KR20220134462A - Antibodies or fragments thereof binding to B7-H3 and use thereof - Google Patents

Abstract

The present invention relates to a B7-H3 antibody or an antigen-binding fragment thereof, and a use thereof. More specifically, the present invention relates to: a B7-H3 antibody or an antigen-binding fragment thereof which specifically binds to a B7-H3 antigen, is internalized into cells, and can be used as an immune checkpoint inhibitor for various diseases, by having a predetermined complementarity determining region; and a use of the B7-H3 antibody or antigen-binding fragment thereof.

Description

B7-H3 antibody or antigen-binding fragment thereof and use thereof {Antibodies or fragments thereof binding to B7-H3 and use thereof}

The present invention relates to a novel antibody B7-H3.

B7 homology 3 protein (B7-H3) (also called CD276 and B7RP-2, collectively referred to herein as B7-H3) is a type I transmembrane glycoprotein of the immunoglobulin superfamily.

Human B7-H3 contains a putative signal peptide, V-like and C-like Ig domains, a transmembrane region and a cytoplasmic domain. Exon duplication in humans is either an IgV-IgC-IgV-IgC-like domain (4IgB7-H3 isoform) or a single IgV-IgC-like domain (2IgB7-H3 isoform) containing several conserved cysteine residues. It leads to the expression of two B7-H3 isoforms with one. The predominant B7-H3 isoform in human tissues and cell lines is the 4IgB7-H3 isoform.

B7-H3 has been reported to have both co-stimulatory and co-inhibitory signaling functions.

B7-H3 is not constitutively expressed on many immune cells (eg, natural killer (NK) cells, T-cells, and antigen-presenting cells (APCs)), and its expression can be induced.

In addition, the expression of B7-H3 is not limited to immune cells. The B7-H3 transcript is expressed in a variety of human tissues, including colon, heart, liver, placenta, prostate, small intestine, testis, and uterus, and in osteoblasts, fibroblasts, epithelial cells, and other non-lymphoid cells; It potentially exhibits immunological and non-immunological functions. However, protein expression in normal tissues is typically maintained at low levels, so post-transcriptional regulation can be applied.

Korean Patent No. 1828570

An object of the present invention is to provide a novel B7-H3 antibody or antigen-binding fragment thereof.

An object of the present invention is to provide a medical use (pharmaceutical composition, therapeutic method, etc.) of a B7-H3 antibody or antigen-binding fragment thereof.

1. B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising the following HCDR and a light chain variable region comprising the following LCDR:

(a) HCDRs of SEQ ID NOs: 1, 10 and 19 and LCDRs of SEQ ID NOs: 28, 37 and 45;

(b) HCDRs of SEQ ID NOs: 2, 11 and 20 and LCDRs of SEQ ID NOs: 29, 38 and 46;

(c) the HCDRs of SEQ ID NOs: 3, 12 and 21 and the LCDRs of SEQ ID NOs: 30, 39 and 47;

(d) HCDRs of SEQ ID NOs: 4, 13 and 22 and LCDRs of SEQ ID NOs: 31, 40 and 48;

(e) HCDRs of SEQ ID NOs: 5, 14 and 23 and LCDRs of SEQ ID NOs: 32, 41 and 49;

(f) HCDRs of SEQ ID NOs: 6, 15 and 24 and LCDRs of SEQ ID NOs: 33, 42 and 50;

(g) HCDRs of SEQ ID NOs: 7, 16 and 25 and LCDRs of SEQ ID NOs: 34, 43 and 51;

(h) HCDRs of SEQ ID NOs: 8, 17 and 26 and LCDRs of SEQ ID NOs: 35, 44 and 52; or

(i) HCDRs of SEQ ID NOs: 9, 18 and 27 and LCDRs of SEQ ID NOs: 36, 42 and 53.

2. The B7-H3 antibody or antigen-binding fragment thereof according to 1 above, wherein the heavy chain variable region comprises any one framework sequence selected from the group consisting of the following HFR:

(hf1) HFRs of SEQ ID NOs: 54, 63, 68 and 334;

(hf2) HFRs of SEQ ID NOs: 55, 63, 69 and 334;

(hf3) HFRs of SEQ ID NOs: 56, 64, 70 and 334;

(hf4) HFRs of SEQ ID NOs: 56, 64, 71 and 334;

(hf5) HFRs of SEQ ID NOs: 57, 64, 70 and 334;

(hf6) HFRs of SEQ ID NOs: 58, 64, 72 and 334;

(hf7) HFRs of SEQ ID NOs: 59, 65, 73 and 334;

(hf8) HFRs of SEQ ID NOs: 60, 65, 73 and 334;

(hf9) HFRs of SEQ ID NOs: 61, 66, 74 and 334; and

(hf10) HFRs of SEQ ID NOs: 62, 67, 75 and 334.

3. The B7-H3 antibody or antigen-binding fragment thereof according to 1 above, wherein the light chain variable region comprises any one framework sequence selected from the group consisting of the following LFR:

(lf1) LFR of SEQ ID NOs: 76, 82, 86 and 335;

(lf2) LFR of SEQ ID NOs: 77, 82, 87 and 335;

(lf3) LFR of SEQ ID NOs: 78, 83, 88 and 335;

(lf4) LFR of SEQ ID NOs: 79, 84, 89 and 335;

(lf5) LFR of SEQ ID NOs: 80, 84, 90 and 335;

(lf6) LFR of SEQ ID NOs: 80, 84, 91 and 335;

(lf7) LFR of SEQ ID NOs: 81, 85, 92 and 335;

(lf8) LFR of SEQ ID NOs: 93, 98, 101 and 336;

(lf9) LFR of SEQ ID NOs: 93, 98, 102 and 336;

(lf10) LFR of SEQ ID NOs: 93, 98, 103 and 336;

(lf11) LFR of SEQ ID NOs: 93, 98, 104 and 336;

(lf12) LFR of SEQ ID NOs: 94, 98, 105 and 336;

(lf13) LFR of SEQ ID NOs: 95, 99, 106 and 336;

(lf14) LFR of SEQ ID NOs: 96, 99, 107 and 336; and

(lf15) LFR of SEQ ID NOs: 97, 100, 108 and 336.

4. The B7-H3 antibody or antigen-binding fragment thereof according to 1 above, wherein the heavy chain variable region is any one selected from the group consisting of SEQ ID NOs: 127, 128, 129, 130, 131, 132, 135, 142 and 152.

5. The B7-H3 antibody or antigen-binding fragment thereof according to 1 above, wherein the light chain variable region is any one selected from the group consisting of SEQ ID NOs: 211, 221, 223, 224, 225, 231, 307, 309 and 317.

6. A gene encoding the B7-H3 antibody or antigen-binding fragment thereof according to any one of 1 to 5 above.

7. Cells into which the vector into which the above 6 gene is inserted.

8. A method for producing a B7-H3 antibody or antigen-binding fragment thereof comprising culturing the cells of 7 above.

9. A pharmaceutical composition for the treatment or prevention of cancer comprising the B7-H3 antibody or antigen-binding fragment thereof of any one of 1 to 5 above.

10. The method of 9 above, wherein the cancer is lung cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, glioma, neuroblastoma, prostate cancer, pancreatic cancer, colorectal cancer, colon cancer, head and neck cancer, leukemia, lymphoma, kidney cancer, bladder cancer, For the treatment or prevention of cancer, which is any one selected from the group consisting of gastric cancer, liver cancer, skin cancer, brain tumor, cerebrospinal cancer, adrenal tumor, melanoma, sarcoma, multiple myeloma, nervous system endocrine tumor, peripheral nerve sheath tumor and small cell tumor pharmaceutical composition.

11. A method of treating cancer comprising administering to a subject the B7-H3 antibody or antigen-binding fragment thereof according to any one of 1 to 5 above, or a gene encoding the same.

12. The method of 11 above, wherein the cancer is lung cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, glioma, neuroblastoma, prostate cancer, pancreatic cancer, colorectal cancer, colon cancer, head and neck cancer, leukemia, lymphoma, kidney cancer, bladder cancer, Stomach cancer, liver cancer, skin cancer, brain tumor, cerebrospinal cancer, adrenal tumor, melanoma, sarcoma, multiple myeloma, neuroendocrine tumor, peripheral nerve sheath tumor and any one selected from the group consisting of small cell tumor, the treatment method of cancer.

13. The B7-H3 antibody or antigen-binding fragment thereof according to any one of 1 to 5 above for use as a medicament.

14. The B7-H3 antibody or antigen-binding fragment thereof according to any one of 1 to 5 above, wherein the drug is an anticancer agent according to the above 13.

