand binding molecule comprises a VH antibody and a VL antibody, wherein the ligand binding molecule has:

(a) an antibody VH that contains H-CDR1 shown in SEQ ID NO: 398, an H-CDR2 shown in SEQ ID NO: 399, and an H-CDR3 shown in SEQ ID NO: 400, and an antibody VL that contains L-CDR1 presented in SEQ ID NO: 401, L-CDR2 presented in SEQ ID NO: 402, and L-CDR3 presented in SEQ ID NO: 403;

(b) VH antibodies and VL antibodies that compete with the VH antibodies and VL antibodies described in subparagraph (a); or

(c) VH antibodies and VL antibodies that bind to the same epitope as the VH antibodies and VL antibodies described in subparagraph (a).

(35) The ligand-binding molecule according to claim (34), wherein the ligand-binding molecule is an antibody that contains an antibody heavy chain selected from the sequences shown in SEQ ID NOs: 153-156, 157-159 and 404-470, or a light chain antibodies selected from the sequences presented in SEQ ID NO: 471-535.

(36) Ligand-binding molecule according to one of paragraphs. (1)-(35), where the ligand binding molecule is an IgG-type antibody.

(37) Ligand-binding molecule according to one of paragraphs. (1)-(36), where the ligand-binding molecule is bound to the ligand.

(38) Ligand-binding molecule according to one of paragraphs. (1)-(36), where the ligand-binding molecule is fused to the ligand.

(39) The ligand-binding molecule according to claim (38), wherein the ligand-binding molecule fused to a ligand does not further bind to another ligand.

(40) The ligand-binding molecule according to item (38) or item (39), where the ligand-binding molecule is fused to the ligand through a linker.

(41) The ligand-binding molecule according to claim (40), wherein the linker does not contain a protease-cleavable sequence.

(42) Ligand-binding molecule according to one of paragraphs. (38)-(41), where the ligand is CXCL10, and the ligand-binding molecule contains an antibody light chain and an antibody heavy chain, where the antibody light chain or the antibody heavy chain is fused to the ligand.

(43) The ligand-binding molecule according to claim (42), wherein the cleavage site is contained in an antibody light chain or an antibody heavy chain.

(44) The ligand binding molecule of claim (42) or claim (43), wherein the ligand is CXCL10, and an antibody light chain contained in the ligand binding molecule is fused to the ligand, wherein the ligand binding molecule has:

(a) an antibody heavy chain that contains H-CDR1 shown in SEQ ID NO: 374, H-CDR2 shown in SEQ ID NO: 375, and H-CDR3 shown in SEQ ID NO: 376, and an antibody light chain , which contains L-CDR1 presented in SEQ ID NO: 377, L-CDR2 presented in SEQ ID NO: 378, and L-CDR3 presented in SEQ ID NO: 379; or

(b) an antibody heavy chain that contains H-CDR1 shown in SEQ ID NO: 380, H-CDR2 shown in SEQ ID NO: 381, and H-CDR3 shown in SEQ ID NO: 382, and an antibody light chain , which contains L-CDR1 presented in SEQ ID NO: 383, L-CDR2 presented in SEQ ID NO: 384, and L-CDR3 presented in SEQ ID NO: 385.

(45) Ligand-binding molecule according to one of paragraphs. (42)-(44), where the ligand is a variant of CXCL10 presented in SEQ ID NO: 370.

(46) Ligand-binding molecule according to one of paragraphs. (38)-(41), where the ligand is PD1, and the ligand-binding molecule contains an antibody light chain and an antibody heavy chain, where the antibody light chain or the antibody heavy chain is fused to the ligand.

(47) The ligand-binding molecule according to claim (46), wherein the cleavage site is contained in an antibody light chain or an antibody heavy chain.

(48) The ligand binding molecule of claim (46) or (47), wherein the ligand is PD1, the antibody light chain is L-CDR1 shown in SEQ ID NO: 395, L-CDR2 is shown in SEQ ID NO: 396, and L-CDR3, shown in SEQ ID NO: 397, and the heavy chain of the antibody has H-CDR1, shown in SEQ ID NO: 392, H-CDR2, shown in SEQ ID NO: 393, and H-CDR3, shown in SEQ ID NO: 394.

(49) Ligand-binding molecule according to one of paragraphs. (46)-(48), where the ligand is PD1 presented in SEQ ID NO: 320.

(50) Ligand-binding molecule according to one of paragraphs. (46)-(49), wherein the ligand is PD1, and the antibody heavy chain contained in the ligand-binding molecule is fused to the ligand, wherein the set of antibody heavy chain polypeptides fused to PD1 contains a sequence selected from the sequences presented in SEQ ID NO: 323 and 324.

(51) Ligand-binding molecule according to one of paragraphs. (46)-(49), where the ligand is PD1, and the light chain of the antibody contained in the ligand-binding molecule is fused to the ligand, wherein the set of antibody light chain polypeptides fused to PD1 contains a sequence selected from the sequences presented in SEQ ID NO: 325-334.

(52) Ligand-binding molecule according to one of paragraphs. (38)-(41), where the ligand is IL12, and the ligand-binding molecule contains an antibody light chain and an antibody heavy chain, where the antibody light chain or the antibody heavy chain is fused to the ligand.

(53) The ligand-binding molecule according to claim (52), wherein the cleavage site is contained in an antibody light chain or an antibody heavy chain.

(54) The ligand binding molecule according to claim (52) or claim (53), wherein the ligand is IL12, the light chain of the antibody has L-CDR1 represented in SEQ ID NO: 389, L-CDR2 represented in SEQ ID NO: 390, and L-CDR3, shown in SEQ ID NO: 391, and the antibody heavy chain has H-CDR1, shown in SEQ ID NO: 386, H-CDR2, shown in SEQ ID NO: 387, and H-CDR3, shown in in SEQ ID NO: 388.

(55) Ligand-binding molecule according to one of paragraphs. (38)-(41), where the ligand is IL-6R, and the ligand-binding molecule contains an antibody light chain and an antibody heavy chain, where the antibody light chain or the antibody heavy chain is fused to the ligand.

(56) The ligand-binding molecule according to claim (55), wherein the cleavage site is contained in an antibody light chain or an antibody heavy chain.

(57) The ligand binding molecule of claim (55) or claim (56), wherein the ligand is IL-6R, the light chain of the antibody is L-CDR1 as shown in SEQ ID NO: 401, L-CDR2 as shown in SEQ ID NO: 402, and L-CDR3, shown in SEQ ID NO: 403, and the antibody heavy chain has H-CDR1, shown in SEQ ID NO: 398, H-CDR2, shown in SEQ ID NO: 399, and H-CDR3 , presented in SEQ ID NO: 400.

(58) A complex formed by a ligand and a ligand-binding molecule according to one of the paragraphs. (1)-(36) bound to the ligand.

(59) A fusion protein containing a ligand-binding molecule according to one of paragraphs. (1)-(36) fused to a ligand.

(60) The fusion protein of claim (59), wherein the ligand-binding molecule fused to the ligand does not further bind to another ligand.

(61) The fusion protein of claim (59) or claim (60), wherein the ligand-binding molecule is fused to a ligand through a linker.

(62) The fusion protein of claim (61), wherein the linker does not contain a protease cleavable sequence.

(63) The fusion protein of claim (61) or claim (62), wherein the linker is a linker consisting of a glycine-serine polymer.

(64) Fusion protein according to one of paragraphs. (59)-(63), in which the ligand is CXCL10, and the ligand-binding molecule contains an antibody light chain and an antibody heavy chain, wherein the antibody light chain or the antibody heavy chain is fused to the ligand.

(65) The fusion protein of claim (64), wherein the cleavage site is contained in an antibody light chain or an antibody heavy chain of the ligand binding molecule.

(66) The fusion protein of claim (64) or claim (65), wherein the ligand is CXCL10 and an antibody light chain contained in the ligand binding molecule is fused to the ligand, wherein the ligand binding molecule has:

(a) an antibody heavy chain that contains H-CDR1 shown in SEQ ID NO: 374, H-CDR2 shown in SEQ ID NO: 375, and H-CDR3 shown in SEQ ID NO: 376, and an antibody light chain , which contains L-CDR1 presented in SEQ ID NO: 377, L-CDR2 presented in SEQ ID NO: 378, and L-CDR3 presented in SEQ ID NO: 379; or

(b) an antibody heavy chain that contains H-CDR1 shown in SEQ ID NO: 380, H-CDR2 shown in SEQ ID NO: 381, and H-CDR3 shown in SEQ ID NO: 382, and an antibody light chain , which contains L-CDR1 presented in SEQ ID NO: 383, L-CDR2 presented in SEQ ID NO: 384, and L-CDR3 presented in SEQ ID NO: 385.

(67) Fusion protein according to one of paragraphs. (64)-(66), in which the ligand is a variant of CXCL10 presented in SEQ ID NO: 370.

(68) Fusion protein according to one of paragraphs. (59)-(63), in which the ligand is PD1, and the ligand-binding molecule contains an antibody light chain and an antibody heavy chain, wherein the antibody light chain or the antibody heavy chain is fused to a ligand.

(69) The ligand-binding molecule according to claim (68), wherein the cleavage site is in an antibody light chain or an antibody heavy chain.

(70) The fusion protein of claim (68) or claim (69), wherein the ligand is PD1, the light chain of the antibody is L-CDR1, shown in SEQ ID NO: 395, L-CDR2, shown in SEQ ID NO: : 396, and L-CDR3, shown in SEQ ID NO: 397, and the antibody heavy chain has H-CDR1, shown in SEQ ID NO: 392, H-CDR2, shown in SEQ ID NO: 393, and H-CDR3, presented in SEQ ID NO: 394.

(71) Fusion protein according to one of paragraphs. (68)-(70), in which the ligand is PD1 having SEQ ID NO: 320.

(72) Fusion protein according to one of paragraphs. (68)-(71), wherein the ligand is PD1, and the antibody heavy chain contained in the ligand-binding molecule is fused to the ligand, wherein the set of antibody heavy chain polypeptides fused to PD1 contains a sequence selected from the sequences presented in SEQ ID NO: 323 and 324.

(73) Fusion protein according to one of paragraphs. (68)-(71), wherein the ligand is PD1, and an antibody light chain contained in the ligand-binding molecule is fused to the ligand, wherein the set of antibody light chain polypeptides fused to PD1 contains a sequence selected from the sequences presented in SEQ ID NO: 325-334.

(74) Fusion protein according to one of paragraphs. (59)-(63), in which the ligand is IL12, and the ligand-binding molecule contains an antibody light chain and an antibody heavy chain, wherein the antibody light chain or the antibody heavy chain is fused to the ligand.

(75) The fusion protein of claim (74), wherein the cleavage site is contained in an antibody light chain or an antibody heavy chain.

(76) The fusion protein of claim (74) or claim (75), wherein the ligand is IL12, the light chain of the antibody has L-CDR1 shown in SEQ ID NO: 389, L-CDR2 shown in SEQ ID NO: : 390, and L-CDR3, shown in SEQ ID NO: 391, and the antibody heavy chain has H-CDR1, shown in SEQ ID NO: 386, H-CDR2, shown in SEQ ID NO: 387, and H-CDR3, presented in SEQ ID NO: 388.

(77) Fusion protein according to one of paragraphs. (59)-(63), in which the ligand is IL-6R, and the ligand-binding molecule contains an antibody light chain and an antibody heavy chain, wherein the antibody light chain or the antibody heavy chain is fused to the ligand.

(78) The fusion protein of claim (77), wherein the cleavage site is contained in an antibody light chain or an antibody heavy chain.

(79) The fusion protein of claim (77) or claim (78), wherein the ligand is IL-6R, the light chain of the antibody has L-CDR1 shown in SEQ ID NO: 401, L-CDR2 shown in SEQ ID NO: 402, and L-CDR3, shown in SEQ ID NO: 403, and the antibody heavy chain has H-CDR1, shown in SEQ ID NO: 398, H-CDR2, shown in SEQ ID NO: 399, and H- CDR3 shown in SEQ ID NO: 400.

(80) A pharmaceutical composition containing a ligand-binding molecule according to one of paragraphs. (1)-(57).

(81) Pharmaceutical composition containing a ligand-binding molecule according to one of paragraphs. (1)-(37) and ligand.

(82) Pharmaceutical composition containing the complex according to claim (58).

(83) A pharmaceutical composition containing a fusion protein according to one of paragraphs. (59)-(79).

(84) A method for producing a ligand-binding molecule according to one of paragraphs. (1)-(57).

(85) The production method according to claim (84), comprising introducing a protease-cleavable sequence into a molecule that has the ability to bind a ligand.

(86) A method for producing a fusion protein according to one of claims. (59)-(79), involving the fusion of a ligand-binding molecule that has a protease-cleavable sequence with its ligand.

(87) A polynucleotide encoding a ligand-binding molecule according to one of the paragraphs. (1)-(57).

(88) A vector containing the polynucleotide according to claim (87).

(89) A host cell containing the polynucleotide of claim (87) or the vector of claim (88).

(90) A method for producing a ligand-binding molecule according to one of paragraphs. (1) to (57), comprising the step of culturing a host cell according to claim (89).

(91) A polynucleotide encoding a fusion protein according to one of the paragraphs. (59)-(79).

(92) A vector containing the polynucleotide according to claim (91).

(93) A host cell containing the polynucleotide of claim (91) or the vector of claim (92).

(94) A method for producing a fusion protein according to one of claims. (59)-(79), comprising the step of culturing a host cell according to claim (93).

Brief description of drawings

The drawings show:

in fig. 1 is a diagram showing an IgG-type antibody-ligand fusion protein that contains a ligand-linker-VH antibody molecule to a ligand specifically released in a target tissue and one of its activation pathways. The ligand and the antibody to the ligand are fused through a linker;

in fig. 2 is a diagram illustrating an IgG antibody that releases a ligand specifically in a target tissue and one mechanism for its activation. An anti-ligand antibody carrying a protease-cleavable sequence near the interface between VH and CH1 is mixed with the ligand and administered to the individual;

in fig. 3 is a diagram illustrating an IgG antibody that releases a ligand specifically in a target tissue and one of its activation mechanisms. An anti-ligand antibody carrying a protease-cleavable sequence near the boundary between VH and CH1 is administered to the individual. The injected antibody binds to the ligand originally present in the body. The subsequent process is the same as the activation mechanism shown in FIG. 2;

in fig. 4 is a diagram showing the results of the interaction between MabCXCL10 and human CXCL10 obtained using Biacore;

in fig. 5A is a diagram showing models of antibody molecules obtained by inserting a protease-cleavable sequence near the gracin between the variable region and constant region of the MabCXCL10 antibody;

in fig. 5B is a diagram showing the designation of each heavy chain variant produced, the position at which the protease cleavage sequence is inserted, and the inserted amino acid sequence. The insertion site is indicated as [insert];

in fig. 5B is a diagram showing the designation of each light chain variant produced, the position at which the protease cleavable sequence is inserted, and the inserted amino acid sequence. The insertion site is indicated as [insert];

in fig. 6A is a diagram showing the results of an assessment of the interaction of human CXCL10 with each antibody molecule obtained by inserting a protease recognition sequence near the boundary between the variable region and the heavy chain constant region of MabCXCL10, obtained using Biacore;

in fig. 6B is a diagram showing the results of evaluating the interaction of human CXCL10 with each antibody molecule obtained by inserting a protease recognition sequence near the boundary between the variable region and the light chain constant region of MabCXCL10, obtained using Biacore;

in fig. 7-1 is a diagram showing (A) the results of evaluation of the degree of cleavage by migration using SDS-PAGE under reducing conditions and detection using Coomassie Brilliant Blue (CBB) after treatment with protease (MT-SP1) of antibody molecules obtained by embedding protease-cleavable sequence near the boundary between the variable region and constant region of the MabCXCL10 heavy chain. Of the two new bands generated by protease treatment, the band corresponding to about 15 kDa is the band derived from VH, and the band corresponding to about 25-50 kDa is the band derived from the constant region;

in fig. 7-2 is a diagram showing the continuation of the results (A) and (B) of the evaluation of the degree of cleavage by migration using SDS-PAGE under reducing conditions and detection using Coomassie Brilliant Blue (CBB) after treatment with protease (MT-SP1) molecules antibodies obtained by inserting a protease-cleavable sequence into the variable region or constant region of the MabCXCL10 light chain. Protease treatment resulted in the formation of two new bands derived from the cleaved light chain;

in fig. 7-3 - diagram, which is a continuation of (B);

in fig. 8 is a diagram showing the designation of each heavy chain variant obtained by inserting a protease-cleavable sequence and a flexible linker sequence near the boundary between the variable and constant regions of MabCXCL10, the position at which the protease-cleavable sequence and the flexible linker sequence are inserted, and the inserted amino acid sequence. The insertion site is indicated as [insert];

in fig. 9 is a diagram showing the results of evaluating the interaction of human CXCL10 with each antibody molecule obtained by inserting a protease recognition sequence and a flexible linker sequence near the boundary between the variable region and the heavy chain constant region of MabCXCL10, obtained using Biacore;

in fig. 10-A is a graph showing the results of migration cleavage assessment using SDS-PAGE under reducing conditions and detection using SBB after protease (uPA or MT-SP1) treatment of antibody molecules obtained by insertion of a protease recognition sequence and a linker sequence near the boundary between the variable region and constant region of the MabCXCL10 heavy chain. Of the two new bands generated by protease treatment, the band corresponding to about 15 kDa is the band derived from VH, and the band corresponding to about 25-50 kDa is the band derived from the constant region;

in fig. 10B is a diagram that is a continuation of FIG. 10A.

in fig. 11A is a graph showing the results of determining whether CXCL10 is released from the complex of MabCXCL10a and CXCL10 as a result of treatment with protease (MT-SP1);

in fig. 11B is a graph showing the results of determining whether CXCL10 is released from the EEIVHC006a/EEIVL and CXCL10 complex as a result of treatment with protease (MT-SP1);

in fig. 12 is a diagram showing the designation of each of the heavy chains obtained by replacing part of the amino acid sequence near the boundary between the variable and constant regions of MabCXCL10 with a protease recognition sequence and a flexible linker sequence, sites of insertion and amino acid changes, the inserted sequence and the amino acid sequence after the insertion, and changes. The insertion site is indicated as [insert]. Amino acid residues indicated by a strikethrough in the “Insertion Position and Modification Position” column were removed, i.e. replaced by the C-terminal first amino acid of the built-in sequence at the time of insertion of the built-in sequence;

in fig. 13 is a diagram showing the results of assessing the degree of cleavage by migration using SDS-PAGE under reducing conditions and detection using SBB after treatment with a protease (uPA or MT-SP1) of antibody molecules obtained by replacing part of the amino acid sequence near the boundary between variable and constant regions of MabCXCL10 into a protease-cleavable sequence and a flexible linker. Of the two new bands generated by protease treatment, the band corresponding to about 15 kDa is the band derived from VH, and the band corresponding to about 25-50 kDa is the band derived from the constant region;

in fig. 14 - diagram showing data on luciferase activity (luminescence intensity);

in fig. 15 - SDS-PAGE results before and after protease digestion of the CXCL10-anti-CXCL10 fusion protein;

in fig. 16 is a diagram showing data on luciferase activity (luminescence intensity);

in fig. 17 shows results obtained by SDS-PAGE before and after protease digestion of neutralizing antibodies to IL-12 carrying a protease recognition sequence and a flexible linker sequence;

in fig. 18 is a graph showing interferon gamma production data upon addition of IL-12 and antibody. NoAb denotes a sample to which only IL-12 is added without the addition of antibody, and NoIL-12 denotes a sample to which neither IL-12 nor antibody is added;

in fig. 19A is a diagram showing the results of protease digestion of an antibody;

in fig. 19B is a diagram showing the results of protease digestion of an antibody;

in fig. 20A is a diagram showing the results of digestion by various proteases;

in fig. 20B is a diagram showing the results of digestion by various proteases;

in fig. 21 is a diagram showing the results of digestion by various proteases;

in fig. 22A is a diagram showing the results of protease digestion of MRA antibody variants;

in fig. 22B is a diagram showing the results of protease digestion of MRA antibody variants;

in fig. 22B is a diagram showing the results of protease digestion of MRA antibody variants;

in fig. 22D is a diagram showing the results of protease digestion of MRA antibody variants;

in fig. 22D is a diagram showing the results of protease digestion of MRA antibody variants;

in fig. 22E is a diagram showing the results of protease digestion of MRA antibody variants;

in fig. 22G is a diagram showing the results of protease digestion of MRA antibody variants;

in fig. 223 is a diagram showing the results of protease digestion of MRA antibody variants;

in fig. 22I is a diagram showing the results of protease digestion of MRA antibody variants;

in fig. 23A is a diagram showing the results of protease digestion of MRA antibody variants;

in fig. 23B is a diagram showing the results of protease digestion of MRA antibody variants;

in fig. 23B is a diagram showing the results of protease digestion of MRA antibody variants;

in fig. 24A is a diagram showing the results of protease digestion of MRA antibody variants;

in fig. 24B is a diagram showing the results of protease digestion of MRA antibody variants;

in fig. 24B is a diagram showing the results of protease digestion of MRA antibody variants;

in fig. 24D is a diagram showing the results of protease digestion of MRA antibody variants;

in fig. 24D is a diagram showing the results of protease digestion of MRA antibody variants;

in fig. 25A is a diagram showing the results of protease digestion of MRA antibody variants;

in fig. 25B is a diagram showing the results of protease digestion of MRA antibody variants;

in fig. 26 is a graph comparing real-time plots of 5C4-bio binding to PD1 in binding assay samples containing protease-treated antibody or protease-untreated antibody and PD1. Thick black lines indicate binding assay samples containing protease-treated antibody, and thin gray lines indicate binding assay samples containing protease-untreated antibody. The X-axis represents the measurement time (s), and the start of the measurement is designated as 0 s. The Y-axis represents the level of binding. The title of each graph corresponds to the antibody contained in the sample to be evaluated. The “none (antigen only)” plot corresponds to the option in which only the antigen was used as the target sample and was not mixed with the antibody;

in fig. 27 - results of an electrophoretic study of protease-treated antibodies and protease-untreated antibodies. Lanes labeled protease (+) correspond to protease-treated samples, and lanes labeled protease (-) correspond to protease-untreated samples;

in fig. 28 is a graph comparing real-time graphs showing PD1 binding by protease-treated antibodies and non-protease-treated antibodies. Thick black lines indicate samples containing protease-treated antibody, and thin gray lines indicate samples containing non-protease-treated antibody. The X-axis represents the measurement time (s), and the start of the measurement is designated as 0 s. The Y-axis represents the level of binding. The title of each graph corresponds to the antibody contained in the sample. The “no” plot corresponds to the sample in which only PBS buffer was used without the use of antibody;

in fig. 29 is a graph comparing real-time plots demonstrating the binding of 5C4-bio to released PD1 that is present in samples treated with protease in the presence of PD1 and in samples not treated with protease in the presence of PD1. Thick black lines indicate protease-treated samples, and thin gray lines indicate protease-untreated samples. The X-axis represents the measurement time (s), and the start of the measurement is designated as 0 s. The Y-axis represents the level of binding. The title of each graph corresponds to the antibody contained in the sample. The antigen and protease plot corresponds to a sample containing only PD1 and no antibody;

in fig. 30 is a graph comparing real-time graphs demonstrating the binding of 5C4-bio to released PD1 that is present in solutions of protease-treated fusion protein and non-protease-treated protein. Thick black lines indicate protease-treated samples, and thin gray lines indicate protease-untreated samples. The X-axis represents the measurement time (s), and the start of the measurement is designated as 0 s. The Y-axis represents the level of binding. The title of each graph corresponds to the antibody in the fusion protein. The “none (antigen only)” plot corresponds to the option in which only the PD1 antigen was used as the sample to be evaluated, without using the fusion protein. The graph “5C4H-G1T4/5C4L-KT0” corresponds to the variant in which only the 5C4H-G1T4/5C4L-KT0 antibody was used, without using the fusion protein;

in fig. 31 - results of an electrophoretic study of antibody-PD1 fusion proteins treated with protease. Lanes labeled protease (+) correspond to protease-treated fusion proteins, and lanes labeled protease (-) correspond to protease-untreated fusion proteins.

Description of Embodiments of the Invention

According to the present invention, the polypeptide is generally a peptide having a length of about 4 amino acids or more, and a protein. In addition, according to the present invention, the polypeptide generally consists of (but is not limited to) an artificially created sequence. For example, a polypeptide derived from an organism may be used. Alternatively, the polypeptide of the present invention may be any naturally occurring polypeptide, synthetic polypeptide, recombinant polypeptide, or the like. Moreover, according to the present invention, fragments of said polypeptides also fall under the term polypeptide.

In the present description, each amino acid is designated by a one-letter code, a three-letter code, or both, for example, as follows: Ala/A, Leu/L, Arg/R, Lys/K, Asn/N, Met/M, Asp/D, Phe/F , Cys/C, Pro/P, Gln/Q, Ser/S, Glu/E, Thr/T, Gly/G, Trp/W, His/H, Tyr/Y, Ile/I or Val/V.

To change an amino acid in the amino acid sequence of a polypeptide, a method known in the art, such as site-directed mutagenesis (Kunkel et al., Proc. Natl. Acad. Sci. USA 82, 1985, pp. 488-492) or extension PCR, can be appropriately adapted floors. Many methods known in the art can also be adapted as alternative methods for replacing amino acids with amino acids other than naturally occurring amino acids (Annu. Rev. Biophys. Biomol. Struct. 35, 2006, pp. 225-249; and Proc. Natl Acad Sci USA 100(11), 2003, pp. 6353-6357). For example, a cell-free translation system containing a tRNA in which a non-naturally occurring amino acid is fused to an amber mutation suppressor tRNA complementary to a UAG codon (amber codon), which is a stop codon, can be used (Clover Direct (Protein Express)).

As used herein, the term “and/or” as used to refer to amino acid change sites is intended to include every combination to which “and” and “or” apply. In particular, for example, the phrase “amino acids at positions 37, 45 and/or 47 are replaced” includes the following variations of amino acid changes:

(a) provision 37, (b) provision 45, (c) provision 47, (d) provisions 37 and 45, (e) provisions 37 and 47, (f) provisions 45 and 47 and (g) provisions 37, 45 and 47.

In the present specification, an expression in which one-letter codes or three-letter codes of amino acids before and after a change are used before or after a number indicating a specific position can be used respectively to indicate an amino acid change. For example, the change F37V or Phe37Val used to replace an amino acid contained in the variable region of an antibody is the replacement of Phe at position 37 according to the Cabot numbering with Val. In particular, the number denotes the amino acid position according to Cabot numbering; the one- or three-letter amino acid code preceding the number indicates the amino acid before the substitution; and a one-letter code or a three-letter amino acid code after the number indicates the amino acid after the substitution. Similarly, the change P238A or Pro238Ala used to replace an amino acid in the Fc region in the constant region of an antibody means replacing Pro at EU numbering position 238 with Ala. In particular, the number indicates the amino acid position according to EU numbering; the one- or three-letter amino acid code preceding the number indicates the amino acid before the substitution; and a one-letter code or a three-letter amino acid code after the number indicates the amino acid after the substitution.

The present invention relates to a ligand binding molecule having a cleavage site, in which the binding of a ligand by a ligand binding molecule cleaved at the cleavage site is weakened. The ligand-binding molecule of the present invention is a polypeptide, which refers to a molecule that has the ability to bind a ligand.

The ligand-binding molecule of the present invention is a molecule that has the ability to bind to a ligand, in particular, a molecule that has the ability to bind to a ligand while not cleaved. In this context, the term "bonding" generally refers to bonding through interactions based primarily on non-covalent bonding, such as electrostatic force, Van der Waals force, or hydrogen bonding. Preferred examples of the ligand binding form of the ligand binding molecule of the present invention include, but are not limited to, an antigen-antibody interaction whereby an antigen binding region, an antigen binding molecule, an antibody, an antibody fragment, or the like. binds to antigen.

The phrase “has the ability to bind to a ligand” means that the ligand-binding molecule has the ability to bind to the ligand even if the ligand-binding molecule and the ligand are different molecules, and does not mean that the ligand-binding molecule and the ligand are connected through a covalent bond. For example, the phrase “has the ability to bind a ligand” does not mean that the ligand and the ligand-binding molecule are connected covalently through a linker. In addition, the phrase “ligand binding is weakened” means that the above-described binding ability (binding ability) is weakened. For example, when a ligand and a ligand-binding molecule are connected by a covalent bond through a linker, cleavage of the linker does not mean that the binding of the ligand is weakened. In the present invention, the ligand-binding molecule may be connected to the ligand through a linker or the like, as long as the ligand-binding molecule has the ability to bind to the ligand.

The ligand-binding molecule of the present invention is not limited to only binding to a ligand while being uncleaved, but can be a molecule that has any structure as long as the molecule used can bind to the ligand of interest while being uncleaved. Examples of a ligand binding molecule include, but are not limited to, an antibody heavy chain variable region (VH), an antibody light chain variable region (VL), a single domain antibody (sdAb), a module of about 35 amino acids designated the A domain, which is part of Avimer, a cell membrane protein present in vivo (publication of international patent applications WO 2004/044011 and WO 2005/040229), Adnectin containing a 10Fn3 domain serving as a protein binding domain obtained from the fibronectin glycoprotein expressed on cell membranes (Publication International Patent Application WO 2002/032925), Affibody having an IgG binding domain framework consisting of a trihelix bundle comprising 58 amino acids of Protein A (Publication International Patent Application WO 1995 /001937), DARPins (designed ankyrin repeat proteins), which are regions exposed on the molecular surface of ankyrin repeats (AR), each of which has a structure in which a folded subunit with a bend containing 33 amino acid residues, two antiparallel helices and loop (International Patent Application Publication WO 2002/020565), Anticalin, which have four-loop regions supporting one side of a centrally twisted barrel-shaped structure consisting of eight antiparallel chains that are highly conserved among lipocaine molecules such as neutrophil gelatinase associated lipocaine (NGAL) (international patent application publication WO 2003/029462), and a concave region formed by a parallel strand structure within a horseshoe-shaped structure formed by stacked repeats that consist of leucine-rich repeat (LRR) modules variable lymphocyte receptor (VLR), which does not have an immunoglobulin structure and is used in the acquired resistance system in jawless vertebrates such as lampreys or hagfish (international patent application publication WO 2008/016854).

As used herein, the term “antibody” is used in its broadest sense and refers to a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, provided that that they have the required antigen-binding activity.

A method for producing an antibody having the desired binding activity is known in the art. A method for producing an antibody that binds to IL-6R (anti-IL-6R antibody) is given below as an example. Antibodies that bind to antigens other than IL-6R can also be prepared accordingly using the example below.

Anti-IL-6R antibody can be produced as a polyclonal or monoclonal antibody using an approach known in the art. The mammalian-derived monoclonal antibody can be prepared as an anti-IL-6R antibody. Mammalian-derived monoclonal antibodies include, for example, antibodies produced by hybridomas or antibodies produced by host cells genetically transformed with expression vectors that carry the antibody gene. An antibody as used herein includes a "humanized antibody" and a "chimeric antibody".

Monoclonal antibody-producing hybridomas can be produced using techniques known in the art, for example as follows: mammals are immunized with IL-6R protein, which is used as a sensitizing antigen, according to a conventional immunization method. The immunocytes thus obtained are fused with parent cells known in the art according to conventional cell fusion techniques. Cells producing the monoclonal antibody can then be screened according to a conventional screening method to select anti-IL-6R antibody-producing hybridomas.

Specifically, a monoclonal antibody is produced, for example, as follows: First, the IL-6R gene can be expressed to produce IL-6R protein, which is used as a sensitizing antigen to produce the antibody. Specifically, the gene sequence encoding IL-6R is inserted into an expression vector known in the art, which is then transformed into suitable host cells. The desired human IL-6R protein is purified from host cells or their culture supernatant using a method known in the art. To obtain soluble IL-6R from culture supernatant, for example, express soluble IL-6R according to the method described in Mullberg et al., J. Immunol. 152 (10), 1994, cc. 4958-4968. Alternatively, purified naturally occurring IL-6R protein can be used as the sensitizing antigen.

Purified IL-6R protein can be used as a sensitizing antigen for immunization of mammals. IL-6R partial peptide can also be used as a sensitizing antigen. This partial peptide can be obtained by chemical synthesis from the amino acid sequence of human IL-6R. Alternatively, a partial peptide can be produced by integrating a portion of the IL-6R gene into an expression vector and then expressing it. In addition, a partial peptide can also be obtained by digesting the IL-6R protein with a proteolytic enzyme. The scope and size of the IL-6R peptide used as a partial peptide is not particularly limited to specific variants. The number of amino acid residues forming a peptide used as a sensitizing antigen is preferably at least 5 or more, for example 6 or more or 7 or more. More specifically, a peptide consisting of 8-50, preferably 10-30 residues can be used as a sensitizing antigen.

In addition, a fusion protein consisting of a desired partial polypeptide or IL-6R protein peptide fused to another polypeptide can be used as a sensitizing antigen. For example, an antibody Fc fragment or peptide tag may preferably be used to produce a fusion protein for use as a sensitizing antigen. A fusion protein expression vector can be prepared by in-frame fusion of genes encoding two or more types of desired polypeptide fragments and inserting the fusion gene into the expression vector described above. The method for preparing the fusion protein is described in Molecular Cloning, 2nd edition (Sambrook J. et al., Molecular Cloning, 2nd ed., 1989, 9.47-9.58, Cold Spring Harbor Lab. Press). A method for producing IL-6R for use as a sensitizing antigen and a method for immunization using said sensitizing antigen are also specifically described in WO 2003/000883, WO 2004/022754, WO 2006/006693, etc.

Mammals to be immunized with a sensitizing antigen are not limited to specific animals. The mammals to be immunized are preferably selected for compatibility with the parent cells to be used for cell fusion. In general, rodents (eg mice, rats and hamsters), rabbits, monkeys or the like are preferably used.

These animals are immunized with a sensitizing antigen according to a method known in the art. For example, a conventional immunization method involves administering a sensitizing antigen to a mammal by intraperitoneal or subcutaneous injection. Specifically, the sensitizing antigen diluted in PBS (phosphate buffered saline), saline or the like at the required dilution is mixed, if necessary, with a conventional adjuvant, for example, Freund's complete adjuvant, and emulsified. The resulting sensitizing antigen is then administered to the mammal several times at 4-21 day intervals. In addition, when immunizing with a sensitizing antigen, an appropriate carrier can be used. In particular, when using a low molecular weight partial peptide as a sensitizing antigen, immunization with a sensitizing antigen peptide bound to a carrier protein such as albumin or cochlear hemocyanin may be required in some cases.

Alternatively, hybridomas that produce the desired antibody can also be prepared according to the method described below using DNA immunization. DNA immunization is an immunization method that involves immunostimulating immunized animals by in vivo expression of a sensitizing antigen in immunized animals that have been administered a specific DNA vector that has been constructed in a form having the ability to express a gene that encodes an antigenic protein in the immunized animals. It can be expected that DNA immunization should have advantages over the conventional immunization method, which involves administering a protein antigen to the animals to be immunized, for the following reasons:

- DNA immunization can provide immunostimulation while maintaining the structure of the membrane protein (for example, IL-6R); And

- with DNA immunization, there is no need to purify the immunizing antigen.

To produce the monoclonal antibody of the present invention by DNA immunization, DNA is first introduced into the animals to be immunized to express the IL-6R protein. DNA encoding IL-6R can be synthesized by a method known in the art, such as PCR. The resulting DNA is inserted into a suitable expression vector, which is then administered to the animals to be immunized. For example, a commercially available expression vector such as pcDNA3.1 can preferably be used as the expression vector. The conventional method can be used as a method for introducing the vector into organisms. For example, gold particles with an expression vector adsorbed on them are used to transfect cells of animals to be immunized using a gene gun, thereby performing DNA immunization. In addition, an antibody recognizing IL-6R can also be produced using the method described in international patent application publication WO 2003/104453.

An increase in the titer of antibody binding to IL-6R was confirmed in the serum of mammals thus immunized. Immunocytes are then obtained from the mammalian body and subjected to cell fusion. In particular, spleen cells can be used as preferred immunocytes.

Mammalian myeloma cells are used for cell fusion with immunocytes. The myeloma cells preferably have a suitable selection marker that can be used for screening. The concept of “marker for selection” refers to a trait for which survival occurs (or does not survive) under specific cultural conditions. For example, hypoxanthine guanine phosphoribosyltransferase deficiency (referred to below as HGPRT deficiency) or thymidine kinase deficiency (referred to below as TK deficiency) is known in the art as a selection marker. Cells deficient in HGPRT or TK are sensitive to hypoxanthine-aminopterin-thymidine (referred to below as HAT-sensitive). HAT-sensitive cells die in the HAT selective environment because the cells cannot synthesize DNA. In contrast, these cells fused to normal cells gain the ability to grow even in a HAT selective environment because the fused cells can continue to perform DNA synthesis by utilizing the normal cell rescue pathway.

Cells deficient in HGPRT or TK can be selected in media containing 6-thioguanine or 8-azaguanine (abbreviated hereinafter as 8AG) in the case of HGPRT deficiency or 5'-bromodeoxyuridine in the case of TK deficiency. Normal cells die when these pyrimidine analogues are incorporated into their DNA. In contrast, cells deficient in these enzymes can survive in a selective environment because these cells cannot incorporate pyrimidine analogues into their DNA. In addition, a selection marker designated “G418 resistance” confers resistance to the antibiotic 2-deoxystreptamine (a gentamicin analogue) via a neomycin resistance gene. Various myeloma cells that can be used for cell fusion are known in the art.

For example, P3 cells (P3x63Ag8.653) (J. Immunol. 123 (4), 1979, cc. 1548-1550), P3x63Ag8U.1 (Current Topics in Microbiology and Immunology 81, 1978, cc. 1-7), NS-1 (C. Eur. J. Immunol. 6 (7), 1976, cc. 511-519), MPC-11 (Cell 8 (3), 1976, cc. 405-415 ), SP2/0 (Nature 276 (5685), 1978, pp. 269-270), FO (J. Immunol. Methods 35 (1-2), 1980, pp. 1-21), S194/5.XX0. BU.1 (J. Exp. Med. 148 (1), 1978, pp. 313-323) and R210 (Nature 277 (5692), 1979, pp. 131-133).

Typically, cellular fusion of immunocytes with myeloma cells is accomplished using a method known in the art, for example, the method of Kohler and Milstein et al., Methods Enzymol. 73, 1981, cc. 3-46.

More specifically, cell fusion can be carried out, for example, in a conventional nutrient medium in the presence of a cell fusion enhancing agent. For example, polyethylene glycol (PEG) or hemagglutinating Japanese virus (HVJ) are used as fusion enhancing agents. In addition, when used, an auxiliary substance such as dimethyl sulfoxide is added, if necessary, to improve the fusion efficiency.

Moreover, the ratio used between immunocytes and myeloma cells is arbitrary. For example, immunocytes are preferably used in an amount ranging from 1 to 10 relative to the number of myeloma cells. For example, RPMI1640 medium or MEM medium suitable for the growth of a myeloma cell line, as well as a conventional medium for the specified type of cell culture, are used as the cell fusion medium. Preferably, a solution supplemented with serum (eg fetal calf serum (FCS)) may be added to the medium.

To achieve cell fusion, immunocytes and myeloma cells are thoroughly mixed in the medium in predetermined quantities. A solution of PEG (eg PEG with an average molecular weight: about 1000-6000), preheated to approximately 37°C, is typically added at a concentration of 30-60% (w/v). The mixture solution is gently stirred so that the desired fused cells (hybridomas) are formed. The appropriate medium above is then gradually added to the cell cultures and the supernatant is removed by centrifugation. This operation can be repeated to remove cell fusion agents or the like that are unsuitable for the growth of hybridomas.

The hybridomas thus obtained can be cultured in a conventional selection medium, for example, HAT medium (medium containing hypoxanthine, aminopterin and thymidine), for selection. Culture using HAT medium can be continued for a period of time sufficient to kill cells (unfused cells) other than the desired hybridomas (generally, a period of time ranging from several days to several weeks is sufficient). Hybridomas producing the desired antibody can then be screened and single cells cloned using the conventional serial dilution method.

The hybridomas thus obtained can be selected using a selection medium corresponding to the marker for selecting myeloma cells used in cell fusion. For example, cells deficient in HGPRT or TK can be selected by culturing in HAT medium (medium containing hypoxanthine, aminopterin and thymidine). In particular, when used for cell fusion of HAT-sensitive myeloma cells, only cells successfully fused with normal cells can selectively grow in HAT media. Culture using HAT medium can be continued for a time sufficient to kill cells (unfused cells) other than the desired hybridomas. In particular, to select the desired hybridomas, cultivation is typically carried out for a period of time ranging from several days to several weeks. Hybridomas producing the desired antibody can then be screened and single cells cloned using the conventional serial dilution method.

Screening for the desired antibody and cloning of single cells can be accomplished by a screening method based on antigen-antibody interaction known in the art. For example, a monoclonal antibody that binds to IL-6R can bind to IL-6R expressed on the cell surface. To screen said monoclonal antibody, for example, FACS (fluorescence-activated cell sorting) can be used. FACS is a system that measures the binding of an antibody to a cell surface by analyzing cells in contact with a fluorescent antibody using a laser beam and measuring the fluorescence emitted by individual cells.

To screen for hybridomas producing the monoclonal antibody of the present invention, IL-6R-expressing cells are first generated by FACS. Preferred cells for screening are mammalian cells with enhanced IL-6R expression. Untransformed mammalian cells used as host cells can be used as a control to selectively determine the binding activity of the anti-IL-6R antibody on the cell surface. In particular, hybridomas that produce a monoclonal antibody to IL-6R can be obtained by selecting hybridomas that produce an antibody that binds to cells overexpressing IL-6R but does not bind to host cells.

Alternatively, the binding activity of the antibody to immobilized IL-6R expressing cells can be assessed based on the ELISA principle. IL-6R expressing cells are immobilized on each well of, for example, an ELISA plate. The hybridoma culture supernatant is contacted with immobilized cells in the well to determine antibody binding to the immobilized cells. When the monoclonal antibody is of murine origin, the cell-bound antibody can be detected using an anti-mouse immunoglobulin antibody. Hybridomas producing a desired antibody that has the ability to bind an antigen selected by said screening can be cloned by serial dilution or the like.

The monoclonal antibody-producing hybridomas thus obtained can be subcultured into normal medium. Hybridomas can also be stored for long periods of time in liquid nitrogen.

Hybridomas are cultured by conventional methods and the desired monoclonal antibody can be obtained from the culture supernatant. Alternatively, hybridomas can be administered to mammals suitable for the procedure and grown and the monoclonal antibody can be obtained from their ascites fluids. The first method is suitable for obtaining highly purified antibodies.

Preferably, an antibody encoded by an antibody gene cloned in antibody-producing cells such as hybridomas can also be used. The cloned antibody gene is integrated into an appropriate vector, which is then transfected into hosts so that the antibody encoded by the gene is expressed. Methods for isolating the antibody gene, integrating into a vector and transforming host cells are already known and are described, for example, in Vandamme et al., Eur. J. Biochem. 192 (3), 1990, cc. 767-775. The method for producing a recombinant antibody described below is also known in the art.

For example, cDNA encoding the variable region (V region) of an anti-IL-6R antibody is obtained from hybridoma cells that produce an anti-IL-6R antibody. For this purpose, as a rule, total RNA is first extracted from hybridomas. For example, any of the following methods can be used to extract mRNA from cells:

- ultracentrifugation method in the presence of guanidide (Biochemistry 18, (24), 1979, pp. 5294-5299) and

- AGPC method (Anal. Biochem. 162 (1), 1987, pp. 156-159).

The extracted mRNA can be purified using an mRNA purification kit (manufactured by GE Healthcare Bio-Sciences Corp.) or the like. Alternatively, a kit for direct extraction of total mRNA from cells, such as the QuickPrep mRNA purification kit (manufactured by GE Healthcare Bio-Sciences Corp.), is also commercially available. mRNA can be obtained from hybridomas using the specified kit. From the resulting mRNA, cDNA encoding the antibody V region can be synthesized using reverse transcriptase. The cDNA can be synthesized, for example, using an AMV Reverse Transcriptase First-strand cDNA Synthesis Kit (manufactured by Seikagaku Corp.). Alternatively, the 5'-RACE method can be used for cDNA synthesis and amplification, respectively (Proc. Natl. Acad. Sci. USA 85 (23), 1988, cc. 8998-9002; and Nucleic Acids Res. 17 (8), 1989 , pp. 2919-2932) using the SMART RACE cDNA amplification kit (manufactured by Clontech Laboratories, Inc.) and PCR. During such cDNA synthesis, the appropriate restriction sites mentioned below can be further introduced at both ends of the cDNA.

The cDNA fragment of interest is purified from the PCR product and then inserted by ligation into a DNA vector. The thus obtained recombinant vector is transfected with E. coli or the like. After colony selection, the desired recombinant vector can be obtained from the E. coli cells that have formed the colony. It is then confirmed whether the recombinant vector has the nucleotide sequence of the cDNA of interest using a method known in the art, such as dideoxynucleotide chain termination.

The 5'-RACE method using variable region gene amplification primers is conveniently used to obtain the gene encoding the variable region. First, a rapid amplification of cDNA ends (5'-RACE) cDNA library is prepared by synthesizing cDNAs with RNA extracted from hybridoma cells as templates. A commercially available kit, such as the SMART RACE cDNA Amplification Kit, can be used to synthesize a 5'RACE cDNA library.

The antibody gene is amplified by PCR to produce a 5'-RACE cDNA library as a template. Primers for amplifying a mouse antibody gene can be designed based on the antibody gene sequence known in the art. These primers have nucleotide sequences that differ from each other depending on the immunoglobulin subclasses. Thus, it is first necessary to determine the subclass using a commercially available kit, such as the Iso Strip Mouse Monoclonal Antibody Isotyping Kit (Roche Diagnostics K.K.).

In particular, it is possible to use, for example, primers having the ability to amplify genes encoding γ1, γ2a, γ2b and γ3 heavy chains and κ and λ light chains to obtain a gene encoding murine IgG. To amplify the IgG variable region gene, a primer that hybridizes to a fragment corresponding to the constant region adjacent to the variable region is usually used as a 3' primer. On the other hand, the primer included in the kit for preparing the 5' RACE cDNA library is used as the 5' primer.

The PCR products thus obtained by amplification can be used to reconstruct immunoglobulins consisting of a combination of heavy and light chains. The desired antibody can be screened for reshaped immunoglobulin binding activity against IL-6R as an indicator. More preferably, the binding of the antibody to IL-6R is specific, for example, for the purpose of producing an anti-IL-6R antibody. Antibody binding to IL-6R can be screened for, for example, using the following steps:

(1) contacting an antibody containing a V region encoded by the hybridoma-derived cDNA with IL-6R expressing cells;

(2) detecting binding of the antibody to IL-6R expressing cells; And

(3) selecting an antibody that binds to IL-6R expressing cells. A method for detecting antibody binding to IL-6R expressing cells is known in the art. In particular, antibody binding to IL-6R expressing cells can be determined using an approach such as FACS mentioned above. A fixed preparation of IL-6R expressing cells can accordingly be used to assess antibody binding activity.

The panning method using phage vectors is also preferably used as a method for screening antibodies for binding activity as an indicator. When antibody genes are obtained as heavy chain and light chain subclass libraries from a polyclonal antibody expressing cell population, a screening method using phage vectors is preferred. The genes encoding the heavy chain and light chain variable regions can be linked through an appropriate linker sequence to produce a gene encoding a single chain Fv (scFv). The gene encoding scFv can be inserted into phage vectors to produce phages that express scFv on their surface. After contacting the phages with the desired antigen, the phages bound to the antigen can be isolated to yield DNA encoding a scFv that has the binding activity of interest. This operation can be repeated as necessary to increase the number of scFvs that have the desired binding activity.

After obtaining a cDNA encoding the V region of an anti-IL-6R antibody of interest, the cDNA is digested with restriction enzymes that recognize restriction sites built into both ends of the cDNA. These restriction enzymes preferably recognize and cleave the nucleotide sequence consisting of the antibody gene. Insertion of sites recognized by restriction enzymes that create sticky ends is preferable to insert one copy of the cleaved fragment in the correct orientation into the vector. The cDNA thus digested, which encodes the V region of the anti-IL-6R antibody, can be inserted into an appropriate expression vector to obtain an antibody expression vector. In this case, the gene encoding the antibody constant region (C region) and the gene encoding the V region are fused in frame to produce a chimeric antibody. In this context, the term "chimeric antibody" refers to an antibody having constant and variable regions from various sources. Thus, heterogeneous (e.g., mouse-human" chimeric antibodies, as well as human-human homogeneous chimeric antibodies also fall under the concept of a chimeric antibody according to the present invention. The V region gene can be inserted into an expression vector already having a constant region gene to create expression vector of the chimeric antibody. In particular, for example, sequences recognized by restriction enzymes that cleave the V region gene can be placed respectively in the 5' region of the expression vector, which carries DNA encoding the constant region (C region) of the desired antibody. a vector having a C region gene and a V region gene is digested with the same combination of restriction enzymes and fused in frame to create a chimeric antibody expression vector.

To produce a monoclonal antibody to IL-6R, the antibody gene is integrated into an expression vector so that the antibody gene is expressed under the control of expression control regions. Expression control regions for antibody expression include, for example, an enhancer and a promoter. In addition, an appropriate signal sequence can be added to the amino terminus for extracellular secretion of the expressed antibody. For example, a peptide having the amino acid sequence MGWSCIILFLVATATGVHS (SEQ ID NO: 536) can be used as a signal sequence. Any other suitable signal sequences may be added. The expressed polypeptide is cleaved at the carboxyl fragment of the specified sequence. The cleaved polypeptide can be secreted outside the cell as a mature polypeptide. Suitable host cells can then be transformed with the expression vector to produce recombinant cells expressing DNA that encodes the anti-IL-6R antibody.

The term "antibody fragment" refers to a molecule, other than a full antibody, that contains a portion of the full antibody that binds to the antigen to which the full antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab') ₂ , dimeric antibodies (diabody), linear antibodies, single chain antibody molecules (eg, scFv) and multispecific antibodies formed from antibody fragments.

The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used interchangeably as used herein to refer to an antibody having a structure substantially similar to that of a naturally occurring antibody or having heavy chains that contain the Fc described herein -region.

The term "variable region" or "variable domain" refers to the heavy or light chain domain of an antibody that is involved in the binding of the antibody to its antigen. The heavy chain and light chain variable domains (VH and VL, respectively) of a native antibody generally have similar structures, with each domain containing four conserved framework regions (FR) and three hypervariable regions (CDR) (see, for example, Kindt and al., Kuby Immunology, 6th ed., W.H. Freeman and Co., 2007, p. 91). A single VH or VL domain may be sufficient to provide antigen binding specificity.

The term “hypervariable region” or “CDR” as used herein refers to each of the regions of an antibody variable domain whose sequence is hypervariable and/or forms loops of a particular structure (“hypervariable loops”), and/or refers to antigen-contacting residues ( "contacts with antigen"). Typically, antibodies contain six CDRs: three in VH (H1, H2, H3) and three in VL (L1, L2, L3). As used herein, examples of HVR include

(a) hypervariable loops including amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2) and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196, 1987, cc. 901-917);

(b) CDRs including amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2) and 95-102 (H3) ( Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service Publishing, National Institutes of Health, Bethesda, MD, 1991, NIH publication 91-3242);

(c) areas of contact with the antigen, including amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2) and 93-101 ( H3) (MacCallum et al., J. Mol. Biol. 262, 1996, pp. 732-745); And

(d) combinations of residues specified in subparagraphs (a), (b) and/or (c), including amino acid residues HVR 46-56 (L2), 47-56 (L2), 48-56 (L2), 49- 56 (L2), 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3) and 94-102 (H3).

Unless specifically stated otherwise, herein, residues in the CDR and other residues in the variable domain (eg, residues in FR) are numbered according to Kabat et al., supra.

"Framework region" or "FR" means variable domain residues other than hypervariable region residues (CDR). The FR variable domain generally consists of four FR domains: FR1, FR2, FR3 and FR4. Thus, the CDR and FR sequences typically have the following arrangement in the VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4. As used herein, the term “constant region” or “constant domain” refers to a region or domain other than the variable regions of an antibody. For example, an IgG antibody is a heterotetrameric glycoprotein with a molecular weight of approximately 150,000 Da, consisting of two identical light chains and two identical heavy chains linked by disulfide bridges. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or heavy chain variable domain, followed by three constant domains (CH1, CH2 and CH3). Likewise, in the direction from the N-terminus to the C-terminus, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a light chain constant domain (CL). The light chain of an antibody, depending on the amino acid sequence of its constant domain, can belong to one of two types, designated kappa (κ) and lambda (λ).

The term "class" of an antibody refers to the type of constant domain or constant region that is included in its heavy chain. There are five main classes of antibodies: IgA, IgD, IgE, IgG and IgM. Some of these classes can be further subdivided into subclasses (isotypes), for example, IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. The heavy chain constant domains that correspond to the various immunoglobulin classes are designated α, δ, ε, γ, and μ, respectively.

