Bispecific antibody that binds to TfR

Abstract

The present invention relates to a bispecific antibody in which an IgG portion bound to TfR is bound to a polypeptide on the N-terminal side, a fragment of the bispecific antibody, DNA encoding the bispecific antibody or the fragment of the bispecific antibody, a vector containing the DNA, a hybridoma and a transformant for producing the bispecific antibody or the fragment of the bispecific antibody, a method for producing the bispecific antibody or the fragment of the bispecific antibody, a therapeutic and diagnostic drug containing the bispecific antibody or the fragment of the bispecific antibody, a therapeutic and diagnostic method using the bispecific antibody or the fragment of the bispecific antibody, and a detection or assay reagent containing the bispecific antibody or the fragment of the bispecific antibody.

Description

Technical Field

[0001] The present invention relates to a bispecific antibody comprising an antigen binding site that binds to transferrin receptor (TfR) and an antigen binding site that binds to a cell surface antigen, a bispecific antibody fragment, a DNA encoding the bispecific antibody or the bispecific antibody fragment, a vector comprising the DNA, a hybridoma and a transformant that produce the bispecific antibody or the bispecific antibody fragment, a method for producing the bispecific antibody or the bispecific antibody fragment, a therapeutic and diagnostic drug comprising the bispecific antibody or the bispecific antibody fragment, a therapeutic and diagnostic method using the bispecific antibody or the bispecific antibody fragment, and a detection or measurement reagent comprising the bispecific antibody or the bispecific antibody fragment. Background Art

[0002] Antibodies are glycoproteins present in the serum or tissue fluids of all mammals, and they recognize foreign antigens in the body. Antibodies activate the complement system or bind to receptors (FcR) on the cell surface, thereby activating effector functions such as the phagocytic ability, antibody-dependent cellular cytotoxicity, mediator free ability, and antigen presentation ability of FcR-expressing cells, thereby participating in the defense of the organism.

[0003] One antibody molecule is composed of two identical light chains (L chains) and two identical heavy chains (H chains), and has two antigen binding sites. The class and subclass of the antibody are determined by the H chain, and each class and subclass have different inherent functions. There are five different classes of human antibodies: IgG, IgA, IgM, IgD, and IgE. IgG is further divided into subclasses of IgG1, IgG2, IgG3, and IgG4, and IgA is divided into subclasses of IgA1 and IgA2 (Charles AJ et al., Immunobiology, 1997, Current Biology Ltd / Garland Publishing Inc.).

[0004] Multivalent antibodies are antibodies with multiple antigen binding sites in one molecule. As an example of a multivalent antibody, it is reported that a secondary hybridoma is used to express H chains and L chains from two different antibodies in one cell, thereby making a bivalent antibody (non-patent literature 1) that is respectively bound to two different antigens with a monovalent. However, in this method, a combination of H chains and L chains of about 10 antibodies will be produced. Therefore, the production amount of the multivalent antibody with the combination of the desired H chain and L chain is low, and it is also difficult to selectively separate and purify such a multivalent antibody, so the yield of the desired antibody is reduced.

[0005] In order to overcome this problem, attempts have been reported to express multiple antigen-binding sites linked together as a single polypeptide chain, thereby reducing the variation of combinations between subunits and producing antibodies with a desired combination.

[0006] As an example, a single chain (single chain Fv, scFv) antibody comprising an antigen binding site of an H chain and an L chain linked by a single polypeptide is known (Non-patent Document 2). Furthermore, there are reports of antibodies in which two antigen binding sites are linked using the CH1 domain of the H chain constant region of IgG1 or a partial fragment of the domain and the L chain constant region, or a flexible linker (Gly-Gly-Gly-Gly-Ser) (Patent Documents 1 and 2).

[0007] These existing multivalent antibodies have the disadvantages of being easy to aggregate, and having low stability or productivity. However, on the other hand, it has been found that multivalent antibodies having multiple antigen-binding sites in a single H chain polypeptide and bound to the antibody heavy chain variable region via a linker having an amino acid sequence of an immunoglobulin domain or a fragment thereof have high stability and good productivity (Patent Document 3).

[0008] Transferrin receptor (hereinafter also referred to as TfR) is identified as a cell membrane structure expressed on the surface of reticulocytes. TfR has the function of taking in the iron combined with transferrin (hereinafter also referred to as Tf) into the cell. Iron is an indispensable metal for the maintenance of cell homeostasis and cell proliferation, so the TfR used to take in it is expressed in large quantities in the trophoblast cells, reticulocytes, activated lymphocytes or normal tissues that frequently take in iron of the placenta. In addition, it is also known to be expressed in large quantities in various tumor cells (non-patent literature 3, non-patent literature 4) that are active in proliferation. If TfR is cross-linked on the cell membrane, the internalization caused by the endocytosis of the clathrin-dependent protein will be promoted and decomposed (non-patent literature 5, non-patent literature 6).

[0009] It is known that the expression level of TfR in normal cells other than bone marrow cells is low, and the expression level in actively proliferating cancer cells is high, so TfR has been identified as a molecular target for cancer treatment in the past. As a molecule targeting TfR, for example, a TfR neutralizing antibody that shows a strong efficacy in a mouse tumor model is known (Patent Document 4).

[0010] It is known that the expression of specific membrane proteins is enhanced in cancer cells compared to normal cells. Pharmaceuticals have been developed that have the function of killing only cancer cells by antibodies that selectively recognize such membrane proteins. For example, antibody pharmaceuticals targeting epidermal growth factor receptor (EGFR) have been clinically confirmed to be effective against colorectal cancer or head and neck cancer (Non-patent Document 7).

[0011] EGFR is a tyrosine kinase receptor discovered as a receptor for epidermal growth factor (EGF). EGFR is a transmembrane glycoprotein with a molecular weight of 170 kDa. When bound to a ligand, it forms a dimer and promotes cell proliferation, differentiation, invasion, metastasis, etc. by activating downstream intracellular signal transduction pathways.

[0012] EGFR is expressed in various cells of the epithelial system, mesenchymal system, and nervous system, and is highly expressed in various cancer cells such as brain tumors and squamous cell carcinoma (Non-Patent Documents 8 and 9), and is therefore known as a cancer antigen.

[0013] It is known that by using a molecule that can bind to two membrane proteins, one antigen molecule can be used as a scaffold to internalize and decompose another antigen molecule (Patent Document 5, Patent Document 6). In addition, it is reported that if a peptide that recognizes a membrane protein specific to cancer cells is chemically bound to a peptide that recognizes TfR, or is linked using a hybridoma fusion method, then under the condition of adding an iron chelator, proliferation inhibition activity is shown for cells expressing two antigens (Patent Document 7).

[0014] Prior art literature

[0015] Patent Literature

[0016] Patent Document 1: U.S. Patent Application Publication No. 2007 / 0071675

[0017] Patent Document 2: International Publication No. 2001 / 077342

[0018] Patent Document 3: International Publication No. 2009 / 131239

[0019] Patent Document 4: International Publication No. 2012 / 153707

[0020] Patent Document 5: International Publication No. 2013 / 138400

[0021] Patent Document 6: European Patent Application Publication No. 2808035

[0022] Patent Document 7: U.S. Patent No. 570561

[0023] Non-patent literature

[0024] Non-patent document 1: Suresh et al., Methods Enzymol. 121, 210-228, 1986 Non-patent document 2: Kranz et al., J. Hematother. 5, 403-408, 1995

[0025] Non-patent document 3: Hamilton TA et al., PNAS USA 76 6406-10, 1979

[0026] Non-patent document 4: Larson SM et al., J Natl Cancer Inst. 64 41-53, 1980 Non-patent document 5: Liu AP et al., J Cell Biol. 191 1381-93, 2010

[0027] Non-patent document 6: Weissman AM et al., J Cell Biol. 102 951-8, 1986

[0028] Non-patent literature 7: Erbitux US Appendix (revised in June 2018)

[0029] Non-patent document 8: Libermann TA et al., Cancer Res. 44 753-60, 1984

[0030] Non-patent literature 9: Hendler FJ et al., J Clin Invest. 74 647-51, 1984 Summary of the invention

[0031] Problem that the invention aims to solve

[0032] The object of the present invention is to provide a novel bispecific antibody that binds to TfR and a cell surface antigen, a bispecific antibody fragment, a DNA encoding the bispecific antibody or a bispecific antibody fragment, a vector comprising the DNA, a hybridoma and a transformant that produce the bispecific antibody or a bispecific antibody fragment, a method for producing the bispecific antibody or a bispecific antibody fragment, a therapeutic and diagnostic drug comprising the bispecific antibody or a bispecific antibody fragment, a therapeutic and diagnostic method using the bispecific antibody or a bispecific antibody fragment, and a detection or measurement reagent comprising the bispecific antibody or a bispecific antibody fragment.

[0033] Solutions to the problem

[0034] As a method for solving the above-mentioned problems, the present invention provides a bispecific antibody or a bispecific antibody fragment that binds to TfR and a cell surface antigen, wherein a polypeptide having an antigen binding site for a cell surface antigen (also referred to as an N-terminal side polypeptide) is bound directly or via a linker to the N-terminal side of the IgG part that binds to TfR.

[0035] That is, the present invention relates to the following contents.

[0036] 1. A bispecific antibody or a bispecific antibody fragment that binds to TfR and a cell surface antigen, comprising an IgG portion that binds to a transferrin receptor (TfR) and an N-terminal side polypeptide that binds to a cell surface antigen, wherein the polypeptide binds directly or via a linker to the N-terminus of the heavy chain of the IgG portion.

[0037] 2. The bispecific antibody or the bispecific antibody fragment according to 1 above, wherein the IgG portion comprises:

[0038] The heavy chain variable region (VH) contains:

[0039] a complementarity determining region (CDR) 1 comprising the amino acid sequence shown in SEQ ID NO: 32 or an amino acid sequence altered by at least one substitution selected from the group consisting of substitution of tyrosine at position 2 with alanine or phenylalanine and substitution of threonine at position 3 with alanine or glycine in the amino acid sequence shown in SEQ ID NO: 32,

[0040] CDR2, comprising the amino acid sequence shown in SEQ ID NO: 33, or an amino acid sequence altered by at least one substitution selected from the group consisting of substitution of valine at position 1 with alanine, substitution of isoleucine at position 2 with alanine or leucine, substitution of valine at position 7 with glutamic acid, substitution of aspartic acid at position 10 with alanine, and substitution of aspartic acid at position 13 with proline in the amino acid sequence shown in SEQ ID NO: 33, and

[0041] CDR3, comprising the amino acid sequence shown in SEQ ID NO: 34, or an amino acid sequence altered by at least one substitution selected from the group consisting of substitution of glutamine at position 3 with alanine or aspartic acid, substitution of proline at position 4 with any natural amino acid, substitution of tryptophan at position 5 with alanine, phenylalanine, histidine or tyrosine, substitution of tyrosine at position 7 with alanine or phenylalanine, and substitution of valine at position 13 with leucine in the amino acid sequence shown in SEQ ID NO: 34; and

[0042] The light chain variable region (VL) comprises CDR1 to 3 comprising the amino acid sequences shown in SEQ ID NOs: 17 to 19, respectively.

[0043] 3. The bispecific antibody or the bispecific antibody fragment according to 1 above, wherein the IgG portion comprises: a VH selected from the following (ai) to (ci), and a VL comprising CDR1 to 3 comprising the amino acid sequences shown in SEQ ID NOs: 17 to 19, respectively.

[0044] (ai) VH comprising CDR1 to 3 comprising the amino acid sequences shown in SEQ ID NOs: 32 to 34, respectively,

[0045] (bi) VH comprising CDR1 to 3 comprising the amino acid sequences shown in SEQ ID NOs: 42 to 44, respectively,

[0046] (ci) VH comprising CDR1 to 3 comprising the amino acid sequences shown in SEQ ID NOs: 47 to 49, respectively.

[0047] 4. The bispecific antibody or the bispecific antibody fragment according to 1 or 2 above, wherein the IgG portion comprises: a VH comprising an amino acid sequence represented by any one of SEQ ID NOs: 26, 31, 36, 41 and 46, and a VL comprising an amino acid sequence represented by SEQ ID NO: 16.

[0048] 5. The bispecific antibody or the bispecific antibody fragment according to 1 above, wherein the IgG portion comprises: a VL comprising CDR1 to 3 comprising the amino acid sequences shown in SEQ ID NOs: 17 to 19, respectively, and a VH selected from the following (a) to (m).

[0049] (a) a VH comprising CDR2 and CDR3 comprising the amino acid sequences shown in SEQ ID NOs: 33 and 34, respectively, and CDR1 comprising an amino acid sequence altered by substitution of tyrosine at position 2 with alanine or phenylalanine in the amino acid sequence shown in SEQ ID NO: 32,

[0050] (b) a VH comprising CDR2 and CDR3 comprising the amino acid sequences shown in SEQ ID NOs: 33 and 34, respectively, and CDR1 comprising an amino acid sequence altered by substituting threonine at position 3 with alanine or glycine in the amino acid sequence shown in SEQ ID NO: 32,

[0051] (c) a VH comprising CDR1 and CDR3 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 34, respectively, and CDR2 comprising the amino acid sequence shown in SEQ ID NO: 33, wherein the valine at position 1 is substituted with alanine,

[0052] (d) a VH comprising CDR1 and CDR3 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 34, respectively, and CDR2 comprising an amino acid sequence altered by replacing the isoleucine at position 2 with alanine or leucine in the amino acid sequence shown in SEQ ID NO: 33,

[0053] (e) a VH comprising CDR1 and CDR3 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 34, respectively, and CDR2 comprising the amino acid sequence shown in SEQ ID NO: 33, wherein valine at position 7 is substituted with glutamic acid,

[0054] (f) a VH comprising CDR1 and CDR3 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 34, respectively, and CDR2 comprising the amino acid sequence shown in SEQ ID NO: 33, wherein the aspartic acid at position 10 is substituted with alanine,

[0055] (g) a VH comprising CDR1 and CDR3 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 34, respectively, and a CDR2 comprising an amino acid sequence altered by substituting aspartic acid at position 13 with proline in the amino acid sequence shown in SEQ ID NO: 33,

[0056] (h) a VH comprising CDR1 and CDR2 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 33, respectively, and CDR3 comprising an amino acid sequence altered by replacing glutamine at position 3 with alanine or aspartic acid in the amino acid sequence shown in SEQ ID NO: 34,

[0057] (i) a VH comprising CDR1 and CDR2 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 33, respectively, and CDR3 comprising an amino acid sequence altered by replacing proline at position 4 with any natural amino acid in the amino acid sequence shown in SEQ ID NO: 34,

[0058] (j) a VH comprising CDR1 and 2 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 33, respectively, and a CDR3 comprising an amino acid sequence altered by replacing the proline at position 4 with alanine, tyrosine, serine, aspartic acid, glutamine, glutamic acid, threonine, arginine, glycine, lysine, methionine, valine, leucine, isoleucine, tryptophan, phenylalanine or histidine in the amino acid sequence shown in SEQ ID NO: 34,

[0059] (k) a VH comprising CDR1 and CDR2 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 33, respectively, and a CDR3 comprising an amino acid sequence altered by replacing the tryptophan at position 5 with alanine, phenylalanine, histidine or tyrosine in the amino acid sequence shown in SEQ ID NO: 34,

[0060] (1) a VH comprising CDR1 and CDR2 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 33, respectively, and a CDR3 comprising an amino acid sequence altered by replacing tyrosine at position 7 with alanine or phenylalanine in the amino acid sequence shown in SEQ ID NO: 34,

[0061] (m) VH comprising CDR1 and 2 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 33, respectively, and CDR3 comprising the amino acid sequence shown in SEQ ID NO: 34, in which valine is substituted with leucine.

[0062] 6. The bispecific antibody or the bispecific antibody fragment according to 1 above, wherein the IgG portion comprises: a VL comprising the amino acid sequence shown in SEQ ID NO: 16, and a VH comprising an amino acid sequence modified by substitution of at least one of Y32A, Y32F, T33A, T33G, L45A, V48A, V50A, I51A, I51L, V55E, D58A, D61P, Q97A, Q97D, W99A, W99F, W99H, W99Y, Y100AA, Y100AF, V102L and P98 as shown in the EU index of Kabat et al. (hereinafter referred to as the EU index) in the amino acid sequence shown in SEQ ID NO: 31 with any amino acid.

[0063] 7. The bispecific antibody or bispecific antibody fragment according to 1 above, wherein the IgG portion comprises: a VL comprising the amino acid sequence shown in SEQ ID NO: 16, and a VL comprising Y32A, Y32F, T33A, T33G, L45A, V48A, V50A, I51A, I51L, V55E, D58A, D61P, Q61P, and the like as shown in the EU index in the amino acid sequence shown in SEQ ID NO: 31. VH of the amino acid sequence changed by substitution of any one of 97A, Q97D, W99A, W99F, W99H, W99Y, Y100AA, Y100AF, V102L, P98A, P98Y, P98S, P98D, P98Q, P98E, P98T, P98R, P98G, P98K, P98M, P98V, P98L, P98I, P98W, P98F and P98H.

[0064] 8. According to the bispecific antibody or the bispecific antibody fragment described in 1 above, wherein the IgG portion recognizes at least one amino acid residue selected from Asp at position 352, Ser at position 355, Asp at position 356 and Lys at position 358 of the amino acid sequence of TfR shown in sequence number 6, and at least one amino acid residue selected from Met at position 365, Val at position 366 and Glu at position 369.

[0065] 9. The bispecific antibody or the bispecific antibody fragment according to any one of 1 to 8 above, wherein the heavy chain constant region of the IgG portion comprises the amino acid sequence shown in SEQ ID NO: 84 or SEQ ID NO: 86.

[0066] 10. The bispecific antibody or the bispecific antibody fragment according to any one of 1 to 9 above, wherein the cell surface antigen is EGFR or GPC3.

[0067] 11. The bispecific antibody or the bispecific antibody fragment according to any one of 1 to 10 above, wherein the cell surface antigen is EGFR.

[0068] 12. The bispecific antibody or the bispecific antibody fragment according to any one of 1 to 11 above, wherein the N-terminal polypeptide is any one of Fab, Fab', scFv, dsFv and VHH of an antibody against the cell surface antigen.

[0069] 13. The bispecific antibody or the bispecific antibody fragment according to any one of 1 to 12 above, wherein the N-terminal polypeptide is a Fab of an antibody against the cell surface antigen.

[0070] 14. The bispecific antibody or the bispecific antibody fragment according to any one of 1 to 9 above, wherein the N-terminal polypeptide is a Fab of an antibody against EGFR, and the antibody comprises: a VH comprising CDR1 to 3 comprising the amino acid sequences shown in SEQ ID NOs: 60 to 62, respectively, or comprising CDR1 to 3 comprising the amino acid sequences shown in SEQ ID NOs: 65 to 67, respectively, and a VL comprising CDR1 to 3 comprising the amino acid sequences shown in SEQ ID NOs: 17 to 19, respectively.

[0071] 15. The bispecific antibody or the bispecific antibody fragment according to 14 above, wherein the antibody against EGFR is an antibody selected from the following (a) to (e).

[0072] (a) an antibody comprising a VH comprising the amino acid sequence shown in SEQ ID NO: 59 or SEQ ID NO: 64, and a VL comprising the amino acid sequence shown in SEQ ID NO: 16,

[0073] (b) an antibody comprising a VH comprising the amino acid sequence shown in SEQ ID NO: 110 and a VL comprising the amino acid sequence shown in SEQ ID NO: 111,

[0074] (c) an antibody comprising a VH comprising the amino acid sequence shown in SEQ ID NO: 112 and a VL comprising the amino acid sequence shown in SEQ ID NO: 113,

[0075] (d) an antibody comprising a VH comprising the amino acid sequence shown in SEQ ID NO: 114 and a VL comprising the amino acid sequence shown in SEQ ID NO: 115,

[0076] (e) An antibody comprising VH comprising the amino acid sequence shown in SEQ ID NO: 116 and VL comprising the amino acid sequence shown in SEQ ID NO: 117.

[0077] 16. The bispecific antibody or the bispecific antibody fragment according to any one of 13 to 15 above, wherein the heavy chain C-terminus of the Fab is directly bound to the heavy chain N-terminus of the IgG part.

[0078] 17. The bispecific antibody or the bispecific antibody fragment according to any one of 13 to 15 above, wherein the heavy chain C-terminus of the Fab is linked to the heavy chain N-terminus of the IgG part via a linker.

[0079] 18. The bispecific antibody or the bispecific antibody fragment according to 17 above, wherein the amino acid sequence of the linker is composed of a part or the whole of the amino acid sequence of the hinge region of IgG.

[0080] 19. The bispecific antibody or the bispecific antibody fragment according to any one of 13 to 18 above, wherein the Fab and the IgG parts contain light chains consisting of the same amino acid sequence.

[0081] 20. A DNA encoding the bispecific antibody or the bispecific antibody fragment according to any one of 1 to 19 above.

[0082] 21. A recombinant vector comprising the DNA described in 20 above.

[0083] 22. A transformant obtained by introducing the recombinant vector described in 21 above into a host cell.

[0084] 23. A method for producing the bispecific antibody or the bispecific antibody fragment described in any one of 1 to 19 above, characterized in that the transformant described in 22 above is cultured in a culture medium, so that the bispecific antibody or the bispecific antibody fragment described in any one of 1 to 19 is produced and accumulated in the culture, and the bispecific antibody or the bispecific antibody fragment is collected from the culture.

[0085] 24. A therapeutic and / or diagnostic drug for a disease related to at least one of human TfR and a cell surface antigen, comprising the bispecific antibody or the bispecific antibody fragment according to any one of 1 to 19 above as an active ingredient.

[0086] 25. The therapeutic agent and / or diagnostic agent according to 24 above, wherein the disease associated with at least one of human TfR and a cell surface antigen is cancer.

[0087] 26. A method for treating and / or diagnosing a disease associated with at least one of human TfR and a cell surface antigen, using the bispecific antibody or the bispecific antibody fragment according to any one of 1 to 19 above.

[0088] 27. The method according to 26 above, wherein the disease associated with at least one of human TfR and a cell surface antigen is cancer.

[0089] 28. The bispecific antibody or the bispecific antibody fragment according to any one of 1 to 19 above, which is used for treating and / or diagnosing a disease associated with at least one of human TfR and a cell surface antigen.

[0090] 29. The bispecific antibody or the bispecific antibody fragment according to 28 above, wherein the disease associated with at least one of human TfR and a cell surface antigen is cancer.

[0091] 30. Use of the bispecific antibody or the bispecific antibody fragment according to any one of 1 to 19 above for producing a therapeutic and / or diagnostic agent for a disease associated with at least one of human TfR and a cell surface antigen.

[0092] 31. The use according to 30 above, wherein the disease associated with at least one of human TfR and cell surface antigen is cancer.

[0093] 32. A reagent for detecting or measuring at least one of human TfR and a cell surface antigen, comprising the bispecific antibody or the bispecific antibody fragment according to any one of 1 to 19 above.