15. The method of 13 above, wherein the cancer is lung cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, glioma, neuroblastoma, prostate cancer, pancreatic cancer, colorectal cancer, colon cancer, head and neck cancer, leukemia, lymphoma, kidney cancer, bladder cancer, Any one of 1 to 5 above, which is any one selected from the group consisting of gastric cancer, liver cancer, skin cancer, brain tumor, cerebrospinal cancer, adrenal tumor, melanoma, sarcoma, multiple myeloma, nervous system endocrine tumor, peripheral nerve sheath tumor and small cell tumor One B7-H3 antibody or antigen-binding fragment thereof.

The B7-H3 antibody or antigen-binding fragment thereof of the present invention specifically binds to B7-H3.

The B7-H3 antibody or antigen-binding fragment thereof of the present invention can introduce B7-H3 into a cell.

The B7-H3 antibody or antigen-binding fragment thereof of the present invention may be utilized as an immune checkpoint inhibitor.

A disease can be treated by administering the B7-H3 antibody or antigen-binding fragment thereof of the present invention, or a gene encoding the same to a subject.

The B7-H3 antibody or antigen-binding fragment thereof of the present invention, or a gene encoding the same may be administered in combination with an anticancer agent having a different pharmacological mechanism.

1 shows the binding affinity and EC ₅₀ values according to the concentrations of #1 to #9 antibodies to B7-H3.
Figure 2 shows the binding affinity according to the concentration of antibodies #1 to #9 for the MCF-7 cell line.
Figure 3 shows the binding affinity according to the concentration of antibodies #1 to #9 for the RKO cell line.
4 shows the binding affinity of antibodies #1 to #9 according to the concentration of the B7-H3 protein overexpressed RKO cells (RKO/B7H3).
Figure 5 shows the internalization of the antibodies after treatment with each of the pHAb amine-labeled antibodies in the MCF-7 cell line.
Figure 6 shows the internalization of the antibodies after treating each of the pHAb amine-labeled antibodies to the RKO cell line and the RKO/B7H3 cell line with the secondary antibody.
7 and 8 show the results of the invasion assay of RKO, RKO/B7H3 and RKO/B7H3 treated with each antibody. 7 is a photograph of the degree of invasion using a microscope, and FIG. 8 is a calculation of the percentage of cells invaded using Image J.
9 and 10 show the migration assay results of RKO, RKO/B7H3 and RKO/B7H3 treated with each antibody. 9 is a photograph of the degree of migration using a microscope, and FIG. 10 is a calculation of the ratio of OD values measured by extracting the color of cells stained with crystal violet.
11 is a classification of antibodies #1 to #9 according to a common epitope.
12 shows the results of TGFβ secretion assay after #1 to #9 antibody treatment in RKO/B7H3 cell line.
13 shows the standard dilution process in the TGFβ secretion assay.
14 shows changes in tumor volume after antibody administration in mice transplanted with the CT26-TN cell line overexpressing B7-H3 into the colorectal cancer cell line CT26. G1 (vehicle) and G2 (IgG) denote a negative control group, G3 (#5) denotes a group administered with the #5 antibody, and G4 (#5)+Co denotes a group administered with the #5 antibody and anti-PD-1 antibody in combination.
15 shows the change in TGFβ concentration by the #5 antibody in mouse serum. Vehicle, IgG denotes a negative control group, #5 denotes a group administered with the #5 antibody, and #5+Co denotes a group administered with the #5 antibody and anti-PD-1 antibody in combination. * : p value < 0.5 (compared to vehicle group)
16 shows the number of immune cells in the tumor after antibody treatment. G1 (vehicle) and G2 (IgG) denote a negative control group, G3 (#5) denotes a group administered with the #5 antibody, and G4 (#5)+Co denotes a group administered with the #5 antibody and anti-PD-1 antibody in combination.

The present invention relates to a B7-H3 antibody or antigen-binding fragment thereof.

In the present invention, the antigen-binding fragment of the B7-H3 antibody refers to one or more fragments of the antibody that retain the ability to specifically bind to B7-H3.

Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA, IgA2, etc.) or subclass .

Antigen-binding fragments include (i) Fab fragments, which are monovalent fragments consisting of VH, VL, CH1 and CL domains; (ii) F(ab') ₂ fragment, which is a bivalent fragment comprising two Fab fragments linked by disulfide bonds in the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains, (iv) an Fv fragment consisting of the VL and VH domains of one arm of an antibody, (v) a single domain or dAb fragment consisting of the VH domain; (vi) an isolated complementarity determining region (CDR); and (vii) combinations of two or more separate CDRs, optionally joined by synthetic linkers.

In addition, the VL and VH domains of Fv fragments are encoded by separate genes, but they pair with the VL and VH domains to form a single protein chain with monovalent molecules (called single chain Fv (scFv) or single chain antibodies). can be linked by a synthetic linker using recombinant methods to generate Such single chain antibodies (scFvs) are also included in antigen binding fragments.

Antigen-binding fragments are obtained using conventional techniques known in the art, and functional screening of fragments is used in the same manner as intact antibodies. Antigen binding sites can be produced by recombinant DNA techniques or by enzymatic or chemical disruption of intact immunoglobulins. Antibodies may exist in different phenotypes, for example IgG (eg, IgGl, IgG2, IgG3 or IgG4 subtypes), IgA1, IgA2, IgD, IgE or IgM antibodies.

The B7-H3 antibody or antigen-binding fragment thereof of the present invention includes a heavy chain variable region (VH) and a light chain variable region (VL).

The heavy chain variable region of the present invention includes the following heavy chain complementarity determining region (HCDR), and the light chain variable region includes the following light chain complementarity determining region (LCDR). (a) HCDRs of SEQ ID NOs: 1, 10 and 19 and LCDRs of SEQ ID NOs: 28, 37 and 45; (b) HCDRs of SEQ ID NOs: 2, 11 and 20 and LCDRs of SEQ ID NOs: 29, 38 and 46; (c) the HCDRs of SEQ ID NOs: 3, 12 and 21 and the LCDRs of SEQ ID NOs: 30, 39 and 47; (d) HCDRs of SEQ ID NOs: 4, 13 and 22 and LCDRs of SEQ ID NOs: 31, 40 and 48; (e) HCDRs of SEQ ID NOs: 5, 14 and 23 and LCDRs of SEQ ID NOs: 32, 41 and 49; (f) HCDRs of SEQ ID NOs: 6, 15 and 24 and LCDRs of SEQ ID NOs: 33, 42 and 50; (g) HCDRs of SEQ ID NOs: 7, 16 and 25 and LCDRs of SEQ ID NOs: 34, 43 and 51; (h) HCDRs of SEQ ID NOs: 8, 17 and 26 and LCDRs of SEQ ID NOs: 35, 44 and 52; or (i) the HCDRs of SEQ ID NOs: 9, 18 and 27 and the LCDRs of SEQ ID NOs: 36, 42 and 53.

The heavy chain complementarity determining region (HCDR) consists of HCDR1, HCDR2 and HCDR3 and the light chain complementarity determining region (LCDR) consists of LCDR1, LCDR2 and LCDR3. For example, in the above sequence (a), the amino acid sequence of SEQ ID NO: 1 is HCDR1, the amino acid sequence of SEQ ID NO: 10 is HCDR2, the amino acid sequence of SEQ ID NO: 19 is HCDR3, the amino acid sequence of SEQ ID NO: 28 is LCDR1, the amino acid sequence of SEQ ID NO: 37 is The amino acid sequence of LCDR2, SEQ ID NO: 45 is LCDR3.

The B7-H3 antibody or antigen-binding fragment thereof of the present invention specifically binds to the B7-H3 antigen regardless of the framework sequence as long as it contains the above-mentioned complementarity determining region.

The heavy chain variable region and light chain variable region of the present invention may include various framework sequences.

The heavy chain variable region of the present invention may include, for example, any one sequence selected from the group consisting of the following heavy chain framework sequences (HFR): (hf1) HFR of SEQ ID NOs: 54, 63, 68 and 334; (hf2) HFRs of SEQ ID NOs: 55, 63, 69 and 334; (hf3) HFRs of SEQ ID NOs: 56, 64, 70 and 334; (hf4) HFRs of SEQ ID NOs: 56, 64, 71 and 334; (hf5) HFRs of SEQ ID NOs: 57, 64, 70 and 334; (hf6) HFRs of SEQ ID NOs: 58, 64, 72 and 334; (hf7) HFRs of SEQ ID NOs: 59, 65, 73 and 334; (hf8) HFRs of SEQ ID NOs: 60, 65, 73 and 334; (hf9) HFRs of SEQ ID NOs: 61, 66, 74 and 334; and (hf10) HFRs of SEQ ID NOs: 62, 67, 75 and 334.