As used herein, the term "Fc region" is used to refer to the C-terminal region of immunoglobulin heavy chains, which contains at least a portion of the constant regions. This concept includes an Fc region having a naturally occurring sequence and a mutant Fc region. In one aspect of the invention, the Fc region of the human IgG heavy chain extends from Cys226 or Pro230 to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) or glycine-lysine (Gly446-Lys447) Fc region may or may not be present. Unless specifically stated otherwise, in the present description the numbering of amino acid residues in the Fc region or constant region corresponds to the EU numbering system (which is also referred to as the EU index) described by Kabat E.A. et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

The ligand binding molecule of the present invention is a polypeptide containing a cleavage site. The cleavage site can be cleaved, for example, by an enzyme, can be reduced with a reducing agent, or can be photodegraded. The cleavage site can be placed at any position in the polypeptide as long as the binding of the ligand by the ligand-binding molecule can be weakened by cleavage of the cleavage site. A polypeptide may contain one or more cleavage sites.

The ligand-binding molecule of the present invention binds to the ligand more weakly (ie, the ligand binding is weakened) in the cleaved state compared to the uncleaved state. In one embodiment of the invention, in which the binding of a ligand by a ligand-binding molecule is based on an antigen-antibody interaction, the attenuation of ligand binding can be assessed based on the ligand-binding activity of the ligand-binding molecule.

The ligand binding activity of a ligand binding molecule can be tested using a well known method such as FACS, ELISA format, BIACORE screening using ALPHA (Proximity Enhanced Luminescence Homogeneous Assay) or Surface Plasmon Resonance (SPR) phenomenon, or BLI (Biolayer Interferometry) (Octet system) (Proc. Natl. Acad. Sci. USA 103 (11), 2006, cc. 4005-4010).

ALPHA-based screening is carried out using ALPHA technology, which is based on the principle described below, using two types of beads, donors and acceptors. Luminescent signals are only detectable when molecules bound to donor beads physically interact with molecules bound to acceptor beads, and when both beads are in close proximity to each other. The photosensitizer in the donor granule, excited by a laser beam, converts ambient oxygen into excited singlet oxygen. When singlet oxygen diffuses from a donor granule and reaches an acceptor granule located in the immediate vicinity, a chemiluminescent reaction is induced in the granule, which ultimately leads to the emission of light. If the molecule bound to the donor bead does not interact with the molecule bound to the acceptor bead, then the chemiluminescent reaction does not occur because the singlet oxygen that is produced by the donor bead does not reach the acceptor bead.

For example, a biotin-labeled ligand-binding molecule is coupled to a donor bead, and a glutathione S-transferase (GST)-labeled ligand is coupled to an acceptor bead. In the absence of an unlabeled competing ligand-binding molecule, the ligand-binding molecule interacts with the ligand and generates signals at wavelengths between 520 and 620 nm. The unlabeled ligand-binding molecule competes with the labeled ligand-binding molecule for interaction with the ligand. Relative binding affinity can be assessed by quantifying the decrease in fluorescence due to competition. Biotinylation of a ligand binding molecule, such as an antibody, using sulfo-NHS-biotin or similar agents is well known in the art. A method that includes, for example: fusion of a polynucleotide encoding a ligand in frame with a polynucleotide encoding GST; expressing a GST fusion ligand from cells or the like carrying a vector that allows expression of the resulting fusion gene; and purification of the GST-fused ligand using a glutathione-containing column can be suitably adapted as a method for labeling the ligand with GST. The resulting signals are preferably analyzed, for example, using software such as GRAPHPAD PRISM GRAPHPAD PRISM (GraphPad Software, Inc., San Diego) adapted for a single-site competition model based on nonlinear regression analysis.

One of the substances (ligand) intended for studying the interaction is immobilized on a thin gold film of a sensor chip. The sensor chip is illuminated with light from the back surface so that there is total reflection at the interface between the thin gold film and the glass. As a result, an area with reduced reflection intensity (SPR signal) is formed in part of the reflected light. Another substance (analyte) intended for studying the interaction is passed over the surface of the sensor chip, and when the ligand binds to the analyte, the mass of the immobilized ligand molecule increases and the refractive index of the solvent on the surface of the sensor chip changes. As a result of this change in the refractive index, the position of the SPR signal shifts (and vice versa, the signal returns to its original position if dissociation of bound molecules occurs). Using the Biacore system, a graph is built, plotting the shift value along the ordinate axis, i.e. change in mass on the surface of the sensor chip, and thus obtain as the results of the analysis the dependence of the change in mass on time (sensogram). Kinetic parameters, such as association rate constants (ka) and dissociation rate constants (kd), are determined from sensorgrams presented in the form of curves, and the dissociation constant (KD) is calculated as the ratio of these constants. The BIACORE method is also preferably used as a method for inhibition or equilibrium analysis. Examples of such a method for inhibition assays are described in Proc. Natl. Acad. Sci. USA 103(11), 2006, cc. 4005-4010, and examples of equilibrium assays are described in Methods Enzymol. 323, 2000, cc. 325-340.

The phrase "the ligand-binding function of the ligand-binding molecule is weakened" means that the amount of the test ligand-binding molecule bound to the ligand is 50% or less, preferably 45% or less, 40% or less, 35% or less, 30% or less, 20% or less, or 15% or less, most preferably 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less, of the amount of control ligand-binding molecule bound to the ligand determined based on the measurement method described above. The desired index can be used accordingly as an index of binding activity. For example, you can use the dissociation constant (KD). When using the dissociation constant (KD) as an indicator in assessing binding activity, a higher dissociation constant (KD) value indicative of the ligand binding of the test ligand-binding molecule compared to the value indicative of the ligand binding of the control ligand-binding molecule indicates that the test ligand-binding molecule has weaker ligand binding activity than the control ligand binding molecule. The phrase “ligand-binding function is attenuated” means that the dissociation constant (KD) value of the ligand binding of the test ligand-binding molecule is at least 2-fold, preferably at least 5-fold, or at least 10-fold, especially preferably at least 10-fold higher. 100 times greater than the dissociation constant (KD) characterizing the binding of a ligand by a control ligand-binding molecule.

Examples of a control ligand binding molecule include an uncleaved form of the ligand binding molecule.

In one embodiment of the present invention, the ligand is released from the ligand binding molecule of the present invention as a result of cleavage of a cleavage site in the ligand binding molecule. In this context, when a ligand is bound to a site of a ligand-binding molecule through a linker that does not have a cleavage site, the ligand is released while bound to the site of the ligand-binding molecule through the linker (see FIG. 1). Even when the ligand is released along with a portion of the ligand-binding molecule, as stated above, the ligand can be considered to be released from the ligand-binding molecule if the ligand is released from most of the ligand-binding molecule.

A method for detecting the release of a ligand from a ligand-binding molecule by cleavage of a cleavage site includes a detection method using a ligand, for example, a ligand detection antibody that recognizes a ligand. When the ligand binding molecule is an antibody fragment, the ligand detection antibody preferably binds to the same epitope as the epitope for the ligand binding molecule. The ligand detected using a ligand detection antibody can be detected using a well known method such as FACS, ELISA format, BIACORE screening using ALPHA (Proximity Enhanced Luminescence Homogeneous Assay) or Surface Plasmon Resonance (SPR) phenomenon, or BLI (Biolayer Interferometry) (Octet system) (Proc. Natl. Acad. Sci. USA 103 (11), 2006, cc. 4005-4010).

When, for example, the Octet system is used to assess ligand release, a ligand detection antibody that recognizes the ligand is biotinylated and contacted with the biosensor. Ligand binding in the sample can then be measured to assess ligand release. Specifically, the amount of ligand is measured in a sample containing the ligand-binding molecule before protease treatment and after protease treatment and the ligand using an antibody designed to detect the ligand. The amount of ligand detected in a sample can be compared before and after protease treatment, determining the release of the ligand. Alternatively, the amount of ligand is measured in a sample containing a protease, a ligand-binding molecule and a ligand, and a sample containing a ligand-binding molecule and a ligand but not containing a protease, using an antibody designed to detect the ligand. The amount of ligand detected in a sample can be compared with and without the presence of protease to assess ligand release. More specifically, ligand release can be assessed using the method described in the Examples section herein. When a ligand binding molecule is fused to a ligand to form a fusion protein, the amount of ligand is measured in a sample containing the fusion protein before or after protease treatment using the antibody used to detect the ligand. To assess ligand release, the amounts of ligand found in a sample before and after protease treatment can be compared. Alternatively, the amount of ligand is measured in a sample containing the protease and the fusion protein, and in a sample containing the fusion protein but not the protease, using an antibody designed to detect the ligand. The amount of ligand detected in a sample can be compared with and without the presence of protease to assess ligand release. More specifically, ligand release can be assessed using the method described in the Examples section herein.

In an embodiment of the invention in which the physiological activity of a ligand is inhibited by binding to a ligand-binding molecule, release from the ligand-binding molecule can be assessed using a method for measuring the physiological activity of the ligand in a sample. In particular, the physiological activity of a ligand can be measured in a sample containing a ligand-binding molecule before and after protease treatment and the ligand, and comparing before and after protease treatment to assess ligand release. Alternatively, the physiological activity of a ligand can be measured in a sample containing a protease, a ligand binding molecule and a ligand, and in a sample containing a ligand binding molecule and a ligand but without the protease, comparing these samples to assess ligand release. When a ligand-binding molecule is fused to a ligand to form a fusion protein, the physiological activity of the ligand can be measured in a sample containing the fusion protein before or after protease treatment and comparing before and after protease treatment to assess ligand release. Alternatively, the physiological activity of the ligand can be measured in a sample containing the protease and the fusion protein and in a sample containing the fusion protein but not the protease and compared between these samples to assess ligand release.

In one embodiment of the present invention, the cleavage site contains a protease-cleavable sequence and is cleaved by the protease.

As used herein, the term “protease” refers to an enzyme, such as endopeptidase or exopeptidase, that hydrolyzes a peptide bond, typically an endopeptidase. The protease used in the present invention is limited only by the ability to cleave the sequence cleaved by the protease, and is essentially not limited by its type. In some embodiments, a target tissue-specific protease is used. The target tissue-specific protease may be, for example, any of the following proteases:

(1) a protease that is expressed at a higher level in the target tissue than in normal tissues,

(2) a protease, which has higher activity in the target tissue than in normal tissues,

(3) a protease, which is expressed at a higher level in target cells than in normal cells, and

(4) a protease that has higher activity in target cells than in normal cells.

In a more specific embodiment of the invention, a cancer tissue-specific protease or an inflammatory tissue-specific protease is used.

As used herein, the term “target tissue” refers to tissue containing at least one target cell. In some embodiments of the present invention, the target tissue is cancerous tissue. In some embodiments of the present invention, the target tissue is inflammatory tissue.

The term "cancer tissue" refers to tissue containing at least one cancer cell. Thus, given that, for example, cancer tissue contains cancer cells and blood vessels, each cell type that participates in the formation of a tumor mass containing cancer cells and endothelial cells falls within the scope of the present invention. As used herein, a tumor mass refers to a nidus of tumor tissue. The term “tumor” is usually used to refer to benign neoplasm or malignant neoplasm.

As used herein, examples of “inflammatory tissue” include:

joint tissue in rheumatoid arthritis or osteoarthritis,

lung (alveolar) tissue in bronchial asthma or COPD,

tissue of the digestive system organ with inflammatory bowel disease, Crohn's disease or ulcerative colitis,

fibrous tissue with fibrosis of the liver, kidney or lung,

tissue after organ transplant rejection,

tissue of a blood vessel or heart (heart muscle) for arteriosclerosis or heart failure,

visceral adipose tissue in metabolic syndrome,

skin tissue for atopic dermatitis and other dermatitis, and

tissue of the spinal nerve in case of disc herniation or chronic lumbago.

In particular, a specifically expressed or specifically activated protease or a protease that is considered to be associated with a disease state of the target tissue (target tissue-specific protease) is known for certain types of target tissues. For example, international patent application publications WO 2013/128194, WO 2010/081173 and WO 2009/025846 describe a protease specifically expressed in cancer tissue. Also in J Inflamm (Lond). 7, 2010, p. 45, Nat Rev Immunol. 6(7), July 2006, cc. 541-550, Nat Rev Drug Discov. 13(12), December 2014, cc. 904-927, Respir Res. 17, March 4, 2016, p. 23, Dis Model Mech. 7(2), February 2014, cc. 193-203 and Biochim Biophys Acta. 1824(1), January 2012, cc. 133-145 describe a protease that is thought to be associated with inflammation.

In addition to the protease specifically expressed in the target tissue, there is also a protease that is specifically activated in the target tissue. For example, a protease may be expressed in an inactive form and then converted to an active form. Many tissues contain a substance that inhibits the active protease and controls the activity as a result of the activation process and the presence of the inhibitor (Nat Rev Cancer. 3 (7), July 2003, cc. 489-501). In the target tissue, the active protease can be specifically activated, avoiding inhibition.

Active protease can be assessed using a method using an antibody that recognizes the active protease (PNAS 110 (1), 2 January 2013, pp. 93-98), or a method using a fluorescently labeled peptide recognized by the protease, the fluorescence of which is quenched before cleavage , but is emitted after cleavage (Nat Rev Drug Discov. 9 (9), September 2010, cc. 690-701. doi: 10.1038/nrd3053).

According to one view, the term "target tissue-specific protease" can refer to any of the following proteases:

(I) a protease that has a higher level of expression in the target tissue than in normal tissues,

(ii) a protease that has higher activity in the target tissue than in normal tissues,

(III) a protease that is expressed at a higher level in target cells than in normal cells, and

(IV) a protease that has higher activity in target cells than in normal cells.

Specific examples of protease include, but are not limited to, cysteine protease (including the cathepsin B, L, S, etc. families),

aspartyl protease (cathepsins D, E, K, O, etc.), serine protease (including matriptase (including MT-SP1), cathepsins A and G, thrombin, plasmin, urokinase (uPA), tissue plasminogen activator (tPA ), elastase, proteinase 3, thrombin, kallikrein, tryptase and chymase), metalloproteinase (metalloproteinase (MMP1-28), including both membrane-bound forms (MMP14-17 and MMP24-25) and secreted forms (MMP1-13, MMP18-23 and MMP26-28), disintegrin and metalloproteinase (ADAM), disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), meprin (meprin alpha and meprin beta), CD 10 (CALLA), prostate antigen (PSA), legumain, TMPRSS3 , TMPRSS4, human neutrophil elastase (HNE), beta secretase (BACE), fibroblast activating protein alpha (FAP), granzyme B, guanidinobenzoatase (GB), hepsin, neprilysin, NS3/4A, HCV-NS3/4, calpain, ADAMDEC1 , renin, cathepsin C, cathepsin V/L2, cathepsin X/Z/P, cruzipain, otubain 2, kallikrein-related peptidases (KLKs (KLK3, KLK4, KLK5, KLK6, KLK7, KLK8, KLK10, KLK11, KLK13 and KLK14)) , osteogenesis protein 1 (BMP-1), activated protein C, blood coagulation-associated protease (factor VIIa, factor IXa, factor Xa, factor XIa and factor XIIa), HtrA1, lactoferrin, marapsin, PACE4, DESC1, dipeptidyl peptidase 4 (DPP-4), TMPRSS2, cathepsin F, cathepsin H, cathepsin L2, cathepsin O, cathepsin S, granzyme A, hepsin, calpain 2, glutamate carboxypeptidase 2, AMSH-like proteases, AMSH, gamma secretase, antiplasmin-cleaving enzyme (APCE) , decisin 1, N-acetylated alpha-linked acid dipeptidase 1-like enzyme (NAALADL1), and furin.

According to another view, the term “target tissue-specific protease” may refer to a cancer tissue-specific protease or an inflammatory tissue-specific protease.

Examples of cancer tissue-specific protease include the protease that is specifically expressed in cancer tissue described in international patent application publications WO 2013/128194, WO 2010/081173 and WO 2009/025846.

With regard to the type of cancer tissue-specific protease, treatment with a protease that has higher expression specificity in cancer tissue is more effective in reducing adverse reactions. The preferred cancer tissue-specific protease has a concentration in the cancer tissue that is at least 5 times, more preferably at least 10 times, even more preferably at least 500 times, most preferably at least 1000 times its concentration in healthy tissues. In addition, the preferred cancer tissue-specific protease has activity in cancer tissue that is at least 2-fold, more preferably at least 3-fold, at least 4-fold, at least 5-fold, or at least 5-fold. 10 times, even more preferably at least 100 times, especially preferably at least 500 times, most preferably at least 1000 times its activity in healthy tissues.

The cancer tissue-specific protease may be in a form associated with the cancer cell membrane or may be in a secreted extracellular form not associated with the cell membrane. When the cancer tissue-specific protease is not bound to the cancer cell membrane, this is advantageous for cancer cell-specific immunocyte-mediated cytotoxicity because the cancer tissue-specific protease must be present in or in close proximity to the cancer tissue. As used herein, the term “in the vicinity of cancer tissue” means the location at which a protease-cleavable sequence specific for cancer tissue is cleaved so as to exhibit a ligand-binding activity-reducing effect. However, it is preferable that damage to healthy cells in a given location be minimized.

Another view is that the cancer tissue-specific protease is any of the following:

(I) a protease, which is expressed at a higher level in cancer tissue than in healthy tissue,

(ii) a protease, which has higher activity in cancerous tissue than in healthy tissues,

(III) a protease, which is expressed at a higher level in cancer cells than in healthy cells, and

(IV) a protease, which has higher activity in cancer cells than in healthy cells.

One type of cancer tissue-specific protease can be used individually, or two or more types of cancer tissue-specific proteases can be combined. The number of types of cancer tissue-specific protease can be determined accordingly by those skilled in the art based on the type of cancer to be treated.

From these points of view, the cancer tissue-specific protease is preferably a serine protease or metalloproteinase, more preferably matriptase (including MT-SP1), urokinase (uPA) or metalloproteinase, preferably also MT-SP1, uPA, MMP2 or MMP9, among the listed higher than proteases.

Regarding the type of inflammatory tissue-specific protease, treatment with a protease that has a higher specificity of expression in inflammatory tissue is more effective in reducing adverse reactions. The preferred inflammatory tissue-specific protease has a concentration in the inflammatory tissue that is at least 5 times, more preferably at least 10 times, even more preferably at least 500 times, most preferably at least 1000 times its concentration in healthy tissues. In addition, the preferred inflammatory tissue-specific protease has an activity in inflammatory tissue of at least 2-fold, more preferably at least 3-fold, at least 4-fold, at least 5-fold, or at least 5-fold. 10 times, even more preferably at least 100 times, especially preferably at least 500 times, most preferably at least 1000 times its activity in healthy tissues.

The inflammatory tissue-specific protease may be in a form associated with the inflammatory cell membrane or may be in a secreted extracellular form not associated with the cell membrane. When the inflammatory tissue-specific protease is not bound to the inflammatory cell membrane, this is advantageous for inflammatory cell-specific immunocyte-mediated cytotoxicity because the inflammatory tissue-specific protease must be present in or in close proximity to the inflammatory tissue. As used herein, the term “in the vicinity of inflammatory tissue” means the location at which a protease-cleavable sequence specific for inflammatory tissue is cleaved so as to exhibit a ligand-binding activity-reducing effect. However, it is preferable that damage to healthy cells in a given location be minimized.

Another view is that the cancer tissue-specific protease is any of the following:

(I) a protease, which is expressed at a higher level in inflammatory tissue than in healthy tissue,

(ii) a protease, which has higher activity in inflammatory tissue than in healthy tissue,

(iii) a protease that is expressed at a higher level in inflammatory cells than in healthy cells, and

(IV) a protease, which has higher activity in inflammatory cells than in healthy cells.

One type of inflammatory tissue-specific protease may be used individually, or two or more types of inflammatory tissue-specific proteases may be combined. The number of types of inflammatory tissue-specific protease can be determined accordingly by those skilled in the art, taking into account the pathological condition to be treated.

From these points of view, the inflammatory tissue-specific protease is preferably one of the above proteases and is a metalloproteinase. The metalloproteinase is more preferably ADAMTS5, MMP2, MMP7, MMP9 or MMP13.

The protease cleavable sequence is a specific amino acid sequence that is specifically recognized by a target tissue-specific protease when the polypeptide is hydrolyzed by the target tissue-specific protease in an aqueous solution.

The protease-cleavable sequence is preferably an amino acid sequence that is hydrolyzed with high specificity by a protease that is specific to the target tissue, more specifically expressed in the target tissue or cells to be treated, or more specifically activated in the target tissue/cells to be treated , from the point of view of reducing adverse reactions.

Specific examples of protease-cleavable sequences include target sequences that are specifically hydrolyzed by the above protease specifically expressed in cancer tissue, which are described in international patent application publications WO 2013/128194, WO 2010/081173 and WO 2009/025846 specific for inflammatory tissue protease, etc. It is also possible to use a sequence that has been artificially altered, for example by appropriately introducing an amino acid mutation into the target sequence, which is specifically hydrolyzed by a known protease. Alternatively, a protease-cleavable sequence identified by a method known to those skilled in the art, as described in Nature Biotechnology 19, 2001, cc, can be used. 661-667.

In addition, a naturally occurring protease cleavable sequence may be used. For example, TGFβ is converted to a latent form by protease cleavage. Likewise, it is possible to employ a protease-cleavable sequence in a protein that changes molecular shape when cleaved by the protease.

Examples of protease-cleavable sequences that can be used include, but are not limited to, those described in international patent application publications WO 2015/116933, WO 2015/048329, WO 2016/118629, WO 2016/179257, WO 2016/ 179285, WO 2016/179335, WO 2016/179003, WO 2016/046778, WO 2016/014974, in US patent publications US 2016/0289324, US 2016/0311903, in PNAS 97, 2000, cc. 7754-7759, Biochemical Journal 426, 2010, cc. 219-228, and Beilstein J Nanotechnol. 7, 2016, cc. 364-373.

The protease-cleavable sequence is more preferably an amino acid sequence that is specifically hydrolyzed by the target tissue-acceptable specific protease mentioned above. The amino acid sequence that is specifically hydrolyzed by a target tissue-specific protease is preferably any of the following amino acid sequences:

LSGRSDNH (SEQ ID NO: 3, cleavable MT-SP1 or uPA),

PLGLAG (SEQ ID NO: 34, MMP2 or MMP9 cleavable) and

VPLSLTMG (SEQ ID NO: 35, MMP7 cleavable).

Any of the following sequences can also be used as a protease cleavable sequence:

TSTSGRSANPRG (SEQ ID NO: 66, cleavable MT-SP1 or uPA),

ISSGLLSGRSDNH (SEQ ID NO: 67, cleavable MT-SP1 or uPA),

AVGLLAPPGGLSGRSDNH (SEQ ID NO: 68, cleavable by MT-SP1 or uPA),

GAGVPMSMRGGAG (SEQ ID NO: 69, MMP1 cleavable),

GAGIPVSLRSGAG (SEQ ID NO: 70, MMP2 cleavable),

GPLGIAGQ (SEQ ID NO: 71, MMP2 cleavable),

GGPLGMLSQS (SEQ ID NO: 72, MMP2 cleavable),

PLGLWA (SEQ ID NO: 73, MMP2 cleavable),

GAGRPFSMIMGAG (SEQ ID NO: 74, MMP3 cleavable),

GAGVPLSLTMGAG (SEQ ID NO: 75, MMP7 cleavable),

GAGVPLSLYSGAG (SEQ ID NO: 76, MMP9 cleavable),

AANLRN (SEQ ID NO: 77, MMP11 cleavable),

AQAYVK (SEQ ID NO: 78, MMP11 cleavable),

AANYMR (SEQ ID NO: 79, MMP11 cleavable),

AAALTR (SEQ ID NO: 80, MMP11 cleavable),

AQNLMR (SEQ ID NO: 81, MMP11 cleavable),

AANYTK (SEQ ID NO: 82, MMP11 cleavable),

GAGPQGLAGQRGIVAG (SEQ ID NO: 83, MMP13 cleavable),

PRFKIIGG (SEQ ID NO: 84, prourokinase cleavable),

PRFRIIGG (SEQ ID NO: 85, prourokinase cleavable),

GAGSGRSAG (SEQ ID NO: 86, uPA cleavable),

SGRSA (SEQ ID NO: 87, cleaved uPA),

GSGRSA (SEQ ID NO: 88, uPA cleavable),

SGKSA (SEQ ID NO: 89, cleaved uPA),

SGRSS (SEQ ID NO: 90, uPA cleavable),

SGRRA (SEQ ID NO: 91, uPA cleavable),

SGRNA (SEQ ID NO: 92, uPA-cleavable),

SGRKA (SEQ ID NO: 93, cleaved uPA),

QRGRSA (SEQ ID NO: 94, tPA cleavable),

GAGSLLKSRMVPNFNAG (SEQ ID NO: 95, cathepsin B cleavable)

TQGAAA (SEQ ID NO: 96, cathepsin B cleavable),

GAAAAA (SEQ ID NO: 97, cathepsin B cleavable),

GAGAAG (SEQ ID NO: 98, cathepsin B cleavable),

AAAAAG (SEQ ID NO: 99, cathepsin B cleavable),

LCGAAI (SEQ ID NO: 100, cathepsin B cleavable),

FAQALG (SEQ ID NO: 101, cathepsin B cleavable),

LLQANP (SEQ ID NO: 102, cathepsin B cleavable),

LAAANP (SEQ ID NO: 103, cathepsin B cleavable),

LYGAQF (SEQ ID NO: 104, cathepsin B cleavable),

LSQAQG (SEQ ID NO: 105, cathepsin B cleavable),

ASAASG (SEQ ID NO: 106, cathepsin B cleavable),

FLGASL (SEQ ID NO: 107, cathepsin B cleavable),

AYGATG (SEQ ID NO: 108, cathepsin B cleavable),

LAQATG (SEQ ID NO: 109, cathepsin B cleavable),

GAGSGVVIATVIVITAG (SEQ ID NO: 110, cathepsin L cleavable),

APMAEGGG (SEQ ID NO: 111, meprin alpha or meprin beta cleavable),

EAQGDKII (SEQ ID NO: 112, meprin alpha or meprin beta cleavable),

LAFSDAGP (SEQ ID NO: 113, meprin alpha or meprin beta cleavable),

YVADAPK (SEQ ID NO: 114, meprin alpha or meprin beta cleavable),

RRRRR (SEQ ID NO: 115, furin cleavable),

RRRRRR (SEQ ID NO: 116, furin cleavable),

GQSSRHRRAL (SEQ ID NO: 117, furin cleavable),

SSRHRRALD (SEQ ID NO: 118),

RKSSIIIRMRDVVL (SEQ ID NO: 119, plasminogen-cleavable),

SSSFDKGKYKKGDDA (SEQ ID NO: 120, staphylokinase cleavable),

SSSFDKGKYKRGDDA (SEQ ID NO: 121, staphylokinase-cleavable),

IEGR (SEQ ID NO: 122, cleaved by factor IXa),

IDGR (SEQ ID NO: 123, cleaved by factor IXa),

GGSIDGR (SEQ ID NO: 124, factor IXa cleavable),

GPQGIAGQ (SEQ ID NO: 125, collagenase digestible),

GPQGLLGA (SEQ ID NO: 126, collagenase digestible),

GIAGQ (SEQ ID NO: 127, collagenase-cleavable),

GPLGIAG (SEQ ID NO: 128, collagenase cleavable),

GPEGLRVG (SEQ ID NO: 129, collagenase-cleavable),

YGAGLGVV (SEQ ID NO: 130, collagenase digestible),

AGLGVVER (SEQ ID NO: 131, collagenase-cleavable),

AGLGISST (SEQ ID NO: 132, collagenase-cleavable),

EPQALAMS (SEQ ID NO: 133, collagenase digestible),

QALAMSAI (SEQ ID NO: 134, collagenase-cleavable),

AAYHLVSQ (SEQ ID NO: 135, collagenase digestible),

MDAFLESS (SEQ ID NO: 136, collagenase digestible),

ESLPVVAV (SEQ ID NO: 137, collagenase-cleavable),

SAPAVESE (SEQ ID NO: 138, collagenase digestible),

DVAQFVLT (SEQ ID NO: 139, collagenase digestible),

VAQFVLTE (SEQ ID NO: 140, collagenase-cleavable),

AQFVLTEG (SEQ ID NO: 141, collagenase cleavable),

PVQPIGPQ (SEQ ID NO: 142, collagenase cleavable),

LVPRGS (SEQ ID NO: 143, thrombin-cleavable) and

TSTSGRSANPRG (SEQ ID NO: 345).

In one embodiment of the present invention, a flexible linker is further attached to one or both ends of the protease recognition sequence. The flexible linker at one end of the protease cleavable sequence may be referred to as a first flexible linker, and the flexible linker at the other end may be referred to as a second flexible linker. In a specific embodiment, one of the following combinations of a protease cleavable sequence and flexible linker is used:

(protease-cleavable sequence),

(first flexible linker) - (protease cleavable sequence),

(protease cleavable sequence)-(second flexible linker), and

(first flexible linker) - (protease cleavable sequence) - (second flexible linker).

The flexible linker specified in this embodiment of the invention is preferably a peptide linker. The first flexible linker and the second flexible linker are each present independently and randomly, and they are identical or different flexible linkers, each containing at least one flexible amino acid (Gly, etc.). The flexible linker contains, for example, a sufficient number of residues (amino acids randomly selected from Arg, Ile, Gln, Glu, Cys, Tyr, Trp, Thr, Val, His, Phe, Pro, Met, Lys, Gly, Ser, Asp, Asn , Ala, etc., especially Gly, Ser, Asp, Asn and Ala, in particular Gly and Ser, especially preferably Gly, etc.) for the protease cleavable sequence to obtain the required protease accessibility.

A flexible linker that can be used at both ends of a protease-cleavable sequence is typically a flexible linker that facilitates access of the protease to the protease-cleavable sequence and increases the cleavage efficiency of the protease. A suitable flexible linker can be easily selected and may preferably be selected from linkers of various lengths, such as those having a length of from 1 amino acid (Gly, etc.) to 20 amino acids, from 2 amino acids to 15 amino acids, or from 3 amino acids to 12 amino acids, in including from 4 amino acids to 10 amino acids from 5 amino acids to 9 amino acids, from 6 amino acids to 8 amino acids or from 7 amino acids to 8 amino acids. In some embodiments of the present invention, the flexible linker is a peptide linker consisting of 1-7 amino acids.

Examples of the flexible linker include, but are not limited to, glycine polymers (G)n, glycine-serine polymers (including, for example, (GS)n, (GSGGS: SEQ ID NO: 45)n and (GGGS: SEQ ID NO : 36)n, in which n is an integer equal to at least 1), glycine-alanine polymers, alanine-serine polymers and other flexible linkers widely used in conventional techniques.

Among them, glycine and glycine-serine polymers deserve attention due to the fact that these amino acids are relatively unstructured and are able to function as neutral linkages between components.

Examples of a flexible linker consisting of a glycine-serine polymer may include, but are not limited to:

where n denotes an integer 1 or more.

However, the length and sequence of the peptide linker can be selected accordingly by those skilled in the art depending on the purpose.

In some embodiments of the present invention, the ligand binding molecule comprises VH antibodies and VL antibodies. Examples of a ligand binding molecule containing VH and VL include, but are not limited to, Fv, scFv, Fab, Fab', Fab'-SH, F(ab') ₂ and full antibodies.

In some embodiments of the present invention, the ligand binding molecule comprises an Fc region. When the Fc region of an IgG class antibody is used, its type is not limited, and, for example, the Fc region of IgG1, IgG2, IgG3 or IgG4 can be used. For example, an Fc region containing one sequence selected from the amino acid sequences shown in SEQ ID NOs: 55, 56, 57 and 58, or a mutant Fc region obtained by introducing a change in the Fc region, can be used. In some embodiments of the present invention, the ligand binding molecule comprises an antibody constant region.

In some more specific embodiments of the present invention, the ligand binding molecule is an antibody. When an antibody is used as a ligand-binding molecule, binding to the ligand is mediated by the variable region. In some additional specific embodiments of the invention, the ligand binding molecule is an IgG antibody. When an IgG class antibody is used as the ligand binding molecule, its type is not limited, and IgG1, IgG2, IgG3, IgG4 or the like can be used. When an IgG antibody is used as a ligand-binding molecule, binding to the ligand is also provided by the variable region. One of two variable regions or both variable regions of an IgG antibody may mediate ligand binding.

In some more specific embodiments of the present invention, the domain having ligand-binding activity is separated from the ligand-binding molecule by cleavage of a cleavage site or protease-cleavable sequence in the ligand-binding molecule, thereby reducing binding to the ligand. In one embodiment, when using an IgG antibody as a ligand-binding molecule, for example, a cleavage site or protease-cleavable sequence is created in the variable region of the antibody, and the complete variable region of the antibody cannot be formed in the cleaved state, resulting in weakened binding to the ligand.

As used herein, the term “association” may refer, for example, to a state in which two or more polypeptide regions interact with each other. Typically, a hydrophobic bond, a hydrogen bond, an ionic bond, or the like. formed between the required peptide regions to form an association. As one example of a common association, it is known that an antibody which is a naturally occurring antibody retains the paired structure of a heavy chain variable region (VH) and a light chain variable region (VL) due to a non-covalent bond or the like. between them.

In some embodiments of the present invention, the VH and VL contained in the ligand binding molecule are associated with each other. The association between the antibody VH and the antibody VL can be abrogated, for example, by cleavage of the cleavage site or protease-cleavable sequence. Association cancellation can be used interchangeably, for example, with complete or partial cancellation of a condition in which two or more polypeptide regions interact with each other. To annul the association between VH and VL, the interaction between VH and VL may be completely abrogated, or the interaction between VH and VL may be partially abrogated.

The ligand-binding molecule of the present invention is a ligand-binding molecule in which the association between the VL of an antibody or a portion thereof and the VH of an antibody or a portion thereof is abrogated by cleavage of a cleavage site or abrogated by protease cleavage of a protease-cleavable sequence.

In some embodiments of the present invention, the ligand binding molecule comprises a VH antibody and a VL antibody, and the VH antibodies and VL antibodies in the ligand binding molecule are associated with each other in a state in which a cleavage site or protease cleavable sequence of the ligand binding molecule is not cleaved, wherein the association between the VH antibodies and the antibody VL in the ligand binding molecule is abrogated by cleavage of the cleavage site or protease cleavable sequence. The cleavage site or protease-cleavable sequence in the ligand-binding molecule can be placed at any position in the ligand-binding molecule if the binding of the ligand by the ligand-binding molecule can be weakened by cleavage of the cleavage site or protease-cleavable sequence.

In some embodiments of the present invention, the ligand binding molecule comprises a VH antibody, a VL antibody, and an antibody constant region.

As noted in Rothlisberger et al., J Mol Biol. 347 (4), April 8, 2005, pp. 773-789, it is known that the VH and VL domains or CH and CL domains of an antibody interact with each other through several amino acid side chains. It is known that VH-CH1 and VL-CL have the ability to form a stable structure in the form of a Fab domain. As described earlier, in general, the interaction between VH and VL occurs through amino acid side chains and is characterized by a dissociation constant ranging from 10 ^-5 M to 10 ^-8 M. When only the VH and VL domains are present, only a small part of them can be in an associated state.

In some embodiments of the present invention, the ligand binding molecule is designed such that a cleavage site or protease cleavage sequence is present in the ligand binding molecule comprising VH antibodies and VL antibodies, and such that a complete heavy chain-light chain interaction occurs between the two peptides in the Fab structure before cleavage, wherein the interaction between the VH (or part of VH) containing peptide and the VL (or part of VL) containing peptide is weakened by cleavage of the cleavage site or protease cleavable sequence, thereby abolishing the association between VH and VL.

In one embodiment of the present invention, the cleavage site or protease-cleavable sequence is/is located in the constant region of the antibody. In a more specific embodiment of the present invention, the cleavage site or protease cleavable sequence is located/localized on the variable region side of amino acid position 140 (EU numbering) in the constant region of the antibody heavy chain, preferably on the variable region side of amino acid position 122 (EU numbering) in the constant region of the antibody heavy chain. In some specific embodiments, the cleavage site or protease cleavable sequence is inserted at any position in the sequence from amino acid position 118 (EU numbering) of the antibody heavy chain constant region to amino acid position 140 (EU numbering) of the antibody heavy chain constant region. In another more specific embodiment of the invention, the cleavage site or protease-cleavable sequence is located/localized at the variable region side relative to amino acid position 130 (EU numbering) (Cabot position number 130) in the constant region of the light chain of the antibody, preferably at the variable region side relative to amino acid position 113 (EU numbering) (Cabot position number 113) in the constant region of an antibody light chain, or on the variable region side relative to amino acid position 112 (EU numbering) (Cabot position number 112) in the constant region of an antibody light chain. In some more specific embodiments of the invention, the cleavage site or protease cleavable sequence is inserted at any position in the sequence from amino acid position 108 (EU numbering) (Cabot position number 108) in the constant region of the antibody light chain to amino acid position 131 (EU numbering) (Cabot position number 131) in the constant region of the antibody light chain.

In one embodiment of the present invention, the cleavage site or protease-cleavable sequence is located/localized in the VH of the antibody or VL of the antibody. In a more specific embodiment of the invention, the cleavage site or protease-cleavable sequence is located/localized on the antibody constant region side relative to amino acid position 7 (Cabot numbering) of the antibody VH, preferably on the antibody constant region side relative to amino acid position 40 (Cabot numbering) of the antibody VH, more preferably from the antibody constant region side relative to amino acid position 101 (Cabot numbering) of the antibody VH, even more preferably from the antibody constant region side relative to amino acid position 109 (Cabot numbering) of the antibody VH, or from the antibody constant region side relative to amino acid position 111 ( Cabot numbering) VH antibodies. In a more specific embodiment of the invention, the cleavage site or protease-cleavable sequence is located/localized on the antibody constant region side relative to amino acid position 7 (Cabot numbering) of the VL antibody, preferably on the antibody constant region side relative to amino acid position 39 (Cabot numbering) of the VL antibody, more preferably on the antibody constant region side relative to amino acid position 96 (Cabot numbering) of the antibody VL, even more preferably on the antibody constant region side relative to amino acid position 104 (Cabot numbering) of the antibody VL, or on the antibody constant region side relative to amino acid position 105 ( Cabot numbering) VL antibodies.

In some more specific embodiments of the invention, the cleavage site or protease cleavable sequence is inserted at the position of residues that form a loop structure in the VH of an antibody or in the VL of an antibody and residues adjacent to the loop structure. A loop-type structure in an antibody VH or an antibody VL means a fragment that does not form a secondary structure, such as an α-helix or a β-sheet, in an antibody VH or an antibody VL. In particular, the position of the residues forming the loop structure and the residues adjacent to the loop structure may range from amino acid position 7 (Cabot numbering) to amino acid position 16 (Cabot numbering), from amino acid position 40 (Cabot numbering ) to amino acid position 47 (Cabot numbering), from amino acid position 55 (Cabot numbering) to amino acid position 69 (Cabot numbering), from amino acid position 73 (Cabot numbering) to amino acid position 79 (Cabot numbering), from amino acid position 83 (Cabot numbering) to amino acid position 89 (Cabot numbering), amino acid position 95 (Cabot numbering) to amino acid position 99 (Cabot numbering) or amino acid position 101 (Cabot numbering) to amino acid position 113 (Cabot numbering) in the VH of an antibody, or from amino acid position 7 (Cabot numbering) to amino acid position 19 (Cabot numbering), from amino acid position 39 (Cabot numbering) to amino acid position 46 (Cabot numbering), from amino acid position 49 (Cabot numbering) to amino acid position 62 (Cabot numbering) or from amino acid position 96 (Cabot numbering) to amino acid position 107 (Cabot numbering) in the VL of the antibody.

In some more specific embodiments of the invention, the cleavage site or protease cleavable sequence is inserted at any position in the sequence from amino acid position 7 (Cabot numbering) to amino acid position 16 (Cabot numbering), from amino acid position 40 (Cabot numbering) to amino acid position 47 (Cabot numbering), from amino acid position 55 (Cabot numbering) to amino acid position 69 (Cabot numbering), from amino acid position 73 (Cabot numbering) to amino acid position 79 (Cabot numbering), from amino acid position 83 ( Cabot numbering) to amino acid position 89 (Cabot numbering), from amino acid position 95 (Cabot numbering) to amino acid position 99 (Cabot numbering) or from amino acid position 101 (Cabot numbering) to amino acid position 113 (Cabot numbering) ) in VH antibodies.

In some more specific embodiments of the invention, the cleavage site or protease cleavable sequence is inserted at any position in the sequence from amino acid position 7 (Cabot numbering) to amino acid position 19 (Cabot numbering), from amino acid position 39 (Cabot numbering) to amino acid position 46 (Cabot numbering), from amino acid position 49 (Cabot numbering) to amino acid position 62 (Cabot numbering) or from amino acid position 96 (Cabot numbering) to amino acid position 107 (Cabot numbering) in the VL of the antibody.

In one embodiment of the present invention, the cleavage site or protease-cleavable sequence is located/localized near the boundary between the VH of the antibody and the constant region of the antibody. The phrase “near the boundary between the antibody VH and the antibody heavy chain constant region” may mean a position between amino acid position 101 (Cabot numbering) of the antibody VH and amino acid position 140 (EU numbering) of the antibody heavy chain constant region, and may preferably mean the position , located between amino acid position 109 (Cabot numbering) of the antibody VH and amino acid position 122 (EU numbering) of the constant region of the antibody heavy chain or between amino acid position 111 (Cabot numbering) of the VH antibody and amino acid position 122 (EU numbering) of the constant region antibody heavy chain. When an antibody VH is fused to an antibody light chain constant region, the phrase "near the boundary between the antibody VH and the antibody light chain constant region" may mean a position between amino acid position 101 (Cabot numbering) of the antibody VH and amino acid position 130 (EU numbering) ) (Cabot position numbering 130) of the antibody light chain constant regions, and may preferably mean a position located between amino acid position 109 (Cabot numbering) of the VH antibody and amino acid position 113 (EU numbering) (Cabot position numbering 113) of the constant regions the antibody light chain, or between amino acid position 111 (Cabot numbering) of the antibody VH and amino acid position 112 (EU numbering) (Cabot numbering position 112) of the antibody light chain constant regions.

In one embodiment of the invention, the cleavage site or protease-cleavable sequence is located/localized near the boundary between the VL of the antibody and the constant region of the antibody. The phrase “near the boundary between the antibody VL and the antibody light chain constant region” may mean a position located between amino acid position 96 (Cabot numbering) of the antibody VL and amino acid position 130 (EU numbering) (Cabot numbering position 130) of the light chain constant region antibodies and may preferably mean a position located between amino acid position 104 (Cabot numbering) of the antibody VL and amino acid position 113 (EU numbering) (Cabot numbering position 113) of the antibody light chain constant region or between amino acid position 105 (Cabot numbering) VL of the antibody and amino acid position 112 (EU numbering) (Cabot position numbering 112) of the antibody light chain constant region. When an antibody VL is fused to an antibody heavy chain constant region," the phrase "near the boundary between the antibody VL and the antibody heavy chain constant region" may mean a position between amino acid position 96 (Cabot numbering) of the antibody VL and amino acid position 140 (EU- numbering) of the antibody heavy chain constant region, and may preferably mean a position located between amino acid position 104 (Cabot numbering) of the VL antibody and amino acid position 122 (EU numbering) of the heavy chain constant region of the antibody or between amino acid position 105 (Cabot numbering) VL of the antibody and amino acid position 122 (EU numbering) of the constant region of the antibody heavy chain.

The cleavage site or protease cleavable sequence can be created at a variety of positions in the ligand binding molecule and can be created at a variety of positions selected, for example, in the antibody constant region, antibody VH, antibody VL, near the boundary between the antibody VH and the antibody constant region, and near the boundary between VL antibodies and the antibody constant region. Those skilled in the art, given the present disclosure, can alter the form of a molecule comprising a VH antibody, a VL antibody, and an antibody constant region, for example, by replacing a VH antibody with a VL antibody. Said molecular form falls within the scope of the present invention.

As used herein, the term “ligand” means a molecule having biological activity. A molecule having biological activity typically functions by interacting with a cell surface receptor and thereby exerting biological stimulation, inhibition, or other modulation. These functions are generally likely to be involved in extracellular signaling pathways of receptor-bearing cells.

As used herein, a ligand is a desired molecule that has biological activity when interacting with a biomolecule. For example, a ligand means not only a molecule that interacts with a receptor, but also includes a molecule that exhibits biological activity when interacting with a molecule, such as a receptor that interacts with the molecule, or a binding fragment thereof. For example, a ligand-binding site of a protein known as a receptor and a protein containing a site for interaction of the receptor with another molecule fall under the term "ligand" according to the present invention. In particular, for example, a soluble receptor, a soluble receptor fragment, an extracellular domain of a transmembrane receptor, and polypeptides containing them are included within the concept of a “ligand” according to the present invention.

The ligand proposed in the present invention can, as a rule, exhibit the desired biological activity upon binding to one or more binding partners. The ligand binding partner may be an extracellular, intracellular or transmembrane protein. In one embodiment, the ligand binding partner is an extracellular protein, such as a soluble receptor. In another embodiment of the invention, the ligand binding partner is a membrane-bound receptor.

The ligand proposed in the present invention can specifically bind to a binding partner with a dissociation constant (KD) of 10 μM, 1 μM, 100 nM, 50 nM, 10 nM, 5 nM, 1 nM, 500 pM, 400 pM, 350 pM, 300 pM, 250 pM, 200 pM, 1 50pm , 100pM, 50pM, 25pM, 10pM, 5pM, 1pM, 0.5pM or 0.1pM or less.

Examples of molecules having biological activity include, but are not limited to, cytokines, chemokines, polypeptide hormones, growth factors, apoptosis-inducing factors, PAMPs, DAMPs, nucleic acids, and fragments thereof. In a specific embodiment, the ligand may be an interleukin, an interferon, a hematopoietic factor, a member of the TNF superfamily, a chemokine, a cell growth factor, a member of the TGF-β family, a myokine, an adipokine, or a neurotrophic factor. In a more specific embodiment of the invention, CXCL10, IL-2, IL-7, IL-12, IL-15, IL-18, IL-21, IFN-α, IFN-β, IFN-g, MIG can be used as a ligand , I-TAC, RANTES, MIP-1a or MIP-1b.

Chemokines are a homogeneous family of serum proteins with a molecular weight ranging from 7 to 16 kDa, initially distinguished by their ability to induce leukocyte migration. Most chemokines have four characteristic cysteine residues (Cys) and are classified as CXC or alpha, CC or beta, C or gamma, and CX3C or delta classes of chemokines depending on the motifs formed by the first two cysteines. Two disulfide bonds are formed between the first and third cysteines and between the second and fourth cysteines. Generally, disulfide bridges are considered essential. Clark-Lewis and co-workers described that disulfide bonds are critical for the activity of the chemokine, at least CXCL10 (Clark-Lewis et al., J. Biol. Chem. 269, 1994, cc. 16075-16081). One single exception to the presence of four cysteines is lymphotactin, which has only two cysteine residues. Thus, lymphotactin strictly maintains its structure with only one disulfide bond.

The CXC or alpha subfamilies are further classified by the presence of an ELR motif (Glu-Leu-Arg) before the first cysteine, into two groups: ELR-CXC chemokines and non-ELR-CXC chemokines (see, e.g., Clark-Lewis, supra; and Belperio et al., "CXC Chemokines in Angiogenesis," J. Leukoc. Biol. 68, 2000, pp. 1-8).

Interferon-inducible protein-10 (IP-10 or CXCL10) is induced by interferon-γ and TNF-α and is produced by keratinocytes, endothelial cells, fibroblasts, and monocytes. IP-10 is thought to play a role in mobilizing activated T cells to the site of tissue inflammation (Dufour et al., “IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking), J Immunol., 168, 2002, cc. 3195-3204). In addition, there is a possibility that IP-10 is involved in the hypersensitivity reaction. There is a possibility that IP-10 also plays a role in the incidence of inflammatory demyelinating neuropathies (Kieseier et al., “Chemokines and chemokine receptors in inflammatory demyelinating neuropathies: a central role for IP-10,” Brain 125, 2002, pp. 823- 834).

Studies have demonstrated the possibility that IP-10 is valuable for the engraftment of stem cells after transplantation (Nagasawa T., Int. J. Hematol. 72, 2000, cc. 408-411), for the mobilization of stem cells (Gazitt Y., J. Hematother Stem Cell Res 10, 2001, pp. 229-236; and Hattori et al., Blood 97, 2001, pp. 3354-3359) and for antitumor hyperimmunity (Nomura et al., Int. J. Cancer 91, 2001, 597-606; and Mach and Dranoff, Curr. Opin. Immunol. 12, 2000, 571-575). For example, previous studies known to those skilled in the art discuss the biological activity of chemokines (Bruce L. et al., “Radiolabeled Chemokine binding assays”), Methods in Molecular Biology vol. 138, 2000, cc. 129-134; Raphaele V. et al., “Calcium Mobilization”), Methods in Molecular Biology, vol. 138, 2000, cc. 143-148; and Paul D. Ponath et al., “Transwell Chemotaxis,” Methods in Molecular Biology, vol. 138, 2000, cc. 113-120, Humana Press. Totowa, New Jersey).

Examples of the biological activities of CXCL10 include binding to the CXCL10 receptor (CXCR3), CXCL10-induced calcium flux, CXCL10-induced cellular chemotaxis, CXCL10 binding to glycosaminoglycan, and CXCL10 oligomerization.

Examples of a method for measuring the physiological activity of CXCL10 include a method for measuring the cellular chemotactic activity of CXCL10, a reporter assay using a cell line stably expressing CXCR3 (see PLoS One. 5 (9), September 13, 2010, e12700), and a PathHunter™ recruitment assay β-arrestin using B-arrestin recruitment induced early in GPCR signal transduction.

Interleukin 12 (IL-12) is a heterodimeric cytokine consisting of disulfide-linked glycosylated polypeptide chains with molecular weights of 30 and 40 kDa. Cytokines are synthesized and then secreted by dendritic cells, monocytes, macrophages, B cells, Langerhans cells and keratinocytes, and antigen presenting cells, including natural killer cells (NK cells). IL-12 mediates various biological processes and is referred to as NK cell stimulatory factor (NKSF), T cell stimulatory factor, cytotoxic T lymphocyte maturation factor, and EBV-transformed B cell lineage factor.

Interleukin 12 can bind to the IL-12 receptor, which is expressed on the cytoplasmic membranes of cells (eg, T cells and NK cells) and thereby alter (eg, initiate or block) a biological process. For example, the binding of IL-12 to the IL-12 receptor stimulates the growth of pre-activated T cells and NK cells, enhances the cytotoxic activity of cytotoxic T cells (CTL), NK cells and LAK (lymphokine-activated killer cells), induces the production of γ -interferon (IFNγ) by T cells and NK cells and induces the differentiation of naïve Th0 cells into Th1 cells that produce IFNγ and IL-2. In particular, IL-12 is essential for regulating the production and cellular immune response (eg, Th1 cell-mediated immune response) of cytotoxic cells (eg, NK and CTL). Thus, IL-12 is essential for the generation and regulation of both protective immunity (eg, to cure an infectious disease) and pathological immune responses (eg, autoimmunity).

Examples of the method for measuring the physiological activity of IL12 include a method for measuring the activity of IL12 on cell growth, a STAT4 reporter assay, a method for measuring cell activation (cell surface marker expression, cytokine production, etc.) using IL12, and a method for measuring the enhancement of cell differentiation using IL12 .

Programmed cell death protein 1 (PD-1) is an inhibitory member of the CD28 receptor family. The CD28 family also includes CD28, CTLA-4, ICOS and BTLA. PD-1 is expressed on activated B cells, T cells, and bone marrow cells (Okazaki et al., Curr. Opin. Immunol. 14, 2002, pp. 391779-391782; and Bennett et al., J Immunol 170, 2003 , pp. 711-718). CD28 and ICOS, the first members of the family were described on the basis of a functional effect on enhancing T cell growth after the addition of a monoclonal antibody (Hutloff et al., Nature 397, 1999, pp. 263-266; and Hansen et al., Immunogenics 10, 1980 , pp. 247-260). PD-1 was discovered by screening for differential expression in apoptotic cells (Ishida et al., EMBO J 11, 1992, cc. 3887-3895). CTLA-4 and BTLA, other members of the family, were discovered by screening for differential expression in cytotoxic T lymphocytes and TH1 cells, respectively. CD28, ICOS, and CTLA-4 all have an unpaired cysteine residue that mediates homodimerization. In contrast, PD-1 is thought to be present as a monomer and does not have an unpaired cysteine residue, which is characteristic of other CD28 family members.

The PD-1 gene encodes a 55 kDa type I transmembrane protein that is part of the Ig superfamily. PD-1 contains a membrane-proximal tyrosine-based immunoreceptor inhibitory motif (ITIM) and a membrane-distal tyrosine-based switch motif (ITSM). PD-1 is structurally similar to CTLA-4 but lacks the MYPPPY motif (SEQ ID NO: 537), which is important for the binding of B7-1 and B7-2. Two ligands, PD-L1 and PD-L2, for PD-1 have been identified and found to negatively regulate T cell activation upon binding to PD-1 (Freeman et al., J Exp Med 192, 2000, pp. 1027 -1034; Latchman et al., Nat Immunol 2, 2001, pp. 261-268; and Carter et al., Eur J Immunol 32, 2002, pp. 634-643). Both PD-L1 and PD-L2 are B7 homologs that bind to PD-1 but not to other CD28 family members. PD-L1, one of the ligands of PD-1, is present in large quantities in various human cancers (Dong et al., Nat. Med. 8, 2002, pp. 787-789). The interaction between PD-1 and PD-L1 leads to a decrease in the number of tumor-infiltrating lymphocytes, a decrease in T-cell receptor-mediated growth, and the escape of cancer cells from immunological surveillance (Dong et al., J. Mol. Med. 81, 2003, cc. 281 -287; Blank et al., Cancer Immunol. Immunother. 54, 2005, pp. 307-314; and Konishi et al., Clin. Cancer Res. 10, 2004, pp. 5094-5100). Immunosuppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1, and this effect is additive when the interaction of PD-2 with PD-L2 is also inhibited (Iwai et al., Proc. Natl. Acad. Sci. USA 99, 2002 , pp. 12293-12297; and Brown et al., J. Immunol. 170, 2003, pp. 1257-1266).