[0094] Effects of the Invention

[0095] According to the present invention, it is possible to provide a novel bispecific antibody that binds to TfR and a cell surface antigen, a bispecific antibody fragment, a DNA encoding the bispecific antibody or a bispecific antibody fragment, a vector comprising the DNA, a hybridoma and a transformant that produce the bispecific antibody or a bispecific antibody fragment, a method for producing the bispecific antibody or a bispecific antibody fragment, a therapeutic and diagnostic drug comprising the bispecific antibody or a bispecific antibody fragment, a therapeutic and diagnostic method using the bispecific antibody or a bispecific antibody fragment, and a detection or measurement reagent comprising the bispecific antibody or a bispecific antibody fragment. Sequence Listing <110> Kyowa Kirin Co., Ltd. <120> Bispecific antibodies binding to TfR <130> W528470 <150> JP2018-248334 <151> 2018-12-28 <160> 117 <170> PatentIn version 3.5 <210> 1 <211> 1643 <212> DNA <213> Homo sapiens <400> 1 tggagaatcc tgggggttat gtggcgtata gtaaggctgc aacagttact ggtaaactgg 60 tccatgctaa ttttggtact aaaaaagatt ttgaggattt atacactcct gtgaatggat 120 ctatagtgat tgtcagagca gggaaaatca cctttgcaga aaaggttgca aatgctgaaa 180 gcttaaatgc aattggtgtg ttgatataca tggaccagac taaatttccc attgttaacg 240 cagaactttc attctttgga catgctcatc tggggacagg tgacccttac acacctggat 300 tcccttcctt caatcacact cagtttccac catctcggtc atcaggattg cctaatatac 360 ctgtccagac aatctccaga gctgctgcag aaaagctgtt tgggaatatg gaaggagact 420 gtccctctga ctggaaaaca gactctacat gtaggatggt aacctcagaa agcaagaatg 480 tgaagctcac tgtgagcaat gtgctgaaag agataaaaat tcttaacatc tttggagtta 540 ttaaaggctt tgtagaacca gatcactatg ttgtagttgg ggcccagaga gatgcatggg 600 gccctggagc tgcaaatcc ggtgtaggca cagctctcct attgaactt gcccagatgt 660 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Gly Lys Ile Thr Phe 165 170 175 Ala Glu Lys Val Ala Asn Ala Glu Ser Leu Asn Ala Ile Gly Val Leu 180 185 190 Ile Tyr Met Asp Gln Thr Lys Phe Pro Ile Val Asn Ala Glu Leu Ser 195 200 205 Phe Phe Gly His Ala His Leu Gly Thr Gly Asp Pro Tyr Thr Pro Gly 210 215 220 Phe Pro Ser Phe Asn His Thr Gln Phe Pro Pro Ser Arg Ser Ser Gly 225 230 235 240 Leu Pro Asn Ile Pro Val Gln Thr Ile Ser Arg Ala Ala Ala Glu Lys 245 250 255 Leu Phe Gly Asn Met Glu Gly Asp Cys Pro Ser Asp Trp Lys Thr Asp 260 265 270 Ser Thr Cys Arg Met Val Thr Ser Glu Ser Lys Asn Val Lys Leu Thr 275 280 285 Val Ser Asn Val Leu Lys Glu Ile Lys Ile Leu Asn Ile Phe Gly Val 290 295 300 Ile Lys Gly Phe Val Glu Pro Asp His Tyr Val Val Val Gly Ala Gln 305 310 315 320 Arg Asp Ala Trp Gly Pro Gly Ala Ala Lys Ser Gly Val Gly Thr Ala 325 330 335 Leu Leu Leu Lys Leu Ala Gln Met Phe Ser Asp Met Val Leu Lys Asp 340 345 350 Gly Phe Gln Pro Ser Arg Ser Ile Ile Phe Ala Ser Trp Ser Ala Gly 355 360 365 Asp Phe Gly Ser Val Gly Ala Thr Glu Trp Leu Glu Gly Tyr Leu Ser 370 375 380 Ser Leu His Leu Lys Ala Phe Thr Tyr Ile Asn Leu Asp Lys Ala Val 385 390 395 400 Leu Gly Thr Ser Asn Phe Lys Val Ser Ala Ser Pro Leu Leu Tyr Thr 405 410 415 Leu Ile Glu Lys Thr Met Gln Asn Val Lys His Pro Val Thr Gly Gln 420 425 430 Phe Leu Tyr Gln Asp Ser Asn Trp Ala Ser Lys Val Glu Lys Leu Thr 435 440 445 Leu Asp Asn Ala Ala Phe Pro Phe Leu Ala Tyr Ser Gly Ile Pro Ala 450 455 460 Val Ser Phe Cys Phe Cys Glu Asp Thr Asp Tyr Pro Tyr Leu Gly Thr 465 470 475 480 Thr Met Asp Thr Tyr Lys Glu Leu Ile Glu Arg Ile Pro Glu Leu Asn 485 490 495 Lys Val Ala Arg Ala Ala Ala Glu Val Ala Gly Gln Phe Val Ile Lys 500 505 510 Leu Thr His Asp Val Glu Leu Asn Leu Asp Tyr Glu Arg Tyr Asn Ser 515 520 525 Gln Leu Leu Ser Phe Val Arg Asp Leu Asn Gln Tyr Arg Ala Asp Ile 530 535 540 Lys Glu Met Gly Leu Ser Leu Gln Trp Leu Tyr Ser Ala Arg Gly Asp 545 550 555 560 Phe Phe Arg Ala Thr Ser Arg Leu Thr Thr Asp Phe Gly Asn Ala Glu 565 570 575 Lys Thr Asp Arg Phe Val Met Lys Lys Leu Asn Asp Arg Val Met Arg 580 585 590 Val Glu Tyr His Phe Leu Ser Pro Tyr Val Ser Pro Lys Glu Ser Pro 595 600 605 Phe Arg His Val Phe Trp Gly Ser Gly Ser His Thr Leu Pro Ala Leu 610 615 620 Leu Glu Asn Leu Lys Leu Arg Lys Gln Asn Asn Gly Ala Phe Asn Glu 625 630 635 640 Thr Leu Phe Arg Asn Gln Leu Ala Leu Ala Thr Trp Thr Ile Gln Gly 645 650 655 Ala Ala Asn Ala Leu Ser Gly Asp Val Trp Asp Ile Asp Asn Glu Phe 660 665 670 <210> 3 <211> 2016 <212> DNA <213> Monkey <400> 3 tgtaaagggg tagaaccaaa aactgagtgt gagagactgg caggcaccga gtctccagcg 60 agggaggagc cagaagagga cttccctgcg gcaccgcgct tatactggga cgacctgaag 120 agaaagttgt cagagaaact ggacaccaca gacttcacca gcaccatcaa gctgctgaat 180 gaaaatttat atgtccctcg tgaggctgga tctcaaaaag atgaaaatct tgcattgtat 240 attgaaaatc aatttcgtga atttaaacta agcaaagtct ggcgtgatca acattttgtt 300 aagattcagg tcaaggacag tgctcaaaac tcggtgatca tagttgataa gaatggtgga 360 cttgtttacc tggtggagaa tcctgggggt tatgtggcat atagtaaggc tgcaacagtt 420 actggtaaac tggtccatgc taattttggt actaaaaaag actttgagga tttagactct 480 cctgtgaatg gatctatagt gattgtcaga gcaggaaaaa tcacctttgc agaaaaggtt 540 gcaaatgctg aaagcttaaa tgcaattggt gtcttgatat atatggacca gactaaattt 600 cctattgtta aggcagacct ttcattcttt ggacatgctc atctgggaac aggtgaccct 660 tacacacctg gattcccttc cttcaatcac actcagtttc caccatctca gtcgtcagga 720 ttgcctaata tacctgtcca aacgatctcc agagctgctg cagaaaagct gtttggaaat 780 atggagggag actgtccctc tgactggaaa acagactcta cgtgtaagat ggtaacctcg 840 gaaaacaaga gtgtgaagct cacggtgagc aatgtgctga aagagacaaa aattcttaac 900 atctttggag ttattaaagg cttcgtagaa ccagatcact atgttgtggt tggggcccag 960 agagatgcgt ggggccccgg agctgcaaaa tccagtgtgg ggacagctct cctgttgaaa 1020 cttgcccaga tgttctcaga tatggtctta aaagatgggt ttcagcccag cagaagcatt 1080 atctttgcca gttggagtgc tggagacttt ggatcggttg gtgccactga atggctagag 1140 ggataccttt catccttgca tttaaaggct ttcacttaca ttaatctgga taaagcggtg 1200 cttggaacca gcaacttcaa ggtttctgcc agcccgttgt tgtatacgct gattgagaaa 1260 acaatgcaag atgtgaaaca tccggttact gggcgatctc tatatcagga cagcaactgg 1320 gccagcaaag ttgagaaact cactttagac aatgctgctt tccctttcct tgcgtattct 1380 ggaatcccag cagtttcttt ctgtttttgt gaggacacag attatcctta cttgggcacc 1440 accatggaca cctataagga actggtggag aggattcctg agctgaacaa agtggcacga 1500 gcagcggcag aagtagctgg tcagttcgtg attaaactga cccatgatac tgaattgaac 1560 ctggactatg agaggtacaa cagccagctg cttttgtttt tgagggatct gaaccagtac 1620 agagcagatg taaaggaaat gggcctgagc ttgcagtggc tgtattctgc tcgtggagac 1680 tttttccgtg ctacttccag gctaacaaca gatttcagga atgctgagaa aagggacaag 1740 tttgtcatga agaagctcaa tgatcgtgtc atgagagtcg agtattactt cctctcaccc 1800 tatgtgtctc caaaagagtc tcctttccgg cacgtcttct ggggctcggg ctcccacacg 1860 ctgtccgctt tactggagag cttgaaactg cgtagacaga ataacagtgc ttttaatgaa 1920 acgctgttca gaaaccagct ggctctcgcg acttggacta ttcagggagc tgcaaatgcc 1980 ctttctggtg acgtttggga cattgacaat gagttt 2016 <210> 4 <211> 672 <212> PRT <213> Monkey <400> 4 Cys Lys Gly Val Glu Pro Lys Thr Glu Cys Glu Arg Leu Ala Gly Thr 1 5 10 15 Glu Ser Pro Ala Arg Glu Glu Pro Glu Glu Asp Phe Pro Ala Ala Pro 20 25 30 Arg Leu Tyr Trp Asp Asp Leu Lys Arg Lys Leu Ser Glu Lys Leu Asp 35 40 45 Thr Thr Asp Phe Thr Ser Thr Ile Lys Leu Leu Asn Glu Asn Leu Tyr 50 55 60 Val Pro Arg Glu Ala Gly Ser Gln Lys Asp Glu Asn Leu Ala Leu Tyr 65 70 75 80 Ile Glu Asn Gln Phe Arg Glu Phe Lys Leu Ser Lys Val Trp Arg Asp 85 90 95 Gln His Phe Val Lys Ile Gln Val Lys Asp Ser Ala Gln Asn Ser Val 100 105 110 Ile Ile Val Asp Lys Asn Gly Gly Leu Val Tyr Leu Val Glu Asn Pro 115 120 125 Gly Gly Tyr Val Ala Tyr Ser Lys Ala Ala Thr Val Thr Gly Lys Leu 130 135 140 Val His Ala Asn Phe Gly Thr Lys Lys Asp Phe Glu Asp Leu Asp Ser 145 150 155 160 Pro Val Asn Gly Ser Ile Val Ile Val Arg Ala Gly Lys Ile Thr Phe 165 170 175 Ala Glu Lys Val Ala Asn Ala Glu Ser Leu Asn Ala Ile Gly Val Leu 180 185 190 Ile Tyr Met Asp Gln Thr Lys Phe Pro Ile Val Lys Ala Asp Leu Ser 195 200 205 Phe Phe Gly His Ala His Leu Gly Thr Gly Asp Pro Tyr Thr Pro Gly 210 215 220 Phe Pro Ser Phe Asn His Thr Gln Phe Pro Pro Ser Gln Ser Ser Gly 225 230 235 240 Leu Pro Asn Ile Pro Val Gln Thr Ile Ser Arg Ala Ala Ala Glu Lys 245 250 255 Leu Phe Gly Asn Met Glu Gly Asp Cys Pro Ser Asp Trp Lys Thr Asp 260 265 270 Ser Thr Cys Lys Met Val Thr Ser Glu Asn Lys Ser Val Lys Leu Thr 275 280 285 Val Ser Asn Val Leu Lys Glu Thr Lys Ile Leu Asn Ile Phe Gly Val 290 295 300 Ile Lys Gly Phe Val Glu Pro Asp His Tyr Val Val Val Gly Ala Gln 305 310 315 320 Arg Asp Ala Trp Gly Pro Gly Ala Ala Lys Ser Ser Val Gly Thr Ala 325 330 335 Leu Leu Leu Lys Leu Ala Gln Met Phe Ser Asp Met Val Leu Lys Asp 340 345 350 Gly Phe Gln Pro Ser Arg Ser Ile Ile Phe Ala Ser Trp Ser Ala Gly 355 360 365 Asp Phe Gly Ser Val Gly Ala Thr Glu Trp Leu Glu Gly Tyr Leu Ser 370 375 380 Ser Leu His Leu Lys Ala Phe Thr Tyr Ile Asn Leu Asp Lys Ala Val 385 390 395 400 Leu Gly Thr Ser Asn Phe Lys Val Ser Ala Ser Pro Leu Leu Tyr Thr 405 410 415 Leu Ile Glu Lys Thr Met Gln Asp Val Lys His Pro Val Thr Gly Arg 420 425 430 Ser Leu Tyr Gln Asp Ser Asn Trp Ala Ser Lys Val Glu Lys Leu Thr 435 440 445 Leu Asp Asn Ala Ala Phe Pro Phe Leu Ala Tyr Ser Gly Ile Pro Ala 450 455 460 Val Ser Phe Cys Phe Cys Glu Asp Thr Asp Tyr Pro Tyr Leu Gly Thr 465 470 475 480 Thr Met Asp Thr Tyr Lys Glu Leu Val Glu Arg Ile Pro Glu Leu Asn 485 490 495 Lys Val Ala Arg Ala Ala Ala Glu Val Ala Gly Gln Phe Val Ile Lys 500 505 510 Leu Thr His Asp Thr Glu Leu Asn Leu Asp Tyr Glu Arg Tyr Asn Ser 515 520 525 Gln Leu Leu Leu Phe Leu Arg Asp Leu Asn Gln Tyr Arg Ala Asp Val 530 535 540 Lys Glu Met Gly Leu Ser Leu Gln Trp Leu Tyr Ser Ala Arg Gly Asp 545 550 555 560 Phe Phe Arg Ala Thr Ser Arg Leu Thr Thr Asp Phe Arg Asn Ala Glu 565 570 575 Lys Arg Asp Lys Phe Val Met Lys Lys Leu Asn Asp Arg Val Met Arg 580 585 590 Val Glu Tyr Tyr Phe Leu Ser Pro Tyr Val Ser Pro Lys Glu Ser Pro 595 600 605 Phe Arg His Val Phe Trp Gly Ser Gly Ser His Thr Leu Ser Ala Leu 610 615 620 Leu Glu Ser Leu Lys Leu Arg Arg Gln Asn Asn Ser Ala Phe Asn Glu 625 630 635 640 Thr Leu Phe Arg Asn Gln Leu Ala Leu Ala Thr Trp Thr Ile Gln Gly 645 650 655 Ala Ala Asn Ala Leu Ser Gly Asp Val Trp Asp Ile Asp Asn Glu Phe 660 665 670 <210> 5 <211> 2280 <212> DNA <213> Homo sapiens <400> 5 atgatggatc aagctagatc agcattctct aacttgtttg gtggagaacc attgtcatat 60 acccggttca gcctggctcg gcaagtagat ggcgataaca gtcatgtgga gatgaaactt 120 gctgtagatg aagaagaaaa tgctgacaat aacacaaagg ccaatgtcac aaaaccaaaa 180 aggtgtagtg gaagtatctg ctatgggact attgctgtga tcgtcttttt cttgattgga 240 tttatgattg gctacttggg ctattgtaaa ggggtagaac caaaaactga gtgtgagaga 300 ctggcaggaa ccgagtctcc agtgagggag gagccaggag aggacttccc tgcagcacgt 360 cgcttatatt gggatgacct gaagagaaag ttgtcggaga aactggacag cacagacttc 420 accggcacca tcaagctgct gaatgaaaat tcatatgtcc ctcgtgaggc tggatctcaa 480 aaagatgaaa atcttgcgtt gtatgttgaa aatcaatttc gtgaatttaa actcagcaaa 540 gtctggcgtg atcaacattt tgttaagatt caggtcaaag acagcgctca aaactcggtg 600 atcatagttg ataagaacgg tagacttgtt tacctggtgg agaatcctgg gggttatgtg 660 gcgtatagta aggctgcaac agttactggt aaactggtcc atgctaattt tggtactaaa 720 aaagattttg aggattttata cactcctgtg aatggatcta tagtgattgt cagagcaggg 780 aaaatcacct ttgcagaaaa ggttgcaaat gctgaaagct taaatgcaat tggtgtgttg 840 atatacatgg accagactaa atttcccatt gttaacgcag aactttcatt ctttggacat 900 gctcatctgg ggacaggtga cccttacaca cctggattcc cttccttcaa tcacactcag 960 tttccaccat ctcggtcatc aggattgcct aatatacctg tccagacaat ctccagagct 1020 gctgcagaaa agctgtttgg gaatatggaa ggagactgtc cctctgactg gaaaacagac 1080 tctacatgta ggatggtaac ctcagaaagc aagaatgtga agctcactgt gagcaatgtg 1140 ctgaaagaga taaaaattct taacatcttt ggagttatta aaggctttgt agaaccagat 1200 cactatgttg tagttggggc ccagagagat gcatggggcc ctggagctgc aaaatccggt 1260 gtaggcacag ctctcctatt gaaacttgcc cagatgttct cagatatggt cttaaaagat 1320 gggtttcagc ccagcagaag cattatcttt gccagttgga gtgctggaga ctttggatcg 1380 gttggtgcca ctgaatggct agagggatac ctttcgtccc tgcatttaaa ggctttcact 1440 tatattaatc tggataaagc ggttcttggt accagcaact tcaaggtttc tgccagccca 1500 ctgttgtata cgcttattga gaaaacaatg caaaatgtga agcatccggt tactgggcaa 1560 tttctatatc aggacagcaa ctgggccagc aaagttgaga aactcacttt agacaatgct 1620 gctttccct tccttgcata ttctggaatc ccagcagttt cttctgttt ttgcgaggac 1680 acagattatc cttattggg taccaccatg gacacctata aggaactgat tgagaggatt 1740 cctgagttga acaaagtggc acgagcagct gcagaggtcg ctggtcagtt cgtgattaaa 1800 ctaacccatg atgttgaatt gaacctggac tatgagaggt acaacagcca actgctttca 1860 tttgtgaggg atctgaacca atacagagca gacataaagg aaatgggcct gagtttacag 1920 tggctgtatt ctgctcgtgg agactttcttc cgtgctactt ccagactaac aacagatttc 1980 gggaatgctg agaaaacaga cagatttgtc atgaagaaac tcaatgatcg tgtcatgaga 2040 gtggagtatc acttcctctc tccctacgta tctccaaaag agtctccttt ccgacatgtc 2100 ttctggggct ccggctctca cacgctgcca gctttactgg agaacttgaa actgcgtaaa 2160 caaaataacg gtgcttttaa tgaaacgctg ttcagaaacc agttggctct agctacttgg 2220 actattcagg gagctgcaaa tgccctctct ggtgacgttt gggacattga caatgagttt 2280 <210> 6 <211> 760 <212> PRT <213> Homo sapiens <400> 6 Met Met Asp Gln Ala Arg Ser Ala Phe Ser Asn Leu Phe Gly Gly Glu 1 5 10 15 Pro Leu Ser Tyr Thr Arg Phe Ser Leu Ala Arg Gln Val Asp Gly Asp 20 25 30 Asn Ser His Val Glu Met Lys Leu Ala Val Asp Glu Glu Glu Asn Ala 35 40 45 Asp Asn Asn Thr Lys Ala Asn Val Thr Lys Pro Lys Arg Cys Ser Gly 50 55 60 Ser Ile Cys Tyr Gly Thr Ile Ala Val Ile Val Phe Phe Leu Ile Gly 65 70 75 80 Phe Met Ile Gly Tyr Leu Gly Tyr Cys Lys Gly Val Glu Pro Lys Thr 85 90 95 Glu Cys Glu Arg Leu Ala Gly Thr Glu Ser Pro Val Arg Glu Glu Pro 100 105 110 Gly Glu Asp Phe Pro Ala Ala Arg Arg Leu Tyr Trp Asp Asp Leu Lys 115 120 125 Arg Lys Leu Ser Glu Lys Leu Asp Ser Thr Asp Phe Thr Gly Thr Ile 130 135 140 Lys Leu Leu Asn Glu Asn Ser Tyr Val Pro Arg Glu Ala Gly Ser Gln 145 150 155 160 Lys Asp Glu Asn Leu Ala Leu Tyr Val Glu Asn Gln Phe Arg Glu Phe 165 170 175 Lys Leu Ser Lys Val Trp Arg Asp Gln His Phe Val Lys Ile Gln Val 180 185 190 Lys Asp Ser Ala Gln Asn Ser Val Ile Ile Val Asp Lys Asn Gly Arg 195 200 205 Leu Val Tyr Leu Val Glu Asn Pro Gly Gly Tyr Val Ala Tyr Ser Lys 210 215 220 Ala Ala Thr Val Thr Gly Lys Leu Val His Ala Asn Phe Gly Thr Lys 225 230 235 240 Lys Asp Phe Glu Asp Leu Tyr Thr Pro Val Asn Gly Ser Ile Val Ile 245 250 255 Val Arg Ala Gly Lys Ile Thr Phe Ala Glu Lys Val Ala Asn Ala Glu 260 265 270 Ser Leu Asn Ala Ile Gly Val Leu Ile Tyr Met Asp Gln Thr Lys Phe 275 280 285 Pro Ile Val Asn Ala Glu Leu Ser Phe Phe Gly His Ala His Leu Gly 290 295 300 Thr Gly Asp Pro Tyr Thr Pro Gly Phe Pro Ser Phe Asn His Thr Gln 305 310 315 320 Phe Pro Pro Ser Arg Ser Ser Gly Leu Pro Asn Ile Pro Val Gln Thr 325 330 335 Ile Ser Arg Ala Ala Ala Glu Lys Leu Phe Gly Asn Met Glu Gly Asp 340 345 350 Cys Pro Ser Asp Trp Lys Thr Asp Ser Thr Cys Arg Met Val Thr Ser 355 360 365 Glu Ser Lys Asn Val Lys Leu Thr Val Ser Asn Val Leu Lys Glu Ile 370 375 380 Lys Ile Leu Asn Ile Phe Gly Val Ile Lys Gly Phe Val Glu Pro Asp 385 390 395 400 His Tyr Val Val Val Gly Ala Gln Arg Asp Ala Trp Gly Pro Gly Ala 405 410 415 Ala Lys Ser Gly Val Gly Thr Ala Leu Leu Leu Lys Leu Ala Gln Met 420 425 430 Phe Ser Asp Met Val Leu Lys Asp Gly Phe Gln Pro Ser Arg Ser Ile 435 440 445 Ile Phe Ala Ser Trp Ser Ala Gly Asp Phe Gly Ser Val Gly Ala Thr 450 455 460 Glu Trp Leu Glu Gly Tyr Leu Ser Ser Leu His Leu Lys Ala Phe Thr 465 470 475 480 Tyr Ile Asn Leu Asp Lys Ala Val Leu Gly Thr Ser Asn Phe Lys Val 485 490 495 Ser Ala Ser Pro Leu Leu Tyr Thr Leu Ile Glu Lys Thr Met Gln Asn 500 505 510 Val Lys His Pro Val Thr Gly Gln Phe Leu Tyr Gln Asp Ser Asn Trp 515 520 525 Ala Ser Lys Val Glu Lys Leu Thr Leu Asp Asn Ala Ala Phe Pro Phe 530 535 540 Leu Ala Tyr Ser Gly Ile Pro Ala Val Ser Phe Cys Phe Cys Glu Asp 545 550 555 560 Thr Asp Tyr Pro Tyr Leu Gly Thr Thr Met Asp Thr Tyr Lys Glu Leu 565 570 575 Ile Glu Arg Ile Pro Glu Leu Asn Lys Val Ala Arg Ala Ala Ala Glu 580 585 590 Val Ala Gly Gln Phe Val Ile Lys Leu Thr His Asp Val Glu Leu Asn 595 600 605 Leu Asp Tyr Glu Arg Tyr Asn Ser Gln Leu Leu Ser Phe Val Arg Asp 610 615 620 Leu Asn Gln Tyr Arg Ala Asp Ile Lys Glu Met Gly Leu Ser Leu Gln 625 630 635 640 Trp Leu Tyr Ser Ala Arg Gly Asp Phe Phe Arg Ala Thr Ser Arg Leu 645 650 655 Thr Thr Asp Phe Gly Asn Ala Glu Lys Thr Asp Arg Phe Val Met Lys 660 665 670 Lys Leu Asn Asp Arg Val Met Arg Val Glu Tyr His Phe Leu Ser Pro 675 680 685 Tyr Val Ser Pro Lys Glu Ser Pro Phe Arg His Val Phe Trp Gly Ser 690 695 700 Gly Ser His Thr Leu Pro Ala Leu Leu Glu Asn Leu Lys Leu Arg Lys 705 710 715 720 Gln Asn Asn Gly Ala Phe Asn Glu Thr Leu Phe Arg Asn Gln Leu Ala 725 730 735 Leu Ala Thr Trp Thr Ile Gln Gly Ala Ala Asn Ala Leu Ser Gly Asp 740 745 750 Val Trp Asp Ile Asp Asn Glu Phe 755 760 <210> 7 <211> 2280 <212> DNA <213> Cynomolgus monkey <400> 7 atgatggatc aagctagatc agcattctct aacttgtttg gtggagaacc attgtcatat 60 acccggttca gcctggctcg gcaagtagac ggcgataaca gtcatgtgga gatgaaactt 120 gctgtagatg atgaagaaaa tgctgacaat aacacaaagg ccaatggcac aaaaccaaaa 180 aggtgtggtg gaaatatctg ctatgggact attgccgtga tcatcttttt cttgattggg 240 tttatgattg gctacttggg ctattgtaaa ggggtagaac caaaaactga gtgtgagaga 300 ctggcaggca ccgagtctcc agcgagggag gagccagaag aggacttccc tgcggcaccg 360 cgcttatact gggacgacct gaagagaaag ttgtcagaga aactggacac cacagacttc 420 accagcacca tcaagctgct gaatgaaaat ttatatgtcc ctcgtgaggc tggatctcaa 480 aaagatgaaa atcttgcatt gtatattgaa aatcaatttc gtgaatttaa actaagcaaa 540 gtctggcgtg atcaacattt tgttaagatt caggtcaagg acagtgctca aaactcggtg 600 atcatagttg ataagaatgg tggacttgtt tacctggtgg agaatcctgg gggttatgtg 660 gcatatagta aggctgcaac agttactggt aaactggtcc atgctaattt tggtactaaa 720 aaagactttg aggatttaga ctctcctgtg aatggatcta tagtgattgt cagagcagga 780 aaaatcacct ttgcagaaaa ggttgcaaat gctgaaagct taaatgcaat tggtgtcttg 840 atatatatgg accagactaa atttcctatt gttaaggcag acctttcatt ctttggacat 900 gctcatctgg gaacaggtga cccttacaca cctggattcc cttccttcaa tcacactcag 960 tttccaccat ctcagtcgtc aggattgcct aatatacctg tccaaacgat ctccagagct 1020 gctgcagaaa agctgtttgg aaatatggag ggagactgtc cctctgactg gaaaacagac 1080 tctacgtgta agatggtaac ctcggaaaac aagagtgtga agctcacggt gagcaatgtg 1140 ctgaaagaga caaaaattct taacatcttt ggagttatta aaggcttcgt agaaccagat 1200 cactatgttg tggttggggc ccagagagat gcgtggggcc ccggagctgc aaaatccagt 1260 gtggggacag ctctcctgtt gaaacttgcc cagatgttct cagatatggt cttaaaagat 1320 gggtttcagc ccagcagaag cattatcttt gccagttgga gtgctggaga ctttggatcg 1380 gttggtgcca ctgaatggct agagggatac ctttcatcct tgcatttaaa ggctttcact 1440 tacattaatc tggataaagc ggtgcttgga accagcaact tcaaggtttc tgccagcccg 1500 ttgttgtata cgctgattga gaaaacaatg caagatgtga aacatccggt tactgggcga 1560 tctctatatc aggacagcaa ctgggccagc aaagttgaga aactcacttt agacaatgct 1620 gctttccctt tccttgcgta ttctggaatc ccagcagttt ctttctgttt ttgtgaggac 1680 acagattatc cttacttggg caccaccatg gacacctata aggaactggt ggagaggatt 1740 cctgagctga acaaagtggc acgagcagcg gcagaagtag ctggtcagtt cgtgattaaa 1800 ctgacccatg atactgaatt gaacctggac tatgagaggt acaacagcca gctgcttttg 1860 tttttgaggg atctgaacca gtacagagca gatgtaaagg aaatgggcct gagcttgcag 1920 tggctgtatt ctgctcgtgg agactttttc cgtgctactt ccaggctaac aacagatttc 1980 aggaatgctg agaaaaggga caagtttgtc atgaagaagc tcaatgatcg tgtcatgaga 2040 gtcgagtatt acttcctctc accctatgtg tctccaaaag agtctccttt ccggcacgtc 2100 ttctggggct cgggctccca cacgctgtcc gctttactgg agagcttgaa actgcgtaga 2160 cagaataaca gtgcttttaa tgaaacgctg ttcagaaacc agctggctct cgcgacttgg 2220 actattcagg gagctgcaaa tgccctttct ggtgacgttt gggacattga caatgagttt 2280 <210> 8 <211> 760 <212> PRT <213> Cynomolgus monkey <400> 8 Met Met Asp Gln Ala Arg Ser Ala Phe Ser Asn Leu Phe Gly Gly Glu 1 5 10 15 Pro Leu Ser Tyr Thr Arg Phe Ser Leu Ala Arg Gln Val Asp Gly Asp 20 25 30 Asn Ser His Val Glu Met Lys Leu Ala Val Asp Asp Glu Glu Asn Ala 35 40 45 Asp Asn Asn Thr Lys Ala Asn Gly Thr Lys Pro Lys Arg Cys Gly Gly 50 55 60 Asn Ile Cys Tyr Gly Thr Ile Ala Val Ile Ile Phe Phe Leu Ile Gly 65 70 75 80 Phe Met Ile Gly Tyr Leu Gly Tyr Cys Lys Gly Val Glu Pro Lys Thr 85 90 95 Glu Cys Glu Arg Leu Ala Gly Thr Glu Ser Pro Ala Arg Glu Glu Pro 100 105 110 Glu Glu Asp Phe Pro Ala Ala Pro Arg Leu Tyr Trp Asp Asp Leu Lys 115 120 125 Arg Lys Leu Ser Glu Lys Leu Asp Thr Thr Asp Phe Thr Ser Thr Ile 130 135 140 Lys Leu Leu Asn Glu Asn Leu Tyr Val Pro Arg Glu Ala Gly Ser Gln 145 150 155 160 Lys Asp Glu Asn Leu Ala Leu Tyr Ile Glu Asn Gln Phe Arg Glu Phe 165 170 175 Lys Leu Ser Lys Val Trp Arg Asp Gln His Phe Val Lys Ile Gln Val 180 185 190 Lys Asp Ser Ala Gln Asn Ser Val Ile Ile Val Asp Lys Asn Gly Gly 195 200 205 Leu Val Tyr Leu Val Glu Asn Pro Gly Gly Tyr Val Ala Tyr Ser Lys 210 215 220 Ala Ala Thr Val Thr Gly Lys Leu Val His Ala Asn Phe Gly Thr Lys 225 230 235 240 Lys Asp Phe Glu Asp Leu Asp Ser Pro Val Asn Gly Ser Ile Val Ile 245 250 255 Val Arg Ala Gly Lys Ile Thr Phe Ala Glu Lys Val Ala Asn Ala Glu 260 265 270 Ser Leu Asn Ala Ile Gly Val Leu Ile Tyr Met Asp Gln Thr Lys Phe 275 280 285 Pro Ile Val Lys Ala Asp Leu Ser Phe Phe Gly His Ala His Leu Gly 290 295 300 Thr Gly Asp Pro Tyr Thr Pro Gly Phe Pro Ser Phe Asn His Thr Gln 305 310 315 320 Phe Pro Pro Ser Gln Ser Ser Gly Leu Pro Asn Ile Pro Val Gln Thr 325 330 335 Ile Ser Arg Ala Ala Ala Glu Lys Leu Phe Gly Asn Met Glu Gly Asp 340 345 350 Cys Pro Ser Asp Trp Lys Thr Asp Ser Thr Cys Lys Met Val Thr Ser 355 360 365 Glu Asn Lys Ser Val Lys Leu Thr Val Ser Asn Val Leu Lys Glu Thr 370 375 380 Lys Ile Leu Asn Ile Phe Gly Val Ile Lys Gly Phe Val Glu Pro Asp 385 390 395 400 His Tyr Val Val Val Gly Ala Gln Arg Asp Ala Trp Gly Pro Gly Ala 405 410 415 Ala Lys Ser Ser Val Gly Thr Ala Leu Leu Leu Lys Leu Ala Gln Met 420 425 430 Phe Ser Asp Met Val Leu Lys Asp Gly Phe Gln Pro Ser Arg Ser Ile 435 440 445 Ile Phe Ala Ser Trp Ser Ala Gly Asp Phe Gly Ser Val Gly Ala Thr 450 455 460 Glu Trp Leu Glu Gly Tyr Leu Ser Ser Leu His Leu Lys Ala Phe Thr 465 470 475 480 Tyr Ile Asn Leu Asp Lys Ala Val Leu Gly Thr Ser Asn Phe Lys Val 485 490 495 Ser Ala Ser Pro Leu Leu Tyr Thr Leu Ile Glu Lys Thr Met Gln Asp 500 505 510 Val Lys His Pro Val Thr Gly Arg Ser Leu Tyr Gln Asp Ser Asn Trp 515 520 525 Ala Ser Lys Val Glu Lys Leu Thr Leu Asp Asn Ala Ala Phe Pro Phe 530 535 540 Leu Ala Tyr Ser Gly Ile Pro Ala Val Ser Phe Cys Phe Cys Glu Asp 545 550 555 560 Thr Asp Tyr Pro Tyr Leu Gly Thr Thr Met Asp Thr Tyr Lys Glu Leu 565 570 575 Val Glu Arg Ile Pro Glu Leu Asn Lys Val Ala Arg Ala Ala Ala Glu 580 585 590 Val Ala Gly Gln Phe Val Ile Lys Leu Thr His Asp Thr Glu Leu Asn 595 600 605 Leu Asp Tyr Glu Arg Tyr Asn Ser Gln Leu Leu Leu Phe Leu Arg Asp 610 615 620 Leu Asn Gln Tyr Arg Ala Asp Val Lys Glu Met Gly Leu Ser Leu Gln 625 630 635 640 Trp Leu Tyr Ser Ala Arg Gly Asp Phe Phe Arg Ala Thr Ser Arg Leu 645 650 655 Thr Thr Asp Phe Arg Asn Ala Glu Lys Arg Asp Lys Phe Val Met Lys 660 665 670 Lys Leu Asn Asp Arg Val Met Arg Val Glu Tyr Tyr Phe Leu Ser Pro 675 680 685 Tyr Val Ser Pro Lys Glu Ser Pro Phe Arg His Val Phe Trp Gly Ser 690 695 700 Gly Ser His Thr Leu Ser Ala Leu Leu Glu Ser Leu Lys Leu Arg Arg 705 710 715 720 Gln Asn Asn Ser Ala Phe Asn Glu Thr Leu Phe Arg Asn Gln Leu Ala 725 730 735 Leu Ala Thr Trp Thr Ile Gln Gly Ala Ala Asn Ala Leu Ser Gly Asp 740 745 750 Val Trp Asp Ile Asp Asn Glu Phe 755 760 <210> 9 <211> 1914 <212> DNA <213> Homo sapiens <400> 9 atgcgaccct ccgggacggc cggggcagcg ctcctggcgc tgctggctgc gctctgcccg 60 gcgagtcggg ctctggagga aaagaaagtt tgccaaggca cgagtaacaa gctcacgcag 120 ttgggcactt ttgaagatca ttttctcagc ctccagagga tgttcaataa ctgtgaggtg 180 <h2 style=";text-align:left;direction:ltr">gtccttggga atttggaaat tacctatgtg cagaggaatt atgatctttc cttcttaaag 240<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> accatccagg aggtggctgg ttatgtcctc attgccctca acacagtgga gcgaattcct 300<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> ttggaaaacc tgcagatcat cagaggaaat atgtactacg aaaattccta tgccttagca 360<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> gtcttatcta actatgatgc aaataaaacc ggactgaagg agctgcccat gagaaattta 420<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> caggaaatcc tgcatggcgc cgtgcggttc agcaacaacc ctgccctgtg caacgtggag 480<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> agcatccagt ggcgggacat agtcagcagt gactttctca gcaacatgtc gatggacttc 540<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> cagaaccacc tgggcagctg ccaaaagtgt gatccaagct gtcccaatgg gagctgctgg 600<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> ggtgcaggag aggagaactg ccagaaactg accaaaatca tctgtgccca gcagtgctcc 660<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> gggcgctgcc gtggcaagtc ccccagtgac tgctgccaca accagtgtgc tgcaggctgc 720<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> acaggccccc gggagagcga ctgcctggtc tgccgcaaat tccgagacga agccacgtgc 780<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> aaggacacct gccccccact catgctctac aaccccacca cgtaccagat ggatgtgaac 840<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> cccgagggca aatacagctt tggtgccacc tgcgtgaaga agtgtccccg taattatgtg 900<h2 style=";text-align:left;direction:ltr"> gtgacagatc acggctcgtg cgtccgagcc tgtggggccg acagctatga gatggagga gacggcgtcc gcaagtgtaa gaagtgcgaa gggccttgcc gcaaagtgtg taacggaata ggtattggtg father ctcactctcc father cgate acacttcaaa aactgcacct ccatcagtgg cgatctccac atcctgccgg tggcatttag gggtgactcc ttcacacata ctcctcctct ggatccacag gaactggata ttctgaaaac cgtaagga atcacagggt ttttgctgat tcaggcttgg cctgaaaaca ggacggacct ccatgccttt gagaacctag aaatcatacg cggcaggacc aagcaacatg gtcagttttc tcttgcagtc gtcagcctga acataacatc cttgggatta cgctccctca aggagataag tgatggagat gtgataattt cage aaatttgtgc tatgcaata caataactg gaaaaaactg tttgggacct ccggtcagaa aaccaaaatt ataagcaaca gaggtgaaaa cagctgcaag gccacaggcc aggtctgcca tgccttgtgc tccccgagg gctgctgggg cccggagccc 1560 agggactgcg tctcttgccg gaatgtcagc cgaggcaggg aatgcgtgga caagtgcaac cttctggagg gtgagccaag ggagtttgtg gagaactctg agtgcataca gtgccaccca 1680 gagtgcctgc ctcaggccat gaacatcacc tgcacaggac ggggaccaga caactgtatc 1740 cagtgtgccc actacattga cggcccccac tgcgtcaaga cctgcccggc aggagtcatg 1800 ggagaaaaca acaccctggt ctggaagtac gcagacgccg gccatgtgtg ccacctgtgc 1860 catccaaact gcacctacgg atgcactggg ccaggtcttg aaggctgtcc aacg 1914 <210> 10 <211> 638 <212> PRT <213> Homo sapiens <400> 10 Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala 1 5 10 15 Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gln 20 25 30 Gly Thr Ser Asn Lys Leu Thr Gln Leu Gly Thr Phe Glu Asp His Phe 35 40 45 Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn 50 55 60 Leu Glu Ile Thr Tyr Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys 65 70 75 80 Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val 85 90 95 Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr 100 105 110 Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn 115 120 125 Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Glu Ile Leu 130 135 140 His Gly Ala Val Arg Phe Ser Asn Asn Pro Ala Leu Cys Asn Val Glu 145 150 155 160 Ser Ile Gln Trp Arg Asp Ile Val Ser Ser Asp Phe Leu Ser Asn Met 165 170 175 Ser Met Asp Phe Gln Asn His Leu Gly Ser Cys Gln Lys Cys Asp Pro 180 185 190 Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu Asn Cys Gln 195 200 205 Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly Arg Cys Arg 210 215 220 Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala Ala Gly Cys 225 230 235 240 Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys Phe Arg Asp 245 250 255 Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu Tyr Asn Pro 260 265 270 Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr Ser Phe Gly 275 280 285 Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val Thr Asp His 290 295 300 Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu Met Glu Glu 305 310 315 320 Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys Arg Lys Val 325 330 335 Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu Ser Ile Asn 340 345 350 Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp 355 360 365 Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr 370 375 380 Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu 385 390 395 400 Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn Arg Thr Asp 405 410 415 Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg Thr Lys Gln 420 425 430 His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile Thr Ser Leu 435 440 445 Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val Ile Ile Ser 450 455 460 Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp Lys Lys Leu 465 470 475 480 Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn Arg Gly Glu 485 490 495 Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu Cys Ser Pro 500 505 510 Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser Cys Arg Asn 515 520 525 Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu Leu Glu Gly 530 535 540 Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln Cys His Pro 545 550 555 560 Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly Arg Gly Pro 565 570 575 Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro His Cys Val 580 585 590 Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp 595 600 605 Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His Pro Asn Cys 610 615 620 Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro Thr 625 630 635 <210> 11 <211> 1914 <212> DNA <213> Monkey <400> 11 atgcgaccct ccgggacggc cggggccgcg ctcctggcgc tgctggctgc gctctgcccc 60 gcgagtcggg ctctggagga aaagaaagtt tgccaaggca cgagtaacaa actcacgcag 120 ttgggcactt ttgaagatca ttttctcagc ctccagagga tgttcaataa ctgtgaggtg 180 <h2 style=";text-align:left;direction:ltr">gtccttggga atttggaaat tacctacgtg cagaggaatt atgatctttc cttcttaaag 240<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> accatccagg aggtggctgg ttatgtcctc atcgccctca acacagtgga gcggattcct 300<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> ttggaaaacc tgcagatcat cagaggaaac atgtactatg aaaattccta tgccttagca 360<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> gtcttatcta actatgatgc aaataaaacc ggactgaagg agctgcccat gagaaactta 420<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> caggaaatcc tgcatggcgc cgtgcggttc agcaacaacc ctgccctgtg caacgtggag 480<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> agcatccagt ggcgggacat agtcagcagc gagtttctca gcaacatgtc gatggacttc 540<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> cagaaccacc tgggcagctg ccaaaagtgt gatccaagct gtcccaatgg gagctgctgg 600<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> ggtgcaggag aggagaactg ccagaaactg accaaaatca tctgtgccca gcagtgctcc 660<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> gggcgctgcc gcggcaagtc ccccagtgac tgctgccaca accagtgtgc cgcgggctgc 720<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> acgggccccc gggagagcga ctgcctggtc tgccgcaaat tccgagacga agccacgtgc 780<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> aaggacacct gccccccact catgctctac aaccccacca cataccagat ggatgtgaac 840<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> cccgagggca aatacagctt tggtgccacc tgcgtgaaga agtgtccccg taattatgtg 900<h2 style=";text-align:left;direction:ltr"> gtgacagatc acggctcgtg cgtccgagcc tgcggggccg acagctatga gatggagga gacggcgtcc gcaagtgtaa gaagtgcgaa gggccttgcc gcaaagtgtg taatggaata ggtattggtg aatttaaaga cacactctcc aataatgcta caatatta acacttcaaa aactgcacct ccatcagtgg cgatctccac atcctgccgg tggcatttag gggtgactcc ttcacacaca ctccgcctct ggatccacag gactggata ttctgaaaac cgtaagga atcacagggt ttttgctgat tcaggcttgg cctgaaaaca ggacggacct ccatgctttt gagaacctag aaatcatacg tggcaggacc aagcaacacg gtcagttttc tcttgcggtc gtcagcctga acataacatc cttgggatta cgctccctca aggagataag cgatggagat gtgataattt cage aaatttgtgc tatgcaata caataactg gaaaaaactg tttgggacct ccagtcagaa aaccaaaatt ataagcaaca gaggtgaaaa cagctgcaag gccacgggcc aggtctgcca tgccttgtgc tccccgagg gctgctgggg cccggagccc 1560 agggactgcg tctcctgtca gaatgtcagc cgaggcagag aatgcgtgga caagtgcaac 1620. atcctggagg gcgagccaag ggagtttgtg gagaactctg agtgcataca gtgccaccca 1680 gaatgcctgc cccaggtcat gaacatcacc tgcacaggac ggggaccaga caactgtatc 1740 cagtgtgccc actacattga cggcccccac tgcgtcaaga cctgcccagc aggagtcatg 1800 ggagaaaaca acaccctggt ctggaagtac gcagacgccg gccacgtgtg ccacttgtgc 1860 catccaaact gcacctacgg atgcactggg ccaggtcttg aaggctgtgc aagg 1914 <210> 12 <211> 638 <212> PRT <213> Monkey <400> 12 Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala 1 5 10 15 Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gln 20 25 30 Gly Thr Ser Asn Lys Leu Thr Gln Leu Gly Thr Phe Glu Asp His Phe 35 40 45 Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn 50 55 60 Leu Glu Ile Thr Tyr Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys 65 70 75 80 Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val 85 90 95 Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr 100 105 110 Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn 115 120 125 Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Glu Ile Leu 130 135 140 His Gly Ala Val Arg Phe Ser Asn Asn Pro Ala Leu Cys Asn Val Glu 145 150 155 160 Ser Ile Gln Trp Arg Asp Ile Val Ser Ser Glu Phe Leu Ser Asn Met 165 170 175 Ser Met Asp Phe Gln Asn His Leu Gly Ser Cys Gln Lys Cys Asp Pro 180 185 190 Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu Asn Cys Gln 195 200 205 Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly Arg Cys Arg 210 215 220 Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala Ala Gly Cys 225 230 235 240 Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys Phe Arg Asp 245 250 255 Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu Tyr Asn Pro 260 265 270 Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr Ser Phe Gly 275 280 285 Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val Thr Asp His 290 295 300 Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu Met Glu Glu 305 310 315 320 Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys Arg Lys Val 325 330 335 Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Thr Leu Ser Ile Asn 340 345 350 Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp 355 360 365 Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr 370 375 380 Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu 385 390 395 400 Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn Arg Thr Asp 405 410 415 Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg Thr Lys Gln 420 425 430 His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile Thr Ser Leu 435 440 445 Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val Ile Ile Ser 450 455 460 Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp Lys Lys Leu 465 470 475 480 Phe