The light chain variable region of the present invention may include, for example, any one sequence selected from the group consisting of the following light chain framework sequences (LFR): (lf1) LFR of SEQ ID NOs: 76, 82, 86 and 335; (lf2) LFR of SEQ ID NOs: 77, 82, 87 and 335; (lf3) LFR of SEQ ID NOs: 78, 83, 88 and 335; (lf4) LFR of SEQ ID NOs: 79, 84, 89 and 335; (lf5) LFR of SEQ ID NOs: 80, 84, 90 and 335; (lf6) LFR of SEQ ID NOs: 80, 84, 91 and 335; (lf7) LFR of SEQ ID NOs: 81, 85, 92 and 335; (lf8) LFR of SEQ ID NOs: 93, 98, 101 and 336; (lf9) LFR of SEQ ID NOs: 93, 98, 102 and 336; (lf10) LFR of SEQ ID NOs: 93, 98, 103 and 336; (lf11) LFR of SEQ ID NOs: 93, 98, 104 and 336; (lf12) LFR of SEQ ID NOs: 94, 98, 105 and 336; (lf13) LFR of SEQ ID NOs: 95, 99, 106 and 336; (lf14) LFR of SEQ ID NOs: 96, 99, 107 and 336; and (lf15) LFRs of SEQ ID NOs: 97, 100, 108 and 336.

The heavy chain framework sequence (HFR) of the present invention consists of HFR1, HFR2, HFR3 and HFR4, and the light chain framework sequence (LFR) consists of LFR1, LFR2, LFR3 and LFR4. For example, in the above sequence (hf1), the amino acid sequence of SEQ ID NO: 54 is HFR1, the amino acid sequence of SEQ ID NO: 63 is HFR2, the amino acid sequence of SEQ ID NO: 68 is HFR3, and the amino acid sequence of SEQ ID NO: 334 is HFR4. Also, for example, in the above sequence (lf1), the amino acid sequence of SEQ ID NO: 76 is LFR1, the amino acid sequence of SEQ ID NO: 82 is LFR2, the amino acid sequence of SEQ ID NO: 86 is LFR3, and the amino acid sequence of SEQ ID NO: 335 is LFR4.

The framework sequences (hf1 to hf10) of the heavy chain variable region and the framework sequences (lf1 to lf15) of the light chain variable region of the present invention may be arbitrarily combined.

The heavy and light chain complementarity determining region sequences of the present invention and heavy and light chain framework sequences may be arbitrarily combined. For example, the heavy and light chain complementarity determining region sequence of any one of (a) to (i), the heavy chain framework sequence of any one of (hf1) to (hf10), and the light chain framework of any one of (lf1) to (lf15) Sequences can be arbitrarily combined.

The heavy chain variable region of the present invention may consist of, for example, any one amino acid sequence selected from the group consisting of SEQ ID NOs: 127, 128, 129, 130, 131, 132, 135, 142 and 152.

The light chain variable region of the present invention may consist of, for example, any one amino acid sequence selected from the group consisting of SEQ ID NOs: 211, 221, 223, 224, 225, 231, 307, 309 and 317.

The antibodies or antigen-binding fragments thereof having the complementarity determining regions of (a) to (i) of the present invention may have the same or different epitopes. An epitope (antigenic determinant) refers to a region of the B7-H3 antigen to which an antibody or antigen-binding fragment specifically binds. The epitopes of the antibodies or antigen-binding fragments thereof having the complementarity determining regions of (a), (d), (e), (g), (h) and (i) of the present invention are the same, and (b) and (c) ) of the antibody or antigen-binding fragment thereof having the complementarity determining region are identical.

In one embodiment of the present invention, antibodies #1 to #9 among B7-H3 antibodies include the following heavy chain variable regions and light chain variable regions: #1: heavy chain variable region of SEQ ID NO: 127 and light chain variable region of SEQ ID NO: 307 area; #2: the heavy chain variable region of SEQ ID NO: 128 and the light chain variable region of SEQ ID NO: 317; #3: the heavy chain variable region of SEQ ID NO: 129 and the light chain variable region of SEQ ID NO: 309; #4: the heavy chain variable region of SEQ ID NO: 130 and the light chain variable region of SEQ ID NO: 211; #5: the heavy chain variable region of SEQ ID NO: 131 and the light chain variable region of SEQ ID NO: 221; #6: the heavy chain variable region of SEQ ID NO: 132 and the light chain variable region of SEQ ID NO: 231; #7: heavy chain variable region of SEQ ID NO: 142 and light chain variable region of SEQ ID NO: 223; #8: the heavy chain variable region of SEQ ID NO: 152 and the light chain variable region of SEQ ID NO: 224; and #9: the heavy chain variable region of SEQ ID NO: 135 and the light chain variable region of SEQ ID NO: 225.

The epitopes of antibodies #1, #4, #5, #7, #8 and #9 of the present invention are identical, and the epitopes of antibodies #2 and #3 are identical.

Antibodies #1 to #9 of the present invention exhibit strong binding to B7-H3 and introduce B7-H3 into cells.

The present invention provides a gene encoding the aforementioned B7-H3 antibody or antigen-binding fragment thereof.

A gene encoding the B7-H3 antibody or antigen-binding fragment thereof of the present invention may be included in an expression vector. The expression vector includes a promoter, a gene of the B7-H3 antibody or antigen-binding fragment thereof operably linked to the promoter, a restriction enzyme cleavage site, and the like.

The expression vector of the present invention may be a viral vector, a naked DNA or RNA vector, a plasmid, a cosmid or phage vector, a DNA or RNA vector associated with a cationic condensing agent, or a DNA or RNA vector encapsulated in liposomes.

The expression vector of the present invention can be introduced into a host cell.

The host cells of the present invention may be eukaryotic cells such as animal cells, plant cells, eukaryotic microorganisms, for example, NS0 cells, Vero cells, Hela cells, COS cells, CHO cells, HEK293 cells, BHK cells, MDCKII cells, Sf9 cells, etc. can

The host cell of the present invention may be a prokaryotic cell, for example, E. coli, Bacillus subtilis, or the like.

The present invention provides a method for producing the B7-H3 antibody or antigen-binding fragment thereof by culturing the aforementioned host cell. Culturing may be performed according to a well-known method, and conditions such as culture temperature, culture time, medium type, and pH may be appropriately adjusted according to the type of cell.

The method for producing the B7-H3 antibody or antigen-binding fragment thereof of the present invention may further include isolating, purifying and recovering the produced antibody or antigen-binding fragment thereof. For example, for the recovery of the antibody or antigen-binding fragment thereof, there are methods such as filtration, affinity chromatography, ion exchange chromatography, hydrophobic chromatography, and HPLC.

The present invention provides a pharmaceutical composition for treating or preventing cancer comprising the aforementioned B7-H3 antibody or antigen-binding fragment thereof.

The B7-H3 antibody or antigen-binding fragment thereof of the present invention binds to B7-H3 of cancer cells expressing B7-H3, neutralizes (inhibits) the activity of B7-H3, and introduces B7-H3 into the cell to be removed. It can induce the activation of immune cells and, through this, can cure cancer.

The cancer of the present invention may be an EGFR-overexpressing cancer.

Cancers of the present invention include lung cancer (small cell lung cancer and non-small cell lung cancer), breast cancer, ovarian cancer, uterine cancer, cervical cancer, glioma, neuroblastoma, prostate cancer, pancreatic cancer, colorectal cancer, colon cancer, head and neck cancer, leukemia, lymphoma, kidney cancer , bladder cancer, stomach cancer, liver cancer, skin cancer, brain tumor, cerebrospinal cancer, adrenal tumor, melanoma, sarcoma (osteosarcoma and soft tissue sarcoma), multiple myeloma, neuroendocrine tumor, peripheral nerve sheath tumor and small cell tumor It can be any one.

The pharmaceutical composition of the present invention may be more effective against solid cancer.

The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier and may be formulated together with the carrier. A pharmaceutically acceptable carrier refers to a carrier or diluent that does not irritate the organism and does not impair the biological activity and properties of the administered compound.

Pharmaceutically acceptable carriers of the liquid composition include saline, sterile water, Ringer's solution, buffered saline, albumin injection, dextrose solution, maltodextrin solution, glycerol, ethanol, and mixtures thereof. If necessary, other conventional additives such as antioxidants, buffers, and bacteriostats may be added. In addition, diluents, dispersants, surfactants, binders and lubricants may be additionally added to form an injectable formulation such as an aqueous solution, suspension, emulsion, etc., pills, capsules, granules or tablets.

The pharmaceutical composition of the present invention is not limited in formulation. For example, it may be prepared in oral or parenteral formulations. More specifically oral, rectal, nasal, topical (including buccal and sublingual), subcutaneous, vaginal or intramuscular, subcutaneous and intravenous administration. Also included are forms suitable for administration by inhalation or insufflation.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. The effective amount may be determined according to the patient's disease type, severity, drug activity, sensitivity to drug, administration time, administration route and excretion rate, duration of treatment, factors including concomitant drugs, and other factors well known in the medical field. have.