PD-1 is an inhibitory member of the CD28 family that is expressed on activated B cells, T cells, and bone marrow cells. Animals with PD-1 deficiency develop various autoimmune phenotypes, including autoimmune cardiomyopathy and lupus-type syndrome with arthritis and nephritis (Nishimura et al., Immunity 11, 1999, pp. 141-151; and Nishimura et al., Science 291, 2001 , pp. 319-322). In addition, PD-1 has been shown to play an important role in autoimmune encephalomyelitis, systemic lupus erythematosus, graft-versus-host disease (GVHD), type I diabetes mellitus, and rheumatoid arthritis (Salama et al., J Exp Med 198, 2003, 71-78; Prokunia and Alarcon-Riquelme Hum Mol Genet 13, 2004, R143; and Nielsen et al., Lupus 13, 2004, p. 510). In a murine B cell tumor line, ITSM in PD-1 was found to be important for inhibition of BCR-mediated Ca ²⁺ flux and tyrosine phosphorylation by downstream effector molecules (Okazaki et al., PNAS 98, 2001, pp. 13866-13871 ).

In some embodiments of the present invention, the ligand is a cytokine.

Cytokines are families of cell-secreted signaling proteins that are involved in immunomodulation and inflammation. These cytokines are secreted by glial cells of the nervous system and many cells of the immune system. Cytokines can be classified as proteins, peptides, and glycoproteins and include highly diverse families of regulators. Cytokines can induce intracellular signal transduction by binding to their cell surface receptors, thereby causing regulation of enzymatic activity, up- or down-regulation of certain genes and their transcription factors, or feedback inhibition, etc.

In some embodiments, the cytokine of the present invention includes immunomodulatory factors such as interleukins (IL) and interferons (IFN). A suitable cytokine may comprise a protein derived from one or more of the following types: the four α-helical bundle family (which includes the IL-2 subfamily, the IFN subfamily, and the IL-10 subfamily); the IL-1 family (which includes IL-1 and IL-8); and the IL-17 family. A cytokine may also include cytokines classified as type 1 cytokines (eg, IFN-γ and TGF-β), which enhance the cellular immune response, or type 2 cytokines (eg, IL-4, IL-10 and IL-13), which have a beneficial effect on the humoral response.

In some embodiments of the present invention, the ligand is a chemokine. Chemokines typically act as chemoattractants that mobilize immune effector cells to areas of chemokine expression. Expression of a particular chemokine gene, for example in combination with a cytokine gene, is considered beneficial for the purpose of mobilizing other components of the immune system to the area to be treated. These chemokines include CXCL10, RANTES, MCAF, MIP-α and MIP1-β. It will be apparent to those skilled in the art that some cytokines also have chemoattractive effects and it is accepted that these cytokines can be classified as “chemokines”.

In some embodiments of the present invention, a cytokine variant, a chemokine variant, or the like may be used as the ligand. (eg, Annu Rev Immunol. 33, 2015, pp. 139-167) or a fusion protein containing variants (eg, Stem Cells Transl Med. 4 (1), Jan. 2015, pp. 66-73).

In some embodiments of the present invention, the ligand is selected from CXCL10, PD1, IL12 and IL6R. CXCL10, PD1, IL12, or IL6R may have the same sequence as naturally occurring CXCL10, PD1, IL12, or IL6R, or may be a variant ligand whose sequence differs from that of naturally occurring CXCL10, PD1, IL12, or IL6R , but retains the physiological activity of the corresponding natural ligand. To obtain a variant ligand, a change can be artificially added to the ligand sequence for various purposes. Preferably, a change resulting in resistance to protease cleavage (protease resistance change) is added to produce a variant ligand.

In some embodiments of the present invention, the biological activity of the ligand is inhibited by binding to an uncleaved ligand-binding molecule. Examples of embodiments in which the biological activity of a ligand is inhibited include, but are not limited to, embodiments in which binding of the ligand to an uncleaved ligand-binding molecule substantially or substantially interferes with or competes with the binding of the ligand to its binding partner . When used as a ligand-binding molecule, an antibody or a fragment thereof having ligand-neutralizing activity, the ligand-binding molecule associated with the ligand has the ability to inhibit the biological activity of the ligand by exerting its neutralizing activity.

In one embodiment of the present invention, the preferably uncleaved ligand-binding molecule can substantially neutralize the biological activity of the ligand by binding to the ligand. In particular, the biological activity of a ligand bound to an uncleaved ligand-binding molecule is lower than that of a ligand not bound to an uncleaved ligand-binding molecule. The biological activity of the ligand bound to the uncleaved ligand binding molecule may be, but is not limited to, 90% or less, preferably 80% or less, 70% or less, 60% or less, 50% or less, 40 % or less, or 30% or less, especially preferably 20% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less, of the biological activity of the ligand not associated with an uncleaved ligand-binding molecule. It can be expected that the introduction of a ligand-binding molecule, which substantially neutralizes the biological activity of the ligand, prevents the manifestation of the biological activity of the ligand before it reaches the target tissue.

In one embodiment of the present invention, the binding activity of the cleaved ligand binding molecule to the ligand is preferably lower than the in vivo ligand binding activity of the naturally occurring ligand binding partner (eg, the naturally occurring receptor for the ligand). The binding activity of the cleaved ligand binding molecule to the ligand is (but is not limited to), for example, 90% or less, preferably 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, or 30% or less, particularly preferably 20% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less, of the amount of ligand bound in vivo by a naturally occurring binding partner (not a unit of binding partner). The selected indicator can be used accordingly as an indicator of binding activity. For example, you can use the dissociation constant (KD). When using the dissociation constant (KD) as a metric for assessing binding activity, a higher dissociation constant (KD) value of a cleaved ligand-binding molecule indicative of ligand binding than that of the naturally occurring ligand binding partner in vivo indicates that the cleaved ligand-binding molecule the molecule has weaker ligand binding activity than its naturally occurring in vivo binding partner. The dissociation constant (KD) of the cleaved ligand-binding molecule, indicative of binding to the ligand, is at least 1.1 times, preferably at least 1.5 times, at least 2 times, at least 5 times, or at least at least 10 times, particularly preferably at least 100 times the dissociation constant (KD) characterizing the binding of a naturally occurring ligand binding partner in vivo. A ligand-binding molecule having only little or little ligand-binding activity after cleavage causes the ligand to be released upon cleavage of the ligand-binding molecule, and it can be expected that there is a barrier to the molecule binding again to another ligand.

Preferably, the ligand retains suppressed biological activity after cleavage of the ligand-binding molecule. Preferably, the binding of the ligand by the cleaved ligand-binding molecule is weakened, whereby the biological activity-inhibiting function of the ligand of the ligand-binding molecule is weakened. Those skilled in the art can determine the biological activity of a ligand using a known method, for example, a method for assessing the binding of a ligand to its binding partner.

In some embodiments of the present invention, the uncleaved ligand-binding molecule forms a complex with a ligand through antigen-antibody binding. In a more specific embodiment of the invention, the ligand-binding molecule-ligand complex is formed through a non-covalent bond, such as antigen-antibody binding, between the ligand-binding molecule and the ligand.

In some embodiments of the present invention, an uncleaved ligand-binding molecule is fused to a ligand to form a fusion protein. The ligand-binding molecule moiety and the ligand moiety in the fusion protein further interact with each other through antigen-antibody binding. The ligand binding molecule and the ligand can be fused via a linker or without a linker. Even when the ligand binding molecule and the ligand in the fusion protein are fused through a linker or without a linker, a non-covalent bond is still present between the ligand binding molecule moiety and the ligand moiety. In other words, even in those embodiments in which the ligand binding molecule is fused to a ligand, the non-covalent bond between the ligand binding molecule moiety and the ligand moiety is similar to those embodiments in which the ligand binding molecule is not fused to a ligand. The noncovalent bond is weakened by cleavage of the ligand-binding molecule. In general, the binding of a ligand by a ligand-binding molecule is weakened.

In a preferred embodiment of the present invention, the ligand binding molecule and the ligand are fused through a linker. For example, an arbitrary peptide linker can be introduced by genetic engineering, or a synthetic linker can be used (see, for example, Protein Engineering, 9 (3), 1996, pp. 299-305) as a linker to fuse the ligand binding molecule with ligand. In the present embodiment, a peptide linker is preferred. There is no limitation on the length of the peptide linker and accordingly those skilled in the art can select it depending on the purpose. Examples of a peptide linker may include (but are not limited to):

where n denotes an integer 1 or more.

However, the length and sequence of the peptide linker can be selected accordingly by those skilled in the art depending on the purpose.

A synthetic linker (chemical crosslinker) is a crosslinker that is commonly used to crosslink peptides, e.g. N-hydroxysuccinimide (NHS), disuccinimidyl suberate (DSS), bis(sulfosuccinimidyl)suberate (BS3), dithiobis(succinimidylpropionate) (DSP) , dithiobis(sulfosuccinimidyl propionate) (DTSSP), ethylene glycolbis(succinimidyl succinate) (EGS), ethylene glycolbis(sulfosuccinimidyl succinate) (sulfo-EGS), disuccinimidyl tartrate (DST), disulfosuccinimidyl tartrate (sulfo-DST), bis[2-(succinimidoxycarbonyloxy)ethyl]sulfone ( BSOCOES) or bis[2-(sulfosuccinimidoxycarbonyloxy)ethyl]sulfone (sulfo-BSOCOES). These cross-linking agents are commercially available.

The present invention also relates to a pharmaceutical composition (drug) containing a ligand binding molecule proposed in the present invention and a pharmaceutically acceptable carrier, a pharmaceutical composition (drug) containing a ligand binding molecule proposed in the present invention, a ligand and a pharmaceutically acceptable carrier, and a pharmaceutical a composition (drug) containing a fusion protein of the ligand binding molecule of the present invention with a ligand, and a pharmaceutically acceptable carrier.

As used herein, the concept of “treatment” (and its grammatical variations such as “to treat” or “the process of treatment”) refers to a clinical intervention with the purpose of changing the natural history of a disease in the individual being treated, and can be carried out either for prevention or during the development of a clinical pathological condition. The desired treatment actions include, but are not limited to, prevention of onset or recurrence of the disease, relief of symptoms, reduction of any direct or indirect pathological consequences of the disease, prevention of metastases, reduction in the rate of disease progression, alleviation or temporary relief of the disease state, and remission or improvement of prognosis. In some embodiments, the ligand binding molecule of the present invention can control the biological activity of a ligand and is used to delay the onset of a disease or slow the progression of a disease.

In the present invention, the term "pharmaceutical composition" generally refers to a medicinal product intended for the treatment or prevention of a disease or for examination or diagnosis.

In the present invention, the term "pharmaceutical composition containing a ligand binding molecule" can be used interchangeably with the term "a method of treating a disease comprising administering a ligand binding molecule to an individual to be treated" and can be used interchangeably with the term "using a ligand binding molecule to produce a medicament for treating a disease " In addition, the term “pharmaceutical composition containing a ligand binding molecule” can be used interchangeably with the term “using a ligand binding molecule to treat a disease.”

The term "pharmaceutical composition comprising a ligand binding molecule and a ligand" may be used interchangeably with the term "a method of treating a disease comprising administering a ligand binding molecule and a ligand to an individual to be treated" and may be used interchangeably with the term "using a ligand binding molecule and a ligand to produce a medicament intended for for the treatment of the disease." In addition, the term “pharmaceutical composition containing a ligand binding molecule and a ligand” can be used interchangeably with the term “using a ligand binding molecule and a ligand for treating a disease.”

The term “pharmaceutical composition containing a fusion protein” can be used interchangeably with the term “a method of treating a disease comprising administering the fusion protein to an individual to be treated” and can be used interchangeably with the term “using the fusion protein to produce a medicament for treating a disease.” In addition, the term “pharmaceutical composition containing a fusion protein” can be used interchangeably with the term “use of a fusion protein to treat a disease.”

In some embodiments of the present invention, a composition containing a ligand binding molecule can be administered to an individual. A ligand binding molecule administered to an individual is bound by a ligand originally present in the individual's body, such as blood or tissue, and the ligand binding molecule in said ligand bound state is then transported in vivo. A ligand-binding molecule transported to a target tissue may be cleaved in the target tissue, such that its binding to the ligand may be weakened, releasing the bound ligand in the target tissue. The released ligand can exhibit biological activity in the target tissue and treat a disease associated with the target tissue. In embodiments of the invention in which the ligand-binding molecule inhibits the biological activity of the ligand upon binding to the ligand and is cleaved specifically in the target tissue, the ligand has no biological activity during transport and exhibits biological activity only when the ligand-binding molecule is cleaved in the target tissue. As a result, the disease can be treated with reduced systemic adverse reactions.

In some embodiments of the present invention, the composition containing the ligand binding molecule and the composition containing the ligand can be administered to an individual separately or simultaneously. Alternatively, a composition containing both a ligand binding molecule and a ligand can be administered to an individual. When a composition containing both a ligand-binding molecule and a ligand is administered to an individual, the ligand-binding molecule and the ligand in the composition may form a complex. When both a ligand binding molecule and a ligand are administered to an individual, the ligand binding molecule binds to the ligand administered to the individual and the ligand binding molecule in said ligand bound state is transported in vivo. A ligand-binding molecule transported to a target tissue may be cleaved in the target tissue, causing the ligand binding to be weakened, resulting in the release of the bound ligand into the target tissue. The released ligand can exhibit biological activity in the target tissue and treat a disease associated with the target tissue. In one embodiment of the invention, in which the ligand-binding molecule inhibits the biological activity of the ligand upon binding to the ligand and is cleaved specifically in the target tissue, the ligand does not exhibit biological activity during transport and exhibits biological activity only when the ligand-binding molecule is cleaved in the target tissue. As a result, the disease can be treated with reduced systemic adverse reactions. A ligand binding molecule administered to an individual also has the ability to bind to a ligand originally present in the individual's body in addition to the ligand that is administered to the individual. A ligand-binding molecule in a state bound to a ligand that is initially present in the individual, or to a ligand administered to the individual, can be transported in vivo.

In some embodiments of the present invention, a fusion protein comprising a ligand binding molecule coupled to a ligand can be administered to an individual. In these certain embodiments, the ligand binding molecule and the ligand in the fusion protein are fused through or without a linker. The non-covalent bond is still present between the ligand-binding molecule moiety and the ligand moiety. When a fusion protein containing a ligand binding molecule fused to a ligand is administered to an individual, the fusion protein is transported in vivo. The ligand binding molecule fragment in the fusion protein is cleaved in the target tissue, causing the non-covalent bond linking the ligand binding molecule fragment to the ligand to be weakened, releasing the ligand and portion of the ligand binding molecule from the fusion protein. The released ligand and the released portion of the ligand-binding molecule can exhibit the biological activity of the ligand in the target tissue and treat a disease associated with the target tissue. In embodiments of the invention in which the ligand-binding molecule inhibits the biological activity of the ligand upon binding to the ligand and is cleaved specifically in the target tissue, the ligand in the fusion protein does not exhibit biological activity during transport and exhibits biological activity only when the fusion protein is cleaved in the target tissue. As a result, the disease can be treated with reduced systemic adverse reactions.

The pharmaceutical composition of the present invention can be prepared for use by a method well known to those skilled in the art. For example, the pharmaceutical composition can be administered parenterally, for example, in the form of a sterile solution or suspension for injection in water or any other pharmaceutically acceptable liquid. The pharmaceutical composition can be prepared, for example, by combining the polypeptide with a pharmacologically acceptable carrier or vehicle, in particular sterile water or physiological saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, excipient, excipient, antiseptic , binding agent, etc., and mix them to obtain the unit dose of drug required for standard pharmaceutical practice. The amount of active substance in these compositions is adjusted so as to obtain an acceptable volume within a predetermined range.

A sterile injectable composition can be prepared according to standard pharmaceutical practice using an excipient such as distilled water suitable for injection. Examples of an injectable aqueous solution include isotonic solutions that contain physiological saline, glucose, or other adjuvants (eg, D-sorbitol, D-mannose, D-mannitol, and sodium chloride). The aqueous solution can be used in combination with an appropriate stabilizer, such as an alcohol (ethanol, etc.), a polyhydric alcohol (propylene glycol, polyethylene glycol, etc.) or a nonionic surfactant (Polysorbate 80™, HCO-50, etc. .d.).

Examples of the oil solution include sesame oil and soybean oil. The oil solution can also be used in combination with benzyl benzoate and/or benzyl alcohol as a solubilizer. The oil solution may be supplemented with a buffer (eg, phosphate buffer solution and sodium acetate buffer solution), an emollient (eg, procaine hydrochloride), a stabilizer (eg, benzyl alcohol and phenol), and an antioxidant. The resulting injection solution is usually filled into the appropriate ampoule.

The pharmaceutical composition proposed in the present invention is preferably administered by the parenteral route. For example, the composition is administered in a dosage form suitable for injection, transnasal, transpulmonary or transdermal administration. The pharmaceutical composition can be administered systemically or applied locally, for example, by intravenous injection, intramuscular injection, intraperitoneal injection or subcutaneous injection.

The method of administration can be selected accordingly depending on the age and symptoms of the patient. The dose of the pharmaceutical composition containing the ligand binding molecule can be selected from a range of, for example, 0.0001 to 1000 mg per kg body weight per dose. Alternatively, the dose of the pharmaceutical composition containing the polypeptide may be selected from, for example, 0.001 to 100,000 mg per patient. However, the present invention is not necessarily limited to these numerical values. Although the dose and method of administration vary depending on body weight, age, symptoms, etc. patient, those skilled in the art can determine the appropriate dosage and method of administration based on the circumstances.

The present invention also relates to a method for producing a ligand binding molecule in which the binding of a ligand is weakened by cleavage, or a fusion protein containing a ligand binding molecule fused to a ligand. In one embodiment, the present invention provides a method for producing a ligand binding molecule or fusion protein, comprising introducing a protease cleavable sequence into a molecule that has the ability to bind a ligand.

Examples of a method of introducing a protease-cleavable sequence into a molecule that has the ability to bind a ligand include a method of inserting a protease-cleavable sequence into the amino acid sequence of a polypeptide that has the ability to bind a ligand, and a method of replacing part of the amino acid sequence of a polypeptide that has the ability to bind a ligand with protease-cleavable sequence.

Examples of a method for producing a molecule that has the ability to bind a ligand include a method for producing a ligand-binding region that has the ability to bind a ligand. The ligand binding region is prepared using, for example, a method known in the art for generating antibodies.

The antibody generated by this production method can be used directly in the ligand binding region, or only the Fv region of the resulting antibody can be used. When the Fv region is in a single chain (also referred to as "sc") form having the ability to recognize antigen, then only one chain can be used. Alternatively, a Fab region containing an Fv region can be used.

The specific method for preparing the antibody is well known to those skilled in the art. For example, monoclonal antibodies can be produced by the hybridoma method (Kohler and Milstein, Nature 256, 1975, p. 495) or by the recombination method (US No. 4816567). Alternatively, monoclonal antibodies can be isolated from phage antibody display libraries (Clackson et al., Nature 352, 1991, pp. 624-628); and Marks et al., J. Mol. Biol. 222, 1991, cc. 581-597). In addition, monoclonal antibodies can be isolated from single B cell clones (N. Biotechnol. 28 (5), 2011, pp. 253-457).

Humanized antibodies are also called reconstituted human antibodies. In particular, what is known in the art is, for example, a humanized antibody consisting of CDRs from a non-human animal (eg, mouse) antibody transplanted into a human antibody. General approaches based on gene recombination are also known for the production of humanized antibodies. In particular, for example, PCR with overlapping primers is a method known in the art for translating mouse antibody CDRs into human FRs.

DNA encoding the variable region of an antibody, which contains linked three CDRs and four FRs, and DNA encoding the constant region of a human antibody can be inserted into an expression vector so that these DNAs are fused in frame to obtain a vector for expressing a humanized antibody. The vector containing the inserts is transfected into hosts to create recombinant cells. The recombinant cells are then cultured to express DNA encoding the humanized antibody to produce the humanized antibody in cultured cells (see European Patent Publication No. 239400 and International Patent Application Publication WO 1996/002576).

If necessary, amino acid residues of FR can be replaced so that the CDRs of the reshaped human antibody form the appropriate antigen binding site. For example, a mutation can be introduced into the amino acid sequence of an FR using a PCR technique known for transplanting murine CDRs into human FRs.

The desired human antibody can be produced by DNA immunization using transgenic animals having the full spectrum of human antibody genes as the target animals (see international patent application publications WO 1993/012227, WO 1992/003918, WO 1994/002602, WO 1994 /025585, WO 1996/034096 and WO 1996/033735).

In addition, techniques for producing human antibodies by panning using libraries of human antibodies are known. For example, the Fv region of a human antibody is expressed as a single chain antibody (scFv) on the surface of a phage using a phage display technique. Phages that express a scFv that binds to an antigen can be selected. The DNA sequence encoding the Fv region of a human antibody that binds the antigen can be determined by analyzing the genes of selected phages. Once the DNA sequence of the antigen-binding scFv has been determined, the Fv region sequence can be fused in frame to the C region sequence of the desired human antibody and then inserted into an appropriate expression vector to produce an expression vector. The expression vector is used to transfect the expression-preferred cells described above for expression of a gene encoding a human antibody to produce a human antibody. Such methods are already known in this field (see publications of international patent applications WO 1992/001047, WO 1992/020791, WO 1993/006213, WO 1993/011236, WO 1993/019172, WO 1995/001438 and WO 1995/015388) .

A molecule carrying a protease cleavable sequence in a molecule that has the ability to bind a ligand serves as the ligand binding molecule of the present invention. Optionally, it is possible to determine whether the ligand binding molecule is cleaved by treatment with a protease suitable for the sequence being cleaved by the protease. The presence or absence of cleavage in a protease-cleavable sequence can be determined, for example, by contacting the protease with a molecule carrying the protease-cleavable sequence in a molecule that has the ability to bind a ligand and determining the molecular weight of the protease-treated product by an electrophoretic method such as SDS-PAGE. .

The present invention also relates to a polynucleotide encoding a ligand-binding molecule whose binding of a ligand is weakened by cleavage, or a polynucleotide encoding a fusion protein containing a ligand-binding molecule fused to a ligand.

The polynucleotide of the present invention is typically present in (or inserted into) a suitable vector and is transfected into host cells. The vector is not limited to a particular vector as long as it stably retains the integrated nucleic acid. For example, when E. coli is used as the host, the pBluescript vector (manufactured by Stratagene Corp.) or the like is preferred as the cloning vector. Various commercially available vectors can be used. When using a vector to produce a ligand binding molecule or fusion protein as proposed in the present invention, the expression vector is most valuable. The expression vector is not limited to a particular vector as long as it retains the ability to express the ligand binding molecule in vitro, in E. coli, in cultured cells or in individuals. For example, it is preferable to use an expression vector such as the pBEST vector (manufactured by Promega Corp.) for in vitro expression; pET vector (manufactured by Invitrogen Corp.) for expression in E. coli; vector pME18S-FL3 (GenBank accession no. AB009864) for expression in cell culture; and vector pME18S (Takebe et al., Mol. Cell Biol. 8, 1988, pp. 466-472) for expression in individuals. Incorporation of the DNA of the present invention into a vector can be accomplished by conventional methods, for example, by a ligase reaction using restriction enzyme sites (Current protocols in Molecular Biology, ed. Ausubel et al., Publish. John Wiley & Sons, section 11.4-11.11, 1987).

Host cells are not limited to specific cells, and different host cells can be used depending on the purpose. Examples of cells for expressing a ligand binding molecule or fusion protein may include bacterial cells (eg, Streptococcus, Staphylococcus, E. coli, Streptomyces and Bacillus subtilis), fungal cells (eg, yeast and Aspergillus), insect cells (eg, Drosophila S2 and Spodoptera SF9 ), animal cells (eg CHO, COS, HeLa, C127, 3T3, BHK, HEK293 and bovine melanoma cells) and plant cells. Transfection of the vector into host cells can be accomplished using a method known in the art, for example, the calcium phosphate precipitation method and the electroporation method (Current protocols in Molecular Biology, edited by Ausubel et al., Publish. John Wiley & Sons, section 9.1-9.9, 1987), the Lipofectamine method (manufactured by GIBCO-BRL/Thermo Fisher Scientific Inc.), or the microinjection method.

An appropriate secretory signal can be included in a ligand binding molecule or fusion protein of interest to secrete the ligand binding molecule or fusion protein expressed/expressed in host cells into the endoplasmic reticulum lumen, periplasmic space or extracellular environment. The signal may be endogenous to the ligand binding molecule or fusion protein of interest or may be a foreign signal.

When a ligand binding molecule of interest or a fusion protein of interest according to the present invention is secreted into a medium, the ligand binding molecule or fusion protein is released into the medium during production. When the ligand binding molecule of interest or fusion protein of interest of the present invention is produced in cells, the cells are first lysed and then the ligand binding molecule or fusion protein of interest is isolated.

A method known in the art, including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxyapatite chromatography and lectin chromatography can be used to isolate and purify the ligand binding molecule or fusion protein proposed/offered in the present invention from recombinant cell cultures.

It will be apparent to those skilled in the art that arbitrary combinations of one or more embodiments of the invention presented herein may also be included in the present invention as long as they are technically within the scope of those skilled in the art. Likewise, the present invention, which excludes arbitrary combinations of one or more embodiments of the invention presented in the present description, should be considered as the invention presented in the present description, unless technically inconsistent with the principles known to specialists in the art.

Examples

Below are examples of methods and compositions proposed in the present invention. It should be obvious that various other embodiments can be carried out in light of the above general description of the invention.

Example 1 Previously described problem associated with immunocytokines and protease-activated cytokines

Immunocytokines that target antigens that are expressed in cancer tissues have typically been produced by fusing the cytokine of interest to the target end of an IgG or scFv (Expert Opin Investig Drugs. 18 (7), July 2009, pp. 991-1000; and Curr Opin Immunol 40, June 2016, pp. 96-102). Since cytokines including IL2, IL12 and TNF are highly toxic, with regard to the local effect of these cytokines on cancer, it is expected that local delivery to the cancerous area by an antibody will enhance their effectiveness while reducing adverse reactions (Non-Patent Documents 4, 5 and 6). However, there are problems associated with all these cytokines, such as: they do not have sufficient effectiveness in clinical settings when administered systemically; their therapeutic windows are narrow; they cannot be administered systemically due to severe toxicity. This is mainly due to the fact that cytokines, including immunocytokines, when administered systemically, have effects throughout the body and therefore may exhibit toxicity through systemic action, or cytokines can only be administered in very low doses to avoid toxicity. In addition, immunocytokines that bind to cancer antigens are lost as a result of internalization by cancer cells in tumors and therefore, in some cases, there are difficulties regarding the local effect of cytokines on cancer. It was found that an immunocytokine containing IL2 fused to an antibody that binds to a cancer antigen and an immunocytokine containing IL2 fused to an antibody that does not bind to a cancer antigen did not differ in antitumor effect (Non-Patent Document 7).

A molecule containing a cytokine and a cytokine receptor connected through a linker that is cleaved by a protease highly expressed in cancer is described in a method to reduce systemic exposure, which is a major problem with the use of immunocytokines. The cytokine is inhibited by the cytokine receptor bound to it through the linker, and the cytokine is released from the cytokine receptor as a result of cleavage of the linker by a protease and thereby acquires an active form. As an example, a molecule containing TNF-alpha and TNFR connected through a linker that is cleaved by uPA is described (Non-Patent Literature 8), and a molecule containing IL2 and IL2R connected through a linker that is cleaved by MMP2 (Non-Patent Literature 9). However, the cytokines in these molecules are biologically active even before linker cleavage, and linker cleavage increases their activity only by about 10-fold.

The reason for this is that: cytokines do not have a strong affinity for their receptors and are therefore active to some extent even before protease cleavage; and cytokine receptors can bind to cytokines even after protease cleavage of the linker and can therefore inhibit the biological activity of cytokines.

A molecule containing IL2 linked to an anti-IL2 scFv instead of IL2R through a linker that is cleavable by MMP-2 is described (Non-Patent Document 9). The anti-IL2 scFv used in this molecule containing IL2 linked to the anti-IL2 scFv via a protease cleavable linker does not have strong affinity for IL2, which is evident, suggesting that IL2 is released as a result of cleavage of the linker, similar to the molecule which contains a cytokine coupled to a cytokine receptor.

Unlike the IgG-IL2 fusion mentioned above, these described protease-activated cytokines did not have an Fc region and therefore likely had a short half-life. This made it difficult to maintain high exposure. Cytokines do not differ significantly in pharmacokinetic parameters before and after activation by protease cleavage (they have a short half-life both before and after activation). Thus, it is difficult to expand their therapeutic windows.

Example 2 Problem associated with the use of chemokines in anticancer immunotherapy

Chemokines (Nature Immunology 9, 2008, pp. 949-952) are basic proteins that exert their actions through G protein-linked receptors and belong to the group of cytokines. Chemokines act on certain leukocytes expressing the receptor and have activity associated with the migration (chemotaxis) of leukocytes depending on the concentration gradients of the agents (Nat Cell Biol. 18 (1), January 2016, pp. 43-53). Chemokines are produced in large quantities in areas of inflammation and are known to induce the migration of leukocytes from blood vessels into inflammatory tissues.

Chemokines can be used in anticancer immunotherapy because the migration of leukocytes can be controlled by chemokines. If local migration of T cells, antigen presenting cells, Ml-macrophages, etc. is achieved. to a solid tumor, this may cause an antitumor effect. Cytokines can function even when administered systemically, while chemokines direct cells to tissues in increasing concentrations through their concentration gradients and therefore cannot be expected to achieve the desired effect when administered systemically. As a result, anticancer immunotherapy using chemokines via systemic administration (chemokine therapy) is considered to be of little practical value.

Example 3 Concept of Using a Ligand-Binding Molecule Which Carries a Protease-Cleavable Sequence and Has the Capacity to Release a Target Tissue-Specific Ligand

As indicated in Examples 1 and 2, the following problems are associated with previously described cytokine or chemokine therapy:

1. Immunocytokines, even if they provide cytokine targeting in solid cancer with the help of an antibody, cause adverse reactions because cytokines act systemically or are administered only in low doses to avoid these adverse reactions, and therefore they cannot provide high tumor exposure.

2. In the case of protease-activated cytokines containing a cytokine receptor (or antibody) and a cytokine connected by a protease-cleavable linker, the cytokine is somewhat active even before cleavage by the protease due to insufficient neutralization of the cytokine's activity.

3. In the case of protease-activated cytokines, the cytokine receptor (or antibody) can bind to the cytokine even after protease cleavage of the linker and therefore inhibits the biological activity of the cytokine.

4. In the case of protease-activated cytokines, the required dose is high because the inactive cytokine has a short half-life and has a short circulation time in the blood.

When creating the invention, it was suggested that in order to solve these problems it is important to fulfill the following conditions:

1. A ligand, such as a cytokine or chemokine, is substantially inhibited (its biological activity is minimized) throughout the body by a ligand-binding molecule.

2. The ligand retains its biological activity (becomes an active ligand) when cleaved by a protease.

3. The ligand-binding molecule loses its ligand-binding activity when cleaved by a protease.

4. A ligand activated by protease cleavage has a shorter half-life compared to a ligand bound to a ligand-binding molecule prior to protease cleavage.

The present invention provides a molecule whose ability to bind a ligand is attenuated by cleavage at a cleavage site as a pharmaceutical composition that satisfies the above conditions. Said ligand-binding molecule can be created by first producing a ligand-binding molecule and then inserting a cleavage site into the binding molecule.

Example 4 Example of an Anti-Ligand Antibody Carrying a Protease-Cleavable Sequence

In fig. 1, 2 and 3 provide examples of molecules prepared using an antibody as a ligand binding molecule. In these examples, a neutralizing antibody against the ligand was first prepared. The protease-cleavable sequence was then inserted near the boundary between the variable region (VH or VL) and the constant region (CH1 or CL) of the neutralizing antibody to the ligand. It has been found that the anti-ligand antibody retains its ligand-binding activity after insertion of a protease-cleavable sequence. It has been found that dissociation of the ligand from the anti-ligand neutralizing antibody occurs upon protease cleavage of the anti-ligand neutralizing antibody fused or bound to the ligand. It has been established that the ligand separated as a result of this dissociation exhibits biological activity.

As shown in FIG. 1, the C-terminus of the ligand and the N-terminus of the VH of the anti-ligand antibody were connected through a linker, and a protease-cleavable sequence was inserted near the boundary between VH and CH1. Provided that the antibody to the ligand has a sufficiently strong affinity for the ligand, the biological activity of the ligand is significantly inhibited. This ligand-antibody-to-ligand fusion does not exhibit biological activity even when administered systemically, since the ligand is neutralized. In addition, the ligand-antibody to ligand fusion has an Fc region and therefore has a long half-life. From a systemically administered ligand-antibody-to-ligand fusion, a ligand-linker-VH antibody-to-ligand molecule is released when a protease-cleavable sequence near the interface between VH and CH1 is cleaved by a protease that is highly expressed in tumor tissue. Since VH or VL individually cannot bind to the ligand (both VH and VL are required for ligand binding), neutralization of the ligand is abolished, allowing the ligand to exert its biological effects in tumor tissue. In addition, said released ligand-linker-VH antibody ligand molecule has a small molecular weight in the absence of the Fc region and therefore has a very short half-life and quickly disappears from the whole organism. Consequently, systemic adverse reactions caused by the ligand can be minimized.

As shown in FIG. 2, the ligand and anti-ligand antibody were not connected through a linker; unlike the design shown in FIG. 1, an anti-ligand antibody carrying a protease-cleavable sequence near the interface between VH and CH1 was mixed with the ligand and administered. Provided that the antibody to the ligand has a sufficiently strong affinity for the ligand, and provided that the required level of ligand concentration is present, significant inhibition of biological activity occurs. This ligand-antibody complex to the ligand does not exhibit biological activity even when administered systemically, since the ligand is neutralized. In addition, the ligand-antibody complex to the ligand has an Fc region and therefore has a long half-life. From a systemically administered ligand-anti-ligand antibody complex, the anti-ligand antibody VH molecule is released when a protease-cleavable sequence near the interface between VH and CH1 is cleaved by a protease that is highly expressed in tumor tissue. Since VH or VL individually cannot bind to the ligand (both VH and VL are required for ligand binding), neutralization of the ligand is abolished, allowing the ligand to exert its biological effects in tumor tissue. In addition, said released ligand-linker-VH antibody ligand molecule has a small molecular weight in the absence of the Fc region and therefore has a very short half-life and quickly disappears from the whole organism. Consequently, systemic adverse reactions caused by the ligand can be minimized.

As shown in FIG. 3, an anti-ligand antibody carrying a protease-cleavable sequence near the boundary between VH and CH1 was administered systemically. The injected antibody bound to the ligand originally present in the body. The subsequent process was as described above in FIG. 2.

Thus, by applying an antibody to a ligand that carries a protease-cleavable sequence near the interface between VH and CH1, selective release of the ligand in protease-expressing tissue can occur and this allows the ligand to exert its biological effects. When the ligand is a cytokine, the cytokine can act selectively in tissue expressing the protease. When the ligand is a chemokine, the chemokine can direct chemokine receptor-expressing cells to protease-expressing tissue because the chemokine is present in high concentration in protease-expressing tissue and has low concentration in peripheral blood.

Example 5 Preparation and Evaluation of CXCL10-Releasing Antibody

5-1. Introduction of a protease-cleavable sequence into a neutralizing antibody to CXCL10

CXCL10 is a chemokine that has chemotactic effects on effector T cells. An expression vector for a neutralizing antibody to human CXCL10 was prepared, i.e. MabCXCL10 (heavy chain: EEIVH (SEQ ID NO: 1), light chain: EEIVL (SEQ ID NO: 2)), using a method known to those skilled in the art, and expressed using FreeStyle 293 (Life Technologies Corp.) and purified using methods known to those skilled in the art. Antibody MabCXCL10 contained the following CDR sequences: H-CDR1 (NNGMH; SEQ ID NO: 380), H-CDR2 (VIWFDGMNKFYVDSVKG; SEQ ID NO: 381), H-CDR3 (EGDGSGIYYYYGMDV; SEQ ID NO: 382), L-CDR1 (RASQSVSSSYLA; SEQ ID NO: 383), L-CDR2 (GASSRAT; SEQ ID NO: 384) and L-CDR3 (QQYGSSPIFT; SEQ ID NO: 385).

The interaction between MabCXCL10 and human CXCL10 (266-IP-010/CF, R&D Systems, Inc.) was assessed using Biacore. In particular, R PROTEIN A (recombinant protein A) (SURE) (28-4018-60, GE Healthcare Japan Corp.) was immobilized on the CM3 sensor chip (BR100536, GE Healthcare Japan Corp.) by amine coupling using NHS⋅ EDC. The running buffer used contained 20 mM ACES, 0.05% Tween 20, and 200 mM NaCl (pH 7.4). 1.563 nM human CXCL10 dissolved in the indicated buffer was injected as an analyte for the captured antibody and antibody-antigen binding was assessed at 37°C. A sensorgram showing the SPR response profiles as a function of time after subtraction of a blank control in which an analyte consisting of running buffer only was used is shown in FIG. 4. The time point corresponding to the beginning of the analyte injection corresponded to the starting point on the x-axis. The response at each time point was plotted on the y-axis, taking the response at the initial time point when the analyte was injected to be 0. As demonstrated in the sensorgram presented in FIG. 4, the binding of MabCXCL10 to human CXCL10 was confirmed.

A study was carried out to insert a protease cleavable sequence near the boundary between the variable region of the heavy chain or light chain and the constant region of MabCXCL10. The heavy chains and light chains shown in FIG. 5 was designed to insert peptide sequence A (SEQ ID NO: 3), the described cancer-specific urokinase expressed (uPA) and matriptase (MT-SP1) cleavable sequence, into 7 sites near the border between the heavy chain variable region and the light chain variable region. circuit and constant region. Variants were also created in which the cleavable sequence was inserted, and glycosylation was eliminated. Expression vectors encoding heavy chain variants EEIVHA (SEQ ID NO: 4), EEIVHB (SEQ ID NO: 5), EEIVHC (SEQ ID NO: 6), EEIVHD (SEQ ID NO: 7), EEIVHE (SEQ ID NO: 8 ), EEIVHF (SEQ ID NO: 9), EEIVHG (SEQ ID NO: 10), EEIVHBG (SEQ ID NO: 11), EEIVHCG (SEQ ID NO: 12), EEIVHDG (SEQ ID NO: 13) and EEIVHEG (SEQ ID NO: 14) and light chain variants EEIVLA (SEQ ID NO: 15), EEIVLB (SEQ ID NO: 16), EEIVLC (SEQ ID NO: 17), EEIVLD (SEQ ID NO: 18), EEIVLE (SEQ ID NO : 19), EEIVLF (SEQ ID NO: 20), EEIVLG (SEQ ID NO: 21) and EEIVLEG (SEQ ID NO: 22), were prepared using a method known to those skilled in the art.

IgG1 isotype antibodies EEIVHA/EEIVL (heavy chain: SEQ ID NO: 4, light chain: SEQ ID NO: 2), EEIVHB/EEIVL (heavy chain: SEQ ID NO: 5, light chain: SEQ ID NO: 2), EEIVHC/EEIVL (heavy chain: SEQ ID NO: 6, light chain: SEQ ID NO: 2), EEIVHD/EEIVL (heavy chain: SEQ ID NO: 7, light chain: SEQ ID NO: 2), EEIVHE/EEIVL ( heavy chain: SEQ ID NO: 8, light chain: SEQ ID NO: 2), EEIVHF/EEIVL (heavy chain: SEQ ID NO: 9, light chain: SEQ ID NO: 2), EEIVHG/EEIVL (heavy chain: SEQ ID NO: 10, light chain: SEQ ID NO: 2), EEIVHBG/EEIVL (heavy chain: SEQ ID NO: 11, light chain: SEQ ID NO: 2), EEI VHC G/EEI VL (heavy chain: SEQ ID NO: 12, light chain: SEQ ID NO: 2), EEI VHD G/EEI VL (heavy chain: SEQ ID NO: 13, light chain: SEQ ID NO: 2) and EEIVHEG/EEIVL (heavy chain: SEQ ID NO: : 14, light chain: SEQ ID NO: 2), carrying a protease cleavable sequence near the interface between the heavy chain variable region and the constant region, and IgG1 isotype antibodies EEIVH/EEIVLA (heavy chain: SEQ ID NO: 1, light chain: SEQ ID NO: 15), EEIVH/EEIVLB (heavy chain: SEQ ID NO: 1, light chain: SEQ ID NO: 16), EEIVH/EEIVLC (heavy chain: SEQ ID NO: 1, light chain: SEQ ID NO: 17 ), EEIVH/EEIVLD (heavy chain: SEQ ID NO: 1, light chain: SEQ ID NO: 18), EEIVH/EEIVLE (heavy chain: SEQ ID NO: 1, light chain: SEQ ID NO: 19), EEIVH/ EEIVLF (heavy chain: SEQ ID NO: 1, light chain: SEQ ID NO: 20), EEIVH/EEIVLG (heavy chain: SEQ ID NO: 1, light chain: SEQ ID NO: 21) and EEIVH/EEIVLEG (heavy chain : SEQ ID NO: 1, light chain: SEQ ID NO: 22), carrying a protease cleavable sequence near the boundary between the light chain variable region and the constant region, were expressed by transient expression using the indicated heavy chain variants in combination with a naturally occurring heavy chain chain or light chain variants in combination with a naturally occurring heavy chain using FreeStyle 293 (Life Technologies Corp.) using a method known to those skilled in the art, and purified using a method known to those skilled in the art using the protein A.

5-2. Evaluation of the binding activity of a neutralizing antibody to CXCL10 carrying a protease-cleavable sequence

Antibodies prepared according to the method described in Example 5-1 were evaluated for their interaction with human CXCL10 (266-IP-010/CF, R&D Systems, Inc.) using Biacore. The results are presented in Fig. 6. In particular, R PROTEIN A (SURE) (28-4018-60, GE Healthcare Japan Corp.) was immobilized on the CM3 sensor chip (BR100536, GE Healthcare Japan Corp.) by amine coupling using NHS⋅EDC. The running buffer used contained 20 mM ACES, 0.05% Tween 20, and 150 mM NaCl (pH 7.4). 3.125, 1.563 or 0.781 nM human CXCL10 was injected as an analyte for each captured antibody and antibody-antigen binding was assessed at 25°C. Sensorgrams showing SPR response profiles as a function of time after subtraction of a blank control in which an analyte consisting of running buffer only was used are presented in FIG. 6. The time point corresponding to the beginning of the analyte injection corresponded to the starting point on the x-axis. The response at each time point was plotted on the y-axis, taking the response at the initial time point when the analyte was injected to be 0. As demonstrated in the sensorgrams in FIG. 6, all antibodies bound to human CXCL10. Thus, a protease-cleavable sequence can be inserted near the boundary between the variable region and the constant region of an antibody without reducing antigen-binding activity.

5-3. Evaluation of protease cleavage of a neutralizing antibody to CXCL10 carrying a protease-cleavable sequence

It was confirmed that the antibodies obtained by the method described in Example 5-1 could be cleaved by protease. The protease used was recombinant human matriptase/catalytic domain ST14 (MT-SP1) (R&D Systems, Inc., 3946-SE-010). 20 nM protease and 60 or 100 μg/ml of each antibody were reacted in PBS at 37°C for 20 hours. Protease cleavage was then assessed by SDS-PAGE under reducing conditions. The results are presented in Fig. 7. As a result, it was found that treatment with protease EEIVHA/EEIVL, EEIVHE/EEIVL, EEIVHF/EEIVL, EEIVHG/EEIVL, EEIVHEG/EEIVL and EEIVHBG/EEIVL led to the appearance of a new band corresponding to a molecular weight from 25 to 50 kDa. Protease treatment with EEIVH/EEIVLEG, EEIVH/EEIVLF and EEIVH/EEIVLG resulted in a band corresponding to a molecular mass of 25 kDa or less. Thus, protease cleavage was confirmed for antibodies EEIVHA/EEIVL, EEIVHE/EEIVL, EEIVHF/EEIVL, EEIVHG/EEIVL, EEIVHEG/EEIVL, EEIVHBG/EEIVL, EEIVH/EEIVLEG, EEIVH/EEIVLF and EEIVH/EEIVLG.

5-4. Introduction of a flexible linker sequence in the vicinity of a protease-cleavable sequence into a neutralizing antibody to CXCL10 carrying the protease-cleavable sequence

A study was carried out to insert a sequence containing a linker that consists of a glycine-serine polymer in the vicinity of a protease-cleavable sequence into an EEIVHC/EEIVL antibody that has not been digested with recombinant human matriptase/ST14 (MT-SP1) (R&D Systems, Inc., 3946 -SE-010), described in example 5-3. 5 types of heavy chains were created, shown in FIG. 8. Expression vectors encoding heavy chain variants EEIVHC002 (SEQ ID NO: 23), EEIVHC003 (SEQ ID NO: 24), EEIVHC004 (SEQ ID NO: 25), EEIVHC005 (SEQ ID NO: 26) and EEIVHC006 (SEQ ID NO : 27) was obtained using a method known to those skilled in the art.

IgG1 isotype antibodies EEIVHC002/EEIVL (heavy chain: SEQ ID NO: 23, light chain: SEQ ID NO: 2), EEIVHC003/EEIVL (heavy chain: SEQ ID NO: 24, light chain: SEQ ID NO: 2), EEIVHC004/EEIVL (heavy chain: SEQ ID NO: 25, light chain: SEQ ID NO: 2), EEIVHC005/EEIVL (heavy chain: SEQ ID NO: 26, light chain: SEQ ID NO: 2) and EEIVHC006/EEIVL ( heavy chain: SEQ ID NO: 27, light chain: SEQ ID NO: 2), carrying a protease-cleavable sequence near the border between the heavy chain variable region and the constant region, were expressed by transient expression using the indicated heavy chain variants in combination with those found in natural light chain and using FreeStyle 293 (Life Technologies Corp.) using a method known to those skilled in the art, and purified using a method known to those skilled in the art using Protein A.

5-5. Evaluation of the binding activity of a neutralizing antibody to CXCL10 carrying a protease-cleavable sequence and a flexible linker sequence

Antibodies prepared according to the method described in Example 5-4 were evaluated for their interaction with human CXCL10 (266-IP-010/CF, R&D Systems, Inc.) using Biacore. The results are presented in Fig. 9. Specifically, R PROTEIN A (SURE) (28-4018-60, GE Healthcare Japan Corp.) was immobilized on an SMZ sensor chip (BR100536, GE Healthcare Japan Corp.) by amine coupling using NHSEDC. The running buffer used contained 20 mM ACES, 0.05% Tween 20, and 300 mM NaCl (pH 7.4). 6.25, 3.125, 1.563, or 0.781 nM human CXCL10 was injected as an analyte for each captured antibody, and antibody-antigen binding was assessed at 25°C. Sensorgrams showing SPR response profiles as a function of time after subtraction of a blank control in which an analyte consisting of running buffer only was used are presented in FIG. 9. The time point corresponding to the beginning of the analyte injection corresponded to the starting point on the x-axis. The response at each time point was plotted on the y-axis, taking the response at the initial time point when the analyte was injected to be 0. As demonstrated in the sensorgrams in FIG. 9, all antibodies bound to human CXCL10. Thus, the protease-cleavable sequence and the flexible linker sequence can be inserted near the boundary between the variable region and the constant region of the antibody without reducing antigen-binding activity.

5-6. Evaluation of protease cleavage of an anti-CXCL10 neutralizing antibody carrying a protease cleavable sequence and a flexible linker sequence

It was confirmed that the antibodies obtained by the method described in example 5-5 can be cleaved by protease. The protease used was human urokinase (uPA) (R&D Systems, Inc., 1310-SE-010) or recombinant human matriptase/ST14 catalytic domain (MT-SP1) (R&D Systems, Inc., 3946-SE-010) . 12.5 nM protease and 133 μg/ml of each antibody were reacted in PBS at 37°C for 2 or 20 hours. Protease cleavage was then assessed by SDS-PAGE under reducing conditions. The results are presented in Fig. 10. As a result, it was found that treatment with protease EEIVHC002/EEIVL, EEIVHC003/EEIVL, EEIVHC004/EEIVL, EEIVHC005/EEIVL and EEIVHEC006/EEIVL led to the formation of a new band corresponding to a molecular weight from 25 to 50 kDa. Thus, antibodies EEIVHC002/EEIVL, EEIVHC003/EEIVL, EEIVHC004/EEIVL, EEIVHC005/EEIVL and EEIVHEC006/EEIVL were confirmed to be protease-cleavable.

These results demonstrated that even an antibody such as EEIVHC/EEIVL, which is not subject to protease cleavage when it carries only a protease cleavage site near the boundary between the variable and constant regions, can be produced as a protease-cleavable molecule by introducing a flexible linker sequence in the vicinity of the cleavable sequence . The results described above demonstrate that an antibody that is protease-cleavable can also be produced by randomly combining a protease-cleavable sequence with a flexible linker.

5-7. Ligand activation by protease cleavage of the CXCL10-neutralizing antibody to CXCL10 construct

It was then examined whether human CXCL10 bound to the antibody prepared according to the method described in Example 5-5 would be released upon protease treatment using Biacore. Specifically, the antibody EEIVHC006a/EEIVL (heavy chain: SEQ ID NO: 33, light chain: SEQ ID NO: 2), obtained using the method described in Example 5-5, was used to create an antigen(+)/protease( +), antigen(-)/protease(+) analyte and antigen(+)/protease(-) analyte. The antigen(+)/protease(+) analyte used was antibody bound to human CXCL10 and then treated with 20nM recombinant human matriptase/ST14 catalytic domain (MT-SP1) (R&D Systems, Inc., 3946-SE-010) within 20 hours

The antigen(-)/protease(+) analyte used was antibody alone treated with 20 nM recombinant human matriptase/ST14 catalytic domain (MT-SP1) (R&D Systems, Inc., 3946-SE-010) for 20 hours. the antigen(+)/protease(-) analyte was an antibody bound to human CXCL10. To monitor the system confirming CXCL10 binding-based responses, CXCL10 was also used as an antigen-only analyte. The anti-CXCL10 antibody was immobilized onto a CM3 sensor chip (BR100536, GE Healthcare Japan Corp.) using a method known to those skilled in the art. The running buffer used contained 20 mM ACES and 0.05% Tween 20 (pH 7.4). Each of the four types of analytes was injected into it, i.e. antigen(+)/protease(+) analyte, antigen(-)/protease(+) analyte, antigen(+)/protease(-) analyte and antigen only, and binding of human CXCL10 to anti-CXCL10 antibody on the sensor chip was assessed at 25 °C.

Antibody MabCXCL10a (heavy chain: EEIVHa (SEQ ID NO: 65), light chain: EEIVL (SEQ ID NO: 2)), having the same Fab region as antibody MabCXCL10, which lacked the protease cleavable sequence, was used to generate antigen(+)/protease(+) analyte, antigen(-)/protease(+) analyte and antigen(+)/protease(-) analyte in the same manner as for antibody EEIVHC006a/EEIVL. Similar to the above, the anti-CXCL10 antibody was immobilized on a CM3 sensor chip (BR100536, GE Healthcare Japan Corp.) using a method known to those skilled in the art. The running buffer used contained 20 mM ACES and 0.05% Tween 20 (pH 7.4). Each of the four types of analytes was injected into it, i.e. antigen(+)/protease(+) analyte, antigen(-)/protease(+) analyte, antigen(+)/protease(-) analyte and antigen only, and binding of human CXCL10 to anti-CXCL10 antibody on the sensor chip was assessed at 25 °C.

Sensograms showing SPR response profiles as a function of time after subtraction of a control in which flow cells without immobilized anti-CXCL10 antibody were used are presented in FIG. 11. The time point corresponding to the beginning of the analyte injection corresponded to the starting point on the x-axis. The response at each time point was plotted along the ordinate, taking the response at the initial time point when the analyte was injected to be 100. As a result, it was found that, as demonstrated in FIG. 11(A), CXCL10 was not released by protease treatment with MabCXCL10a, which lacks a cleavable sequence. In contrast, as shown in FIG. 11(B), it was confirmed that CXCL10 was released when treated with EEIVHC006a/EEIVL protease.

5-8. Preparation of a neutralizing antibody to CXCL10 by replacing a portion of the amino acid sequence near the boundary between the variable region and the constant region of the antibody with a portion of the protease cleavable sequence and the flexible linker sequence, and assessing protease cleavage

A study was carried out in which a portion of the amino acid sequence near the interface between the heavy chain variable region and the constant region of MabCXCL10 was replaced with a portion of the protease cleavable sequence and the flexible linker sequence. The heavy chains shown in FIG. 12 was designed to replace portions of the heavy chain amino acids with a peptide A sequence (SEQ ID NO: 3), a described cancer-specific expressed urokinase (uPA) and matriptase (MT-SP1) cleavable sequence. Expression vectors encoding the heavy chain variants EESVHA009 (SEQ ID NO: 59) and EESVHA012 (SEQ ID NO: 60) were prepared using a method known to those skilled in the art.