Gly Thr Ser Ser Gln Lys Thr Lys Ile Ile Ser Asn Arg Gly Glu 485 490 495 Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu Cys Ser Pro 500 505 510 Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser Cys Gln Asn 515 520 525 Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Ile Leu Glu Gly 530 535 540 Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln Cys His Pro 545 550 555 560 Glu Cys Leu Pro Gln Val Met Asn Ile Thr Cys Thr Gly Arg Gly Pro 565 570 575 Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro His Cys Val 580 585 590 Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp 595 600 605 Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His Pro Asn Cys 610 615 620 Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Ala Arg 625 630 635 <210> 13 <211> 3630 <212> DNA <213> Homo sapiens <400> 13 atgcgaccct ccgggacggc cggggcagcg ctcctggcgc tgctggctgc gctctgcccg 60 gcgagtcggg ctctggagga aaagaaagtt tgccaaggca cgagtaacaa gctcacgcag 120 ttgggcactt ttgaagatca ttttctcagc ctccagagga tgttcaataa ctgtgaggtg 180 <h2 style=";text-align:left;direction:ltr">gtccttggga atttggaaat tacctatgtg cagaggaatt atgatctttc cttcttaaag 240<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> accatccagg aggtggctgg ttatgtcctc attgccctca acacagtgga gcgaattcct 300<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> ttggaaaacc tgcagatcat cagaggaaat atgtactacg aaaattccta tgccttagca 360<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> gtcttatcta actatgatgc aaataaaacc ggactgaagg agctgcccat gagaaattta 420<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> caggaaatcc tgcatggcgc cgtgcggttc agcaacaacc ctgccctgtg caacgtggag 480<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> agcatccagt ggcgggacat agtcagcagt gactttctca gcaacatgtc gatggacttc 540<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> cagaaccacc tgggcagctg ccaaaagtgt gatccaagct gtcccaatgg gagctgctgg 600<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> ggtgcaggag aggagaactg ccagaaactg accaaaatca tctgtgccca gcagtgctcc 660<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> gggcgctgcc gtggcaagtc ccccagtgac tgctgccaca accagtgtgc tgcaggctgc 720<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> acaggccccc gggagagcga ctgcctggtc tgccgcaaat tccgagacga agccacgtgc 780<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> aaggacacct gccccccact catgctctac aaccccacca cgtaccagat ggatgtgaac 840<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> cccgagggca aatacagctt tggtgccacc tgcgtgaaga agtgtccccg taattatgtg 900<h2 style=";text-align:left;direction:ltr"> gtgacagatc acggctcgtg cgtccgagcc tgtggggccg acagctatga gatggagga gacggcgtcc gcaagtgtaa gaagtgcgaa gggccttgcc gcaaagtgtg taacggaata ggtattggtg father ctcactctcc father cgate acacttcaaa aactgcacct ccatcagtgg cgatctccac atcctgccgg tggcatttag gggtgactcc ttcacacata ctcctcctct ggatccacag gaactggata ttctgaaaac cgtaagga atcacagggt ttttgctgat tcaggcttgg cctgaaaaca ggacggacct ccatgccttt gagaacctag aaatcatacg cggcaggacc aagcaacatg gtcagttttc tcttgcagtc gtcagcctga acataacatc cttgggatta cgctccctca aggagataag tgatggagat gtgataattt cage aaatttgtgc tatgcaata caataactg gaaaaaactg tttgggacct ccggtcagaa aaccaaaatt ataagcaaca gaggtgaaaa cagctgcaag gccacaggcc aggtctgcca tgccttgtgc tccccgagg gctgctgggg cccggagccc 1560 agggactgcg tctcttgccg gaatgtcagc cgaggcaggg aatgcgtgga caagtgcaac cttctggagg gtgagccaag ggagtttgtg gagaactctg agtgcataca gtgccaccca 1680 gagtgcctgc ctcaggccat gaacatcacc tgcacaggac ggggaccaga caactgtatc 1740 cagtgtgccc actacattga cggcccccac tgcgtcaaga cctgcccggc aggagtcatg 1800 ggagaaaaca acaccctggt ctggaagtac gcagacgccg gccatgtgtg ccacctgtgc 1860 catccaaact gcacctacgg atgcactggg ccaggtcttg aaggctgtcc aacgaatggg 1920 cctaagatcc cgtccatcgc cactgggatg gtgggggccc tcctcttgct gctggtggtg 1980 gccctgggga tcggcctctt catgcgaagg cgccacatcg ttcggaagcg cacgctgcgg 2040 aggctgctgc aggagaggga gcttgtggag cctcttacac ccagtggaga agctcccaac 2100 caagctctct tgaggatctt gaaggaaact gaattcaaaa agatcaaagt gctgggctcc 2160 ggtgcgttcg gcacggtgta taagggactc tggatcccag aaggtgagaa agttaaaatt 2220 cccgtcgcta tcaaggaatt aagagaagca acatctccga aagccaacaa ggaaatcctc 2280 gatgaagcct acgtgatggc cagcgtggac aacccccacg tgtgccgcct gctgggcatc 2340 tgcctcacct ccaccgtgca gctcatcacg cagctcatgc ccttcggctg cctcctggac 2400 tatgtccggg aacacaaaga caatattggc tcccagtacc tgctcaactg gtgtgtgcag 2460 atcgcaaagg gcatgaacta cttggaggac cgtcgcttgg tgcaccgcga cctggcagcc 2520 aggaacgtac tggtgaaaac accgcagcat gtcaagatca cagatttgg gctggccaaa 2580 ctgctgggtg cggaagagaa agaataccat gcagaaggag gcaaagtgcc tatcaagtgg 2640 atggcattgg aatcaatttt acacagaatc tatacccacc agagtgatgt ctggagctac 2700 ggggtgactg tttgggagtt gatgaccttt ggatccaagc catatgacgg aatccctgcc 2760 agcgagatct cctccatcct ggagaaagga gaacgcctcc ctcagccacc catatgtacc 2820 atcgatgtct acatgatcat ggtcaagtgc tggatgatag acgcagatag tcgcccaaag 2880 ttccgtgagt tgatcatcga attctccaaa atggcccgag acccccagcg ctaccttgtc 2940 attcaggggg atgaaagaat gcatttgcca agtcctacag actccaactt ctaccgtgcc 3000 ctgatggatg aagaagacat ggacgacgtg gtggatgccg acgagtacct catcccacag 3060 cagggcttct tcagcagccc ctccacgtca cggactcccc tcctgagctc tctgagtgca 3120 accagcaaca attccaccgt ggcttgcatt gatagaaatg ggctgcaaag ctgtcccatc 3180 aaggaagaca gcttcttgca gcgatacagc tcagacccca caggcgcctt gactgaggac 3240 agcatagacg acaccttcct cccagtgcct gaatacataa accagtccgt tcccaaaagg 3300 cccgctggct ctgtgcagaa tcctgtctat cacaatcagc ctctgaaccc cgcgcccagc 3360 agagacccac actaccagga cccccacagc actgcagtgg gcaaccccga gtatctcaac 3420 actgtccagc ccacctgtgt caacagcaca ttcgacagcc ctgcccactg ggcccagaaa 3480 ggcagccacc aaattagcct ggacaaccct gactaccagc aggacttctt tcccaaggaa 3540 gccaagccaa atggcatctt taagggctcc acagctgaaa atgcagaata cctaagggtc 3600 gcgccacaaa gcagtgaatt tattggagca 3630 <210> 14 <211> 1210 <212> PRT <213> Homo sapiens <400> 14 Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala 1 5 10 15 Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gln 20 25 30 Gly Thr Ser Asn Lys Leu Thr Gln Leu Gly Thr Phe Glu Asp His Phe 35 40 45 Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn 50 55 60 Leu Glu Ile Thr Tyr Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys 65 70 75 80 Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val 85 90 95 Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr 100 105 110 Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn 115 120 125 Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Glu Ile Leu 130 135 140 His Gly Ala Val Arg Phe Ser Asn Asn Pro Ala Leu Cys Asn Val Glu 145 150 155 160 Ser Ile Gln Trp Arg Asp Ile Val Ser Ser Asp Phe Leu Ser Asn Met 165 170 175 Ser Met Asp Phe Gln Asn His Leu Gly Ser Cys Gln Lys Cys Asp Pro 180 185 190 Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu Asn Cys Gln 195 200 205 Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly Arg Cys Arg 210 215 220 Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala Ala Gly Cys 225 230 235 240 Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys Phe Arg Asp 245 250 255 Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu Tyr Asn Pro 260 265 270 Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr Ser Phe Gly 275 280 285 Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val Thr Asp His 290 295 300 Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu Met Glu Glu 305 310 315 320 Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys Arg Lys Val 325 330 335 Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu Ser Ile Asn 340 345 350 Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp 355 360 365 Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr 370 375 380 Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu 385 390 395 400 Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn Arg Thr Asp 405 410 415 Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg Thr Lys Gln 420 425 430 His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile Thr Ser Leu 435 440 445 Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val Ile Ile Ser 450 455 460 Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp Lys Lys Leu 465 470 475 480 Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn Arg Gly Glu 485 490 495 Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu Cys Ser Pro 500 505 510 Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser Cys Arg Asn 515 520 525 Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu Leu Glu Gly 530 535 540 Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln Cys His Pro 545 550 555 560 Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly Arg Gly Pro 565 570 575 Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro His Cys Val 580 585 590 Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp 595 600 605 Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His Pro Asn Cys 610 615 620 Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro Thr Asn Gly 625 630 635 640 Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val Gly Ala Leu Leu Leu 645 650 655 Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe Met Arg Arg Arg His 660 665 670 Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu Gln Glu Arg Glu Leu 675 680 685 Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro Asn Gln Ala Leu Leu 690 695 700 Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile Lys Val Leu Gly Ser 705 710 715 720 Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp Ile Pro Glu Gly Glu 725 730 735 Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu Arg Glu Ala Thr Ser 740 745 750 Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala Tyr Val Met Ala Ser 755 760 765 Val Asp Asn Pro His Val Cys Arg Leu Leu Gly Ile Cys Leu Thr Ser 770 775 780 Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe Gly Cys Leu Leu Asp 785 790 795 800 Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser Gln Tyr Leu Leu Asn 805 810 815 Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr Leu Glu Asp Arg Arg 820 825 830 Leu Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Val Lys Thr Pro 835 840 845 Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala Lys Leu Leu Gly Ala 850 855 860 Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys Val Pro Ile Lys Trp 865 870 875 880 Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr Thr His Gln Ser Asp 885 890 895 Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe Gly Ser 900 905 910 Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile Ser Ser Ile Leu Glu 915 920 925 Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys Thr Ile Asp Val Tyr 930 935 940 Met Ile Met Val Lys Cys Trp Met Ile Asp Ala Asp Ser Arg Pro Lys 945 950 955 960 Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met Ala Arg Asp Pro Gln 965 970 975 Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met His Leu Pro Ser Pro 980 985 990 Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp Glu Glu Asp Met Asp 995 1000 1005 Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro Gln Gln Gly Phe 1010 1015 1020 Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu Ser Ser Leu 1025 1030 1035 Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp Arg Asn 1040 1045 1050 Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln Arg 1055 1060 1065 Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp 1070 1075 1080 Asp Thr Phe Leu Pro Val Pro Glu Tyr Ile Asn Gln Ser Val Pro 1085 1090 1095 Lys Arg Pro Ala Gly Ser Val Gln Asn Pro Val Tyr His Asn Gln 1100 1105 1110 Pro Leu Asn Pro Ala Pro Ser Arg Asp Pro His Tyr Gln Asp Pro 1115 1120 1125 His Ser Thr Ala Val Gly Asn Pro Glu Tyr Leu Asn Thr Val Gln 1130 1135 1140 Pro Thr Cys Val Asn Ser Thr Phe Asp Ser Pro Ala His Trp Ala 1145 1150 1155 Gln Lys Gly Ser His Gln Ile Ser Leu Asp Asn Pro Asp Tyr Gln 1160 1165 1170 Gln Asp Phe Phe Pro Lys Glu Ala Lys Pro Asn Gly Ile Phe Lys 1175 1180 1185 Gly Ser Thr Ala Glu Asn Ala Glu Tyr Leu Arg Val Ala Pro Gln 1190 1195 1200 Ser Ser Glu Phe Ile Gly Ala 1205 1210 <210> 15 <211> 327 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequence: Base sequence of A27 VL <400> 15 gaaatagtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120 cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180 gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240 cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcacctcc gtggacgttc 300 ggccaaggga ccaaggtgga aatcaaa 327 <210> 16 <211> 109 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of A27 VL <400> 16 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln 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 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 17 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of A27 LCDR1 <400> 17 Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala 1 5 10 <210> 18 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of A27 LCDR2 <400> 18 Gly Ala Ser Ser Arg Ala Thr 1 5 <210> 19 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of A27 LCDR3 <400> 19 Gln Gln Tyr Gly Ser Ser Pro Pro Trp Thr 1 5 10 <210> 20 <211> 366 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequence: Base sequence of PSM4072 VH <400> 20 gaggtgcagc tggtggagac tgggggaggc ttggtgcaac ctggggggtc cctgagactc 60 tcctgtacag cctctggatt cacctttgaa agtcatgcca tgtactgggt ccggcaagct 120 ccagggaagg ggctggagtg ggtctcgggt attagtaatg gaggtagtag cacagagtac 180 gcagactccg tgaggggccg gttcaccatt tccagagaca attccaagaa tacggtgtat 240 ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gagaccaaga 300 tctccatatc tcttctacga tgctgctggt gtctggggcc aagggaccct ggtcaccgtc 360 tcctca 366 <210> twenty one <211> 122 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of PSM4072 VH <400> twenty one Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Glu Ser His 20 25 30 Ala Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Asn Gly Gly Ser Ser Thr Glu Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Pro Arg Ser Pro Tyr Leu Phe Tyr Asp Ala Ala Gly Val Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> twenty two <211> 5 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of PSM4072 HCDR1 <400> twenty two Ser His Ala Met Tyr 1 5 <210> twenty three <211> 17 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of PSM4072 HCDR2 <400> twenty three Gly Ile Ser Asn Gly Gly Ser Ser Thr Glu Tyr Ala Asp Ser Val Arg 1 5 10 15 Gly <210> twenty four <211> 13 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of PSM4072 HCDR3 <400> twenty four Pro Arg Ser Pro Tyr Leu Phe Tyr Asp Ala Ala Gly Val 1 5 10 <210> 25 <211> 366 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequence: Base sequence of R327 VH <400> 25 gaggtgcagc tggtggagac cgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cagctttgac aagtatacca tgaactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagtt atttctaatg ggggagtttc tacagactac 180 gcagactccg ttaagggccg gttcaccgtc tccagagaca attccaagaa cacactgtac 240 ctgcaaatga acagcctgag agccgaggat atggccacat attactgtgc gcgtgcgagc 300 cagccgtggc tctataggac cggtgcggat gtgtggggcc aggggacaat ggtcaccgtc 360 tcttca 366 <210> 26 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of R327 VH <400> 26 Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Asp Lys Tyr 20 25 30 Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Ser Asn Gly Gly Val Ser Thr Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Met Ala Thr Tyr Tyr Cys 85 90 95 Ala Arg Ala Ser Gln Pro Trp Leu Tyr Arg Thr Gly Ala Asp Val Trp 100 105 110 Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 27 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of R327 HCDR1 <400> 27 Lys Tyr Thr Met Asn 1 5 <210> 28 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of R327 HCDR2 <400> 28 Val Ile Ser Asn Gly Gly Val Ser Thr Asp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 29 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of R327 HCDR3 <400> 29 Ala Ser Gln Pro Trp Leu Tyr Arg Thr Gly Ala Asp Val 1 5 10 <210> 30 <211> 366 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequence: Base sequence of TfR1071 VH <400> 30 tacgtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cagctttgac aagtatacca tgaactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagtt atttctaatg ggggagtttc tacagactac 180 gcagactccg ttaagggccg gttcaccgtc tccagagaca attccaagaa cacactgtac 240 ctgcaaatga acagcctgag agccgaggat atggccacat attactgtgc gcgtgcgagc 300 cagccgtggc tctataggac cggtgcggat gtgtggggcc aggggaccct ggtcaccgtc 360 tcctca 366 <210> 31 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Description of artificial sequence: Amino acid sequence of TfR1071 VH <400> 31 Tyr Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Asp Lys Tyr 20 25 30 Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Ser Asn Gly Gly Val Ser Thr Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Met Ala Thr Tyr Tyr Cys 85 90 95 Ala Arg Ala Ser Gln Pro Trp Leu Tyr Arg Thr Gly Ala Asp Val Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 32 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of TfR1071 HCDR1 <400> 32 Lys Tyr Thr Met Asn 1 5 <210> 33 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of TfR1071 HCDR2 <400> 33 Val Ile Ser Asn Gly Gly Val Ser Thr Asp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 34 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of TfR1071 HCDR3 <400> 34 Ala Ser Gln Pro Trp Leu Tyr Arg Thr Gly Ala Asp Val 1 5 10 <210> 35 <211> 366 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequence: Base sequence of TfR4016 VH <400> 35 tacgtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cagctttgac aagtatacca tgaactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagtt atttctaatg ggggagtttc tacagactac 180 gcagactccg ttaagggccg gttcaccgtc tccagagaca attccaagaa cacactgtac 240 ctgcaaatga acagcctgag agccgaggat atggccacat attactgtgc gcgtgcgagc 300 cagccgtggc tctataggac cggtgcggat gtgtggggcc aggggaccac ggtcaccgtc 360 tcctca 366 <210> 36 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of TfR4016 VH <400> 36 Tyr Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Asp Lys Tyr 20 25 30 Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Ser Asn Gly Gly Val Ser Thr Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Met Ala Thr Tyr Tyr Cys 85 90 95 Ala Arg Ala Ser Gln Pro Trp Leu Tyr Arg Thr Gly Ala Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 37 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of TfR4016 HCDR1 <400> 37 Lys Tyr Thr Met Asn 1 5 <210> 38 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of TfR4016 HCDR2 <400> 38 Val Ile Ser Asn Gly Gly Val Ser Thr Asp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 39 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of TfR4016 HCDR3 <400> 39 Ala Ser Gln Pro Trp Leu Tyr Arg Thr Gly Ala Asp Val 1 5 10 <210> 40 <211> 366 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequence: Base sequence of cyno186 VH <400> 40 caggtgcagc tggtggagtc tggggggagaa ttcgtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cccctttaaa ggctatgcca tgaattgggt ccgccaggct 120 ccagggaagg gattggagtg ggtctcaaga ataagtaatg gtggtagcta catagactac 180 gcagactccg taaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240 ttgcaaatag acagcctgag aaccgaggac acggccgtat attactgtgc gaaagcgaag 300 gacgcctata ggtggaacaa cgctatagac gaatggggcc aagggaccct ggtcaccgtc 360 tcctca 366 <210> 41 <211> 122 <212> PRT <213> artificial sequence <220> <223> Artificial sequence Description: Amino acid sequence of cyno186 VH <400> 41 Gln Val Gln Leu Val Glu Ser Gly Gly Glu Phe Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Pro Phe Lys Gly Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Arg Ile Ser Asn Gly Gly Ser Tyr Ile Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Ile Asp Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ala Lys Asp Ala Tyr Arg Trp Asn Asn Ala Ile Asp Glu Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 42 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of cyno186 HCDR1 <400> 42 Gly Tyr Ala Met Asn 1 5 <210> 43 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of cyno186 HCDR2 <400> 43 Arg Ile Ser Asn Gly Gly Ser Tyr Ile Asp Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 44 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of cyno186 HCDR3 <400> 44 Ala Lys Asp Ala Tyr Arg Trp Asn Asn Ala Ile Asp Glu 1 5 10 <210> 45 <211> 366 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequence: Base sequence of cyno292 VH <400> 45 caggtgcagc tggtgcaatc tgggggaggc ctggtcaagc ctggggggtc cctgagaatc 60 tcctgtacaa cctctggatt cccctttgat ggctatacca tgacctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcaagt attagtaatg gtggtagcac cattttcgtc 180 tcagactcag tgagaggccg attcaccatc tccagagaca acgccaagaa ttcactgtat 240 ctccaaatga acaacgtggg agccgaggac acggctgtgt attactgtgc gagagctcga 300 gatgcgtatg gctggacgct tccttctgac atctggggcc aagggacaat ggtcaccgtc 360 tcttca 366 <210> 46 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of cyno292 VH <400> 46 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Ile Ser Cys Thr Thr Ser Gly Phe Pro Phe Asp Gly Tyr 20 25 30 Thr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Asn Gly Gly Ser Thr Ile Phe Val Ser Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Asn Val Gly Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Arg Asp Ala Tyr Gly Trp Thr Leu Pro Ser Asp Ile Trp 100 105 110 Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 47 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of cyno292 HCDR1 <400> 47 Gly Tyr Thr Met Thr 1 5 <210> 48 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of cyno292 HCDR2 <400> 48 Ser Ile Ser Asn Gly Gly Ser Thr Ile Phe Val Ser Asp Ser Val Arg 1 5 10 15 Gly <210> 49 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of cyno292 HCDR3 <400> 49 Ala Arg Asp Ala Tyr Gly Trp Thr Leu Pro Ser Asp Ile 1 5 10 <210> 50 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of TfR1007 VH <400> 50 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Lys Gly Tyr 20 25 30 Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Leu Ser Asn Gly Gly Gly Ser Ser Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Thr Leu Gly Ala Tyr Tyr Ile Lys Ser Ala Met Asp Val Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 51 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of cyno163 VH <400> 51 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Asn Gly Gly Ser Ser Thr Glu Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Pro Arg Ser Pro Tyr Leu Phe Tyr Asp Ala Ala Gly Val Trp 100 105 110 Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 52 <211> 123 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: 22-30 VH amino acid sequence <400> 52 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Arg Leu Ser Ser Val Thr Thr Ala Asp Thr Ala Leu Tyr Tyr Cys Thr 85 90 95 Arg Glu Ala Gly Tyr Tyr Asp Ser Ser Gly Tyr Tyr Gly Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 53 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: 22-30 VL amino acid sequence <400> 53 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 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr Tyr Asn Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 54 <211> 114 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of T14 VH <400> 54 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Val Ser Gly Gly Thr Phe Ser Asn Phe 20 25 30 Asn Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Gly Ser Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Ser Ser Ser Trp Tyr Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser <210> 55 <211> 123 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of TfR434 VH <400> 55 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Pro Phe Lys Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Ser Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Gly Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Asn Phe Trp Ser Gly Tyr Tyr Ser Pro Val Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 56 <211> 123 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of TfR435 VH <400> 56 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Pro Phe Lys Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Gly Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Asn Phe Trp Ser Gly Tyr Tyr Ser Pro Val Asp Val 100 105 110 Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 57 <211> 111 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of TfR434,435 VL <400> 57 Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu Ser Pro Gly Lys 1 5 10 15 Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Ser Ile Ala Ser Asn 20 25 30 Ser Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ala Pro Ile Thr Val 35 40 45 Ile Tyr Glu Asp Thr Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Ile Asp Ser Ser Ser Asn Ser Ala Ser Leu Thr Ile Ser Gly 65 70 75 80 Leu Gln Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser 85 90 95 Ala Tyr His Trp Val Phe Gly Gly Gly Thr Lys Leu Ala Val Leu 100 105 110 <210> 58 <211> 366 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequence: Base sequence of E08 VH <400> 58 gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly tcctgtgcag cctctggatt cagctttaac aacaatgcca tgaactgggt ccgtcaggct 120 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Asn Asn Asn Ala Met Asn Trp Val Arg Gln Ala ccagggaagg ggctggagtg ggtctcaggt attcgtgccg atggcggtac gacatactac 180 Pro Gly Lys Gly Leu Glu Trp Val Ser Arg Ile Ser Cys Arg Met Ala Gly Tyr Asp Ile Tyr Tyr gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacactgtat 240 Ala Asp Ser Val Lys Gly Pro Val His Ile Ser Arg Asp Asn Pro Lys Asn Thr Cys Tyr ctgcaaatga acagcctgag agccgaggac acggccgtat atttctgtgg aaagacgcct 300 Leu Gln Met Asn Ser Leu Glu Ser Glu Asp Thr Ala Val Tyr Ile Ser Trp Lys Asp Ala Pro gactgggaaa tcttctacta cgctatggac gcctggggcc aagggaccac ggtcaccgtc 360 Asp Trp Glu Ile Phe Tyr Tyr Ala Met Asp Ala Trp Gly Gln Gly Thr His Val Thr Val tcctca 366 Ser Leu <210> 59<210> 59 <211> 122<211> 122 <212> PRT<212> PRT <213> 人工序列<213> Artificial Sequence <220><220> <223> 人工序列的描述: E08 VH的氨基酸序列 <223> Description of Artificial Sequence: Amino acid sequence of E08 VH <400> 59 <400> 59 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Asn Asn Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Asn Asn Asn 20 25 30 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 35 40 45 Ser Gly Ile Arg Ala Asp Gly Gly Thr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Gly Lys Thr Pro Asp Trp Glu Ile Phe Tyr Tyr Ala Met Asp Ala Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 60 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: E08 HCDR1 amino acid sequence <400> 60 Asn Asn Ala Met Asn 1 5 <210> 61 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: E08 HCDR2 amino acid sequence <400> 61 Gly Ile Arg Ala Asp Gly Gly Thr Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 62 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: E08 HCDR3 amino acid sequence <400> 62 Thr Pro Asp Trp Glu Ile Phe Tyr Tyr Ala Met Asp Ala 1 5 10 <210> 63 <211> 363 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequence: Base sequence of E12 VH <400> 63 caggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctagatt cacctttagc gcctatgcca tgggctgggt gcgccaggct 120 ccagggaagg ggctggagtg ggtctcaatt attgatagtg gtggtgtgta cacatactac 180 gcagactcca tgaagggccg cttcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agccgaggac acggccgtatattactgtgc gagagatcat 300 tatggtgttg tttggggact tggagattac tggggccagg gaaccctggt cactgtctcc 360 tca 363 <210> 64 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of E12 VH <400> 64 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Ser Ala Tyr 20 25 30 Ala Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ile Ile Asp Ser Gly Gly Val Tyr Thr Tyr Tyr Tyr Ala Asp Ser Met 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp His Tyr Gly Val Val Trp Gly Leu Gly Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 65 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of E12 HCDR1 <400> 65 Ala Tyr Ala Met Gly 1 5 <210> 66 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of E12 HCDR2 <400> 66 Ile Ile Asp Ser Gly Gly Val Tyr Thr Tyr Tyr Tyr Ala Asp Ser Met Lys 1 5 10 15 Gly <210> 67 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of E12 HCDR3 <400> 67 Asp His Tyr Gly Val Val Trp Gly Leu Gly Asp Tyr 1 5 10 <210> 68 <211> 354 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequence: Base sequence of E17 VH <400> 68 caggtgcagc tacagcagtg gggcgcagga ctgttgaagc cttcggagac tctgtccctc 60 acctgcgcac tgtacagtgg gtccttcagt gctcaggact ggagctggat ccgccagtcc 120 ccagagaagg ggctggagtg gattggggaa atctggcaag ggggaaaaac caactacaac 180 ccgtccctca agagtcgagt tagtatatca agagacaact ccaagaacca gttgtccctg 240 cagctgagct ctgtgaccgc cgcggacacg gctgtgtatt actgtgcgag ggtggactgg 300 tcttatcgtg tttttgaaat ctggggccaa gggacaatgg tcaccgtctc ttca 354 <210> 69 <211> 118 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: E17 VH amino acid sequence <400> 69 Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Leu Tyr Ser Gly Ser Phe Ser Ala Gln 20 25 30 Asp Trp Ser Trp Ile Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Trp Gln Gly Gly Lys Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Ser Ile Ser Arg Asp Asn Ser Lys Asn Gln Leu Ser Leu 65 70 75 80 Gln Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Val Asp Trp Ser Tyr Arg Val Phe Glu Ile Trp Gly Gln Gly Thr 100 105 110 Met Val Thr Val Ser Ser 115 <210> 70 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of E17 HCDR1 <400> 70 Ala Gln Asp Trp Ser 1 5 <210> 71 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of E17 HCDR2 <400> 71 Glu Ile Trp Gln Gly Gly Lys Thr Asn Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <210> 72 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of E17 HCDR3 <400> 72 Val Asp Trp Ser Tyr Arg Val Phe Glu Ile 1 5 10 <210> 73 <211> 123 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of KME07 VH <400> 73 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Phe 20 25 30 Ala Phe Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Glu Val Arg Pro Gly Phe Gly Thr Glu Ile Leu Thr Gln Asn Phe 50 55 60 Gln Asp Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Thr Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Lys Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Leu Leu Arg Gly Gly Tyr Ile Glu Asn Pro Phe Glu Ile 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 74 <211> 123 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of KME09 VH <400> 74 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Phe 20 25 30 Ala Trp Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Glu Ile Arg Pro Gly Phe Gly Thr Glu Ile Tyr Ala Gln Asn Phe 50 55 60 Gln Asp Arg Val Thr Phe Ile Thr Asp Glu Ala Thr Ser Thr Thr Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Lys Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Leu Leu Arg Ser Gly Tyr Ile Asp Asn Pro Cys Asp Ile 100 105 110 Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 75 <211> 125 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of KME11 VH <400> 75 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Leu Ser Thr Tyr 20 25 30 Gly Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Phe Ala Trp Met 35 40 45 Gly Glu Ile Ile Pro Ser Leu Gly Ile Val Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Val Thr Tyr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Gly Asp Glu Leu Ser Glu Gly His Ser Glu Tyr Tyr His Gly Met 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 76 <211> 119 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of Cetuximab VH <400> 76 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala 115 <210> 77 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of Cetuximab VL <400> 77 Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn 20 25 30 Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile 35 40 45 Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser 65 70 75 80 Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <210> 78 <211> 117 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of HN3 VH <400> 78 Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Tyr Phe Asp Phe Asp Ser Tyr 20 25 30 Glu Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr His Ser Gly Ser Thr Thr Tyr Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Thr Leu Arg Ala Glu Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Arg Val Asn Met Asp Arg Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Ser 115 <210> 79 <211> 2 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of linker <400> 79 Glu Ser 1 <210> 80 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of linker <400> 80 Glu Ser Lys Tyr Gly 1 5 <210> 81 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of linker <400> 81 Glu Ser Lys Tyr Gly Pro Pro 1 5 <210> 82 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of linker <400> 82 Gly Gly Gly Gly Ser 1 5 <210> 83 <211> 981 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequence: IgG4PE R409K constant region base sequence <400> 83 gctagcacca aggggccatc cgtcttcccc ctggcgccct gctccaggag cacctccgag 60 agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 240 tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 300 aaatatggtc ccccatgccc accatgccca gcacctgagt tcgagggggg accatcagtc 360 ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 420 tgcgtggtgg tggacgtgag ccaggaagac cccgaggtcc agttcaactg gtacgtggat 480 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 540 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 600 tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 660 gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 720 aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 780 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 840 gacggctcct tcttcctcta cagcaagcta accgtggaca agagcaggtg gcaggagggg 900 aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 960 ctctccctgt ctctgggtaa a 981 <210> 84 <211> 327 <212> PRT <213> Artificial Sequence <220> <223> Description of artificial sequence: Amino acid sequence of the constant region of IgG4PE R409K <400> 84 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 100 105 110 Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 145 150 155 160 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 