The dosage of the pharmaceutical composition of the present invention may vary depending on the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate, severity of disease, and the like. The appropriate dosage may vary depending on, for example, the amount of drug accumulated in the patient's body and/or the degree of efficacy of the active ingredient of the present invention used.

In general, it can be calculated based on the EC ₅₀ measured to be effective in an in vivo animal model and in vitro, for example, it can be 0.01 μg to 1 g per 1 kg of body weight, and a unit period of daily, weekly, monthly or yearly As such, it may be administered once to several times per unit period, or may be administered continuously for a long period of time using an infusion pump. The number of repeated administrations is determined in consideration of the length of time the drug stays in the body, the concentration of the drug in the body, and the like. According to the course of disease treatment, the composition may be administered for recurrence even after treatment.

The pharmaceutical composition of the present invention may be administered in combination with other anticancer substances. For example, it may be administered in combination with an immuno-oncology agent such as a PD-1 inhibitor.

The pharmaceutical composition of the present invention may further contain a component that maintains or increases the solubility and absorption of the active ingredient. In addition, it may further include a chemotherapeutic agent, an anti-inflammatory agent, an antiviral agent, an immunomodulatory agent, and the like.

The pharmaceutical compositions of the present invention may be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. Formulations may be in the form of powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, sterile powders.

The present invention provides a method for treating cancer, comprising administering to a subject a B7-H3 antibody or antigen-binding fragment thereof, or a gene encoding the same. Treatable cancers are as described above.

The B7-H3 antibody or antigen-binding fragment thereof of the present invention, or a gene encoding the same, may be administered to a human subject for therapeutic purposes.

The B7-H3 antibody or antigen-binding fragment thereof of the present invention, or a gene encoding the same, can be administered to a non-human mammal expressing B7-H3 for veterinary purposes or as an animal model of a human disease.

The present invention provides a B7-H3 antibody or antigen-binding fragment thereof for use as a medicament.

The B7-H3 antibody or antigen-binding fragment thereof of the present invention may be administered to a subject suffering from “a disease or disorder in which B7-H3 activity is detrimental” for therapeutic purposes.

A “disease or disorder in which B7-H3 activity is detrimental” of the present invention means that in a subject suffering from a particular disease or disorder, the presence of B7-H3 is found to be responsible for the pathophysiology of the disorder or a factor contributing to the exacerbation of the disorder, or suspected diseases and disorders.

The agent of the present invention may be an anticancer agent. Cancer is as described above.

Hereinafter, the present invention will be described in more detail through examples.

Example 1: B7-H3 binding affinity test using ELISA method

This experiment was performed to confirm the binding affinity of the B7-H3 antibody to the protein B7-H3.

Experimental method

Binding ability to B7-H3 according to the concentration of antibodies #1 to #9 was confirmed by the following method.

After coating the plate with recombinant human B7-H3 protein (Rndsystem, Cat# 1027-B3-100) (30 μL, 20 nM) in 1X PBS solution, the plate was covered and coated overnight at 2-8°C. After that, it was washed once with 150 μL PBS per well, and blocking buffer (1X PBS-T w/3% BSA) was blocked at 120 μL per well for 2 hours at room temperature. Discard the blocking buffer, add 30 μL of antibody solution using a serial dilution solution, react at room temperature for 1 hour, and wash the wells 3 times with 150 μL wash buffer per well. 30 μL of HRP conjugate of anti-HA Tag antibody diluted in blocking buffer was added to each well and reacted for 1 hour at room temperature. Then, the wells were washed 3 times with 150 μL wash buffer per well, the HRP reaction was developed using TMB, and the optical density (OD) was measured at 450 nm.

result

Binding ability to B7-H3 according to the concentration of antibodies #1 to #9, and the concentration of each antibody (EC ₅₀ ) was confirmed ( FIG. 1 ). It was confirmed that antibodies #1 to #9 specifically bind to B7-H3 with excellent binding ability.

Example 2: B7-H3 binding affinity test of antibody using Cell ELISA method

This experiment was performed to confirm the binding ability of the B7-H3 antibody to the B7-H3 expressed on the cell membrane.

Experimental method

2.1. Preparation of reagents

1X PBS and 1X PBS-T (0.05% tween-20) were prepared. Blocking buffer was prepared so that BSA was 3% BSA in 1X PBS-T (0.05% Tween 20). Antibody dilution buffer was prepared so that BSA was 1% BSA in 1X PBS-T (0.05% Tween 20).

2.2. Cell harvesting and seeding

After cell collection from MCF-7 cell line, RKO cell line, and RKO/B7H3 cell line, the cell concentration was adjusted by diluting with a culture medium (added with 10% FBS) so that it could be seeded at 3x10 ⁴ cells, 100 μL/well. After seeding at 100 μL/well in a cell culture plate, 96 well plate, 5% CO ₂ , and incubation overnight at 37° C. in an incubator.

2.3. Cell fixation and blocking

1) 100 μL of 8% paraformaldehyde solution was added to a 96 well plate, centrifuged at 300 g for 10 minutes, and then fixed at room temperature for a total of 20 minutes including centrifugation time.

2) After that, the fixation solution was removed and 1X PBS was added at 250 μL/well to wash the wells.

3) After washing, 100 μL/well of blocking buffer was added and incubated for 1 hour at room temperature. After removing the blocking buffer, 1X PBS-T was added at 250 μL/well to wash the wells again, and PBS-T remaining in the wells was shaken off (this washing process was repeated 3 times).

2.4. antibody reaction

After diluting the antibodies #1 to #9 by serial dilution, 100 μL of the diluted samples (antibodies) at the concentrations shown in Table 1 were dispensed in duplicate in a 96-well plate, and the antibody was incubated at room temperature for 2 hours. made to combine. After that, washing was performed.

The concentrations of the antibodies used in this experiment are shown in Table 1 below.

division #1 to #9 antibodies density
(MCF-7 cell ELISA) 4 fold serial dilution from 10 μg/mL density
(RKO and RKO/B7H3 cell ELISA) 4 fold serial dilution from 2.5 μg/mL

2.5. detection antibody reaction

Peroxidase AffiniPure Rabbit Anti-Human IgG,F(ab')2 fragment specific antibody was diluted 1:5,000 using antibody dilution buffer, and 100 μL was dispensed into each well, followed by reaction at room temperature for one hour. After that, the wells were washed and 100 μL of 1-step TMB substrate solution was dispensed into each well, and reacted at room temperature for 10 minutes, avoiding light. After 10 minutes, 50 μL of 1 N hydrochloric acid was added to each well to stop the TMB reaction, and the O.D value was measured at 450 nm.

result

As a result of confirming the binding affinity to MCF-7 cells according to the concentration of antibodies #1 to #9, excellent binding ability of antibodies #1 to #9 to the MCF-7 cell line was confirmed (FIG. 2 and Table 2).

Table 2 shows the EC ₅₀ concentrations of each antibody against MCF-7 cells.

division EC ₅₀ (nM) #One 0.605 #2 0.061 #3 0.197 #4 0.502 #5 1.740 #6 0.234 #7 1.012 #8 0.159 #9 0.322

In addition, to the RKO cell line that did not overexpress B7-H3, all of the antibodies #1 to #9 had weak binding affinity (FIG. 3), but showed excellent binding affinity in the binding affinity experiment for the RKO/B7H3 cell line overexpressing B7-H3. (Fig. 4 and Table 3).

Table 3 shows the EC ₅₀ concentrations of each antibody against RKO/B7H3 cells.

division EC ₅₀ (nM) #One 0.015 #2 0.036 #3 0.065 #4 0.042 #5 0.091 #6 0.065 #7 0.187 #8 0.060 #9 0.050

Example 3: Cell internalization test

This experiment was conducted to confirm the B7-H3 internalization ability of the B7-H3 antibody.

Experimental method

3.1. Antibody-pHAb amine reactive dye conjugation

After dissolving 0.084 g sodium bicarbonate in distilled water, adjust the pH to 8.5 using a pH meter, adjust the final volume to 100 mL, and filter foreign substances with a syringe filter to prepare amine conjugation buffer (10 mM sodium bicarbonate buffer (pH 8.5)) did.

Using a desalting column, the antibody buffer was changed to an amine conjugation buffer, the bottom closure of the column was removed, and then put into a 1.5 mL microcentrifuge tube (hereinafter referred to as a collection tube). Centrifugation was performed at 1,500 g for 1 minute to remove the storage solution from the column. The collection tube was removed and replaced with a new collection tube.

After that, washing was performed. Equilibration buffer (10 mM sodium bicarbonate buffer) was added 300 μL and centrifuged at 1,500 g for 1 minute, followed by 2 times. After proceeding twice, 300 μL of equilibration buffer (10 mM sodium bicarbonate buffer) was added and centrifuged at 1,500 g for 2 minutes. After that, 70 μL of each antibody was added and centrifuged at 1,500 g for 2 minutes.