IgG1 isotype antibodies EESVHA009/EEIVL (heavy chain: SEQ ID NO: 59, light chain: SEQ ID NO: 2) and EESVHA012/EEIVL (heavy chain: SEQ ID NO: 60, light chain: SEQ ID NO: 2) expressed by transient expression using variants of these heavy chains in combination with a naturally occurring light chain and using FreeStyle 293 (Life Technologies Corp.) using a method known to those skilled in the art, and purified using a method known to those skilled in the art areas using protein A.

It was confirmed that EESVHA009/EEIVL and EESVHA012/EEIVL could be cleaved by protease. The protease used was human urokinase (uPA) (R&D Systems, Inc., 1310-SE-010) or recombinant human matriptase/ST14 catalytic domain (MT-SP1) (R&D Systems, Inc., 3946-SE-010) . 12.5 nM protease and 100 μg/ml of each antibody were reacted in PBS at 37°C for 20 hours. Protease cleavage was then assessed by SDS-PAGE under reducing conditions. The results are presented in Fig. 13. As a result, it was found that treatment with EESVHA009/EEIVL and EESVHA012/EEIVL protease led to the formation of a new band corresponding to a molecular weight from 25 to 50 kDa. Thus, it was confirmed that antibodies EESVHA009/EEIVL and EESVHA012/EEIVL are protease-cleavable.

Example 6 Discussion of a Suitable Site for Insertion of a Cleavage Sequence for Elimination of Antigen-Binding Capacity by Protease Cleavage

There is information about the preparation and evaluation of the functional activity in vitro of an antibody carrying a protease-cleavable sequence immediately upstream of aspartic acid at position 216 in the heavy chain of a human IgG1 isotype antibody (publication of international patent application WO 2004/021861A2). This document does not describe experimental data, but states that after mixing the antibody with its antigen, the antigen was released from the antigen-antibody complex upon treatment with a medium containing the appropriate protease.

The amino acid at position 216 of the heavy chain of the human IgG1 isotype antibody claimed in the document into which the protease cleavable sequence is inserted is not aspartic acid according to any of the numbering systems such as Cabot numbering, EU numbering and OU numbering, which described in Kabat E. et al., Sequences of Proteins of Immunological Interest, 5th ed. On the other hand, the amino acid at position 216 of the heavy chain of the human IgG1 isotype antibody is likely to be aspartic acid, located immediately after the cysteine that forms the disulfide bond between the heavy and light chains, according to other literature data (Nature 344, April 12, 1990 g., pp. 667-670 and Kabat E. et al., Sequences of Proteins of Immunological Interest, 4th ed.). When a protease-cleavable sequence is inserted immediately upstream of said aspartic acid at position 216, the resulting protease-cleavable antibody may form the same Fab regions as the Fab regions that are formed by papain cleavage of the antibody hinge region. It is generally believed that papain cleavage of the hinge region of an antibody has a low probability of abolishing antigen binding ability. Therefore, it can be assumed that the antibody, which carries a protease-cleavable sequence immediately upstream of aspartic acid at position 216, should not lose the ability to bind antigen, even when cleaved by the corresponding protease.

Also worth discussing is the case where a protease-cleavable sequence is inserted immediately before amino acid position 216 of the heavy chain (Cabot numbering) of a human IgG1 isotype antibody according to the Cabot numbering described in Kabat E. et al., Sequences of Proteins of Immunological Interest, 5th ed. . This site is present on the N-terminal side at a distance of several amino acids from the cysteine at position 220 (Cabot numbering), forming a disulfide bond between the heavy and light chains. Thus, the effect of protease cleavage of the heavy chain at this site is likely to be similar to the effect of deletion of the disulfide bond formed between the heavy and light chains. Based on the last link, even a Fab region that is unable to form a disulfide bond between the heavy and light chains has a low probability of losing the ability to bind to its antigen (MAbs. 6 (1), January-February 2014, pp. 204-218 ). Therefore, it can be assumed that the antibody does not lose the ability to bind its antigen when cleaved by a protease, even if the protease-cleavable sequence is inserted immediately before the amino acid at position 216 in the heavy chain (Cabot numbering) of a human IgG1 isotype antibody according to the Cabot numbering described in Kabat E. et al., Sequences of Proteins of Immunological Interest, 5th ed.

Example 7: Evaluation of chemotactic activity associated with protease cleavage of the anti-CXCL10/CXCL10 neutralizing antibody complex carrying a protease-cleavable sequence

The question was examined whether a complex formed by CXCL10 and a neutralizing antibody to CXCL10 that carries a protease-cleavable sequence prepared according to the method described in Example 5 could release CXCL10 upon protease cleavage, resulting in CXCL10 exhibiting chemotactic activity against cells.

The cell chemotactic activity of CXCL10 was assessed by preparing transfected Ba/F3 cells that express mouse CXCR3 (mCXCR3) (hereinafter referred to as BaF3/mCXCR3) and using these cells and an HTS Transwell™-96 permeable support with a polycarbonate membrane with pore size 5.0 µm (catalog no. 3387, Corning Inc.). Five types of analytes were obtained: CXCL10 + protease, EEIVHC006a/EEIVL + CXCL10, EEIVHC006a/EEIVL + CXCL10 + protease, EEIVHC006a/EEIVL + protease, and MabCXCL10 + CXCL10 + protease. Either each antibody (MabCXCL10 or EEIVHC006a/EEIVL) at a concentration of 10 μg/ml (final concentration), or hCXCL10 (cat. no. 300-12, PeproTech, Inc.) at a concentration of 100 ng/ml (final concentration), or both antibody , and hCXCL10 were placed in a 1.5 ml Proteosave microtube (cat. no. MS-4265M, Sumitomo Bakelite Co., Ltd.) and kept at ambient temperature for 30 min. Mouse MT-SP1 (mMT-SP1, catalog no. 4735-SE-010, R&D Systems, Inc.) was added to the protease analytes after the reaction at a final concentration of 12.5 nM.

235 μl of each analyte was transferred to the lower chamber and 2.0 x 10 ⁵ BaF3/mCXCR3 cells/well was inoculated at a rate of 75 μl/well to the upper chamber, allowing the reaction to proceed for 6 hours. The reaction was carried out at 5% CO ₂ and 37 °C. After a 6-hour reaction, 100 μL of the solution from the lower chamber was transferred to a Fluorescent Luminescent 96-well plate (catalog #3912, Corning Inc.) and 100 μl of CellTiter-Glo™ Fluorescent Cell Viability Assay Solution (catalog #G7571) was added. , Promega Corp.). After reaction at room temperature for 10 min, luminescence intensity was measured using a SpectraMax M3 multimodal microplate reader (Molecular Devices, LLC) to assess the level of cell migration into the lower chamber. The results are presented in Fig. 14.

Luminescence intensity decreased with the addition of the EEIVHC006a/EEIVL + CXCL10 analyte compared to the CXCL10 + protease analyte. Luminescence intensity reflects the number of migrating cells. Therefore, it is found that EEIVHC006a/EEIVL forms a complex with CXCL10 and neutralizes the effect of CXCL10. On the other hand, the luminescence intensity was restored by the addition of the EEIVHC006a/EEIVL + CXCL10 + protease analyte compared to the addition of the EEIVHC006a/EEIVL + CXCL10 analyte, demonstrating that the addition of the said analyte caused the same cell migration as the addition of the CXCL10 + protease analyte. No recovery of luminescence intensity was detected when the MabCXCL10 + CXCL10 + protease analyte containing the MabCXCL10 antibody, which does not have a cleavable sequence, was added. This result demonstrated that the ability of EEIVHC006a/EEIVL to neutralize CXCL10 is reduced upon protease cleavage of the antibody.

Example 8: Evaluation of chemotactic activity associated with protease cleavage of the anti-CXCL10/CXCL10 neutralizing antibody complex carrying a protease-cleavable sequence

8-1 Preparation and evaluation of protease cleavage of the CXCL10-CXCL10 neutralizing antibody fusion protein

A ligand-fused light chain hCXCL10R75A.G4SGGGG.G7L-LT0 (SEQ ID NO: 371) was generated using the anti-human CXCL10 neutralizing antibody light chain MabCXCL10_G7 (heavy chain: G7H-G1T4 (SEQ ID NO: 368), light chain: G7L- LT0 (SEQ ID NO: 369)), and fused with the human CXCL10 mutant hCXCL10R75A (SEQ ID NO: 370), which has a protease resistance mutation, via a linker sequence consisting of a glycine-serine polymer with the N-terminus of the light chain . The G7H-G1T4/hCXCL10R75A.G4SGGGG.G7L-LT0 fusion protein (heavy chain: SEQ ID NO: 368, liganded light chain: SEQ ID NO: 371) was expressed by transient expression using the liganded light chain in combination with the heavy chain chain G7H-G1T4 MabCXCL10_G7 and using Expi293 (Life Technologies Corp.) using a method known to those skilled in the art, and purified using a method known to those skilled in the art using Protein A.

MabCXCL10_G7 had the following CDR sequences: H-CDR1 (SFSIT; SEQ ID NO: 374), H-CDR2 (EITPMFGIANYAQKFQG; SEQ ID NO: 375), H-CDR3 (DGRFDVSDLLTDKPKVTINYNGMDV; SEQ ID NO: 376), L-CDR1 ( SGSSSNIGSNTVN; SEQ ID NO: 377), L-CDR2 (NNDQRPS; SEQ ID NO: 378) and L-CDR3 (ASWDDSLNGRV; SEQ ID NO: 379).

The fact that the fusion protein can be cleaved by protease was confirmed. Human urokinase (human uPA, huPA) (R&D Systems, Inc., 1310-SE-010) was used as a protease. Protease cleavage of the fusion protein was assessed by SDS-PAGE under reducing conditions. 0.1 mg/ml of the fusion protein was reacted with 30 nM huPA at 37°C for 1 hour. The cleavage of the fusion protein was then assessed by SDS-PAGE under reducing conditions. It was found that the G7H-G1T4/hCXCL10R75A.G4SGGGG.G7L-LT0 antibody was not cleaved by protease treatment (Fig. 15).

8-2 Evaluation of chemotactic activity associated with protease cleavage of fusion protein: neutralizing antibody to CXCL10-CXCL10

The question was examined whether a fusion protein: an anti-CXCL10-CXCL10 neutralizing antibody containing CXCL10 fused to an anti-CXCL10 neutralizing antibody that carries a protease-cleavable sequence, prepared according to the method described in Example 5, could release CXCL10 upon protease cleavage, resulting in whereby CXCL10 will induce cell migration.

As a reference for comparison with the activity of hCXCL10R75A released from the fusion protein, hCXCL10R75A-His (SEQ ID NO: 373), which has the activity of only hCXCL10R75A, was prepared and purified by the following method: the human CXCL10 mutant hCXCL10R75A (SEQ ID NO: 370) carrying the conditioning the protease resistance mutation was tagged at the C-terminus with a histidine tag to generate the histidine-tagged human CXCL10 mutant hCXCL10R75A-His (SEQ ID NO: 373). hCXCL10R75A-His (SEQ ID NO: 373) was expressed by transient expression using Expi293 (Life Technologies Corp.) using a method known to those skilled in the art, and purified using a method known to those skilled in the art using nickel Sepharose .

Cell chemotactic activity was assessed by preparing transfected Ba/F3 cells that express mouse CXCR3 (mCXCR3) (hereinafter referred to as BaF3/mCXCR3) and using these cells and an HTS Transwell™-96 permeable support with a polycarbonate membrane of pores 5.0 µm (catalog no. 3387, Corning Inc.).

Recombinant huPA (catalog no. 1310-SE, R&D Systems, Inc.) was added at a final concentration of 30 nM to hCXCL10R75A-His at a concentration of 0.15 μg/ml or to the G7H-G1T4/hCXCL10R75A.G4SGGGG.G7L-LT0 fusion protein, not having a protease-cleavable sequence, at a concentration of 1.5 μg/ml in a 96-well plate with a well depth of 2.0 ml (catalog no. P-DW-20-C-S, AxyGen Scientific, Inc.), obtaining uPA(+) analytes . The 1.5 μg/ml dose of G7H-G1T4/hCXCL10R75A.G4SGGGG.G7L-LT0 contained hCXCL10R75A at an amount corresponding to 0.15 μg/ml. 0.15 μg/ml hCXCL10R75A-His and 1.5 μg/ml G7H-G1T4/hCXCL10R75A.G4SGGGG.G7L-LT0 fusion protein lacking the protease cleavable sequence were used as uPA(-) analytes.

235 μl of each test solution was transferred to the lower chamber and 2.0×10 ⁵ BaF3/mCXCR3 cells/well was inoculated at the rate of 75 μl/well in the upper chamber, allowing the reaction to proceed for 6 hours. The reaction was carried out at 5% CO ₂ and 37°C. After reacting for 6 hours, 100 μL of solution from the lower chamber was transferred to an OptiPlate-96 (catalog #6005299, PerkinElmer, Inc.) and 100 μL of CellTiter-Glo™ Fluorescent Cell Viability Assay Solution (cat# G7571) was added. , Promega Corp.). After reaction at room temperature for 10 min, luminescence intensity was measured using a SpectraMax M3 multimodal microplate reader (Molecular Devices, LLC) to assess the level of cell migration into the lower chamber. The results are presented in Fig. 16. No recovery of luminescence intensity was detected when the G7H-G1T4/hCXCL10R75A.G4SGGGG.G7L-LT0 antibody, which does not have a cleavable sequence, was treated with protease compared to the addition of CXCL10R75A-His.

8-3 Construction of a neutralizing antibody to CXCL10 - CXCL10 fusion protein carrying a protease-cleavable sequence and evaluation of chemotactic activity associated with protease cleavage

The amino acid sequence was designed such that the protease-cleavable sequence was located near the boundary between the variable and constant regions of the ligand-bound light chain hCXCL10R75A.G4SGGGG.G7L-LT0 (SEQ ID NO: 371), designed according to the method described in Example 8-1. The fusion protein was expressed by transient expression using a ligand-linked light chain carrying a protease cleavable sequence in combination with a G7H-G1T4 MabCXCL10_G7 heavy chain and using Expi293 (Life Technologies Corp.) using a method known to those skilled in the art, and purified using a method known to those skilled in the art using protein A.

The fact that the fusion protein can be cleaved by protease was confirmed. Human urokinase (human uPA, huPA) (R&D Systems, Inc., 1310-SE-010) was used as a protease. Protease cleavage of the fusion protein was assessed by SDS-PAGE under reducing conditions. 0.1 mg/ml of the fusion protein was reacted with 30 nM huPA at 37°C for 1 hour. The cleavage of the fusion protein was then assessed by SDS-PAGE under reducing conditions.

The question was examined whether an anti-CXCL10-CXCL10 neutralizing antibody fusion protein containing CXCL10 fused to an anti-CXCL10 neutralizing antibody that carries a protease-cleavable sequence could release CXCL10 upon protease cleavage, resulting in cell migration. Chemotactic activity was assessed by generating transfected Ba/F3 cells expressing mouse CXCR3 (mCXCR3) (hereinafter referred to as BaF3/mCXCR3) and using these cells and HTS Transwell™-96 Permeable Support with a 5.0 pore size polycarbonate membrane µm.

Recombinant huPA (catalog no. 1310-SE, R&D Systems, Inc.) was added at a final concentration of 30 nM to the hCXCL10R75A-His construct prepared according to the method described in Example 8-2 at a concentration of 0.15 μg/ml or to the fusion protein , carrying the protease-cleavable sequence, at a concentration of 1.5 μg/mL in a 2-mL volume in a 96-well deep well plate (catalog #P-DW-20-C-S, AxyGen Scientific, Inc.), yielding uPA(+ ). A 1.5 μg/ml dose of the fusion protein having a protease cleavable sequence contained hCXCL10R75A in an amount corresponding to 0.15 μg/ml. 0.15 μg/ml hCXCL10R75A-His and 1.5 μg/ml fusion protein having a protease cleavable sequence were used as uPA(-) analytes.

235 μl of each test solution was transferred to the lower chamber and 2.0 x 10 ⁵ BaF3/mCXCR3 cells/well was inoculated at a rate of 75 μl/well into the upper chamber, allowing the reaction to proceed for 6 hours. The reaction was carried out at 5% CO ₂ and 37°C. After a 6-hour reaction, 100 µl of the solution from the lower chamber was transferred to an OptiPlate-96 plate (catalog no. 6005299, PerkinElmer, Inc.) and 100 µl of CellTiter-Glo™ luminescent cell viability assay solution (catalog no. G7571, PerkinElmer, Inc.) was added to it. Promega Corp.). After reaction at room temperature for 10 min, luminescence intensity was measured using a SpectraMax M3 multimodal microplate reader (Molecular Devices, LLC) to assess the level of cell migration into the lower chamber. Chemotactic activity was assessed based on luminescence intensity.

Example 9: Preparation of a Neutralizing Anti-IL-12 Antibody Carrying a Protease Cleavable Sequence and a Flexible Linker Sequence and Evaluation of IL-12 Activation Associated with Protease Cleavage

9-1. Preparation of a Neutralizing Anti-IL-12 Antibody Carrying a Protease-Cleavable Sequence and a Flexible Linker Sequence

IL-12 is a cytokine with immunostimulatory effects. IL-12 activates immunocytes and thereby has an antitumor effect, while it is described that with systemic exposure IL-12 also causes serious adverse reactions (Nat Immunol. 13 (8), July 19, 2012, pp. 722-728) .

UstkH-G1T4CYTM1inP 1 (SEQ ID NO: 146) was created as a heavy chain variant of the anti-human IL-12 neutralizing antibody ustekinumab by inserting a sequence containing a peptide A sequence (SEQ ID NO: 3) which is described to be cleaved by urokinase (uPA) and matriptase (MT-SP1), and a flexible linker consisting of a glycine-serine polymer near the interface between the variable and constant regions of the heavy chain (UstkH-G1T4, heavy chain: SEQ ID NO: 144) of an anti-IL12 antibody having the same variable region as ustekinumab. An expression vector encoding the ustekinumab antibody variant UstkH-G1T4CYTM1inP1/UstkL-kT0 (heavy chain: SEQ ID NO: 146, light chain: SEQ ID NO: 145) was prepared using a method known to those skilled in the art using the heavy chain variant in combinations with the light chain (UstkL-kT0; SEQ ID NO: 145) of ustekinumab. This ustekinumab antibody variant UstkH-G1T4CYTM1inP1/UstkL-kT0 was also expressed by transient expression using FreeStyle 293 (Life Technologies Corp.) using a method known to those skilled in the art, and purified using a method known to those skilled in the art using protein A. In this example, the anti-IL12 antibody and its variant contained the following CDR sequences: H-CDR1 (TYWLG; SEQ ID NO: 386), H-CDR2 (IMSPVDSDIRYSPSFQG; SEQ ID NO: 387), H-CDR3 (RRPGQGYFDF ; SEQ ID NO: 388), L-CDR1 (RASQGISSWLA; SEQ ID NO: 389), L-CDR2 (AASSLQS; SEQ ID NO: 390) and L-CDR3 (QQYNIYPYT; SEQ ID NO: 391).

9-2. Protease cleavage of an anti-IL-12 neutralizing antibody that carries a protease cleavable sequence and a flexible linker sequence

It was confirmed that the antibody produced by the method described in Example 9-1 could be cleaved by protease. The protease used was human-derived matriptase/ST14 catalytic domain (human MT-SP1, hMT-SP1) (R&D Systems, Inc., 3946-SE-010), recombinant mouse-derived matriptase/ST14 catalytic domain (mouse MT-SP1, mMT-SP1) (R&D Systems, Inc., 4735-SE-010) or human-derived urokinase (human uPA, huPA) (R&D Systems, Inc., 1310-SE-010) . For protease treatment, hMT-SP1, mMT-SP1, or huPA was added at a final concentration of 10.1, 16.9, or 9.17 μM to ustekinumab (UstkH-G1T4/UstkL-kT0) or the ustekinumab antibody variant UstkH-G1T4CYTM1inP1/UstkL-kT0 , after which the reaction was carried out overnight at 37°C.

9-3. Confirmation of cleavage of a cleavable anti-IL-12 neutralizing antibody that carries a protease-cleavable sequence and a flexible linker sequence and assessment of IL-12 activation

Antibody protease cleavage was assessed by SDS-PAGE under reducing conditions. As a result, it was found that the UstkH-G1T4/UstkL-kT0 antibody was not subject to cleavage by any of the proteases, while treatment with each of the proteases UstkH-G1T4CYTM1inP1/UstkL-kT0, which carries a protease-cleavable sequence and a flexible linker, led to the formation of a new band , corresponding to a molecular weight from 25 to 50 kDa. (Fig. 17). Thus, it was confirmed that the anti-IL-12 neutralizing antibody (UstkH-G1T4CYTM1inP1/UstkL-kT0), which carries a protease-cleavable sequence and a flexible linker sequence, was cleaved by the protease.

It was then examined whether IL-12, released from its complex with the antibody by protease cleavage of the antibody, could exhibit physiological activity. The physiological activity of IL-12 was assessed based on the production of IFN-γ (also referred to as interferon gamma or IFN-g) by the human NK92 cell line. NK92 cells were inoculated at 1×10 ⁵ cells/well into a 96-well cell culture plate. 10 ng/ml IL-12 and a protease-treated antibody was added to it (UstkH-G1T4/UstkL-kT0 or UstkH-G1T4CYTM1inP1/UstkL-kT0; concentration of each antibody: 20, 4, 0.8, 0.16, 0.032, 0 .0054 and 0.0013 μg/ml). After 48 h, the amount of IFN-γ produced was measured by ELISA. To evaluate the effect of the antibody on the activity of IL12, the experiment (without At (No Ab)) was also carried out by adding only protease-treated IL12 without adding antibody. In fig. Figure 18 presents the results of measuring the concentration of interferon gamma. UstkH-G1T4/UstkL-kT0 (which does not have a protease cleavable sequence) treated with each protease inhibited (or neutralized) interferon gamma production by IL-12, and the antibody at a concentration of 0.8 μg/ml inhibited interferon gamma production to the same level that occurred in the absence of IL-12 (no IL-12). On the other hand, UstkH-G1T4CYTM1inP1/UstkL-kT0 (containing a protease-cleavable sequence) treated with each of the proteases resulted in the production of interferon gamma at all antibody concentrations, in contrast to the addition of UstkH-G1T4/UstkL-kT0, which does not have a protease-cleavable sequence . Based on this result, it is confirmed that UstkH-G1T4CYTM1inP1/UstkL-kT0 allows IL-12 to exert its effects on cells by attenuating its ability to neutralize IL-12 in combination with protease cleavage.

Example 10: Evaluation of Antibody Carrying a Protease-Cleavable Sequence in Anti-Human CXCL10 Neutralizing Antibody

10-1. Introduction of a protease-cleavable sequence into a neutralizing anti-human CXCL10 antibody

Expression vectors for neutralizing antibodies to CXCL10 MabCXCL10 (heavy chain: EEIVH (SEQ ID NO: 1), light chain: EEIVL (SEQ ID NO: 2)) and MabCXCL10_G7 (heavy chain: G7H-G1T4 (SEQ ID NO: 368), light chain: G7L-LT0 (SEQ ID NO: 369)) was prepared using a method known to those skilled in the art and expressed using FreeStyle 293 cells (Invitrogen Corp.) or Expi293 cells (Life Technologies Corp.) and purified using methods known to those skilled in the art.

The cleavage sequence shown in SEQ ID NO: 345 was inserted near the boundary between the variable region and the heavy chain constant region of MabCXCL10 or MabCXCL10_G7 to produce the heavy chain variant MabCXCL10 EldHA0003-G1T4 (SEQ ID NO: 356) and the heavy chain variant MabCXCL10_G7 G7H. 12aa-G1T4 (SEQ ID NO: 367).

Antibody variant MabCXCL10 EldHA0003 (heavy chain: SEQ ID NO: 356, light chain: SEQ ID NO: 2) and antibody variant MabCXCL10_G7 G7H. 12aa (heavy chain: SEQ ID NO: 367, light chain: SEQ ID NO: 369) was expressed by transient expression using these two types of heavy chain variants in combination with a light chain and using FreeStyle 293 cells (Invitrogen Corp.) or cells Expi293 (Life Technologies Corp.) using a method known to those skilled in the art, and purified using a method known to those skilled in the art using Protein A.

10-2. Evaluation of protease cleavage of an anti-human CXCL10 neutralizing antibody carrying a protease-cleavable sequence in its heavy chain region

It was confirmed that the antibodies obtained using the method described in Example 10-1 could be cleaved by protease. The protease used was recombinant human matriptase/catalytic domain ST14 (human MT-SP1, hMT-SP1) (R&D Systems, Inc., 3946-SE-010). 10 nM protease and each antibody at a concentration of 50 μg/ml were reacted in PBS at 37°C for 20 hours, after which SDS-PAGE was performed under reducing conditions. The results are presented in Fig. 19A and 19B. Treatment with hMT-SP1 of the MabCXCL10 EldHA0003 antibody variant or the MabCXCL10_G7 G7H antibody variant was found. 12aa led to the creation of a new band corresponding to a molecular mass of about 37 kDa. Thus, it is confirmed that the protease cleavable sequence shown in SEQ ID NO: 345 can be cleaved by hMT-SP1. In addition, using the same method, it was found that the protease cleavable sequence shown in SEQ ID NO: 345 can be cleaved by human uPA and mouse uPA.

Example 11: Preparation and Evaluation of Polypeptides Carrying Various Protease-Cleavable Sequences

11-1 Preparation of polypeptides carrying sequences recognized by various proteases

An expression vector for an anti-human IL6R MRA neutralizing antibody (heavy chain: MRAH-G1T4 (SEQ ID NO: 147), light chain: MRAL-k0 (SEQ ID NO: 148)) was prepared using a method known to those skilled in the art. MRA has the following CDR sequences: H-CDR1 (SDHAWS; SEQ ID NO: 398), H-CDR2 (YISYSGITTYNPSLKS; SEQ ID NO: 399), H-CDR3 (SLARTTAMDY; SEQ ID NO: 400), L-CDR1 ( RASQDISSYLN; SEQ ID NO: 401), L-CDR2 (YTSRLHS; SEQ ID NO: 402) and L-CDR3 (QQGNTLPYT; SEQ ID NO: 403).

Table 1 shows peptide sequences known to be cleaved by MMP-2, MMP-7 or MMP-9, and peptide sequences containing a flexible linker, which consists of a glycine-serine polymer, in the vicinity of these sequences.

Heavy chain variants were created: MEIVHG4SMP2MP9G4S-MEIVHG4SMP2MP9G4SG1T4 (SEQ ID NO: 153), MEIVHG4SMP2.2G4S-MEIVHG4SMP2.2G4SG1T4 (SEQ ID NO: 154), MEIVHG4SMP2.4G4S-MEIVHG4SMP2.4G4SG1T4 (SEQ ID NO: 155), MEIVHG4SMP9G4S-MEIVHG4SMP9G4SG1T4 (SEQ ID NO: 156), MEIVHMP2.1-MEIVHMP2.1G1T4 (SEQ ID NO: 157), MEIVHMP2.3-MEIVHMP2.3G1T4 (SEQ ID NO: 158) and MEIVHMP7.2-MEIVHMP7.2G1T4 (heavy chain: SEQ ID NO : 159) such that the inserted sequences are located near the boundary between the variable region and the constant region of the heavy chain of the MRA antibody. Expression vectors encoding these heavy chain variants were prepared using a method known to those skilled in the art.

The MRA antibody variants shown in Table 2 were expressed by transient expression using the indicated heavy chain variants in combination with the MRA light chain and using FreeStyle 293 cells (Invitrogen Corp.) or Expi293 cells (Life Technologies Corp.) using the method known to those skilled in the art, and purified using a method known to those skilled in the art using Protein A.

11-2. Evaluation of protease cleavage of polypeptides carrying sequences recognized by various proteases

It was confirmed that the MRA antibody variants produced by the method described in Example 11-1 could be protease cleaved. The protease used was recombinant human MMP-2 (R&D Systems, Inc., 902-MP-010), recombinant human MMP-7 (R&D Systems, Inc., 907-MP-010) or recombinant human MMP-9 ( R&D Systems, Inc., 911-MR-010). Each protease was used after mixing with 1 mM para-aminophenylmercuric acetate (APMA; Abcam PLC, ab112146) and activated at 37°C for 1 hour or 24 hours. The protease was reacted at a concentration of 50, 100 or 500 nM and each antibody at a concentration 50 μg/ml in assay buffer (MMP activity assay kit (fluorometric - green) (ab112146), component C: assay buffer) or in buffer containing 20 mM Tris-HCl, 150 mM NaCl and 5 mM CaCl ₂ (pH 7.2) (hereinafter referred to as Tris in the context of this description), at 37°C for 20 hours. Protease digestion was then assessed by SDS-PAGE under reducing conditions. The results are presented in Fig. 20A, 20B and 21. Each of the MRA antibody variants interacted with the protease presented in Table 2. Cleavage by MMP-2 was detected for MEIVHG4SMP2MP9G4S-MEIVHG4SMP2MP9G4SG1T4/MRAL-k0, MEIVHG4SMP2.2G4S-MEIVHG4SMP2.2G4SG1 T4/MRAL-k0 , MEIVHG4SMP2 .4G4S-MEIVHG4SMP2.4G4SG1T4/MRAL-k0, MEIVHMP2.1-MEIVHMP2.1G1T4/MRAL-k0 and MEIVHMP2.3-MEIVHMP2.3G1T4/MRAL-k0. Cleavage by MMP-7 was detected for MEIVHMP7.2-MEIVHMP7.2G1T4/MRAL-k0. Cleavage by MMP-9 was detected for MEIVHG4SMP2MP9G4S-MEIVHG4SMP2MP9G4SG1T4/MRAL-k0 and MEIVHG4SMP9G4S-MEIVHG4SMP9G4SG1T4/MRAL-k0.

Example 12: Evaluation of Antibodies Carrying a Protease-Cleavable Sequence at Various Heavy Chain Positions

12-1 Preparation of antibodies carrying protease-cleavable sequences at various positions on the heavy chain

The Peptide B sequence (SEQ ID NO: 160), found to be cleaved by urokinase (uPA) and matriptase (MT-SP1), was inserted into each of the different positions in the MRA heavy chain variable region (MRAH; SEQ ID NO: 161 ) to produce MRA heavy chain variable region variants, which are shown in Table 3. Each of these MRA heavy chain variable region variants was fused to an MRA heavy chain constant region (G1T4; SEQ ID NO: 162) to produce MRA heavy chain variants. Appropriate gene expression vectors were prepared using a method known to those skilled in the art. In addition, the sequence of peptide B (SEQ ID NO: 160) was inserted into each of the various positions in the MRA heavy chain constant region (G1T4; SEQ ID NO: 162) to produce MRA heavy chain constant region variants, which are presented in Table 4. Each of these MRA heavy chain constant region variants was fused to the MRA heavy chain variable region (MRAH; SEQ ID NO: 161) to produce MRA heavy chain variants. Appropriate gene expression vectors were prepared using a method known to those skilled in the art. Tables 3 and 4 also show the positions at which the protease cleavable sequence is inserted in the resulting MRA heavy chain variable region variants and MRA heavy chain constant region variants. The inserted sequence shown in Table 3 was located so that it was adjacent on the constant region side to the indicated position (Cabot numbering) in the variable region of the antibody heavy chain. The inserted sequence presented in Table 4 was located so that it was adjacent on the variable region side to the indicated position (EU numbering) in the constant region of the antibody heavy chain.

The MRA antibody variants shown in Table 5 were expressed by transient expression using the MRA heavy chain variants obtained in this manner in combination with the MRA light chain using FreeStyle 293 cells (Invitrogen Corp.) or Expi293 cells (Life Technologies Corp.) with using a method known to those skilled in the art, and purified using a method known to those skilled in the art using Protein A.

12-2. Evaluation of protease cleavage of a neutralizing antibody to human IL6R carrying a protease-cleavable sequence in the heavy chain of the antibody

It was confirmed that the MRA antibody variants produced by the method described in Example 12-1 could be protease cleaved. The protease used was recombinant human matriptase/catalytic domain ST14 (human MT-SP1, hMT-SP1) (R&D Systems, Inc., 3946-SE-010). 10 nM protease and each antibody were reacted at a concentration of 50 μg/ml in PBS at 37°C for 20 hours, after which SDS-PAGE was carried out under reducing conditions. The results are presented in Fig. 22A, 22B, 22B, 22G, 22D, 22E, 22G, 22Z, 22I, 23A, 23B and 23B. The protease-treated MRA antibody variants were cleaved at the heavy chains and produced a heavy chain band at a lower molecular weight position compared to the heavy chain band of the non-protease-treated MRA antibody variants (in the figures, the band corresponds to a molecular mass of approximately 50 kDa in the MT- SP1(-)). These results confirmed that the MRA antibody variants produced by the method specified in Example 12-1 were cleaved by hMT-SP1.

Example 13: Evaluation of Antibodies Carrying a Protease-Cleavable Sequence at Various Light Chain Positions

13-1 Preparation of Antibodies Carrying a Protease-Cleavable Sequence at Various Positions of the Light Chain

The Peptide B sequence (SEQ ID NO: 160), found to be cleaved by urokinase (uPA) and matriptase (MT-SP1), was inserted into each of the different positions in the MRA light chain variable region (MRAL; SEQ ID NO: 230 ) to produce MRA light chain variable region variants, which are shown in Table 6. Each of these MRA light chain variable region variants was fused to an MRA light chain constant region (k0; SEQ ID NO: 231) to produce MRA light chain variants. Appropriate gene expression vectors were prepared using a method known to those skilled in the art. In addition, the sequence of peptide B (SEQ ID NO: 160) was inserted into each of the various positions in the MRA light chain constant region (k0; SEQ ID NO: 231) to produce MRA light chain constant region variants, which are presented in Table 7. Each These MRA light chain constant region variants were fused to the MRA light chain variable region (MRAL; SEQ ID NO: 230) to produce MRA light chain variants. Appropriate gene expression vectors were prepared using a method known to those skilled in the art. Tables 6 and 7 also show the positions of the protease cleavable sequence in the resulting MRA light chain variable region variants and MRA light chain constant region variants. The inserted sequence shown in Table 6 was located so that it was adjacent on the constant region side to the indicated position (Cabot numbering) in the variable region of the antibody light chain. The inserted sequence shown in Table 7 was located so that it was adjacent on the variable region side to the indicated position (EU numbering) in the constant region of the antibody light chain.

The MRA antibody variants shown in Table 8 were expressed by transient expression using the MRA light chain variants obtained by this method in combination with the MRA heavy chain using FreeStyle 293 cells (Invitrogen Corp.) or Expi293 cells (Life Technologies Corp.) with using a method known to those skilled in the art, and purified using a method known to those skilled in the art using Protein A.

13-2. Evaluation of protease cleavage of a neutralizing antibody to human IL6R carrying a protease-cleavable sequence in the antibody light chain variable region

It was confirmed that the MRA antibody variants produced by the method described in Example 13-1 could be cleaved by protease. The protease used was recombinant human matriptase/catalytic domain ST14 (human MT-SP1, hMT-SP1) (R&D Systems, Inc., 3946-SE-010). 10 nM protease and each antibody were reacted at a concentration of 50 μg/ml in PBS at 37°C for 20 hours, after which SDS-PAGE was carried out under reducing conditions. The results are presented in Fig. 24A, 24B, 24B, 24G, 24D, 25A and 25B. The protease-treated MRA antibody variants were cleaved at the light chains and produced a light chain band at a lower molecular weight position compared to the light chain band of the non-protease-treated MRA antibody variants (in the figures, the band corresponds to a molecular weight of approximately 25 kDa in the MT- SP1(-)).

Example 14: Preparation of an Anti-Human PD1 Neutralizing Antibody Carrying a Protease-Cleavable Sequence and Evaluation of Its Binding to Human PD1

14-1. Introduction of a protease-cleavable sequence into a neutralizing anti-human PD1 antibody

The protease-cleavable sequence was inserted into the heavy or light chain of the anti-human PD1 neutralizing antibody 5C4H-G1T4/5C4L-KT0 (heavy chain: 5C4H-G1T4, SEQ ID NO: 297; heavy chain variable region: 5C4H, SEQ ID NO: 300; constant region heavy chain: G1T4, SEQ ID NO: 301; light chain: 5C4L-KT0, SEQ ID NO: 298; light chain variable region: 5C4L, SEQ ID NO: 302; light chain constant region: KT0, SEQ ID NO: 303; H-CDR1 (NSGMH, SEQ ID NO: 392), H-CDR2 (VIWYDGSKRYYADSVKG, SEQ ID NO: 393), H-CDR3 (NDDY, SEQ ID NO: 394), L-CDR1 (RASQSVSSYLA, SEQ ID NO: 395 ), L-CDR2 (DASNRAT, SEQ ID NO: 396), L-CDR3 (QQSSNWPRT, SEQ ID NO: 397)) to obtain an antibody carrying a protease cleavable sequence.

First, a peptide sequence (SEQ ID NO: 299) known to be cleaved by cancer-specific matriptase (MT-SP1) was inserted into the heavy chain 5C4H-G1T4 or light chain 5C4L-KT0 of the above antibody to produce heavy chain variants , which are presented in table 9 and light chain variants, which are presented in table 10. They were expressed using a method known to specialists in this field.

IgG1 isotype antibodies (Table 11) carrying the protease cleavable sequence were expressed by transient expression using the heavy chain variants shown in Table 9 in combination with the 5C4L-KT0 light chain or the light chain variants shown in Table 10 in combination with heavy chain 5C4H-G1T4 and used Expi293 (Life Technologies Corp.) using a method known to those skilled in the art, and purified using a method known to those skilled in the art using protein A. 5C4H-G1T4/5C4L-KT0 (heavy chain: SEQ ID NO: 297, light chain: SEQ ID NO: 298) was expressed and purified as a control antibody lacking the protease cleavable sequence.

14-2. Assessment of human PD1 binding by anti-human PD1 neutralizing antibodies carrying a protease-cleavable sequence

14-2-1 Protease treatment

To prepare protease-treated antibodies, 10 μl of recombinant human matriptase/ST14 catalytic domain (hMT-SP1, R&D Systems, Inc., 3946-SE-010) adjusted to 1.8 μg/ml with PBS was added to each antibody (final concentration: 0.111 mg/ml) obtained according to the method described in Example 14-1. To obtain protease-untreated antibodies, 10 μl of PBS alone (final concentration: 0.111 mg/ml) was added to each antibody prepared according to the method described in Example 14-1. The sample volume during the reaction was 90 μl, and the final protease concentration was 0.2 μg/ml. Each sample was incubated at 37°C for 12 h.

14-2-2 Preparation of biotinylated anti-human PD1 neutralizing antibody

A biotinylated anti-human PD1 neutralizing antibody was generated that has the same variable region sequence as 5C4H-G1T4/5C4L-KT0. In particular, a gene fragment encoding 5C4VH-G1dGSBAP (SEQ ID NO: 317), which encodes the constant region of the antibody heavy chain and biotin (AviTag sequence SEQ ID NO: 316), associated with the variable region of the heavy chain 5C4H, was obtained (SEQ ID NO: 300), and integrated into an expression vector in animal cells using a method known to those skilled in the art. The constructed expression vector and the light chain expression vector 5C4L-KT0B (SEQ ID NO: 298) were transfected into FreeStyle 293 cells (Invitrogen Corp.) using 293Fectin (Invitrogen Corp.). In this procedure, cells were co-transfected with an EBNA1 expression gene (SEQ ID NO: 318) and a biotin ligase expression gene (BirA; SEQ ID NO: 319) and biotin was added to introduce a biotin tag. Cells thus transfected were cultured at 37°C in an atmosphere of 8% CO ₂ and induced to secrete a biotinylated neutralizing antibody to human PD1 (5C4-bio) into the culture supernatant. 5C4-bio was purified from the culture supernatant using a method known to those skilled in the art.

14-2-3 Evaluation of human PD1 binding by each antibody before and after protease treatment

Human PD1 was added at a final concentration of 0.67 μM to 80 μl of each protease-treated antibody or protease-untreated antibody prepared according to the method described in Example 14-2-1 and allowed to bind at room temperature for 30 min to obtain samples in which Binding assessment was performed. The amount of PD1 unbound to the antibody was determined to evaluate antibody binding to PD1 with and without protease treatment.

Specifically, the amount of PD1 unbound to the antibody was assessed by biolayer interferometry (BLI) using a biotinylated anti-human PD1 neutralizing antibody (5C4-bio) prepared according to the method described in Example 14-2-2.

Samples for binding assessment, 5C4-bio and PBS were dispensed into different wells of slanted bottom microplates (TW384) (Pall ForteBio Corp., 18-5076). Streptavidin biosensor (Pall ForteBio Corp., 18-0009) was hydrogenated with PBS followed by analysis using an Octet RED 384 device set at 30°C. To assess the baseline level, measurements were carried out for 30 s in wells containing PBS. 5C4-bio was then coupled to the streptavidin sensor for 200 s. The baseline level was assessed again for 30 s in the wells containing PBS. Binding was then measured for 180 s in wells containing samples to be assessed for binding, and dissociation was measured for 180 s in wells containing PBS. Graphs demonstrating real-time binding patterns are presented in FIG. 26. As shown in FIG. 26, for antibodies carrying a protease-cleavable sequence, the measured amount of human PD1 bound to 5C4-bio was greater in binding assay samples that contained protease-treated antibodies than in binding assay samples. which contained protease-untreated antibodies. Thus, the PD1 binding activity of any of the antibodies bearing the protease cleavable sequence was attenuated by protease treatment, causing PD1 to be released from it by binding to 5C4-bio.

14-2-4 Confirmation of antibody cleavage by protease (SDS-PAGE)

Whether the antibodies used in Example 14-2-3 were cleaved by protease treatment was confirmed by SDS-PAGE. 10 μl of each protease-digested antibody or protease-untreated antibody prepared according to the method described in Example 14-2-3 was mixed with 3.3 μl of sample buffer and incubated at 95°C for 5 minutes. Electrophoresis was then performed using Mini-PROTEAN TGX Gel (4-20%, 15 wells) (Bio-Rad Laboratories, Inc., #456-1096) and proteins were stained with Sample Blue Safe Stain ) (Novex, LC6065). The results are presented in Fig. 27. As shown in FIG. 27, each antibody bearing a protease-cleavable sequence was cleaved by protease treatment.

14-2-5 Evaluation of PD1 antibody binding before and after protease treatment

The PD1 binding activity of each antibody carrying a protease cleavable sequence before and after protease treatment was also measured using a different method.

10 μl of each protease-treated antibody or protease-untreated antibody prepared according to the method described in Example 14-2-1 was mixed with 70 μl of PBS to obtain samples for PD1 binding assay. PD1 binding in the samples was assessed using biolayer interferometry (BLI). Protease-treated antibodies or protease-untreated antibodies prepared according to the method described in Example 14-2-1 and human PD1 (250 nM) were distributed into different wells of slanted bottom microplates (TW384) (Pall ForteBio Corp., 18-5076). . The Protein G sensor (Pall ForteBio Corp., 18-0022) was hydrogenated with PBS followed by analysis using an Octet RED 384 set at 30°C. To assess the baseline level, measurements were carried out for 30 s in wells containing PBS. The antibodies were then bound to protein G on the sensor for 200 s. The baseline level was assessed again for 30 s in the wells containing PBS. Binding was then measured for 180 s in wells containing human PD1, and dissociation was measured for 180 s in wells containing PBS. Graphs demonstrating real-time binding patterns are presented in FIG. 28. As shown in FIG. 28, for each of the antibodies carrying a protease-cleavable sequence, the amount of bound human PD1 was reduced with the protease-treated antibody compared to the non-protease-treated antibody.

14-3. Evaluation of protease-mediated ligand release from a complex containing a ligand (human PD1) and a neutralizing anti-human PD1 antibody carrying a protease-cleavable sequence

14-3-1 Protease treatment in the presence of ligand 10 μl of human PD1, the concentration of which was adjusted to 6.67 μM with PBS, was added to each antibody (final concentration: 0.100 mg/ml) obtained according to the method described in example 14 -1, to obtain solutions of the antibody-PD1 complex. To prepare protease-treated samples, 10 μl of recombinant human matriptase/ST14 catalytic domain (hMT-SP1, R&D Systems, Inc., 3946-SE-010), adjusted to 5.28 μg/ml with PBS, was added to each solution of the antibody-PD1 complex. To prepare protease-untreated samples, 10 μl of PBS alone was added. The final concentration of protease during the reaction was 0.528 μg/ml. Each sample was incubated at 37°C for 12 h.

14-3-2 Evaluation of PD1 release after protease treatment

The amount of uncomplexed PD1 was assessed by biolayer interferometry (BLI) using a biotinylated anti-human PD1 neutralizing antibody (5C4-bio) prepared according to the method described in Example 14-2-2.

Each sample prepared according to the method described in Example 14-3-1, 5C4-bio and PBS were distributed into different wells of tilt-bottom microplates (TW384) (Pall ForteBio Corp., 18-5076). Streptavidin biosensor (Pall ForteBio Corp., 18-0009) was hydrogenated with PBS followed by analysis using an Octet RED 384 device set at 30°C. To assess the baseline level, measurements were carried out for 30 s in wells containing PBS. 5C4-bio was then coupled to the streptavidin sensor for 200 s. The baseline level was assessed again for 30 s in the wells containing PBS. Binding was then measured for 180 s in wells containing protease-treated or protease-untreated samples, and dissociation was measured for 180 s in wells containing PBS. Graphs demonstrating real-time binding patterns are presented in FIG. 29. As shown in FIG. 29, for each antibody carrying a protease-cleavable sequence, the amount of human PD1 bound to 5C4-bio increased in the protease-treated sample compared to the protease-untreated sample. Thus, the PD1 binding activity of each antibody was attenuated by protease treatment, causing PD1 to be released and dissociated from the antibody-PD1 complex.

Example 15: Preparation and Evaluation of a Fusion Protein Comprising an Anti-Human PD1 Neutralizing Antibody Which Carries a Protease-Cleavable Sequence and Human PD1 (Anti-PD1-PD1 Neutralizing Antibody Fusion Protein)

15-1. Preparation of a fusion protein containing a neutralizing antibody to human PD1 and human PD1

The human PD1 sequence (SEQ ID NO: 320) was linked to the N-terminus of the heavy chain or heavy chain variant of each antibody prepared according to the method described in Example 14-1 through a flexible linker consisting of a glycine-serine polymer (SEQ ID NO: 321), yielding PD1-fused heavy chains (Table 12).

In addition, the human PD1 sequence (SEQ ID NO: 320) was linked to the N-terminus of the light chain or light chain variant of each antibody prepared according to the method described in Example 14-1 through a flexible linker consisting of a glycine-serine polymer (SEQ ID NO: 321) to produce PD1-fused light chains 13).

Anti-PD1-PD1 neutralizing antibody fusion proteins listed below:

hPD15C4HA12aa-G1T4/5C4L-KT0 (PD1 fused heavy chain: SEQ ID NO: 323, light chain: SEQ ID NO: 298),

hPD15C4HE12aa-G1T4E/5C4L-KT0 (PD1 fused heavy chain: SEQ ID NO: 324, light chain: SEQ ID NO: 298),

5C4H-G1T4/hPD15C4LH12aa-KT0 (heavy chain: SEQ ID NO: 297, light chain: SEQ ID NO: 325),

5C4H-G1T4/hPD15C4LI12aa-KT0 (heavy chain: SEQ ID NO: 297, PD1 fused light chain: SEQ ID NO: 326),

5C4H-G1T4/hPD15C4LC12aa-KT0 (heavy chain: SEQ ID NO: 297, PD1 fused light chain: SEQ ID NO: 327),

5C4H-G1T4/hPD15C4LD12aa-KT0 (heavy chain: SEQ ID NO: 297, PD1 fused light chain: SEQ ID NO: 328),

5C4H-G1T4/hPD15C4LE12aa-KT0E (heavy chain: SEQ ID NO: 297, PD1 fused light chain: SEQ ID NO: 329),

5C4H-G1T4/hPD15C4LB12aa-KT0B (heavy chain: SEQ ID NO: 297, PD1 fused light chain: SEQ ID NO: 330),

5C4H-G1T4/hPD15C4LF12aa-KT0F (heavy chain: SEQ ID NO: 297, PD1 fused light chain: SEQ ID NO: 331),

5C4H-G1T4/hPD15C4LG12aa-KT0G (heavy chain: SEQ ID NO: 297, PD1 fused light chain: SEQ ID NO: 332),

5C4H-G1T4/hPD15C4LJ12aa-KT0J (heavy chain: SEQ ID NO: 297, PD1 fused light chain: SEQ ID NO: 333) and

5C4H-G1T4/hPD15C4LK12aa-KT0K (heavy chain: SEQ ID NO: 297, PD1 fused light chain: SEQ ID NO: 334),

which combined the PD1 fused heavy chains shown in Table 12 with the 5C4L-KT0 light chain, or combined the PD1 fused light chains shown in Table 13 with the 5C4H-G1T4 heavy chain, expressed by transient expression using Expi293 (company Life Technologies Corp.) using a method known to those skilled in the art and purified using a method known to those skilled in the art using Protein A. Likewise, 5C4H-G1T4/5C4L-KT0 (heavy chain: SEQ ID NO) was expressed and purified : 297, light chain: SEQ ID NO: 298) as a control antibody lacking the protease cleavable sequence.

15-2. Assessment of protease cleavage of anti-PD1-PD1 neutralizing antibody fusion protein

15-2-1 Protease treatment

To prepare protease-treated fusion proteins, 4.9 μl of recombinant human matriptase/ST14 catalytic domain (hMT-SP1, R&D Systems, Inc., 3946-SE-010) was added at a concentration adjusted to 16.7 μg/ml with PBS , to 30 μg of each fusion protein prepared according to the method described in Example 15-1. To prepare protease-untreated fusion proteins, only 4.9 μl of PBS was added to 30 μg of each fusion protein prepared according to the method described in Example 15-1. Protease-treated fusion proteins or non-protease-treated fusion proteins were incubated at 37°C for 12 hours.

15-2-2 Evaluation of PD1 release following protease treatment

Release of PD1 by protease treatment was assessed by biolayer interferometry (BLI) using a biotinylated anti-human PD1 neutralizing antibody (5C4-bio) prepared according to the method described in Example 14-2-2.

Protease-treated fusion proteins or non-protease-treated fusion proteins prepared according to the method described in Example 15-2-1, 5C4-bio and PBS were distributed into different wells of tilt-bottom microplates (TW384) (Pall ForteBio Corp., 18-5076). . Streptavidin biosensor (Pall ForteBio Corp., 18-0009) was hydrogenated with PBS followed by analysis using an Octet RED 384 device set at 30°C. To assess the baseline level, measurements were carried out for 30 s in wells containing PBS. 5C4-bio was then coupled to the streptavidin sensor for 200 s. The baseline level was assessed again for 30 s in the wells containing PBS. Binding was then measured for 180 s in wells containing protease-treated fusion proteins or protease-untreated fusion proteins, and dissociation was measured for 180 s in wells containing PBS. Graphs demonstrating real-time binding patterns are presented in FIG. 30. As shown in FIG. 30, for each antibody-PD1 fusion protein containing an antibody that carried a protease-cleavable sequence, the amount of human PD1 bound to 5C4-bio increased in the protease-treated sample compared to the non-protease-treated sample. Thus, the PD1 binding activity of the antibody in each of the fusion proteins was attenuated by protease treatment, resulting in the release of PD1 from the fusion protein.

15-2-3 Confirmation of cleavage of PD1-PD1 neutralizing antibody fusion protein (SDS-PAGE)

Whether the protease-treated fusion proteins prepared according to the method described in Example 15-2-1 were cleaved by protease treatment was determined by SDS-PAGE. 10 μl of each protease-treated fusion protein or non-protease-treated fusion protein prepared according to the method described in Example 15-2-1 was mixed with 3.3 μl of sample buffer and incubated at 95°C for 5 minutes. Electrophoresis was then performed using Mini-PROTEAN TGX Gel (4-20%, 15 wells) (Bio-Rad Laboratories, Inc., #456-1096) and proteins were stained with Sample Blue Safe Stain ) (Novex, LC6065). The results are presented in Fig. 31. As shown in FIG. 31, each fusion protein containing an antibody carrying a protease-cleavable sequence was cleaved by protease treatment.

For the purpose of better understanding, the above-mentioned embodiments of the invention are described in detail with reference to actual examples and illustrative examples. However, the description and illustrations presented herein should not be interpreted as limiting the scope of the present invention. The contents of all patent literature and scientific literature cited herein are expressly incorporated by reference in their entirety.

Industrial applicability

The ligand-binding molecule of the present invention, in its ligand-bound state, can be transported in vivo and degraded in diseased tissue, thereby weakening its binding to the ligand, resulting in specific release of the ligand in the diseased tissue. Thus, diseased tissue can be specifically exposed to the ligand. In addition, the ligand-binding molecule inhibits the biological activity of the ligand during transport and therefore reduces the risk of systemic exposure to the ligand. Thus, the ligand binding molecule is of great value for the treatment of disease.