165 170 175 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys 225 230 235 240 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 260 265 270 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 305 310 315 320 Leu Ser Leu Ser Leu Gly Lys 325 <210> 85 <211> 294 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequence: Base sequence of modified codons of IgG4 CH1 <400> 85 gctagcacca aaggaccttc tgtatttcct cttgcgccat gctctcgctc tacgtcagaa 60 tcaactgccg ctctggggtg cctggttaaa gactacttcc cggagcctgt gacagtgagt 120 tggaactccg gcgccctgac atcaggagtg catacatttc ccgccgtgct tcagagcagc 180 ggactttata gcctcagcag tgtggtgacc gtgccatctt ccagcctggg gaccaagacc 240 tacacctgta acgtggacca caaacccagc aacaccaagg ttgataagag ggtc 294 <210> 86 <211> 327 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of IgG4PE constant region <400> 86 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr 65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 100 105 110 Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 145 150 155 160 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 165 170 175 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys 225 230 235 240 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 260 265 270 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 305 310 315 320 Leu Ser Leu Ser Leu Gly Lys 325 <210> 87 <211> 763 <212> PRT <213> Mouse <400> 87 Met Met Asp Gln Ala Arg Ser Ala Phe Ser Asn Leu Phe Gly Gly Glu 1 5 10 15 Pro Leu Ser Tyr Thr Arg Phe Ser Leu Ala Arg Gln Val Asp Gly Asp 20 25 30 Asn Ser His Val Glu Met Lys Leu Ala Ala Asp Glu Glu Glu Asn Ala 35 40 45 Asp Asn Asn Met Lys Ala Ser Val Arg Lys Pro Lys Arg Phe Asn Gly 50 55 60 Arg Leu Cys Phe Ala Ala Ile Ala Leu Val Ile Phe Phe Leu Ile Gly 65 70 75 80 Phe Met Ser Gly Tyr Leu Gly Tyr Cys Lys Arg Val Glu Gln Lys Glu 85 90 95 Glu Cys Val Lys Leu Ala Glu Thr Glu Glu Thr Asp Lys Ser Glu Thr 100 105 110 Met Glu Thr Glu Asp Val Pro Thr Ser Ser Arg Leu Tyr Trp Ala Asp 115 120 125 Leu Lys Thr Leu Leu Ser Glu Lys Leu Asn Ser Ile Glu Phe Ala Asp 130 135 140 Thr Ile Lys Gln Leu Ser Gln Asn Thr Tyr Thr Pro Arg Glu Ala Gly 145 150 155 160 Ser Gln Lys Asp Glu Ser Leu Ala Tyr Tyr Ile Glu Asn Gln Phe His 165 170 175 Glu Phe Lys Phe Ser Lys Val Trp Arg Asp Glu His Tyr Val Lys Ile 180 185 190 Gln Val Lys Ser Ser Ile Gly Gln Asn Met Val Thr Ile Val Gln Ser 195 200 205 Asn Gly Asn Leu Asp Pro Val Glu Ser Pro Glu Gly Tyr Val Ala Phe 210 215 220 Ser Lys Pro Thr Glu Val Ser Gly Lys Leu Val His Ala Asn Phe Gly 225 230 235 240 Thr Lys Lys Asp Phe Glu Glu Leu Ser Tyr Ser Val Asn Gly Ser Leu 245 250 255 Val Ile Val Arg Ala Gly Glu Ile Thr Phe Ala Glu Lys Val Ala Asn 260 265 270 Ala Gln Ser Phe Asn Ala Ile Gly Val Leu Ile Tyr Met Asp Lys Asn 275 280 285 Lys Phe Pro Val Val Glu Ala Asp Leu Ala Leu Phe Gly His Ala His 290 295 300 Leu Gly Thr Gly Asp Pro Tyr Thr Pro Gly Phe Pro Ser Phe Asn His 305 310 315 320 Thr Gln Phe Pro Pro Ser Gln Ser Ser Gly Leu Pro Asn Ile Pro Val 325 330 335 Gln Thr Ile Ser Arg Ala Ala Ala Glu Lys Leu Phe Gly Lys Met Glu 340 345 350 Gly Ser Cys Pro Ala Arg Trp Asn Ile Asp Ser Ser Cys Lys Leu Glu 355 360 365 Leu Ser Gln Asn Gln Asn Val Lys Leu Ile Val Lys Asn Val Leu Lys 370 375 380 Glu Arg Arg Ile Leu Asn Ile Phe Gly Val Ile Lys Gly Tyr Glu Glu 385 390 395 400 Pro Asp Arg Tyr Val Val Val Gly Ala Gln Arg Asp Ala Leu Gly Ala 405 410 415 Gly Val Ala Ala Lys Ser Ser Val Gly Thr Gly Leu Leu Leu Lys Leu 420 425 430 Ala Gln Val Phe Ser Asp Met Ile Ser Lys Asp Gly Phe Arg Pro Ser 435 440 445 Arg Ser Ile Ile Phe Ala Ser Trp Thr Ala Gly Asp Phe Gly Ala Val 450 455 460 Gly Ala Thr Glu Trp Leu Glu Gly Tyr Leu Ser Ser Leu His Leu Lys 465 470 475 480 Ala Phe Thr Tyr Ile Asn Leu Asp Lys Val Val Leu Gly Thr Ser Asn 485 490 495 Phe Lys Val Ser Ala Ser Pro Leu Leu Tyr Thr Leu Met Gly Lys Ile 500 505 510 Met Gln Asp Val Lys His Pro Val Asp Gly Lys Ser Leu Tyr Arg Asp 515 520 525 Ser Asn Trp Ile Ser Lys Val Glu Lys Leu Ser Phe Asp Asn Ala Ala 530 535 540 Tyr Pro Phe Leu Ala Tyr Ser Gly Ile Pro Ala Val Ser Phe Cys Phe 545 550 555 560 Cys Glu Asp Ala Asp Tyr Pro Tyr Leu Gly Thr Arg Leu Asp Thr Tyr 565 570 575 Glu Ala Leu Thr Gln Lys Val Pro Gln Leu Asn Gln Met Val Arg Thr 580 585 590 Ala Ala Glu Val Ala Gly Gln Leu Ile Ile Lys Leu Thr His Asp Val 595 600 605 Glu Leu Asn Leu Asp Tyr Glu Met Tyr Asn Ser Lys Leu Leu Ser Phe 610 615 620 Met Lys Asp Leu Asn Gln Phe Lys Thr Asp Ile Arg Asp Met Gly Leu 625 630 635 640 Ser Leu Gln Trp Leu Tyr Ser Ala Arg Gly Asp Tyr Phe Arg Ala Thr 645 650 655 Ser Arg Leu Thr Thr Asp Phe His Asn Ala Glu Lys Thr Asn Arg Phe 660 665 670 Val Met Arg Glu Ile Asn Asp Arg Ile Met Lys Val Glu Tyr His Phe 675 680 685 Leu Ser Pro Tyr Val Ser Pro Arg Glu Ser Pro Phe Arg His Ile Phe 690 695 700 Trp Gly Ser Gly Ser His Thr Leu Ser Ala Leu Val Glu Asn Leu Lys 705 710 715 720 Leu Arg Gln Lys Asn Ile Thr Ala Phe Asn Glu Thr Leu Phe Arg Asn 725 730 735 Gln Leu Ala Leu Ala Thr Trp Thr Ile Gln Gly Val Ala Asn Ala Leu 740 745 750 Ser Gly Asp Ile Trp Asn Ile Asp Asn Glu Phe 755 760 <210> 88 <211> 672 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of the mouse chimera of the apical domain of the human TfR extracellular domain <400> 88 Cys Lys Gly Val Glu Pro Lys Thr Glu Cys Glu Arg Leu Ala Gly Thr 1 5 10 15 Glu Ser Pro Val Arg Glu Glu Pro Gly Glu Asp Phe Pro Ala Ala Arg 20 25 30 Arg Leu Tyr Trp Asp Asp Leu Lys Arg Lys Leu Ser Glu Lys Leu Asp 35 40 45 Ser Thr Asp Phe Thr Gly Thr Ile Lys Leu Leu Asn Glu Asn Ser Tyr 50 55 60 Val Pro Arg Glu Ala Gly Ser Gln Lys Asp Glu Asn Leu Ala Leu Tyr 65 70 75 80 Val Glu Asn Gln Phe Arg Glu Phe Lys Leu Ser Lys Val Trp Arg Asp 85 90 95 Gln His Phe Val Lys Ile Gln Val Lys Ser Ser Ile Gly Gln Asn Met 100 105 110 Val Thr Ile Val Gln Ser Asn Gly Asn Leu Asp Pro Val Glu Ser Pro 115 120 125 Glu Gly Tyr Val Ala Phe Ser Lys Pro Thr Glu Val Ser Gly Lys Leu 130 135 140 Val His Ala Asn Phe Gly Thr Lys Lys Asp Phe Glu Glu Leu Ser Tyr 145 150 155 160 Ser Val Asn Gly Ser Leu Val Ile Val Arg Ala Gly Glu Ile Thr Phe 165 170 175 Ala Glu Lys Val Ala Asn Ala Gln Ser Phe Asn Ala Ile Gly Val Leu 180 185 190 Ile Tyr Met Asp Lys Asn Lys Phe Pro Val Val Glu Ala Asp Leu Ala 195 200 205 Leu Phe Gly His Ala His Leu Gly Thr Gly Asp Pro Tyr Thr Pro Gly 210 215 220 Phe Pro Ser Phe Asn His Thr Gln Phe Pro Pro Ser Gln Ser Ser Gly 225 230 235 240 Leu Pro Asn Ile Pro Val Gln Thr Ile Ser Arg Ala Ala Ala Glu Lys 245 250 255 Leu Phe Gly Lys Met Glu Gly Ser Cys Pro Ala Arg Trp Asn Ile Asp 260 265 270 Ser Ser Cys Lys Leu Glu Leu Ser Gln Asn Gln Asn Val Lys Leu Ile 275 280 285 Val Lys Asn Val Leu Lys Glu Ile Lys Ile Leu Asn Ile Phe Gly Val 290 295 300 Ile Lys Gly Phe Val Glu Pro Asp His Tyr Val Val Val Gly Ala Gln 305 310 315 320 Arg Asp Ala Trp Gly Pro Gly Ala Ala Lys Ser Gly Val Gly Thr Ala 325 330 335 Leu Leu Leu Lys Leu Ala Gln Met Phe Ser Asp Met Val Leu Lys Asp 340 345 350 Gly Phe Gln Pro Ser Arg Ser Ile Ile Phe Ala Ser Trp Ser Ala Gly 355 360 365 Asp Phe Gly Ser Val Gly Ala Thr Glu Trp Leu Glu Gly Tyr Leu Ser 370 375 380 Ser Leu His Leu Lys Ala Phe Thr Tyr Ile Asn Leu Asp Lys Ala Val 385 390 395 400 Leu Gly Thr Ser Asn Phe Lys Val Ser Ala Ser Pro Leu Leu Tyr Thr 405 410 415 Leu Ile Glu Lys Thr Met Gln Asn Val Lys His Pro Val Thr Gly Gln 420 425 430 Phe Leu Tyr Gln Asp Ser Asn Trp Ala Ser Lys Val Glu Lys Leu Thr 435 440 445 Leu Asp Asn Ala Ala Phe Pro Phe Leu Ala Tyr Ser Gly Ile Pro Ala 450 455 460 Val Ser Phe Cys Phe Cys Glu Asp Thr Asp Tyr Pro Tyr Leu Gly Thr 465 470 475 480 Thr Met Asp Thr Tyr Lys Glu Leu Ile Glu Arg Ile Pro Glu Leu Asn 485 490 495 Lys Val Ala Arg Ala Ala Ala Glu Val Ala Gly Gln Phe Val Ile Lys 500 505 510 Leu Thr His Asp Val Glu Leu Asn Leu Asp Tyr Glu Arg Tyr Asn Ser 515 520 525 Gln Leu Leu Ser Phe Val Arg Asp Leu Asn Gln Tyr Arg Ala Asp Ile 530 535 540 Lys Glu Met Gly Leu Ser Leu Gln Trp Leu Tyr Ser Ala Arg Gly Asp 545 550 555 560 Phe Phe Arg Ala Thr Ser Arg Leu Thr Thr Asp Phe Gly Asn Ala Glu 565 570 575 Lys Thr Asp Arg Phe Val Met Lys Lys Leu Asn Asp Arg Val Met Arg 580 585 590 Val Glu Tyr His Phe Leu Ser Pro Tyr Val Ser Pro Lys Glu Ser Pro 595 600 605 Phe Arg His Val Phe Trp Gly Ser Gly Ser His Thr Leu Pro Ala Leu 610 615 620 Leu Glu Asn Leu Lys Leu Arg Lys Gln Asn Asn Gly Ala Phe Asn Glu 625 630 635 640 Thr Leu Phe Arg Asn Gln Leu Ala Leu Ala Thr Trp Thr Ile Gln Gly 645 650 655 Ala Ala Asn Ala Leu Ser Gly Asp Val Trp Asp Ile Asp Asn Glu Phe 660 665 670 <210> 89 <211> 675 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of the mouse chimera of the protease-like domain of the human TfR extracellular domain <400> 89 Cys Lys Arg Val Glu Gln Lys Glu Glu Cys Val Lys Leu Ala Glu Thr 1 5 10 15 Glu Glu Thr Asp Lys Ser Glu Thr Met Glu Thr Glu Asp Val Pro Thr 20 25 30 Ser Ser Arg Leu Tyr Trp Ala Asp Leu Lys Thr Leu Leu Ser Glu Lys 35 40 45 Leu Asn Ser Ile Glu Phe Ala Asp Thr Ile Lys Gln Leu Ser Gln Asn 50 55 60 Thr Tyr Thr Pro Arg Glu Ala Gly Ser Gln Lys Asp Glu Ser Leu Ala 65 70 75 80 Tyr Tyr Ile Glu Asn Gln Phe His Glu Phe Lys Phe Ser Lys Val Trp 85 90 95 Arg Asp Glu His Tyr Val Lys Ile Gln Val Lys Asp Ser Ala Gln Asn 100 105 110 Ser Val Ile Ile Val Asp Lys Asn Gly Arg Leu Val Tyr Leu Val Glu 115 120 125 Asn Pro Gly Gly Tyr Val Ala Tyr Ser Lys Ala Ala Thr Val Thr Gly 130 135 140 Lys Leu Val His Ala Asn Phe Gly Thr Lys Lys Asp Phe Glu Asp Leu 145 150 155 160 Tyr Thr Pro Val Asn Gly Ser Ile Val Ile Val Arg Ala Gly Lys Ile 165 170 175 Thr Phe Ala Glu Lys Val Ala Asn Ala Glu Ser Leu Asn Ala Ile Gly 180 185 190 Val Leu Ile Tyr Met Asp Gln Thr Lys Phe Pro Ile Val Asn Ala Glu 195 200 205 Leu Ser Phe Phe Gly His Ala His Leu Gly Thr Gly Asp Pro Tyr Thr 210 215 220 Pro Gly Phe Pro Ser Phe Asn His Thr Gln Phe Pro Pro Ser Arg Ser 225 230 235 240 Ser Gly Leu Pro Asn Ile Pro Val Gln Thr Ile Ser Arg Ala Ala Ala 245 250 255 Glu Lys Leu Phe Gly Asn Met Glu Gly Asp Cys Pro Ser Asp Trp Lys 260 265 270 Thr Asp Ser Thr Cys Arg Met Val Thr Ser Glu Ser Lys Asn Val Lys 275 280 285 Leu Thr Val Ser Asn Val Leu Lys Glu Arg Arg Ile Leu Asn Ile Phe 290 295 300 Gly Val Ile Lys Gly Tyr Glu Glu Pro Asp Arg Tyr Val Val Val Gly 305 310 315 320 Ala Gln Arg Asp Ala Leu Gly Ala Gly Val Ala Ala Lys Ser Ser Val 325 330 335 Gly Thr Gly Leu Leu Leu Lys Leu Ala Gln Val Phe Ser Asp Met Ile 340 345 350 Ser Lys Asp Gly Phe Arg Pro Ser Arg Ser Ile Ile Phe Ala Ser Trp 355 360 365 Thr Ala Gly Asp Phe Gly Ala Val Gly Ala Thr Glu Trp Leu Glu Gly 370 375 380 Tyr Leu Ser Ser Leu His Leu Lys Ala Phe Thr Tyr Ile Asn Leu Asp 385 390 395 400 Lys Val Val Leu Gly Thr Ser Asn Phe Lys Val Ser Ala Ser Pro Leu 405 410 415 Leu Tyr Thr Leu Met Gly Lys Ile Met Gln Asp Val Lys His Pro Val 420 425 430 Asp Gly Lys Ser Leu Tyr Arg Asp Ser Asn Trp Ile Ser Lys Val Glu 435 440 445 Lys Leu Ser Phe Asp Asn Ala Ala Tyr Pro Phe Leu Ala Tyr Ser Gly 450 455 460 Ile Pro Ala Val Ser Phe Cys Phe Cys Glu Asp Ala Asp Tyr Pro Tyr 465 470 475 480 Leu Gly Thr Arg Leu Asp Thr Tyr Glu Ala Leu Thr Gln Lys Val Pro 485 490 495 Gln Leu Asn Gln Met Val Arg Thr Ala Ala Glu Val Ala Gly Gln Leu 500 505 510 Ile Ile Lys Leu Thr His Asp Val Glu Leu Asn Leu Asp Tyr Glu Arg 515 520 525 Tyr Asn Ser Gln Leu Leu Ser Phe Val Arg Asp Leu Asn Gln Tyr Arg 530 535 540 Ala Asp Ile Lys Glu Met Gly Leu Ser Leu Gln Trp Leu Tyr Ser Ala 545 550 555 560 Arg Gly Asp Phe Phe Arg Ala Thr Ser Arg Leu Thr Thr Asp Phe Gly 565 570 575 Asn Ala Glu Lys Thr Asp Arg Phe Val Met Lys Lys Leu Asn Asp Arg 580 585 590 Val Met Arg Val Glu Tyr His Phe Leu Ser Pro Tyr Val Ser Pro Lys 595 600 605 Glu Ser Pro Phe Arg His Val Phe Trp Gly Ser Gly Ser His Thr Leu 610 615 620 Pro Ala Leu Leu Glu Asn Leu Lys Leu Arg Lys Gln Asn Asn Gly Ala 625 630 635 640 Phe Asn Glu Thr Leu Phe Arg Asn Gln Leu Ala Leu Ala Thr Trp Thr 645 650 655 Ile Gln Gly Ala Ala Asn Ala Leu Ser Gly Asp Val Trp Asp Ile Asp 660 665 670 Asn Glu Phe 675 <210> 90 <211> 672 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of A01 <400> 90 Cys Lys Gly Val Glu Pro Lys Thr Glu Cys Glu Arg Leu Ala Gly Thr 1 5 10 15 Glu Ser Pro Val Arg Glu Glu Pro Gly Glu Asp Phe Pro Ala Ala Arg 20 25 30 Arg Leu Tyr Trp Asp Asp Leu Lys Arg Lys Leu Ser Glu Lys Leu Asp 35 40 45 Ser Thr Asp Phe Thr Gly Thr Ile Lys Leu Leu Asn Glu Asn Ser Tyr 50 55 60 Val Pro Arg Glu Ala Gly Ser Gln Lys Asp Glu Asn Leu Ala Leu Tyr 65 70 75 80 Val Glu Asn Gln Phe Arg Glu Phe Lys Leu Ser Lys Val Trp Arg Asp 85 90 95 Gln His Phe Val Lys Ile Gln Val Lys Asp Ser Ala Gln Asn Ser Val 100 105 110 Ile Ile Val Asp Lys Asn Gly Arg Leu Val Tyr Leu Val Glu Asn Pro 115 120 125 Gly Gly Tyr Val Ala Tyr Ser Lys Ala Ala Thr Val Thr Gly Lys Leu 130 135 140 Val His Ala Asn Phe Gly Thr Lys Lys Asp Phe Glu Asp Leu Tyr Thr 145 150 155 160 Pro Val Asn Gly Ser Ile Val Ile Val Arg Ala Gly Lys Ile Thr Phe 165 170 175 Ala Glu Lys Val Ala Asn Ala Glu Ser Leu Asn Ala Ile Gly Val Leu 180 185 190 Ile Tyr Met Asp Lys Asn Lys Phe Pro Ile Val Asn Ala Glu Leu Ser 195 200 205 Phe Phe Gly His Ala His Leu Gly Thr Gly Asp Pro Tyr Thr Pro Gly 210 215 220 Phe Pro Ser Phe Asn His Thr Gln Phe Pro Pro Ser Arg Ser Ser Gly 225 230 235 240 Leu Pro Asn Ile Pro Val Gln Thr Ile Ser Arg Ala Ala Ala Glu Lys 245 250 255 Leu Phe Gly Asn Met Glu Gly Asp Cys Pro Ser Asp Trp Lys Thr Asp 260 265 270 Ser Ser Cys Arg Met Val Thr Ser Glu Ser Lys Asn Val Lys Leu Thr 275 280 285 Val Ser Asn Val Leu Lys Glu Ile Lys Ile Leu Asn Ile Phe Gly Val 290 295 300 Ile Lys Gly Phe Val Glu Pro Asp His Tyr Val Val Val Gly Ala Gln 305 310 315 320 Arg Asp Ala Trp Gly Pro Gly Ala Ala Lys Ser Gly Val Gly Thr Ala 325 330 335 Leu Leu Leu Lys Leu Ala Gln Met Phe Ser Asp Met Val Leu Lys Asp 340 345 350 Gly Phe Gln Pro Ser Arg Ser Ile Ile Phe Ala Ser Trp Ser Ala Gly 355 360 365 Asp Phe Gly Ser Val Gly Ala Thr Glu Trp Leu Glu Gly Tyr Leu Ser 370 375 380 Ser Leu His Leu Lys Ala Phe Thr Tyr Ile Asn Leu Asp Lys Ala Val 385 390 395 400 Leu Gly Thr Ser Asn Phe Lys Val Ser Ala Ser Pro Leu Leu Tyr Thr 405 410 415 Leu Ile Glu Lys Thr Met Gln Asn Val Lys His Pro Val Thr Gly Gln 420 425 430 Phe Leu Tyr Gln Asp Ser Asn Trp Ala Ser Lys Val Glu Lys Leu Thr 435 440 445 Leu Asp Asn Ala Ala Phe Pro Phe Leu Ala Tyr Ser Gly Ile Pro Ala 450 455 460 Val Ser Phe Cys Phe Cys Glu Asp Thr Asp Tyr Pro Tyr Leu Gly Thr 465 470 475 480 Thr Met Asp Thr Tyr Lys Glu Leu Ile Glu Arg Ile Pro Glu Leu Asn 485 490 495 Lys Val Ala Arg Ala Ala Ala Glu Val Ala Gly Gln Phe Val Ile Lys 500 505 510 Leu Thr His Asp Val Glu Leu Asn Leu Asp Tyr Glu Arg Tyr Asn Ser 515 520 525 Gln Leu Leu Ser Phe Val Arg Asp Leu Asn Gln Tyr Arg Ala Asp Ile 530 535 540 Lys Glu Met Gly Leu Ser Leu Gln Trp Leu Tyr Ser Ala Arg Gly Asp 545 550 555 560 Phe Phe Arg Ala Thr Ser Arg Leu Thr Thr Asp Phe Gly Asn Ala Glu 565 570 575 Lys Thr Asp Arg Phe Val Met Lys Lys Leu Asn Asp Arg Val Met Arg 580 585 590 Val Glu Tyr His Phe Leu Ser Pro Tyr Val Ser Pro Lys Glu Ser Pro 595 600 605 Phe Arg His Val Phe Trp Gly Ser Gly Ser His Thr Leu Pro Ala Leu 610 615 620 Leu Glu Asn Leu Lys Leu Arg Lys Gln Asn Asn Gly Ala Phe Asn Glu 625 630 635 640 Thr Leu Phe Arg Asn Gln Leu Ala Leu Ala Thr Trp Thr Ile Gln Gly 645 650 655 Ala Ala Asn Ala Leu Ser Gly Asp Val Trp Asp Ile Asp Asn Glu Phe 660 665 670 <210> 91 <211> 672 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of A02 <400> 91 Cys Lys Gly Val Glu Pro Lys Thr Glu Cys Glu Arg Leu Ala Gly Thr 1 5 10 15 Glu Ser Pro Val Arg Glu Glu Pro Gly Glu Asp Phe Pro Ala Ala Arg 20 25 30 Arg Leu Tyr Trp Asp Asp Leu Lys Arg Lys Leu Ser Glu Lys Leu Asp 35 40 45 Ser Thr Asp Phe Thr Gly Thr Ile Lys Leu Leu Asn Glu Asn Ser Tyr 50 55 60 Val Pro Arg Glu Ala Gly Ser Gln Lys Asp Glu Asn Leu Ala Leu Tyr 65 70 75 80 Val Glu Asn Gln Phe Arg Glu Phe Lys Leu Ser Lys Val Trp Arg Asp 85 90 95 Gln His Phe Val Lys Ile Gln Val Lys Asp Ser Ala Gln Asn Ser Val 100 105 110 Ile Ile Val Asp Lys Asn Gly Arg Leu Val Tyr Leu Val Glu Asn Pro 115 120 125 Gly Gly Tyr Val Ala Tyr Ser Lys Ala Ala Thr Val Thr Gly Lys Leu 130 135 140 Val His Ala Asn Phe Gly Thr Lys Lys Asp Phe Glu Asp Leu Tyr Thr 145 150 155 160 Pro Val Asn Gly Ser Ile Val Ile Val Arg Ala Gly Lys Ile Thr Phe 165 170 175 Ala Glu Lys Val Ala Asn Ala Glu Ser Leu Asn Ala Ile Gly Val Leu 180 185 190 Ile Tyr Met Asp Gln Thr Lys Phe Pro Ile Val Asn Ala Glu Leu Ser 195 200 205 Phe Phe Gly His Ala His Leu Gly Thr Gly Asp Pro Tyr Thr Pro Gly 210 215 220 Phe Pro Ser Phe Asn His Thr Gln Phe Pro Pro Ser Arg Ser Ser Gly 225 230 235 240 Leu Pro Asn Ile Pro Val Gln Thr Ile Ser Arg Ala Ala Ala Glu Lys 245 250 255 Leu Phe Gly Asn Met Glu Gly Ser Cys Pro Ala Arg Trp Asn Thr Asp 260 265 270 Ser Thr Cys Arg Met Val Thr Ser Glu Ser Lys Asn Val Lys Leu Thr 275 280 285 Val Ser Asn Val Leu Lys Glu Ile Lys Ile Leu Asn Ile Phe Gly Val 290 295 300 Ile Lys Gly Phe Val Glu Pro Asp His Tyr Val Val Val Gly Ala Gln 305 310 315 320 Arg Asp Ala Trp Gly Pro Gly Ala Ala Lys Ser Gly Val Gly Thr Ala 325 330 335 Leu Leu Leu Lys Leu Ala Gln Met Phe Ser Asp Met Val Leu Lys Asp 340 345 350 Gly Phe Gln Pro Ser Arg Ser Ile Ile Phe Ala Ser Trp Ser Ala Gly 355 360 365 Asp Phe Gly Ser Val Gly Ala Thr Glu Trp Leu Glu Gly Tyr Leu Ser 370 375 380 Ser Leu His Leu Lys Ala Phe Thr Tyr Ile Asn Leu Asp Lys Ala Val 385 390 395 400 Leu Gly Thr Ser Asn Phe Lys Val Ser Ala Ser Pro Leu Leu Tyr Thr 405 410 415 Leu Ile Glu Lys Thr Met Gln Asn Val Lys His Pro Val Thr Gly Gln 420 425 430 Phe Leu Tyr Gln Asp Ser Asn Trp Ala Ser Lys Val Glu Lys Leu Thr 435 440 445 Leu Asp Asn Ala Ala Phe Pro Phe Leu Ala Tyr Ser Gly Ile Pro Ala 450 455 460 Val Ser Phe Cys Phe Cys Glu Asp Thr Asp Tyr Pro Tyr Leu Gly Thr 465 470 475 480 Thr Met Asp Thr Tyr Lys Glu Leu Ile Glu Arg Ile Pro Glu Leu Asn 485 490 495 Lys Val Ala Arg Ala Ala Ala Glu Val Ala Gly Gln Phe Val Ile Lys 500 505 510 Leu Thr His Asp Val Glu Leu Asn Leu Asp Tyr Glu Arg Tyr Asn Ser 515 520 525 Gln Leu Leu Ser Phe Val Arg Asp Leu Asn Gln Tyr Arg Ala Asp Ile 530 535 540 Lys Glu Met Gly Leu Ser Leu Gln Trp Leu Tyr Ser Ala Arg Gly Asp 545 550 555 560 Phe Phe Arg Ala Thr Ser Arg Leu Thr Thr Asp Phe Gly Asn Ala Glu 565 570 575 Lys Thr Asp Arg Phe Val Met Lys Lys Leu Asn Asp Arg Val Met Arg 580 585 590 Val Glu Tyr His Phe Leu Ser Pro Tyr Val Ser Pro Lys Glu Ser Pro 595 600 605 Phe Arg His Val Phe Trp Gly Ser Gly Ser His Thr Leu Pro Ala Leu 610 615 620 Leu Glu Asn Leu Lys Leu Arg Lys Gln Asn Asn Gly Ala Phe Asn Glu 625 630 635 640 Thr Leu Phe Arg Asn Gln Leu Ala Leu Ala Thr Trp Thr Ile Gln Gly 645 650 655 Ala Ala Asn Ala Leu Ser Gly Asp Val Trp Asp Ile Asp Asn Glu Phe 660 665 670 <210> 92 <211> 672 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of A03 <400> 92 Cys Lys Gly Val Glu Pro Lys Thr Glu Cys Glu Arg Leu Ala Gly Thr 1 5 10 15 Glu Ser Pro Val Arg Glu Glu Pro Gly Glu Asp Phe Pro Ala Ala Arg 20 25 30 Arg Leu Tyr Trp Asp Asp Leu Lys Arg Lys Leu Ser Glu Lys Leu Asp 35 40 45 Ser Thr Asp Phe Thr Gly Thr Ile Lys Leu Leu Asn Glu Asn Ser Tyr 50 55 60 Val Pro Arg Glu Ala Gly Ser Gln Lys Asp Glu Asn Leu Ala Leu Tyr 65 70 75 80 Val Glu Asn Gln Phe Arg Glu Phe Lys Leu Ser Lys Val Trp Arg Asp 85 90 95 Gln His Phe Val Lys Ile Gln Val Lys Asp Ser Ala Gln Asn Ser Val 100 105 110 Ile Ile Val Asp Lys Asn Gly Arg Leu Val Tyr Leu Val Glu Asn Pro 115 120 125 Gly Gly Tyr Val Ala Tyr Ser Lys Ala Ala Thr Val Thr Gly Lys Leu 130 135 140 Val His Ala Asn Phe Gly Thr Lys Lys Asp Phe Glu Glu Leu Tyr Thr 145 150 155 160 Pro Val Asn Gly Ser Ile Val Ile Val Arg Ala Gly Glu Ile Thr Phe 165 170 175 Ala Glu Lys Val Ala Asn Ala Glu Ser Leu Asn Ala Ile Gly Val Leu 180 185 190 Ile Tyr Met Asp Gln Thr Lys Phe Pro Ile Val Asn Ala Glu Leu Ser 195 200 205 Phe Phe Gly His Ala His Leu Gly Thr Gly Asp Pro Tyr Thr Pro Gly 210 215 220 Phe Pro Ser Phe Asn His Thr Gln Phe Pro Pro Ser Arg Ser Ser Gly 225 230 235 240 Leu Pro Asn Ile Pro Val Gln Thr Ile Ser Arg Ala Ala Ala Glu Lys 245 250 255 Leu Phe Gly Asn Met Glu Gly Asp Cys Pro Ser Asp Trp Lys Thr Asp 260 265 270 Ser Thr Cys Arg Met Val Thr Ser Glu Ser Lys Asn Val Lys Leu Thr 275 280 285 Val Ser Asn Val Leu Lys Glu Ile Lys Ile Leu Asn Ile Phe Gly Val 290 295 300 Ile Lys Gly Phe Val Glu Pro Asp His Tyr Val Val Val Gly Ala Gln 305 310 315 320 Arg Asp Ala Trp Gly Pro Gly Ala Ala Lys Ser Gly Val Gly Thr Ala 325 330 335 Leu Leu Leu Lys Leu Ala Gln Met Phe Ser Asp Met Val Leu Lys Asp 340 345 350 Gly Phe Gln Pro Ser Arg Ser Ile Ile Phe Ala Ser Trp Ser Ala Gly 355 360 365 Asp Phe Gly Ser Val Gly Ala Thr Glu Trp Leu Glu Gly Tyr Leu Ser 370 375 380 Ser Leu His Leu Lys Ala Phe Thr Tyr Ile Asn Leu Asp Lys Ala Val 385 390 395 400 Leu Gly Thr Ser Asn Phe Lys Val Ser Ala Ser Pro Leu Leu Tyr Thr 405 410 415 Leu Ile Glu Lys Thr Met Gln Asn Val Lys His Pro Val Thr Gly Gln 420 425 430 Phe Leu Tyr Gln Asp Ser Asn Trp Ala Ser Lys Val Glu Lys Leu Thr 435 440 445 Leu Asp Asn Ala Ala Phe Pro Phe Leu Ala Tyr Ser Gly Ile Pro Ala 450 455 460 Val Ser Phe Cys Phe Cys Glu Asp Thr Asp Tyr Pro Tyr Leu Gly Thr 465 470 475 480 Thr Met Asp Thr Tyr Lys Glu Leu Ile Glu Arg Ile Pro Glu Leu Asn 485 490 495 Lys Val Ala Arg Ala Ala Ala Glu Val Ala Gly Gln Phe Val Ile Lys 500 505 510 Leu Thr His Asp Val Glu Leu Asn Leu Asp Tyr Glu Arg Tyr Asn Ser 515 520 525 Gln Leu Leu Ser Phe Val Arg Asp Leu Asn Gln Tyr Arg Ala Asp Ile 530 535 540 Lys Glu Met Gly Leu Ser Leu Gln Trp Leu Tyr Ser Ala Arg Gly Asp 545 550 555 560 Phe Phe Arg Ala Thr Ser Arg Leu Thr Thr Asp Phe Gly Asn Ala Glu 565 570 575 Lys Thr Asp Arg Phe Val Met Lys Lys Leu Asn Asp Arg Val Met Arg 580 585 590 Val Glu Tyr His Phe Leu Ser Pro Tyr Val Ser Pro Lys Glu Ser Pro 595 600 605 Phe Arg His Val Phe Trp Gly Ser Gly Ser His Thr Leu Pro Ala Leu 610 615 620 Leu Glu Asn Leu Lys Leu Arg Lys Gln Asn Asn Gly Ala Phe Asn Glu 625 630 635 640 Thr Leu Phe Arg Asn Gln Leu Ala Leu Ala Thr Trp Thr Ile Gln Gly 645 650 655 Ala Ala Asn Ala Leu Ser Gly Asp Val Trp Asp Ile Asp Asn Glu Phe 660 665 670 <210> 93 <211> 672 <212> PRT <213> Artificial Sequence <220> <223> Description of artificial sequence: the amino acid sequence of A04 <400> 93 Cys Lys Gly Val Glu Pro Lys Thr Glu Cys Glu Arg Leu Ala Gly Thr 1 5 10 15 Glu Ser Pro Val Arg Glu Glu Pro Gly Glu Asp Phe Pro Ala Ala Arg 20 25 30 Arg Leu Tyr Trp Asp Asp Leu Lys Arg Lys Leu Ser Glu Lys Leu Asp 35 40 45 Ser Thr Asp Phe Thr Gly Thr Ile Lys Leu Leu Asn Glu Asn Ser Tyr 50 55 60 Val Pro Arg Glu Ala Gly Ser Gln Lys Asp Glu Asn Leu Ala Leu Tyr 65 70 75 80 Val Glu Asn Gln Phe Arg Glu Phe Lys Leu Ser Lys Val Trp Arg Asp 85 90 95 Gln His Phe Val Lys Ile Gln Val Lys Asp Ser Ala Gln Asn Ser Val 100 105 110 Ile Ile Val Asp Lys Asn Gly Arg Leu Val Tyr Leu Val Glu Asn Pro 115 120 125 Gly Gly Tyr Val Ala Tyr Ser Lys Ala Ala Thr Val Thr Gly Lys Leu 130 135 140 Val His Ala Asn Phe Gly Thr Lys Lys Asp Phe Glu Glu Leu Tyr Thr 145 150 155 160 Pro Val Asn Gly Ser Ile Val Ile Val Arg Ala Gly Glu Ile Thr Phe 165 170 175 Ala Glu Lys Val Ala Asn Ala Glu Ser Leu Asn Ala Ile Gly Val Leu 180 185 190 Ile Tyr Met Asp Gln Thr Lys Phe Pro Ile Val Asn Ala Glu Leu Ser 195 200 205 Phe Phe Gly His Ala His Leu Gly Thr Gly Asp Pro Tyr Thr Pro Gly 210 215 220 Phe Pro Ser Phe Asn His Thr Gln Phe Pro Pro Ser Arg Ser Ser Gly 225 230 235 240 Leu Pro Asn Ile Pro Val Gln Thr Ile Ser Arg Ala Ala Ala Glu Lys 245 250 255 Leu Phe Gly Asn Met Glu Gly Asp Cys Pro Ser Arg Trp Lys Thr Asp 260 265 270 Ser Thr Cys Arg Met Val Thr Ser Glu Ser Lys Asn Val Lys Leu Thr 275 280 285 Val Ser Asn Val Leu Lys Glu Ile Lys Ile Leu Asn Ile Phe Gly Val 290 295 300 Ile Lys Gly Phe Val Glu Pro Asp His Tyr Val Val Val Gly Ala Gln 305 310 315 320 Arg Asp Ala Trp Gly Pro Gly Ala Ala Lys Ser Gly Val Gly Thr Ala 325 330 335 Leu Leu Leu Lys Leu Ala Gln Met Phe Ser Asp Met Val Leu Lys Asp 340 345 350 Gly Phe Gln Pro Ser Arg Ser Ile Ile Phe Ala Ser Trp Ser Ala Gly 355 360 365 Asp Phe Gly Ser Val Gly Ala Thr Glu Trp Leu Glu Gly Tyr Leu Ser 370 375 380 Ser Leu His Leu Lys Ala Phe Thr Tyr Ile Asn Leu Asp Lys Ala Val 385 390 395 400 Leu Gly Thr Ser Asn Phe Lys Val Ser Ala Ser Pro Leu Leu Tyr Thr 405 410 415 Leu Ile Glu Lys Thr Met Gln Asn Val Lys His Pro Val Thr Gly Gln 420 425 430 Phe Leu Tyr Gln Asp Ser Asn Trp Ala Ser Lys Val Glu Lys Leu Thr 435 440 445 Leu Asp Asn Ala Ala Phe Pro Phe Leu Ala Tyr Ser Gly Ile Pro Ala 450 455 460 Val Ser Phe Cys Phe Cys Glu Asp Thr Asp Tyr Pro Tyr Leu Gly Thr 465 470 475 480 Thr Met Asp Thr Tyr Lys Leu Glu Ile Glu Arg Ile Pro Glu Asn 485,490,495 Lys Val Ala Arg Ala Ala Ala Glu Val Ala Gly Gln Phe Val Ile Lys 500 505 510 Leu Thr His Asp Val Glu Leu Asn Leu Asp Tyr Glu Arg Tyr Asn Ser 515,520,525 Gln Leu Leu Ser Phe Val Arg Asp Leu Asn Gln Tyr Arg Ala Asp Ile 530 535 540 Lys Glu Met Gly Served Gln Trp and Tyr Served Arg Gly Asp 545 550 555 560 Phe Phe Arg Ala Thr Ser Arg Leu Thr Thr Asp Phe Gly Asn Ala Glu 565,570,575 Lys Thr Asp Arg Phe Val Met Lys Leu Asn Asp Arg Val Met Arg 580,585,590 Val Glu Tyr His Phe Leu Ser Pro Tyr Val Ser Pro Lys Glu Ser Pro 595,600,605 Phe Arg His Val Phe Trp Gly Ser Gly Ser His Thr Leu Pro Ala Leu 610 615 620 Leu Glu Asn Leu Lys Leu Arg Lys Gln Asn Asn Gly Ala Phe Asn Glu 625 630 635 640 Thr Leu Phe Arg Asn Gln Leu Ala Leu Ala Thr Trp Thr Ile Gln Gly 645 650 655 Ala Ala Asn Ala Leu Ser Gly Asp Val Trp Asp Ile Asp Asn Glu Phe 660 665 670 <210> 94 <211> 672 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of A05 <400> 94 Cys Lys Gly Val Glu Pro Lys Thr Glu Cys Glu Arg Leu Ala Gly Thr 1 5 10 15 Glu Ser Pro Val Arg Glu Glu Pro Gly Glu Asp Phe Pro Ala Ala Arg 20 25 30 Arg Leu Tyr Trp Asp Asp Leu Lys Arg Lys Leu Ser Glu Lys Leu Asp 35 40 45 Ser Thr Asp Phe Thr Gly Thr Ile Lys Leu Leu Asn Glu Asn Ser Tyr 50 55 60 Val Pro Arg Glu Ala Gly Ser Gln Lys Asp Glu Asn Leu Ala Leu Tyr 65 70 75 80 Val Glu Asn Gln Phe Arg Glu Phe Lys Leu Ser Lys Val Trp Arg Asp 85 90 95 Gln His Phe Val Lys Ile Gln Val Lys Asp Ser Ala Gln Asn Ser Val 100 105 110 Ile Ile Val Asp Lys Asn Gly Arg Leu Val Tyr Leu Val Glu Asn Pro 115 120 125 Gly Gly Tyr Val Ala Tyr Ser Lys Ala Ala Thr Val Thr Gly Lys Leu 130 135 140 Val His Ala Asn Phe Gly Thr Lys Lys Asp Phe Glu Asp Leu Tyr Thr 145 150 155 160 Ser Val Asn Gly Ser Ile Val Ile Val Arg Ala Gly Lys Ile Thr Phe 165 170 175 Ala Glu Lys Val Ala Asn Ala Glu Ser Phe Asn Ala Ile Gly Val Leu 180 185 190 Ile Tyr Met Asp Gln Thr Lys Phe Pro Ile Val Asn Ala Glu Leu Ser 195 200 205 Phe Phe Gly His Ala His Leu Gly Thr Gly Asp Pro Tyr Thr Pro Gly 210 215 220 Phe Pro Ser Phe Asn His Thr Gln Phe Pro Pro Ser Arg Ser Ser Gly 225 230 235 240 Leu Pro Asn Ile Pro Val Gln Thr Ile Ser Arg Ala Ala Ala Glu Lys 245 250 255 Leu Phe Gly Asn Met Glu Gly Asp Cys Pro Ser Asp Trp Lys Thr Asp 260 265 270 Ser Thr Cys Arg Met Val Thr Ser Glu Ser Lys Asn Val Lys Leu Thr 275 280 285 Val Ser Asn Val Leu Lys Glu Ile Lys Ile Leu Asn Ile Phe Gly Val 290 295 300 Ile Lys Gly Phe Val Glu Pro Asp His Tyr Val Val Val Gly Ala Gln 305 310 315 320 Arg Asp Ala Trp Gly Pro Gly Ala Ala Lys Ser Gly Val Gly Thr Ala 325 330 335 Leu Leu Leu Lys Leu Ala Gln Met Phe Ser Asp Met Val Leu Lys Asp 340 345 350 Gly Phe Gln Pro Ser Arg Ser Ile Ile Phe Ala Ser Trp Ser Ala Gly 355 360 365 Asp Phe Gly Ser Val Gly Ala Thr Glu Trp Leu Glu Gly Tyr Leu Ser 370 375 380 Ser Leu His Leu Lys Ala Phe Thr Tyr Ile Asn Leu Asp Lys Ala Val 385 390 395 400 Leu Gly Thr Ser Asn Phe Lys Val Ser Ala Ser Pro Leu Leu Tyr Thr 405 410 415 Leu Ile Glu Lys Thr Met Gln Asn Val Lys His Pro Val Thr Gly Gln 420 425 430 Phe Leu Tyr Gln Asp Ser Asn Trp Ala Ser Lys Val Glu Lys Leu Thr 435 440 445 Leu Asp Asn Ala Ala Phe Pro Phe Leu Ala Tyr Ser Gly Ile Pro Ala 450 455 460 Val Ser Phe Cys Phe Cys Glu Asp Thr Asp Tyr Pro Tyr Leu Gly Thr 465 470 475 480 Thr Met Asp Thr Tyr Lys Glu Leu Ile Glu Arg Ile Pro Glu Leu Asn 485 490 495 Lys Val Ala Arg Ala Ala Ala Glu Val Ala Gly Gln Phe Val Ile Lys 500 505 510 Leu Thr His Asp Val Glu Leu Asn Leu Asp Tyr Glu Arg Tyr Asn Ser 515 520 525 Gln Leu Leu Ser Phe Val Arg Asp Leu Asn Gln Tyr Arg Ala Asp Ile 530 535 540 Lys Glu Met Gly Leu Ser Leu Gln Trp Leu Tyr Ser Ala Arg Gly Asp 545 550 555 560 Phe Phe Arg Ala Thr Ser Arg Leu Thr Thr Asp Phe Gly Asn Ala Glu 565 570 575 Lys Thr Asp Arg Phe Val Met Lys Lys Leu Asn Asp Arg Val Met Arg 580 585 590 Val Glu Tyr His Phe Leu Ser Pro Tyr Val Ser Pro Lys Glu Ser Pro 595 600 605 Phe Arg His Val Phe Trp Gly Ser Gly Ser His Thr Leu Pro Ala Leu 610 615 620 Leu Glu Asn Leu Lys Leu Arg Lys Gln Asn Asn Gly Ala Phe Asn Glu 625 630 635 640 Thr Leu Phe Arg Asn Gln Leu Ala Leu Ala Thr Trp Thr Ile Gln Gly 645 650 655 Ala Ala Asn Ala Leu Ser Gly Asp Val Trp Asp Ile Asp Asn Glu Phe 660 665 670 <210> 95 <211> 672 <212> PRT <213> Artificial Sequence <220> <223> Description of artificial sequence: the amino acid sequence of A06 <400> 95 Cys Lys Gly Val Glu Pro Lys Thr Glu Cys Glu Arg Leu Ala Gly Thr 1 5 10 15 Glu Ser Pro Val Arg Glu Glu Pro Gly Glu Asp Phe Pro Ala Ala Arg 20 25 30 Arg Leu Tyr Trp Asp Asp Leu Lys Arg Lys Leu Ser Glu Lys Leu Asp 35 40 45 Ser Thr Asp Phe Thr Gly Thr Ile Lys Leu Leu Asn Glu Asn Ser Tyr 50 55 60 Val Pro Arg Glu Ala Gly Ser Gln Lys Asp Glu Asn Leu Ala Leu Tyr 65 70 75 80 Val Glu Asn Gln Phe Arg Glu Phe Lys Leu Ser Lys Val Trp Arg Asp 85 90 95 Gln His Phe Val Lys Ile Gln Val Lys Asp Ser Ala Gln Asn Ser Val 100 105 110 Ile Ile Val Asp Lys Asn Gly Arg Leu Val Tyr Leu Val Glu Asn Pro 115 120 125 Gly Gly Tyr Val Ala Tyr Ser Lys Ala Ala Thr Val Thr Gly Lys Leu 130 135 140 Val His Ala Asn Phe Gly Thr Lys Lys Asp Phe Glu Asp Leu Tyr Thr 145 150 155 160 Pro Val Asn Gly Ser Ile Val Ile Val Arg Ala Gly Lys Ile Thr Phe 165 170 175 Ala Glu Lys Val Ala Asn Ala Gln Ser Leu Asn Ala Ile Gly Val Leu 180 185 190 Ile Tyr Met Asp Gln Thr Lys Phe Pro Ile Val Asn Ala Glu Leu Ser 195 200 205 Phe Phe Gly His Ala His Leu Gly Thr Gly Asp Pro Tyr Thr Pro Gly 210 215 220 Phe Pro Ser Phe Asn His Thr Gln Phe Pro Pro Ser Arg Ser Ser Gly 225 230 235 240 Leu Pro Asn Ile Pro Val Gln Thr Ile Ser Arg Ala Ala Ala Glu Lys 245 250 255 Leu Phe Gly Asn Met Glu Gly Asp Cys Pro Ser Asp Trp Lys Thr Asp 260 265 270 Ser Thr Cys Arg Met Val Thr Ser Glu Ser Lys Asn Val Lys Leu Thr 275 280 285 Val Ser Asn Val Leu Lys Glu Ile Lys Ile Leu Asn Ile Phe Gly Val 290 295 300 Ile Lys Gly Phe Val Glu Pro Asp His Tyr Val Val Val Gly Ala Gln 305 310 315 320 Arg Asp Ala Trp Gly Pro Gly Ala Ala Lys Ser Gly Val Gly Thr Ala 325 330 335 Leu Leu Leu Lys Leu Ala Gln Met Phe Ser Asp Met Val Leu Lys Asp 340 345 350 Gly Phe Gln Pro Ser Arg Ser Ile Ile Phe Ala Ser Trp Ser Ala Gly 355 360 365 Asp Phe Gly Ser Val Gly Ala Thr Glu Trp Leu Glu Gly Tyr Leu Ser 370 375 380 Ser Leu His Leu Lys Ala Phe Thr Tyr Ile Asn Leu Asp Lys Ala Val 385 390 395 400 Leu Gly Thr Ser Asn Phe Lys Val Ser Ala Ser Pro Leu Leu Tyr Thr 405 410 415 Leu Ile Glu Lys Thr Met Gln Asn Val Lys His Pro Val Thr Gly Gln 420 425 430 Phe Leu Tyr Gln Asp Ser Asn Trp Ala Ser Lys Val Glu Lys Leu Thr 435 440 445 Leu Asp Asn Ala Ala Phe Pro Phe Leu Ala Tyr Ser Gly Ile Pro Ala 450 455 460 Val Ser Phe Cys Phe Cys Glu Asp Thr Asp Tyr Pro Tyr Leu Gly Thr 465 470 475 480 Thr Met Asp Thr Tyr Lys Glu Leu Ile Glu Arg Ile Pro Glu Leu Asn 485 490 495 Lys Val Ala Arg Ala Ala Ala Glu Val Ala Gly Gln Phe Val Ile Lys 500 505 510 Leu Thr His Asp Val Glu Leu Asn Leu Asp Tyr Glu Arg Tyr Asn Ser 515 520 525 Gln Leu Leu Ser Phe Val Arg Asp Leu Asn Gln Tyr Arg Ala Asp Ile 530 535 540 Lys Glu Met Gly Leu Ser Leu Gln Trp Leu Tyr Ser Ala Arg Gly Asp 545 550 555 560 Phe Phe Arg Ala Thr Ser Arg Leu Thr Thr Asp Phe Gly Asn Ala Glu 565 570 575 Lys Thr Asp Arg Phe Val Met Lys Lys Leu Asn Asp Arg Val Met Arg 580 585 590 Val Glu Tyr His Phe Leu Ser Pro Tyr Val Ser Pro Lys Glu Ser Pro 595 600 605 Phe Arg His Val Phe Trp Gly Ser Gly Ser His Thr Leu Pro Ala Leu 610 615 620 Leu Glu Asn Leu Lys Leu Arg Lys Gln Asn Asn Gly Ala Phe Asn Glu 625 630 635 640 Thr Leu Phe Arg Asn Gln Leu Ala Leu Ala Thr Trp Thr Ile Gln Gly 645 650 655 Ala Ala Asn Ala Leu Ser Gly Asp Val Trp Asp Ile Asp Asn Glu Phe 660 665 670 <210> 96 <211> 672 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of A07 <400> 96 Cys Lys Gly Val Glu Pro Lys Thr Glu Cys Glu Arg Leu Ala Gly Thr 1 5 10 15 Glu Ser Pro Val Arg Glu Glu Pro Gly Glu Asp Phe Pro Ala Ala Arg 20 25 30 Arg Leu Tyr Trp Asp Asp Leu Lys Arg Lys Leu Ser Glu Lys Leu Asp 35 40 45 Ser Thr Asp Phe Thr Gly Thr Ile Lys Leu Leu Asn Glu Asn Ser Tyr 50 55 60 Val Pro Arg Glu Ala Gly Ser Gln Lys Asp Glu Asn Leu Ala Leu Tyr 65 70 75 80 Val Glu Asn Gln Phe Arg Glu Phe Lys Leu Ser Lys Val Trp Arg Asp 85 90 95 Gln His Phe Val Lys Ile Gln Val Lys Asp Ser Ala Gln Asn Ser Val 100 105 110 Ile Ile Val Asp Lys Asn Gly Arg Leu Val Tyr Leu Val Glu Asn Pro 115 120 125 Gly Gly Tyr Val Ala Tyr Ser Lys Ala Ala Thr Val Thr Gly Lys Leu 130 135 140 Val His Ala Asn Phe Gly Thr Lys Lys Asp Phe Glu Asp Leu Tyr Thr 145 150 155 160 Pro Val Asn Gly Ser Ile Val Ile Val Arg Ala Gly Lys Ile Thr Phe 165 170 175 Ala Glu Lys Val Ala Asn Ala Glu Ser Leu Asn Ala Ile Gly Val Leu 180 185 190 Ile Tyr Met Asp Gln Thr Lys Phe Pro Ile Val Asn Ala Glu Leu Ser 195 200 205 Phe Phe Gly His Ala His Leu Gly Thr Gly Asp Pro Tyr Thr Pro Gly 210 215 220 Phe Pro Ser Phe Asn His Thr Gln Phe Pro Pro Ser Arg Ser Ser Gly 225 230 235 240 Leu Pro Asn Ile Pro Val Gln Thr Ile Ser Arg Ala Ala Ala Glu Lys 245 250 255 Leu Phe Gly Asn Met Glu Gly Asp Cys Pro Ser Asp Trp Lys Thr Asp 260 265 270 Ser Thr Cys Arg Leu Glu Thr Ser Gln Ser Lys Asn Val Lys Leu Thr 275 280 285 Val Ser Asn Val Leu Lys Glu Ile Lys Ile Leu Asn Ile Phe Gly Val 290 295 300 Ile Lys Gly Phe Val Glu Pro Asp His Tyr Val Val Val Gly Ala Gln 305 310 315 320 Arg Asp Ala Trp Gly Pro Gly Ala Ala Lys Ser Gly Val Gly Thr Ala 325 330 335 Leu Leu Leu Lys Leu Ala Gln Met Phe Ser Asp Met Val Leu Lys Asp 340 345 350 Gly Phe Gln Pro Ser Arg Ser Ile Ile Phe Ala Ser Trp Ser Ala Gly 355 360 365 Asp Phe Gly Ser Val Gly Ala Thr Glu Trp Leu Glu Gly Tyr Leu Ser 370 375 380 Ser Leu His Leu Lys Ala Phe Thr Tyr Ile Asn Leu Asp Lys Ala Val 385 390 395 400 Leu Gly Thr Ser Asn Phe Lys Val Ser Ala Ser Pro Leu Leu Tyr Thr 405 410 415 Leu Ile Glu Lys Thr Met Gln Asn Val Lys His Pro Val Thr Gly Gln 420 425 430 Phe Leu Tyr Gln Asp Ser Asn Trp Ala Ser Lys Val Glu Lys Leu Thr 435 440 445 Leu Asp Asn Ala Ala Phe Pro Phe Leu Ala Tyr Ser Gly Ile Pro Ala 450 455 460 Val Ser Phe Cys Phe Cys Glu Asp Thr Asp Tyr Pro Tyr Leu Gly Thr 465 470 475 480 Thr Met Asp Thr Tyr Lys Glu Leu Ile Glu Arg Ile Pro Glu Leu Asn 485 490 495 Lys Val