Amine Reactive Dye was taken out from -80°C, centrifuged at 14,000 g for 10 seconds, mixed 1:1 with DMSO and distilled water, and 25 μL of 10 mg/mL was added to the dye, followed by vortexing for 3 minutes to fully dissolve.

After that, antibody-pHAb amine Reactive Dye conjugation was performed.

After adding 1.2 μL of pHAb amine Reactive Dye to 100 μg of antibody, the mixture was slowly mixed at room temperature for 1 hour. Then, the antibody and pHAb amine reactive dye conjugation reagent were added to the desalting column and centrifuged at 1,500 g for 2 minutes to remove unreactive dye.

The concentration of the antibody conjugated with the pHAb amine dye was converted using the following formula.

(However, Molecular weight of antibody = 150,000, Extinction coefficient of pHAb Reactive Dye = 75,000, Correction factor for pHAb Reactive Dye = 0.256)

3.2. Cell seeding

After collecting the MCF-7 cell line, the RKO cell line and the RKO/B7H3 cell line, cell counting was performed. It was suspended at a cell concentration of 3x10 ⁵ cells/mL using a culture medium.

In a 96-well black, clear-bottom plate, 100 μL of 3X10 ⁴ cells per well was dispensed and incubated for 24 hours at 5% CO ₂ , 37°C in an incubator.

3.3. Conjugation of primary antibody with secondary antibody labeled with pHAb amine

4 μg/mL of primary antibody (control IgG, #1 to #9) and pHAb amine-labeled secondary antibody were added to RPMI1640 (phenol free, serum free) media at a ratio of 1:4 and mixed. Then, it was placed in a constant temperature water bath at 37° C. and reacted for 1 hour.

3.4. Conjugated Antibody Treatment

After removing the culture solution added when seeding cells, 100 μL of a solution in which the primary antibody and the pHAb amine-labeled secondary antibody were conjugated was dispensed per well. 5% CO ₂ , and reacted for 24 hours in an incubator at 37°C.

3.5. Fixing and cleaning

8% paraformaldehyde was diluted with 4% paraformaldehyde using 1X PBS. The culture solution treated with the conjugated antibody was removed, and 100 μL of 4% paraformaldehyde was dispensed. A 96 well plate was centrifuged at 300 g for 10 minutes. After centrifugation, the reaction was performed at room temperature for 10 minutes. After that, 250 μL of 1X PBS per well was washed 3 times, and 100 μL of 1X PBS was added per well.

3.6. analysis

Using a microplate reader, the fluorescence value was measured with an OD value of Ex 520 nm/Em 565 nm.

result

Antibodies #1 to #9 bound to B7-H3 present in cells as shown in FIGS. 5 and 6, and it was confirmed that B7-H3 was introduced into the cell (cell internalization) ( FIGS. 5 and 6 ).

For the MCF-7 cell line, it was confirmed that the B7-H3 internalization ability of antibodies #1 to #9 was excellent, and in particular, seven antibodies (#1, #4, #5, #6, #7, #8 and #9) ), it was confirmed that the B7-H3 internalization ability was very good.

In addition, it was confirmed that the B7-H3 internalization ability of antibodies #1 to #9 was significantly superior in the RKO/B7H3 cell line overexpressing B7-H3 compared to the RKO cell line not overexpressing B7-H3.

Example 4: Invasion test

This experiment was carried out to confirm the inhibitory effect of the B7-H3 antibody against cancer cell invasion.

Experimental method

4.1 Preparation of reagents

Culture medium: 50 mL FBS, 5 mL antibiotic-antimycotic (100X), 5 mL NEAA, and 5 mL sodium pyrubate were added to 500 mL RPMI 1640 medium. 1X PBS: It was prepared by mixing 100 mL 10x PBS with 900 mL tertiary distilled water. 0.2% crystal violet: 10 mL 1% crystal violet solution was added to 40 mL methanol, inverted, and mixed, and stored at room temperature in a shaded condition.

4.2. Trasnwell insert and Matrigel coating

Heat the forceps with an alcohol lamp and let it cool. Transwells were mounted on an SPL 24 well plate. After dispensing 22 μL of matrigel diluted 1:10 with serum free media (SFM) into the inner well (inside the transwell), it was spread evenly on the membrane. After that, the matrigel was dried at room temperature for 1-2 hours to harden.

4.3. RKO, RKO/B7H3 seeding and culture

Remove the medium of RKO and RKO/B7H3 that were being cultured in a 10 cm dish, wash with 8 mL of DPBS, add 1 mL of trypsin-EDTA (T/E) solution, and place in a 37°C incubator for 2-3 minutes to detach the cells. paid The detached cells were collected in a 15 mL tube using 6 mL of SFM and centrifuged at 700 rpm for 3 minutes. After removing the supernatant, the cell pellet was released with 3 mL of SFM, and cell counting was performed. SFM was added to make the cell concentration to 5x10 ⁶ cells/mL.

RKO and RKO/B7H3 were slowly put into the insert well by 1X10 ⁶ cells/200 μL, respectively, and 600 μL of culture medium supplemented with 10% FBS was added to the outer well.

To check the effect of antibody treatment, mix #1 to #9 antibodies at a concentration of 20 µg/mL in RKO/B7H3 (1X10 ⁶ cells/200 µL) cell line, respectively, and slowly put them into the insert well, and culture medium with 10% FBS added 600 μL was added to the outer well. Then, it was cultured for 48 hours at 37°C, 5% CO ₂ incubator.

4.4. Crystal violet staining

In a 24-well plate, 600 μL of PBS, 0.2% crystal violet, and tertiary distilled water were dispensed into each well.

The cultured cells were taken out, the insert well was turned upside down to remove the medium inside, washed in PBS, and the insert well was put in 0.2% crystal violet and stained at room temperature for 30 minutes.

Take out the insert well, turn it upside down, remove the crystal violet inside, and immerse it in tertiary distilled water to stop staining.

Hold the insert well with forceps and wash it by shaking in the tertiary distilled water in a wide container, and then use a cotton swab to wipe off the cells that have not invaded the inner membrane.

4.5. Photography and data analysis

The degree of cell invasion was photographed, and the number of infiltrated cells was counted using Image J.

result

It was confirmed that cancer cell invasion actively progressed in the RKO/B7H3 cell line compared to the RKO cell line. It was confirmed that invasion was reduced by about 60 to 85% when cultured by treatment with #1 to #9 antibody treatment in RKO/B7H3 cell lines (see FIGS. 7 and 8). That is, when B7-H3 is overexpressed, the invasion of cancer cells proceeds actively, and it was confirmed that the invasion was inhibited by the B7-H3 antibody, and it was confirmed that the #1 to #9 antibodies were excellent in the invasion inhibitory effect.

Example 5: Migration test

This experiment was conducted to confirm the inhibitory effect of the B7-H3 antibody on cancer cell migration.

Experimental method

5.1. Preparation of reagents

Culture medium: 50 mL FBS, 5 mL antibiotic-antimycotic (100X), 5 mL NEAA, and 5 mL sodium pyrubate were added to 500 mL RPMI 1640 medium. 1X PBS: It was prepared by mixing 100 mL 10x PBS with 900 mL tertiary distilled water. 0.2% crystal violet: 10 mL 1% crystal violet solution was added to 40 mL methanol, inverted, and mixed, and stored at room temperature in a shaded state.

5.2. Trasnwell Insert

After heating the forceps with an alcohol lamp, it was cooled, and the transwell was mounted in an SPL 24 well plate according to the amount used.

5.3. RKO, RKO/B7H3 seeding and culture

Remove the medium of RKO and RKO/B7H3 cultured in a 10 cm dish, wash with 8 mL of DPBS, add 1 mL of T/E solution, and place in a 37°C incubator for 2-3 minutes to detach the cells. The detached cells were collected in a 15 mL tube using 6 mL of SFM and centrifuged at 700 rpm for 3 minutes. After removing the supernatant, the cell pellet was released with 3 mL of SFM, and cell counting was performed. After adding SFM to make the cell concentration 1X10 ⁶ cells/mL, slowly add 2x10 ⁵ cells/200 μL cells to the insert well, and then add 600 μL of culture medium with 10% FBS to the outer well. did. Then, it was cultured for 16 hours at 37°C, 5% CO ₂ incubator.

5.4. Crystal violet staining

In a 24-well plate, 600 μL of PBS, 0.2% crystal violet, and tertiary distilled water were dispensed into each well.

The cultured cells were taken out, the insert well was turned upside down to remove the medium inside, washed in PBS, and the insert well was put in 0.2% crystal violet and stained at room temperature for 30 minutes.

Take out the insert well, turn it upside down, remove the crystal violet inside, and immerse it in tertiary distilled water to stop staining.

Hold the insert well with forceps and shake it a few times in tertiary distilled water in a wide tub to wash it, and then use a cotton swab to wipe off the non-migrated cells from the inner membrane.