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LIST OF SEQUENCES

<110> CHUGAI SEYAKU KABUSHIKI REPENT

5 <120> LIGAND BINDING MOLECULE WITH REGULATED LIGAND BINDING

ACTIVITY

<130> C1-A1615P

10 <150> JP 2016-229882

<151> 2016-11-28

<160> 537

15 <170> Patent In version 3.5

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

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

20 25 30

35 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

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Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

40 50 55 60

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

65 70 75 80

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

85 90 95

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Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

100 105 110

Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys

115 120 125

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

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Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

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

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Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

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Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro

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Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

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Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

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Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

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Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

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

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Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

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Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

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

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

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Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser

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Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys

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Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

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

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Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

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Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

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Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

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Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

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Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

50 305 310 315 320

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

325 330 335

5 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

340 345 350

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

10 355 360 365

Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

370 375 380

15

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

385 390 395 400

20

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

405 410 415

25 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

420 425 430

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

30 435 440 445

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455 460

35

<210> 5

<211> 460

<212>PRT

40 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

45 <400> 5

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

1 5 10 15

50

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

20 25 30

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

35 40 45

5

Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

50 55 60

10

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

65 70 75 80

15 Leu Glu Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys

85 90 95

Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

20 100 105 110

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

115 120 125

25

Gly Arg Ser Asp Asn His Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

130 135 140

thirty

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

145 150 155 160

35 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

165 170 175

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

40 180 185 190

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

195 200 205

45

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

210 215 220

50

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

225 230 235 240

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

245 250 255

5

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

260 265 270

10

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

275 280 285

15 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

290 295 300

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

20 305 310 315 320

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

325 330 335

25

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

340 345 350

thirty

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

355 360 365

35 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

370 375 380

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

40 385 390 395 400

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

405 410 415

45

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

420 425 430

50

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

435 440 445

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455 460

5

<210> 6

<211> 460

<212>PRT

10 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15 <400> 6

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

1 5 10 15

20

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

20 25 30

25 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

30 50 55 60

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

65 70 75 80

35

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

85 90 95

40

Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

100 105 110

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

115 120 125

Asn His Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

50 130 135 140

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

145 150 155 160

5 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

165 170 175

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

10 180 185 190

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

195 200 205

15

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

210 215 220

20

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

225 230 235 240

25 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

245 250 255

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

30 260 265 270

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

275 280 285

35

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

290 295 300

40

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

305 310 315 320

45 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

325 330 335

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

50 340 345 350

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

355 360 365

5 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

370 375 380

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

10 385 390 395 400

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

405 410 415

15

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

420 425 430

20

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

435 440 445

25 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455 460

<210> 7

30 <211> 460

<212>PRT

<213> Artificial Sequence

<220>

35 <223> an artificially synthesized sequence

<400> 7

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

40 1 5 10 15

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

20 25 30

45

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

35 40 45

50

Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

50 55 60

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

65 70 75 80

5

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

85 90 95

10

Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

100 105 110

15 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Leu Ser Gly Arg Ser

115 120 125

Asp Asn His Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

20 130 135 140

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

145 150 155 160

25

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

165 170 175

thirty

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

180 185 190

35 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

195 200 205

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

40 210 215 220

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

225 230 235 240

45

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

245 250 255

50

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

260 265 270

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

275 280 285

5

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

290 295 300

10

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

305 310 315 320

15 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

325 330 335

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

20 340 345 350

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

355 360 365

25

Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

370 375 380

thirty

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

385 390 395 400

35 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

405 410 415

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

40 420 425 430

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

435 440 445

45

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455 460

50

<210> 8

<211> 460

<212>PRT

<213> Artificial Sequence

<220>

5 <223> an artificially synthesized sequence

<400> 8

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

10 1 5 10 15

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

20 25 30

15

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

35 40 45

20

Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

50 55 60

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

65 70 75 80

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

30 85 90 95

Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

100 105 110

35

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

115 120 125

40

Arg Ser Asp Asn His Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

130 135 140

45 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

145 150 155 160

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

50 165 170 175

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

180 185 190

5 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

195 200 205

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

10 210 215 220

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

225 230 235 240

15

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

245 250 255

20

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

260 265 270

25 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

275 280 285

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

30 290 295 300

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

305 310 315 320

35

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

325 330 335

40

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

340 345 350

45 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

355 360 365

Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

50 370 375 380

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

385 390 395 400

5 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

405 410 415

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

10 420 425 430

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

435 440 445

15

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455 460

20

<210> 9

<211> 460

<212>PRT

<213> Artificial Sequence

25

<220>

<223> an artificially synthesized sequence

<400> 9

thirty

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

1 5 10 15

35 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Asn Asn

20 25 30

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

40 35 40 45

Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

50 55 60

45

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

65 70 75 80

50

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

85 90 95

Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

100 105 110

5

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

115 120 125

10

Ser Gly Arg Ser Asp Asn His Lys Gly Pro Ser Val Phe Pro Leu Ala

130 135 140

15 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

145 150 155 160

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

20 165 170 175

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

180 185 190

25

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

195 200 205

thirty

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

210 215 220

35 Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

225 230 235 240

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

40 245 250 255

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

260 265 270

45

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

275 280 285

50

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

290 295 300

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

305 310 315 320

5

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

325 330 335

10

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

340 345 350

15 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

355 360 365

Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

20 370 375 380

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

385 390 395 400

25

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

405 410 415

thirty

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

420 425 430

35 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

435 440 445

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

40 450 455 460

<210> 10

<211> 460

45 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

50

<400> 10

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

1 5 10 15

5 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Asn Asn

20 25 30

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

10 35 40 45

Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

50 55 60

15

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

65 70 75 80

20

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

85 90 95

25 Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

100 105 110

Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys

30 115 120 125

Leu Ser Gly Arg Ser Asp Asn His Gly Pro Ser Val Phe Pro Leu Ala

130 135 140

35

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

145 150 155 160

40

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

165 170 175

45 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

180 185 190

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

50 195 200 205

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

210 215 220

5 Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

225 230 235 240

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

10 245 250 255

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

260 265 270

15

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

275 280 285

20

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

290 295 300

25 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

305 310 315 320

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

30 325 330 335

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

340 345 350

35

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

355 360 365

40

Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

370 375 380

45 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

385 390 395 400

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

50 405 410 415

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

420 425 430

5 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

435 440 445

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

10 450 455 460

<210> 11

<211> 460

15 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

20

<400> 11

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

1 5 10 15

25

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

20 25 30

thirty

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

35 40 45

35 Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

50 55 60

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

40 65 70 75 80

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

85 90 95

45

Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

100 105 110

50

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

115 120 125

Gly Arg Ser Asp Asn His Gly Lys Gly Pro Ser Val Phe Pro Leu Ala

130 135 140

5

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

145 150 155 160

10

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

165 170 175

15 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

180 185 190

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

20 195 200 205

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

210 215 220

25

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

225 230 235 240

thirty

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

245 250 255

35 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

260 265 270

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

40 275 280 285

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

290 295 300

45

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

305 310 315 320

50

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

325 330 335

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

340 345 350

5

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

355 360 365

10

Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

370 375 380

15 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

385 390 395 400

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

20 405 410 415

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

420 425 430

25

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

435 440 445

thirty

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455 460

35 <210> 12

<211> 460

<212>PRT

<213> Artificial Sequence

40 <220>

<223> an artificially synthesized sequence

<400> 12

45 Gln Met Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

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

50 20 25 30

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

35 40 45

5 Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

50 55 60

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

10 65 70 75 80

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

85 90 95

15

Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

100 105 110

20

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

115 120 125

25 Asn His Gly Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

130 135 140

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

30 145 150 155 160

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

165 170 175

35

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

180 185 190

40

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

195 200 205

45 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

210 215 220

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

50 225 230 235 240

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

245 250 255

5 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

260 265 270

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

10 275 280 285

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

290 295 300

15

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

305 310 315 320

20

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

325 330 335

25 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

340 345 350

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

30 355 360 365

Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

370 375 380

35

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

385 390 395 400

40

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

405 410 415

45 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

420 425 430

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

50 435 440 445

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455 460

5 <210> 13

<211> 460

<212>PRT

<213> Artificial Sequence

10 <220>

<223> an artificially synthesized sequence

<400> 13

15 Gln Met Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

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

20 20 25 30

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

35 40 45

25

Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

50 55 60

thirty

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

65 70 75 80

35 Leu Glu Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys

85 90 95

Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

40 100 105 110

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

115 120 125

45

Asp Asn His Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

130 135 140

50

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

145 150 155 160

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

165 170 175

5

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

180 185 190

10

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

195 200 205

15 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

210 215 220

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

20 225 230 235 240

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

245 250 255

25

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

260 265 270

thirty

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

275 280 285

35 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

290 295 300

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

40 305 310 315 320

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

325 330 335

45

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

340 345 350

50

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

355 360 365

Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

370 375 380

5

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

385 390 395 400

10

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

405 410 415

15 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

420 425 430

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

20 435 440 445

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455 460

25

<210> 14

<211> 460

<212>PRT

30 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

35 <400> 14

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

1 5 10 15

40

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

20 25 30

45 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

50 50 55 60

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

65 70 75 80

5 Leu Glu Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys

85 90 95

Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

10 100 105 110

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

115 120 125

15

Arg Ser Asp Asn His Gly Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

130 135 140

20

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

145 150 155 160

25 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

165 170 175

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

30 180 185 190

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

195 200 205

35

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

210 215 220

40

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

225 230 235 240

45 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

245 250 255

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

50 260 265 270

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

275 280 285

5 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

290 295 300

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

10 305 310 315 320

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

325 330 335

15

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

340 345 350

20

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

355 360 365

25 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

370 375 380

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

30 385 390 395 400

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

405 410 415

35

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

420 425 430

40

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

435 440 445

45 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455 460

<210> 15

50 <211> 224

<212>PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

5 <400> 15

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

1 5 10 15

10

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

20 25 30

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

35 40 45

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

20 50 55 60

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

65 70 75 80

25

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

85 90 95

thirty

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

100 105 110

35 Arg Ser Asp Asn His Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe

115 120 125

Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys

40 130 135 140

Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val

145 150 155 160

45

Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln

165 170 175

50

Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser

180 185 190

Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His

195 200 205

5

Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215 220

10

<210> 16

<211> 224

<212>PRT

<213> Artificial Sequence

15

<220>

<223> an artificially synthesized sequence

<400> 16

20

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

1 5 10 15

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

20 25 30

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

30 35 40 45

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

50 55 60

35

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

65 70 75 80

40

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

85 90 95

45 Ile Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Leu

100 105 110

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

50 115 120 125

Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys

130 135 140

5 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val

145 150 155 160

Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln

10 165 170 175

Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser

180 185 190

15

Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His

195 200 205

20

Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215 220

25 <210> 17

<211> 224

<212>PRT

<213> Artificial Sequence

30 <220>

<223> an artificially synthesized sequence

<400> 17

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

1 5 10 15

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

40 20 25 30

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

35 40 45

45

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

50 55 60

50

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

65 70 75 80

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

85 90 95

5

Ile Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Leu Ser Gly Arg Ser

100 105 110

10

Asp Asn His Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe

115 120 125

15 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys

130 135 140

Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val

20 145 150 155 160

Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln

165 170 175

25

Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser

180 185 190

thirty

Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His

195 200 205

35 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215 220

<210> 18

40 <211> 224

<212>PRT

<213> Artificial Sequence

<220>

45 <223> an artificially synthesized sequence

<400> 18

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

50 1 5 10 15

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

20 25 30

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

35 40 45

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

10 50 55 60

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

65 70 75 80

15

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

85 90 95

20

Ile Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Leu Ser Gly Arg

100 105 110

25 Ser Asp Asn His Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe

115 120 125

Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys

30 130 135 140

Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val

145 150 155 160

35

Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln

165 170 175

40

Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser

180 185 190

45 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His

195 200 205

Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

50 210 215 220

<210> 19

<211> 224

<212>PRT

<213> Artificial Sequence

5

<220>

<223> an artificially synthesized sequence

<400> 19

10

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

1 5 10 15

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

20 25 30

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

20 35 40 45

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

50 55 60

25

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

65 70 75 80

thirty

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

85 90 95

35 Ile Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Leu Ser

100 105 110

Gly Arg Ser Asp Asn His Thr Val Ala Ala Pro Ser Val Phe Ile Phe

40 115 120 125

Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys

130 135 140

45

Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val

145 150 155 160

50

Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln

165 170 175

Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser

180 185 190

5

Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His

195 200 205

10

Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215 220

15 <210> 20

<211> 224

<212>PRT

<213> Artificial Sequence

20 <220>

<223> an artificially synthesized sequence

<400> 20

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

1 5 10 15

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

30 20 25 30

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

35 40 45

35

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

50 55 60

40

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

65 70 75 80

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

85 90 95

Ile Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val

50 100 105 110

Leu Ser Gly Arg Ser Asp Asn His Ala Ala Pro Ser Val Phe Ile Phe

115 120 125

5 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys

130 135 140

Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val

10 145 150 155 160

Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln

165 170 175

15

Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser

180 185 190

20

Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His

195 200 205

25 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215 220

<210> 21

30 <211> 224

<212>PRT

<213> Artificial Sequence

<220>

35 <223> an artificially synthesized sequence

<400> 21

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

40 1 5 10 15

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

20 25 30

45

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

35 40 45

50

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

50 55 60

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

65 70 75 80

5

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

85 90 95

10

Ile Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val

100 105 110

15 Ala Leu Ser Gly Arg Ser Asp Asn His Ala Pro Ser Val Phe Ile Phe

115 120 125

Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys

20 130 135 140

Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val

145 150 155 160

25

Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln

165 170 175

thirty

Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser

180 185 190

35 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His

195 200 205

Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

40 210 215 220

<210> 22

<211> 224

45 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

50

<400> 22

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

1 5 10 15

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

20 25 30

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

10 35 40 45

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

50 55 60

15

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

65 70 75 80

20

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

85 90 95

25 Ile Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Leu Ser

100 105 110

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

30 115 120 125

Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys

130 135 140

35

Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val

145 150 155 160

40

Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln

165 170 175

45 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser

180 185 190

Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His

50 195 200 205

Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215 220

5 <210> 23

<211> 462

<212>PRT

<213> Artificial Sequence

10 <220>

<223> an artificially synthesized sequence

<400> 23

15 Gln Met Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

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

20 20 25 30

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

35 40 45

25

Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

50 55 60

thirty

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

65 70 75 80

35 Leu Glu Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys

85 90 95

Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

40 100 105 110

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

115 120 125

45

Asp Asn His Gly Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro

130 135 140

50

Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly

145 150 155 160

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn

165 170 175

5

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln

180 185 190

10

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser

195 200 205

15 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser

210 215 220

Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr

20 225 230 235 240

His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser

245 250 255

25

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

260 265 270

thirty

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro

275 280 285

35 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

290 295 300

Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val

40 305 310 315 320

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

325 330 335

45

Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr

340 345 350

50

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

355 360 365

Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

370 375 380

5

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

385 390 395 400

10

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

405 410 415

15 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser

420 425 430

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

20 435 440 445

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455 460

25

<210> 24

<211> 464

<212>PRT

30 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

35 <400> 24

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

1 5 10 15

40

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

20 25 30

45 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

50 50 55 60

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

65 70 75 80

5 Leu Glu Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys

85 90 95

Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

10 100 105 110

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

115 120 125

15

Ser Asp Asn His Gly Ser Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

130 135 140

20

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

145 150 155 160

25 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

165 170 175

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

30 180 185 190

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

195 200 205

35

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

210 215 220

40

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

225 230 235 240

45 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

245 250 255

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

50 260 265 270

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

275 280 285

5 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

290 295 300

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

10 305 310 315 320

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

325 330 335

15

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

340 345 350

20

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

355 360 365

25 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

370 375 380

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

30 385 390 395 400

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

405 410 415

35

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

420 425 430

40

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

435 440 445

45 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455 460

<210> 25

50 <211> 466

<212>PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

5 <400> 25

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

1 5 10 15

10

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

20 25 30

15 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

20 50 55 60

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

65 70 75 80

25

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

85 90 95

thirty

Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

100 105 110

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

115 120 125

Arg Ser Asp Asn His Gly Ser Ser Ser Ser Ala Ser Thr Lys Gly Pro

40 130 135 140

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

145 150 155 160

45

Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr

165 170 175

50

Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro

180 185 190

Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr

195 200 205

5

Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn

210 215 220

10

His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser

225 230 235 240

15 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu

245 250 255

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

20 260 265 270

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

275 280 285

25

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu

290 295 300

thirty

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr

305 310 315 320

35 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

325 330 335

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro

40 340 345 350

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

355 360 365

45

Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val

370 375 380

50

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

385 390 395 400

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

405 410 415

5

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

420 425 430

10

Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val

435 440 445

15 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

450 455 460

Ser Pro

20 465

<210> 26

<211> 468

25 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

thirty

<400> 26

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

1 5 10 15

35

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

20 25 30

40

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

35 40 45

45 Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

50 55 60

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

50 65 70 75 80

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

85 90 95

5 Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

100 105 110

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

10 115 120 125

Gly Arg Ser Asp Asn His Gly Ser Ser Gly Ser Ser Ala Ser Thr Lys

130 135 140

15

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

145 150 155 160

20

Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

165 170 175

25 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

180 185 190

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

30 195 200 205

Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

210 215 220

35

Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro

225 230 235 240

40

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

245 250 255

45 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

260 265 270

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

50 275 280 285

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

290 295 300

5 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

305 310 315 320

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

10 325 330 335

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

340 345 350

15

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

355 360 365

20

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

370 375 380

25 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

385 390 395 400

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

30 405 410 415

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

420 425 430

35

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

435 440 445

40

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

450 455 460

45 Ser Leu Ser Pro

465

<210> 27

50 <211> 470

<212>PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

5 <400> 27

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

1 5 10 15

10

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

20 25 30

15 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

20 50 55 60

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

65 70 75 80

25

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

85 90 95

thirty

Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

100 105 110

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

115 120 125

Ser Gly Arg Ser Asp Asn His Gly Ser Ser Gly Thr Ser Ser Ala Ser

40 130 135 140

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

145 150 155 160

45

Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro

165 170 175

50

Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val

180 185 190

His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser

195 200 205

5

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

210 215 220

10

Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val

225 230 235 240

15 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

245 250 255

Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

20 260 265 270

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

275 280 285

25

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

290 295 300

thirty

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

305 310 315 320

35 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

325 330 335

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

40 340 345 350

Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

355 360 365

45

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr

370 375 380

50

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

385 390 395 400

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

405 410 415

5

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

420 425 430

10

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

435 440 445

15 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

450 455 460

Ser Leu Ser Leu Ser Pro

20 465 470

<210> 28

<211> 10

25 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

thirty

<400> 28

Gly Leu Ser Gly Arg Ser Asp Asn His Gly

1 5 10

35

<210> 29

<211> 12

<212>PRT

40 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

45 <400> 29

Ser Gly Leu Ser Gly Arg Ser Asp Asn His Gly Ser

1 5 10

50

<210> 30

<211> 14

<212>PRT

<213> Artificial Sequence

<220>

5 <223> an artificially synthesized sequence

<400> 30

Gly Ser Gly Leu Ser Gly Arg Ser Asp Asn His Gly Ser Ser

10 1 5 10

<210> 31

<211> 16

15 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

20

<400> 31

Gly Gly Ser Gly Leu Ser Gly Arg Ser Asp Asn His Gly Ser Ser Gly

1 5 10 15

25

<210> 32

<211> 18

<212>PRT

30 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

35 <400> 32

Ser Gly Gly Ser Gly Leu Ser Gly Arg Ser Asp Asn His Gly Ser Ser

1 5 10 15

40

Gly Thr

45 <210> 33

<211> 472

<212>PRT

<213> Artificial Sequence

50 <220>

<223> an artificially synthesized sequence

<400> 33

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

1 5 10 15

5

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

20 25 30

10

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

35 40 45

15 Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

50 55 60

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

20 65 70 75 80

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

85 90 95

25

Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

100 105 110

thirty

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

115 120 125

35 Ser Gly Arg Ser Asp Asn His Gly Ser Ser Gly Thr Ser Ser Ala Ser

130 135 140

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

40 145 150 155 160

Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro

165 170 175

45

Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val

180 185 190

50

His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser

195 200 205

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

210 215 220

5

Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val

225 230 235 240

10

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

245 250 255

15 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

260 265 270

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

20 275 280 285

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

290 295 300

25

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

305 310 315 320

thirty

Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

325 330 335

35 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

340 345 350

Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

40 355 360 365

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr

370 375 380

45

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

385 390 395 400

50

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

405 410 415

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

420 425 430

5

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

435 440 445

10

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

450 455 460

15 Ser Leu Ser Leu Ser Pro Gly Lys

465 470

<210> 34

20 <211> 6

<212>PRT

<213> Artificial Sequence

<220>

25 <223> an artificially synthesized sequence

<400> 34

Pro Leu Gly Leu Ala Gly

30 1 5

<210> 35

<211> 8

35 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

40

<400> 35

Val Pro Leu Ser Leu Thr Met Gly

15

45

<210> 36

<211> 4

<212>PRT

50 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

<400> 36

5 Gly Gly Gly Ser

1

<210> 37

10 <211> 4

<212>PRT

<213> Artificial Sequence

<220>

15 <223> an artificially synthesized sequence

<400> 37

Gly Gly Ser Gly

20 1

<210> 38

<211> 4

25 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

thirty

<400> 38

Gly Ser Gly Gly

1

35

<210> 39

<211> 4

<212>PRT

40 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

45 <400> 39

Ser Gly Gly Gly

1

50

<210> 40

<211> 4

<212>PRT

<213> Artificial Sequence

<220>

5 <223> an artificially synthesized sequence

<400> 40

Gly Ser Ser Gly

10 1

<210> 41

<211> 5

15 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

20

<400> 41

Gly Gly Gly Gly Ser

15

25

<210> 42

<211> 5

<212>PRT

30 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

35 <400> 42

Gly Gly Gly Ser Gly

15

40

<210> 43

<211> 5

<212>PRT

<213> Artificial Sequence

45

<220>

<223> an artificially synthesized sequence

<400> 43

50

Gly Gly Ser Gly Gly

15

<210> 44

<211> 5

5 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

10

<400> 44

Gly Ser Gly Gly Gly

15

15

<210> 45

<211> 5

<212>PRT

20 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

25 <400> 45

Gly Ser Gly Gly Ser

15

thirty

<210> 46

<211> 5

<212>PRT

<213> Artificial Sequence

35

<220>

<223> an artificially synthesized sequence

<400> 46

40

Ser Gly Gly Gly Gly

15

45 <210> 47

<211> 5

<212>PRT

<213> Artificial Sequence

50 <220>

<223> an artificially synthesized sequence

<400> 47

Gly Ser Ser Gly Gly

15

5

<210> 48

<211> 5

<212>PRT

10 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15 <400> 48

Gly Ser Gly Ser Gly

15

20

<210> 49

<211> 5

<212>PRT

<213> Artificial Sequence

25

<220>

<223> an artificially synthesized sequence

<400> 49

thirty

Ser Gly Gly Ser Gly

15

35 <210> 50

<211> 5

<212>PRT

<213> Artificial Sequence

40 <220>

<223> an artificially synthesized sequence

<400> 50

45 Gly Ser Ser Ser Gly

15

<210> 51

50 <211> 6

<212>PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

5 <400> 51

Gly Gly Gly Gly Gly Ser

15

10

<210> 52

<211> 6

<212>PRT

<213> Artificial Sequence

15

<220>

<223> an artificially synthesized sequence

<400> 52

20

Ser Gly Gly Gly Gly Gly

15

25 <210> 53

<211> 7

<212>PRT

<213> Artificial Sequence

30 <220>

<223> an artificially synthesized sequence

<400> 53

35 Gly Gly Gly Gly Gly Gly Ser

15

<210> 54

40 <211> 7

<212>PRT

<213> Artificial Sequence

<220>

45 <223> an artificially synthesized sequence

<400> 54

Ser Gly Gly Gly Gly Gly Gly

50 1 5

<210> 55

<211> 330

<212>PRT

<213> Homo sapiens

5

<400> 55

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

1 5 10 15

10

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

20 25 30

15

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

35 40 45

20 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

25 65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

thirty

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

35

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

40 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

45 145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

50

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

5 195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

10

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

225 230 235 240

15

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

245 250 255

20 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

25 275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

thirty

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

35

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

40 <210> 56

<211> 326

<212>PRT

<213> Homo sapiens

45 <400> 56

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg

1 5 10 15

50

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

5

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

10

Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr

65 70 75 80

15 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

20 100 105 110

Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

115 120 125

25

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

130 135 140

thirty

Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly

145 150 155 160

35 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn

165 170 175

Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp

40 180 185 190

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

195 200 205

45

Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu

210 215 220

50

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

225 230 235 240

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

245 250 255

5

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

260 265 270

10

Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

275 280 285

15 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

290 295 300

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

20 305 310 315 320

Ser Leu Ser Pro Gly Lys

325

25

<210> 57

<211> 377

<212>PRT

30 <213> Homo sapiens

<400> 57

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg

35 1 5 10 15

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

20 25 30

40

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

35 40 45

45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

50 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Thr Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

5

Arg Val Glu Leu Lys Thr Pro Leu Gly Asp Thr Thr His Thr Cys Pro

100 105 110

10 Arg Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg

115 120 125

Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys

15 130 135 140

Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro

145 150 155 160

20

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

165 170 175

25

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val

180 185 190

30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Lys Trp Tyr

195 200 205

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu

35 210 215 220

Gln Tyr Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Leu His

225 230 235 240

40

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys

245 250 255

45

Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln

260 265 270

50 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met

275 280 285

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

290 295 300

5

Ser Asp Ile Ala Val Glu Trp Glu Ser Ser Gly Gln Pro Glu Asn Asn

305 310 315 320

10 Tyr Asn Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu

325 330 335

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

15 340 345 350

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln

355 360 365

20

Lys Ser Leu Ser Leu Ser Pro Gly Lys

370 375

25

<210> 58

<211> 327

<212>PRT

<213> Homo sapiens

thirty

<400> 58

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg

1 5 10 15

35

Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

40

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

35 40 45

45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

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

50 65 70 75 80

Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

5 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro

100 105 110

Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

10 115 120 125

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

130 135 140

15

Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp

145 150 155 160

20

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe

165 170 175

25 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

180 185 190

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu

30 195 200 205

Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

210 215 220

35

Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys

225 230 235 240

40

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

245 250 255

45 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

260 265 270

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

50 275 280 285

Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser

290 295 300

5 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

305 310 315 320

Leu Ser Leu Ser Leu Gly Lys

10 325

<210> 59

<211> 462

15 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

20

<400> 59

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

1 5 10 15

25

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

20 25 30

thirty

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

35 40 45

35 Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

50 55 60

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

40 65 70 75 80

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

85 90 95

45

Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

100 105 110

50

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

115 120 125

Arg Ser Asp Asn His Gly Ser Ser Thr Lys Gly Pro Ser Val Phe Pro

130 135 140

5

Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly

145 150 155 160

10

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn

165 170 175

15 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln

180 185 190

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser

20 195 200 205

Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser

210 215 220

25

Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr

225 230 235 240

thirty

His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser

245 250 255

35 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

260 265 270

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro

40 275 280 285

Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

290 295 300

45

Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val

305 310 315 320

50

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

325 330 335

Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr

340 345 350

5

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

355 360 365

10

Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

370 375 380

15 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

385 390 395 400

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

20 405 410 415

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser

420 425 430

25

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

435 440 445

thirty

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455 460

35 <210> 60

<211> 468

<212>PRT

<213> Artificial Sequence

40 <220>

<223> an artificially synthesized sequence

<400> 60

45 Gln Met Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

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

50 20 25 30

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

35 40 45

5 Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

50 55 60

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

10 65 70 75 80

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

85 90 95

15

Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

100 105 110

20

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

115 120 125

25 Leu Ser Gly Arg Ser Asp Asn His Gly Ser Ser Gly Thr Ser Thr Lys

130 135 140

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

30 145 150 155 160

Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

165 170 175

35

Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

180 185 190

40

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

195 200 205

45 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

210 215 220

Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro

50 225 230 235 240

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

245 250 255

5 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

260 265 270

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

10 275 280 285

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

290 295 300

15

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

305 310 315 320

20

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

325 330 335

25 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

340 345 350

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

30 355 360 365

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

370 375 380

35

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

385 390 395 400

40

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

405 410 415

45 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

420 425 430

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

50 435 440 445

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

450 455 460

5 Ser Leu Ser Pro

4 65

<210> 61

10 <211> 11

<212>PRT

<213> Artificial Sequence

<220>

15 <223> an artificially synthesized sequence

<400> 61

Gly Leu Ser Gly Arg Ser Asp Asn His Gly Ser

20 1 5 1о

<210> 62

<211> 20

25 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

thirty

<400> 62

Thr Val Ser Ser Gly Leu Ser Gly Arg Ser Asp Asn His Gly Ser Ser

1 5 10 15

35

Thr Lys Gly Pro

20

40

<210> 63

<211> 17

<212>PRT

<213> Artificial Sequence

45

<220>

<223> an artificially synthesized sequence

<400> 63

50

Gly Gly Ser Gly Leu Ser Gly Arg Ser Asp Asn His Gly Ser Ser Gly

1 5 10 15

Thr

5

<210> 64

<211> 26

<212>PRT

10 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15 <400> 64

Thr Val Ser Ser Gly Gly Ser Gly Leu Ser Gly Arg Ser Asp Asn His

1 5 10 15

20

Gly Ser Ser Gly Thr Ser Thr Lys Gly Pro

20 25

25 <210> 65

<211> 454

<212>PRT

<213> Artificial Sequence

30 <220>

<223> an artificially synthesized sequence

<400> 65

35 Gln Met Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

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

40 20 25 30

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

35 40 45

45

Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

50 55 60

50

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

65 70 75 80

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

85 90 95

5

Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

100 105 110

10

Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys

115 120 125

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

130 135 140

Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

20 145 150 155 160

Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

165 170 175

25

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

180 185 190

thirty

Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

195 200 205

35 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro

210 215 220

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

40 225 230 235 240

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

245 250 255

45

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

260 265 270

50

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

275 280 285

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

290 295 300

5

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

305 310 315 320

10

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

325 330 335

15 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

340 345 350

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

20 355 360 365

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

370 375 380

25

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

385 390 395 400

thirty

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

405 410 415

35 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

420 425 430

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

40 435 440 445

Ser Leu Ser Pro Gly Lys

450

45

<210> 66

<211> 12

<212>PRT

50 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

<400> 66

5 Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

1 5 10

<210> 67

10 <211> 13

<212>PRT

<213> Artificial Sequence

<220>

15 <223> an artificially synthesized sequence

<400> 67

Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Asp Asn His

20 1 5 10

<210> 68

<211> 18

25 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

thirty

<400> 68

Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Leu Ser Gly Arg Ser Asp

1 5 10 15

35

Asn His

40

<210> 69

<211> 13

<212>PRT

<213> Artificial Sequence

45

<220>

<223> an artificially synthesized sequence

<400> 69

50

Gly Ala Gly Val Pro Met Ser Met Arg Gly Gly Ala Gly

1 5 10

<210> 70

<211> 13

5 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

10

<400> 70

Gly Ala Gly Ile Pro Val Ser Leu Arg Ser Gly Ala Gly

1 5 10

15

<210> 71

<211> 8

<212>PRT

20 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

25 <400> 71

Gly Pro Leu Gly Ile Ala Gly Gln

15

thirty

<210> 72

<211> 10

<212>PRT

<213> Artificial Sequence

35

<220>

<223> an artificially synthesized sequence

<400> 72

40

Gly Gly Pro Leu Gly Met Leu Ser Gln Ser

1 5 10

45 <210> 73

<211> 6

<212>PRT

<213> Artificial Sequence

50 <220>

<223> an artificially synthesized sequence

<400> 73

Pro Leu Gly Leu Trp Ala

15

5

<210> 74

<211> 13

<212>PRT

10 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15 <400> 74

Gly Ala Gly Arg Pro Phe Ser Met Ile Met Gly Ala Gly

1 5 10

20

<210> 75

<211> 13

<212>PRT

<213> Artificial Sequence

25

<220>

<223> an artificially synthesized sequence

<400> 75

thirty

Gly Ala Gly Val Pro Leu Ser Leu Thr Met Gly Ala Gly

1 5 10

35 <210> 76

<211> 13

<212>PRT

<213> Artificial Sequence

40 <220>

<223> an artificially synthesized sequence

<400> 76

45 Gly Ala Gly Val Pro Leu Ser Leu Tyr Ser Gly Ala Gly

1 5 10

<210> 77

50 <211> 6

<212>PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

5 <400> 77

Ala Ala Asn Leu Arg Asn

15

10

<210> 78

<211> 6

<212>PRT

<213> Artificial Sequence

15

<220>

<223> an artificially synthesized sequence

<400> 78

20

Ala Gln Ala Tyr Val Lys

15

25 <210> 79

<211> 6

<212>PRT

<213> Artificial Sequence

30 <220>

<223> an artificially synthesized sequence

<400> 79

35 Ala Ala Asn Tyr Met Arg

15

<210> 80

40 <211> 6

<212>PRT

<213> Artificial Sequence

<220>

45 <223> an artificially synthesized sequence

<400> 80

Ala Ala Ala Leu Thr Arg

50 1 5

<210> 81

<211> 6

<212>PRT

<213> Artificial Sequence

5

<220>

<223> an artificially synthesized sequence

<400> 81

10

Ala Gln Asn Leu Met Arg

15

15 <210> 82

<211> 6

<212>PRT

<213> Artificial Sequence

20 <220>

<223> an artificially synthesized sequence

<400> 82

25 Ala Ala Asn Tyr Thr Lys

15

<210> 83

30 <211> 16

<212>PRT

<213> Artificial Sequence

<220>

35 <223> an artificially synthesized sequence

<400> 83

Gly Ala Gly Pro Gln Gly Leu Ala Gly Gln Arg Gly Ile Val Ala Gly

40 1 5 10 15

<210> 84

<211> 8

45 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

50

<400> 84

Pro Arg Phe Lys Ile Ile Gly Gly

15

5 <210> 85

<211> 8

<212>PRT

<213> Artificial Sequence

10 <220>

<223> an artificially synthesized sequence

<400> 85

15 Pro Arg Phe Arg Ile Ile Gly Gly

15

<210> 86

20 <211> 9

<212>PRT

<213> Artificial Sequence

<220>

25 <223> an artificially synthesized sequence

<400> 86

Gly Ala Gly Ser Gly Arg Ser Ala Gly

30 1 5

<210> 87

<211> 5

35 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

40

<400> 87

Ser Gly Arg Ser Ala

15

45

<210> 88

<211> 6

<212>PRT

50 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

<400> 88

5 Gly Ser Gly Arg Ser Ala

15

<210> 89

10 <211> 5

<212>PRT

<213> Artificial Sequence

<220>

15 <223> an artificially synthesized sequence

<400> 89

Ser Gly Lys Ser Ala

20 1 5

<210> 90

<211> 5

25 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

thirty

<400> 90

Ser Gly Arg Ser Ser

15

35

<210> 91

<211> 5

<212>PRT

40 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

45 <400> 91

Ser Gly Arg Arg Ala

15

50

<210> 92

<211> 5

<212>PRT

<213> Artificial Sequence

<220>

5 <223> an artificially synthesized sequence

<400> 92

Ser Gly Arg Asn Ala

10 1 5

<210> 93

<211> 5

15 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

20

<400> 93

Ser Gly Arg Lys Ala

15

25

<210> 94

<211> 6

<212>PRT

30 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

35 <400> 94

Gln Arg Gly Arg Ser Ala

15

40

<210> 95

<211> 17

<212>PRT

<213> Artificial Sequence

45

<220>

<223> an artificially synthesized sequence

<400> 95

50

Gly Ala Gly Ser Leu Leu Lys Ser Arg Met Val Pro Asn Phe Asn Ala

1 5 10 15

Gly

5

<210> 96

<211> 6

<212>PRT

10 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15 <400> 96

Thr Gln Gly Ala Ala Ala

15

20

<210> 97

<211> 6

<212>PRT

<213> Artificial Sequence

25

<220>

<223> an artificially synthesized sequence

<400> 97

thirty

Gly Ala Ala Ala Ala Ala

15

35 <210> 98

<211> 6

<212>PRT

<213> Artificial Sequence

40 <220>

<223> an artificially synthesized sequence

<400> 98

45 Gly Ala Gly Ala Ala Gly

15

<210> 99

50 <211> 6

<212>PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

5 <400> 99

Ala Ala Ala Ala Ala Gly

15

10

<210> 100

<211> 6

<212>PRT

<213> Artificial Sequence

15

<220>

<223> an artificially synthesized sequence

<400> 100

20

Leu Cys Gly Ala Ala Ile

15

25 <210> 101

<211> 6

<212>PRT

<213> Artificial Sequence

30 <220>

<223> an artificially synthesized sequence

<400> 101

35 Phe Ala Gln Ala Leu Gly

15

<210> 102

40 <211> 6

<212>PRT

<213> Artificial Sequence

<220>

45 <223> an artificially synthesized sequence

<400> 102

Leu Leu Gln Ala Asn Pro

50 1 5

<210> 103

<211> 6

<212>PRT

<213> Artificial Sequence

5

<220>

<223> an artificially synthesized sequence

<400> 103

10

Leu Ala Ala Ala Asn Pro

15

15 <210> 104

<211> 6

<212>PRT

<213> Artificial Sequence

20 <220>

<223> an artificially synthesized sequence

<400> 104

25 Leu Tyr Gly Ala Gln Phe

15

<210> 105

30 <211> 6

<212>PRT

<213> Artificial Sequence

<220>

35 <223> an artificially synthesized sequence

<400> 105

Leu Ser Gln Ala Gln Gly

40 1 5

<210> 106

<211> 6

45 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

50

<400> 106

Ala Ser Ala Ala Ser Gly

15

5 <210> 107

<211> 6

<212>PRT

<213> Artificial Sequence

10 <220>

<223> an artificially synthesized sequence

<400> 107

15 Phe Leu Gly Ala Ser Leu

15

<210> 108

20 <211> 6

<212>PRT

<213> Artificial Sequence

<220>

25 <223> an artificially synthesized sequence

<400> 108

Ala Tyr Gly Ala Thr Gly

30 1 5

<210> 109

<211> 6

35 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

40

<400> 109

Leu Ala Gln Ala Thr Gly

15

45

<210> 110

<211> 17

<212>PRT

50 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

<400> 110

5 Gly Ala Gly Ser Gly Val Val Ile Ala Thr Val Ile Val Ile Thr Ala

1 5 10 15

Gly

10

<210> 111

<211> 8

15 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

20

<400> 111

Ala Pro Met Ala Glu Gly Gly Gly

15

25

<210> 112

<211> 8

<212>PRT

30 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

35 <400> 112

Glu Ala Gln Gly Asp Lys Ile Ile

15

40

<210> 113

<211> 8

<212>PRT

<213> Artificial Sequence

45

<220>

<223> an artificially synthesized sequence

<400> 113

50

Leu Ala Phe Ser Asp Ala Gly Pro

15

<210> 114

<211> 7

5 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

10

<400> 114

Tyr Val Ala Asp Ala Pro Lys

15

15

<210> 115

<211> 5

<212>PRT

20 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

25 <400> 115

Arg Arg Arg Arg Arg

15

thirty

<210> 116

<211> 6

<212>PRT

<213> Artificial Sequence

35

<220>

<223> an artificially synthesized sequence

<400> 116

40

Arg Arg Arg Arg Arg Arg

15

45 <210> 117

<211> 10

<212>PRT

<213> Artificial Sequence

50 <220>

<223> an artificially synthesized sequence

<400> 117

Gly Gln Ser Ser Arg His Arg Arg Ala Leu

1 5 1о

5

<210> 118

<211> 9

<212>PRT

10 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15 <400> 118

Ser Ser Arg His Arg Arg Ala Leu Asp

15

20

<210> 119

<211> 14

<212>PRT

<213> Artificial Sequence

25

<220>

<223> an artificially synthesized sequence

<400> 119

thirty

Arg Lys Ser Ser Ile Ile Ile Arg Met Arg Asp Val Val Leu

1 5 1о

35 <210> 120

<211> 15

<212>PRT

<213> Artificial Sequence

40 <220>

<223> an artificially synthesized sequence

<400> 120

45 Ser Ser Ser Phe Asp Lys Gly Lys Tyr Lys Lys Gly Asp Asp Ala

1 5 10 15

<210> 121

50 <211>

<212>

<213> 15

PRT

Artificial Sequence

<220>

<223> an artificially synthesized sequence

5 <400> 121

Ser Ser Ser Phe Asp Lys Gly Lys Tyr Lys Arg Gly Asp Asp Ala

1 5 10 15

10

<210> 122

<211> 4

<212>PRT

<213> Artificial Sequence

15

<220>

<223> an artificially synthesized sequence

<400> 122

20

Ile Glu Gly Arg

1

25 <210> 123

<211> 4

<212>PRT

<213> Artificial Sequence

30 <220>

<223> an artificially synthesized sequence

<400> 123

35 Ile Asp Gly Arg

1

<210> 124

40 <211> 7

<212>PRT

<213> Artificial Sequence

<220>

45 <223> an artificially synthesized sequence

<400> 124

Gly Gly Ser Ile Asp Gly Arg

50 1 5

<210> 125

<211> 8

<212>PRT

<213> Artificial Sequence

5

<220>

<223> an artificially synthesized sequence

<400> 125

10

Gly Pro Gln Gly Ile Ala Gly Gln

15

15 <210> 126

<211> 8

<212>PRT

<213> Artificial Sequence

20 <220>

<223> an artificially synthesized sequence

<400> 126

25 Gly Pro Gln Gly Leu Leu Gly Ala

15

<210> 127

30 <211> 5

<212>PRT

<213> Artificial Sequence

<220>

35 <223> an artificially synthesized sequence

<400> 127

Gly Ile Ala Gly Gln

40 1 5

<210> 128

<211> 7

45 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

50

<400> 128

Gly Pro Leu Gly Ile Ala Gly

15

5 <210> 129

<211> 8

<212>PRT

<213> Artificial Sequence

10 <220>

<223> an artificially synthesized sequence

<400> 129

15 Gly Pro Glu Gly Leu Arg Val Gly

15

<210> 130

20 <211> 8

<212>PRT

<213> Artificial Sequence

<220>

25 <223> an artificially synthesized sequence

<400> 130

Tyr Gly Ala Gly Leu Gly Val Val

30 1 5

<210> 131

<211> 8

35 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

40

<400> 131

Ala Gly Leu Gly Val Val Glu Arg

15

45

<210> 132

<211> 8

<212>PRT

50 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

<400> 132

5 Ala Gly Leu Gly Ile Ser Ser Thr

15

<210> 133

10 <211> 8

<212>PRT

<213> Artificial Sequence

<220>

15 <223> an artificially synthesized sequence

<400> 133

Glu Pro Gln Ala Leu Ala Met Ser

20 1 5

<210> 134

<211> 8

25 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

thirty

<400> 134

Gln Ala Leu Ala Met Ser Ala Ile

15

35

<210> 135

<211> 8

<212>PRT

40 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

45 <400> 135

Ala Ala Tyr His Leu Val Ser Gln

15

50

<210> 136

<211> 8

<212>PRT

<213> Artificial Sequence

<220>

5 <223> an artificially synthesized sequence

<400> 136

Met Asp Ala Phe Leu Glu Ser Ser

10 1 5

<210> 137

<211> 8

15 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

20

<400> 137

Glu Ser Leu Pro Val Val Ala Val

15

25

<210> 138

<211> 8

<212>PRT

30 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

35 <400> 138

Ser Ala Pro Ala Val Glu Ser Glu

15

40

<210> 139

<211> 8

<212>PRT

<213> Artificial Sequence

45

<220>

<223> an artificially synthesized sequence

<400> 139

50

Asp Val Ala Gln Phe Val Leu Thr

15

<210> 140

<211> 8

5 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

10

<400> 140

Val Ala Gln Phe Val Leu Thr Glu

15

15

<210> 141

<211> 8

<212>PRT

20 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

25 <400> 141

Ala Gln Phe Val Leu Thr Glu Gly

15

thirty

<210> 142

<211> 8

<212>PRT

<213> Artificial Sequence

35

<220>

<223> an artificially synthesized sequence

<400> 142

40

Pro Val Gln Pro Ile Gly Pro Gln

15

45 <210> 143

<211> 6

<212>PRT

<213> Artificial Sequence

50 <220>

<223> an artificially synthesized sequence

<400> 143

Leu Val Pro Arg Gly Ser

15

5

<210> 144

<211> 447

<212>PRT

10 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15 <400> 144

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

1 5 10 15

20

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

20 25 30

25 Trp Leu Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Asp Trp Ile

35 40 45

Gly Ile Met Ser Pro Val Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe

30 50 55 60

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

65 70 75 80

35

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

85 90 95

40

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

100 105 110

45 Thr 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

50 130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

5 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu

165 170 175

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

10 180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

15

Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys

210 215 220

20

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro

225 230 235 240

25 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

30 260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

35

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

40

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

45 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

50 340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

5 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

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

10 385 390 395 400

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

405 410 415

15

Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

20

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

25 <210> 145

<211> 214

<212>PRT

<213> Artificial Sequence

30 <220>

<223> an artificially synthesized sequence

<400> 145

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

1 5 10 15

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

40 20 25 30

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

35 40 45

45

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

50 55 60

50

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

65 70 75 80

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

85 90 95

5

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

10

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

15 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

20 145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

25

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

thirty

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

35 Phe Asn Arg Gly Glu Cys

210

<210> 146

40 <211> 461

<212>PRT

<213> Artificial Sequence

<220>

45 <223> an artificially synthesized sequence

<400> 146

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

50 1 5 10 15

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

20 25 30

5 Trp Leu Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Asp Trp Ile

35 40 45

Gly Ile Met Ser Pro Val Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe

10 50 55 60

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

65 70 75 80

15

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

85 90 95

20

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

100 105 110

25 Thr Leu Val Thr Val Ser Ser Ala Ser Gly Ser Gly Leu Ser Gly Arg

115 120 125

Ser Asp Asn His Gly Ser Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

30 130 135 140

Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys

145 150 155 160

35

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

165 170 175

40

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

180 185 190

45 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

195 200 205

Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn

50 210 215 220

Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His

225 230 235 240

5 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val

245 250 255

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

10 260 265 270

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu

275 280 285

15

Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

290 295 300

20

Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser

305 310 315 320

25 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

325 330 335

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

30 340 345 350

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

355 360 365

35

Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

370 375 380

40

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

385 390 395 400

45 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

405 410 415

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

50 420 425 430

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

435 440 445

5 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455 460

<210> 147

10 <211> 447

<212>PRT

<213> Artificial Sequence

<220>

15 <223> an artificially synthesized sequence

<400> 147

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

20 1 5 10 15

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

20 25 30

25

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

thirty

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

50 55 60

35 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

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

40 85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

45

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

115 120 125

50

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

5

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu

165 170 175

10

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

180 185 190

15 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys

20 210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro

225 230 235 240

25

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

245 250 255

thirty

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

35 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

40 290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

45

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

325 330 335

50

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

5

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

10

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

385 390 395 400

15 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

405 410 415

Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu

20 420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

25

<210> 148

<211> 214

<212>PRT

30 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

35 <400> 148

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

1 5 10 15

40

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

20 25 30

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

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 50 55 60

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

65 70 75 80

5 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

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

10 100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

15

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

130 135 140

20

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

25 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

30 180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

35

Phe Asn Arg Gly Glu Cys

210

40

<210> 149

<211> 16

<212>PRT

<213> Artificial Sequence

45

<220>

<223> an artificially synthesized sequence

<400> 149

50

Gly Gly Gly Gly Ser Pro Leu Gly Leu Ala Gly Gly Gly Gly Gly Ser

1 5 10 15

<210> 150

<211> 18

5 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

10

<400> 150

Gly Gly Gly Gly Ser Gly Pro Leu Gly Ile Ala Gly Gln Gly Gly Gly

1 5 10 15

15

Gly Ser

20

<210> 151

<211> 16

<212>PRT

<213> Artificial Sequence

25

<220>

<223> an artificially synthesized sequence

<400> 151

thirty

Gly Gly Gly Gly Ser Pro Leu Gly Leu Trp Ala Gly Gly Gly Gly Ser

1 5 10 15

35 <210> 152

<211> 23

<212>PRT

<213> Artificial Sequence

40 <220>

<223> an artificially synthesized sequence

<400> 152

45 Gly Gly Gly Gly Ser Gly Ala Gly Val Pro Leu Ser Leu Tyr Ser Gly

1 5 10 15

Ala Gly Gly Gly Gly Gly Ser

50 20

<210> 153

<211> 463

<212>PRT

<213> Artificial Sequence

5

<220>

<223> an artificially synthesized sequence

<400> 153

10

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

1 5 10 15

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

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

20 35 40 45

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

50 55 60

25

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

65 70 75 80

thirty

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

85 90 95

35 Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Ser Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Pro Leu Gly Leu

40 115 120 125

Ala Gly Gly Gly Gly Gly Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

130 135 140

45

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu

145 150 155 160

50

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

165 170 175

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu

180 185 190

5

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

195 200 205

10

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

210 215 220

15 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys

225 230 235 240

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro

20 245 250 255

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

260 265 270

25

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

275 280 285

thirty

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

290 295 300

35 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

305 310 315 320

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

40 325 330 335

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

340 345 350

45

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

355 360 365

50

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

370 375 380

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

385 390 395 400

5

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

405 410 415

10

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

420 425 430

15 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu

435 440 445

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

20 450 455 460

<210> 154

<211> 465

25 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

thirty

<400> 154

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

1 5 10 15

35

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

20 25 30

40

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

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

50 55 60

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

50 65 70 75 80

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

85 90 95

5 Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Ser Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Pro Leu Gly