Ala Arg Ala Ala Ala Glu Val Ala Gly Gln Phe Val Ile Lys 500 505 510 Leu Thr His Asp Val Glu Leu Asn Leu Asp Tyr Glu Arg Tyr Asn Ser 515 520 525 Gln Leu Leu Ser Phe Val Arg Asp Leu Asn Gln Tyr Arg Ala Asp Ile 530 535 540 Lys Glu Met Gly Leu Ser Leu Gln Trp Leu Tyr Ser Ala Arg Gly Asp 545 550 555 560 Phe Phe Arg Ala Thr Ser Arg Leu Thr Thr Asp Phe Gly Asn Ala Glu 565 570 575 Lys Thr Asp Arg Phe Val Met Lys Lys Leu Asn Asp Arg Val Met Arg 580 585 590 Val Glu Tyr His Phe Leu Ser Pro Tyr Val Ser Pro Lys Glu Ser Pro 595 600 605 Phe Arg His Val Phe Trp Gly Ser Gly Ser His Thr Leu Pro Ala Leu 610 615 620 Leu Glu Asn Leu Lys Leu Arg Lys Gln Asn Asn Gly Ala Phe Asn Glu 625 630 635 640 Thr Leu Phe Arg Asn Gln Leu Ala Leu Ala Thr Trp Thr Ile Gln Gly 645 650 655 Ala Ala Asn Ala Leu Ser Gly Asp Val Trp Asp Ile Asp Asn Glu Phe 660 665 670 <210> 97 <211> 671 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of A08 <400> 97 Cys Lys Gly Val Glu Pro Lys Thr Glu Cys Glu Arg Leu Ala Gly Thr 1 5 10 15 Glu Ser Pro Val Arg Glu Glu Pro Gly Glu Asp Phe Pro Ala Ala Arg 20 25 30 Arg Leu Tyr Trp Asp Asp Leu Lys Arg Lys Leu Ser Glu Lys Leu Asp 35 40 45 Ser Thr Asp Phe Thr Gly Thr Ile Lys Leu Leu Asn Glu Asn Ser Tyr 50 55 60 Val Pro Arg Glu Ala Gly Ser Gln Lys Asp Glu Asn Leu Ala Leu Tyr 65 70 75 80 Val Glu Asn Gln Phe Arg Glu Phe Lys Leu Ser Lys Val Trp Arg Asp 85 90 95 Gln His Phe Val Lys Ile Gln Val Lys Asp Ser Ala Gln Asn Ser Val 100 105 110 Ile Ile Val Gln Lys Asn Gly Arg Leu Asp Leu Val Glu Asn Pro Gly 115 120 125 Gly Tyr Val Ala Tyr Ser Lys Ala Ala Thr Val Thr Gly Lys Leu Val 130 135 140 His Ala Asn Phe Gly Thr Lys Lys Asp Phe Glu Asp Leu Tyr Thr Pro 145 150 155 160 Val Asn Gly Ser Ile Val Ile Val Arg Ala Gly Lys Ile Thr Phe Ala 165 170 175 Glu Lys Val Ala Asn Ala Glu Ser Leu Asn Ala Ile Gly Val Leu Ile 180 185 190 Tyr Met Asp Gln Thr Lys Phe Pro Ile Val Asn Ala Glu Leu Ser Phe 195 200 205 Phe Gly His Ala His Leu Gly Thr Gly Asp Pro Tyr Thr Pro Gly Phe 210 215 220 Pro Ser Phe Asn His Thr Gln Phe Pro Pro Ser Arg Ser Ser Gly Leu 225 230 235 240 Pro Asn Ile Pro Val Gln Thr Ile Ser Arg Ala Ala Ala Glu Lys Leu 245 250 255 Phe Gly Lys Met Glu Gly Asp Cys Pro Ser Asp Trp Lys Thr Asp Ser 260 265 270 Thr Cys Arg Met Val Thr Ser Glu Ser Gln Asn Val Lys Leu Thr Val 275 280 285 Ser Asn Val Leu Lys Glu Ile Lys Ile Leu Asn Ile Phe Gly Val Ile 290 295 300 Lys Gly Phe Val Glu Pro Asp His Tyr Val Val Val Gly Ala Gln Arg 305 310 315 320 Asp Ala Trp Gly Pro Gly Ala Ala Lys Ser Gly Val Gly Thr Ala Leu 325 330 335 Leu Leu Lys Leu Ala Gln Met Phe Ser Asp Met Val Leu Lys Asp Gly 340 345 350 Phe Gln Pro Ser Arg Ser Ile Ile Phe Ala Ser Trp Ser Ala Gly Asp 355 360 365 Phe Gly Ser Val Gly Ala Thr Glu Trp Leu Glu Gly Tyr Leu Ser Ser 370 375 380 Leu His Leu Lys Ala Phe Thr Tyr Ile Asn Leu Asp Lys Ala Val Leu 385 390 395 400 Gly Thr Ser Asn Phe Lys Val Ser Ala Ser Pro Leu Leu Tyr Thr Leu 405 410 415 Ile Glu Lys Thr Met Gln Asn Val Lys His Pro Val Thr Gly Gln Phe 420 425 430 Leu Tyr Gln Asp Ser Asn Trp Ala Ser Lys Val Glu Lys Leu Thr Leu 435 440 445 Asp Asn Ala Ala Phe Pro Phe Leu Ala Tyr Ser Gly Ile Pro Ala Val 450 455 460 Ser Phe Cys Phe Cys Glu Asp Thr Asp Tyr Pro Tyr Leu Gly Thr Thr 465 470 475 480 Met Asp Thr Tyr Lys Glu Leu Ile Glu Arg Ile Pro Glu Leu Asn Lys 485 490 495 Val Ala Arg Ala Ala Ala Glu Val Ala Gly Gln Phe Val Ile Lys Leu 500 505 510 Thr His Asp Val Glu Leu Asn Leu Asp Tyr Glu Arg Tyr Asn Ser Gln 515 520 525 Leu Leu Ser Phe Val Arg Asp Leu Asn Gln Tyr Arg Ala Asp Ile Lys 530 535 540 Glu Met Gly Leu Ser Leu Gln Trp Leu Tyr Ser Ala Arg Gly Asp Phe 545 550 555 560 Phe Arg Ala Thr Ser Arg Leu Thr Thr Asp Phe Gly Asn Ala Glu Lys 565 570 575 Thr Asp Arg Phe Val Met Lys Lys Leu Asn Asp Arg Val Met Arg Val 580 585 590 Glu Tyr His Phe Leu Ser Pro Tyr Val Ser Pro Lys Glu Ser Pro Phe 595 600 605 Arg His Val Phe Trp Gly Ser Gly Ser His Thr Leu Pro Ala Leu Leu 610 615 620 Glu Asn Leu Lys Leu Arg Lys Gln Asn Asn Gly Ala Phe Asn Glu Thr 625 630 635 640 Leu Phe Arg Asn Gln Leu Ala Leu Ala Thr Trp Thr Ile Gln Gly Ala 645 650 655 Ala Asn Ala Leu Ser Gly Asp Val Trp Asp Ile Asp Asn Glu Phe 660 665 670 <210> 98 <211> 672 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of A09 <400> 98 Cys Lys Gly Val Glu Pro Lys Thr Glu Cys Glu Arg Leu Ala Gly Thr 1 5 10 15 Glu Ser Pro Val Arg Glu Glu Pro Gly Glu Asp Phe Pro Ala Ala Arg 20 25 30 Arg Leu Tyr Trp Asp Asp Leu Lys Arg Lys Leu Ser Glu Lys Leu Asp 35 40 45 Ser Thr Asp Phe Thr Gly Thr Ile Lys Leu Leu Asn Glu Asn Ser Tyr 50 55 60 Val Pro Arg Glu Ala Gly Ser Gln Lys Asp Glu Asn Leu Ala Leu Tyr 65 70 75 80 Val Glu Asn Gln Phe Arg Glu Phe Lys Leu Ser Lys Val Trp Arg Asp 85 90 95 Gln His Phe Val Lys Ile Gln Val Lys Asp Ser Ala Gln Asn Ser Val 100 105 110 Ile Ile Val Asp Lys Asn Gly Arg Leu Val Tyr Leu Val Glu Asn Pro 115 120 125 Gly Gly Tyr Val Ala Tyr Ser Lys Pro Thr Glu Val Ser Gly Lys Leu 130 135 140 Val His Ala Asn Phe Gly Thr Lys Lys Asp Phe Glu Asp Leu Tyr Thr 145 150 155 160 Pro Val Asn Gly Ser Ile Val Ile Val Arg Ala Gly Lys Ile Thr Phe 165 170 175 Ala Glu Lys Val Ala Asn Ala Glu Ser Leu Asn Ala Ile Gly Val Leu 180 185 190 Ile Tyr Met Asp Gln Thr Lys Phe Pro Ile Val Asn Ala Glu Leu Ser 195 200 205 Phe Phe Gly His Ala His Leu Gly Thr Gly Asp Pro Tyr Thr Pro Gly 210 215 220 Phe Pro Ser Phe Asn His Thr Gln Phe Pro Pro Ser Arg Ser Ser Gly 225 230 235 240 Leu Pro Asn Ile Pro Val Gln Thr Ile Ser Arg Ala Ala Ala Glu Lys 245 250 255 Leu Phe Gly Asn Met Glu Gly Asp Cys Pro Ser Asp Trp Lys Thr Asp 260 265 270 Ser Thr Cys Arg Met Val Thr Ser Glu Ser Lys Asn Val Lys Leu Thr 275 280 285 Val Ser Asn Val Leu Lys Glu Ile Lys Ile Leu Asn Ile Phe Gly Val 290 295 300 Ile Lys Gly Phe Val Glu Pro Asp His Tyr Val Val Val Gly Ala Gln 305 310 315 320 Arg Asp Ala Trp Gly Pro Gly Ala Ala Lys Ser Gly Val Gly Thr Ala 325 330 335 Leu Leu Leu Lys Leu Ala Gln Met Phe Ser Asp Met Val Leu Lys Asp 340 345 350 Gly Phe Gln Pro Ser Arg Ser Ile Ile Phe Ala Ser Trp Ser Ala Gly 355 360 365 Asp Phe Gly Ser Val Gly Ala Thr Glu Trp Leu Glu Gly Tyr Leu Ser 370 375 380 Ser Leu His Leu Lys Ala Phe Thr Tyr Ile Asn Leu Asp Lys Ala Val 385 390 395 400 Leu Gly Thr Ser Asn Phe Lys Val Ser Ala Ser Pro Leu Leu Tyr Thr 405 410 415 Leu Ile Glu Lys Thr Met Gln Asn Val Lys His Pro Val Thr Gly Gln 420 425 430 Phe Leu Tyr Gln Asp Ser Asn Trp Ala Ser Lys Val Glu Lys Leu Thr 435 440 445 Leu Asp Asn Ala Ala Phe Pro Phe Leu Ala Tyr Ser Gly Ile Pro Ala 450 455 460 Val Ser Phe Cys Phe Cys Glu Asp Thr Asp Tyr Pro Tyr Leu Gly Thr 465 470 475 480 Thr Met Asp Thr Tyr Lys Glu Leu Ile Glu Arg Ile Pro Glu Leu Asn 485 490 495 Lys Val Ala Arg Ala Ala Ala Glu Val Ala Gly Gln Phe Val Ile Lys 500 505 510 Leu Thr His Asp Val Glu Leu Asn Leu Asp Tyr Glu Arg Tyr Asn Ser 515 520 525 Gln Leu Leu Ser Phe Val Arg Asp Leu Asn Gln Tyr Arg Ala Asp Ile 530 535 540 Lys Glu Met Gly Leu Ser Leu Gln Trp Leu Tyr Ser Ala Arg Gly Asp 545 550 555 560 Phe Phe Arg Ala Thr Ser Arg Leu Thr Thr Asp Phe Gly Asn Ala Glu 565 570 575 Lys Thr Asp Arg Phe Val Met Lys Lys Leu Asn Asp Arg Val Met Arg 580 585 590 Val Glu Tyr His Phe Leu Ser Pro Tyr Val Ser Pro Lys Glu Ser Pro 595 600 605 Phe Arg His Val Phe Trp Gly Ser Gly Ser His Thr Leu Pro Ala Leu 610 615 620 Leu Glu Asn Leu Lys Leu Arg Lys Gln Asn Asn Gly Ala Phe Asn Glu 625 630 635 640 Thr Leu Phe Arg Asn Gln Leu Ala Leu Ala Thr Trp Thr Ile Gln Gly 645 650 655 Ala Ala Asn Ala Leu Ser Gly Asp Val Trp Asp Ile Asp Asn Glu Phe 660 665 670 <210> 99 <211> 672 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of A10 <400> 99 Cys Lys Gly Val Glu Pro Lys Thr Glu Cys Glu Arg Leu Ala Gly Thr 1 5 10 15 Glu Ser Pro Val Arg Glu Glu Pro Gly Glu Asp Phe Pro Ala Ala Arg 20 25 30 Arg Leu Tyr Trp Asp Asp Leu Lys Arg Lys Leu Ser Glu Lys Leu Asp 35 40 45 Ser Thr Asp Phe Thr Gly Thr Ile Lys Leu Leu Asn Glu Asn Ser Tyr 50 55 60 Val Pro Arg Glu Ala Gly Ser Gln Lys Asp Glu Asn Leu Ala Leu Tyr 65 70 75 80 Val Glu Asn Gln Phe Arg Glu Phe Lys Leu Ser Lys Val Trp Arg Asp 85 90 95 Gln His Phe Val Lys Ile Gln Val Lys Asp Ser Ala Gln Asn Ser Val 100 105 110 Ile Ile Val Asp Lys Asn Gly Arg Leu Val Tyr Leu Val Glu Asn Pro 115 120 125 Gly Gly Tyr Val Ala Tyr Ser Lys Pro Thr Glu Val Thr Gly Lys Leu 130 135 140 Val His Ala Asn Phe Gly Thr Lys Lys Asp Phe Glu Asp Leu Tyr Thr 145 150 155 160 Pro Val Asn Gly Ser Ile Val Ile Val Arg Ala Gly Lys Ile Thr Phe 165 170 175 Ala Glu Lys Val Ala Asn Ala Glu Ser Leu Asn Ala Ile Gly Val Leu 180 185 190 Ile Tyr Met Asp Gln Thr Lys Phe Pro Ile Val Asn Ala Glu Leu Ser 195 200 205 Phe Phe Gly His Ala His Leu Gly Thr Gly Asp Pro Tyr Thr Pro Gly 210 215 220 Phe Pro Ser Phe Asn His Thr Gln Phe Pro Pro Ser Arg Ser Ser Gly 225 230 235 240 Leu Pro Asn Ile Pro Val Gln Thr Ile Ser Arg Ala Ala Ala Glu Lys 245 250 255 Leu Phe Gly Asn Met Glu Gly Asp Cys Pro Ser Asp Trp Lys Thr Asp 260 265 270 Ser Thr Cys Arg Met Val Thr Ser Glu Ser Lys Asn Val Lys Leu Thr 275 280 285 Val Ser Asn Val Leu Lys Glu Ile Lys Ile Leu Asn Ile Phe Gly Val 290 295 300 Ile Lys Gly Phe Val Glu Pro Asp His Tyr Val Val Val Gly Ala Gln 305 310 315 320 Arg Asp Ala Trp Gly Pro Gly Ala Ala Lys Ser Gly Val Gly Thr Ala 325 330 335 Leu Leu Leu Lys Leu Ala Gln Met Phe Ser Asp Met Val Leu Lys Asp 340 345 350 Gly Phe Gln Pro Ser Arg Ser Ile Ile Phe Ala Ser Trp Ser Ala Gly 355 360 365 Asp Phe Gly Ser Val Gly Ala Thr Glu Trp Leu Glu Gly Tyr Leu Ser 370 375 380 Ser Leu His Leu Lys Ala Phe Thr Tyr Ile Asn Leu Asp Lys Ala Val 385 390 395 400 Leu Gly Thr Ser Asn Phe Lys Val Ser Ala Ser Pro Leu Leu Tyr Thr 405 410 415 Leu Ile Glu Lys Thr Met Gln Asn Val Lys His Pro Val Thr Gly Gln 420 425 430 Phe Leu Tyr Gln Asp Ser Asn Trp Ala Ser Lys Val Glu Lys Leu Thr 435 440 445 Leu Asp Asn Ala Ala Phe Pro Phe Leu Ala Tyr Ser Gly Ile Pro Ala 450 455 460 Val Ser Phe Cys Phe Cys Glu Asp Thr Asp Tyr Pro Tyr Leu Gly Thr 465 470 475 480 Thr Met Asp Thr Tyr Lys Glu Leu Ile Glu Arg Ile Pro Glu Leu Asn 485 490 495 Lys Val Ala Arg Ala Ala Ala Glu Val Ala Gly Gln Phe Val Ile Lys 500 505 510 Leu Thr His Asp Val Glu Leu Asn Leu Asp Tyr Glu Arg Tyr Asn Ser 515 520 525 Gln Leu Leu Ser Phe Val Arg Asp Leu Asn Gln Tyr Arg Ala Asp Ile 530 535 540 Lys Glu Met Gly Leu Ser Leu Gln Trp Leu Tyr Ser Ala Arg Gly Asp 545 550 555 560 Phe Phe Arg Ala Thr Ser Arg Leu Thr Thr Asp Phe Gly Asn Ala Glu 565 570 575 Lys Thr Asp Arg Phe Val Met Lys Lys Leu Asn Asp Arg Val Met Arg 580 585 590 Val Glu Tyr His Phe Leu Ser Pro Tyr Val Ser Pro Lys Glu Ser Pro 595 600 605 Phe Arg His Val Phe Trp Gly Ser Gly Ser His Thr Leu Pro Ala Leu 610 615 620 Leu Glu Asn Leu Lys Leu Arg Lys Gln Asn Asn Gly Ala Phe Asn Glu 625 630 635 640 Thr Leu Phe Arg Asn Gln Leu Ala Leu Ala Thr Trp Thr Ile Gln Gly 645 650 655 Ala Ala Asn Ala Leu Ser Gly Asp Val Trp Asp Ile Asp Asn Glu Phe 660 665 670 <210> 100 <211> 673 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of A11 <400> 100 Cys Lys Gly Val Glu Pro Lys Thr Glu Cys Glu Arg Leu Ala Gly Thr 1 5 10 15 Glu Ser Pro Val Arg Glu Glu Pro Gly Glu Asp Phe Pro Ala Ala Arg 20 25 30 Arg Leu Tyr Trp Asp Asp Leu Lys Arg Lys Leu Ser Glu Lys Leu Asp 35 40 45 Ser Thr Asp Phe Thr Gly Thr Ile Lys Leu Leu Asn Glu Asn Ser Tyr 50 55 60 Val Pro Arg Glu Ala Gly Ser Gln Lys Asp Glu Asn Leu Ala Leu Tyr 65 70 75 80 Val Glu Asn Gln Phe Arg Glu Phe Lys Leu Ser Lys Val Trp Arg Asp 85 90 95 Gln His Phe Val Lys Ile Gln Val Lys Ser Ser Ile Gly Gln Asn Ser 100 105 110 Val Ile Ile Val Asp Lys Asn Gly Arg Leu Val Tyr Leu Val Glu Asn 115 120 125 Pro Gly Gly Tyr Val Ala Tyr Ser Lys Ala Ala Thr Val Thr Gly Lys 130 135 140 Leu Val His Ala Asn Phe Gly Thr Lys Lys Asp Phe Glu Asp Leu Tyr 145 150 155 160 Thr Pro Val Asn Gly Ser Ile Val Ile Val Arg Ala Gly Lys Ile Thr 165 170 175 Phe Ala Glu Lys Val Ala Asn Ala Glu Ser Leu Asn Ala Ile Gly Val 180 185 190 Leu Ile Tyr Met Asp Gln Thr Lys Phe Pro Ile Val Asn Ala Glu Leu 195 200 205 Ser Phe Phe Gly His Ala His Leu Gly Thr Gly Asp Pro Tyr Thr Pro 210 215 220 Gly Phe Pro Ser Phe Asn His Thr Gln Phe Pro Pro Ser Arg Ser Ser 225 230 235 240 Gly Leu Pro Asn Ile Pro Val Gln Thr Ile Ser Arg Ala Ala Ala Glu 245 250 255 Lys Leu Phe Gly Asn Met Glu Gly Asp Cys Pro Ser Asp Trp Lys Thr 260 265 270 Asp Ser Thr Cys Arg Met Val Thr Ser Glu Ser Lys Asn Val Lys Leu 275 280 285 Thr Val Lys Asn Val Leu Lys Glu Ile Lys Ile Leu Asn Ile Phe Gly 290 295 300 Val Ile Lys Gly Phe Val Glu Pro Asp His Tyr Val Val Val Gly Ala 305 310 315 320 Gln Arg Asp Ala Trp Gly Pro Gly Ala Ala Lys Ser Gly Val Gly Thr 325 330 335 Ala Leu Leu Leu Lys Leu Ala Gln Met Phe Ser Asp Met Val Leu Lys 340 345 350 Asp Gly Phe Gln Pro Ser Arg Ser Ile Ile Phe Ala Ser Trp Ser Ala 355 360 365 Gly Asp Phe Gly Ser Val Gly Ala Thr Glu Trp Leu Glu Gly Tyr Leu 370 375 380 Ser Ser Leu His Leu Lys Ala Phe Thr Tyr Ile Asn Leu Asp Lys Ala 385 390 395 400 Val Leu Gly Thr Ser Asn Phe Lys Val Ser Ala Ser Pro Leu Leu Tyr 405 410 415 Thr Leu Ile Glu Lys Thr Met Gln Asn Val Lys His Pro Val Thr Gly 420 425 430 Gln Phe Leu Tyr Gln Asp Ser Asn Trp Ala Ser Lys Val Glu Lys Leu 435 440 445 Thr Leu Asp Asn Ala Ala Phe Pro Phe Leu Ala Tyr Ser Gly Ile Pro 450 455 460 Ala Val Ser Phe Cys Phe Cys Glu Asp Thr Asp Tyr Pro Tyr Leu Gly 465 470 475 480 Thr Thr Met Asp Thr Tyr Lys Glu Leu Ile Glu Arg Ile Pro Glu Leu 485 490 495 Asn Lys Val Ala Arg Ala Ala Ala Glu Val Ala Gly Gln Phe Val Ile 500 505 510 Lys Leu Thr His Asp Val Glu Leu Asn Leu Asp Tyr Glu Arg Tyr Asn 515 520 525 Ser Gln Leu Leu Ser Phe Val Arg Asp Leu Asn Gln Tyr Arg Ala Asp 530 535 540 Ile Lys Glu Met Gly Leu Ser Leu Gln Trp Leu Tyr Ser Ala Arg Gly 545 550 555 560 Asp Phe Phe Arg Ala Thr Ser Arg Leu Thr Thr Asp Phe Gly Asn Ala 565 570 575 Glu Lys Thr Asp Arg Phe Val Met Lys Lys Leu Asn Asp Arg Val Met 580 585 590 Arg Val Glu Tyr His Phe Leu Ser Pro Tyr Val Ser Pro Lys Glu Ser 595 600 605 Pro Phe Arg His Val Phe Trp Gly Ser Gly Ser His Thr Leu Pro Ala 610 615 620 Leu Leu Glu Asn Leu Lys Leu Arg Lys Gln Asn Asn Gly Ala Phe Asn 625 630 635 640 Glu Thr Leu Phe Arg Asn Gln Leu Ala Leu Ala Thr Trp Thr Ile Gln 645 650 655 Gly Ala Ala Asn Ala Leu Ser Gly Asp Val Trp Asp Ile Asp Asn Glu 660 665 670 Phe <210> 101 <211> 672 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of A12 <400> 101 Cys Lys Gly Val Glu Pro Lys Thr Glu Cys Glu Arg Leu Ala Gly Thr 1 5 10 15 Glu Ser Pro Val Arg Glu Glu Pro Gly Glu Asp Phe Pro Ala Ala Arg 20 25 30 Arg Leu Tyr Trp Asp Asp Leu Lys Arg Lys Leu Ser Glu Lys Leu Asp 35 40 45 Ser Thr Asp Phe Thr Gly Thr Ile Lys Leu Leu Asn Glu Asn Ser Tyr 50 55 60 Val Pro Arg Glu Ala Gly Ser Gln Lys Asp Glu Asn Leu Ala Leu Tyr 65 70 75 80 Val Glu Asn Gln Phe Arg Glu Phe Lys Leu Ser Lys Val Trp Arg Asp 85 90 95 Gln His Phe Val Lys Ile Gln Val Lys Asp Ser Ala Gln Asn Ser Val 100 105 110 Ile Ile Val Asp Lys Asn Gly Arg Leu Val Tyr Leu Val Glu Asn Pro 115 120 125 Glu Gly Tyr Val Ala Tyr Ser Lys Ala Ala Thr Val Thr Gly Lys Leu 130 135 140 Val His Ala Asn Phe Gly Thr Lys Lys Asp Phe Glu Asp Leu Tyr Thr 145 150 155 160 Pro Val Asn Gly Ser Ile Val Ile Val Arg Ala Gly Lys Ile Thr Phe 165 170 175 Ala Glu Lys Val Ala Asn Ala Glu Ser Leu Asn Ala Ile Gly Val Leu 180 185 190 Ile Tyr Met Asp Gln Thr Lys Phe Pro Ile Val Asn Ala Glu Leu Ala 195 200 205 Phe Phe Gly His Ala His Leu Gly Thr Gly Asp Pro Tyr Thr Pro Gly 210 215 220 Phe Pro Ser Phe Asn His Thr Gln Phe Pro Pro Ser Arg Ser Ser Gly 225 230 235 240 Leu Pro Asn Ile Pro Val Gln Thr Ile Ser Arg Ala Ala Ala Glu Lys 245 250 255 Leu Phe Gly Asn Met Glu Gly Asp Cys Pro Ser Asp Trp Lys Thr Asp 260 265 270 Ser Thr Cys Arg Met Val Thr Ser Glu Ser Lys Asn Val Lys Leu Thr 275 280 285 Val Ser Asn Val Leu Lys Glu Ile Lys Ile Leu Asn Ile Phe Gly Val 290 295 300 Ile Lys Gly Phe Val Glu Pro Asp His Tyr Val Val Val Gly Ala Gln 305 310 315 320 Arg Asp Ala Trp Gly Pro Gly Ala Ala Lys Ser Gly Val Gly Thr Ala 325 330 335 Leu Leu Leu Lys Leu Ala Gln Met Phe Ser Asp Met Val Leu Lys Asp 340 345 350 Gly Phe Gln Pro Ser Arg Ser Ile Ile Phe Ala Ser Trp Ser Ala Gly 355 360 365 Asp Phe Gly Ser Val Gly Ala Thr Glu Trp Leu Glu Gly Tyr Leu Ser 370 375 380 Ser Leu His Leu Lys Ala Phe Thr Tyr Ile Asn Leu Asp Lys Ala Val 385 390 395 400 Leu Gly Thr Ser Asn Phe Lys Val Ser Ala Ser Pro Leu Leu Tyr Thr 405 410 415 Leu Ile Glu Lys Thr Met Gln Asn Val Lys His Pro Val Thr Gly Gln 420 425 430 Phe Leu Tyr Gln Asp Ser Asn Trp Ala Ser Lys Val Glu Lys Leu Thr 435 440 445 Leu Asp Asn Ala Ala Phe Pro Phe Leu Ala Tyr Ser Gly Ile Pro Ala 450 455 460 Val Ser Phe Cys Phe Cys Glu Asp Thr Asp Tyr Pro Tyr Leu Gly Thr 465 470 475 480 Thr Met Asp Thr Tyr Lys Glu Leu Ile Glu Arg Ile Pro Glu Leu Asn 485 490 495 Lys Val Ala Arg Ala Ala Ala Glu Val Ala Gly Gln Phe Val Ile Lys 500 505 510 Leu Thr His Asp Val Glu Leu Asn Leu Asp Tyr Glu Arg Tyr Asn Ser 515 520 525 Gln Leu Leu Ser Phe Val Arg Asp Leu Asn Gln Tyr Arg Ala Asp Ile 530 535 540 Lys Glu Met Gly Leu Ser Leu Gln Trp Leu Tyr Ser Ala Arg Gly Asp 545 550 555 560 Phe Phe Arg Ala Thr Ser Arg Leu Thr Thr Asp Phe Gly Asn Ala Glu 565 570 575 Lys Thr Asp Arg Phe Val Met Lys Lys Leu Asn Asp Arg Val Met Arg 580 585 590 Val Glu Tyr His Phe Leu Ser Pro Tyr Val Ser Pro Lys Glu Ser Pro 595 600 605 Phe Arg His Val Phe Trp Gly Ser Gly Ser His Thr Leu Pro Ala Leu 610 615 620 Leu Glu Asn Leu Lys Leu Arg Lys Gln Asn Asn Gly Ala Phe Asn Glu 625 630 635 640 Thr Leu Phe Arg Asn Gln Leu Ala Leu Ala Thr Trp Thr Ile Gln Gly 645 650 655 Ala Ala Asn Ala Leu Ser Gly Asp Val Trp Asp Ile Asp Asn Glu Phe 660 665 670 <210> 102 <211> 672 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of A13 <400> 102 Cys Lys Gly Val Glu Pro Lys Thr Glu Cys Glu Arg Leu Ala Gly Thr 1 5 10 15 Glu Ser Pro Val Arg Glu Glu Pro Gly Glu Asp Phe Pro Ala Ala Arg 20 25 30 Arg Leu Tyr Trp Asp Asp Leu Lys Arg Lys Leu Ser Glu Lys Leu Asp 35 40 45 Ser Thr Asp Phe Thr Gly Thr Ile Lys Leu Leu Asn Glu Asn Ser Tyr 50 55 60 Val Pro Arg Glu Ala Gly Ser Gln Lys Asp Glu Asn Leu Ala Leu Tyr 65 70 75 80 Val Glu Asn Gln Phe Arg Glu Phe Lys Leu Ser Lys Val Trp Arg Asp 85 90 95 Gln His Phe Val Lys Ile Gln Val Lys Asp Ser Ala Gln Asn Ser Val 100 105 110 Ile Ile Val Gln Ser Asn Gly Arg Leu Val Tyr Leu Val Glu Asn Pro 115 120 125 Gly Gly Tyr Val Ala Tyr Ser Lys Ala Ala Thr Val Thr Gly Lys Leu 130 135 140 Val His Ala Asn Phe Gly Thr Lys Lys Asp Phe Glu Asp Leu Tyr Thr 145 150 155 160 Pro Val Asn Gly Ser Ile Val Ile Val Arg Ala Gly Lys Ile Thr Phe 165 170 175 Ala Glu Lys Val Ala Asn Ala Glu Ser Leu Asn Ala Ile Gly Val Leu 180 185 190 Ile Tyr Met Asp Gln Thr Lys Phe Pro Ile Val Asn Ala Glu Leu Ser 195 200 205 Phe Phe Gly His Ala His Leu Gly Thr Gly Asp Pro Tyr Thr Pro Gly 210 215 220 Phe Pro Ser Phe Asn His Thr Gln Phe Pro Pro Ser Arg Ser Ser Gly 225 230 235 240 Leu Pro Asn Ile Pro Val Gln Thr Ile Ser Arg Ala Ala Ala Glu Lys 245 250 255 Leu Phe Gly Asn Met Glu Gly Asp Cys Pro Ser Asp Trp Lys Thr Asp 260 265 270 Ser Thr Cys Arg Met Val Thr Ser Glu Ser Lys Asn Val Lys Leu Thr 275 280 285 Val Ser Asn Val Leu Lys Glu Ile Lys Ile Leu Asn Ile Phe Gly Val 290 295 300 Ile Lys Gly Phe Val Glu Pro Asp His Tyr Val Val Val Gly Ala Gln 305 310 315 320 Arg Asp Ala Trp Gly Pro Gly Ala Ala Lys Ser Gly Val Gly Thr Ala 325 330 335 Leu Leu Leu Lys Leu Ala Gln Met Phe Ser Asp Met Val Leu Lys Asp 340 345 350 Gly Phe Gln Pro Ser Arg Ser Ile Ile Phe Ala Ser Trp Ser Ala Gly 355 360 365 Asp Phe Gly Ser Val Gly Ala Thr Glu Trp Leu Glu Gly Tyr Leu Ser 370 375 380 Ser Leu His Leu Lys Ala Phe Thr Tyr Ile Asn Leu Asp Lys Ala Val 385 390 395 400 Leu Gly Thr Ser Asn Phe Lys Val Ser Ala Ser Pro Leu Leu Tyr Thr 405 410 415 Leu Ile Glu Lys Thr Met Gln Asn Val Lys His Pro Val Thr Gly Gln 420 425 430 Phe Leu Tyr Gln Asp Ser Asn Trp Ala Ser Lys Val Glu Lys Leu Thr 435 440 445 Leu Asp Asn Ala Ala Phe Pro Phe Leu Ala Tyr Ser Gly Ile Pro Ala 450 455 460 Val Ser Phe Cys Phe Cys Glu Asp Thr Asp Tyr Pro Tyr Leu Gly Thr 465 470 475 480 Thr Met Asp Thr Tyr Lys Glu Leu Ile Glu Arg Ile Pro Glu Leu Asn 485 490 495 Lys Val Ala Arg Ala Ala Ala Glu Val Ala Gly Gln Phe Val Ile Lys 500 505 510 Leu Thr His Asp Val Glu Leu Asn Leu Asp Tyr Glu Arg Tyr Asn Ser 515 520 525 Gln Leu Leu Ser Phe Val Arg Asp Leu Asn Gln Tyr Arg Ala Asp Ile 530 535 540 Lys Glu Met Gly Leu Ser Leu Gln Trp Leu Tyr Ser Ala Arg Gly Asp 545 550 555 560 Phe Phe Arg Ala Thr Ser Arg Leu Thr Thr Asp Phe Gly Asn Ala Glu 565 570 575 Lys Thr Asp Arg Phe Val Met Lys Lys Leu Asn Asp Arg Val Met Arg 580 585 590 Val Glu Tyr His Phe Leu Ser Pro Tyr Val Ser Pro Lys Glu Ser Pro 595 600 605 Phe Arg His Val Phe Trp Gly Ser Gly Ser His Thr Leu Pro Ala Leu 610 615 620 Leu Glu Asn Leu Lys Leu Arg Lys Gln Asn Asn Gly Ala Phe Asn Glu 625 630 635 640 Thr Leu Phe Arg Asn Gln Leu Ala Leu Ala Thr Trp Thr Ile Gln Gly 645 650 655 Ala Ala Asn Ala Leu Ser Gly Asp Val Trp Asp Ile Asp Asn Glu Phe 660 665 670 <210> 103 <211> 672 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of A14 <400> 103 Cys Lys Gly Val Glu Pro Lys Thr Glu Cys Glu Arg Leu Ala Gly Thr 1 5 10 15 Glu Ser Pro Val Arg Glu Glu Pro Gly Glu Asp Phe Pro Ala Ala Arg 20 25 30 Arg Leu Tyr Trp Asp Asp Leu Lys Arg Lys Leu Ser Glu Lys Leu Asp 35 40 45 Ser Thr Asp Phe Thr Gly Thr Ile Lys Leu Leu Asn Glu Asn Ser Tyr 50 55 60 Val Pro Arg Glu Ala Gly Ser Gln Lys Asp Glu Asn Leu Ala Leu Tyr 65 70 75 80 Val Glu Asn Gln Phe Arg Glu Phe Lys Leu Ser Lys Val Trp Arg Asp 85 90 95 Gln His Phe Val Lys Ile Gln Val Lys Asp Ser Ala Gln Asn Ser Val 100 105 110 Ile Ile Val Gln Ser Asn Gly Arg Leu Val Tyr Leu Val Glu Asn Pro 115 120 125 Gly Gly Tyr Val Ala Tyr Ser Lys Ala Ala Thr Val Thr Gly Lys Leu 130 135 140 Val His Ala Asn Phe Gly Thr Lys Lys Asp Phe Glu Asp Leu Tyr Thr 145 150 155 160 Pro Val Asn Gly Ser Ile Val Ile Val Arg Ala Gly Lys Ile Thr Phe 165 170 175 Ala Glu Lys Val Ala Asn Ala Glu Ser Leu Asn Ala Ile Gly Val Leu 180 185 190 Ile Tyr Met Asp Gln Thr Lys Phe Pro Ile Val Asn Ala Glu Leu Ser 195 200 205 Phe Phe Gly His Ala His Leu Gly Thr Gly Asp Pro Tyr Thr Pro Gly 210 215 220 Phe Pro Ser Phe Asn His Thr Gln Phe Pro Pro Ser Arg Ser Ser Gly 225 230 235 240 Leu Pro Asn Ile Pro Val Gln Thr Ile Ser Arg Ala Ala Ala Glu Lys 245 250 255 Leu Phe Gly Asn Met Glu Gly Asp Cys Pro Ser Asp Trp Lys Thr Asp 260 265 270 Ser Thr Cys Arg Met Val Thr Ser Gln Ser Lys Asn Val Lys Leu Thr 275 280 285 Val Ser Asn Val Leu Lys Glu Ile Lys Ile Leu Asn Ile Phe Gly Val 290 295 300 Ile Lys Gly Phe Val Glu Pro Asp His Tyr Val Val Val Gly Ala Gln 305 310 315 320 Arg Asp Ala Trp Gly Pro Gly Ala Ala Lys Ser Gly Val Gly Thr Ala 325 330 335 Leu Leu Leu Lys Leu Ala Gln Met Phe Ser Asp Met Val Leu Lys Asp 340 345 350 Gly Phe Gln Pro Ser Arg Ser Ile Ile Phe Ala Ser Trp Ser Ala Gly 355 360 365 Asp Phe Gly Ser Val Gly Ala Thr Glu Trp Leu Glu Gly Tyr Leu Ser 370 375 380 Ser Leu His Leu Lys Ala Phe Thr Tyr Ile Asn Leu Asp Lys Ala Val 385 390 395 400 Leu Gly Thr Ser Asn Phe Lys Val Ser Ala Ser Pro Leu Leu Tyr Thr 405 410 415 Leu Ile Glu Lys Thr Met Gln Asn Val Lys His Pro Val Thr Gly Gln 420 425 430 Phe Leu Tyr Gln Asp Ser Asn Trp Ala Ser Lys Val Glu Lys Leu Thr 435 440 445 Leu Asp Asn Ala Ala Phe Pro Phe Leu Ala Tyr Ser Gly Ile Pro Ala 450 455 460 Val Ser Phe Cys Phe Cys Glu Asp Thr Asp Tyr Pro Tyr Leu Gly Thr 465 470 475 480 Thr Met Asp Thr Tyr Lys Glu Leu Ile Glu Arg Ile Pro Glu Leu Asn 485 490 495 Lys Val Ala Arg Ala Ala Ala Glu Val Ala Gly Gln Phe Val Ile Lys 500 505 510 Leu Thr His Asp Val Glu Leu Asn Leu Asp Tyr Glu Arg Tyr Asn Ser 515 520 525 Gln Leu Leu Ser Phe Val Arg Asp Leu Asn Gln Tyr Arg Ala Asp Ile 530 535 540 Lys Glu Met Gly Leu Ser Leu Gln Trp Leu Tyr Ser Ala Arg Gly Asp 545 550 555 560 Phe Phe Arg Ala Thr Ser Arg Leu Thr Thr Asp Phe Gly Asn Ala Glu 565 570 575 Lys Thr Asp Arg Phe Val Met Lys Lys Leu Asn Asp Arg Val Met Arg 580 585 590 Val Glu Tyr His Phe Leu Ser Pro Tyr Val Ser Pro Lys Glu Ser Pro 595 600 605 Phe Arg His Val Phe Trp Gly Ser Gly Ser His Thr Leu Pro Ala Leu 610 615 620 Leu Glu Asn Leu Lys Leu Arg Lys Gln Asn Asn Gly Ala Phe Asn Glu 625 630 635 640 Thr Leu Phe Arg Asn Gln Leu Ala Leu Ala Thr Trp Thr Ile Gln Gly 645 650 655 Ala Ala Asn Ala Leu Ser Gly Asp Val Trp Asp Ile Asp Asn Glu Phe 660 665 670 <210> 104 <211> 672 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of A15 <400> 104 Cys Lys Gly Val Glu Pro Lys Thr Glu Cys Glu Arg Leu Ala Gly Thr 1 5 10 15 Glu Ser Pro Val Arg Glu Glu Pro Gly Glu Asp Phe Pro Ala Ala Arg 20 25 30 Arg Leu Tyr Trp Asp Asp Leu Lys Arg Lys Leu Ser Glu Lys Leu Asp 35 40 45 Ser Thr Asp Phe Thr Gly Thr Ile Lys Leu Leu Asn Glu Asn Ser Tyr 50 55 60 Val Pro Arg Glu Ala Gly Ser Gln Lys Asp Glu Asn Leu Ala Leu Tyr 65 70 75 80 Val Glu Asn Gln Phe Arg Glu Phe Lys Leu Ser Lys Val Trp Arg Asp 85 90 95 Gln His Phe Val Lys Ile Gln Val Lys Asp Ser Ala Gln Asn Met Val 100 105 110 Thr Ile Val Asp Lys Asn Gly Arg Leu Val Tyr Pro Val Glu Ser Pro 115 120 125 Gly Gly Tyr Val Ala Tyr Ser Lys Ala Ala Thr Val Thr Gly Lys Leu 130 135 140 Val His Ala Asn Phe Gly Thr Lys Lys Asp Phe Glu Asp Leu Tyr Thr 145 150 155 160 Pro Val Asn Gly Ser Ile Val Ile Val Arg Ala Gly Lys Ile Thr Phe 165 170 175 Ala Glu Lys Val Ala Asn Ala Glu Ser Leu Asn Ala Ile Gly Val Leu 180 185 190 Ile Tyr Met Asp Gln Thr Lys Phe Pro Ile Val Asn Ala Glu Leu Ser 195 200 205 Phe Phe Gly His Ala His Leu Gly Thr Gly Asp Pro Tyr Thr Pro Gly 210 215 220 Phe Pro Ser Phe Asn His Thr Gln Phe Pro Pro Ser Arg Ser Ser Gly 225 230 235 240 Leu Pro Asn Ile Pro Val Gln Thr Ile Ser Arg Ala Ala Ala Glu Lys 245 250 255 Leu Phe Gly Asn Met Glu Gly Asp Cys Pro Ser Asp Trp Lys Thr Asp 260 265 270 Ser Thr Cys Arg Met Val Thr Ser Glu Ser Lys Asn Val Lys Leu Thr 275 280 285 Val Ser Asn Val Leu Lys Glu Ile Lys Ile Leu Asn Ile Phe Gly Val 290 295 300 Ile Lys Gly Phe Val Glu Pro Asp His Tyr Val Val Val Gly Ala Gln 305 310 315 320 Arg Asp Ala Trp Gly Pro Gly Ala Ala Lys Ser Gly Val Gly Thr Ala 325 330 335 Leu Leu Leu Lys Leu Ala Gln Met Phe Ser Asp Met Val Leu Lys Asp 340 345 350 Gly Phe Gln Pro Ser Arg Ser Ile Ile Phe Ala Ser Trp Ser Ala Gly 355 360 365 Asp Phe Gly Ser Val Gly Ala Thr Glu Trp Leu Glu Gly Tyr Leu Ser 370 375 380 Ser Leu His Leu Lys Ala Phe Thr Tyr Ile Asn Leu Asp Lys Ala Val 385 390 395 400 Leu Gly Thr Ser Asn Phe Lys Val Ser Ala Ser Pro Leu Leu Tyr Thr 405 410 415 Leu Ile Glu Lys Thr Met Gln Asn Val Lys His Pro Val Thr Gly Gln 420 425 430 Phe Leu Tyr Gln Asp Ser Asn Trp Ala Ser Lys Val Glu Lys Leu Thr 435 440 445 Leu Asp Asn Ala Ala Phe Pro Phe Leu Ala Tyr Ser Gly Ile Pro Ala 450 455 460 Val Ser Phe Cys Phe Cys Glu Asp Thr Asp Tyr Pro Tyr Leu Gly Thr 465 470 475 480 Thr Met Asp Thr Tyr Lys Glu Leu Ile Glu Arg Ile Pro Glu Leu Asn 485 490 495 Lys Val Ala Arg Ala Ala Ala Glu Val Ala Gly Gln Phe Val Ile Lys 500 505 510 Leu Thr His Asp Val Glu Leu Asn Leu Asp Tyr Glu Arg Tyr Asn Ser 515 520 525 Gln Leu Leu Ser Phe Val Arg Asp Leu Asn Gln Tyr Arg Ala Asp Ile 530 535 540 Lys Glu Met Gly Leu Ser Leu Gln Trp Leu Tyr Ser Ala Arg Gly Asp 545 550 555 560 Phe Phe Arg Ala Thr Ser Arg Leu Thr Thr Asp Phe Gly Asn Ala Glu 565 570 575 Lys Thr Asp Arg Phe Val Met Lys Lys Leu Asn Asp Arg Val Met Arg 580 585 590 Val Glu Tyr His Phe Leu Ser Pro Tyr Val Ser Pro Lys Glu Ser Pro 595 600 605 Phe Arg His Val Phe Trp Gly Ser Gly Ser His Thr Leu Pro Ala Leu 610 615 620 Leu Glu Asn Leu Lys Leu Arg Lys Gln Asn Asn Gly Ala Phe Asn Glu 625 630 635 640 Thr Leu Phe Arg Asn Gln Leu Ala Leu Ala Thr Trp Thr Ile Gln Gly 645 650 655 Ala Ala Asn Ala Leu Ser Gly Asp Val Trp Asp Ile Asp Asn Glu Phe 660 665 670 <210> 105 <211> 672 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of A16 <400> 105 Cys Lys Gly Val Glu Pro Lys Thr Glu Cys Glu Arg Leu Ala Gly Thr 1 5 10 15 Glu Ser Pro Val Arg Glu Glu Pro Gly Glu Asp Phe Pro Ala Ala Arg 20 25 30 Arg Leu Tyr Trp Asp Asp Leu Lys Arg Lys Leu Ser Glu Lys Leu Asp 35 40 45 Ser Thr Asp Phe Thr Gly Thr Ile Lys Leu Leu Asn Glu Asn Ser Tyr 50 55 60 Val Pro Arg Glu Ala Gly Ser Gln Lys Asp Glu Asn Leu Ala Leu Tyr 65 70 75 80 Val Glu Asn Gln Phe Arg Glu Phe Lys Leu Ser Lys Val Trp Arg Asp 85 90 95 Gln His Phe Val Lys Ile Gln Val Lys Asp Ser Ala Gln Asn Met Val 100 105 110 Ile Ile Val Asp Lys Asn Gly Arg Leu Val Tyr Leu Val Glu Asn Pro 115 120 125 Gly Gly Tyr Val Ala Tyr Ser Lys Ala Ala Glu Val Thr Gly Lys Leu 130 135 140 Val His Ala Asn Phe Gly Thr Lys Lys Asp Phe Glu Asp Leu Tyr Thr 145 150 155 160 Pro Val Asn Gly Ser Ile Val Ile Val Arg Ala Gly Lys Ile Thr Phe 165 170 175 Ala Glu Lys Val Ala Asn Ala Glu Ser Leu Asn Ala Ile Gly Val Leu 180 185 190 Ile Tyr Met Asp Gln Thr Lys Phe Pro Ile Val Asn Ala Glu Leu Ser 195 200 205 Phe Phe Gly His Ala His Leu Gly Thr Gly Asp Pro Tyr Thr Pro Gly 210 215 220 Phe Pro Ser Phe Asn His Thr Gln Phe Pro Pro Ser Arg Ser Ser Gly 225 230 235 240 Leu Pro Asn Ile Pro Val Gln Thr Ile Ser Arg Ala Ala Ala Glu Lys 245 250 255 Leu Phe Gly Asn Met Glu Gly Asp Cys Pro Ser Asp Trp Lys Thr Asp 260 265 270 Ser Thr Cys Arg Met Val Thr Ser Glu Ser Lys Asn Val Lys Leu Ile 275 280 285 Val Ser Asn Val Leu Lys Glu Ile Lys Ile Leu Asn Ile Phe Gly Val 290 295 300 Ile Lys Gly Phe Val Glu Pro Asp His Tyr Val Val Val Gly Ala Gln 305 310 315 320 Arg Asp Ala Trp Gly Pro Gly Ala Ala Lys Ser Gly Val Gly Thr Ala 325 330 335 Leu Leu Leu Lys Leu Ala Gln Met Phe Ser Asp Met Val Leu Lys Asp 340 345 350 Gly Phe Gln Pro Ser Arg Ser Ile Ile Phe Ala Ser Trp Ser Ala Gly 355 360 365 Asp Phe Gly Ser Val Gly Ala Thr Glu Trp Leu Glu Gly Tyr Leu Ser 370 375 380 Ser Leu His Leu Lys Ala Phe Thr Tyr Ile Asn Leu Asp Lys Ala Val 385 390 395 400 Leu Gly Thr Ser Asn Phe Lys Val Ser Ala Ser Pro Leu Leu Tyr Thr 405 410 415 Leu Ile Glu Lys Thr Met Gln Asn Val Lys His Pro Val Thr Gly Gln 420 425 430 Phe Leu Tyr Gln Asp Ser Asn Trp Ala Ser Lys Val Glu Lys Leu Thr 435 440 445 Leu Asp Asn Ala Ala Phe Pro Phe Leu Ala Tyr Ser Gly Ile Pro Ala 450 455 460 Val Ser Phe Cys Phe Cys Glu Asp Thr Asp Tyr Pro Tyr Leu Gly Thr 465 470 475 480 Thr Met Asp Thr Tyr Lys Leu Glu Ile Glu Arg Ile Pro Glu Asn 485,490,495 Lys Val Ala Arg Ala Ala Ala Glu Val Ala Gly Gln Phe Val Ile Lys 500 505 510 Leu Thr His Asp Val Glu Leu Asn Leu Asp Tyr Glu Arg Tyr Asn Ser 515,520,525 Gln Leu Leu Ser Phe Val Arg Asp Leu Asn Gln Tyr Arg Ala Asp Ile 530 535 540 Lys Glu Met Gly Served Gln Trp and Tyr Served Arg Gly Asp 545 550 555 560 Phe Phe Arg Ala Thr Ser Arg Leu Thr Thr Asp Phe Gly Asn Ala Glu 565,570,575 Lys Thr Asp Arg Phe Val Met Lys Leu Asn Asp Arg Val Met Arg 580,585,590 Val Glu Tyr His Phe Leu Ser Pro Tyr Val Ser Pro Lys Glu Ser Pro 595 600 605 Phe Arg His Val Phe Trp Gly Ser Gly Ser His Thr Leu Pro Ala Leu 610 615 620 Leu Glu Asn Leu Lys Leu Arg Lys Gln Asn Asn Gly Ala Phe Asn Glu 625 630 635 640 Thr Leu Phe Arg Asn Gln Leu Ala Leu Ala Thr Trp Thr Ile Gln Gly 645 650 655 Ala Ala Asn Ala Leu Ser Gly Asp Val Trp Asp Ile Asp Asn Glu Phe 660 665 670 <210> 106 <211> 122 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: The amino acid sequence of VH starting with TfR1071 EVQL <400> 106 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Asp Lys Tyr 20 25 30 Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Ser Asn Gly Gly Val Ser Thr Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Met Ala Thr Tyr Tyr Cys 85 90 95 Ala Arg Ala Ser Gln Pro Trp Leu Tyr Arg Thr Gly Ala Asp Val Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 107 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of TfR1007 HCDR1 <400> 107 Gly Tyr Ser Met Ser 1 5 <210> 108 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of TfR1007 HCDR2 <400> 108 Ser Leu Ser Asn Gly Gly Gly Ser Ser Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 109 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequence: Amino acid sequence of TfR1007 HCDR3 <400> 109 Thr Leu Gly Ala Tyr Tyr Ile Lys Ser Ala Met Asp Val 1 5 10 <210> 110 <211> 119 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of Cetuximab VH <400> 110 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala 115 <210> 111 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of Cetuximab VL <400> 111 Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn 20 25 30 Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile 35 40 45 Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser 65 70 75 80 Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <210> 112 <211> 119 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of Panitumumab VH <400> 112 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30 Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr 85 90 95 Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 <210> 113 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of Panitumumab VL <400> 113 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu 85 90 95 Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 114 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of Necitumumab VH <400> 114 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Asp Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asp Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Val Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Val Ser Ile Phe Gly Val Gly Thr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 115 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of Necitumumab VL <400> 115 Glu Ile Val Met 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 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 50 55 60 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 His Gln Tyr Gly Ser Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Ala Glu Ile Lys 100 105 <210> 116 <211> 123 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of Nimotuzumab VH <400> 116 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Tyr Ile Tyr Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Gly Ile Asn Pro Thr Ser Gly Gly Ser Asn Phe Asn Glu Lys Phe 50 55 60 Lys Thr Lys Ala Thr Leu Thr Val Asp Glu Ser Ser Thr Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Gln Gly Leu Trp Phe Asp Ser Asp Gly Arg Gly Phe Asp Phe 100 105 110 Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser 115 120 <210> 117 <211> 112 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Amino acid sequence of Nimotuzumab VL <400> 117 Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Asn Leu Leu Ile Tyr Lys Val Ser Asn Arg Glu Ser Gly Val Pro 50 55 60 Asp Arg Phe Arg Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Tyr 85 90 95 Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 BRIEF DESCRIPTION OF THE DRAWINGS