5.5. Photo shoot

After confirming the degree of cancer cell migration (migration) using a microscope, it was photographed.

5.6. Crystal violet extraction

After adding 200 μL of 100% methanol to a new 24 well, put the photographed insert well, put 100 μL of 100% methanol inside the insert well, seal with parafilm, and shake at room temperature for 1 hour for staining. The reagents were extracted. After removing the insert well, 200 μL was taken and transferred to a 96 well plate, and the OD value was measured at 590 nm. The degree of migration was compared with the measured OD value.

5.7. data analysis

Analysis of the OD value obtained by crystal violet extraction was compared by dividing the OD value of the experimental group based on the value of non-treated RKO/B7H3 cells to convert the migration degree into a percentage value.

result

It was confirmed that cancer cell migration was actively progressed in the RKO/B7H3 cell line compared to the RKO cell line. It was confirmed that the excellent cancer cell migration (migration) inhibitory effect of #1 to #9 antibodies against the RKO/B7H3 cell line.

When the cancer cell invasion inhibitory effect and the migration inhibitory effect are comprehensively considered, it can be seen that the cancer metastasis inhibitory effects of antibodies #1 to #9 are excellent (see FIGS. 9 and 10 ).

Example 6: Epitope identification experiment using antigen-binding fragments (scFv) of #1 to #9 antibodies.

This experiment was performed to confirm that the epitopes of the #1 to #9 antibodies are the same.

Experimental method

6.1. ingredient

3% BSA in PBST was used as a blocking buffer, and 0.05% PBST was used as a washing buffer, and the materials in Table 4 below were used.

division company Cat No product name Coating Ag. Rndsystem 1027-B3-100 Recombinant Human B7-H3 Fc chimera Protein primary antibody Self-production of antigen-binding fragments of #1 to #9
(9 types of Anti-B7-H3 scFvs) primary antibody Self-production of biotinylated antigen-binding fragments #1 to #9 (9 types of Biotinylated anti-B7-H3 scFvs) secondary antibody Jackson immunoresearch 016-030-084 Peroxidase-conjugated Streptavidin

6.2. Classification of antibodies with the same epitope

Recombinant B7-H3 protein was coated on a 96 well plate, and biotinylated scFv having heavy and light chain variable regions of antibodies #1 to #9 was treated to confirm color development. After that, color development was confirmed when biotinylated scFv and non-biotinylated scFv were treated together. Using the principle that the degree of color development decreases when the binding of antigen (B7-H3) and biotinylated scFv is disturbed, #1 It was confirmed that the epitopes of the to #9 antibodies were the same.

result

It was confirmed that there was no antibody having the same epitope as the #6 antibody, the epitope of the #2 antibody and the #3 antibody were the same, and the epitope of the #1, #4, #5, #7, #8, and #9 antibodies were the same. (Fig. 11).

Example 7: TGFβ secretion assay in B7-H3 overexpressed cells

This experiment was conducted to determine whether the B7-H3 antibody inhibits the secretion of TGFβ, a representative substance that regulates the cancer microenvironment.

Experimental method

7.1. Preparation of reagents

1X PBS and washing buffer (1X PBS-T (0.05% tween-20)) were prepared.

Blocking buffer was prepared with BSA to be 1% BSA in 1X PBS-T (0.05% Tween 20). For the antibody dilution buffer, the same reagent as the washing buffer was used. Sample neutralization buffer was prepared by adding 25 mL of 1 M HEPES, 12 mL of 5 N NaOH, and 13 mL of tertiary distilled water (autoclaved) based on 50 mL, and stored at 4°C.

7.2. Cell Seeding

After harvesting the RKO/B7H3 cell line, cell counting was performed. It was suspended at a cell concentration of 2x10 ⁵ cells/mL using a culture medium. In a 24-well plate, 500 μL was dispensed to make 1X10 ⁵ cells per well, and incubated for 24 hours at 5% CO ₂ , 37°C in an incubator.

7.3. Replacement of culture medium and collection of supernatant

The cell seeding medium was removed, and 200 μL of SFM was dispensed and removed. 500 μL of SFM was dispensed into each well and incubated for 24, 48, 72 hours in 5% CO ₂ , 37° C. incubator. After collecting the supernatant cultured for 24, 48, 72 hours in a 1.5 mL tube, centrifuged at 300 g for 3 minutes to settle cell debris. 400 μL of the supernatant was collected in a new 1.5 mL tube and stored at -80°C.

7.4. Capture antibody coating

After slowly thawing Human TGF-β1 capture antibody (stock concentration: 240 μg/mL, -20℃) on ice in advance, Human TGF-β1 capture antibody was added to a concentration of 2 μg/mL using coating buffer (PBS). It was diluted in a ratio of 1:120. 0.2 μg/well (100 μL/well) each was dispensed into a 96-well plate and reacted overnight at room temperature.

7.5. cleaning and blocking

After washing 3 times with 250 μL washing buffer per well, there was no solution left on the plate. Thereafter, blocking buffer was dispensed at 250 μL/well and reacted at room temperature for 2 hours.

7.6. Standard preparation, sample activation and sample treatment

Standard (mouse TGF-β1 (stock concentration: 190 ng/mL, -20℃) was diluted 1:95 using antibody dilution buffer to 2,000 pg/mL, followed by 2-fold serial dilution (Fig. 13).

After dispensing 100 µL of the sample to a 96-well plate, 20 µL of 1 N HCl was added, and the plate was shaken for 10 seconds to mix, followed by reaction at room temperature for 10 minutes. Then, 1.2 N NaOH/0.5 M HEPES was added at 20 μL to neutralize. After that, it was washed 3 times with 250 μL washing buffer per well, and 100 μL of the standard and sample prepared as above were dispensed per well, and then reacted at room temperature for 2 hours. After the reaction, washing was performed.

7.7. Detection antibody reaction

Detection antibody (stock concentration: 3 μg/mL, -20℃) was diluted 1:60 with antibody dilution buffer to a concentration of 50 ng/mL. 100 μL/well of the diluted detection antibody was dispensed and reacted at room temperature for 2 hours. After that, washing was performed.

7.8. Streptavidin-HRP reaction

After diluting Streptavidin-HRP 1:40 using antibody diluent buffer, the diluted streptavidin-HRP solution was dispensed at 100 μL/well, blocking light, and reacting at room temperature for 20 minutes. After that, washing was performed.

7.9. Substrate Solution reaction and O.D value measurement

After dispensing 100 μL of TMB per well, blocking the light and reacting at room temperature for 20 minutes. After 20 minutes, 50 μL of 1 N HCl, a stop solution, was added to each well to stop the substrate reaction. Thereafter, the O.D value was measured at 450 nm.

result

As a result of treating the B7-H3 overexpressed RKO/B7H3 cell line with antibodies #1 to #9, it was confirmed that the level of secreted TGFβ was inhibited by 25% to 30%, and among them, it was confirmed that the #5 antibody had the best effect. did. Through this, it can be seen that antibodies #1 to #9 (particularly, antibody #5) can effectively improve the cancer microenvironment by inhibiting the secretion of TGFβ, which is a representative substance that regulates the cancer microenvironment.

Example 8: Cancer model anticancer efficacy test (In vivo efficacy test)

This experiment was conducted to confirm that tumor growth was inhibited when B7-H3 antibody was treated in an in vivo mouse cancer model.

Experimental method

8.1. animal model creation

A 7-week-old Balb/c female (Daehan Biolink) was used. CT26-TN cells, a cell line prepared by overexpressing B7-H3 in CT26 cells, a mouse colorectal cancer cell line, were diluted in DPBS at a concentration of 5X10 ⁶ cells/mL, and 100 μL (5X10 ⁵ cells) per individual were subcutaneously transplanted into the right flank. On day 7 after cell line transplantation, the tumor volume was calculated using an electronic caliper by the following formula.

Tumor volume(mm ³ ) = <length(length, mm) x width(mm) ² > x 0.5

8.2. segregation

Measure the right tumor 7 days after transplantation of the tumor cell line. When the tumor size of most individuals reached about 40-120 mm ³ , respectively, the size of the tumor transplanted on both sides in one individual was measured and the average tumor size Group separation was performed according to the Z arrangement method based on .

8.3. Antibody administration

Dosage concentration: #5 antibody administered group - #5 antibody 10 mg/kg, #5 antibody and Anti-PD-1 antibody combination group administered - #5 antibody and anti-PD-1 antibody 10 mg/kg, respectively.

All test substances were administered intravenously (using an insulin syringe) twice a week, for 2 weeks, a total of 4 times, and negative control substances (vehicle (PBS), IgG) were also administered in the same way.

division company Cat No product name Anti-PD-1 antibody BioXcell BE016 InVivoMab Anti-mouse PD-1 (CD279)

8.4. Tumor size and weight measurement

After group separation, both the transplanted tumor sizes were measured twice a week, and the tumor volume was measured for 3 weeks. At the same time, measurements were recorded twice a week for all animals after group separation.