10 115 120 125

Ile Ala Gly Gln Gly Gly Gly Gly Ser Ala Ser Thr Lys Gly Pro Ser

130 135 140

15

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

145 150 155 160

20

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

165 170 175

25 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

180 185 190

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

30 195 200 205

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

210 215 220

35

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys

225 230 235 240

40

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg

245 250 255

45 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

260 265 270

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

50 275 280 285

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

290 295 300

5 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

305 310 315 320

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

10 325 330 335

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

340 345 350

15

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

355 360 365

20

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser

370 375 380

25 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

385 390 395 400

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

30 405 410 415

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

420 425 430

35

Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met

435 440 445

40

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

450 455 460

45 Pro

465

<210> 155

50 <211> 463

<212>PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

5 <400> 155

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

1 5 10 15

10

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

20 25 30

15 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

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

20 50 55 60

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

65 70 75 80

25

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

85 90 95

thirty

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

35 Ser Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Pro Leu Gly Leu

115 120 125

Trp Ala Gly Gly Gly Gly Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

40 130 135 140

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu

145 150 155 160

45

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

165 170 175

50

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu

180 185 190

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

195 200 205

5

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

210 215 220

10

Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys

225 230 235 240

15 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro

245 250 255

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

20 260 265 270

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

275 280 285

25

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

290 295 300

thirty

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

305 310 315 320

35 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

325 330 335

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

40 340 345 350

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

355 360 365

45

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

370 375 380

50

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

385 390 395 400

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

405 410 415

5

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

420 425 430

10

Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu

435 440 445

15 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455 460

<210> 156

20 <211> 470

<212>PRT

<213> Artificial Sequence

<220>

25 <223> an artificially synthesized sequence

<400> 156

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

30 1 5 10 15

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

20 25 30

35

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

40

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

50 55 60

45 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

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

50 85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

5 Ser Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Ala Gly Val

115 120 125

Pro Leu Ser Leu Tyr Ser Gly Ala Gly Gly Gly Gly Gly Ser Ala Ser

10 130 135 140

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

145 150 155 160

15

Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro

165 170 175

20

Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val

180 185 190

25 His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser

195 200 205

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

30 210 215 220

Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val

225 230 235 240

35

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

245 250 255

40

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

260 265 270

45 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

275 280 285

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

50 290 295 300

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

305 310 315 320

5 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

325 330 335

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

10 340 345 350

Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

355 360 365

15

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr

370 375 380

20

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

385 390 395 400

25 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

405 410 415

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

30 420 425 430

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe

435 440 445

35

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

450 455 460

40

Ser Leu Ser Leu Ser Pro

465 470

45 <210> 157

<211> 460

<212>PRT

<213> Artificial Sequence

50 <220>

<223> an artificially synthesized sequence

<400> 157

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

1 5 10 15

5

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

20 25 30

10

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

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

50 55 60

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

20 65 70 75 80

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

85 90 95

25

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

thirty

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

115 120 125

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

130 135 140

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

40 145 150 155 160

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

165 170 175

45

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

180 185 190

50

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

195 200 205

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

210 215 220

5

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

225 230 235 240

10

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

245 250 255

15 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

260 265 270

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

20 275 280 285

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

290 295 300

25

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

305 310 315 320

thirty

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

325 330 335

35 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

340 345 350

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

40 355 360 365

Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

370 375 380

45

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

385 390 395 400

50

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

405 410 415

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

420 425 430

5

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

435 440 445

10

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455 460

15 <210> 158

<211> 457

<212>PRT

<213> Artificial Sequence

20 <220>

<223> an artificially synthesized sequence

<400> 158

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

1 5 10 15

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

30 20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

35

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

50 55 60

40

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

65 70 75 80

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

85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

50 100 105 110

Ser Leu Val Thr Val Ser Ser Gly Gly Pro Leu Gly Met Leu Ser Gln

115 120 125

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

130 135 140

Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp

10 145 150 155 160

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

165 170 175

15

Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr

180 185 190

20

Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln

195 200 205

25 Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp

210 215 220

Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro

30 225 230 235 240

Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

245 250 255

35

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

260 265 270

40

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

275 280 285

45 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

290 295 300

Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

50 305 310 315 320

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

325 330 335

5 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys

340 345 350

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu

10 355 360 365

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

370 375 380

15

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

385 390 395 400

20

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

405 410 415

25 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

420 425 430

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

30 435 440 445

Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

35

<210> 159

<211> 460

<212>PRT

40 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

45 <400> 159

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

1 5 10 15

50

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

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

5

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

50 55 60

10

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

65 70 75 80

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

85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

20 100 105 110

Ser Leu Val Thr Val Ser Ser Gly Ala Gly Val Pro Leu Ser Leu Thr

115 120 125

25

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

130 135 140

thirty

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

145 150 155 160

35 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

165 170 175

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

40 180 185 190

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

195 200 205

45

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

210 215 220

50

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

225 230 235 240

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

245 250 255

5

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

260 265 270

10

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

275 280 285

15 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

290 295 300

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

20 305 310 315 320

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

325 330 335

25

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

340 345 350

thirty

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

355 360 365

35 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

370 375 380

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

40 385 390 395 400

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

405 410 415

45

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

420 425 430

50

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

435 440 445

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455 460

5

<210> 160

<211> 12

<212>PRT

10 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15 <400> 160

Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

1 5 10

20

<210> 161

<211> 119

<212>PRT

<213> Artificial Sequence

25

<220>

<223> an artificially synthesized sequence

<400> 161

thirty

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

1 5 10 15

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

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

40 35 40 45

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

50 55 60

45

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

65 70 75 80

50

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

85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

5

Ser Leu Val Thr Val Ser Ser

115

10

<210> 162

<211> 328

<212>PRT

<213> Artificial Sequence

15

<220>

<223> an artificially synthesized sequence

<400> 162

20

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

1 5 10 15

25 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

30 35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

35

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

40

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

45 Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu Phe Pro Pro

50 115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

5 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

10 165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

15

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

20

Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

25 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu

225 230 235 240

Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

30 245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

35

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

40

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn

290 295 300

45 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro

50 325

<210> 163

<211> 131

<212>PRT

<213> Artificial Sequence

5

<220>

<223> an artificially synthesized sequence

<400> 163

10

Gln Val Gln Leu Gln Glu Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn

1 5 10 15

15 Pro Arg Gly Gly Pro Gly Leu Val Arg Pro Ser Gln Thr Leu Ser Leu

20 25 30

Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser

20 35 40 45

Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

25

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

65 70 75 80

thirty

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

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

100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

40 115 120 125

Val Ser Ser

130

45

<210> 164

<211> 131

<212>PRT

50 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

<400> 164

5 Gln Val Gln Leu Gln Glu Ser Gly Thr Ser Thr Ser Gly Arg Ser Ala

1 5 10 15

Asn Pro Arg Gly Pro Gly Leu Val Arg Pro Ser Gln Thr Leu Ser Leu

10 20 25 30

Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser

35 40 45

15

Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

20

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

65 70 75 80

25 Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

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

30 100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

35

Val Ser Ser

130

40

<210> 165

<211> 131

<212>PRT

<213> Artificial Sequence

45

<220>

<223> an artificially synthesized sequence

<400> 165

50

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

1 5 10 15

Ala Asn Pro Arg Gly Gly Leu Val Arg Pro Ser Gln Thr Leu Ser Leu

20 25 30

5

Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser

35 40 45

10

Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

15 Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

20 85 90 95

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

100 105 110

25

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

thirty

Val Ser Ser

130

35 <210> 166

<211> 131

<212>PRT

<213> Artificial Sequence

40 <220>

<223> an artificially synthesized sequence

<400> 166

45 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Thr Ser Thr Ser Gly Arg

1 5 10 15

Ser Ala Asn Pro Arg Gly Leu Val Arg Pro Ser Gln Thr Leu Ser Leu

50 20 25 30

Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser

35 40 45

5 Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

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

10 65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

15

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

100 105 110

20

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

25 Val Ser Ser

130

<210> 167

30 <211> 131

<212>PRT

<213> Artificial Sequence

<220>

35 <223> an artificially synthesized sequence

<400> 167

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

40 1 5 10 15

Arg Ser Ala Asn Pro Arg Gly Val Arg Pro Ser Gln Thr Leu Ser Leu

20 25 30

45

Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser

35 40 45

50

Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

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

65 70 75 80

5

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

10

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

100 105 110

15 Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

Val Ser Ser

20 130

<210> 168

<211> 131

25 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

thirty

<400> 168

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

1 5 10 15

35

Gly Arg Ser Ala Asn Pro Arg Gly Arg Pro Ser Gln Thr Leu Ser Leu

20 25 30

40

Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser

35 40 45

45 Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

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

50 65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

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

100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

10 115 120 125

Val Ser Ser

130

15

<210> 169

<211> 131

<212>PRT

20 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

25 <400> 169

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

1 5 10 15

thirty

Ser Gly Arg Ser Ala Asn Pro Arg Gly Pro Ser Gln Thr Leu Ser Leu

20 25 30

35 Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser

35 40 45

Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

40 50 55 60

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

65 70 75 80

45

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

50

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

100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

5

Val Ser Ser

130

10

<210> 170

<211> 131

<212>PRT

<213> Artificial Sequence

15

<220>

<223> an artificially synthesized sequence

<400> 170

20

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

1 5 10 15

25 Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Gln Thr Leu Ser Leu

20 25 30

Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser

30 35 40 45

Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

35

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

65 70 75 80

40

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

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

100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

50 115 120 125

Val Ser Ser

130

5 <210> 171

<211> 131

<212>PRT

<213> Artificial Sequence

10 <220>

<223> an artificially synthesized sequence

<400> 171

15 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Thr

1 5 10 15

Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Gln Thr Leu Ser Leu

20 20 25 30

Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser

35 40 45

25

Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

thirty

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

65 70 75 80

35 Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

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

40 100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

45

Val Ser Ser

130

50

<210> 172

<211> 131

<212>PRT

<213> Artificial Sequence

<220>

5 <223> an artificially synthesized sequence

<400> 172

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

10 1 5 10 15

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

20 25 30

15

His Ala Trp Ser Trp Val Arg Gln Pro Thr Ser Thr Ser Gly Arg Ser

35 40 45

20

Ala Asn Pro Arg Gly Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

25 Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

30 85 90 95

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

100 105 110

35

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

40

Val Ser Ser

130

45 <210> 173

<211> 131

<212>PRT

<213> Artificial Sequence

50 <220>

<223> an artificially synthesized sequence

<400> 173

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

1 5 10 15

5

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

20 25 30

10

His Ala Trp Ser Trp Val Arg Gln Pro Pro Thr Ser Thr Ser Gly Arg

35 40 45

15 Ser Ala Asn Pro Arg Gly Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

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

20 65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

25

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

100 105 110

thirty

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

35 Val Ser Ser

130

<210> 174

40 <211> 131

<212>PRT

<213> Artificial Sequence

<220>

45 <223> an artificially synthesized sequence

<400> 174

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

50 1 5 10 15

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

20 25 30

5 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Thr Ser Thr Ser Gly

35 40 45

Arg Ser Ala Asn Pro Arg Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

10 50 55 60

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

65 70 75 80

15

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

20

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

100 105 110

25 Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

Val Ser Ser

30 130

<210> 175

<211> 131

35 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

40

<400> 175

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

1 5 10 15

45

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

20 25 30

50

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Thr Ser Thr Ser

35 40 45

Gly Arg Ser Ala Asn Pro Arg Gly Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

5

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

65 70 75 80

10

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

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

100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

20 115 120 125

Val Ser Ser

130

25

<210> 176

<211> 131

<212>PRT

30 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

35 <400> 176

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

1 5 10 15

40

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

20 25 30

45 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Thr Ser Thr

35 40 45

Ser Gly Arg Ser Ala Asn Pro Arg Gly Leu Glu Trp Ile Gly Tyr Ile

50 50 55 60

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

65 70 75 80

5 Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

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

10 100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

15

Val Ser Ser

130

20

<210> 177

<211> 131

<212>PRT

<213> Artificial Sequence

25

<220>

<223> an artificially synthesized sequence

<400> 177

thirty

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

1 5 10 15

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

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Thr Ser

40 35 40 45

Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Glu Trp Ile Gly Tyr Ile

50 55 60

45

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

65 70 75 80

50

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

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

100 105 110

5

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

10

Val Ser Ser

130

15 <210> 178

<211> 131

<212>PRT

<213> Artificial Sequence

20 <220>

<223> an artificially synthesized sequence

<400> 178

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

1 5 10 15

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

30 20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

35

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

50 55 60

40

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

65 70 75 80

45 Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

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

50 100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

5 Val Ser Ser

130

<210> 179

10 <211> 131

<212>PRT

<213> Artificial Sequence

<220>

15 <223> an artificially synthesized sequence

<400> 179

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

20 1 5 10 15

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

20 25 30

25

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

thirty

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Ser Thr Ser Gly Arg Ser

50 55 60

35 Ala Asn Pro Arg Gly Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

40 85 90 95

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

100 105 110

45

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

50

Val Ser Ser

130

<210> 180

<211> 131

5 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

10

<400> 180

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

1 5 10 15

15

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

20 25 30

20

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

25 Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Ser Thr Ser Gly Arg

50 55 60

Ser Ala Asn Pro Arg Gly Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

30 65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

35

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

100 105 110

40

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

45 Val Ser Ser

130

<210> 181

50 <211> 131

<212>PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

5 <400> 181

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

1 5 10 15

10

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

20 25 30

15 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

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

20 50 55 60

Arg Ser Ala Asn Pro Arg Gly Tyr Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

25

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

thirty

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

100 105 110

35 Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

Val Ser Ser

40 130

<210> 182

<211> 131

45 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

50

<400> 182

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

1 5 10 15

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

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

10 35 40 45

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

50 55 60

15

Gly Arg Ser Ala Asn Pro Arg Gly Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

20

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

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

100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

30 115 120 125

Val Ser Ser

130

35

<210> 183

<211> 131

<212>PRT

40 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

45 <400> 183

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

1 5 10 15

50

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

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

5

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Thr Ser Thr

50 55 60

10

Ser Gly Arg Ser Ala Asn Pro Arg Gly Pro Ser Leu Lys Ser Arg Val

65 70 75 80

15 Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

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

20 100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

25

Val Ser Ser

130

thirty

<210> 184

<211> 131

<212>PRT

<213> Artificial Sequence

35

<220>

<223> an artificially synthesized sequence

<400> 184

40

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

1 5 10 15

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

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

50 35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Thr Ser

50 55 60

5 Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Leu Lys Ser Arg Val

65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

10 85 90 95

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

100 105 110

15

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

20

Val Ser Ser

130

25 <210> 185

<211> 131

<212>PRT

<213> Artificial Sequence

30 <220>

<223> an artificially synthesized sequence

<400> 185

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

1 5 10 15

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

40 20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Thr

50 55 60

50

Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Leu Lys Ser Arg Val

65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

5

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

100 105 110

10

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

15 Val Ser Ser

130

<210> 186

20 <211> 131

<212>PRT

<213> Artificial Sequence

<220>

25 <223> an artificially synthesized sequence

<400> 186

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

30 1 5 10 15

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

20 25 30

35

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

40

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

50 55 60

45 Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Lys Ser Arg Val

65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

50 85 90 95

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

100 105 110

5 Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

Val Ser Ser

10 130

<210> 187

<211> 131

15 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

20

<400> 187

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

1 5 10 15

25

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

20 25 30

thirty

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

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

50 55 60

Lys Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Arg Val

40 65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

45

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

100 105 110

50

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

Val Ser Ser

130

5

<210> 188

<211> 131

<212>PRT

10 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15 <400> 188

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

1 5 10 15

20

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

20 25 30

25 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

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

30 50 55 60

Lys Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Arg Val

65 70 75 80

35

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

40

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

100 105 110

45 Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

Val Ser Ser

50 130

<210> 189

<211> 131

<212>PRT

<213> Artificial Sequence

5

<220>

<223> an artificially synthesized sequence

<400> 189

10

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

1 5 10 15

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

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

20 35 40 45

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

50 55 60

25

Lys Ser Arg Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Val

65 70 75 80

thirty

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

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

100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

40 115 120 125

Val Ser Ser

130

45

<210> 190

<211> 131

<212>PRT

50 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

<400> 190

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

1 5 10 15

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

10 20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

15

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

50 55 60

20

Lys Ser Arg Val Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

65 70 75 80

25 Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

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

30 100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

35

Val Ser Ser

130

40

<210> 191

<211> 131

<212>PRT

<213> Artificial Sequence

45

<220>

<223> an artificially synthesized sequence

<400> 191

50

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

1 5 10 15

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

20 25 30

5

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

10

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

50 55 60

15 Lys Ser Arg Val Thr Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg

65 70 75 80

Gly Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

20 85 90 95

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

100 105 110

25

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

thirty

Val Ser Ser

130

35 <210> 192

<211> 131

<212>PRT

<213> Artificial Sequence

40 <220>

<223> an artificially synthesized sequence

<400> 192

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

1 5 10 15

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

50 20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

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

50 55 60

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

10 65 70 75 80

Ser Ala Asn Pro Arg Gly Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

15

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

100 105 110

20

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

25 Val Ser Ser

130

<210> 193

30 <211> 131

<212>PRT

<213> Artificial Sequence

<220>

35 <223> an artificially synthesized sequence

<400> 193

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

40 1 5 10 15

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

20 25 30

45

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

50

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

50 55 60

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

65 70 75 80

5

Arg Ser Ala Asn Pro Arg Gly Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

10

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

100 105 110

15 Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

Val Ser Ser

20 130

<210> 194

<211> 131

25 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

thirty

<400> 194

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

1 5 10 15

35

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

20 25 30

40

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

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

50 55 60

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

50 65 70 75 80

Gly Arg Ser Ala Asn Pro Arg Gly Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

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

100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

10 115 120 125

Val Ser Ser

130

15

<210> 195

<211> 131

<212>PRT

20 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

25 <400> 195

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

1 5 10 15

thirty

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

20 25 30

35 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

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

40 50 55 60

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

65 70 75 80

45

Ser Gly Arg Ser Ala Asn Pro Arg Gly Gln Phe Ser Leu Arg Leu Ser

85 90 95

50

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

100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

5

Val Ser Ser

130

10

<210> 196

<211> 131

<212>PRT

<213> Artificial Sequence

15

<220>

<223> an artificially synthesized sequence

<400> 196

20

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

1 5 10 15

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

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

30 35 40 45

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

50 55 60

35

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Thr Ser

65 70 75 80

40

Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Phe Ser Leu Arg Leu Ser

85 90 95

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

100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

50 115 120 125

Val Ser Ser

130

5 <210> 197

<211> 131

<212>PRT

<213> Artificial Sequence

10 <220>

<223> an artificially synthesized sequence

<400> 197

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

1 5 10 15

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

20 20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

25

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

50 55 60

thirty

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

65 70 75 80

35 Leu Arg Leu Ser Ser Val Thr Thr Ser Thr Ser Gly Arg Ser Ala Asn

85 90 95

Pro Arg Gly Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

40 100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

45

Val Ser Ser

130

50

<210> 198

<211> 131

<212>PRT

<213> Artificial Sequence

<220>

5 <223> an artificially synthesized sequence

<400> 198

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

10 1 5 10 15

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

20 25 30

15

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

20

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

50 55 60

25 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Thr Ser Thr Ser Gly Arg Ser Ala

30 85 90 95

Asn Pro Arg Gly Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

35

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

40

Val Ser Ser

130

45 <210> 199

<211> 131

<212>PRT

<213> Artificial Sequence

50 <220>

<223> an artificially synthesized sequence

<400> 199

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

1 5 10 15

5

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

20 25 30

10

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

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

50 55 60

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

20 65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Thr Ser Thr Ser Gly Arg Ser

85 90 95

25

Ala Asn Pro Arg Gly Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

thirty

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

35 Val Ser Ser

130

<210> 200

40 <211> 131

<212>PRT

<213> Artificial Sequence

<220>

45 <223> an artificially synthesized sequence

<400> 200

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

50 1 5 10 15

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

20 25 30

5 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

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

10 50 55 60

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

65 70 75 80

15

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

85 90 95

20

Ala Arg Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Leu

100 105 110

25 Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

Val Ser Ser

30 130

<210> 201

<211> 131

35 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

40

<400> 201

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

1 5 10 15

45

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

20 25 30

50

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

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

50 55 60

5

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

65 70 75 80

10

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

85 90 95

15 Ala Arg Ser Leu Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

20 115 120 125

Val Ser Ser

130

25

<210> 202

<211> 131

<212>PRT

30 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

35 <400> 202

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

1 5 10 15

40

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

20 25 30

45 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

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

50 50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Ser Leu Ala Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg

10 100 105 110

Gly Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

15

Val Ser Ser

130

20

<210> 203

<211> 131

<212>PRT

<213> Artificial Sequence

25

<220>

<223> an artificially synthesized sequence

<400> 203

thirty

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

1 5 10 15

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

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

40 35 40 45

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

50 55 60

45

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

65 70 75 80

50

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 Ser Thr Ser Gly Arg Ser Ala Asn Pro

100 105 110

5

Arg Gly Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

10

Val Ser Ser

130

15 <210> 204

<211> 131

<212>PRT

<213> Artificial Sequence

20 <220>

<223> an artificially synthesized sequence

<400> 204

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

1 5 10 15

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

30 20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

35

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

50 55 60

40

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

65 70 75 80

45 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 Thr Ser Thr

50 100 105 110

Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Gln Gly Ser Leu Val Thr

115 120 125

5 Val Ser Ser

130

<210> 205

10 <211> 131

<212>PRT

<213> Artificial Sequence

<220>

15 <223> an artificially synthesized sequence

<400> 205

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

20 1 5 10 15

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

20 25 30

25

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

thirty

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

50 55 60

35 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

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

40 85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Thr Ser

100 105 110

45

Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Gln Gly Ser Leu Val Thr

115 120 125

50

Val Ser Ser

130

<210> 206

<211> 131

5 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

10

<400> 206

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

1 5 10 15

15

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

20 25 30

20

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

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

50 55 60

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

30 65 70 75 80

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

85 90 95

35

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Thr

100 105 110

40

Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Ser Leu Val Thr

115 120 125

45 Val Ser Ser

130

<210> 207

50 <211> 131

<212>PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

5 <400> 207

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

1 5 10 15

10

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

20 25 30

15 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

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

20 50 55 60

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

65 70 75 80

25

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

85 90 95

thirty

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

35 Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Leu Val Thr

115 120 125

Val Ser Ser

40 130

<210> 208

<211> 131

45 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

50

<400> 208

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

1 5 10 15

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

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

10 35 40 45

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

50 55 60

15

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

65 70 75 80

20

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

85 90 95

25 Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Leu Val Thr

30 115 120 125

Val Ser Ser

130

35

<210> 209

<211> 131

<212>PRT

40 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

45 <400> 209

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

1 5 10 15

50

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

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

5

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

50 55 60

10

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

65 70 75 80

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

85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

20 100 105 110

Ser Leu Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Val Thr

115 120 125

25

Val Ser Ser

130

thirty

<210> 210

<211> 131

<212>PRT

<213> Artificial Sequence

35

<220>

<223> an artificially synthesized sequence

<400> 210

40

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

1 5 10 15

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

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

50 35 40 45

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

50 55 60

5 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

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

10 85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

15

Ser Leu Val Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Thr

115 120 125

20

Val Ser Ser

130

25 <210> 211

<211> 131

<212>PRT

<213> Artificial Sequence

30 <220>

<223> an artificially synthesized sequence

<400> 211

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

1 5 10 15

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

40 20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

45

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

50 55 60

50

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

65 70 75 80

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

85 90 95

5

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

10

Ser Leu Val Thr Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

115 120 125

15 Val Ser Ser

130

<210> 212

20 <211> 131

<212>PRT

<213> Artificial Sequence

<220>

25 <223> an artificially synthesized sequence

<400> 212

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

30 1 5 10 15

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

20 25 30

35

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

40

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

50 55 60

45 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

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

50 85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

5 Ser Leu Val Thr Val Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg

115 120 125

Gly Ser Ser

10 130

<210> 213

<211> 131

15 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

20

<400> 213

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

1 5 10 15

25

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

20 25 30

thirty

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

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

50 55 60

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

40 65 70 75 80

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

85 90 95

45

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

50

Ser Leu Val Thr Val Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro

115 120 125

Arg Gly Ser

130

5

<210> 214

<211> 131

<212>PRT

10 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15 <400> 214

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

1 5 10 15

20

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

20 25 30

25 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

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

30 50 55 60

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

65 70 75 80

35

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

85 90 95

40

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

45 Ser Leu Val Thr Val Ser Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn

115 120 125

Pro Arg Gly

50 130

<210> 215

<211> 340

<212>PRT

<213> Artificial Sequence

5

<220>

<223> an artificially synthesized sequence

<400> 215

10

Ala Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Thr Lys

1 5 10 15

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

20 25 30

Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

20 35 40 45

Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

50 55 60

25

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

65 70 75 80

thirty

Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

85 90 95

35 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro

100 105 110

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

40 115 120 125

Leu Arg Arg Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

130 135 140

45

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

145 150 155 160

50

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

165 170 175

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

180 185 190

5

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

195 200 205

10

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

210 215 220

15 Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

225 230 235 240

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

20 245 250 255

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

260 265 270

25

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

275 280 285

thirty

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

290 295 300

35 Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys

305 310 315 320

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

40 325 330 335

Ser Leu Ser Pro

340

45

<210> 216

<211> 340

<212>PRT

50 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

<400> 216

5 Ala Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Thr Lys

1 5 10 15

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

10 20 25 30

Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

35 40 45

15

Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

50 55 60

20

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

65 70 75 80

25 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

85 90 95

Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro

30 100 105 110

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

115 120 125

35

Leu Arg Arg Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

130 135 140

40

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

145 150 155 160

45 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

165 170 175

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

50 180 185 190

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

195 200 205

5 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

210 215 220

Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

10 225 230 235 240

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

245 250 255

15

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

260 265 270

20

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

275 280 285

25 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

290 295 300

Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys

30 305 310 315 320

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

325 330 335

35

Ser Leu Ser Pro

340

40

<210> 217

<211> 340

<212>PRT

<213> Artificial Sequence

45

<220>

<223> an artificially synthesized sequence

<400> 217

50

Ala Ser Thr Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Lys

1 5 10 15

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

20 25 30

5

Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

35 40 45

10

Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

50 55 60

15 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val

65 70 75 80

Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

20 85 90 95

Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro

100 105 110

25

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

115 120 125

thirty

Leu Arg Arg Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

130 135 140

35 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

145 150 155 160

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

40 165 170 175

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

180 185 190

45

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

195 200 205

50

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

210 215 220

Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

225 230 235 240

5

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

245 250 255

10

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

260 265 270

15 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

275 280 285

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

20 290 295 300

Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys

305 310 315 320

25

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

325 330 335

thirty

Ser Leu Ser Pro

340

35 <210> 218

<211> 340

<212>PRT

<213> Artificial Sequence

40 <220>

<223> an artificially synthesized sequence

<400> 218

45 Ala Ser Thr Lys Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

1 5 10 15

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

50 20 25 30

Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

35 40 45

5 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

50 55 60

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

10 65 70 75 80

Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

85 90 95

15

Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro

100 105 110

20

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

115 120 125

25 Leu Arg Arg Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

130 135 140

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

30 145 150 155 160

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

165 170 175

35

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

180 185 190

40

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

195 200 205

45 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

210 215 220

Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

50 225 230 235 240

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

245 250 255

5 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

260 265 270

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

10 275 280 285

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

290 295 300

15

Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys

305 310 315 320

20

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

325 330 335

25 Ser Leu Ser Pro

340

<210> 219

30 <211> 340

<212>PRT

<213> Artificial Sequence

<220>

35 <223> an artificially synthesized sequence

<400> 219

Ala Ser Thr Lys Gly Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg

40 1 5 10 15

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

20 25 30

45

Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

35 40 45

50

Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

50 55 60

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

65 70 75 80

5

Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

85 90 95

10

Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro

100 105 110

15 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

115 120 125

Leu Arg Arg Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

20 130 135 140

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

145 150 155 160

25

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

165 170 175

thirty

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

180 185 190

35 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

195 200 205

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

40 210 215 220

Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

225 230 235 240

45

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

245 250 255

50

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

260 265 270

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

275 280 285

5

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

290 295 300

10

Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys

305 310 315 320

15 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

325 330 335

Ser Leu Ser Pro

20 340

<210> 220

<211> 340

25 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

thirty

<400> 220

Ala Ser Thr Lys Gly Pro Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro

1 5 10 15

35

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

20 25 30

40

Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

35 40 45

45 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

50 55 60

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

50 65 70 75 80

Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

85 90 95

5 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro

100 105 110

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

10 115 120 125

Leu Arg Arg Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

130 135 140

15

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

145 150 155 160

20

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

165 170 175

25 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

180 185 190

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

30 195 200 205

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

210 215 220

35

Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

225 230 235 240

40

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

245 250 255

45 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

260 265 270

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

50 275 280 285

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

290 295 300

5 Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys

305 310 315 320

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

10 325 330 335

Ser Leu Ser Pro

340

15

<210> 221

<211> 340

<212>PRT

20 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

25 <400> 221

Ala Ser Thr Lys Gly Pro Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn

1 5 10 15

thirty

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

20 25 30

35 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

35 40 45

Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

40 50 55 60

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

65 70 75 80

45

Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

85 90 95

50

Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro

100 105 110

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

115 120 125

5

Leu Arg Arg Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

130 135 140

10

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

145 150 155 160

15 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

165 170 175

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

20 180 185 190

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

195 200 205

25

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

210 215 220

thirty

Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

225 230 235 240

35 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

245 250 255

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

40 260 265 270

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

275 280 285

45

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

290 295 300

50

Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys

305 310 315 320

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

325 330 335

5

Ser Leu Ser Pro

340

10

<210> 222

<211> 340

<212>PRT

<213> Artificial Sequence

15

<220>

<223> an artificially synthesized sequence

<400> 222

20

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

1 5 10 15

25 Gly Arg Ser Ala Asn Pro Arg Gly Pro Ser Ser Lys Ser Thr Ser Gly

20 25 30

Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

30 35 40 45

Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

50 55 60

35

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

65 70 75 80

40

Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

85 90 95

45 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro

100 105 110

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

50 115 120 125

Leu Arg Arg Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

130 135 140

5 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

145 150 155 160

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

10 165 170 175

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

180 185 190

15

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

195 200 205

20

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

210 215 220

25 Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

225 230 235 240

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

30 245 250 255

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

260 265 270

35

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

275 280 285

40

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

290 295 300

45 Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys

305 310 315 320

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

50 325 330 335

Ser Leu Ser Pro

340

5 <210> 223

<211> 340

<212>PRT

<213> Artificial Sequence

10 <220>

<223> an artificially synthesized sequence

<400> 223

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

1 5 10 15

Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Ser Lys Ser Thr Ser Gly

20 20 25 30

Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

35 40 45

25

Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

50 55 60

thirty

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

65 70 75 80

35 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

85 90 95

Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro

40 100 105 110

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

115 120 125

45

Leu Arg Arg Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

130 135 140

50

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

145 150 155 160

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

165 170 175

5

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

180 185 190

10

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

195 200 205

15 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

210 215 220

Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

20 225 230 235 240

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

245 250 255

25

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

260 265 270

thirty

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

275 280 285

35 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

290 295 300

Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys

40 305 310 315 320

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

325 330 335

45

Ser Leu Ser Pro

340

50

<210> 224

<211> 340

<212>PRT

<213> Artificial Sequence

<220>

5 <223> an artificially synthesized sequence

<400> 224

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

10 1 5 10 15

Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Lys Ser Thr Ser Gly

20 25 30

15

Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

35 40 45

20

Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

50 55 60

25 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val

65 70 75 80

Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

30 85 90 95

Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro

100 105 110

35

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

115 120 125

40

Leu Arg Arg Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

130 135 140

45 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

145 150 155 160

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

50 165 170 175

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

180 185 190

5 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

195 200 205

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

10 210 215 220

Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

225 230 235 240

15

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

245 250 255

20

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

260 265 270

25 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

275 280 285

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

30 290 295 300

Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys

305 310 315 320

35

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

325 330 335

40

Ser Leu Ser Pro

340

45 <210> 225

<211> 340

<212>PRT

<213> Artificial Sequence

50 <220>

<223> an artificially synthesized sequence

<400> 225

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

1 5 10 15

5

Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Lys Ser Thr Ser Gly

20 25 30

10

Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

35 40 45

15 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

50 55 60

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

20 65 70 75 80

Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

85 90 95

25

Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro

100 105 110

thirty

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

115 120 125

35 Leu Arg Arg Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

130 135 140

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

40 145 150 155 160

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

165 170 175

45

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

180 185 190

50

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

195 200 205

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

210 215 220

5

Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

225 230 235 240

10

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

245 250 255

15 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

260 265 270

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

20 275 280 285

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

290 295 300

25

Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys

305 310 315 320

thirty

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

325 330 335

35 Ser Leu Ser Pro

340

<210> 226

40 <211> 340

<212>PRT

<213> Artificial Sequence

<220>

45 <223> an artificially synthesized sequence

<400> 226

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

50 1 5 10 15

Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Thr Ser Gly

20 25 30

5 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

35 40 45

Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

10 50 55 60

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

65 70 75 80

15

Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

85 90 95

20

Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro

100 105 110

25 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

115 120 125

Leu Arg Arg Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

30 130 135 140

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

145 150 155 160

35

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

165 170 175

40

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

180 185 190

45 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

195 200 205

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

50 210 215 220

Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

225 230 235 240

5 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

245 250 255

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

10 260 265 270

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

275 280 285

15

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

290 295 300

20

Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys

305 310 315 320

25 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

325 330 335

Ser Leu Ser Pro

30 340

<210> 227

<211> 340

35 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

40

<400> 227

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

1 5 10 15

45

Ser Thr Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Gly

20 25 30

50

Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

35 40 45

Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

50 55 60

5

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

65 70 75 80

10

Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

85 90 95

15 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro

100 105 110

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

20 115 120 125

Leu Arg Arg Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

130 135 140

25

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

145 150 155 160

thirty

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

165 170 175

35 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

180 185 190

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

40 195 200 205

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

210 215 220

45

Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

225 230 235 240

50

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

245 250 255

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

260 265 270

5

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

275 280 285

10

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

290 295 300

15 Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys

305 310 315 320

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

20 325 330 335

Ser Leu Ser Pro

340

25

<210> 228

<211> 340

<212>PRT

30 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

35 <400> 228

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

1 5 10 15

40

Ser Thr Ser Gly Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

20 25 30

45 Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

35 40 45

Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

50 50 55 60

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

65 70 75 80

5 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

85 90 95

Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro

10 100 105 110

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

115 120 125

15

Leu Arg Arg Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

130 135 140

20

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

145 150 155 160

25 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

165 170 175

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

30 180 185 190

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

195 200 205

35

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

210 215 220

40

Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

225 230 235 240

45 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

245 250 255

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

50 260 265 270

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

275 280 285

5 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

290 295 300

Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys

10 305 310 315 320

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

325 330 335

15

Ser Leu Ser Pro

340

20

<210> 229

<211> 340

<212>PRT

<213> Artificial Sequence

25

<220>

<223> an artificially synthesized sequence

<400> 229

thirty

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

1 5 10 15

35 Ser Thr Ser Gly Gly Thr Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro

20 25 30

Arg Gly Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

40 35 40 45

Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

50 55 60

45

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

65 70 75 80

50

Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

85 90 95

Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro

100 105 110

5

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

115 120 125

10

Leu Arg Arg Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

130 135 140

15 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

145 150 155 160

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

20 165 170 175

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

180 185 190

25

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

195 200 205

thirty

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

210 215 220

35 Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

225 230 235 240

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

40 245 250 255

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

260 265 270

45

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

275 280 285

50

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

290 295 300

Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys

305 310 315 320

5

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

325 330 335

10

Ser Leu Ser Pro

340

15 <210> 230

<211> 107

<212>PRT

<213> Artificial Sequence

20 <220>

<223> an artificially synthesized sequence

<400> 230

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

1 5 10 15

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

30 20 25 30

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

35 40 45

35

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

40

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

65 70 75 80

45 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

50 100 105

<210> 231

<211> 107

<212>PRT

<213> Artificial Sequence

5

<220>

<223> an artificially synthesized sequence

<400> 231

10

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

1 5 10 15

15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

20 25 30

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

20 35 40 45

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

50 55 60

25

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

65 70 75 80

thirty

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

85 90 95

35 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

100 105

<210> 232

40 <211> 119

<212>PRT

<213> Artificial Sequence

<220>

45 <223> an artificially synthesized sequence

<400> 232

Asp Ile Gln Met Thr Gln Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn

50 1 5 10 15

Pro Arg Gly Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr

20 25 30

5 Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

35 40 45

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

10 50 55 60

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

15

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

85 90 95

20

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

25 Gly Thr Lys Val Glu Ile Lys

115

<210> 233

30 <211> 119

<212>PRT

<213> Artificial Sequence

<220>

35 <223> an artificially synthesized sequence

<400> 233

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

40 1 5 10 15

Asn Pro Arg Gly Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr

20 25 30

45

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

35 40 45

50

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

5

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

85 90 95

10

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

15 Gly Thr Lys Val Glu Ile Lys

115

<210> 234

20 <211> 119

<212>PRT

<213> Artificial Sequence

<220>

25 <223> an artificially synthesized sequence

<400> 234

Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Ser Thr Ser Gly Arg Ser

30 1 5 10 15

Ala Asn Pro Arg Gly Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr

20 25 30

35

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

35 40 45

40

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

45 Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

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

50 85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

5 Gly Thr Lys Val Glu Ile Lys

115

<210> 235

10 <211> 119

<212>PRT

<213> Artificial Sequence

<220>

15 <223> an artificially synthesized sequence

<400> 235

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Thr Ser Thr Ser Gly Arg

20 1 5 10 15

Ser Ala Asn Pro Arg Gly Leu Ser Ala Ser Val Gly Asp Arg Val Thr

20 25 30

25

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

35 40 45

thirty

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

35 Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

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

40 85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

45

Gly Thr Lys Val Glu Ile Lys

115

50

<210> 236

<211> 119

<212>PRT

<213> Artificial Sequence

<220>

5 <223> an artificially synthesized sequence

<400> 236

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

10 1 5 10 15

Arg Ser Ala Asn Pro Arg Gly Ser Ala Ser Val Gly Asp Arg Val Thr

20 25 30

15

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

35 40 45

20

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

25 Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

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

30 85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

35

Gly Thr Lys Val Glu Ile Lys

115

40

<210> 237

<211> 119

<212>PRT

<213> Artificial Sequence

45

<220>

<223> an artificially synthesized sequence

<400> 237

50

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

1 5 10 15

Gly Arg Ser Ala Asn Pro Arg Gly Ala Ser Val Gly Asp Arg Val Thr

20 25 30

5

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

35 40 45

10

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

15 Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

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

20 85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

25

Gly Thr Lys Val Glu Ile Lys

115

thirty

<210> 238

<211> 119

<212>PRT

<213> Artificial Sequence

35

<220>

<223> an artificially synthesized sequence

<400> 238

40

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

1 5 10 15

45 Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Val Gly Asp Arg Val Thr

20 25 30

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

50 35 40 45

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

5 Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

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

10 85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

15

Gly Thr Lys Val Glu Ile Lys

115

20

<210> 239

<211> 119

<212>PRT

<213> Artificial Sequence

25

<220>

<223> an artificially synthesized sequence

<400> 239

thirty

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

1 5 10 15

35 Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Val Gly Asp Arg Val Thr

20 25 30

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

40 35 40 45

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

45

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

50

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

85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

5

Gly Thr Lys Val Glu Ile Lys

115

10

<210> 240

<211> 119

<212>PRT

<213> Artificial Sequence

15

<220>

<223> an artificially synthesized sequence

<400> 240

20

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

1 5 10 15

25 Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Asp Arg Val Thr

20 25 30

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

30 35 40 45

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

35

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

40

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

85 90 95

45 Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

Gly Thr Lys Val Glu Ile Lys

50 115

<210> 241

<211> 119

<212>PRT

<213> Artificial Sequence

5

<220>

<223> an artificially synthesized sequence

<400> 241

10

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

1 5 10 15

15 Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Asp Arg Val Thr

20 25 30

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

20 35 40 45

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

25

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

thirty

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

85 90 95

35 Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

Gly Thr Lys Val Glu Ile Lys

40 115

<210> 242

<211> 119

45 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

50

<400> 242

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

1 5 10 15

5 Asp Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Arg Val Thr

20 25 30

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

10 35 40 45

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

15

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

20

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

85 90 95

25 Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

Gly Thr Lys Val Glu Ile Lys

30 115

<210> 243

<211> 119

35 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

40

<400> 243

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

1 5 10 15

45

Asp Arg Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Val Thr

20 25 30

50

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

35 40 45

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

5

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

10

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

85 90 95

15 Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

Gly Thr Lys Val Glu Ile Lys

20 115

<210> 244

<211> 119

25 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

thirty

<400> 244

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

1 5 10 15

35

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

20 25 30

40

Leu Asn Trp Tyr Gln Gln Lys Thr Ser Thr Ser Gly Arg Ser Ala Asn

35 40 45

45 Pro Arg Gly Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

50 65 70 75 80

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

85 90 95

5 Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

Gly Thr Lys Val Glu Ile Lys

10 115

<210> 245

<211> 119

15 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

20

<400> 245

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

1 5 10 15

25

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

20 25 30

thirty

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

35 40 45

35 Asn Pro Arg Gly Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

40 65 70 75 80

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

85 90 95

45

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

50

Gly Thr Lys Val Glu Ile Lys

115

<210> 246

<211> 119

5 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

10

<400> 246

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

1 5 10 15

15

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

20 25 30

20

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Thr Ser Thr Ser Gly Arg Ser

35 40 45

25 Ala Asn Pro Arg Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

30 65 70 75 80

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

85 90 95

35

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

40

Gly Thr Lys Val Glu Ile Lys

115

45 <210> 247

<211> 119

<212>PRT

<213> Artificial Sequence

50 <220>

<223> an artificially synthesized sequence

<400> 247

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

1 5 10 15

5

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

20 25 30

10

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Thr Ser Thr Ser Gly Arg

35 40 45

15 Ser Ala Asn Pro Arg Gly Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

20 65 70 75 80

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

85 90 95

25

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

thirty

Gly Thr Lys Val Glu Ile Lys

115

35 <210> 248

<211> 119

<212>PRT

<213> Artificial Sequence

40 <220>

<223> an artificially synthesized sequence

<400> 248

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

1 5 10 15

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

50 20 25 30

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

35 40 45

5 Arg Ser Ala Asn Pro Arg Gly Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

10 65 70 75 80

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

85 90 95

15

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

20

Gly Thr Lys Val Glu Ile Lys

115

25 <210> 249

<211> 119

<212>PRT

<213> Artificial Sequence

30 <220>

<223> an artificially synthesized sequence

<400> 249

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

1 5 10 15

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

40 20 25 30

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

35 40 45

45

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

50 55 60

50

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

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

85 90 95

5

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

10

Gly Thr Lys Val Glu Ile Lys

115

15 <210> 250

<211> 119

<212>PRT

<213> Artificial Sequence

20 <220>

<223> an artificially synthesized sequence

<400> 250

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

1 5 10 15

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

30 20 25 30

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

35 40 45

35

Ser Gly Arg Ser Ala Asn Pro Arg Gly Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

40

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

45 Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

50 100 105 110

Gly Thr Lys Val Glu Ile Lys

115

5 <210> 251

<211> 119

<212>PRT

<213> Artificial Sequence

10 <220>

<223> an artificially synthesized sequence

<400> 251

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

1 5 10 15

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

20 20 25 30

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

35 40 45

25

Tyr Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Tyr Thr Ser

50 55 60

thirty

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

35 Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

40 100 105 110

Gly Thr Lys Val Glu Ile Lys

115

45

<210> 252

<211> 119

<212>PRT

50 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

<400> 252

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

1 5 10 15

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

10 20 25 30

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

35 40 45

15

Tyr Tyr Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Thr Ser

50 55 60

20

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

25 Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

30 100 105 110

Gly Thr Lys Val Glu Ile Lys

115

35

<210> 253

<211> 119

<212>PRT

40 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

45 <400> 253

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

1 5 10 15

50

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

20 25 30

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

35 40 45

5

Tyr Tyr Thr Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser

50 55 60

10

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

15 Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

20 100 105 110

Gly Thr Lys Val Glu Ile Lys

115

25

<210> 254

<211> 119

<212>PRT

30 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

35 <400> 254

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

1 5 10 15

40

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

20 25 30

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

35 40 45

Tyr Tyr Thr Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

50 50 55 60

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

5 Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

10 100 105 110

Gly Thr Lys Val Glu Ile Lys

115

15

<210> 255

<211> 119

<212>PRT

20 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

25 <400> 255

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

1 5 10 15

thirty

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

20 25 30

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

35 40 45

Tyr Tyr Thr Ser Arg Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg

40 50 55 60

Gly Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

45

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

85 90 95

50

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

Gly Thr Lys Val Glu Ile Lys

115

5

<210> 256

<211> 119

<212>PRT

10 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15 <400> 256

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

1 5 10 15

20

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

20 25 30

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

35 40 45

Tyr Tyr Thr Ser Arg Leu Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro

30 50 55 60

Arg Gly His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

35

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

85 90 95

40

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

45 Gly Thr Lys Val Glu Ile Lys

115

<210> 257

50 <211> 119

<212>PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

5 <400> 257

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

1 5 10 15

10

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

20 25 30

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

35 40 45

Tyr Tyr Thr Ser Arg Leu His Thr Ser Thr Ser Gly Arg Ser Ala Asn

20 50 55 60

Pro Arg Gly Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

25

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

85 90 95

thirty

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

35 Gly Thr Lys Val Glu Ile Lys

115

<210> 258

40 <211> 119

<212>PRT

<213> Artificial Sequence

<220>

45 <223> an artificially synthesized sequence

<400> 258

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

50 1 5 10 15

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

20 25 30

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

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Thr Ser Thr Ser Gly Arg Ser Ala

10 50 55 60

Asn Pro Arg Gly Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

15

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

85 90 95

20

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

25 Gly Thr Lys Val Glu Ile Lys

115

<210> 259

30 <211> 119

<212>PRT

<213> Artificial Sequence

<220>

35 <223> an artificially synthesized sequence

<400> 259

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

40 1 5 10 15

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

20 25 30

45

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

35 40 45

50

Tyr Tyr Thr Ser Arg Leu His Ser Gly Thr Ser Thr Ser Gly Arg Ser

50 55 60

Ala Asn Pro Arg Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

5

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

85 90 95

10

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

15 Gly Thr Lys Val Glu Ile Lys

115

<210> 260

20 <211> 119

<212>PRT

<213> Artificial Sequence

<220>

25 <223> an artificially synthesized sequence

<400> 260

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

30 1 5 10 15

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

20 25 30

35

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

35 40 45

40

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Thr Ser Thr Ser Gly Arg

50 55 60

45 Ser Ala Asn Pro Arg Gly Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

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

50 85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

5 Gly Thr Lys Val Glu Ile Lys

115

<210> 261

10 <211> 119

<212>PRT

<213> Artificial Sequence

<220>

15 <223> an artificially synthesized sequence

<400> 261

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

20 1 5 10 15

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

20 25 30

25

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

35 40 45

thirty

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Thr Ser Thr Ser Gly

50 55 60

35 Arg Ser Ala Asn Pro Arg Gly Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

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

40 85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

45

Gly Thr Lys Val Glu Ile Lys

115

50

<210> 262

<211> 119

<212>PRT

<213> Artificial Sequence

<220>

5 <223> an artificially synthesized sequence

<400> 262

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

10 1 5 10 15

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

20 25 30

15

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

35 40 45

20

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Thr Ser Thr Ser

50 55 60

25 Gly Arg Ser Ala Asn Pro Arg Gly Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

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

30 85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

35

Gly Thr Lys Val Glu Ile Lys

115

40

<210> 263

<211> 119

<212>PRT

<213> Artificial Sequence

45

<220>

<223> an artificially synthesized sequence

<400> 263

50

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

1 5 10 15

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

20 25 30

5

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

35 40 45

10

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

20 85 90 95

Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Thr Phe Gly Gln

100 105 110

25

Gly Thr Lys Val Glu Ile Lys

115

thirty

<210> 264

<211> 119

<212>PRT

<213> Artificial Sequence

35

<220>

<223> an artificially synthesized sequence

<400> 264

40

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

1 5 10 15

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

20 25 30

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

50 35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

10 85 90 95

Thr Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Phe Gly Gln

100 105 110

15

Gly Thr Lys Val Glu Ile Lys

115

20

<210> 265

<211> 119

<212>PRT

<213> Artificial Sequence

25

<220>

<223> an artificially synthesized sequence

<400> 265

thirty

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

1 5 10 15

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

20 25 30

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

40 35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

45

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

65 70 75 80

50

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Gln

100 105 110

5

Gly Thr Lys Val Glu Ile Lys

115

10

<210> 266

<211> 119

<212>PRT

<213> Artificial Sequence

15

<220>

<223> an artificially synthesized sequence

<400> 266

20

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

1 5 10 15

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

20 25 30

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

30 35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

35

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

65 70 75 80

40

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

45 Thr Phe Gly Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Gln

100 105 110

Gly Thr Lys Val Glu Ile Lys

50 115

<210> 267

<211> 119

<212>PRT

<213> Artificial Sequence

5

<220>

<223> an artificially synthesized sequence

<400> 267

10

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

1 5 10 15

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

20 25 30

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

20 35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

25

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

65 70 75 80

thirty

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

35 Thr Phe Gly Gln Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

100 105 110

Gly Thr Lys Val Glu Ile Lys

40 115

<210> 268

<211> 119

45 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

50

<400> 268

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

1 5 10 15

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

20 25 30

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

10 35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

15

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

65 70 75 80

20

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

25 Thr Phe Gly Gln Gly Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg

100 105 110

Gly Thr Lys Val Glu Ile Lys

30 115

<210> 269

<211> 119

35 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

40

<400> 269

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

1 5 10 15

45

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

20 25 30

50

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

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

5

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

65 70 75 80

10

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

15 Thr Phe Gly Gln Gly Thr Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro

100 105 110

Arg Gly Lys Val Glu Ile Lys

20 115

<210> 270

<211> 119

25 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

thirty

<400> 270

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

1 5 10 15

35

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

20 25 30

40

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

35 40 45

45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

50 65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

5 Thr Phe Gly Gln Gly Thr Lys Thr Ser Thr Ser Gly Arg Ser Ala Asn

100 105 110

Pro Arg Gly Val Glu Ile Lys

10 115

<210> 271

<211> 119

15 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

20

<400> 271

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

1 5 10 15

25

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

20 25 30

thirty

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

35 40 45

35 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

40 65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

45

Thr Phe Gly Gln Gly Thr Lys Val Thr Ser Thr Ser Gly Arg Ser Ala

100 105 110

50

Asn Pro Arg Gly Glu Ile Lys

115

<210> 272

<211> 119

5 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

10

<400> 272

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

1 5 10 15

15

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

20 25 30

20

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

35 40 45

25 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

30 65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

35

Thr Phe Gly Gln Gly Thr Lys Val Glu Thr Ser Thr Ser Gly Arg Ser

100 105 110

40

Ala Asn Pro Arg Gly Ile Lys

115

45 <210> 273

<211> 119

<212>PRT

<213> Artificial Sequence

50 <220>

<223> an artificially synthesized sequence

<400> 273

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

1 5 10 15

5

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

20 25 30

10

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

35 40 45

15 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

20 65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

25

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

100 105 110

thirty

Ser Ala Asn Pro Arg Gly Lys

115

35 <210> 274

<211> 119

<212>PRT

<213> Artificial Sequence

40 <220>

<223> an artificially synthesized sequence

<400> 274

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

1 5 10 15

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

50 20 25 30

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

35 40 45

5 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

10 65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

15

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

100 105 110

20

Arg Ser Ala Asn Pro Arg Gly

115

25 <210> 275

<211> 119

<212>PRT

<213> Artificial Sequence

30 <220>

<223> an artificially synthesized sequence

<400> 275

35 Arg Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Thr Val Ala

1 5 10 15

Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

40 20 25 30

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

35 40 45

45

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

50 55 60

50

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

85 90 95

5

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

100 105 110

10

Ser Phe Asn Arg Gly Glu Cys

115

15 <210> 276

<211> 119

<212>PRT

<213> Artificial Sequence

20 <220>

<223> an artificially synthesized sequence

<400> 276

25 Arg Thr Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Val Ala

1 5 10 15

Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

30 20 25 30

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

35 40 45

35

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

50 55 60

40

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

45 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

85 90 95

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

50 100 105 110

Ser Phe Asn Arg Gly Glu Cys

115

5 <210> 277

<211> 119

<212>PRT

<213> Artificial Sequence

10 <220>

<223> an artificially synthesized sequence

<400> 277

15 Arg Thr Val Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ala

1 5 10 15

Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

20 20 25 30

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

35 40 45

25

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

50 55 60

thirty

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

35 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

85 90 95

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

40 100 105 110

Ser Phe Asn Arg Gly Glu Cys

115

45

<210> 278

<211> 119

<212>PRT

50 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

<400> 278

5 Arg Thr Val Ala Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

1 5 10 15

Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

10 20 25 30

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

35 40 45

15

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

50 55 60

20

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

25 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

85 90 95

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

30 100 105 110

Ser Phe Asn Arg Gly Glu Cys

115

35

<210> 279

<211> 119

<212>PRT

40 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

45 <400> 279

Arg Thr Val Ala Ala Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg

1 5 10 15

50

Gly Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

20 25 30

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

35 40 45

5

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

50 55 60

10

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

15 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

85 90 95

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

20 100 105 110

Ser Phe Asn Arg Gly Glu Cys

115

25

<210> 280

<211> 119

<212>PRT

30 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

35 <400> 280

Arg Thr Val Ala Ala Pro Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro

1 5 10 15

40

Arg Gly Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

20 25 30

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

35 40 45

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

50 50 55 60

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

5 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

85 90 95

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

10 100 105 110

Ser Phe Asn Arg Gly Glu Cys

115

15

<210> 281

<211> 119

<212>PRT

20 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

25 <400> 281

Arg Thr Val Ala Ala Pro Ser Val Thr Ser Thr Ser Gly Arg Ser Ala

1 5 10 15

thirty

Asn Pro Arg Gly Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

20 25 30

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

35 40 45

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

40 50 55 60

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

45

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

85 90 95

50

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

100 105 110

Ser Phe Asn Arg Gly Glu Cys

115

5

<210> 282

<211> 119

<212>PRT

10 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15 <400> 282

Arg Thr Val Ala Ala Pro Ser Val Phe Thr Ser Thr Ser Gly Arg Ser

1 5 10 15

20

Ala Asn Pro Arg Gly Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

20 25 30

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

35 40 45

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

30 50 55 60

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

35

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

85 90 95

40

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

100 105 110

45 Ser Phe Asn Arg Gly Glu Cys

115

<210> 283

50 <211> 119

<212>PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

5 <400> 283

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

1 5 10 15

10

Ser Ala Asn Pro Arg Gly Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

20 25 30

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

35 40 45

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

20 50 55 60

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

25

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

85 90 95

thirty

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

100 105 110

35 Ser Phe Asn Arg Gly Glu Cys

115

<210> 284

40 <211> 119

<212>PRT

<213> Artificial Sequence

<220>

45 <223> an artificially synthesized sequence

<400> 284

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

50 1 5 10 15

Arg Ser Ala Asn Pro Arg Gly Pro Pro Ser Asp Glu Gln Leu Lys Ser

20 25 30

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

35 40 45

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

10 50 55 60

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

15

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

85 90 95

20

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

100 105 110

25 Ser Phe Asn Arg Gly Glu Cys

115

<210> 285

30 <211> 119

<212>PRT

<213> Artificial Sequence

<220>

35 <223> an artificially synthesized sequence

<400> 285

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Thr Ser Thr Ser

40 1 5 10 15

Gly Arg Ser Ala Asn Pro Arg Gly Pro Ser Asp Glu Gln Leu Lys Ser

20 25 30

45

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

35 40 45

50

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

50 55 60

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

5

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

85 90 95

10

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

100 105 110

15 Ser Phe Asn Arg Gly Glu Cys

115

<210> 286

20 <211> 119

<212>PRT

<213> Artificial Sequence

<220>

25 <223> an artificially synthesized sequence

<400> 286

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Thr Ser Thr

30 1 5 10 15

Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Asp Glu Gln Leu Lys Ser

20 25 30

35

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

35 40 45

40

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

50 55 60

45 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

50 85 90 95

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

100 105 110

5 Ser Phe Asn Arg Gly Glu Cys

115

<210> 287

10 <211> 119

<212>PRT

<213> Artificial Sequence

<220>

15 <223> an artificially synthesized sequence

<400> 287

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Thr Ser

20 1 5 10 15

Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Asp Glu Gln Leu Lys Ser

20 25 30

25

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

35 40 45

thirty

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

50 55 60

35 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

40 85 90 95

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

100 105 110

45

Ser Phe Asn Arg Gly Glu Cys

115

50

<210> 288

<211> 119

<212>PRT

<213> Artificial Sequence

<220>

5 <223> an artificially synthesized sequence

<400> 288

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Thr

10 1 5 10 15

Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Glu Gln Leu Lys Ser

20 25 30

15

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

35 40 45

20

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

50 55 60

25 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

30 85 90 95

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

100 105 110

35

Ser Phe Asn Arg Gly Glu Cys

115

40

<210> 289

<211> 119

<212>PRT

<213> Artificial Sequence

45

<220>

<223> an artificially synthesized sequence

<400> 289

50

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

1 5 10 15

Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Gln Leu Lys Ser

20 25 30

5

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

35 40 45

10

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

50 55 60

15 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

20 85 90 95

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

100 105 110

25

Ser Phe Asn Arg Gly Glu Cys

115

thirty

<210> 290

<211> 119

<212>PRT

<213> Artificial Sequence

35

<220>

<223> an artificially synthesized sequence

<400> 290

40

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

1 5 10 15

45 Gln Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Leu Lys Ser

20 25 30

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

50 35 40 45

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

50 55 60

5 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

10 85 90 95

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

100 105 110

15

Ser Phe Asn Arg Gly Glu Cys

115

20

<210> 291

<211> 119

<212>PRT

<213> Artificial Sequence

25

<220>

<223> an artificially synthesized sequence

<400> 291

thirty

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

1 5 10 15

35 Gln Leu Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Lys Ser

20 25 30

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

40 35 40 45

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

50 55 60

45

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

50

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

85 90 95

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

100 105 110

5

Ser Phe Asn Arg Gly Glu Cys

115

10

<210> 292

<211> 119

<212>PRT

<213> Artificial Sequence

15

<220>

<223> an artificially synthesized sequence

<400> 292

20

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

1 5 10 15

25 Gln Leu Lys Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser

20 25 30

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

30 35 40 45

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

50 55 60

35

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

40

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

85 90 95

45 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

100 105 110

Ser Phe Asn Arg Gly Glu Cys

50 115

<210> 293

<211> 119

<212>PRT

<213> Artificial Sequence

5

<220>

<223> an artificially synthesized sequence

<400> 293

10

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

1 5 10 15

15 Gln Leu Lys Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

20 25 30

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

20 35 40 45

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

50 55 60

25

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

thirty

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

85 90 95

35 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

100 105 110

Ser Phe Asn Arg Gly Glu Cys

40 115

<210> 294

<211> 119

45 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

50

<400> 294

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

1 5 10 15

5 Gln Leu Lys Ser Gly Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg

20 25 30

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

10 35 40 45

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

50 55 60

15

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

20

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

85 90 95

25 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

100 105 110

Ser Phe Asn Arg Gly Glu Cys

30 115

<210> 295

<211> 119

35 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

40

<400> 295

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

1 5 10 15

45

Gln Leu Lys Ser Gly Thr Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro

20 25 30

50

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

35 40 45

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

50 55 60

5

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

65 70 75 80

10

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

85 90 95

15 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

100 105 110

Ser Phe Asn Arg Gly Glu Cys

20 115

<210> 296

<211> 119

25 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

thirty

<400> 296

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

1 5 10 15

35

Gln Leu Lys Ser Gly Thr Ala Thr Ser Thr Ser Gly Arg Ser Ala Asn

20 25 30

40

Pro Arg Gly Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu

35 40 45

45 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

50 55 60

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

50 65 70 75 80

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

85 90 95

5 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

100 105 110

Ser Phe Asn Arg Gly Glu Cys

10 115

<210> 297

<211> 441

15 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

20

<400> 297

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

1 5 10 15

25

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

20 25 30

thirty

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

35 40 45

35 Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val

50 55 60

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

40 65 70 75 80

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

85 90 95

45

Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

50

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

115 120 125

Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp

130 135 140

5

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

145 150 155 160

10

Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr

165 170 175

15 Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln

180 185 190

Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp

20 195 200 205

Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro

210 215 220

25

Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

thirty

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

35 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

40 275 280 285

Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

45

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

50

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu

340 345 350

5

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

10

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

15 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

20 405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

25

Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440

thirty

<210> 298

<211> 214

<212>PRT

<213> Artificial Sequence

35

<220>

<223> an artificially synthesized sequence

<400> 298

40

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

1 5 10 15

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

20 25 30

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

50 35 40 45

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

50 55 60

5 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

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

10 85 90 95

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

100 105 110

15

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

20

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

130 135 140

25 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

30 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

35

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

40

Phe Asn Arg Gly Glu Cys

210

45 <210> 299

<211> 12

<212>PRT

<213> Artificial Sequence

50 <220>

<223> an artificially synthesized sequence

<400> 299

Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

1 5 10

5

<210> 300

<211> 113

<212>PRT

10 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15 <400> 300

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

1 5 10 15

20

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

20 25 30

25 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

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

30 50 55 60

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

65 70 75 80

35

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

85 90 95

40

Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

45 Ser

<210> 301

50 <211> 328

<212>PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

5 <400> 301

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

1 5 10 15

10

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

20 25 30

15 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

20 50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

25

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

thirty

Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

35 Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

40 130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

45

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

50

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

5

Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

10

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu

225 230 235 240

15 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

20 260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

25

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn

290 295 300

thirty

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

35 Gln Lys Ser Leu Ser Leu Ser Pro

325

<210> 302

40 <211> 107

<212>PRT

<213> Artificial Sequence

<220>

45 <223> an artificially synthesized sequence

<400> 302

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

50 1 5 10 15

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

20 25 30

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

35 40 45

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

10 50 55 60

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

65 70 75 80

15

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

85 90 95

20

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

25 <210> 303

<211> 107

<212>PRT

<213> Artificial Sequence

30 <220>

<223> an artificially synthesized sequence

<400> 303

35 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

1 5 10 15

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

40 20 25 30

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

35 40 45

45

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

50 55 60

50

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

65 70 75 80

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

85 90 95

5

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

100 105

10

<210> 304

<211> 453

<212>PRT

<213> Artificial Sequence

15

<220>

<223> an artificially synthesized sequence

<400> 304

20

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

1 5 10 15

25 Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser

20 25 30

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

30 35 40 45

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

50 55 60

35

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

65 70 75 80

40

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

85 90 95

45 Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ala Ser Thr

50 115 120 125

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

130 135 140

5 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu

145 150 155 160

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His

10 165 170 175

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

180 185 190

15

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

195 200 205

20

Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu

210 215 220

25 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

225 230 235 240

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

30 245 250 255

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

260 265 270

35

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

275 280 285

40

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

290 295 300

45 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

305 310 315 320

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu

50 325 330 335

Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

340 345 350

5 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys

355 360 365

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

10 370 375 380

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

385 390 395 400

15

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

405 410 415

20

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser

420 425 430

25 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

435 440 445

Leu Ser Leu Ser Pro

30 450

<210> 305

<211> 453

35 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

40

<400> 305

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

1 5 10 15

45

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

20 25 30

50

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

35 40 45

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

50 55 60

5

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

65 70 75 80

10

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

85 90 95

15 Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ser Ala Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Thr