[0096] Figure 1 An example of the structure of the bispecific antibody of the present invention is shown. Figure 1 (A) shows a bispecific antibody in which the N-terminal polypeptide is Fab, and a polypeptide comprising VH of Fab is bound to the N-terminus of the IgG part. Figure 1 (B) shows a bispecific antibody in which the N-terminal polypeptide is VHH. Figure 1 (C) shows a bispecific antibody in which the N-terminal polypeptide is Fab, and the polypeptide comprising VL of Fab is bound to the N-terminus of the IgG part.

[0097] Figure 2 The figures show the results of evaluating the antigen expression levels in various cancer cell lines by flow cytometry. Figure 2 (A) to (C) show the results of evaluating the expression levels of EGFR in OE21 cells, T.Tn cells, and U-937 cells using flow cytometry, respectively. Figure 2 (D) to (F) show the results of evaluating the expression of TfR in OE21 cells, T.Tn cells, and U-937 cells using flow cytometry, respectively. The vertical axis represents the number of cells, and the horizontal axis represents the fluorescence intensity. The solid line represents the binding of anti-TfR antibody or anti-EGFR antibody, and the gray-filled histogram represents the binding of the negative control isotype antibody.

[0098] Figure 3 The graph shows the results of evaluating the antigen expression levels in liver cancer cell lines using flow cytometry. Figure 3 (A) to (C) show the results of evaluating the expression levels of GPC3 in HepG2 cells, HuH-7 cells, and HLE cells using flow cytometry, respectively. Figure 3(D) to (F) show the results of evaluating the TfR expression levels in HepG2 cells, HuH-7 cells, and HLE cells using flow cytometry, respectively. Figure 3 (G) to (I) respectively represent the results of evaluating the EGFR expression in HepG2 cells, HuH-7 cells, and HLE cells using flow cytometry. The vertical axis represents the number of cells, and the horizontal axis represents the fluorescence intensity. The solid line represents the binding of anti-GPC3 antibody, anti-TfR antibody, or anti-EGFR antibody, and the gray-filled histogram represents the binding of the negative control isotype antibody or anti-DNP antibody.

[0099] Figure 4 (A) to (I) show the results of evaluating the binding of each antibody to OE21 cells using flow cytometry. The vertical axis represents the number of cells, and the horizontal axis represents the fluorescence intensity. The solid line represents the binding of anti-EGFR antibody or anti-TfR antibody, and the gray-filled histogram represents the binding of the secondary antibody of the negative control.

[0100] Figure 5 The results of evaluating the proliferation inhibitory activity of each TfR antibody on OE21 cells are shown. The vertical axis represents the cell survival rate expressed as the relative value of the amount of ATP in living cells relative to the negative control. The black bar graph represents the results when only the monoclonal antibody is added, and the white bar graph represents the results when the monoclonal antibody is cross-linked by adding a crosslink antibody.

[0101] Figure 6 The results of evaluating the growth inhibitory activity of each EGFR antibody on OE21 cells are shown. The vertical axis shows the cell survival rate expressed as the relative value of the ATP amount in living cells to the negative control.

[0102] Fig. 7A The results of evaluating the growth inhibitory activity of various bispecific antibodies on OE21 cells are shown. The vertical axis shows the cell survival rate expressed as the relative value of the ATP amount in living cells to the negative control.

[0103] Figure 7B The results of evaluating the growth inhibitory activity of various bispecific antibodies on OE21 cells are shown. The vertical axis shows the cell survival rate expressed as the relative value of the ATP amount in living cells to the negative control.

[0104] Figure 7C The results of evaluating the growth inhibitory activity of various bispecific antibodies on OE21 cells are shown. The vertical axis shows the cell survival rate expressed as the relative value of the ATP amount in living cells to the negative control.

[0105] Fig. 8AThe graph shows the results of evaluating the growth inhibitory activity of the EGFR-TfR bispecific antibody on the EGFR-expressing cancer cell line OE21. The vertical axis shows the cell survival rate expressed as the relative value of the ATP amount in living cells to the negative control.

[0106] Figure 8B The results of evaluating the growth inhibitory activity of the EGFR-TfR bispecific antibody on the EGFR-expressing cancer cell line T.Tn are shown. The vertical axis represents the cell survival rate expressed as the relative value of the ATP amount in living cells to the negative control.

[0107] Figure 8C The results of evaluating the growth inhibitory activity of the EGFR-TfR bispecific antibody on the EGFR-expressing cancer cell line U-937 are shown. The vertical axis represents the cell survival rate expressed as the relative value of the ATP amount in living cells to the negative control.

[0108] Fig. 9 The graph shows the results of evaluating the growth inhibitory activity of the GPC3-TfR bispecific antibody on HepG2 cells. The vertical axis shows the cell survival rate expressed as the relative value of the ATP amount in living cells to the negative control.

[0109] Fig. 10A The results of evaluating the growth inhibitory activity of the GPC3-TfR bispecific antibody on the HepG2 liver cancer cell line expressing GPC3 are shown. The vertical axis represents the cell survival rate expressed as the relative value of the ATP amount in the living cells to the negative control.

[0110] Fig. 10B The graph shows the results of evaluating the growth inhibitory activity of the GPC3-TfR bispecific antibody on the GPC3-expressing liver cancer cell line HuH-7. The vertical axis shows the cell survival rate expressed as the relative value of the ATP amount in living cells to the negative control.

[0111] Fig. 10C The results of evaluating the growth inhibitory activity of the GPC3-TfR bispecific antibody on the hepatoma cell line HLE expressing GPC3 are shown. The vertical axis represents the cell survival rate expressed as the relative value of the ATP amount in the living cells to the negative control.

[0112] Fig.11(A) to (E) represent the results of evaluating the inhibitory activity of each antibody or bispecific antibody on the binding of TfR and Tf on OE21 cells. The vertical axis represents the number of cells, and the horizontal axis represents the fluorescence intensity. The thin solid line represents the binding activity when fluorescently labeled transferrin is added after adding the negative control, the thick solid line represents the binding activity when fluorescently labeled transferrin is added after adding the antibody or bispecific antibody, and the gray-filled histogram represents the negative control without adding fluorescently labeled transferrin.

[0113] Fig.12 The results obtained by Western blotting are shown to evaluate the effect of adding EGFR-TfR bispecific antibodies to OE21 cells on EGFR downstream signals and TfR expression. Each band represents the expression level of each protein recorded on the right side of the figure when each bispecific antibody or antibody is added at the concentration recorded in the upper part of the figure. pEGFR represents phosphorylated EGFR protein, AKT represents the protein of EGFR downstream signal, pAKT represents phosphorylated AKT protein, TFRC represents TfR protein, and ACTB represents β-actin.

[0114] Fig.13 (A) to (D) show the results of evaluating the expression of TfR on the cell surface when EGFR-TfR bispecific antibodies were added to OE21 cells using flow cytometry. The vertical axis represents the number of cells and the horizontal axis represents the fluorescence intensity. The thin solid line represents the binding activity when fluorescently labeled transferrin is added after 24 hours of culture with the negative control, the thick solid line represents the binding activity when fluorescently labeled transferrin is added after 24 hours of culture with the antibody or bispecific antibody, and the gray-filled histogram represents the negative control without the addition of fluorescently labeled transferrin.

[0115] Fig.14 The results are obtained by evaluating whether the proliferation inhibitory activity when the EGFR-TfR bispecific antibody is added to OE21 cells is caused by iron depletion. The vertical axis represents the cell survival rate represented by the relative value of the ATP amount in living cells relative to the negative control under the condition of adding PBS but not adding FAS. The black bar graph represents the survival rate when only the antibody or bispecific antibody is added, and the oblique bar graph represents the survival rate when FAS is added together with the antibody or bispecific antibody.

[0116] Fig.15The results obtained by evaluating the proliferation inhibitory activity when the EGFR-TfR bispecific antibody was added to OE21 cells. The vertical axis represents the proportion of cells in the well (%). The black bar graph represents the proportion of cells in the well when cultured for 7 days in the presence of the antibody or bispecific antibody (%), and the oblique line bar graph represents the proportion of cells in the well when the antibody is removed by replacing the culture medium and cultured for another 7 days in the presence of the antibody or bispecific antibody (%).

[0117] Fig.16 The graph shows the results of evaluating the growth inhibitory activity when the EGFR-TfR bispecific antibody was added to GEMM. The vertical axis shows the survival rate when the ATP amount in the living cells when PBS was added was set to 100%.

[0118] Fig.17A The results obtained by evaluating the growth inhibitory activity of the EGFR-TfR bispecific antibody are shown.

[0119] Fig. 17B The results obtained by evaluating the growth inhibitory activity of the EGFR-TfR bispecific antibody are shown.

[0120] Fig.18 (A) is a schematic diagram showing the structure of the EGFR-TfR bispecific antibody prepared in Example 6. Fig.18 (B) is a schematic diagram showing the structure of the heterodimeric antibody prepared in Example 23.

[0121] Fig.19A The results obtained by evaluating the growth inhibitory activity of the EGFR-TfR bispecific antibody are shown.

[0122] Fig.19B The results obtained by evaluating the growth inhibitory activity of the EGFR-TfR bispecific antibody are shown.

[0123] Fig. 20 The results obtained by evaluating the growth inhibitory activity of the EGFR-TfR bispecific antibody using the growth inhibitory activity against cancer cell lines as an index are shown.

[0124] Fig.21 The results obtained by evaluating the growth inhibitory activity of the EGFR-TfR bispecific antibody are shown.

[0125] Specific embodiments of the invention

[0126] The present invention relates to a bispecific antibody or a bispecific antibody fragment that binds to TfR and a cell surface antigen (hereinafter referred to as the bispecific antibody or the bispecific antibody fragment of the present invention), wherein a polypeptide having an antigen binding site for a cell surface antigen (also referred to as an N-terminal polypeptide) is bound directly or via a linker to the N-terminal side of an IgG part that binds to TfR. ()()

[0127] TfR in the present invention is used with the same meaning as CD71, TFR1, TR, T9, p90, and IMD46. As TfR, for example, human TfR comprising the amino acid sequence shown in GenBank accession No. (GenBank accession number) NP_003225 or sequence number 6 in NCBI (http: / / www.ncbi.nlm.nih.gov / ), and monkey TfR comprising the amino acid sequence shown in sequence number 8, etc. In addition, for example, a polypeptide having the function of TfR can be listed, which is composed of an amino acid sequence in which one or more amino acids are deleted, substituted, or added in the amino acid sequence shown in sequence number 6, GenBank accession No. NP_003225, or sequence number 8.

[0128] The TfR of the present invention includes a polypeptide comprising an amino acid sequence that generally has an identity of more than 70%, preferably more than 80%, and more preferably more than 90% with the amino acid sequence shown in sequence number 6, GenBank accession No. NP_003225, or sequence number 8, and a polypeptide consisting of an amino acid sequence that most preferably has an identity of more than 95%, 96%, 97%, 98%, and 99% and has the function of TfR.

[0129] A polypeptide having an amino acid sequence in which one or more amino acid residues are deleted, substituted or added in the amino acid sequence shown in SEQ ID NO: 6, GenBank accession No. NP_003225 or SEQ ID NO: 8 can be obtained by using a site-directed mutagenesis method [Molecular Cloning, A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press (1989), Current Protocols in Molecular Biology, John Wiley & Sons (1987-1997), Nucleic Acids Research, 10, 6487 (1982), Proc. Natl. Acad. Sci. USA, 79, 6409 (1982), Gene, 34, 315 (1985), Nucleic Acids Research, 13, 4431 (1985), Proceeding of the National Academy of Sciences in USA, 82, 488 (1985)], for example, in the coding sequence No. 6, GenBank accession No. NP_003225 or SEQ ID NO: 8. No. NP_003225 or SEQ ID NO: 8 by introducing site-directed mutations into the DNA of the amino acid sequence shown in SEQ ID NO: 8. The number of amino acids to be deleted, substituted or added is not particularly limited, but is preferably 1 to several dozen, for example 1 to 20, more preferably 1 to several, for example 1 to 5 amino acids.

[0130] Examples of the gene encoding TfR include the base sequence of human TfR shown in SEQ ID NO: 5 or GenBank accession No. NM_003234 and the base sequence of monkey TfR shown in SEQ ID NO: 7. In addition, for example, a gene comprising a base sequence in which one or more bases are deleted, substituted or added in the base sequence shown in sequence number 5, GenBank accession No. NM_003234 or sequence number 7, and encoding a polypeptide having the function of TfR; a gene comprising a base sequence preferably having 60% or more homology, more preferably 80% or more homology, and even more preferably 95% or more homology with the base sequence shown in sequence number 5, GenBank accession No. NM_003234 or sequence number 7, and encoding a polypeptide having the function of TfR; and a gene comprising a DNA that hybridizes under stringent conditions with a DNA consisting of a base sequence shown in sequence number 5, GenBank accession No. NM_003234 or sequence number 7 and encoding a polypeptide having the function of TfR, etc. are also included in the gene encoding TfR of the present invention.

[0131] DNA that hybridizes under stringent conditions refers to, for example, DNA that can hybridize obtained by using a DNA having a base sequence shown in SEQ ID NO: 5 or GenBank accession No. NM_003234 as a probe in colony hybridization, plaque hybridization, Southern blotting, or DNA microarray. Specifically, examples of DNA that can be identified include: using a filter or slide glass to which DNA derived from hybridized colonies or plaques, or a PCR product or oligoDNA having the sequence is fixed, hybridization is carried out at 65°C in the presence of 0.7 to 1.0 mol / L sodium chloride [Molecular Cloning, A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press (1989), Current Protocols in Molecular Biology, John Wiley & Sons (1987-1997), DNA Cloning 1: Core Techniques, A Practical Approach, Second Edition, Oxford University (1995)], and then washing the filter or slide glass at 65°C using a 0.1 to 2-fold concentration SSC solution (the composition of a 1-fold concentration SSC solution contains 150 mmol / L sodium chloride and 15 mmol / L sodium citrate), thereby enabling DNA to be identified. Examples of hybridizable DNA include DNA preferably having 60% or more homology, more preferably 80% or more homology, and even more preferably 95% or more homology to the base sequence shown in SEQ ID NO: 5 or GenBank accession No. NM_003234.

[0132] Gene polymorphism is often found in the base sequence of genes encoding proteins in eukaryotic organisms. Genes used in the present invention that have small-scale variations in base sequence due to such polymorphism are also included in the genes encoding TfR of the present invention.

[0133] Unless otherwise specified, the homology values ​​in the present invention may be values ​​calculated by a person skilled in the art using a known homology search program. For base sequences, examples include values ​​calculated using default parameters in BLAST [J. Mol. Biol., 215, 403 (1990)], and for amino acid sequences, examples include values ​​calculated using default parameters in BLAST2 [Nucleic Acids Research, 25, 3389 (1997), Genome Research, 7, 649 (1997), http: / / www.ncbi.nlm.nih.gov / Education / BLASTinfo / information3.html].

[0134] As default parameters, G (Cost to open gap) is 5 in the case of base sequences and 11 in the case of amino acid sequences, -E (Cost to extend gap) is 2 in the case of base sequences and 1 in the case of amino acid sequences, -q (Penalty for nucleotide mismatch) is -3, -r (reward for nucleotide match) is 1, -e (expect value) is 10, -W (wordsize) is 11 residues in the case of base sequences and 3 residues in the case of amino acid sequences, -y [Dropoff (X) for blast extensions in bits] is 20 in the case of blastn and 7 in programs other than blastn, -X (X dropoff value for gapped alignment in bits) is 15, and -Z (final X dropoff value for gapped alignment in bits) is 1. bits, the drop value of the final gap alignment) is 50 in the case of blastn and 25 in programs other than blastn (http: / / www.ncbi.nlm.nih.gov / blast / html / blastcgihelp.html).

[0135] A polypeptide consisting of a partial sequence of the amino acid sequence of TfR can be produced by a method known to those skilled in the art, for example, by deleting a portion of the DNA encoding the amino acid sequence shown in sequence number 6, GenBank accession No. NP_003225 or sequence number 8, and culturing a transformant into which an expression vector containing the same is introduced. In addition, a polypeptide having an amino acid sequence in which one or more amino acids are deleted, substituted or added in a partial sequence of the amino acid sequence shown in sequence number 6, GenBank accession No. NP_003225 or sequence number 8 can be obtained by the same method as described above, based on the polypeptide or DNA produced using the above method. Furthermore, a polypeptide consisting of a partial sequence of the amino acid sequence of TfR, or a polypeptide having an amino acid sequence in which one or more amino acids are deleted, substituted or added in a partial sequence of the amino acid sequence of TfR can also be produced by chemical synthesis methods such as the fluorenylmethoxycarbonyl (Fmoc) method and the tert-butyloxycarbonyl (tBoc) method.