8.5. autopsy

On the basis of the group separation day as Day 0, tumors were extracted on Day 22, and the tumor weight was measured after taking pictures for each individual.

result

The growth of the transplanted CT26-TN cell line rapidly increased in the negative control group, Vehicle (PBS) and IgG, but tumor growth was inhibited from the 7th day after regrouping in the #5 antibody-administered group. In addition, it was confirmed that tumor growth was significantly inhibited in the group administered with the #5 antibody and anti-PD-1 antibody (BioXcell, cat# BE016) ( FIG. 14 ).

Example 9: Quantification of TGFβ in Serum in a Mouse Cancer Model

This experiment was conducted to confirm the change in TFGβ in serum after treatment with the B7-H3 antibody in an in vivo mouse cancer model.

Experimental method

9.1. ingredient

Mouse TGF-beta 1 DuoSet ELISA kit (cat#: DY1679)

Serum isolated from mice that have completed the in vivo cancer model anticancer test

9.2. Antibody preparation

Mouse TGFβ1 Capture antibody was diluted 1/120 in PBS, mouse TGFβ1 detection antibody was diluted 1/60 in PBS, and streptavidin-HRP was diluted 1/40 in PBS.

9.3. Serum sample preparation

After adding 10 μL 1 N HCl to 40 μL serum, shaking at RT for 10 seconds and incubating for 10 minutes. After that, 10 μL 1.2 N NaOH/0.5 M HEPES was added to stop the reaction, and it was diluted 1/2 with PBS.

9.4. ELISA assay

The day before (15-18 hours ago), 100 μL of the diluted capture antibody was dispensed into a 96 well plate, incubated at room temperature, and washed with 200 μL PBST (PBS+0.05% Tween20).

150 μL blocking solution (PBS+5% Tween20) was added and incubated for 1 hour at room temperature, followed by washing with 200 μL PBST. After that, 100 μL of the standard solution provided in the kit and the serum sample prepared in advance were dispensed into 96 wells by duplication, followed by reaction at room temperature for 2 hours, and then washed with 200 μL PBST.

100 μL detection antibody was dispensed into wells, and after 2 hours of reaction at room temperature, it was washed with 200 μL PBST.

After dispensing 100 μL streptavidin-HRP, the reaction was performed at room temperature for 20 minutes, followed by washing with 200 μL PBST.

After dispensing 100 μL of TMB solution, color development was performed at room temperature while blocking light, and then 50 μL 1 N HCl was added to stop the color reaction. Finally, the O.D value was measured at 450 nm.

result

TGFβ concentration in mouse serum in the #5 antibody-administered group and the #5 antibody and anti-PD-1 antibody-administered group was significantly reduced (based on vehicle group, p value < 0.5) compared to the vehicle (PBS) and IgG-administered groups, which are negative controls. was confirmed (see FIG. 15).

Example 10: Tumor Infiltrating Lymphocytes (TIL) Analysis

In an in vivo mouse cancer model, this experiment was carried out to determine whether the ability of immune cells to penetrate lymphocytes, which are immune cells in cancer tissues, was increased when the B7-H3 antibody was treated.

Experimental method

10.1. Tumor cell isolation

In vivo cancer model, 10 mL of DPBS was added to the tumor removed from the mouse that completed the anticancer test to remove the remaining blood after washing.

Add 6 mL RPMI-1640 (Hyclone, cat. CM058-050) medium, mince with scissors, and then digestion solution (50 mL RPMI-1640 + 100 mg collagenase D (Merck, cat. 11088858001) + 10 mg DNase I (Sigma-) Aldrich, cat. D4513))) 600 μL was added and reacted at 37° C., 120 rpm for 1 hour.

Put in a 70 μm cell strainer (SPL, cat. SPL93070), filter large tissues, put 1 mL in a 15 mL tube, centrifuge at 15 °C 2,000 rpm for 10 minutes, remove the supernatant, wash once with DPBS, and dilute in distilled water 500 μL of 1X RBC lysis buffer (BioLegend, cat. 420301) was added to release the pellet and allowed to react at room temperature for 5 minutes.

After washing twice in DPBS in the same way as above, cells were prepared by dissolving the pellet well in FACS buffer (DPBS+1% FBS+0.1% sodium azide).

10.2. FACS analysis antibody information

Antibodies used for FACS analysis were BioLegend products, and the information is shown in Table 6 below.

Analysis items Antibody used Cat No CD4 APC anti-mouse CD4 116014 CD8 APC/Cyanine7 anti-mouse CD8b.2 140422 CD3 FITC anti-mouse CD3 100204 CD45 PE anti-mouse CD45 103106

10.3. Fluorescent dyeing

Single cells of the tumor isolated according to the cell separation test method were pretreated with Purified Rat anti-Mouse CD16/CD32 (Mouse BD Fc Block™, cat. 553141, BD biosciences) for 10 minutes for FC blocking, followed by FACS buffer (DPBS+). 1% FBS+0.1% sodium azide), the antibody was diluted at the dilution ratio shown in the data sheet provided, and then reacted for 1 hour by blocking light at 4°C.

After the reaction was completed, the cells were washed twice with FACS buffer and fixed with 2% paraformaldehyde (PFA). Stained cells were measured using a flow cytometer (Attune, Thermo Fisher Scientific) and analyzed using FlowJo™ V10 (Flowjo, LLC).

result

As a result of FACS analysis on CD4+, CD8+ T cells of tumors removed from mice, the ability of CD8+ TIL immune cells to penetrate into cancer tissues was significantly higher in the group administered with the #5 antibody and the group administered with the #5 antibody and anti-PD-1 antibody. (PBS) and it was confirmed that the increase compared to the IgG administration group. On the other hand, it was confirmed that there was no difference in CD4+ T cells between the negative control group and the antibody-treated group. Through this, it can be seen that cytotoxic lymphocytes (CD8+ T cells) penetrate into cancer tissues and exert a cytotoxic effect on cancer cells (see FIG. 16 ).