20 115 120 125

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

130 135 140

25

Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu

145 150 155 160

thirty

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His

165 170 175

35 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser

180 185 190

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

40 195 200 205

Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu

210 215 220

45

Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro

225 230 235 240

50

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

245 250 255

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

260 265 270

5

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

275 280 285

10

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

290 295 300

15 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

305 310 315 320

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu

20 325 330 335

Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

340 345 350

25

Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys

355 360 365

thirty

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

370 375 380

35 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

385 390 395 400

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

40 405 410 415

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser

420 425 430

45

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

435 440 445

50

Leu Ser Leu Ser Pro

450

<210> 306

<211> 226

5 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

10

<400> 306

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

1 5 10 15

15

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

20 25 30

20

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

35 40 45

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

50 55 60

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

30 65 70 75 80

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

85 90 95

35

Thr Phe Gly Gln Gly Thr Lys Val Thr Ser Thr Ser Gly Arg Ser Ala

100 105 110

40

Asn Pro Arg Gly Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

45 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

50 145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

5 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

10 195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

15

Glu Cys

225

20

<210> 307

<211> 226

<212>PRT

<213> Artificial Sequence

25

<220>

<223> an artificially synthesized sequence

<400> 307

thirty

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

1 5 10 15

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

20 25 30

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

40 35 40 45

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

50 55 60

45

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

65 70 75 80

50

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

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Thr Ser Thr Ser Gly Arg Ser

100 105 110

5

Ala Asn Pro Arg Gly Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

10

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

130 135 140

15 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

20 165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

25

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

thirty

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

35 Glu Cys

225

<210> 308

40 <211> 226

<212>PRT

<213> Artificial Sequence

<220>

45 <223> an artificially synthesized sequence

<400> 308

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

50 1 5 10 15

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

20 25 30

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

35 40 45

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

10 50 55 60

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

65 70 75 80

15

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

85 90 95

20

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

100 105 110

25 Ser Ala Asn Pro Arg Gly Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

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

30 130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

35

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

40

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

45 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

50 210 215 220

Glu Cys

225

5 <210> 309

<211> 226

<212>PRT

<213> Artificial Sequence

10 <220>

<223> an artificially synthesized sequence

<400> 309

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

1 5 10 15

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

20 20 25 30

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

35 40 45

25

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

50 55 60

thirty

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

65 70 75 80

35 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg

85 90 95

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

40 100 105 110

Arg Ser Ala Asn Pro Arg Gly Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

45

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

130 135 140

50

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

5

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

10

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

15 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

Glu Cys

20 225

<210> 310

<211> 226

25 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

thirty

<400> 310

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

1 5 10 15

35

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

20 25 30

40

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

35 40 45

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

50 55 60

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

50 65 70 75 80

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

85 90 95

5 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Ser Thr Ser

100 105 110

Gly Arg Ser Ala Asn Pro Arg Gly Thr Val Ala Ala Pro Ser Val Phe

10 115 120 125

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

130 135 140

15

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

20

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

25 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

30 195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

35

Glu Cys

225

40

<210> 311

<211> 226

<212>PRT

<213> Artificial Sequence

45

<220>

<223> an artificially synthesized sequence

<400> 311

50

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

1 5 10 15

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

20 25 30

5

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

35 40 45

10

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

50 55 60

15 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

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

20 85 90 95

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

100 105 110

25

Ser Gly Arg Ser Ala Asn Pro Arg Gly Val Ala Ala Pro Ser Val Phe

115 120 125

thirty

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

130 135 140

35 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

40 165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

45

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

50

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

Glu Cys

225

5

<210> 312

<211> 226

<212>PRT

10 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15 <400> 312

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

1 5 10 15

20

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

20 25 30

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

35 40 45

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

30 50 55 60

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

65 70 75 80

35

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

85 90 95

40

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

100 105 110

45 Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ala Ala Pro Ser Val Phe

115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

50 130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

5 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

10 180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

15

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

20

Glu Cys

225

25 <210> 313

<211> 226

<212>PRT

<213> Artificial Sequence

30 <220>

<223> an artificially synthesized sequence

<400> 313

35 Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

40 20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

50

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg

85 90 95

5

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Thr

100 105 110

10

Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ala Pro Ser Val Phe

115 120 125

15 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

20 145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

25

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

thirty

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

35 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

Glu Cys

40 225

<210> 314

<211> 226

45 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

50

<400> 314

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

5 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

10 35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

15

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

20

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg

85 90 95

25 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Pro Ser Val Phe

30 115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

35

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

40

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

45 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

50 195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

5 Glu Cys

225

<210> 315

10 <211> 226

<212>PRT

<213> Artificial Sequence

<220>

15 <223> an artificially synthesized sequence

<400> 315

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

20 1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

25

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

thirty

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

35 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg

40 85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

45

Pro Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Val Phe

115 120 125

50

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

5

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

10

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

15 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

20 210 215 220

Glu Cys

225

25

<210> 316

<211> 15

<212>PRT

30 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

35 <400> 316

Gly Leu Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp His Glu

1 5 10 15

40

<210> 317

<211> 461

<212>PRT

<213> Artificial Sequence

45

<220>

<223> an artificially synthesized sequence

<400> 317

50

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser

20 25 30

5

Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

10

Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val

50 55 60

15 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

20 85 90 95

Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

25

Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser

115 120 125

thirty

Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp

130 135 140

35 Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr

145 150 155 160

Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr

40 165 170 175

Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln

180 185 190

45

Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp

195 200 205

50

Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro

210 215 220

Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

5

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

10

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn

260 265 270

15 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

20 290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

25

Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

thirty

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp

340 345 350

35 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

40 370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

45

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

405 410 415

50

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Leu

435 440 445

5

Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp His Glu

450 455 460

10

<210> 318

<211> 641

<212>PRT

<213> Artificial Sequence

15

<220>

<223> an artificially synthesized sequence

<400> 318

20

Met Ser Asp Glu Gly Pro Gly Thr Gly Pro Gly Asn Gly Leu Gly Glu

1 5 10 15

25 Lys Gly Asp Thr Ser Gly Pro Glu Gly Ser Gly Gly Ser Gly Pro Gln

20 25 30

Arg Arg Gly Gly Asp Asn His Gly Arg Gly Arg Gly Arg Gly Arg Gly

30 35 40 45

Arg Gly Gly Gly Arg Pro Gly Ala Pro Gly Gly Ser Gly Ser Gly Pro

50 55 60

35

Arg His Arg Asp Gly Val Arg Arg Pro Gln Lys Arg Pro Ser Cys Ile

65 70 75 80

40

Gly Cys Lys Gly Thr His Gly Gly Thr Gly Ala Gly Ala Gly Ala Gly

85 90 95

45 Gly Ala Gly Ala Gly Gly Ala Gly Ala Gly Gly Gly Ala Gly Ala Gly

100 105 110

Gly Gly Ala Gly Gly Ala Gly Gly Ala Gly Gly Ala Gly Ala Gly Gly

50 115 120 125

Gly Ala Gly Ala Gly Gly Gly Ala Gly Gly Ala Gly Gly Ala Gly Ala

130 135 140

5 Gly Gly Gly Ala Gly Ala Gly Gly Gly Ala Gly Gly Ala Gly Ala Gly

145 150 155 160

Gly Gly Ala Gly Gly Ala Gly Gly Ala Gly Ala Gly Gly Gly Ala Gly

10 165 170 175

Ala Gly Gly Gly Ala Gly Gly Ala Gly Ala Gly Gly Gly Ala Gly Gly

180 185 190

15

Ala Gly Gly Ala Gly Ala Gly Gly Gly Ala Gly Ala Gly Gly Ala Gly

195 200 205

20

Gly Ala Gly Gly Ala Gly Ala Gly Gly Ala Gly Ala Gly Gly Gly Ala

210 215 220

25 Gly Gly Ala Gly Gly Ala Gly Ala Gly Gly Ala Gly Ala Gly Gly Ala

225 230 235 240

Gly Ala Gly Gly Ala Gly Ala Gly Gly Ala Gly Gly Ala Gly Ala Gly

30 245 250 255

Gly Ala Gly Gly Ala Gly Ala Gly Gly Ala Gly Gly Ala Gly Ala Gly

260 265 270

35

Gly Gly Ala Gly Gly Ala Gly Ala Gly Gly Gly Ala Gly Gly Ala Gly

275 280 285

40

Ala Gly Gly Ala Gly Gly Ala Gly Ala Gly Gly Ala Gly Gly Ala Gly

290 295 300

45 Ala Gly Gly Ala Gly Gly Ala Gly Ala Gly Gly Gly Ala Gly Ala Gly

305 310 315 320

Gly Ala Gly Ala Gly Gly Gly Gly Arg Gly Arg Gly Gly Ser Gly Gly

50 325 330 335

Arg Gly Arg Gly Gly Ser Gly Gly Arg Gly Arg Gly Gly Ser Gly Gly

340 345 350

5 Arg Arg Gly Arg Gly Arg Glu Arg Ala Arg Gly Gly Ser Arg Glu Arg

355 360 365

Ala Arg Gly Arg Gly Arg Gly Arg Gly Glu Lys Arg Pro Arg Ser Pro

10 370 375 380

Ser Ser Gln Ser Ser Ser Gly Ser Pro Pro Arg Arg Pro Pro Pro

385 390 395 400

15

Gly Arg Arg Pro Phe Phe His Pro Val Gly Glu Ala Asp Tyr Phe Glu

405 410 415

20

Tyr His Gln Glu Gly Gly Pro Asp Gly Glu Pro Asp Val Pro Pro Gly

420 425 430

25 Ala Ile Glu Gln Gly Pro Ala Asp Asp Pro Gly Glu Gly Pro Ser Thr

435 440 445

Gly Pro Arg Gly Gln Gly Asp Gly Gly Arg Arg Lys Lys Gly Gly Trp

30 450 455 460

Phe Gly Lys His Arg Gly Gln Gly Gly Ser Asn Pro Lys Phe Glu Asn

465 470 475 480

35

Ile Ala Glu Gly Leu Arg Ala Leu Leu Ala Arg Ser His Val Glu Arg

485 490 495

40

Thr Thr Asp Glu Gly Thr Trp Val Ala Gly Val Phe Val Tyr Gly Gly

500 505 510

45 Ser Lys Thr Ser Leu Tyr Asn Leu Arg Arg Gly Thr Ala Leu Ala Ile

515 520 525

Pro Gln Cys Arg Leu Thr Pro Leu Ser Arg Leu Pro Phe Gly Met Ala

50 530 535 540

Pro Gly Pro Gly Pro Gln Pro Gly Pro Leu Arg Glu Ser Ile Val Cys

545 550 555 560

5 Tyr Phe Met Val Phe Leu Gln Thr His Ile Phe Ala Glu Val Leu Lys

565 570 575

Asp Ala Ile Lys Asp Leu Val Met Thr Lys Pro Ala Pro Thr Cys Asn

10 580 585 590

Ile Arg Val Thr Val Cys Ser Phe Asp Asp Gly Val Asp Leu Pro Pro

595 600 605

15

Trp Phe Pro Pro Met Val Glu Gly Ala Ala Ala Glu Gly Asp Asp Gly

610 615 620

20

Asp Asp Gly Asp Glu Gly Gly Asp Gly Asp Glu Gly Glu Glu Gly Gln

625 630 635 640

25 Glu

<210> 319

30 <211> 347

<212>PRT

<213> Artificial Sequence

<220>

35 <223> an artificially synthesized sequence

<400> 319

Met Val Leu Ala Ser Ser Thr Thr Ser Ile His Thr Met Leu Leu Leu

40 1 5 10 15

Leu Leu Met Leu Ala Gln Pro Ala Met Ala Met Lys Asp Asn Thr Val

20 25 30

45

Pro Leu Lys Leu Ile Ala Leu Leu Ala Asn Gly Glu Phe His Ser Gly

35 40 45

50

Glu Gln Leu Gly Glu Thr Leu Gly Met Ser Arg Ala Ala Ile Asn Lys

50 55 60

His Ile Gln Thr Leu Arg Asp Trp Gly Val Asp Val Phe Thr Val Pro

65 70 75 80

5

Gly Lys Gly Tyr Ser Leu Pro Glu Pro Ile Gln Leu Leu Asn Ala Lys

85 90 95

10

Gln Ile Leu Gly Gln Leu Asp Gly Gly Ser Val Ala Val Leu Pro Val

100 105 110

15 Ile Asp Ser Thr Asn Gln Tyr Leu Leu Asp Arg Ile Gly Glu Leu Lys

115 120 125

Ser Gly Asp Ala Cys Ile Ala Glu Tyr Gln Gln Ala Gly Arg Gly Arg

20 130 135 140

Arg Gly Arg Lys Trp Phe Ser Pro Phe Gly Ala Asn Leu Tyr Leu Ser

145 150 155 160

25

Met Phe Trp Arg Leu Glu Gln Gly Pro Ala Ala Ala Ile Gly Leu Ser

165 170 175

thirty

Leu Val Ile Gly Ile Val Met Ala Glu Val Leu Arg Lys Leu Gly Ala

180 185 190

35 Asp Lys Val Arg Val Lys Trp Pro Asn Asp Leu Tyr Leu Gln Asp Arg

195 200 205

Lys Leu Ala Gly Ile Leu Val Glu Leu Thr Gly Lys Thr Gly Asp Ala

40 210 215 220

Ala Gln Ile Val Ile Gly Ala Gly Ile Asn Met Ala Met Arg Arg Val

225 230 235 240

45

Glu Glu Ser Val Val Asn Gln Gly Trp Ile Thr Leu Gln Glu Ala Gly

245 250 255

50

Ile Asn Leu Asp Arg Asn Thr Leu Ala Ala Met Leu Ile Arg Glu Leu

260 265 270

Arg Ala Ala Leu Glu Leu Phe Glu Gln Glu Gly Leu Ala Pro Tyr Leu

275 280 285

5

Ser Arg Trp Glu Lys Leu Asp Asn Phe Ile Asn Arg Pro Val Lys Leu

290 295 300

10

Ile Ile Gly Asp Lys Glu Ile Phe Gly Ile Ser Arg Gly Ile Asp Lys

305 310 315 320

15 Gln Gly Ala Leu Leu Leu Glu Gln Asp Gly Ile Ile Lys Pro Trp Met

325 330 335

Gly Gly Glu Ile Ser Leu Arg Ser Ala Glu Lys

20 340 345

<210> 320

<211> 147

25 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

thirty

<400> 320

Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr

1 5 10 15

35

Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe

20 25 30

40

Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr

35 40 45

45 Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu

50 55 60

Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu

50 65 70 75 80

Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn

85 90 95

5 Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala

100 105 110

Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg

10 115 120 125

Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly

130 135 140

15

Gln Phe Gln

145

20

<210> 321

<211> 25

<212>PRT

<213> Artificial Sequence

25

<220>

<223> an artificially synthesized sequence

<400> 321

thirty

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

1 5 10 15

35 Gly Gly Gly Ser Gly Gly Gly Gly Ser

20 25

<210> 322

40 <211> 226

<212>PRT

<213> Artificial Sequence

<220>

45 <223> an artificially synthesized sequence

<400> 322

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

50 1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

5 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

10 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

15

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg

85 90 95

20

Thr Phe Gly Gln Gly Thr Lys Thr Ser Thr Ser Gly Arg Ser Ala Asn

100 105 110

25 Pro Arg Gly Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

30 130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

35

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

40

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

45 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

50 210 215 220

Glu Cys

225

5 <210> 323

<211> 625

<212>PRT

<213> Artificial Sequence

10 <220>

<223> an artificially synthesized sequence

<400> 323

15 Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr

1 5 10 15

Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe

20 20 25 30

Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr

35 40 45

25

Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu

50 55 60

thirty

Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu

65 70 75 80

35 Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn

85 90 95

Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala

40 100 105 110

Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg

115 120 125

45

Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly

130 135 140

50

Gln Phe Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

145 150 155 160

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu

165 170 175

5

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu

180 185 190

10

Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser Gly Met His Trp

195 200 205

15 Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Val Ile Trp

210 215 220

Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe

20 225 230 235 240

Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe Leu Gln Met Asn

245 250 255

25

Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Thr Asn Asp

260 265 270

thirty

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Ser Thr

275 280 285

35 Ser Gly Arg Ser Ala Asn Pro Arg Gly Ala Ser Thr Lys Gly Pro Ser

290 295 300

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

40 305 310 315 320

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

325 330 335

45

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

340 345 350

50

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

355 360 365

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

370 375 380

5

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys

385 390 395 400

10

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg

405 410 415

15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

420 425 430

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

20 435 440 445

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

450 455 460

25

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

465 470 475 480

thirty

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

485 490 495

35 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile

500 505 510

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

40 515 520 525

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser

530 535 540

45

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

545 550 555 560

50

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

565 570 575

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

580 585 590

5

Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met

595 600 605

10

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

610 615 620

15 Pro

625

<210> 324

20 <211> 625

<212>PRT

<213> Artificial Sequence

<220>

25 <223> an artificially synthesized sequence

<400> 324

Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr

30 1 5 10 15

Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe

20 25 30

35

Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr

35 40 45

40

Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu

50 55 60

45 Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu

65 70 75 80

Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn

50 85 90 95

Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala

100 105 110

5 Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg

115 120 125

Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly

10 130 135 140

Gln Phe Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

145 150 155 160

15

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu

165 170 175

20

Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu

180 185 190

25 Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser Gly Met His Trp

195 200 205

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Val Ile Trp

30 210 215 220

Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe

225 230 235 240

35

Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe Leu Gln Met Asn

245 250 255

40

Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Thr Asn Asp

260 265 270

45 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Thr Ser

275 280 285

Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Thr Lys Gly Pro Ser

50 290 295 300

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

305 310 315 320

5 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

325 330 335

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

10 340 345 350

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

355 360 365

15

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

370 375 380

20

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys

385 390 395 400

25 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg

405 410 415

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

30 420 425 430

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

435 440 445

35

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

450 455 460

40

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

465 470 475 480

45 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

485 490 495

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile

50 500 505 510

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

515 520 525

5 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser

530 535 540

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

10 545 550 555 560

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

565 570 575

15

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

580 585 590

20

Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met

595 600 605

25 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

610 615 620

Pro

30 625

<210> 325

<211> 398

35 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

40

<400> 325

Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr

1 5 10 15

45

Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe

20 25 30

50

Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr

35 40 45

Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu

50 55 60

5

Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu

65 70 75 80

10

Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn

85 90 95

15 Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala

100 105 110

Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg

20 115 120 125

Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly

130 135 140

25

Gln Phe Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

145 150 155 160

thirty

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu

165 170 175

35 Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr

180 185 190

Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr

40 195 200 205

Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser

210 215 220

45

Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly

225 230 235 240

50

Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala

245 250 255

Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg Thr Phe Gly Gln

260 265 270

5

Gly Thr Lys Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Val

275 280 285

10

Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro

290 295 300

15 Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu

305 310 315 320

Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn

20 325 330 335

Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser

340 345 350

25

Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala

355 360 365

thirty

Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly

370 375 380

35 Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

385 390 395

<210> 326

40 <211> 398

<212>PRT

<213> Artificial Sequence

<220>

45 <223> an artificially synthesized sequence

<400> 326

Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr

50 1 5 10 15

Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe

20 25 30

5 Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr

35 40 45

Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu

10 50 55 60

Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu

65 70 75 80

15

Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn

85 90 95

20

Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala

100 105 110

25 Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg

115 120 125

Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly

30 130 135 140

Gln Phe Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

145 150 155 160

35

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu

165 170 175

40

Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr

180 185 190

45 Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr

195 200 205

Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser

50 210 215 220

Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly

225 230 235 240

5 Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala

245 250 255

Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg Thr Phe Gly Gln

10 260 265 270

Gly Thr Lys Val Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

275 280 285

15

Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro

290 295 300

20

Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu

305 310 315 320

25 Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn

325 330 335

Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser

30 340 345 350

Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala

355 360 365

35

Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly

370 375 380

40

Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

385 390 395

45 <210> 327

<211> 398

<212>PRT

<213> Artificial Sequence

50 <220>

<223> an artificially synthesized sequence

<400> 327

Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr

1 5 10 15

5

Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe

20 25 30

10

Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr

35 40 45

15 Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu

50 55 60

Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu

20 65 70 75 80

Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn

85 90 95

25

Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala

100 105 110

thirty

Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg

115 120 125

35 Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly

130 135 140

Gln Phe Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

40 145 150 155 160

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu

165 170 175

45

Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr

180 185 190

50

Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr

195 200 205

Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser

210 215 220

5

Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly

225 230 235 240

10

Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala

245 250 255

15 Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg Thr Phe Gly Gln

260 265 270

Gly Thr Lys Val Glu Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg

20 275 280 285

Gly Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro

290 295 300

25

Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu

305 310 315 320

thirty

Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn

325 330 335

35 Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser

340 345 350

Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala

40 355 360 365

Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly

370 375 380

45

Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

385 390 395

50

<210> 328

<211> 398

<212>PRT

<213> Artificial Sequence

<220>

5 <223> an artificially synthesized sequence

<400> 328

Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr

10 1 5 10 15

Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe

20 25 30

15

Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr

35 40 45

20

Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu

50 55 60

25 Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu

65 70 75 80

Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn

30 85 90 95

Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala

100 105 110

35

Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg

115 120 125

40

Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly

130 135 140

45 Gln Phe Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

145 150 155 160

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu

50 165 170 175

Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr

180 185 190

5 Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr

195 200 205

Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser

10 210 215 220

Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly

225 230 235 240

15

Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala

245 250 255

20

Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg Thr Phe Gly Gln

260 265 270

25 Gly Thr Lys Val Glu Ile Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro

275 280 285

Arg Gly Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro

30 290 295 300

Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu

305 310 315 320

35

Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn

325 330 335

40

Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser

340 345 350

45 Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala

355 360 365

Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly

50 370 375 380

Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

385 390 395

5 <210> 329

<211> 398

<212>PRT

<213> Artificial Sequence

10 <220>

<223> an artificially synthesized sequence

<400> 329

15 Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr

1 5 10 15

Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe

20 20 25 30

Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr

35 40 45

25

Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu

50 55 60

thirty

Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu

65 70 75 80

35 Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn

85 90 95

Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala

40 100 105 110

Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg

115 120 125

45

Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly

130 135 140

50

Gln Phe Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

145 150 155 160

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu

165 170 175

5

Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr

180 185 190

10

Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr

195 200 205

15 Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser

210 215 220

Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly

20 225 230 235 240

Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala

245 250 255

25

Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg Thr Phe Gly Gln

260 265 270

thirty

Gly Thr Lys Val Glu Ile Lys Arg Thr Ser Thr Ser Gly Arg Ser Ala

275 280 285

35 Asn Pro Arg Gly Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro

290 295 300

Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu

40 305 310 315 320

Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn

325 330 335

45

Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser

340 345 350

50

Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala

355 360 365

Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly

370 375 380

5

Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

385 390 395

10

<210> 330

<211> 398

<212>PRT

<213> Artificial Sequence

15

<220>

<223> an artificially synthesized sequence

<400> 330

20

Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr

1 5 10 15

25 Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe

20 25 30

Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr

30 35 40 45

Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu

50 55 60

35

Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu

65 70 75 80

40

Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn

85 90 95

45 Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala

100 105 110

Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg

50 115 120 125

Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly

130 135 140

5 Gln Phe Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

145 150 155 160

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu

10 165 170 175

Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr

180 185 190

15

Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr

195 200 205

20

Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser

210 215 220

25 Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly

225 230 235 240

Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala

30 245 250 255

Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg Thr Phe Gly Gln

260 265 270

35

Gly Thr Lys Val Glu Ile Lys Arg Thr Thr Ser Thr Ser Gly Arg Ser

275 280 285

40

Ala Asn Pro Arg Gly Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro

290 295 300

45 Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu

305 310 315 320

Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn

50 325 330 335

Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser

340 345 350

5 Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala

355 360 365

Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly

10 370 375 380

Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

385 390 395

15

<210> 331

<211> 398

<212>PRT

20 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

25 <400> 331

Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr

1 5 10 15

thirty

Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe

20 25 30

35 Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr

35 40 45

Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu

40 50 55 60

Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu

65 70 75 80

45

Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn

85 90 95

50

Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala

100 105 110

Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg

115 120 125

5

Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly

130 135 140

10

Gln Phe Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

145 150 155 160

15 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu

165 170 175

Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr

20 180 185 190

Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr

195 200 205

25

Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser

210 215 220

thirty

Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly

225 230 235 240

35 Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala

245 250 255

Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg Thr Phe Gly Gln

40 260 265 270

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Thr Ser Thr Ser Gly Arg

275 280 285

45

Ser Ala Asn Pro Arg Gly Ala Ala Pro Ser Val Phe Ile Phe Pro Pro

290 295 300

50

Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu

305 310 315 320

Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn

325 330 335

5

Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser

340 345 350

10

Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala

355 360 365

15 Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly

370 375 380

Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

20 385 390 395

<210> 332

<211> 398

25 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

thirty

<400> 332

Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr

1 5 10 15

35

Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe

20 25 30

40

Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr

35 40 45

45 Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu

50 55 60

Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu

50 65 70 75 80

Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn

85 90 95

5 Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala

100 105 110

Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg

10 115 120 125

Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly

130 135 140

15

Gln Phe Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

145 150 155 160

20

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu

165 170 175

25 Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr

180 185 190

Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr

30 195 200 205

Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser

210 215 220

35

Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly

225 230 235 240

40

Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala

245 250 255

45 Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg Thr Phe Gly Gln

260 265 270

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Thr Ser Thr Ser Gly

50 275 280 285

Arg Ser Ala Asn Pro Arg Gly Ala Pro Ser Val Phe Ile Phe Pro Pro

290 295 300

5 Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu

305 310 315 320

Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn

10 325 330 335

Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser

340 345 350

15

Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala

355 360 365

20

Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly

370 375 380

25 Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

385 390 395

<210> 333

30 <211> 398

<212>PRT

<213> Artificial Sequence

<220>

35 <223> an artificially synthesized sequence

<400> 333

Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr

40 1 5 10 15

Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe

20 25 30

45

Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr

35 40 45

50

Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu

50 55 60

Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu

65 70 75 80

5

Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn

85 90 95

10

Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala

100 105 110

15 Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg

115 120 125

Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly

20 130 135 140

Gln Phe Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

145 150 155 160

25

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu

165 170 175

thirty

Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr

180 185 190

35 Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr

195 200 205

Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser

40 210 215 220

Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly

225 230 235 240

45

Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala

245 250 255

50

Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg Thr Phe Gly Gln

260 265 270

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Thr Ser Thr Ser

275 280 285

5

Gly Arg Ser Ala Asn Pro Arg Gly Pro Ser Val Phe Ile Phe Pro Pro

290 295 300

10

Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu

305 310 315 320

15 Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn

325 330 335

Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser

20 340 345 350

Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala

355 360 365

25

Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly

370 375 380

thirty

Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

385 390 395

35 <210> 334

<211> 398

<212>PRT

<213> Artificial Sequence

40 <220>

<223> an artificially synthesized sequence

<400> 334

45 Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr

1 5 10 15

Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe

50 20 25 30

Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr

35 40 45

5 Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu

50 55 60

Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu

10 65 70 75 80

Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn

85 90 95

15

Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala

100 105 110

20

Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg

115 120 125

25 Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly

130 135 140

Gln Phe Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

30 145 150 155 160

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu

165 170 175

35

Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr

180 185 190

40

Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr

195 200 205

45 Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser

210 215 220

Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly

50 225 230 235 240

Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala

245 250 255

5 Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg Thr Phe Gly Gln

260 265 270

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Thr Ser Thr

10 275 280 285

Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Val Phe Ile Phe Pro Pro

290 295 300

15

Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu

305 310 315 320

20

Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn

325 330 335

25 Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser

340 345 350

Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala

30 355 360 365

Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly

370 375 380

35

Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

385 390 395

40

<210> 335

<400> 335

000

45

<210> 336

<400> 336

000

50

<210> 337

000

<210> 338

5

<400> 338

000

<210> 339

10

<400> 339

000

<210> 340

15

<400> 340

000

<210> 341

20

<400> 341

000

<210> 342

25

<400> 342

000

<210> 343

thirty

<400> 343

000

<210> 344

35

<400> 344

000

<210> 345

40 <211> 12

<212>PRT

<213> Artificial Sequence

<220>

45 <223> an artificially synthesized sequence

<400> 345

Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

50 1 5 10

<400> 346

000

5

<210> 347

<400> 347

000

10

<210> 348

<400> 348

000

15

<210> 349

<400> 349

000

20

<210> 350

<400> 350

000

25

<210> 351

<400> 351

000

thirty

<210> 352

<400> 352

000

35

<210> 353

<400> 353

000

40

<210> 354

<400> 354

000

45

<210> 355

<400> 355

000

50

<210> 356

<211> 464

<212>PRT

<213> Artificial Sequence

<220>

5 <223> an artificially synthesized sequence

<400> 356

Gln Met Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

10 1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Asn Asn

20 25 30

15

Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

20

Ala Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val

50 55 60

25 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Glu Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys

30 85 90 95

Ala Arg Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp

100 105 110

35

Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Thr Ser Thr Ser

115 120 125

40

Gly Arg Ser Ala Asn Pro Arg Gly Ala Ser Thr Lys Gly Pro Ser Val

130 135 140

45 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

145 150 155 160

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

50 165 170 175

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

180 185 190

5 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

195 200 205

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

10 210 215 220

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp

225 230 235 240

15

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly

245 250 255

20

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

260 265 270

25 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

275 280 285

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

30 290 295 300

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

305 310 315 320

35

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

325 330 335

40

Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu

340 345 350

45 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

355 360 365

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

50 370 375 380

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

385 390 395 400

5 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

405 410 415

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

10 420 425 430

Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His

435 440 445

15

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455 460

20

<210> 357

<400> 357

000

25

<210> 358

<400> 358

000

thirty

<210> 359

<400> 359

000

35

<210> 360

<400> 360

000

40

<210> 361

<400> 361

000

45

<210> 362

<400> 362

000

50

<210> 363

<400> 363

000

<210> 364

5

<400> 364

000

<210> 365

10

<400> 365

000

<210> 366

15

<400> 366

000

<210> 367

20 <211> 474

<212>PRT

<213> Artificial Sequence

<220>

25 <223> an artificially synthesized sequence

<400> 367

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

30 1 5 10 15

Ser Val Thr Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Phe

20 25 30

35

Ser Ile Thr Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

40

Gly Glu Ile Thr Pro Met Phe Gly Ile Ala Asn Tyr Ala Gln Lys Phe

50 55 60

45 Gln Gly Arg Val Thr Ile Ser Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Gly Leu Thr Ser Glu Asp Thr Ala Met Tyr Tyr Cys

50 85 90 95

Ala Arg Asp Gly Arg Phe Asp Val Ser Asp Leu Leu Thr Asp Lys Pro

100 105 110

5 Lys Val Thr Ile Asn Tyr Asn Gly Met Asp Val Trp Gly Gln Gly Thr

115 120 125

Thr Val Thr Val Ser Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro

10 130 135 140

Arg Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser

145 150 155 160

15

Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys

165 170 175

20

Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu

180 185 190

25 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu

195 200 205

Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr

30 210 215 220

Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val

225 230 235 240

35

Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro

245 250 255

40

Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu Phe

260 265 270

45 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val

275 280 285

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe

50 290 295 300

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

305 310 315 320

5 Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

325 330 335

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

10 340 345 350

Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala

355 360 365

15

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg

370 375 380

20

Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

385 390 395 400

25 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

405 410 415

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

30 420 425 430

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu

435 440 445

35

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

450 455 460

40

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

465 470

45 <210> 368

<211> 462

<212>PRT

<213> Artificial Sequence

50 <220>

<223> an artificially synthesized sequence

<400> 368

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

5

Ser Val Thr Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Phe

20 25 30

10

Ser Ile Thr Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

15 Gly Glu Ile Thr Pro Met Phe Gly Ile Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Ser Ala Asp Glu Ser Thr Ser Thr Ala Tyr

20 65 70 75 80

Met Glu Leu Ser Gly Leu Thr Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

25

Ala Arg Asp Gly Arg Phe Asp Val Ser Asp Leu Leu Thr Asp Lys Pro

100 105 110

thirty

Lys Val Thr Ile Asn Tyr Asn Gly Met Asp Val Trp Gly Gln Gly Thr

115 120 125

35 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro

130 135 140

Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly

40 145 150 155 160

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn

165 170 175

45

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln

180 185 190

50

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser

195 200 205

Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser

210 215 220

5

Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr

225 230 235 240

10

His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser

245 250 255

15 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

260 265 270

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro

20 275 280 285

Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

290 295 300

25

Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val

305 310 315 320

thirty

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

325 330 335

35 Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr

340 345 350

Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu

40 355 360 365

Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

370 375 380

45

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

385 390 395 400

50

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

405 410 415

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser

420 425 430

5

Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

435 440 445

10

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455 460

15 <210> 369

<211> 216

<212>PRT

<213> Artificial Sequence

20 <220>

<223> an artificially synthesized sequence

<400> 369

25 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn

30 20 25 30

Thr Val Asn Trp Tyr Gln Arg Leu Pro Gly Ala Ala Pro Gln Leu Leu

35 40 45

35

Ile Tyr Asn Asn Asp Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser

50 55 60

40

Gly Ser Lys Ser Gly Thr Ser Gly Ser Leu Val Ile Ser Gly Leu Gln

65 70 75 80

45 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Asp Asp Ser Leu

85 90 95

Asn Gly Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln

50 100 105 110

Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu

115 120 125

5 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr

130 135 140

Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys

10 145 150 155 160

Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr

165 170 175

15

Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His

180 185 190

20

Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys

195 200 205

25 Thr Val Ala Pro Thr Glu Cys Ser

210 215

<210> 370

30 <211> 77

<212>PRT

<213> Artificial Sequence

<220>

35 <223> an artificially synthesized sequence

<400> 370

Val Pro Leu Ser Arg Thr Val Arg Cys Thr Cys Ile Ser Ile Ser Asn

40 1 5 10 15

Gln Pro Val Asn Pro Arg Ser Leu Glu Lys Leu Glu Ile Ile Pro Ala

20 25 30

45

Ser Gln Phe Cys Pro Arg Val Glu Ile Ile Ala Thr Met Lys Lys Lys

35 40 45

50

Gly Glu Lys Arg Cys Leu Asn Pro Glu Ser Lys Ala Ile Lys Asn Leu

50 55 60

Leu Lys Ala Val Ser Lys Glu Arg Ser Lys Ala Ser Pro

65 70 75

5

<210> 371

<211> 302

<212>PRT

10 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15 <400> 371

Val Pro Leu Ser Arg Thr Val Arg Cys Thr Cys Ile Ser Ile Ser Asn

1 5 10 15

20

Gln Pro Val Asn Pro Arg Ser Leu Glu Lys Leu Glu Ile Ile Pro Ala

20 25 30

25 Ser Gln Phe Cys Pro Arg Val Glu Ile Ile Ala Thr Met Lys Lys Lys

35 40 45

Gly Glu Lys Arg Cys Leu Asn Pro Glu Ser Lys Ala Ile Lys Asn Leu

30 50 55 60

Leu Lys Ala Val Ser Lys Glu Arg Ser Lys Ala Ser Pro Gly Gly Gly

65 70 75 80

35

Gly Ser Gly Gly Gly Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala

85 90 95

40

Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser

100 105 110

45 Ser Asn Ile Gly Ser Asn Thr Val Asn Trp Tyr Gln Arg Leu Pro Gly

115 120 125

Ala Ala Pro Gln Leu Leu Ile Tyr Asn Asn Asp Gln Arg Pro Ser Gly

50 130 135 140

Ile Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Gly Ser Leu

145 150 155 160

5 Val Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala

165 170 175

Ser Trp Asp Asp Ser Leu Asn Gly Arg Val Phe Gly Gly Gly Thr Lys

10 180 185 190

Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe

195 200 205

15

Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys

210 215 220

20

Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala

225 230 235 240

25 Asp Ser Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys

245 250 255

Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro

30 260 265 270

Glu Gln Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu

275 280 285

35

Gly Ser Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

290 295 300

40

<210> 372

<400> 372

000

45

<210> 373

<211> 85

<212>PRT

<213> Artificial Sequence

50

<220>

<223> an artificially synthesized sequence

<400> 373

Val Pro Leu Ser Arg Thr Val Arg Cys Thr Cys Ile Ser Ile Ser Asn

5 1 5 10 15

Gln Pro Val Asn Pro Arg Ser Leu Glu Lys Leu Glu Ile Ile Pro Ala

20 25 30

10

Ser Gln Phe Cys Pro Arg Val Glu Ile Ile Ala Thr Met Lys Lys Lys

35 40 45

15

Gly Glu Lys Arg Cys Leu Asn Pro Glu Ser Lys Ala Ile Lys Asn Leu

50 55 60

20 Leu Lys Ala Val Ser Lys Glu Arg Ser Lys Ala Ser Pro His His His

65 70 75 80

His His His His

25 85

<210> 374

<211> 5

30 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

35

<400> 374

Ser Phe Ser Ile Thr

15

40

<210> 375

<211> 17

<212>PRT

45 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

50 <400> 375

Glu Ile Thr Pro Met Phe Gly Ile Ala Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

5

<210> 376

<211> 25

10 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15

<400> 376

Asp Gly Arg Phe Asp Val Ser Asp Leu Leu Thr Asp Lys Pro Lys Val

1 5 10 15

20

Thr Ile Asn Tyr Asn Gly Met Asp Val

20 25

25

<210> 377

<211> 13

<212>PRT

<213> Artificial Sequence

thirty

<220>

<223> an artificially synthesized sequence

<400> 377

35

Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Thr Val Asn

1 5 10

40 <210> 378

<211> 7

<212>PRT

<213> Artificial Sequence

45 <220>

<223> an artificially synthesized sequence

<400> 378

50 Asn Asn Asp Gln Arg Pro Ser

15

<210> 379

<211> 11

<212>PRT

5 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

10 <400> 379

Ala Ser Trp Asp Asp Ser Leu Asn Gly Arg Val

1 5 10

15

<210> 380

<211> 5

<212>PRT

<213> Artificial Sequence

20

<220>

<223> an artificially synthesized sequence

<400> 380

25

Asn Asn Gly Met His

15

30 <210> 381

<211> 17

<212>PRT

<213> Artificial Sequence

35 <220>

<223> an artificially synthesized sequence

<400> 381

40 Val Ile Trp Phe Asp Gly Met Asn Lys Phe Tyr Val Asp Ser Val Lys

1 5 10 15

Gly

45

<210> 382

<211> 15

50 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

<400> 382

5

Glu Gly Asp Gly Ser Gly Ile Tyr Tyr Tyr Tyr Gly Met Asp Val

1 5 10 15

10 <210> 383

<211> 12

<212>PRT

<213> Artificial Sequence

15 <220>

<223> an artificially synthesized sequence

<400> 383

20 Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala

1 5 10

<210> 384

25 <211> 7

<212>PRT

<213> Artificial Sequence

<220>

30 <223> an artificially synthesized sequence

<400> 384

Gly Ala Ser Ser Arg Ala Thr

35 1 5

<210> 385

<211> 10

40 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

45

<400> 385

Gln Gln Tyr Gly Ser Ser Pro Ile Phe Thr

1 5 10

50

<210> 386

<211> 5

<212>PRT

<213> Artificial Sequence

5 <220>

<223> an artificially synthesized sequence

<400> 386

10 Thr Tyr Trp Leu Gly

15

<210> 387

15 <211> 17

<212>PRT

<213> Artificial Sequence

<220>

20 <223> an artificially synthesized sequence

<400> 387

Ile Met Ser Pro Val Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe Gln

25 1 5 10 15

Gly

thirty

<210> 388

<211> 10

<212>PRT

35 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

40 <400> 388

Arg Arg Pro Gly Gln Gly Tyr Phe Asp Phe

1 5 10

45

<210> 389

<211> 11

<212>PRT

<213> Artificial Sequence

50

<220>

<223> an artificially synthesized sequence

<400> 389

Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala

5 1 5 10

<210> 390

<211> 7

10 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15

<400> 390

Ala Ala Ser Ser Leu Gln Ser

15

20

<210> 391

<211> 9

<212>PRT

25 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

30 <400> 391

Gln Gln Tyr Asn Ile Tyr Pro Tyr Thr

15

35

<210> 392

<211> 5

<212>PRT

<213> Artificial Sequence

40

<220>

<223> an artificially synthesized sequence

<400> 392

45

Asn Ser Gly Met His

15

50 <210> 393

<211> 17

<212>PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

5

<400> 393

Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

10

Gly

15

<210> 394

<211> 4

<212>PRT

<213> Artificial Sequence

20

<220>

<223> an artificially synthesized sequence

<400> 394

25

Asn Asp Asp Tyr

1

30 <210> 395

<211> 11

<212>PRT

<213> Artificial Sequence

35 <220>

<223> an artificially synthesized sequence

<400> 395

40 Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala

1 5 10

<210> 396

45 <211> 7

<212>PRT

<213> Artificial Sequence

<220>

50 <223> an artificially synthesized sequence

<400> 396

Asp Ala Ser Asn Arg Ala Thr

15

5

<210> 397

<211> 9

<212>PRT

<213> Artificial Sequence

10

<220>

<223> an artificially synthesized sequence

<400> 397

15

Gln Gln Ser Ser Asn Trp Pro Arg Thr

15

20 <210> 398

<211> 6

<212>PRT

<213> Artificial Sequence

25 <220>

<223> an artificially synthesized sequence

<400> 398

30 Ser Asp His Ala Trp Ser

15

<210> 399

35 <211> 16

<212>PRT

<213> Artificial Sequence

<220>

40 <223> an artificially synthesized sequence

<400> 399

Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser

45 1 5 10 15

<210> 400

<211> 10

50 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

<400> 400

5

Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr

1 5 10

10 <210> 401

<211> 11

<212>PRT

<213> Artificial Sequence

15 <220>

<223> an artificially synthesized sequence

<400> 401

20 Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn

1 5 10

<210> 402

25 <211> 7

<212>PRT

<213> Artificial Sequence

<220>

30 <223> an artificially synthesized sequence

<400> 402

Tyr Thr Ser Arg Leu His Ser

35 1 5

<210> 403

<211> 9

40 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

45

<400> 403

Gln Gln Gly Asn Thr Leu Pro Tyr Thr

15

50

<210> 404

<211> 459

<212>PRT

<213> Artificial Sequence

5 <220>

<223> an artificially synthesized sequence

<400> 404

10 Gln Val Gln Leu Gln Glu Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn

1 5 10 15

Pro Arg Gly Gly Pro Gly Leu Val Arg Pro Ser Gln Thr Leu Ser Leu

15 20 25 30

Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser

35 40 45

20

Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

25

Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

30 Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

35 100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

40

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

45

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

50 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

5

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

10 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

15 225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

20

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

25

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

30 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

35 305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

40

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

45

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

50 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

5

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

10 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

15 435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

20

<210> 405

<211> 459

<212>PRT

25 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

30 <400> 405

Gln Val Gln Leu Gln Glu Ser Gly Thr Ser Thr Ser Gly Arg Ser Ala

1 5 10 15

35

Asn Pro Arg Gly Pro Gly Leu Val Arg Pro Ser Gln Thr Leu Ser Leu

20 25 30

40 Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser

35 40 45

Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

45 50 55 60

Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

50

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

5 100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

10

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

15

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

20 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

25 180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

thirty

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

35

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

40 Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

45 260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

50

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

5 305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

10

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

15

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

20 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

25 385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

thirty

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

35

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

40 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 406

45 <211> 459

<212>PRT

<213> Artificial Sequence

<220>

50 <223> an artificially synthesized sequence

<400> 406

Gln Val Gln Leu Gln Glu Ser Gly Pro Thr Ser Thr Ser Gly Arg Ser

1 5 10 15

5

Ala Asn Pro Arg Gly Gly Leu Val Arg Pro Ser Gln Thr Leu Ser Leu

20 25 30

10 Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser

35 40 45

Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

15 50 55 60

Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

20

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

25

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

30 Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

35 130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

40

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

45

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

50 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

5

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

10 Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

15 260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

20

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

25

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

30 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

35 340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

40

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

45

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

50 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

5

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

10 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 407

15 <211> 459

<212>PRT

<213> Artificial Sequence

<220>

20 <223> an artificially synthesized sequence

<400> 407

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Thr Ser Thr Ser Gly Arg

25 1 5 10 15

Ser Ala Asn Pro Arg Gly Leu Val Arg Pro Ser Gln Thr Leu Ser Leu

20 25 30

thirty

Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser

35 40 45

35

Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

40 Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

45 85 90 95

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

50

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

5 130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

10

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

15

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

20 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

25 210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

thirty

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

35

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

40 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

45 290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

50

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

5 340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

10

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

15

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

20 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

25 420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

thirty

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

35

<210> 408

<211> 459

<212>PRT

<213> Artificial Sequence

40

<220>

<223> an artificially synthesized sequence

<400> 408

45

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Thr Ser Thr Ser Gly

1 5 10 15

50 Arg Ser Ala Asn Pro Arg Gly Val Arg Pro Ser Gln Thr Leu Ser Leu

20 25 30

Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser

35 40 45

5

Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

10 Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

15 85 90 95

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

20

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

25

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

30 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

35 165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

40

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

45

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

50 Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

5

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

10 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

15 290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

20

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

25

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

30 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

35 370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

40

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

45

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

50 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

5

<210> 409

<211> 459

<212>PRT

<213> Artificial Sequence

10

<220>

<223> an artificially synthesized sequence

<400> 409

15

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Thr Ser Thr Ser

1 5 10 15

20 Gly Arg Ser Ala Asn Pro Arg Gly Arg Pro Ser Gln Thr Leu Ser Leu

20 25 30

Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser

25 35 40 45

Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

thirty

Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

35

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

40 Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

45 115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

50

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

5 165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

10

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

15

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

20 Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

25 245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

thirty

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

35

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

40 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

45 325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

50

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

5 370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

10

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

15

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

20 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

25 450 455

<210> 410

<211> 459

30 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

35

<400> 410

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Thr Ser Thr

1 5 10 15

40

Ser Gly Arg Ser Ala Asn Pro Arg Gly Pro Ser Gln Thr Leu Ser Leu

20 25 30

45

Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser

35 40 45

50 Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

5

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

10 Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

15 115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

20

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

25

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

30 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

35 195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

40

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

45

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

50 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

5

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

10 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

15 325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

20

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

25

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

30 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

35 405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

40

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

45

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

50 <210> 411

<211> 459

<212>PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

5

<400> 411

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Thr Ser

1 5 10 15

10

Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Gln Thr Leu Ser Leu

20 25 30

15

Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser

35 40 45

20 Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

25 65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

thirty

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

35

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

40 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

45 145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

50

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

5 195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

10

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

15

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

20 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

25 275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

thirty

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

35

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

40 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

45 355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

50

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

5 405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

10

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

15

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

20 <210> 412

<211> 459

<212>PRT

<213> Artificial Sequence

25 <220>

<223> an artificially synthesized sequence

<400> 412

30 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Thr

1 5 10 15

Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Gln Thr Leu Ser Leu

35 20 25 30

Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser

35 40 45

40

Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

45

Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

50 Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

5

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

10 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

15 145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

20

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

25

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

30 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

35 225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

40

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

45

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

50 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

5

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

10 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

15 355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

20

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

25

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

30 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

35 435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

40

<210> 413

<211> 459

<212>PRT

45 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

50 <400> 413

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

5 20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Thr Ser Thr Ser Gly Arg Ser

35 40 45

10

Ala Asn Pro Arg Gly Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

15

Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

20 Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

25 100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

thirty

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

35

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

40 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

45 180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

50

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

5 225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

10

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

15

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

20 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

25 305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

thirty

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

35

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

40 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

45 385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

50

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

5 435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

10

<210> 414

<211> 459

<212>PRT

15 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

20 <400> 414

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

25

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

30 His Ala Trp Ser Trp Val Arg Gln Pro Pro Thr Ser Thr Ser Gly Arg

35 40 45

Ser Ala Asn Pro Arg Gly Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

35 50 55 60

Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

40

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

45

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

50 Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

5

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

10 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

15 180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

20

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

25

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

30 Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

35 260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

40

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

45

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

50 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

5

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

10 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

15 385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

20

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

25

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

30 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 415

35 <211> 459

<212>PRT

<213> Artificial Sequence

<220>

40 <223> an artificially synthesized sequence

<400> 415

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

45 1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

50

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Thr Ser Thr Ser Gly

35 40 45

Arg Ser Ala Asn Pro Arg Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile

5 50 55 60

Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

10

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

15

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

20 Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

25 130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

thirty

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

35

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

40 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

45 210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

50

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

5 260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

10

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

15

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

20 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

25 340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

thirty

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

35

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

40 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

45 420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

50

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 416

5 <211> 459

<212>PRT

<213> Artificial Sequence

<220>

10 <223> an artificially synthesized sequence

<400> 416

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

15 1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

20

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Thr Ser Thr Ser

35 40 45

25

Gly Arg Ser Ala Asn Pro Arg Gly Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