[0136] As the extracellular region of TfR in the present invention, for example, the region predicted by using the known transmembrane region prediction program SOSUI (http: / / sosui.proteome.bio.tuat.ac.jp / sosuiframe0.html), TMHMM ver.2 (http: / / www.cbs.dtu.dk / services / TMHMM-2.0 / ) or ExPASy Proteomics Server (http: / / Ca.expasy.org / ) etc. for the amino acid sequence of human TfR shown in GenBank accession No. NP_003225 can be listed. Specifically, the amino acid sequence shown in sequence number 2 or at positions 89 to 760 of GenBank accession No. NP_003225 can be listed.

[0137] As the function of TfR, the intake of iron necessary for the survival and proliferation of cells can be listed. If the complex of iron and transferrin is bound to TfR, it is taken into the cell by endocytosis. If the pH in the endosome is reduced, iron is freed from transferrin and transferred to the cytoplasm via DMT1 for cell proliferation or energy production. It is known that the complex of transferrin and TfR after iron is free is usually not decomposed and will move to the cell surface again (document: Yamashiro DJ et al., Cell 37789-800, 1984).

[0138] Cells expressing TfR include, for example, cells of various normal tissues represented by bone marrow and placental cells, or various cancer cells represented by colorectal cancer, head and neck cancer, brain tumors, hematopoietic organ tumors, liver cancer, and esophageal cancer, or various cancer cell lines such as HT29, HSC-2, RAMOS, K562, HepG2, OE21, T.Tn, U-937, HuH-7, and HLE.

[0139] The cell surface antigen of the present invention refers to an antigen other than TfR in an antigen such as a protein or peptide chain expressed on a cell membrane of a cancer cell or the like. As the cell surface antigen of the present invention, any antigen can be used as long as it can bind to a protein or polypeptide such as an antibody, preferably a cell surface antigen that is internalized and / or decomposed by binding to a protein or polypeptide such as an antibody. In addition, as the cell surface antigen of the present invention, a protein that is highly expressed in a cancer cell or a cell population involved in a specific disease is preferred. As a preferred example of such a cell surface antigen, EGFR, GPC3, etc. can be cited.

[0140] In the present invention, EGFR is used synonymously with ERBB, ERBB1, HER1, PIG61, MENA, NISBD2, SA7, and c-Erb-1.

[0141] Examples of EGFR include human EGFR comprising the amino acid sequence shown in GenBank accession No. NP005219 or SEQ ID NO. 14, and monkey EGFR comprising the amino acid sequence shown in GenBank accession No. XP_005549616.1. In addition, examples include polypeptides having the function of EGFR and consisting of an amino acid sequence in which one or more amino acids are deleted, substituted or added to the amino acid sequence shown in SEQ ID NO. 14, NP005219 or GenBank accession No. XP_005549616.1.

[0142] The EGFR of the present invention also includes a polypeptide comprising an amino acid sequence having preferably 70% or more, more preferably 80% or more, and even more preferably 90% or more homology to the amino acid sequence shown in sequence number 14, NP005219 or GenBank accession No. XP_005549616.1, and a polypeptide consisting of an amino acid sequence having most preferably 95%, 96%, 97%, 98% and 99% or more homology and having the function of EGFR.

[0143] A polypeptide having an amino acid sequence in which one or more amino acid residues are deleted, substituted, or added in the amino acid sequence shown in SEQ ID NO. 14, NP005219 or GenBank accession No. XP_005549616.1 can be obtained by introducing site-directed mutations into DNA encoding, for example, the amino acid sequence shown in SEQ ID NO. 14, NP005219 or GenBank accession No. XP_005549616.1 using the above-mentioned site-directed mutation introduction method, etc. The number of amino acids deleted, substituted or added is not particularly limited, and is preferably 1 to several dozen, for example 1 to 20, more preferably 1 to several, for example 1 to 5 amino acids.

[0144] Examples of the gene encoding EGFR in the present invention include a human EGFR gene containing the base sequence shown in Genbank accession No. NM_005228 or SEQ ID NO: 13.

[0145] In addition, for example, a gene comprising a base sequence in which one or more bases are deleted, substituted or added in the base sequence shown in SEQ ID NO: 13 or Genbank accession No. NM_005228 and encoding a polypeptide having the function of EGFR; a gene comprising a base sequence having 60% or more homology to the base sequence shown in SEQ ID NO: 13 or Genbank accession No. NM_005228, preferably a base sequence having 80% or more homology, and more preferably a base sequence having 95% or more homology and encoding a polypeptide having the function of EGFR; and a gene comprising a DNA that hybridizes with a DNA having a base sequence shown in SEQ ID NO: 13 or Genbank accession No. NM_005228 under stringent conditions and encoding a polypeptide having the function of EGFR, etc. are also included in the gene encoding EGFR of the present invention.

[0146] As the extracellular region of EGFR in the present invention, for example, the region predicted by using the known transmembrane region prediction program SOSUI (http: / / sosui.proteome.bio.tuat.ac.jp / sosuiframe0.html), TMHMM ver.2 (http: / / www.cbs.dtu.dk / services / TMHMM-2.0 / ) or ExPASy Proteomics Server (http: / / Ca.expasy.org / ) etc. for the amino acid sequence of human EGFR shown in GenBank accession No. NP005219 can be listed. Specifically, the amino acid sequence shown in the 25th to the 645th position of sequence number 10 or GenBank accession No. NP005219 can be listed.

[0147] The functions of EGFR include, for example, the function as a receptor for EGF; forming a dimer after binding to EGF and promoting cell proliferation, survival, invasion, migration, etc. through signals of the Ras / Raf / MAPK pathway, PI3K / Akt pathway, Jak / STAT pathway, etc. It is known that EGFR on the cell membrane is internalized by binding to EGF, transferred to lysosomes by endocytosis, and degraded (Ebner R et al., Cell Regul. 2 599-612, 1991).

[0148] Cells expressing EGFR include, for example, epithelial cells of normal tissues such as skin, colon, and lung, epithelial cancer cells such as colon cancer, head and neck cancer, lung cancer, and esophageal cancer, or cancer cell lines such as HT29, HSC-2, NCI-H1975, OE21, T.Tn, and A431.

[0149] In the present invention, GPC3 is used with the same meaning as DGSX, GTR2-2, MXR7, OCI-5, SDYS, SGB, SGBS, and SGBS1.

[0150] Examples of the function of GPC3 include binding to proteins related to the Wnt pathway or the Frizzled pathway and participating in cell division or proliferation of cancer cells such as liver cancer.

[0151] Examples of GPC3 include human GPC3 comprising the amino acid sequence shown in Genbank accession No. P51654.

[0152] Examples of the extracellular region of GPC3 in the present invention include regions predicted using the known transmembrane region prediction programs SOSUI (http: / / sosui.proteome.bio.tuat.ac.jp / sosuiframe0.html), TMHMM ver.2 (http: / / www.cbs.dtu.dk / services / TMHMM-2.0 / ), or ExPASy Proteomics Server (http: / / Ca.expasy.org / ) for the amino acid sequence of human GPC3 shown in GenBank accession No. P51654. Specifically, the amino acid sequence shown in positions 1 to 559 of GenBank accession No. P51654 can be cited.

[0153] Examples of cells expressing GPC3 include fetal liver cells, cancer cells such as hepatoma, and cancer cell lines such as HepG2 and HuH-7.

[0154] Antibodies are proteins derived from genes encoding all or part of the variable region of the heavy chain and the constant region of the heavy chain constituting immunoglobulins (referred to as "antibody genes"). The antibodies of the present invention also include antibodies or antibody fragments having any immunoglobulin class and subclass.

[0155] The heavy chain (H chain) refers to the polypeptide with the larger molecular weight of the two polypeptides that constitute the immunoglobulin molecule. The heavy chain determines the class and subclass of the antibody. IgA, IgD, IgE, IgG, and IgM have α chain, δ chain, ε chain, γ chain, and μ chain as heavy chains, respectively, and the constant region of the heavy chain is characterized by different amino acid sequences. The light chain (L chain) refers to the polypeptide with the smaller molecular weight of the two polypeptides that constitute the immunoglobulin molecule. In the case of human antibodies, there are two types of light chains, namely κ chain and λ chain.

[0156] The variable region (V region) generally refers to the region rich in diversity in the amino acid sequence on the N-terminal side of the immunoglobulin. The part outside the variable region adopts a less diverse structure and is therefore called the constant region (C region). The variable regions of the heavy chain and the light chain associate to form an antigen binding site, which determines the binding properties of the antibody to the antigen.

[0157] In the heavy chain of a human antibody, the variable region corresponds to the amino acid sequence from position 1 to position 117 in the EU index of Kabat et al. (Kabat et al., Sequences of proteins of immunological interest, 1991 Fifth edition), and the constant region corresponds to the amino acid sequence after position 118. In the light chain of a human antibody, the amino acid sequence from position 1 to position 107 in the numbering (Kabat numbering) established by Kabat et al. corresponds to the variable region, and the amino acid sequence after position 108 corresponds to the constant region. Hereinafter, the heavy chain variable region or the light chain variable region is abbreviated as VH or VL.

[0158] The antigen binding site refers to the site in the antibody that recognizes and binds to the antigen, and is a site that forms a complementary three-dimensional structure with the antigenic determinant (epitope). The antigen binding site produces a strong intermolecular interaction with the antigenic determinant. The antigen binding site is composed of VH and VL containing at least 3 complementary determining regions (CDRs). In the case of human antibodies, VH and VL each have 3 CDRs. These CDRs are respectively referred to as CDR1, CDR2 and CDR3 from the N-terminal side.

[0159] In the constant region, the heavy chain constant region or the light chain constant region is denoted as CH or CL, respectively. CH is classified according to the α chain, δ chain, ε chain, γ chain and μ chain, which are subclasses of the heavy chain. CH is composed of the CH1 domain, hinge region, CH2 domain and CH3 domain arranged in sequence from the N-terminal side, and the CH2 domain and CH3 domain are collectively referred to as the Fc region. On the other hand, CL is classified into two subclasses called Cλ chain and Cκ chain.

[0160] Monoclonal antibodies are antibodies secreted by antibody-producing cells that maintain their singleness (monoclonality) and recognize a single epitope (also called antigenic determinant). Monoclonal antibody molecules have the same amino acid sequence (primary structure) and a single structure. Polyclonal antibodies refer to a group of antibody molecules secreted by antibody-producing cells of different clones. Oligoclonal antibodies refer to a group of antibody molecules that are a mixture of multiple different monoclonal antibodies.

[0161] An epitope is a structural part of an antigen that an antibody recognizes and binds to. Examples of epitopes include: a single amino acid sequence that a monoclonal antibody recognizes and binds to, a three-dimensional structure composed of an amino acid sequence, an amino acid sequence bound to a sugar chain, and a three-dimensional structure composed of an amino acid sequence bound to a sugar chain.

[0162] Examples of the monoclonal antibody in the present invention include antibodies produced by hybridomas and genetically recombinant antibodies produced by transformants transformed with expression vectors containing antibody genes.

[0163] Hybridoma can be prepared, for example, by preparing an antigen, obtaining an antibody-producing cell with antigen-specificity from an animal immunized with the antigen, and then fusing the antibody-producing cell with a myeloma cell. The hybridoma ascites can be cancerized by cultivating the hybridoma or administering the hybridoma to an animal, and the culture fluid or ascites can be separated and purified to obtain the desired monoclonal antibody. As an animal immunized with an antigen, any animal can be used as long as hybridomas can be made, preferably mice, rats, hamsters and rabbits. In addition, cells with antibody-producing ability can also be obtained from such an immunized animal, and after the cell is immunized in vitro, it is fused with a myeloma cell to make a hybridoma.

[0164] As the genetically recombinant antibodies in the present invention, for example, antibodies produced by genetic recombination techniques such as recombinant mouse antibodies, recombinant rat antibodies, recombinant hamster antibodies, recombinant rabbit antibodies, human chimeric antibodies (also referred to as chimeric antibodies), humanized antibodies (also referred to as CDR transplanted antibodies), and human antibodies can be listed. In genetically recombinant antibodies, it can be determined which animal's heavy chain and light chain variable regions and constant regions are suitable, depending on the animal species or purpose of the object. For example, when the animal species of the object is human, the variable region can be derived from non-human animals such as humans or mice, and the constant region and linker can be derived from humans.

[0165] Chimeric antibodies refer to antibodies composed of VH and VL of antibodies from animals other than humans (non-human animals) and CH and CL of human antibodies. As non-human animals, any animal such as mice, rats, hamsters and rabbits can be used as long as hybridomas can be produced. Chimeric antibodies can be produced by obtaining cDNA encoding VH and VL from hybridomas derived from non-human animals that produce monoclonal antibodies, inserting them into animal cell expression vectors with DNA encoding CH and CL of human antibodies, respectively, constructing chimeric antibody expression vectors, and introducing them into animal cells to express them.

[0166] Humanized antibody refers to an antibody formed by transplanting the CDRs of VH and VL of non-human animal antibodies to the corresponding CDRs of VH and VL of human antibodies. The region outside the CDRs of VH and VL is referred to as a framework region (hereinafter referred to as FR). Humanized antibodies can be manufactured in the following manner: construct a cDNA encoding an amino acid sequence of VH consisting of an amino acid sequence of the CDRs of VH of a non-human animal antibody and an amino acid sequence of the FRs of VH of any human antibody, and a cDNA encoding an amino acid sequence of VL consisting of an amino acid sequence of the CDRs of VL of a non-human animal antibody and an amino acid sequence of the FRs of VL of any human antibody, and introduce them into an animal cell expression vector having DNA encoding CH and CL of a human antibody, construct a humanized antibody expression vector, and introduce it into an animal cell to express it.

[0167] Human antibodies originally refer to antibodies that exist naturally in the human body, but also include antibodies obtained from human antibody phage libraries and human antibody-producing transgenic animals, which are produced due to recent advances in genetic engineering, cell engineering, and developmental engineering technologies.

[0168] Antibodies naturally present in the human body can be obtained, for example, by immortalizing human peripheral blood lymphocytes by infecting them with Epstein-Barr virus or the like, cloning them, culturing lymphocytes producing the antibodies, and purifying the antibodies from the culture supernatant.

[0169] The human antibody phage library is a library in which antibody fragments such as Fab and scFv are expressed on the surface of phage by inserting antibody genes prepared by human B cells into phage genes. Phages expressing antibody fragments with the desired antigen-binding activity on the surface can be recovered from the library using the binding activity to a substrate immobilized with an antigen as an index. The antibody fragment can be further converted into a human antibody molecule consisting of two complete H chains and two complete L chains by genetic engineering methods.

[0170] Human antibody-producing transgenic animals refer to animals with human antibody genes integrated into their cells. Specifically, for example, human antibody genes can be introduced into mouse ES cells, and the ES cells can be transplanted into early embryos of mice to allow individual development, thereby producing transgenic mice that produce human antibodies. Human antibodies derived from transgenic animals that produce human antibodies can be prepared in the following manner: hybridomas are obtained by hybridoma preparation methods using conventional non-human animals, and the hybridomas are cultured to produce and accumulate antibodies in the culture supernatant.

[0171] As the CH of the genetically recombinant antibody, any CH may be used as long as it belongs to human immunoglobulin, and preferably a CH of human immunoglobulin G (hIgG) class. In addition, any of the subclasses such as hIgG1, hIgG2, hIgG3 and hIgG4 belonging to the hIgG class can be used. In addition, as the CL of the genetically recombinant antibody, any CL may be used as long as it belongs to human immunoglobulin, and a κ class or a λ class CL can be used.

[0172] In the present invention, a bispecific antibody refers to a polypeptide or protein that specifically binds to two different epitopes. Each antigen-binding site of a bispecific antibody may bind to different epitopes of a single antigen or to different antigens.

[0173] In the present invention, for example, the binding of a polypeptide, an antibody or an antibody fragment or a bispecific antibody or a bispecific antibody fragment to any one of a cell surface antigen such as EGFR or GPC3 and TfR can be confirmed by using a known immunological detection method, preferably a fluorescent cell staining method, etc. to confirm the binding of a cell expressing a cell surface antigen or TfR to be evaluated with an antibody. In addition, known immunological detection methods [Monoclonal Antibodies-Principles and Practice, Third Edition, Academic Press (1996), Antibodies-A Laboratory Manual, Cold Spring Harbor Laboratory (1988), Monoclonal Antibody Experiment Manual, Kodansha Scientific (1987)] and the like can also be used in combination.

[0174] In the present invention, the antigen binding site that binds to a cell surface antigen such as EGFR or GPC3 or TfR may be any site as long as it specifically recognizes and binds to a cell surface antigen such as EGFR or GPC3 or TfR. For example, it may be any form such as an antibody, a ligand, a receptor, and a naturally occurring interaction molecule, a polypeptide that can be produced by genetic recombination technology, a protein molecule and its fragment, and a conjugate of the protein molecule with a low molecule or a natural product.

[0175] In addition, as the antigen binding site, it can be a binding protein recombined using the binding domain of a known binding molecule such as an antibody, a ligand, and a receptor, and specifically, it can be listed as: a recombinant protein comprising the CDR of an antibody that binds to each antigen, an antibody variable region comprising the CDR, a recombinant protein comprising the binding domain of a ligand that binds to the antibody variable region and each antigen, etc. Among them, in the present invention, it is preferred that the antigen binding site is an antibody variable region.

[0176] As the bispecific antibody of the present invention or the bispecific antibody fragment, for example, bispecific antibodies or bispecific antibody fragments having internalization and / or decomposition activity of TfR can be cited. As the bispecific antibody of the present invention or the bispecific antibody fragment, it is preferred that cells that do not express cell surface antigens such as EGFR or GPC3 do not show internalization and / or decomposition activity of TfR, and only cells expressing cell surface antigens such as EGFR or GPC3 show internalization and / or decomposition activity of TfR or the bispecific antibody fragment. Such bispecific antibodies or bispecific antibody fragments selectively show internalization and / or decomposition activity of TfR to pathogenic cells such as cancer cells expressing cell surface antigens such as EGFR or GPC3, so it is preferred in terms of not producing the side effects of internalization and / or decomposition of nonspecific TfR.

[0177] The TfR internalization and / or degradation activity possessed by the bispecific antibody or the bispecific antibody fragment of the present invention refers to the activity of introducing TfR into the internalization and / or degradation pathway of the cell surface antigen by binding of the bispecific antibody or the bispecific antibody fragment to both cell surface antigens such as EGFR or GPC3 on the cell and TfR, thereby inducing internalization and / or degradation.

[0178] The bispecific antibody or the bispecific antibody fragment of the present invention can bind to cell surface antigens such as EGFR or GPC3 and TfR expressed on the same cell, or can bind to cell surface antigens such as EGFR or GPC3 and TfR expressed on different cells. Preferably, the bispecific antibody or the bispecific antibody fragment binds to cell surface antigens such as EGFR or GPC3 and TfR expressed on the same cell.

[0179] The bispecific antibody or bispecific antibody fragment of the present invention is preferably a bispecific antibody or bispecific antibody fragment that induces cell death of target cells expressing cell surface antigens such as EGFR or GPC3 by inducing internalization and / or degradation of TfR.

[0180] The internalization and / or degradation activity of TfR possessed by the bispecific antibody of the present invention or the bispecific antibody fragment can be confirmed, for example, by evaluating the amount of TfR protein on the cell surface and inside cells, the number of surviving cells, the cell proliferation rate, the cell survival rate or the iron uptake of cells expressing TfR, such as OE21, T.Tn, TE-8, U-937, HepG2, HuH-7 and HLE.

[0181] That is, examples of the bispecific antibodies or bispecific antibody fragments of the present invention include, specifically, bispecific antibodies or bispecific antibody fragments that induce degradation of TfR when binding to both a cell surface antigen such as EGFR or GPC3 and TfR.

[0182] The number of binding domains for a certain antigen possessed by a bispecific antibody molecule is referred to as the binding valency. For example, in the present invention, when a bispecific antibody molecule has two antigen binding sites that bind to EGFR and two antigen binding sites that bind to TfR, the bispecific antibody binds to EGFR and TfR in two valencies, respectively.

[0183] Furthermore, antibodies containing multiple antigen-binding sites linked via an appropriate linker such as a linker comprising an immunoglobulin domain or a fragment thereof are also encompassed by the bispecific antibodies of the present invention.

[0184] The bispecific antibody of the present invention can be produced by existing production techniques ([Nature Protocols, 9, 2450-2463 (2014)], International Publication No. 1998 / 050431, International Publication No. 2001 / 7734, International Publication No. 2002 / 002773, and International Publication No. 2009 / 131239) and the like.

[0185] The bispecific antibody of the present invention has a structure in which a polypeptide capable of binding to a cell surface antigen (also referred to as an N-terminal polypeptide) is bound directly or via a linker to the heavy chain N-terminus of the IgG part that binds to TfR.

[0186] In the present invention, an immunoglobulin domain is a peptide having an amino acid sequence similar to that of an immunoglobulin and consisting of about 100 amino acid residues with at least two cysteine ​​residues as a minimum unit. In the present invention, an immunoglobulin domain also includes a polypeptide comprising a plurality of the above-mentioned minimum units of immunoglobulin domains. Examples of immunoglobulin domains include VH, CH1, CH2, and CH3 of an immunoglobulin heavy chain, and VL and CL of an immunoglobulin light chain.

[0187] The animal species of immunoglobulin is not particularly limited, but preferably human. In addition, the subclass of the constant region of the heavy chain of immunoglobulin may be any one of IgD, IgM, IgG1, IgG2, IgG3, IgG4, IgA1, IgA2 and IgE, preferably IgG and IgM. In addition, the subclass of the constant region of the light chain of immunoglobulin may be any one of κ and λ.

[0188] In addition, immunoglobulin domains also exist in proteins other than immunoglobulins, for example, immunoglobulin domains contained in proteins belonging to the immunoglobulin superfamily such as major histocompatibility antigens (MHC), CD1, B7, and T cell receptors (TCR). As the immunoglobulin domain used in the bispecific antibody of the present invention, any immunoglobulin domain can be applied.

[0189] In the case of human IgG, CH1 refers to a region having an amino acid sequence from position 118 to position 215 as shown in the EU index. Similarly, CH2 refers to a region having an amino acid sequence from position 231 to position 340 as shown in the EU index of Kabat et al., and CH3 refers to a region having an amino acid sequence from position 341 to position 447 as shown in the EU index of Kabat et al. There is an amino acid region rich in flexibility called a hinge region (hereinafter sometimes referred to as a hinge) between CH1 and CH2. The hinge region refers to a region having an amino acid sequence from position 216 to position 230 as shown in the EU index of Kabat et al.

[0190] In the case of a human antibody κ chain, CL refers to a region having an amino acid sequence from position 108 to position 214 as shown in Kabat numbering, and in the case of a λ chain, CL refers to a region having an amino acid sequence from position 108 to position 215.

[0191] The IgG type antibody of the present invention is also referred to as the IgG part, which refers to the partial structure of the IgG that has been modified to constitute the IgG or Fc part of the bispecific antibody of the present invention, and has a heterotetrameric structure formed by the association of two heterodimers consisting of one light chain and one heavy chain. The IgG part that binds to TfR of the present invention refers to the IgG part that recognizes TfR, that is, the IgG part that has the function of specifically recognizing and binding to the extracellular region of TfR.

[0192] The heavy chain constant region of the above-mentioned IgG can be any subclass of IgG1, IgG2, IgG3, and IgG4. In addition, a part of these amino acid sequences can also be deleted, added, substituted and / or inserted. In addition, all or a part of the amino acid sequence consisting of CH1, hinge, CH2 and CH3 of the heavy chain of IgG can also be appropriately combined for use. In addition, these amino acid sequences can also be partially missing or used in a changed order. In addition, the subclass of IgG used in the IgG part is not particularly limited, preferably IgG4, IgG4 heavy chain constant region Ser residue 228 replaced by Pro, IgG4 mutant (hereinafter also referred to as IgG4PE) substituted by Asn, or IgG4 mutant (hereinafter referred to as IgG4PE R409K) substituted by Pro, Leu residue 235 replaced by Asn, and Arg residue 409 replaced by Lys in the heavy chain constant region of IgG4.

[0193] For example, the heavy chain constant region (CH1-hinge-CH2-CH3 from the N-terminal side) is preferably an IgG part consisting of IgG4PE containing the amino acid sequence shown in SEQ ID NO: 86, or an IgG part consisting of IgG4PE R409K containing the amino acid sequence shown in SEQ ID NO: 84.

[0194] The two variable regions contained in the IgG portion of the present invention preferably recognize the same antigen and preferably have the same structure and amino acid sequence.

[0195] In the present invention, the N-terminal polypeptide that binds to a cell surface antigen is a partial structure constituting the bispecific antibody of the present invention, and refers to a polypeptide that is present on the N-terminal side of the heavy chain or light chain of the IgG portion and specifically recognizes and binds to the extracellular region of each cell surface antigen.

[0196] The bispecific antibody of the present invention may have one N-terminal side polypeptide at the N-terminus of each of the heavy chains or light chains of the two heterodimers constituting the IgG portion, or may have one N-terminal side polypeptide at the N-terminus of only one heterodimer, preferably one N-terminal side polypeptide at the N-terminus of each of the two heavy chains or light chains. When the N-termini of the two heavy chains or light chains each have one N-terminal side polypeptide, they may be the same or different, and are preferably the same N-terminal side polypeptide.

[0197] The N-terminal polypeptide of the present invention may be a single chain or a polymer composed of multiple polypeptide chains as long as it has antigen binding ability to cell surface antigens. Examples of N-terminal polypeptides include Fab, Fab', scFv, dsFv and VHH of antibodies against cell surface antigens, preferably Fab or VHH. In addition, ligand molecules or receptor molecules against cell surface antigens may also be used.

[0198] Antibodies against cell surface antigens refer to monoclonal antibodies that specifically recognize and bind to the extracellular regions of each cell surface antigen, for example, anti-EGFR antibodies and anti-GPC3 antibodies refer to monoclonal antibodies that specifically recognize and bind to the extracellular regions of EGFR and GPC3, respectively.

[0199] In the present invention, the linker can be any linker as long as it is a molecular structure that allows the IgG part to bind to the N-terminal polypeptide, and a peptide chain is preferred. Examples of the amino acid sequence of the peptide chain include a peptide chain consisting of a repeating sequence of ES, ESKYG, ESKYGPP, GGGGS or GGGGS, or a peptide chain consisting of a part or all of the sequence of a constant region such as the hinge region and CH1 domain of an antibody.

[0200] In the case where the bispecific antibody of the present invention has a Fab of an antibody against a cell surface antigen as an N-terminal polypeptide, the light chain contained in the Fab and the light chain of the IgG part may be the same or different, preferably the same. In addition, the light chain may be any of a λ chain and a κ chain, preferably a κ chain.

[0201] In the amino acid sequence constituting the bispecific antibody or the antibody fragment of the present invention, one or more amino acid residues are deleted, added, substituted or inserted, and antibodies or antibody fragments thereof having the same activity as the above-mentioned antibodies or antibody fragments thereof are also included in the bispecific antibodies or antibody fragments of the present invention.

[0202] The number of amino acids to be deleted, substituted, inserted and / or added is one or more, and the number is not particularly limited, and is the number of the extent that can be deleted, substituted, inserted or added by known techniques such as site-directed mutagenesis methods described in Molecular Cloning, The Second Edition, Cold Spring Harbor Laboratory Press (1989), Current Protocols in Molecular Biology, John Wiley & Sons (1987-1997), Nucleic Acids Research, 10, 6487 (1982), Proc. Natl. Acad. Sci., USA, 79, 6409 (1982), Gene, 34, 315 (1985), Nucleic Acids Research, 13, 4431 (1985), Proc. Natl. Acad. Sci USA, 82, 488 (1985), etc. For example, the number is usually 1 to several tens, preferably 1 to 20, more preferably 1 to 10, and even more preferably 1 to 5.

[0203] In the amino acid sequence of the bispecific antibody of the present invention described above, deletion, substitution, insertion or addition of one or more amino acid residues are indicated as follows. It means that one or more amino acid residues are deleted, substituted, inserted or added in any one or more amino acid sequences in the same sequence. In addition, there are also cases where deletion, substitution, insertion or addition occurs simultaneously, and there are also cases where the substituted, inserted or added amino acid residues are either natural or non-natural.

[0204] Examples of the natural amino acid residue include L-alanine, L-asparagine, L-aspartic acid, L-glutamine, L-glutamic acid, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-arginine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, L-valine, and L-cysteine.

[0205] Preferred examples of interchangeable amino acid residues are shown below. Amino acid residues included in the same group are interchangeable.

[0206] Group A: Leucine, Isoleucine, Norleucine, Valine, Norvaline, Alanine, 2-aminobutyric acid, Methionine, O-methylserine, Tert-butylglycine, Tert-butylalanine, Cyclohexylalanine

[0207] Group B: Aspartic acid, Glutamic acid, Isoaspartic acid, Isoglutamic acid, 2-aminoadipic acid, 2-aminosuberic acid

[0208] Group C: Asparagine, Glutamine

[0209] Group D: lysine, arginine, ornithine, 2,4-diaminobutyric acid, 2,3-diaminopropionic acid Group E: proline, 3-hydroxyproline, 4-hydroxyproline

[0210] Group F: serine, threonine, homoserine

[0211] Group G: Phenylalanine, Tyrosine

[0212] The bispecific antibody or antibody fragment of the present invention also includes antibodies containing any amino acid residues that have been post-translationally modified. As post-translational modifications, for example, the deletion of lysine residues at the C-terminus of the H chain [lysine clipping] and the substitution of glutamine residues at the N-terminus of the polypeptide with pyroglutamine (pyroGlu) can be cited [Beck et al, Analytical Chemistry, 85, 715-736 (2013)].

[0213] Specific examples of the bispecific antibody of the present invention include any one of the bispecific antibodies selected from the following (1) to (4).

[0214] (1) a bispecific antibody comprising a Fab comprising a variable region of an antibody against a cell surface antigen and an IgG portion that binds to TfR, wherein the Fab directly binds to the N-terminus of the heavy chain of the IgG portion;

[0215] (2) a bispecific antibody comprising a VH containing CDR1 to 3 of VH and a VL containing CDR1 to 3 of VL of an antibody against a cell surface antigen, and an IgG portion that binds to TfR, wherein the Fab directly binds to the N-terminus of the heavy chain of the IgG portion;

[0216] (3) a bispecific antibody comprising a Fab comprising VH and VL of an antibody against a cell surface antigen, and an IgG portion that binds to TfR, wherein the Fab directly binds to the N-terminus of the heavy chain of the IgG portion; and

[0217] (4) A bispecific antibody comprising a VHH that binds to a cell surface antigen and an IgG part that binds to TfR, wherein the VHH directly binds to the N-terminus of the heavy chain of the IgG part.

[0218] In the bispecific antibodies described in (1) to (3) above, the VL of the IgG part that binds to TfR and the VL of the Fab may be the same or different, but are preferably the same.

[0219] As an example of the IgG portion that binds to TfR of the present invention, there can be listed an IgG portion that binds to TfR comprising: a VL containing CDR1, 2 and 3 comprising the amino acid sequences shown in sequence numbers 17, 18 and 19, respectively, and a VH containing CDR1 to 3 shown in the following 1) to 3).

[0220] 1) A CDR1 comprising the amino acid sequence shown in SEQ ID NO: 32 or an amino acid sequence altered by at least one substitution selected from the group consisting of replacing tyrosine at position 2 with alanine or phenylalanine and replacing threonine at position 3 with alanine or glycine in the amino acid sequence shown in SEQ ID NO: 32.

[0221] 2) A CDR2 comprising the amino acid sequence shown in SEQ ID NO: 33 or an amino acid sequence altered by at least one substitution selected from the group consisting of replacing valine at position 1 with alanine, replacing isoleucine at position 2 with alanine or leucine, replacing valine at position 7 with glutamic acid, replacing aspartic acid at position 10 with alanine, and replacing aspartic acid at position 13 with proline in the amino acid sequence shown in SEQ ID NO: 33.

[0222] 3) A CDR3 comprising the amino acid sequence shown in SEQ ID NO: 34, or an amino acid sequence altered by at least one substitution selected from the group consisting of substitution of glutamine at position 3 with alanine or aspartic acid, substitution of proline at position 4 with any natural amino acid, substitution of tryptophan at position 5 with alanine, phenylalanine, histidine or tyrosine, substitution of tyrosine at position 7 with alanine or phenylalanine, and substitution of valine at position 13 with leucine in the amino acid sequence shown in SEQ ID NO: 34. Examples of substitution of proline at position 4 with any natural amino acid include substitution with alanine, tyrosine, serine, aspartic acid, glutamine, glutamic acid, threonine, arginine, glycine, lysine, methionine, valine, leucine, isoleucine, tryptophan, phenylalanine or histidine.

[0223] The IgG portion that binds to TfR of the present invention also includes: an IgG portion that binds to TfR comprising amino acid sequences of CDR1 to 3 of VH and VL that are at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% homologous to the amino acid sequences of CDR1 to 3 of VH shown in sequence numbers 32, 33, and 34, respectively, and the amino acid sequences of CDR1 to 3 of VL shown in sequence numbers 17 to 19, respectively.

[0224] The IgG portion that binds to TfR of the present invention also includes the antibodies described in (ai) or (aii) below.

[0225] (ai) An IgG portion that binds to TfR and competes with an anti-TfR antibody for binding to TfR, wherein the anti-TfR antibody comprises: a VL comprising CDR1, 2 and 3 comprising the amino acid sequences shown in sequence numbers 17, 18 and 19, respectively, and a VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in sequence numbers 32, 33 and 34, respectively.

[0226] (aii) An IgG portion that binds to TfR and binds to the same epitope as an anti-TfR antibody, wherein the anti-TfR antibody comprises: a VL comprising CDR1, 2 and 3 comprising the amino acid sequences shown in sequence numbers 17, 18 and 19, respectively, and a VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in sequence numbers 32, 33 and 34, respectively.

[0227] The IgG portion that binds to TfR of the present invention also includes the antibodies described in (bi) or (bii) below.

[0228] (bi) An IgG portion that competitively binds to TfR with an anti-TfR antibody, comprising: a VL comprising CDR1, 2 and 3 comprising the amino acid sequences shown in sequence numbers 17, 18 and 19, respectively, and a VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in sequence numbers 42, 43 and 44, respectively.

[0229] (bii) An IgG portion that binds to TfR and binds to the same epitope as an anti-TfR antibody, comprising: a VL comprising CDR1, 2 and 3 comprising the amino acid sequences shown in sequence numbers 17, 18 and 19, respectively, and a VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in sequence numbers 42, 43 and 44, respectively.

[0230] The IgG portion that binds to TfR of the present invention also includes the antibodies described in (ci) or (cii) below.

[0231] (ci) An IgG portion that competitively binds to TfR with an anti-TfR antibody, comprising: a VL comprising CDR1, 2 and 3 comprising the amino acid sequences shown in sequence numbers 17, 18 and 19, respectively, and a VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in sequence numbers 47, 48 and 49, respectively.

[0232] (cii) An IgG portion that binds to TfR and binds to the same epitope as an anti-TfR antibody, comprising: a VL comprising CDR1, 2 and 3 comprising the amino acid sequences shown in sequence numbers 17, 18 and 19, respectively, and a VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in sequence numbers 47, 48 and 49, respectively.

[0233] As another example of the IgG portion that binds to TfR of the present invention, there can be listed an IgG portion that binds to TfR that contains a VL comprising the amino acid sequence shown in SEQ ID NO: 16 and a VH comprising the amino acid sequence shown in SEQ ID NO: 26, 31, 36, 41, 46 or 106.

[0234] An example of the TfR-binding IgG portion of the present invention includes a TfR-binding IgG portion comprising a VL comprising CDR1 to 3 comprising the amino acid sequences shown in SEQ ID NOs: 17 to 19, respectively, and one VH selected from the following.

[0235] (a) a VH comprising CDR2 and CDR3 comprising the amino acid sequences shown in SEQ ID NOs: 33 and 34, respectively, and CDR1 comprising an amino acid sequence altered by substituting tyrosine at position 2 with alanine or phenylalanine in the amino acid sequence shown in SEQ ID NO: 32;

[0236] (b) a VH comprising CDR2 and CDR3 comprising the amino acid sequences shown in SEQ ID NOs: 33 and 34, respectively, and CDR1 comprising an amino acid sequence altered by substituting threonine at position 3 with alanine or glycine in the amino acid sequence shown in SEQ ID NO: 32;

[0237] (c) a VH comprising CDR1 and CDR3 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 34, respectively, and CDR2 comprising an amino acid sequence altered by substituting valine at position 1 with alanine in the amino acid sequence shown in SEQ ID NO: 33;

[0238] (d) a VH comprising CDR1 and CDR3 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 34, respectively, and CDR2 comprising an amino acid sequence altered by substituting isoleucine at position 2 with alanine or leucine in the amino acid sequence shown in SEQ ID NO: 33;

[0239] (e) a VH comprising CDR1 and CDR3 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 34, respectively, and CDR2 comprising an amino acid sequence altered by substituting valine at position 7 with glutamic acid in the amino acid sequence shown in SEQ ID NO: 33;

[0240] (f) a VH comprising CDR1 and CDR3 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 34, respectively, and CDR2 comprising an amino acid sequence altered by substituting aspartic acid at position 10 with alanine in the amino acid sequence shown in SEQ ID NO: 33;

[0241] (g) a VH comprising CDR1 and CDR3 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 34, respectively, and CDR2 comprising an amino acid sequence altered by substituting aspartic acid at position 13 with proline in the amino acid sequence shown in SEQ ID NO: 33;

[0242] (h) a VH comprising CDR1 and 2 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 33, respectively, and CDR3 comprising an amino acid sequence altered by substituting glutamine at position 3 with alanine or aspartic acid in the amino acid sequence shown in SEQ ID NO: 34;

[0243] (i) a VH comprising CDR1 and CDR2 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 33, respectively, and CDR3 comprising an amino acid sequence altered by substituting proline at position 4 of the amino acid sequence shown in SEQ ID NO: 34 with any natural amino acid;

[0244] (j) a VH comprising CDR1 and 2 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 33, respectively, and CDR3 comprising an amino acid sequence altered by substituting proline at position 4 of the amino acid sequence shown in SEQ ID NO: 34 with alanine, tyrosine, serine, aspartic acid, glutamine, glutamic acid, threonine, arginine, glycine, lysine, methionine, valine, leucine, isoleucine, tryptophan, phenylalanine or histidine

[0245] (k) a VH comprising CDR1 and CDR2 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 33, respectively, and CDR3 comprising an amino acid sequence altered by substituting tryptophan at position 5 with alanine, phenylalanine, histidine or tyrosine in the amino acid sequence shown in SEQ ID NO: 34;

[0246] (1) a VH comprising CDR1 and CDR2 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 33, respectively, and CDR3 comprising an amino acid sequence altered by substituting tyrosine at position 7 with alanine or phenylalanine in the amino acid sequence shown in SEQ ID NO: 34;

[0247] (m) a VH comprising CDR1 and CDR2 comprising the amino acid sequences shown in SEQ ID NOs: 32 and 33, respectively, and CDR3 comprising the amino acid sequence altered by substituting valine for leucine in the amino acid sequence shown in SEQ ID NO: 34;

[0248] As an example of the IgG portion that binds to TfR of the present invention, there can be listed an IgG portion that binds to TfR, including: a VL comprising the amino acid sequence shown in sequence number 16, and a VH comprising an amino acid sequence that is changed in the amino acid sequence shown in sequence number 31 by replacing at least one of Y32A, Y32F, T33A, T33G, L45A, V48A, V50A, I51A, I51L, V55E, D58A, D61P, Q97A, Q97D, W99A, W99F, W99H, W99Y, Y100AA, Y100AF, V102L, and P98 as shown in the EU index of Kabat et al. (hereinafter referred to as the EU index).

[0249] As an example of the IgG portion that binds to TfR of the present invention, it can be listed as: VL comprising the amino acid sequence shown in SEQ ID NO: 16, and Y32A, Y32F, T33A, T33G, L45A, V48A, V50A, I51A, I51L, V55E, D58A, D61P, Q97A, Q97D, W99A, The IgG part that binds to TfR of VH whose amino acid sequence is changed by substitution of any one of W99F, W99H, W99Y, Y100AA, Y100AF, V102L, P98A, P98Y, P98S, P98D, P98Q, P98E, P98T, P98R, P98G, P98K, P98M, P98V, P98L, P98I, P98W, P98F, and P98H.

[0250] As an example of the IgG part that binds to TfR of the present invention, there can be listed an IgG part that binds to TfR and recognizes at least one amino acid residue selected from Asp at position 352, Ser at position 355, Asp at position 356, and Lys at position 358, and at least one amino acid residue selected from Met at position 365, Val at position 366, and Glu at position 369 of the amino acid sequence of TfR shown in sequence number 6. As one form of the IgG portion that binds to TfR, for example, there can be listed: an IgG portion that binds to TfR that recognizes at least two amino acid residues selected from Asp at position 352, Ser at position 355, Asp at position 356, and Lys at position 358, and at least two amino acid residues selected from Met at position 365, Val at position 366, and Glu at position 369; an IgG portion that recognizes at least two amino acid residues selected from Asp at position 352, Ser at position 355, Asp at position 356, and Lys at position 358. The IgG part that binds to TfR recognizes at least 3 amino acid residues of Lys at position 365, and all amino acid residues of Met at position 366, Val at position 366, and Glu at position 369; the IgG part that binds to TfR recognizes Asp at position 352, Ser at position 355, Asp at position 356, and all amino acid residues of Lys at position 358, and all amino acid residues of Met at position 365, Val at position 366, and Glu at position 369.

[0251] An example of the anti-EGFR antibody of the present invention includes an anti-EGFR antibody comprising a VL comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 17, 18 and 19, respectively, and any one VH selected from the following (2a) to (2b).

[0252] (2a) VH, VH2 and VH3 comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 60, 61 and 62, respectively.

[0253] (2b) VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 65, 66 and 67, respectively.

[0254] The anti-EGFR antibodies of the present invention also include anti-EGFR antibodies comprising amino acid sequences of CDR1 to 3 of VH and VL that are at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% homologous to the amino acid sequence of CDR1 to 3 of VH shown in any one of (2a) to (2b) above, and the amino acid sequence of CDR1 to 3 of VL shown in SEQ ID NOs: 17 to 19, respectively.

[0255] The anti-EGFR antibody of the present invention also includes the antibody described in the following (i) or (ii).

[0256] (i) An antibody that binds to EGFR competitively with an anti-EGFR antibody, comprising: a VL comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 17, 18 and 19, respectively; and a VH shown in any one of (2a) to (2b) above.

[0257] (ii) An antibody that binds to the same epitope as an anti-EGFR antibody, comprising: a VL comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 17, 18 and 19, respectively, and a VH shown in any one of (2a) to (2b) above.

[0258] Another example of the anti-EGFR antibody of the present invention is a bispecific antibody selected from the following (a) to (e).

[0259] (a) An antibody comprising a VH comprising the amino acid sequence shown in SEQ ID NO: 59 or SEQ ID NO: 64, and a VL comprising the amino acid sequence shown in SEQ ID NO: 16

[0260] (b) An antibody comprising a VH comprising the amino acid sequence shown in SEQ ID NO: 110 and a VL comprising the amino acid sequence shown in SEQ ID NO: 111

[0261] (c) An antibody comprising a VH comprising the amino acid sequence shown in SEQ ID NO: 112 and a VL comprising the amino acid sequence shown in SEQ ID NO: 113

[0262] (d) An antibody comprising a VH comprising the amino acid sequence shown in SEQ ID NO: 114 and a VL comprising the amino acid sequence shown in SEQ ID NO: 115

[0263] (e) An antibody comprising a VH comprising the amino acid sequence shown in SEQ ID NO: 116 and a VL comprising the amino acid sequence shown in SEQ ID NO: 117

[0264] As one embodiment of the present invention, the following bispecific antibody can also be listed: it comprises an N-terminal side polypeptide and an IgG part that binds to TfR, the N-terminal side polypeptide is Fab, and the C-terminus of the VH-CH1 of the Fab is directly or via a linker bound to the heavy chain N-terminus of the IgG part that binds to the above-mentioned TfR.

[0265] In addition, as one embodiment of the present invention, the following bispecific antibodies can also be listed: they comprise an N-terminal side polypeptide and an IgG part that binds to TfR, wherein the N-terminal side polypeptide is Fab, and the C-terminus of the VL-CL of the Fab is directly or via a linker bound to the heavy chain N-terminus of the IgG part that binds to the above-mentioned TfR.

[0266] One embodiment of the present invention includes a bispecific antibody comprising an IgG portion that binds to TfR and an N-terminal polypeptide that binds to EGFR.

[0267] More specifically, the bispecific antibodies of the present invention include the following bispecific antibodies (i) to (iv).

[0268] (i) The following bispecific antibody, comprising: an anti-EGFR antibody Fab, comprising: a VL comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 17, 18 and 19, respectively, and a VH represented by SEQ ID NOs: 60, 61 and 62, respectively; and an IgG portion that binds to TfR, comprising: a VL comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 17, 18 and 19, respectively, and any one of the following VHs (a) to (f);

[0269] And the Fab is bound directly or via a linker to the N-terminus of the heavy chain of the IgG part that binds to the TfR.

[0270] (a) VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 22, 23 and 24, respectively

[0271] (b) VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 27, 28 and 29, respectively

[0272] (c) VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 32, 33 and 34, respectively

[0273] (d) VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 37, 38 and 39, respectively

[0274] (e) VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 42, 43 and 44, respectively

[0275] (f) VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 47, 48 and 49, respectively

[0276] (ii) The following bispecific antibody, comprising: an anti-EGFR antibody Fab, comprising: a VL comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 17, 18 and 19, respectively, and a VH represented by SEQ ID NOs: 65, 66 and 67, respectively; and an IgG portion that binds to TfR, comprising: a VL comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 17, 18 and 19, respectively, and any one of the following VHs (a) to (f);

[0277] And the Fab is bound directly or via a linker to the N-terminus of the heavy chain of the IgG part that binds to the TfR.

[0278] (a) VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 22, 23 and 24, respectively

[0279] (b) VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 27, 28 and 29, respectively

[0280] (c) VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 32, 33 and 34, respectively

[0281] (d) VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 37, 38 and 39, respectively

[0282] (e) VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 42, 43 and 44, respectively

[0283] (f) VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 47, 48 and 49, respectively

[0284] (iii) The following bispecific antibody, comprising: an anti-EGFR antibody Fab, comprising: a VL comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 17, 18 and 19, respectively, and a VH represented by SEQ ID NOs: 70, 71 and 72, respectively; and an IgG portion that binds to TfR, comprising: a VL comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 17, 18 and 19, respectively, and any one of the VHs of (a) to (f) below;

[0285] And the Fab is bound directly or via a linker to the N-terminus of the heavy chain of the IgG part that binds to the TfR.

[0286] (a) VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 22, 23 and 24, respectively

[0287] (b) VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 27, 28 and 29, respectively

[0288] (c) VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 32, 33 and 34, respectively

[0289] (d) VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 37, 38 and 39, respectively

[0290] (e) VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 42, 43 and 44, respectively

[0291] (f) VH comprising CDR1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 47, 48 and 49, respectively

[0292] (iv) a bispecific antibody comprising: an anti-EGFR antibody Fab comprising: a VL comprising the amino acid sequence shown in SEQ ID NO: 16 and a VH comprising the amino acid sequence shown in SEQ ID NO: 59; and an IgG portion that binds to TfR comprising: a VL comprising the amino acid sequence shown in SEQ ID NO: 16 and a VH comprising the amino acid sequence shown in SEQ ID NO: 21, 26, 31, 36, 41 or 46;

[0293] And the Fab is bound directly or via a linker to the N-terminus of the heavy chain of the IgG part that binds to the TfR.

[0294] (v) a bispecific antibody comprising: an anti-EGFR antibody Fab comprising: a VL comprising the amino acid sequence shown in SEQ ID NO: 16 and a VH comprising the amino acid sequence shown in SEQ ID NO: 64; and an IgG portion that binds to TfR comprising: a VL comprising the amino acid sequence shown in SEQ ID NO: 16 and a VH comprising the amino acid sequence shown in SEQ ID NO: 21, 26, 31, 36, 41 or 46,

[0295] And the Fab is bound directly or via a linker to the N-terminus of the heavy chain of the IgG part that binds to the TfR.

[0296] (vi) The following bispecific antibody, comprising: an anti-EGFR antibody Fab, comprising: a VL comprising the amino acid sequence shown in SEQ ID NO: 16 and a VH comprising the amino acid sequence shown in SEQ ID NO: 69; and an IgG portion that binds to TfR, comprising: a VL comprising the amino acid sequence shown in SEQ ID NO: 16, and a VH comprising the amino acid sequence shown in SEQ ID NO: 21, 26, 31, 36, 41 or 46;

[0297] And the Fab is bound directly or via a linker to the N-terminus of the heavy chain of the IgG part that binds to the TfR.

[0298] In the bispecific antibodies shown in (i) to (vi) above, VH-CH1 or VL-CL of the Fab may be bound directly or via a linker to the N-terminus of the heavy chain of the IgG portion that binds to the TfR, and VH-CH1 may be preferred.

[0299] As one embodiment of the present invention, the following bispecific antibodies can be cited, which are bispecific antibodies in which the N-terminal side polypeptide is directly or via a linker bound to the heavy chain C-terminus of the IgG part that binds to TfR, and the constant region of the IgG part that binds to TfR is IgG1, IgG4, or a variant thereof. As a more preferred embodiment of the present invention, the following bispecific antibodies can be cited, wherein the heavy chain constant region of the IgG part that binds to TfR comprises IgG4PE or IgG4PE R409K,

[0300] The N-terminal polypeptide is bound directly or via a linker to the N-terminus of the heavy chain of the IgG portion that binds to the TfR.

[0301] As one embodiment of the present invention, the following bispecific antibody can be cited, which comprises an IgG portion that binds to TfR and an N-terminal polypeptide that binds to EGFR, wherein the N-terminal polypeptide is Fab, and the Fab is bound to the heavy chain N-terminus of the IgG portion via a linker. As a more preferred embodiment, a bispecific antibody in which the amino acid sequence of the linker is selected from one of the repeating sequences of ES, ESKYG, ESKYGPP, GGGGS, or GGGGS can be cited.

[0302] Examples of the bispecific antibody of the present invention include E08-TfR1071 and E12-TfR1071.

[0303] The bispecific antibodies or antibody fragments of the present invention also include antibodies or antibody fragments having effector activity.

[0304] Effector activity refers to antibody-dependent cellular cytotoxic activity caused by the Fc region of an antibody, and examples thereof include antibody-dependent cellular cytotoxicity activity (ADCC activity), complement-dependent cytotoxicity activity (CDC activity), antibody-dependent cellular phagocytosis activity (ADCP activity) caused by phagocytes such as macrophages and dendritic cells, and opsonin effects.

[0305] In the present invention, ADCC activity and CDC activity can be measured using a known measurement method [Cancer Immunol. Immunother., 36, 373 (1993)].

[0306] ADCC activity refers to the activity of an antibody that has bound to an antigen on a target cell to bind to an Fc receptor of an immune cell via the Fc region of the antibody, thereby activating immune cells (natural killer cells, etc.) to kill the target cell.

[0307] Fc receptor (FcR) is a receptor that binds to the Fc region of an antibody, and various effector activities are induced by the binding of the antibody. Each FcR corresponds to a subclass of an antibody, and IgG, IgE, IgA, and IgM specifically bind to FcγR, FcεR, FcαR, and FcμR, respectively. In addition, there are subtypes of FcγR, namely FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16), and each subtype has isotypes of FcγRIA, FcγRIB, FcγRIC, FcγRIIA, FcγRIIB, FcγRIIC, FcγRIIIA, and FcγRIIIB. These different FcγRs are present on different cells [Annu. Rev. Immunol. 9: 457-492 (1991)]. In humans, FcγRIIIB is specifically expressed on neutrophils, and FcγRIIIA is expressed on monocytes, natural killer cells (NK cells), macrophages, and a portion of T cells. NK cell-dependent ADCC activity is induced by antibody binding to FcγRIIIA.

[0308] CDC activity refers to the activity of antibodies that have bound to antigens on target cells to activate a series of cascade reactions (complement activation pathway) consisting of complement-related protein groups in the blood and kill target cells. In addition, protein fragments produced by complement activation induce the migration and activation of immune cells. The cascade reaction of CDC activity begins with the formation of the C1 complex by first binding to the Fc region through C1q, and then binding to two serine proteases C1r and C1s.

[0309] The CDC activity or ADCC activity of the bispecific antibody or the antibody fragment of the present invention on antigen-expressing cells can be evaluated by a known measurement method [Cancer Immunol. Immunother., 36, 373 (1993)].

[0310] As methods for controlling the effector activity of the bispecific antibody of the present invention, there are known methods for controlling the amount of α-1,6-linked fucose (also called core fucose) present at the reducing end of the N-acetylglucosamine (GlcNAc) of the N-linked complex sugar chain bound to asparagine (Asn) at position 297 of the Fc region (constant region composed of CH2 and CH3 domains) of the antibody (International Publication Nos. 2005 / 035586, 2002 / 31140, and 00 / 61739), or a method for controlling by modifying the amino acid residues in the Fc region of the antibody (International Publication No. 00 / 42072), etc.

[0311] By controlling the amount of fucose added to the bispecific antibody, the ADCC activity of the antibody can be increased or decreased. For example, as a method for reducing the content of fucose bound to the N-bound complex sugar chain bound to the Fc of the antibody, a bispecific antibody with high ADCC can be obtained by expressing the bispecific antibody using a host cell with a defective α1,6-fucosyltransferase gene. On the other hand, as a method for increasing the content of fucose bound to the N-bound complex sugar chain bound to the Fc of the bispecific antibody, a bispecific antibody with low ADCC activity can be obtained by expressing the antibody using a host cell into which the α1,6-fucosyltransferase gene is introduced.

[0312] In addition, by changing the amino acid residues in the Fc region of the bispecific antibody, ADCC activity or CDC activity can be increased or decreased. For example, by using the amino acid sequence of the Fc region recorded in the U.S. Patent Application Publication No. 2007 / 0148165 specification, the CDC activity of the bispecific antibody can be increased. In addition, by carrying out the amino acid changes recorded in the U.S. Patent No. 6,737,056 specification, the U.S. Patent No. 7,297,775 specification or the U.S. Patent No. 7,317,091 specification, etc., ADCC activity or CDC activity can also be increased or decreased.

[0313] Furthermore, bispecific antibodies with controlled effector activity can also be obtained by combining the above methods.

[0314] The stability of the bispecific antibody of the present invention can be evaluated by measuring the amount of aggregates (oligomers) formed in the sample stored during the purification process or under certain conditions. That is, the decrease in the amount of aggregates under the same conditions is evaluated as an improvement in the stability of the antibody. The amount of aggregates can be measured by separating the aggregated antibodies from the non-aggregated antibodies using appropriate chromatography including gel filtration chromatography.

[0315] The productivity of the bispecific antibody of the present invention can be evaluated by measuring the amount of antibody produced in the culture medium of the antibody-producing cells. More specifically, it can be evaluated by measuring the amount of antibody contained in the culture supernatant after removing the producing cells from the culture medium by an appropriate method such as HPLC or ELISA.

[0316] In the present invention, antibody fragments refer to proteins that contain an antigen-binding site and have antigen-binding activity to the antigen, and examples thereof include Fab, Fab', F(ab')2, scFv, Diabody, dsFv, VHH, or peptides containing CDRs.

[0317] Fab is an antibody fragment with antigen-binding activity of about 50,000 molecular weight, in which about half of the N-terminal side of the H chain is bound to the entire L chain by a disulfide bond (SS bond) among the fragments obtained by treating an IgG antibody with the protease papain (amino acid residue at position 224 of the H chain). The H chain of Fab containing VH and CH1 is referred to as VH-CH1. In addition, the L chain of Fab containing VL and CL is referred to as VL-CL.

[0318] F(ab')2 is an antibody fragment obtained by treating IgG with the protease pepsin (amino acid residue 234 of the H chain is cleaved), which is slightly larger than the fragment of Fab bound via the SS bond of the hinge region and has a molecular weight of about 100,000 and antigen-binding activity.

[0319] Fab' is an antibody fragment having an antigen-binding activity and a molecular weight of about 50,000, obtained by cleaving the SS bond of the hinge region of the above-mentioned F(ab')2.

[0320] scFv is a VH-P-VL or VL-P-VH polypeptide in which one VH and one VL are linked using an appropriate peptide linker (P) of 12 residues or more, and is an antibody fragment having antigen-binding activity.

[0321] Diabodies are antibody fragments formed by dimerization of scFvs with the same or different antigen-binding specificities, and have bivalent antigen-binding activity to the same antigen, or have antigen-binding activity specific to different antigens.

[0322] dsFv refers to a fragment in which polypeptides obtained by substituting one amino acid residue each in VH and VL with a cysteine ​​residue are linked via an SS bond between the cysteine ​​residues.

[0323] VHH (also called nanobody) refers to the heavy chain variable region in a VHH antibody that is able to bind to an antigen in the absence of other polypeptides.

[0324] VHH antibodies are antibodies found in camelids such as alpacas and cartilaginous fish such as sharks. They have no light chains and CH1 and are composed only of heavy chains.

[0325] The peptide comprising CDR is composed of at least one region of CDR comprising VH or VL. The peptide comprising multiple CDRs can be made by combining CDRs directly or via an appropriate peptide linker. The peptide comprising CDR can be made by constructing a DNA encoding the CDRs of VH and VL of the bispecific antibody of the present invention, inserting the DNA into an expression vector for prokaryotes or an expression vector for eukaryotes, and importing the expression vector into a prokaryote or a eukaryote to express it. In addition, the peptide comprising CDR can also be made by chemical synthesis methods such as the Fmoc method or the tBoc method.

[0326] In the present invention, a bispecific antibody fragment refers to a bispecific antibody fragment that essentially consists of a partial structure of a bispecific antibody and has antigen-binding activity to two antigens.

[0327] The present invention also includes a fusion protein in which the Fc of the bispecific antibody of the present invention is bound to an antibody fragment, an Fc fusion protein (also called an immunoadhesin) in which the Fc is bound to a naturally occurring ligand or receptor, and an Fc fusion protein in which multiple Fc regions are fused. In addition, an Fc region containing amino acid residues modified for the purpose of enhancing or depleting the effector activity of the antibody, stabilizing the antibody, and controlling the half-life in the blood can also be used in the bispecific antibody of the present invention.

[0328] The bispecific antibodies or bispecific antibody fragments of the present invention include antibody derivatives obtained by chemically or genetically binding radioactive isotopes, low molecular weight drugs, high molecular weight drugs, proteins, antibody drugs, etc. to the bispecific antibodies or bispecific antibody fragments of the present invention.

[0329] The antibody derivatives of the present invention can be produced by binding a radioactive isotope, a low molecular weight drug, a high molecular weight drug, an immunostimulator, a protein or an antibody drug to the N-terminal side or C-terminal side of the H chain or L chain of the bispecific antibody of the present invention or the bispecific antibody fragment, to an appropriate substituent or side chain in the antibody or its antibody fragment, or to a sugar chain in the antibody or its antibody fragment, by a chemical method [Introduction to Antibody Engineering, Jiren Shuguan (1994)].

[0330] In addition, the antibody derivatives of the present invention can be produced by a genetic engineering method in which a DNA encoding the bispecific antibody or the bispecific antibody fragment of the present invention is linked to a DNA encoding a desired protein or antibody drug and inserted into an expression vector, and the expression vector is introduced into an appropriate host cell to express it.

[0331] Examples of radioactive isotopes include 111 In, 131 I. 125 I. 90 Y. 64 Cu, 99 Tc, 77 Lu or 211 At, etc. The radioactive isotope can be directly bound to the antibody by the chloramine T method, etc. In addition, the antibody can also be bound to a substance that chelates the radioactive isotope. As a chelating agent, for example, 1-isothiocyanate benzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) and the like can be cited.

[0332] Examples of low molecular weight drugs include anticancer agents such as alkylating agents, nitroureas, metabolic antagonists, antibiotics, alkaloids, topoisomerase inhibitors, hormone therapy agents, hormone antagonists, aromatase inhibitors, P-glycoprotein inhibitors, platinum coordination compound derivatives, M phase inhibitors, or kinase inhibitors [Clinical Oncology, Cancer and Chemotherapy Society (1996)], steroid agents such as hydrocortisone or prednisone, non-steroidal agents such as aspirin or indomethacin, immunomodulators such as gold mercaptides or penicillamine, immunosuppressants such as cyclophosphamide or azathioprine, or anti-inflammatory agents such as antihistamines such as chlorpheniramine maleate or clemacetin [Inflammation and Anti-Inflammatory Therapy, Ichiyaku Publishing Co., Ltd. (1982)].

[0333] Examples of the anticancer agent include amifostine (amifostine), cisplatin, dacarbazine (DTIC), actinomycin, mechlorethamine (nitrogen mustard), streptozotocin, cyclophosphamide, ifosfamide, carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), epirubicin, gemcitabine (gemzar), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, 5-fluorouracil, fluorouracil, vinblastine, vincristine, bleomycin, daunomycin, propamycin, estramustine, paclitaxel (Taxol), docetaxel (Taxotea), aldesleukin, asparaginase, busulfan, carboplatin, oxaliplatin, nedaplatin, cladribine, camptothecin, 10-hydroxy-7-ethyl-camptothecin (SN38), floxuridine, fludarabine , hydroxyurea, idarubicin, mesna, irinotecan (CPT-11), topotecan, mitoxantrone, topotecan, leuprorelin, megestrol acetate, melphalan, mercaptopurine, hydroxyurea (Hydroxycarbamide), plicamycin, mitotane, pegaspargase, pentostatin, pipobroman, streptozotocin, tamoxifen, goserelin, liuprorelin, flutamide, teniposide, testolactone, thioguanine, thiotepa, uracil nitrogen, vinorelbine, chlorambucil, hydrocortisone, prednisolone, methylprednisolone, vindesine, nimustine, selimus, capecitabine, raltitrexed, azacitidine, UFT, oxaliplatin, gefitinib (Iressa), imatinib (STI571), erlotinib, FMS-like tyrosine kinase (FMS-like tyrosine kinase 3, Flt3) inhibitors, vascular endothelial growth factor receptor (VEGFR) inhibitors, fibroblast growth factor receptor (FGFR) inhibitors, epidermal growth factor receptor (EGFR) inhibitors such as Tarceva, radicicol, 17-allylamino-17-demethoxygeldanamycin, rapamycin, amsacrine, all-trans retinoic acid, thalidomide, lenalidomide, anastrozole, fadrozole, letrozole, exemestane, gold mercaptan, D-penicillamine, bucillamine, azathioprine, imidazolidinedione, cyclosporine, rapamycin, hydrocortisone, bexarotene (tagrelide) tin), tamoxifen, dexamethasone, progestins, estrogens, anastrozole (Rui Ning), mercaptopurine, aspirin, indomethacin, celecoxib, azathioprine, penicillamine, gold mercaptan salt, chlorpheniramine maleate, chlorpheniramine, clemacitin, vitamin A acid, bexarotene, arsenic, bortezomib, allopurinol, calicheamicin, ibrutinum, tagagliptin, ozogamicin, clarithromycin, folinic acid, ketoconazole, aminoglutamine, suramin, methotrexate or maytansine alkaloids or their derivatives, etc. ,

[0334] Examples of methods for binding a low molecular weight drug to the bispecific antibody or bispecific antibody fragment of the present invention include a method in which the drug is bound to an amino group of the antibody via glutaraldehyde, and a method in which the amino group of the drug is bound to a carboxyl group of the antibody via a water-soluble carbodiimide.

[0335] Examples of high molecular weight drugs include polyethylene glycol (PEG), albumin, dextran, polyoxyethylene, styrene maleic acid copolymer, polyvinyl pyrrolidone, pyran copolymer, or hydroxypropyl methacrylamide. By binding these high molecular weight compounds to the bispecific antibody or antibody fragment of the present invention, the following effects can be expected: (1) improving the stability of various chemical, physical or biological factors; (2) significantly prolonging the half-life in the blood; or (3) inhibiting the disappearance of immunogenicity or antibody production [Bioconjugate Pharmaceuticals, Hirokawa Bookstore (1993)].

[0336] For example, as a method for binding PEG to the bispecific antibody of the present invention, a method of reacting it with a PEGylation modification agent can be cited [Bioconjugate Pharmaceuticals, Hirokawa Shoten (1993)]. Examples of PEGylation modification agents include: a modification agent for lysine to ε-amino group (Japanese Patent Application Laid-Open No. 61-178926), a modification agent for aspartic acid and glutamic acid to carboxyl group (Japanese Patent Application Laid-Open No. 56-23587), or a modification agent for arginine to guanidine group (Japanese Patent Application Laid-Open No. 2-117920).

[0337] The immunostimulator may be a natural product known as an immunoadjuvant. Specific examples thereof include immunopotentiating agents such as β(1→3) glucan (eg, lentinan or schizophyllin) or α-galactosylceramide (KRN7000).

[0338] Examples of the protein include cytokines or growth factors or toxin proteins that activate cells responsible for immunity such as NK cells, macrophages, and neutrophils.

[0339] Examples of cytokines or growth factors include interferon (hereinafter referred to as IFN)-α, IFN-β, IFN-γ, interleukin (hereinafter referred to as IL)-2, IL-12, IL-15, IL-18, IL-21, IL-23, granulocyte colony stimulating factor (G-CSF), granulocyte / macrophage colony stimulating factor (GM-CSF) or macrophage colony stimulating factor (M-CSF), etc.

[0340] Examples of toxin proteins include ricin, diphtheria toxin, and ONTAK, and also include protein toxins in which mutations are introduced into the protein in order to adjust the toxicity.

[0341] Fusion antibodies fused to proteins or antibody drugs can be produced by linking cDNA encoding the protein with cDNA encoding the bispecific antibody or antibody fragment of the present invention, constructing a DNA encoding the fusion antibody, inserting the DNA into an expression vector for prokaryotes or eukaryotes, and introducing the expression vector into prokaryotes or eukaryotes to express the expression vector.

[0342] When the derivatives of the above antibodies are used as detection methods, quantitative methods, detection reagents, quantitative reagents or diagnostic drugs, the agents that bind to the bispecific antibodies of the present invention or antibody fragments thereof include markers used in conventional immunological detection or assays. As markers, for example, enzymes such as alkaline phosphatase, peroxidase or luciferase, luminescent substances such as acridinium esters or porphyrins, or fluorescent substances such as fluorescein isothiocyanate (FITC) or tetramethylrhodamine isothiocyanate (RITC), Alexa (registered trademark) Fluor 488, R-phycoerythrin (R-PE), etc. can be listed.

[0343] The present invention includes bispecific antibodies and bispecific antibody fragments having cytotoxic activity such as CDC activity or ADCC activity. The CDC activity or ADCC activity of the bispecific antibody or bispecific antibody fragment of the present invention on antigen-expressing cells can be evaluated by a known assay method [Cancer Immunol. Immunother., 36, 373 (1993)].

[0344] In addition, the present invention relates to a composition comprising a bispecific antibody or a fragment of the bispecific antibody that specifically recognizes and binds to cell surface antigens such as TfR and EGFR, or a therapeutic agent containing the bispecific antibody or the bispecific antibody fragment as an active ingredient for a disease associated with at least one of cell surface antigens such as TfR and EGFR, preferably a disease in which cells expressing cell surface antigens such as TfR and EGFR are involved.

[0345] The disease associated with at least one of the cell surface antigens such as TfR and EGFR may be any disease as long as it is associated with at least one of the cell surface antigens such as TfR and EGFR, and examples thereof include malignant tumors and cancers.

[0346] In the present invention, examples of malignant tumors and cancers include colon cancer, colorectal cancer, lung cancer, breast cancer, glioma, malignant melanoma, thyroid cancer, renal cell carcinoma, leukemia, lymphoma, T-cell lymphoma, gastric cancer, pancreatic cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, esophageal cancer, liver cancer, head and neck cancer, skin cancer, urethral cancer, bladder cancer, prostate cancer, choriocarcinoma, pharyngeal cancer, laryngeal cancer, mesothelioma, pleural tumor, male embryonal tumor, endometrial hyperplasia, endometriosis, germinal tumor, fibrosarcoma, Kaposi's sarcoma, hemangioma, cavernous hemangioma, hemangioblastoma, retinoblastoma, astrocytoma, neurofibroma, oligodendroglioma, medulloblastoma, neuroblastoma, glioma, rhabdomyosarcoma, glioblastoma, osteogenic sarcoma, leiomyosarcoma and Wilms' tumor.

[0347] The therapeutic drug containing the bispecific antibody or the bispecific antibody fragment or the derivative thereof of the present invention may be a drug containing only the bispecific antibody or the bispecific antibody fragment or the derivative thereof as an active ingredient, and is usually preferably provided as a pharmaceutical preparation prepared by any method known in the technical field of pharmaceutical pharmaceutics by mixing with one or more pharmacologically acceptable carriers.

[0348] The administration route is preferably the most effective route for treatment, and examples thereof include oral administration, or parenteral administration such as oral, intratracheal, intrarectal, subcutaneous, intramuscular, or intravenous administration. Among them, intravenous administration is preferred.

[0349] Examples of the administration form include sprays, capsules, tablets, powders, granules, syrups, emulsions, suppositories, injections, ointments, and patches.

[0350] The dosage or frequency of administration varies depending on the target therapeutic effect, administration method, duration of treatment, age and body weight, and is generally 10 μg / kg to 10 mg / kg per day for adults.

[0351] In addition, the present invention relates to a reagent for immunological detection or measurement of at least one of cell surface antigens such as TfR and EGFR, containing the bispecific antibody of the present invention or the bispecific antibody fragment, or a diagnostic drug for a disease related to at least one of cell surface antigens such as TfR and EGFR, preferably a disease in which cells expressing cell surface antigens such as TfR and EGFR participate. In addition, the present invention relates to a method for immunological detection or measurement of at least one of cell surface antigens such as TfR and EGFR, using the bispecific antibody of the present invention or the bispecific antibody fragment, a method for treating a disease related to at least one of cell surface antigens such as TfR and EGFR, preferably a disease in which cells expressing cell surface antigens such as TfR and EGFR participate, or a method for diagnosing a disease related to at least one of cell surface antigens such as TfR and EGFR, preferably a disease in which cells expressing cell surface antigens such as TfR and EGFR participate.

[0352] As a method for detecting or measuring the amount of at least one of cell surface antigens such as TfR and EGFR in the present invention, any known method can be mentioned, for example, immunological detection or measurement methods and the like can be mentioned.

[0353] Immunological detection or determination method refers to a method for detecting or determining the amount of antibody or antigen using a labeled antigen or antibody. As immunological detection or determination method, for example, radioimmunoassay (RIA), enzyme immunoassay (EIA or ELISA), fluorescent immunoassay (FIA), luminescent immunoassay (luminescent immunoassay), protein blotting or physicochemical methods can be cited.

[0354] By using the bispecific antibody of the present invention or the bispecific antibody fragment to detect or measure cells expressing at least one of cell surface antigens such as TfR and EGFR, it is possible to diagnose diseases related to at least one of cell surface antigens such as TfR and EGFR, preferably diseases in which cells expressing cell surface antigens such as TfR and EGFR are involved.

[0355] In the detection of cells expressing at least one of the cell surface antigens such as TfR and EGFR, known immunological detection methods can be used, for example, immunoprecipitation, immunocytostaining, immunohistostaining or fluorescent antibody staining, etc. In addition, for example, fluorescent antibody staining methods such as FMAT8100HTS system (Applied Biosystems) can also be listed.

[0356] The biological sample used as the object of detecting or measuring at least one of the cell surface antigens such as TfR and EGFR in the present invention is not particularly limited, such as tissue cells, blood, plasma, serum, pancreatic juice, urine, feces, tissue fluid or culture fluid, as long as it has the possibility of containing cells expressin...

Claims

1. A bispecific antibody or a fragment thereof that binds to transferrin receptor TfR and a cell surface antigen, comprising: an IgG portion that binds to transferrin receptor TfR and an N-terminal polypeptide that binds to the cell surface antigen, and the N-terminal polypeptide binds directly or via a linker to the N-terminus of the heavy chain of the IgG portion; wherein the IgG portion comprises: VH of the following (ai) and VL containing CDR1-3 consisting of the amino acid sequences shown in SEQ ID NOs: 17-19 respectively, (ai) VH containing CDR1-3 consisting of the amino acid sequences shown in SEQ ID NOs: 32-34 respectively, the cell surface antigen is EGFR; and the N-terminal polypeptide is the Fab of an antibody against EGFR, and the antibody comprises: VH containing CDR1-3 consisting of the amino acid sequences shown in SEQ ID NOs: 60-62 or SEQ ID NOs: 65-67 respectively, and VL containing CDR1-3 consisting of the amino acid sequences shown in SEQ ID NOs: 17-19 respectively.

2. The bispecific antibody or the fragment thereof according to claim 1, which binds to the transferrin receptor TfR and the cell surface antigen bivalently.

3. The bispecific antibody or the fragment thereof according to claim 1, wherein, the IgG portion comprises: VH consisting of the amino acid sequence shown in SEQ ID NO: 31 and VL consisting of the amino acid sequence shown in SEQ ID NO:

16.

4. The bispecific antibody or the fragment thereof according to claim 3, which binds to the transferrin receptor TfR and the cell surface antigen bivalently.

5. The bispecific antibody or the fragment thereof according to claim 1 or 3, wherein, the heavy chain constant region of the IgG portion consists of the amino acid sequence shown in SEQ ID NO: 84 or SEQ ID NO:

86.

6. The bispecific antibody or the fragment thereof according to claim 1 or 3, wherein, the antibody against EGFR is one antibody selected from the following (a): (a) An antibody comprising VH consisting of the amino acid sequence shown in SEQ ID NO: 59 or SEQ ID NO: 64 and VL consisting of the amino acid sequence shown in SEQ ID NO:

16.

7. The bispecific antibody or the fragment thereof according to claim 1 or 3, wherein, the C-terminus of the heavy chain of the Fab binds directly to the N-terminus of the heavy chain of the IgG portion.

8. The bispecific antibody or the fragment thereof according to claim 1 or 3, wherein, the C-terminus of the heavy chain of the Fab binds to the N-terminus of the heavy chain of the IgG portion via a linker.

9. The bispecific antibody or the fragment thereof according to claim 8, wherein, the amino acid sequence of the linker consists of a part or all of the amino acid sequence of the hinge region of IgG.

10. The bispecific antibody or the fragment thereof according to claim 1 or 3, wherein, the Fab and the IgG portion contain a light chain consisting of the same amino acid sequence.

11. The bispecific antibody or bispecific antibody fragment according to claim 2, wherein, the IgG portion comprises: VH consisting of the amino acid sequence shown in SEQ ID NO: 31 and VL consisting of the amino acid sequence shown in SEQ ID NO: 16; and the antibody against EGFR comprises: VH consisting of the amino acid sequence shown in SEQ ID NO: 64 and VL consisting of the amino acid sequence shown in SEQ ID NO:

16.

12. The bispecific antibody or bispecific antibody fragment according to claim 11, wherein the N-terminal side polypeptide directly binds to the N-terminus of the heavy chain of the IgG portion.

13. A DNA encoding the bispecific antibody or bispecific antibody fragment according to any one of claims 1 to 12.

14. A recombinant vector containing the DNA according to claim 13.

15. A method for producing the bispecific antibody or bispecific antibody fragment according to any one of claims 1 to 12, characterized in that, a transformant obtained by introducing the recombinant vector according to claim 14 into a host cell is cultured in a medium, and the bispecific antibody or bispecific antibody fragment according to any one of claims 1 to 12 is produced and accumulated in the culture, and the bispecific antibody or bispecific antibody fragment is collected from the culture.

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