30 Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

35 85 90 95

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

40

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

45

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

50 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

5

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

10 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

15 210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

20

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

25

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

30 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

35 290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

40

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

45

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

50 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

5

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

10 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

15 420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

20

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

25

<210> 417

<211> 459

<212>PRT

<213> Artificial Sequence

thirty

<220>

<223> an artificially synthesized sequence

<400> 417

35

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

40 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Thr Ser Thr

45 35 40 45

Ser Gly Arg Ser Ala Asn Pro Arg Gly Leu Glu Trp Ile Gly Tyr Ile

50 55 60

50

Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

5 85 90 95

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

10

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

15

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

20 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

25 165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

thirty

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

35

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

40 Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

45 245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

50

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

5 290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

10

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

15

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

20 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

25 370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

thirty

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

35

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

40 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

45 450 455

<210> 418

<211> 459

50 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

<400> 418

5

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

10 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Thr Ser

15 35 40 45

Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Glu Trp Ile Gly Tyr Ile

50 55 60

20

Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

25

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

30 Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

35 115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

40

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

45

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

50 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

5

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

10 Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

15 245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

20

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

25

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

30 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

35 325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

40

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

45

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

50 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

5

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

10 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

15 450 455

<210> 419

<211> 459

20 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

25

<400> 419

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

thirty

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

35

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

40 Ile Gly Tyr Ile Ser Tyr Ser Gly Thr Ser Thr Ser Gly Arg Ser Ala

50 55 60

Asn Pro Arg Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

45 65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

50

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

5 115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

10

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

15

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

20 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

25 195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

thirty

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

35

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

40 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

45 275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

50

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

5 325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

10

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

15

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

20 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

25 405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

thirty

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

35

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

40 <210> 420

<211> 459

<212>PRT

<213> Artificial Sequence

45 <220>

<223> an artificially synthesized sequence

<400> 420

50 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

5

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

10 Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Ser Thr Ser Gly Arg Ser

50 55 60

Ala Asn Pro Arg Gly Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

15 65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

20

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

25

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

30 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

35 145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

40

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

45

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

50 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

5

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

10 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

15 275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

20

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

25

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

30 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

35 355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

40

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

45

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

50 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

5

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

10 <210> 421

<211> 459

<212>PRT

<213> Artificial Sequence

15 <220>

<223> an artificially synthesized sequence

<400> 421

20 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

25 20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

thirty

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Ser Thr Ser Gly Arg

50 55 60

35

Ser Ala Asn Pro Arg Gly Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

40 Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

45 100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

50

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

5 145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

10

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

15

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

20 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

25 225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

thirty

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

35

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

40 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

45 305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

50

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

5 355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

10

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

15

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

20 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

25 435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

thirty

<210> 422

<211> 459

<212>PRT

35 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

40 <400> 422

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

45

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

50 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Thr Ser Thr Ser Gly

50 55 60

5

Arg Ser Ala Asn Pro Arg Gly Tyr Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

10 Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

15 100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

20

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

25

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

30 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

35 180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

40

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

45

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

50 Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

5

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

10 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

15 305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

20

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

25

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

30 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

35 385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

40

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

45

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

50 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 423

<211> 459

<212>PRT

5 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

10 <400> 423

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

20 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Thr Ser Thr Ser

25 50 55 60

Gly Arg Ser Ala Asn Pro Arg Gly Asn Pro Ser Leu Lys Ser Arg Val

65 70 75 80

thirty

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

35

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

40 Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

45 130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

50

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

5 180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

10

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

15

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

20 Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

25 260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

thirty

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

35

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

40 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

45 340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

50

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

5 385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

10

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

15

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

20 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 424

25 <211> 459

<212>PRT

<213> Artificial Sequence

<220>

30 <223> an artificially synthesized sequence

<400> 424

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

35 1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

40

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Thr Ser Thr

50 55 60

50 Ser Gly Arg Ser Ala Asn Pro Arg Gly Pro Ser Leu Lys Ser Arg Val

65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

5

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

10 Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

15 130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

20

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

25

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

30 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

35 210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

40

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

45

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

50 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

5

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

10 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

15 340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

20

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

25

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

30 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

35 420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

40

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

45

<210> 425

<211> 459

<212>PRT

<213> Artificial Sequence

50

<220>

<223> an artificially synthesized sequence

<400> 425

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

5 1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

10

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

15

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Thr Ser

50 55 60

20 Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Leu Lys Ser Arg Val

65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

25 85 90 95

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

thirty

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

35

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

40 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

45 165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

50

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

5 210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

10

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

15

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

20 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

25 290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

thirty

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

35

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

40 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

45 370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

50

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

5 420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

10

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

15

<210> 426

<211> 459

<212>PRT

<213> Artificial Sequence

20

<220>

<223> an artificially synthesized sequence

<400> 426

25

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

30 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Thr

50 55 60

40

Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Leu Lys Ser Arg Val

65 70 75 80

45

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

50 Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

5

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

10 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

15 165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

20

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

25

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

30 Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

35 245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

40

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

45

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

50 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

5

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

10 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

15 370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

20

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

25

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

30 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

35 450 455

<210> 427

<211> 459

40 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

45

<400> 427

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

50

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

5 35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

10

Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Lys Ser Arg Val

65 70 75 80

15

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

20 Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

25 115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

thirty

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

35

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

40 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

45 195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

50

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

5 245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

10

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

15

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

20 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

25 325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

thirty

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

35

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

40 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

45 405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

50

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

5 450 455

<210> 428

<211> 459

10 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15

<400> 428

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

20

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

25

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

30 Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

Lys Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Arg Val

35 65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

40

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

45

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

50 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

5

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

10 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

15 195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

20

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

25

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

30 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

35 275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

40

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

45

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

50 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

5

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

10 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

15 405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

20

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

25

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

30 <210> 429

<211> 459

<212>PRT

<213> Artificial Sequence

35 <220>

<223> an artificially synthesized sequence

<400> 429

40 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

45 20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

50

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Arg Val

5 65 70 75 80

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

10

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

15

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

20 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

25 145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

thirty

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

35

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

40 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

45 225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

50

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

5 275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

10

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

15

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

20 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

25 355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

thirty

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

35

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

40 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

45 435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

50

<210> 430

<211> 459

<212>PRT

<213> Artificial Sequence

5 <220>

<223> an artificially synthesized sequence

<400> 430

10 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

15 20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

20

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

25

Lys Ser Arg Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Val

65 70 75 80

30 Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

35 100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

40

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

45

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

50 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

5

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

10 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

15 225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

20

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

25

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

30 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

35 305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

40

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

45

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

50 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

5

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

10 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

15 435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

20

<210> 431

<211> 459

<212>PRT

25 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

30 <400> 431

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

35

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

40 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

45 50 55 60

Lys Ser Arg Val Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

65 70 75 80

50

Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

5 100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

10

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

15

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

20 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

25 180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

thirty

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

35

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

40 Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

45 260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

50

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

5 305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

10

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

15

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

20 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

25 385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

thirty

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

35

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

40 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 432

45 <211> 459

<212>PRT

<213> Artificial Sequence

<220>

50 <223> an artificially synthesized sequence

<400> 432

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

5

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

10 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

15 50 55 60

Lys Ser Arg Val Thr Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg

65 70 75 80

20

Gly Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

25

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

30 Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

35 130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

40

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

45

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

50 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

5

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

10 Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

15 260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

20

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

25

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

30 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

35 340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

40

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

45

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

50 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

5

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

10 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 433

15 <211> 459

<212>PRT

<213> Artificial Sequence

<220>

20 <223> an artificially synthesized sequence

<400> 433

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

25 1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

thirty

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

35

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

40 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Thr Ser Thr Ser Gly Arg

65 70 75 80

Ser Ala Asn Pro Arg Gly Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser

45 85 90 95

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

50

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

5 130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

10

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

15

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

20 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

25 210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

thirty

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

35

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

40 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

45 290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

50

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

5 340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

10

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

15

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

20 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

25 420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

thirty

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

35

<210> 434

<211> 459

<212>PRT

<213> Artificial Sequence

40

<220>

<223> an artificially synthesized sequence

<400> 434

45

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

50 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

5

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

10 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Thr Ser Thr Ser Gly

65 70 75 80

Arg Ser Ala Asn Pro Arg Gly Lys Asn Gln Phe Ser Leu Arg Leu Ser

15 85 90 95

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

20

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

25

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

30 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

35 165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

40

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

45

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

50 Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

5

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

10 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

15 290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

20

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

25

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

30 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

35 370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

40

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

45

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

50 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

5

<210> 435

<211> 459

<212>PRT

<213> Artificial Sequence

10

<220>

<223> an artificially synthesized sequence

<400> 435

15

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

20 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

25 35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

thirty

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Thr Ser Thr Ser

65 70 75 80

35

Gly Arg Ser Ala Asn Pro Arg Gly Asn Gln Phe Ser Leu Arg Leu Ser

85 90 95

40 Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

45 115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

50

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

5 165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

10

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

15

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

20 Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

25 245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

thirty

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

35

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

40 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

45 325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

50

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

5 370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

10

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

15

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

20 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

25 450 455

<210> 436

<211> 459

30 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

35

<400> 436

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

40

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

45

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

50 Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Thr Ser Thr

65 70 75 80

5

Ser Gly Arg Ser Ala Asn Pro Arg Gly Gln Phe Ser Leu Arg Leu Ser

85 90 95

10 Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

15 115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

20

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

25

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

30 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

35 195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

40

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

45

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

50 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

5

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

10 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

15 325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

20

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

25

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

30 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

35 405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

40

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

45

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

50 <210> 437

<211> 459

<212>PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

5

<400> 437

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

10

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

15

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

20 Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Thr Ser

25 65 70 75 80

Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Phe Ser Leu Arg Leu Ser

85 90 95

thirty

Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

35

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

40 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

45 145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

50

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

5 195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

10

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

15

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

20 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

25 275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

thirty

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

35

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

40 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

45 355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

50

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

5 405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

10

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

15

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

20 <210> 438

<211> 459

<212>PRT

<213> Artificial Sequence

25 <220>

<223> an artificially synthesized sequence

<400> 438

30 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

35 20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

40

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

45

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

50 Leu Arg Leu Ser Ser Val Thr Thr Ser Thr Ser Gly Arg Ser Ala Asn

85 90 95

Pro Arg Gly Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

5

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

10 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

15 145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

20

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

25

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

30 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

35 225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

40

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

45

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

50 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

5

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

10 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

15 355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

20

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

25

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

30 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

35 435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

40

<210> 439

<211> 459

<212>PRT

45 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

50 <400> 439

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

5 20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

10

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

15

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

20 Leu Arg Leu Ser Ser Val Thr Ala Thr Ser Thr Ser Gly Arg Ser Ala

85 90 95

Asn Pro Arg Gly Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

25 100 105 110

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

thirty

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

35

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

40 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

45 180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

50

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

5 225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

10

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

15

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

20 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

25 305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

thirty

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

35

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

40 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

45 385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

50

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

5 435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

10

<210> 440

<211> 459

<212>PRT

15 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

20 <400> 440

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

25

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

30 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

35 50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

40

Leu Arg Leu Ser Ser Val Thr Ala Ala Thr Ser Thr Ser Gly Arg Ser

85 90 95

45

Ala Asn Pro Arg Gly Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu

100 105 110

50 Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

5

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

10 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

15 180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

20

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

25

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

30 Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

35 260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

40

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

45

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

50 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

5

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

10 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

15 385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

20

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

25

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

30 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 441

35 <211> 459

<212>PRT

<213> Artificial Sequence

<220>

40 <223> an artificially synthesized sequence

<400> 441

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

45 1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

50

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

5 50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

10

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

15

Ala Arg Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Leu

100 105 110

20 Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

25 130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

thirty

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

35

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

40 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

45 210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

50

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

5 260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

10

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

15

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

20 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

25 340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

thirty

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

35

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

40 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

45 420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

50

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 442

5 <211> 459

<212>PRT

<213> Artificial Sequence

<220>

10 <223> an artificially synthesized sequence

<400> 442

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

15 1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

20

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

25

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

30 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

35 85 90 95

Ala Arg Ser Leu Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

100 105 110

40

Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

45

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

50 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

5

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

10 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

15 210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

20

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

25

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

30 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

35 290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

40

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

45

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

50 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

5

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

10 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

15 420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

20

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

25

<210> 443

<211> 459

<212>PRT

<213> Artificial Sequence

thirty

<220>

<223> an artificially synthesized sequence

<400> 443

35

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

40 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

45 35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

50

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

5 85 90 95

Ala Arg Ser Leu Ala Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg

100 105 110

10

Gly Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

115 120 125

15

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

20 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

25 165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

thirty

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

35

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

40 Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

45 245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

50

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

5 290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

10

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

15

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

20 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

25 370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

thirty

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

35

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

40 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

45 450 455

<210> 444

<211> 459

50 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

<400> 444

5

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

10 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

15 35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

20

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

25

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

30 Ala Arg Ser Leu Ala Arg Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro

100 105 110

Arg Gly Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr

35 115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

40

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

45

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

50 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

5

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

10 Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

15 245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

20

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

25

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

30 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

35 325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

40

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

45

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

50 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

5

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

10 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

15 450 455

<210> 445

<211> 459

20 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

25

<400> 445

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

thirty

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

35

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

40 Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

45 65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

50

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Thr Ser Thr

100 105 110

Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Gln Gly Ser Leu Val Thr

5 115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

10

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

15

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

20 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

25 195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

thirty

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

35

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

40 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

45 275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

50

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

5 325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

10

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

15

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

20 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

25 405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

thirty

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

35

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

40 <210> 446

<211> 459

<212>PRT

<213> Artificial Sequence

45 <220>

<223> an artificially synthesized sequence

<400> 446

50 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

5

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

10 Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

15 65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

20

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Thr Ser

100 105 110

25

Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Gln Gly Ser Leu Val Thr

115 120 125

30 Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

35 145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

40

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

45

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

50 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

5

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

10 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

15 275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

20

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

25

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

30 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

35 355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

40

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

45

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

50 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

5

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

10 <210> 447

<211> 459

<212>PRT

<213> Artificial Sequence

15 <220>

<223> an artificially synthesized sequence

<400> 447

20 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

25 20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

thirty

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

35

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

40 Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Thr

45 100 105 110

Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Ser Leu Val Thr

115 120 125

50

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

5 145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

10

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

15

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

20 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

25 225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

thirty

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

35

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

40 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

45 305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

50

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

5 355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

10

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

15

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

20 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

25 435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

thirty

<210> 448

<211> 459

<212>PRT

35 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

40 <400> 448

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

45

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

50 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

5

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

10 Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

15 100 105 110

Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Leu Val Thr

115 120 125

20

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

25

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

30 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

35 180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

40

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

45

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

50 Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

5

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

10 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

15 305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

20

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

25

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

30 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

35 385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

40

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

45

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

50 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 449

<211> 459

<212>PRT

5 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

10 <400> 449

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

20 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

25 50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

thirty

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

35

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

40 Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Leu Val Thr

115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

45 130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

50

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

5 180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

10

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

15

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

20 Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

25 260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

thirty

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

35

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

40 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

45 340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

50

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

5 385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

10

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

15

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

20 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 450

25 <211> 459

<212>PRT

<213> Artificial Sequence

<220>

30 <223> an artificially synthesized sequence

<400> 450

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

35 1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

40

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

50 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

5

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

10 Ser Leu Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Val Thr

115 120 125

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

15 130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

20

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

25

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

30 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

35 210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

40

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

45

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

50 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

5

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

10 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

15 340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

20

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

25

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

30 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

35 420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

40

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

45

<210> 451

<211> 459

<212>PRT

<213> Artificial Sequence

50

<220>

<223> an artificially synthesized sequence

<400> 451

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

5 1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

10

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

15

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

20 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

25 85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

thirty

Ser Leu Val Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Thr

115 120 125

35

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

40 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

45 165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

50

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

5 210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

10

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

15

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

20 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

25 290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

thirty

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

35

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

40 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

45 370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

50

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

5 420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

10

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

15

<210> 452

<211> 459

<212>PRT

<213> Artificial Sequence

20

<220>

<223> an artificially synthesized sequence

<400> 452

25

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

30 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

40

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

45

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

50 Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Ser Leu Val Thr Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

115 120 125

5

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

10 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

15 165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

20

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

25

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

30 Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

35 245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

40

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

45

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

50 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

5

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

10 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

15 370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

20

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

25

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

30 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

35 450 455

<210> 453

<211> 459

40 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

45

<400> 453

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

50

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

5 35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

10

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

15

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

20 Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Ser Leu Val Thr Val Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg

25 115 120 125

Gly Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

thirty

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

35

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

40 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

45 195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

50

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

5 245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

10

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

15

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

20 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

25 325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

thirty

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

35

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

40 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

45 405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

50

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

5 450 455

<210> 454

<211> 459

10 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15

<400> 454

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

20

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

25

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

30 Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

35 65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

40

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

45

Ser Leu Val Thr Val Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro

115 120 125

50 Arg Gly Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

5

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

10 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

15 195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

20

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

25

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

30 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

35 275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

40

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

45

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

50 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

5

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

10 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

15 405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

20

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

25

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

30 <210> 455

<211> 459

<212>PRT

<213> Artificial Sequence

35 <220>

<223> an artificially synthesized sequence

<400> 455

40 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

45 20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

50

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

5 65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

10

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

15

Ser Leu Val Thr Val Ser Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn

115 120 125

20 Pro Arg Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

25 145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

thirty

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

35

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

40 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

45 225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

50

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

5 275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

10

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

15

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

20 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

25 355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

thirty

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

35

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

40 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

45 435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

50

<210> 456

<211> 459

<212>PRT

<213> Artificial Sequence

5 <220>

<223> an artificially synthesized sequence

<400> 456

10 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

15 20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

20

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

25

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

30 Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

35 100 105 110

Ser Leu Val Thr Val Ser Ser Ala Thr Ser Thr Ser Gly Arg Ser Ala

115 120 125

40

Asn Pro Arg Gly Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

45

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

50 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

5

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

10 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

15 225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

20

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

25

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

30 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

35 305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

40

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

45

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

50 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

5

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

10 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

15 435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

20

<210> 457

<211> 459

<212>PRT

25 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

30 <400> 457

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

35

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

40 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

45 50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

50

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

5 100 105 110

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Ser Thr Ser Gly Arg Ser

115 120 125

10

Ala Asn Pro Arg Gly Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

15

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

20 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

25 180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

thirty

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

35

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

40 Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

45 260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

50

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

5 305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

10

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

15

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

20 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

25 385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

thirty

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

35

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

40 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 458

45 <211> 459

<212>PRT

<213> Artificial Sequence

<220>

50 <223> an artificially synthesized sequence

<400> 458

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

5

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

10 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

15 50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

20

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

25

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

30 Ser Leu Val Thr Val Ser Ser Ala Ser Thr Thr Ser Thr Ser Gly Arg

115 120 125

Ser Ala Asn Pro Arg Gly Lys Gly Pro Ser Val Phe Pro Leu Ala Pro

35 130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

40

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

45

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

50 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

5

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

10 Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

15 260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

20

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

25

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

30 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

35 340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

40

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

45

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

50 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

5

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

10 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 459

15 <211> 459

<212>PRT

<213> Artificial Sequence

<220>

20 <223> an artificially synthesized sequence

<400> 459

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

25 1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

thirty

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

35

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

40 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

45 85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

50

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Thr Ser Thr Ser Gly

115 120 125

Arg Ser Ala Asn Pro Arg Gly Gly Pro Ser Val Phe Pro Leu Ala Pro

5 130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

10

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

15

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

20 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

25 210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

thirty

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

35

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

40 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

45 290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

50

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

5 340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

10

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

15

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

20 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

25 420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

thirty

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

35

<210> 460

<211> 459

<212>PRT

<213> Artificial Sequence

40

<220>

<223> an artificially synthesized sequence

<400> 460

45

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

50 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

5

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

10 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

15 85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

20

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Thr Ser Thr Ser

115 120 125

25

Gly Arg Ser Ala Asn Pro Arg Gly Pro Ser Val Phe Pro Leu Ala Pro

130 135 140

30 Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

35 165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

40

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

45

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

50 Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

5

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

10 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

15 290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

20

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

25

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

30 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

35 370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

40

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

45

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

50 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

5

<210> 461

<211> 459

<212>PRT

<213> Artificial Sequence

10

<220>

<223> an artificially synthesized sequence

<400> 461

15

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

20 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

25 35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

thirty

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

35

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

40 Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Thr Ser Thr

45 115 120 125

Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Val Phe Pro Leu Ala Pro

130 135 140

50

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

5 165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

10

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

15

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

20 Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

25 245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

thirty

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

35

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

40 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

45 325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

50

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

5 370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

10

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

15

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

20 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

25 450 455

<210> 462

<211> 459

30 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

35

<400> 462

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

40

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

45

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

50 Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

5

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

10 Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Thr Ser

15 115 120 125

Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Val Phe Pro Leu Ala Pro

130 135 140

20

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

25

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

30 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

35 195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

40

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

45

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

50 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

5

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

10 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

15 325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

20

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

25

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

30 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

35 405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

40

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

45

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

50 <210> 463

<211> 459

<212>PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

5

<400> 463

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

10

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

15

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

20 Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

25 65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

thirty

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

35

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

40 Pro Leu Ala Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Pro

130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

45 145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

50

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

5 195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

10

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

15

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

20 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

25 275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

thirty

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

35

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

40 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

45 355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

50

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

5 405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

10

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

15

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

20 <210> 464

<211> 459

<212>PRT

<213> Artificial Sequence

25 <220>

<223> an artificially synthesized sequence

<400> 464

30 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

35 20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

40

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

45

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

50 Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

5

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

10 Pro Leu Ala Pro Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

130 135 140

Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

15 145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

20

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

25

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

30 Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

35 225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

40

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

45

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

50 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

5

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

10 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

15 355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

20

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

25

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

30 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

35 435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

40

<210> 465

<211> 459

<212>PRT

45 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

50 <400> 465

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

5 20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

10

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

15

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

20 Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

25 100 105 110

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

thirty

Pro Leu Ala Pro Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg

130 135 140

35

Gly Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

40 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

45 180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

50

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

5 225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

10

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

15

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

20 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

25 305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

thirty

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

35

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

40 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

45 385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

50

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

5 435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

10

<210> 466

<211> 459

<212>PRT

15 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

20 <400> 466

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

25

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

30 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

35 50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

40

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

45

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

50 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 Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro

130 135 140

5

Arg Gly Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

10 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

15 180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

20

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

25

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

30 Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

35 260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

40

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

45

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

50 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

5

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

10 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

15 385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

20

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

25

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

30 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 467

35 <211> 459

<212>PRT

<213> Artificial Sequence

<220>

40 <223> an artificially synthesized sequence

<400> 467

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

45 1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

50

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

5 50 55 60

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

10

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

15

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

20 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 Thr Ser Gly Arg Ser Ala

25 130 135 140

Asn Pro Arg Gly Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

thirty

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

35

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

40 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

45 210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

50

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

5 260 265 270

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

10

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

15

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

20 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

25 340 345 350

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

thirty

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

35

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

40 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

45 420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

50

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

<210> 468

5 <211> 459

<212>PRT

<213> Artificial Sequence

<220>

10 <223> an artificially synthesized sequence

<400> 468

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

15 1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

20

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

35 40 45

25

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

30 Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

35 85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

40

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

45

Pro Leu Ala Pro Ser Ser Lys Ser Thr Thr Ser Thr Ser Gly Arg Ser

130 135 140

50 Ala Asn Pro Arg Gly Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

5

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

10 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

15 210 215 220

Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

20

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

245 250 255

25

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

30 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

35 290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

40

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

45

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

50 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

5

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

10 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

15 420 425 430

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

20

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

450 455

25

<210> 469

<211> 459

<212>PRT

<213> Artificial Sequence

thirty

<220>

<223> an artificially synthesized sequence

<400> 469

35

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

40 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

45 35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

50

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

5 85 90 95

Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

10

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

15

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Thr Ser Thr Ser Gly

130 135 140

20 Arg Ser Ala Asn Pro Arg Gly Gly Thr Ala Ala Leu Gly Cys Leu Val

145 150 155 160

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

25 165 170 175

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

thirty

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

35

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

40 Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

45 245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

50

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

5 290 295 300

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

10

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

325 330 335

15

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

20 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

25 370 375 380

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

thirty

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

35

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

40 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

45 450 455

<210> 470

<211> 459

50 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

<400> 470

5

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln

1 5 10 15

10 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp

20 25 30

His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp

15 35 40 45

Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu

50 55 60

20

Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

25

Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys

85 90 95

30 Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

35 115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Thr Ser Thr

130 135 140

40

Ser Gly Arg Ser Ala Asn Pro Arg Gly Ala Ala Leu Gly Cys Leu Val

145 150 155 160

45

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala

165 170 175

50 Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly

180 185 190

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly

195 200 205

5

Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys

210 215 220

10 Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

225 230 235 240

Pro Pro Cys Pro Ala Pro Glu Leu Arg Arg Gly Pro Ser Val Phe Leu

15 245 250 255

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

260 265 270

20

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

275 280 285

25

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

290 295 300

30 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

305 310 315 320

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

35 325 330 335

Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys

340 345 350

40

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

355 360 365

45

Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

370 375 380

50 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

385 390 395 400

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

405 410 415

5

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

420 425 430

10 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

435 440 445

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

15 450 455

<210> 471

<211> 226

20 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

25

<400> 471

Asp Ile Gln Met Thr Gln Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn

1 5 10 15

thirty

Pro Arg Gly Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr

20 25 30

35

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

35 40 45

40 Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

45 65 70 75 80

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

50

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

5 115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

10

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

15

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

20 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

25 195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

thirty

Glu Cys

225

35

<210> 472

<211> 226

<212>PRT

<213> Artificial Sequence

40

<220>

<223> an artificially synthesized sequence

<400> 472

45

Asp Ile Gln Met Thr Gln Ser Pro Thr Ser Thr Ser Gly Arg Ser Ala

1 5 10 15

50 Asn Pro Arg Gly Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr

20 25 30

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

35 40 45

5

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

10 Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

15 85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

20

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

25

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

30 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

35 165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

40

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

45

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

50 Glu Cys

225

<210> 473

<211> 226

<212>PRT

5 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

10 <400> 473

Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Ser Thr Ser Gly Arg Ser

1 5 10 15

15

Ala Asn Pro Arg Gly Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr

20 25 30

20 Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

35 40 45

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

25 50 55 60

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

thirty

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

35

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

40 Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

45 130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

50

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

5 180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

10

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

15

Glu Cys

225

20 <210> 474

<211> 226

<212>PRT

<213> Artificial Sequence

25 <220>

<223> an artificially synthesized sequence

<400> 474

30 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Thr Ser Thr Ser Gly Arg

1 5 10 15

Ser Ala Asn Pro Arg Gly Leu Ser Ala Ser Val Gly Asp Arg Val Thr

35 20 25 30

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

35 40 45

40

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

45

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

50 Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

5

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

10 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

15 145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

20

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

25

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

30 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

Glu Cys

35 225

<210> 475

<211> 226

40 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

45

<400> 475

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Thr Ser Thr Ser Gly

1 5 10 15

50

Arg Ser Ala Asn Pro Arg Gly Ser Ala Ser Val Gly Asp Arg Val Thr

20 25 30

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

5 35 40 45

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

10

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

15

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

20 Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

25 115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

thirty

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

35

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

40 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

45 195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

50

Glu Cys

225

<210> 476

5 <211> 226

<212>PRT

<213> Artificial Sequence

<220>

10 <223> an artificially synthesized sequence

<400> 476

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser Thr Ser

15 1 5 10 15

Gly Arg Ser Ala Asn Pro Arg Gly Ala Ser Val Gly Asp Arg Val Thr

20 25 30

20

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

35 40 45

25

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

30 Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

35 85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

40

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

45

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

50 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

5

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

10 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

15 210 215 220

Glu Cys

225

20

<210> 477

<211> 226

<212>PRT

25 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

30 <400> 477

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Thr Ser Thr

1 5 10 15

35

Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Val Gly Asp Arg Val Thr

20 25 30

40 Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

35 40 45

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

45 50 55 60

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

50

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

5 100 105 110

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

10

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

15

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

20 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

25 180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

thirty

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

35

Glu Cys

225

40 <210> 478

<211> 226

<212>PRT

<213> Artificial Sequence

45 <220>

<223> an artificially synthesized sequence

<400> 478

50 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Thr Ser

1 5 10 15

Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Val Gly Asp Arg Val Thr

20 25 30

5

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

35 40 45

10 Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

15 65 70 75 80

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

20

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

25

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

30 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

35 145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

40

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

45

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

50 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

Glu Cys

225

5

<210> 479

<211> 226

<212>PRT

<213> Artificial Sequence

10

<220>

<223> an artificially synthesized sequence

<400> 479

15

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Thr

1 5 10 15

20 Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Asp Arg Val Thr

20 25 30

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

25 35 40 45

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

thirty

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

35

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

40 Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

45 115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

50

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

5 165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

10

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

15

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

20 Glu Cys

225

<210> 480

25 <211> 226

<212>PRT

<213> Artificial Sequence

<220>

30 <223> an artificially synthesized sequence

<400> 480

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

35 1 5 10 15

Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Asp Arg Val Thr

20 25 30

40

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

35 40 45

45

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

50 Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

5

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

10 Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

15 130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

20

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

25

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

30 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

35 210 215 220

Glu Cys

225

40

<210> 481

<211> 226

<212>PRT

45 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

50 <400> 481

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Arg Val Thr

5 20 25 30

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

35 40 45

10

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

15

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

20 Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

25 100 105 110

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

thirty

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

35

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

40 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

45 180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

50

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

Glu Cys

5 225

<210> 482

<211> 226

10 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15

<400> 482

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

20

Asp Arg Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Val Thr

20 25 30

25

Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr

35 40 45

30 Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

35 65 70 75 80

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

40

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

45

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

50 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

5

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

10 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

15 195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

20

Glu Cys

225

25

<210> 483

<211> 226

<212>PRT

<213> Artificial Sequence

thirty

<220>

<223> an artificially synthesized sequence

<400> 483

35

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

40 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Thr Ser Thr Ser Gly Arg Ser Ala Asn

45 35 40 45

Pro Arg Gly Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

50

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

5 85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

10

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

15

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

20 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

25 165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

thirty

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

35

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

40 Glu Cys

225

<210> 484

45 <211> 226

<212>PRT

<213> Artificial Sequence

<220>

50 <223> an artificially synthesized sequence

<400> 484

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

5

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

10 Leu Asn Trp Tyr Gln Gln Lys Pro Thr Ser Thr Ser Gly Arg Ser Ala

35 40 45

Asn Pro Arg Gly Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

15 50 55 60

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

20

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

25

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

30 Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

35 130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

40

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

45

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

50 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

5

Glu Cys

225

10 <210> 485

<211> 226

<212>PRT

<213> Artificial Sequence

15 <220>

<223> an artificially synthesized sequence

<400> 485

20 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

25 20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Thr Ser Thr Ser Gly Arg Ser

35 40 45

thirty

Ala Asn Pro Arg Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

35

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

40 Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

45 100 105 110

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

50

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

5 145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

10

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

15

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

20 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

Glu Cys

25 225

<210> 486

<211> 226

30 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

35

<400> 486

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

40

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

45

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Thr Ser Thr Ser Gly Arg

35 40 45

50 Ser Ala Asn Pro Arg Gly Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

5

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

10 Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

15 115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

20

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

25

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

30 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

35 195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

40

Glu Cys

225

45

<210> 487

<211> 226

<212>PRT

<213> Artificial Sequence

50

<220>

<223> an artificially synthesized sequence

<400> 487

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

5 1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

10

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Thr Ser Thr Ser Gly

35 40 45

15

Arg Ser Ala Asn Pro Arg Gly Pro Lys Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

20 Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

25 85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

thirty

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

35

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

40 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

45 165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

50

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

5 210 215 220

Glu Cys

225

10

<210> 488

<211> 226

<212>PRT

15 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

20 <400> 488

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

25

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Thr Ser Thr Ser

35 40 45

Gly Arg Ser Ala Asn Pro Arg Gly Lys Leu Leu Ile Tyr Tyr Thr Ser

35 50 55 60

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

40

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

45

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

50 Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

5

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

10 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

15 180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

20

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

25

Glu Cys

225

30 <210> 489

<211> 226

<212>PRT

<213> Artificial Sequence

35 <220>

<223> an artificially synthesized sequence

<400> 489

40 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

45 20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Ser Thr

35 40 45

50

Ser Gly Arg Ser Ala Asn Pro Arg Gly Leu Leu Ile Tyr Tyr Thr Ser

50 55 60

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

5 65 70 75 80

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

10

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

15

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

20 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

25 145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

thirty

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

35

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

40 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

Glu Cys

45 225

<210> 490

<211> 226

50 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

<400> 490

5

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

10 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

15 35 40 45

Tyr Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Tyr Thr Ser

50 55 60

20

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

25

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

30 Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

35 115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

40

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

45

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

50 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

5

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

10 Glu Cys

225

<210> 491

15 <211> 226

<212>PRT

<213> Artificial Sequence

<220>

20 <223> an artificially synthesized sequence

<400> 491

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

25 1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

thirty

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

35

Tyr Tyr Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Thr Ser

50 55 60

40 Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

45 85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

50

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

5 130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

10

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

15

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

20 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

25 210 215 220

Glu Cys

225

thirty

<210> 492

<211> 226

<212>PRT

35 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

40 <400> 492

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

45

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

50 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser

50 55 60

5

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

10 Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

15 100 105 110

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

20

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

25

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

30 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

35 180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

40

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

45

Glu Cys

225

50 <210> 493

<211> 226

<212>PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

5

<400> 493

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

10

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

15

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

20 Tyr Tyr Thr Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

50 55 60

Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

25 65 70 75 80

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

thirty

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

35

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

40 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

45 145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

50

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

5 195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

10

Glu Cys

225

15

<210> 494

<211> 226

<212>PRT

<213> Artificial Sequence

20

<220>

<223> an artificially synthesized sequence

<400> 494

25

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

30 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 35 40 45

Tyr Tyr Thr Ser Arg Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg

50 55 60

40

Gly Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

45

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

50 Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

5

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

10 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

15 165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

20

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

25

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

30 Glu Cys

225

<210> 495

35 <211> 226

<212>PRT

<213> Artificial Sequence

<220>

40 <223> an artificially synthesized sequence

<400> 495

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

45 1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

50

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro

5 50 55 60

Arg Gly His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

10

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

15

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

20 Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

25 130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

thirty

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

35

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

40 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

45 210 215 220

Glu Cys

225

50

<210> 496

<211> 226

<212>PRT

<213> Artificial Sequence

5 <220>

<223> an artificially synthesized sequence

<400> 496

10 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

15 20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

20

Tyr Tyr Thr Ser Arg Leu His Thr Ser Thr Ser Gly Arg Ser Ala Asn

50 55 60

25

Pro Arg Gly Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

30 Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

35 100 105 110

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

40

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

45

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

50 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

5

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

10 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

Glu Cys

15 225

<210> 497

<211> 226

20 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

25

<400> 497

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

thirty

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

35

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

40 Tyr Tyr Thr Ser Arg Leu His Ser Thr Ser Thr Ser Gly Arg Ser Ala

50 55 60

Asn Pro Arg Gly Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

45 65 70 75 80

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

50

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

5 115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

10

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

15

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

20 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

25 195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

thirty

Glu Cys

225

35

<210> 498

<211> 226

<212>PRT

<213> Artificial Sequence

40

<220>

<223> an artificially synthesized sequence

<400> 498

45

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

50 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

5

Tyr Tyr Thr Ser Arg Leu His Ser Gly Thr Ser Thr Ser Gly Arg Ser

50 55 60

10 Ala Asn Pro Arg Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

15 85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

20

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

25

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

30 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

35 165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

40

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

45

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

50 Glu Cys

225

<210> 499

<211> 226

<212>PRT

5 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

10 <400> 499

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

20 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Thr Ser Thr Ser Gly Arg

25 50 55 60

Ser Ala Asn Pro Arg Gly Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

thirty

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

35

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

40 Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

45 130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

50

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

5 180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

10

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

15

Glu Cys

225

20 <210> 500

<211> 226

<212>PRT

<213> Artificial Sequence

25 <220>

<223> an artificially synthesized sequence

<400> 500

30 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

35 20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

40

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Thr Ser Thr Ser Gly

50 55 60

45

Arg Ser Ala Asn Pro Arg Gly Ser Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

50 Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

5

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

10 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

15 145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

20

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

25

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

30 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

Glu Cys

35 225

<210> 501

<211> 226

40 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

45

<400> 501

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

50

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

5 35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Thr Ser Thr Ser

50 55 60

10

Gly Arg Ser Ala Asn Pro Arg Gly Arg Phe Ser Gly Ser Gly Ser Gly

65 70 75 80

15

Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala

85 90 95

20 Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln

100 105 110

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

25 115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

thirty

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

35

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

40 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

45 195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

50

Glu Cys

225

<210> 502

5 <211> 226

<212>PRT

<213> Artificial Sequence

<220>

10 <223> an artificially synthesized sequence

<400> 502

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

15 1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

20

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

25

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

30 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

35 85 90 95

Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Thr Phe Gly Gln

100 105 110

40

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

45

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

50 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

5

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

10 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

15 210 215 220

Glu Cys

225

20

<210> 503

<211> 226

<212>PRT

25 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

30 <400> 503

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

35

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

40 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

45 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

50

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Phe Gly Gln

5 100 105 110

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

10

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

15

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

20 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

25 180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

thirty

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

35

Glu Cys

225

40 <210> 504

<211> 226

<212>PRT

<213> Artificial Sequence

45 <220>

<223> an artificially synthesized sequence

<400> 504

50 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

5

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

10 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

15 65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

20

Thr Phe Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Gln

100 105 110

25

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

30 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

35 145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

40

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

45

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

50 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

Glu Cys

225

5

<210> 505

<211> 226

<212>PRT

<213> Artificial Sequence

10

<220>

<223> an artificially synthesized sequence

<400> 505

15

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

20 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

25 35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

thirty

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

35

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

40 Thr Phe Gly Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Gln

100 105 110

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

45 115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

50

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

5 165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

10

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

15

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

20 Glu Cys

225

<210> 506

25 <211> 226

<212>PRT

<213> Artificial Sequence

<220>

30 <223> an artificially synthesized sequence

<400> 506

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

35 1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

40

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

50 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

5

Thr Phe Gly Gln Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

100 105 110

10 Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

15 130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

20

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

25

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

30 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

35 210 215 220

Glu Cys

225

40

<210> 507

<211> 226

<212>PRT

45 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

50 <400> 507

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

5 20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

10

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

15

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

20 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg

25 100 105 110

Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

thirty

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

35

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

40 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

45 180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

50

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

Glu Cys

5 225

<210> 508

<211> 226

10 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15

<400> 508

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

20

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

25

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

30 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

35 65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

40

Thr Phe Gly Gln Gly Thr Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro

100 105 110

45

Arg Gly Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

50 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

5

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

10 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

15 195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

20

Glu Cys

225

25

<210> 509

<211> 226

<212>PRT

<213> Artificial Sequence

thirty

<220>

<223> an artificially synthesized sequence

<400> 509

35

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

40 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

45 35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

50

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

5 85 90 95

Thr Phe Gly Gln Gly Thr Lys Thr Ser Thr Ser Gly Arg Ser Ala Asn

100 105 110

10

Pro Arg Gly Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

15

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

20 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

25 165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

thirty

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

35

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

40 Glu Cys

225

<210> 510

45 <211> 226

<212>PRT

<213> Artificial Sequence

<220>

50 <223> an artificially synthesized sequence

<400> 510

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

5

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

10 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

15 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

20

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

25

Thr Phe Gly Gln Gly Thr Lys Val Thr Ser Thr Ser Gly Arg Ser Ala

100 105 110

30 Asn Pro Arg Gly Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

35 130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

40

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

45

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

50 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

5

Glu Cys

225

10 <210> 511

<211> 226

<212>PRT

<213> Artificial Sequence

15 <220>

<223> an artificially synthesized sequence

<400> 511

20 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

25 20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

thirty

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

35

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

40 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Thr Ser Thr Ser Gly Arg Ser

45 100 105 110

Ala Asn Pro Arg Gly Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

50

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

5 145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

10

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

15

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

20 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

Glu Cys

25 225

<210> 512

<211> 226

30 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

35

<400> 512

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

40

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

45

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

50 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

5

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

10 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Thr Ser Thr Ser Gly Arg

100 105 110

Ser Ala Asn Pro Arg Gly Lys Arg Thr Val Ala Ala Pro Ser Val Phe

15 115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

20

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

25

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

30 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

35 195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

40

Glu Cys

225

45

<210> 513

<211> 226

<212>PRT

<213> Artificial Sequence

50

<220>

<223> an artificially synthesized sequence

<400> 513

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

5 1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

10

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

15

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

20 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

25 85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Thr Ser Thr Ser Gly

100 105 110

thirty

Arg Ser Ala Asn Pro Arg Gly Arg Thr Val Ala Ala Pro Ser Val Phe

115 120 125

35

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

40 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

45 165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

50

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

5 210 215 220

Glu Cys

225

10

<210> 514

<211> 226

<212>PRT

15 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

20 <400> 514

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

25

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

35 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

40

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

45

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Ser Thr Ser

100 105 110

50 Gly Arg Ser Ala Asn Pro Arg Gly Thr Val Ala Ala Pro Ser Val Phe

115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

5

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

10 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

15 180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

20

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

25

Glu Cys

225

30 <210> 515

<211> 226

<212>PRT

<213> Artificial Sequence

35 <220>

<223> an artificially synthesized sequence

<400> 515

40 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

45 20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

50

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

5 65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

10

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Thr Ser Thr

100 105 110

15

Ser Gly Arg Ser Ala Asn Pro Arg Gly Val Ala Ala Pro Ser Val Phe

115 120 125

20 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

25 145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

thirty

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

35

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

40 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

Glu Cys

45 225

<210> 516

<211> 226

50 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

<400> 516

5

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

10 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

15 35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

20

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

25

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

30 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Thr Ser

100 105 110

Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ala Ala Pro Ser Val Phe

35 115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

40

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

45

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

50 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

5

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

10 Glu Cys

225

<210> 517

15 <211> 226

<212>PRT

<213> Artificial Sequence

<220>

20 <223> an artificially synthesized sequence

<400> 517

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

25 1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

thirty

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

35

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

40 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

45 85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Thr

100 105 110

50

Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ala Pro Ser Val Phe

115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

5 130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

10

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

15

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

20 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

25 210 215 220

Glu Cys

225

thirty

<210> 518

<211> 226

<212>PRT

35 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

40 <400> 518

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

45

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

50 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

5

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

10 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

15 100 105 110

Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Pro Ser Val Phe

115 120 125

20

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

25

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

30 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

35 180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

40

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

45

Glu Cys

225

50 <210> 519

<211> 226

<212>PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

5

<400> 519

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

10

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

15

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

20 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

25 65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

thirty

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

35

Pro Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Val Phe

115 120 125

40 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

45 145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

50

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

5 195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

10

Glu Cys

225

15

<210> 520

<211> 226

<212>PRT

<213> Artificial Sequence

20

<220>

<223> an artificially synthesized sequence

<400> 520

25

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

30 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

40

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

45

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

50 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Phe

115 120 125

5

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

10 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

15 165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

20

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

25

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

30 Glu Cys

225

<210> 521

35 <211> 226

<212>PRT

<213> Artificial Sequence

<220>

40 <223> an artificially synthesized sequence

<400> 521

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

45 1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

50

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

5 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

10

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

15

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

20 Pro Ser Val Phe Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly

115 120 125

Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

25 130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

thirty

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

35

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

40 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

45 210 215 220

Glu Cys

225

50

<210> 522

<211> 226

<212>PRT

<213> Artificial Sequence

5 <220>

<223> an artificially synthesized sequence

<400> 522

10 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

15 20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

20

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

25

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

30 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

35 100 105 110

Pro Ser Val Phe Ile Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg

115 120 125

40

Gly Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

45

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

50 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

5

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

10 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

Glu Cys

15 225

<210> 523

<211> 226

20 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

25

<400> 523

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

thirty

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

35

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

40 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

45 65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

50

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro

5 115 120 125

Arg Gly Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

10

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

15

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

20 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

25 195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

thirty

Glu Cys

225

35

<210> 524

<211> 226

<212>PRT

<213> Artificial Sequence

40

<220>

<223> an artificially synthesized sequence

<400> 524

45

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

50 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

5

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

10 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

15 85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

20

Pro Ser Val Phe Ile Phe Pro Thr Ser Thr Ser Gly Arg Ser Ala Asn

115 120 125

25

Pro Arg Gly Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

30 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

35 165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

40

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

45

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

50 Glu Cys

225

<210> 525

<211> 226

<212>PRT

5 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

10 <400> 525

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

20 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

25 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

thirty

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

35

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

40 Pro Ser Val Phe Ile Phe Pro Pro Thr Ser Thr Ser Gly Arg Ser Ala

115 120 125

Asn Pro Arg Gly Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

45 130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

50

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

5 180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

10

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

15

Glu Cys

225

20 <210> 526

<211> 226

<212>PRT

<213> Artificial Sequence

25 <220>

<223> an artificially synthesized sequence

<400> 526

30 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

35 20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

40

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

45

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

50 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

5

Pro Ser Val Phe Ile Phe Pro Pro Ser Thr Ser Thr Ser Gly Arg Ser

115 120 125

10 Ala Asn Pro Arg Gly Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

15 145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

20

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

25

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

30 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

Glu Cys

35 225

<210> 527

<211> 226

40 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

45

<400> 527

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

50

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

5 35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

10

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

15

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

20 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Thr Ser Thr Ser Gly Arg

25 115 120 125

Ser Ala Asn Pro Arg Gly Glu Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

thirty

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

35

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

40 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

45 195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

50

Glu Cys

225

<210> 528

5 <211> 226

<212>PRT

<213> Artificial Sequence

<220>

10 <223> an artificially synthesized sequence

<400> 528

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

15 1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

20

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

25

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

30 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

35 85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

40

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Thr Ser Thr Ser Gly

115 120 125

45

Arg Ser Ala Asn Pro Arg Gly Gln Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

50 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

5

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

10 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

15 210 215 220

Glu Cys

225

20

<210> 529

<211> 226

<212>PRT

25 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

30 <400> 529

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

35

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

40 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

45 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

50

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

5 100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Thr Ser Thr Ser

115 120 125

10

Gly Arg Ser Ala Asn Pro Arg Gly Leu Lys Ser Gly Thr Ala Ser Val

130 135 140

15

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

20 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

25 180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

thirty

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

35

Glu Cys

225

40 <210> 530

<211> 226

<212>PRT

<213> Artificial Sequence

45 <220>

<223> an artificially synthesized sequence

<400> 530

50 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

5

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

10 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

15 65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

20

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

25

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Thr Ser Thr

115 120 125

30 Ser Gly Arg Ser Ala Asn Pro Arg Gly Lys Ser Gly Thr Ala Ser Val

130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

35 145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

40

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

45

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

50 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

Glu Cys

225

5

<210> 531

<211> 226

<212>PRT

<213> Artificial Sequence

10

<220>

<223> an artificially synthesized sequence

<400> 531

15

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

20 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

25 35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

thirty

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

35

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

40 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Thr Ser

45 115 120 125

Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Gly Thr Ala Ser Val

130 135 140

50

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

5 165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

10

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

15

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

20 Glu Cys

225

<210> 532

25 <211> 226

<212>PRT

<213> Artificial Sequence

<220>

30 <223> an artificially synthesized sequence

<400> 532

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

35 1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

40

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

50 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

5

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

10 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Thr

115 120 125

Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Thr Ala Ser Val

15 130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

20

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

25

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

30 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

35 210 215 220

Glu Cys

225

40

<210> 533

<211> 226

<212>PRT

45 <213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

50 <400> 533

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

5 20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

10

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

15

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

20 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

25 100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

thirty

Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Thr Ala Ser Val

130 135 140

35

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

40 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

45 180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

50

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

Glu Cys

5 225

<210> 534

<211> 226

10 <212> PRT

<213> Artificial Sequence

<220>

<223> an artificially synthesized sequence

15

<400> 534

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

20

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

25

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

30 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

35 65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

40

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

45

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

50 Thr Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ala Ser Val

130 135 140

Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

5

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

165 170 175

10 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

15 195 200 205

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

20

Glu Cys

225

25

<210> 535

<211> 226

<212>PRT

<213> Artificial Sequence

thirty

<220>

<223> an artificially synthesized sequence

<400> 535

35

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

40 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

45 35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

50

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr

5 85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

10

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

15

Thr Ala Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Ser Val

130 135 140

20 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp

145 150 155 160

Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr

25 165 170 175

Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr

180 185 190

thirty

Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val

195 200 205

35

Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly

210 215 220

40 Glu Cys

225

<210> 536

45 <211> 19

<212>PRT

<213> Artificial Sequence

<220>

50 <223> an artificially synthesized sequence

<400> 536

Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly

1 5 10 15

5

Val His Ser

10 <210> 537

<211> 6

<212>PRT

<213> Homo sapiens

15 <400> 537

Met Tyr Pro Pro Pro Tyr

15

<---

Claims (17)

1. A ligand-binding molecule that selectively activates a ligand in a target tissue, where the ligand is a cytokine or chemokine, where the molecule is a polypeptide having at least one urokinase (uPA), matriptase (MT-SP1) or metalloproteinase cleavage site, at this polypeptide contains an antibody VH, an antibody VL and an IgG antibody constant region, wherein the cleavage site is located at the boundary between the antibody VH and the antibody constant region or at the boundary between the antibody VL and the antibody constant region, where the ligand is a molecule having biological activity, where the cleavage site is a protease-cleavable sequence or a combination of a protease-cleavable sequence and a flexible linker, wherein the VH antibodies and the VL antibodies are linked to each other, and this linkage is canceled by protease cleavage of the cleavage site, and the binding of the ligand by a molecule cleaved at at least one cleavage site protease, is weakened, and the biological activity of the ligand is inhibited upon binding to an antibody whose VH and VL are linked to each other, and the ligand is released when the ligand-binding molecule is cleaved at the cleavage site. 2. The ligand-binding molecule of claim 1, wherein the ligand is a ligand selected from interleukin, interferon, hematopoietic factor, a member of the TNF superfamily, a chemokine, a cell growth factor, and a member of the TGF-β family. 3. The ligand binding molecule of claim 2, wherein the ligand is IL12, CXCL10, PD1 or IL6R. 4. Ligand-binding molecule according to any one of paragraphs. 1-3, wherein the cleavage site is located at any position selected from the group consisting of (1) - (4): (1) a position between amino acid position 101 (Cabot numbering) of the VH antibody and amino acid position 140 (EU numbering) of the constant antibody heavy chain regions; (2) a position between amino acid position 101 (Cabot numbering) of the VH antibody and amino acid position 130 (EU numbering) (Cabot numbering position 130) of the light chain constant region of the antibody; (3) a position between amino acid position 96 (Cabot numbering) of the VL antibody and amino acid position 130 (EU numbering) (Cabot numbering position 130) of the antibody light chain constant region; and (4) a position between amino acid position 96 (Cabot numbering) of the antibody VL and amino acid position 140 (EU numbering) of the antibody heavy chain constant region. 5. The ligand-binding molecule according to claim 4, wherein the cleavage site is located at any position selected from the group consisting of (1) - (4): (1) a position between amino acid position 109 (Cabot numbering) of the VH antibody and amino acid position 122 (EU numbering) antibody heavy chain constant region; (2) a position between amino acid position 109 (Cabot numbering) of the VH antibody and amino acid position 113 (EU numbering) (Cabot numbering position 113) of the light chain constant region of the antibody; (3) a position between amino acid position 104 (Cabot numbering) of the VL antibody and amino acid position 113 (EU numbering) (Cabot numbering position 113) of the light chain constant region of the antibody; (4) a position between amino acid position 104 (Cabot numbering) of the VL antibody and amino acid position 122 (EU numbering) of the heavy chain constant region of the antibody. 6. Ligand-binding molecule according to any one of paragraphs. 1-5, where the flexible linker consists of a glycine-serine polymer. 7. Ligand-binding molecule according to any one of paragraphs. 1-6, wherein the ligand binding molecule is bound to a ligand. 8. Ligand-binding molecule according to any one of paragraphs. 1-6, where the ligand-binding molecule is fused to a ligand. 9. A complex that selectively activates a ligand in a target tissue, wherein the complex contains a ligand-binding molecule according to any one of claims. 1-6. 10. A fusion protein that selectively activates a ligand in a target tissue, where the fusion protein contains a ligand-binding molecule fused to the ligand through a linker according to any one of claims. 1-6. 11. A pharmaceutical composition for the treatment of a disease associated with a target tissue, containing an effective amount of a ligand binding molecule according to any one of paragraphs. 1-6, its corresponding ligand and a pharmaceutically acceptable carrier. 12. A pharmaceutical composition for the treatment of a disease associated with a target tissue, containing an effective amount of the complex according to claim 9 and a pharmaceutically acceptable carrier. 13. A pharmaceutical composition for treating a disease associated with a target tissue, comprising an effective amount of the fusion protein of claim 10 and a pharmaceutically acceptable carrier. 14. Pharmaceutical composition according to any one of paragraphs. 11-13, wherein said disease can be mitigated or prevented by increasing or enhancing the biological activity of the ligand. 15. A method for producing a ligand-binding molecule according to any one of claims. 1-6, including the stages: transformation of the host cell with an expression vector, where the polynucleotide encodes an integrated ligand-binding molecule according to any one of paragraphs. 1-6, culturing the transformed host cell and isolating the target molecule. 16. A method for obtaining a complex according to claim 9, comprising the steps of: transforming a host cell with an expression vector, where the polynucleotide encodes an integrated ligand-binding molecule according to any one of claims. 1-6, culturing the transformed host cell, isolating the target molecule, followed by binding the ligand to the ligand-binding molecule. 17. A method for producing a fusion protein according to claim 10, comprising the steps of: transforming a host cell with an expression vector, where the polynucleotide encodes an integrated ligand-binding molecule according to any one of claims. 1-6, culturing the transformed host cell, isolating the target molecule, then fusing the ligand with a ligand-binding molecule.

Images