<110> Theranotics Co., Ltd. <120> Antibodies or fragments thereof binding to B7-H3 and use thereof <130> 22P02043 <150> KR 10-2021-0039913 <151> 2021-03-26 <160> 336 <170> KoPatentIn 3.0 <210> 1 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 1 Ser Tyr Ala Met Ser 1 5 <210> 2 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 2 Ala Tyr Tyr Met Ile 1 5 <210> 3 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 3 Thr Tyr Tyr Met Thr 1 5 <210> 4 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 4 Ser Tyr Gly Met His 1 5 <210> 5 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 5 Thr Tyr Ala Met Ser 1 5 <210> 6 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 6 Thr Tyr Ala Ile Ser 1 5 <210> 7 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 7 Asn Phe Trp Ile Gly 1 5 <210> 8 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 8 Ser Tyr Trp Ile Ser 1 5 <210> 9 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 9 Ser Tyr Ala Met Asn 1 5 <210> 10 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 10 Thr Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 11 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 11 Ile Thr Asn Pro Ser Gly Gly Val Thr Ser Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <210> 12 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 12 Ile Ile Asn Pro Arg Gly Gly Ser Thr Ser Tyr Ala Glu Lys Phe Gln 1 5 10 15 Gly <210> 13 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 13 Ala Ile Ser Gly Ser Gly Thr Ser Ile Tyr Tyr Ala Asn Ser Val Lys 1 5 10 15 Ser <210> 14 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 14 Ala Ile Ser Gly Ser Gly Gly Ser Thr Leu Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 15 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 15 Ser Ile Tyr Tyr Ser Gly Tyr Thr His Tyr Asn Pro Ser Leu Glu Ser 1 5 10 15 <210> 16 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 16 Trp Ile Asn Pro Gly Ser Ile Thr Ser Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 17 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 17 Glu Ile Ser Pro Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <210> 18 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 18 Thr Ile Ser Gly Ser Gly Gly Gln Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 19 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 19 Ala Arg Tyr Lys Ser Gly Ala Phe Asp Ile 1 5 10 <210> 20 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 20 Ala Arg Val Gly Gly Arg Gly Phe Asp Ile 1 5 10 <210> 21 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 21 Ala Arg Trp Asn Leu Gly Met Asp Val 1 5 <210> 22 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 22 Ala Arg Gly Ala Gly Trp Phe Asp Tyr 1 5 <210> 23 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 23 Ala Arg Gly Gly Ser Ala Thr Trp Ala Phe Asp Leu 1 5 10 <210> 24 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 24 Ala Arg Gly Tyr Ser Gly Trp Met Asp Val 1 5 10 <210> 25 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 25 Ala Arg Glu Val Gly Asp Val Leu Asp Tyr 1 5 10 <210> 26 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 26 Ala Arg Glu Val Gly Asp Leu Leu Asp Tyr 1 5 10 <210> 27 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 27 Ala Arg Trp Arg Ser Ile Trp Ala Phe Asp Tyr 1 5 10 <210> 28 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 28 Arg Ala Ser Gln Gly Ile Gly Asn Tyr Leu Gly 1 5 10 <210> 29 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 29 His Ala Ser Gln Gly Ile Ser Asn Tyr Val Ala 1 5 10 <210> 30 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 30 Arg Val Ser Gln Ser Ile Ser Ser Tyr Leu Asn 1 5 10 <210> 31 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 31 Ser Gly Ser Thr Ser Asn Ile Gly Ser Asn Thr Val Asn 1 5 10 <210> 32 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 32 Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Tyr 1 5 10 <210> 33 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 33 Gly Gly Asn Asn Ile Gly Ser Lys Ser Val His 1 5 10 <210> 34 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 34 Thr Gly Thr Ser Ser Asp Ile Gly Arg Tyr Asn Tyr Val Ser 1 5 10 <210> 35 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 35 Ser Gly Ser Asn Ile Gly Asn Asn Tyr Val Ser 1 5 10 <210> 36 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 36 Ser Asp Asn Asn Ile Gly Ser Lys Ser Val His 1 5 10 <210> 37 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 37 Thr Ala Ser Ser Leu Gln Ser 1 5 <210> 38 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 38 Asp Ala Ser Asn Arg Ala Thr 1 5 <210> 39 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 39 Asp Ala Ser His Arg Ala Thr 1 5 <210> 40 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 40 Gly Lys Asn Ile Arg Pro Asn 1 5 <210> 41 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 41 Arg Asn Asn Gln Arg Pro Ser 1 5 <210> 42 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 42 Asp Asn Asn Lys Arg Pro Ser 1 5 <210> 43 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 43 Arg Asn Thr Gln Arg Pro Ser 1 5 <210> 44 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 44 Gln Asp Ser Lys Arg Pro Ser 1 5 <210> 45 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 45 Gln Gln Gly Tyr Ser Thr Pro Ser Trp Thr 1 5 10 <210> 46 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 46 Gln Gln Ser Tyr Ser Thr Leu Leu Thr 1 5 <210> 47 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 47 Gln Gln Tyr Tyr Ala Pro Ser Val Thr 1 5 <210> 48 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 48 Gln Ser Tyr Asp Ser Ser Leu Ser Gly Trp Val 1 5 10 <210> 49 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 49 Gly Thr Trp Asp Ser Ser Leu Ser Gly Val Val 1 5 10 <210> 50 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 50 Ala Ala Trp Asp Asp Ser Leu Asn Val Pro Val 1 5 10 <210> 51 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 51 Gly Thr Trp Asp Ser Ser Leu Asn Ala Tyr Val 1 5 10 <210> 52 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 52 Leu Val Trp Asp Arg Ser Ser Asp His Phe Val 1 5 10 <210> 53 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 53 Gly Thr Trp Asp Asp Ser Leu Ser Gly Pro Val 1 5 10 <210> 54 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> VH_FR1 <400> 54 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 20 25 30 <210> 55 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> VH_FR1 <400> 55 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 20 25 30 <210> 56 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> VH_FR1 <400> 56 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 20 25 30 <210> 57 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> VH_FR1 <400> 57 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Ser 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 20 25 30 <210> 58 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> VH_FR1 <400> 58 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 20 25 30 <210> 59 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> VH_FR1 <400> 59 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 Val Tyr Gly Gly Ser Phe Ser 20 25 30 <210> 60 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> VH_FR1 <400> 60 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 20 25 30 <210> 61 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> VH_FR1 <400> 61 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr 20 25 30 <210> 62 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> VH_FR1 <400> 62 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser 20 25 30 <210> 63 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> VH_FR2 <400> 63 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly 1 5 10 <210> 64 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> VH_FR2 <400> 64 Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser 1 5 10 <210> 65 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> VH_FR2 <400> 65 Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly 1 5 10 <210> 66 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> VH_FR2 <400> 66 Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met Gly 1 5 10 <210> 67 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> VH_FR2 <400> 67 Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu Trp Leu Gly 1 5 10 15 <210> 68 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> VH_FR3 <400> 68 Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr Met Glu 1 5 10 15 Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 20 25 30 <210> 69 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> VH_FR3 <400> 69 Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr Met Glu 1 5 10 15 Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 20 25 30 <210> 70 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> VH_FR3 <400> 70 Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln 1 5 10 15 Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 20 25 30 <210> 71 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> VH_FR3 <400> 71 Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asp Thr Leu Tyr Leu Gln 1 5 10 15 Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 20 25 30 <210> 72 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> VH_FR3 <400> 72 Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln 1 5 10 15 Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 20 25 30 <210> 73 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> VH_FR3 <400> 73 Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys 1 5 10 15 Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 20 25 30 <210> 74 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> VH_FR3 <400> 74 Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln 1 5 10 15 Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 20 25 30 <210> 75 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> VH_FR3 <400> 75 Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn Gln Phe Ser Leu Gln 1 5 10 15 Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val Tyr Tyr Cys 20 25 30 <210> 76 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> VL(kappa)_FR1 <400> 76 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> 77 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> VL(kappa)_FR1 <400> 77 Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> 78 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> VL(kappa)_FR1 <400> 78 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys 20 <210> 79 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> VL(kappa)_FR1 <400> 79 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys 20 <210> 80 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> VL(kappa)_FR1 <400> 80 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 20 <210> 81 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> VL(kappa)_FR1 <400> 81 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys 20 <210> 82 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> VL(kappa)_FR2 <400> 82 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> 83 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> VL(kappa)_FR2 <400> 83 Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr 1 5 10 15 <210> 84 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> VL(kappa)_FR2 <400> 84 Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr 1 5 10 15 <210> 85 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> VL(kappa)_FR2 <400> 85 Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> 86 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> VL(kappa)_FR3 <400> 86 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 20 25 30 <210> 87 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> VL(kappa)_FR3 <400> 87 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 20 25 30 <210> 88 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> VL(kappa)_FR3 <400> 88 Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys 20 25 30 <210> 89 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> VL(kappa)_FR3 <400> 89 Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys 20 25 30 <210> 90 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> VL(kappa)_FR3 <400> 90 Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys 20 25 30 <210> 91 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> VL(kappa)_FR3 <400> 91 Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser His Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys 20 25 30 <210> 92 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> VL(kappa)_FR3 <400> 92 Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys 20 25 30 <210> 93 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> VL(lambda)_FR1 <400> 93 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys 20 <210> 94 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> VL(lambda)_FR1 <400> 94 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys 20 <210> 95 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> VL(lambda)_FR1 <400> 95 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys 20 <210> 96 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> VL(lambda)_FR1 <400> 96 Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys 20 <210> 97 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> VL(lambda)_FR1 <400> 97 Ser Tyr Glu Leu Thr Gln Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Ser Ile Thr Cys 20 <210> 98 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> VL(lambda)_FR2 <400> 98 Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> 99 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> VL(lambda)_FR2 <400> 99 Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 1 5 10 15 <210> 100 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> VL(lambda)_FR2 <400> 100 Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr 1 5 10 15 <210> 101 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> VL(lambda)_FR3 <400> 101 Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser 1 5 10 15 Leu Ala Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys 20 25 30 <210> 102 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> VL(lambda)_FR3 <400> 102 Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser 1 5 10 15 Leu Ala Ile Ser Gly Leu His Ser Glu Asp Glu Ala Asp Tyr Tyr Cys 20 25 30 <210> 103 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> VL(lambda)_FR3 <400> 103 Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser 1 5 10 15 Leu Ala Ile Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys 20 25 30 <210> 104 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> VL(lambda)_FR3 <400> 104 Gly Val Pro Asn Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser 1 5 10 15 Leu Ala Ile Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys 20 25 30 <210> 105 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> VL(lambda)_FR3 <400> 105 Gly Ile Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Thr 1 5 10 15 Leu Gly Ile Thr Gly Leu Gln Thr Gly Asp Glu Ala Asp Tyr Tyr Cys 20 25 30 <210> 106 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> VL(lambda)_FR3 <400> 106 Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser 1 5 10 15 Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys 20 25 30 <210> 107 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> VL(lambda)_FR3 <400> 107 Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser 1 5 10 15 Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys 20 25 30 <210> 108 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> VL(lambda)_FR3 <400> 108 Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr 1 5 10 15 Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp Tyr Tyr Cys 20 25 30 <210> 109 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 109 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Thr Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Lys Ser Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 110 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 110 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 Ala Tyr 20 25 30 Tyr Met Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ile Thr Asn Pro Ser Gly Gly Val Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Gly Gly Arg Gly Phe Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 111 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 111 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 Thr Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Asn Pro Arg Gly Gly Ser Thr Ser Tyr Ala Glu Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Asn Leu Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 112 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 112 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Ser Gly Ser Gly Thr Ser Ile Tyr Tyr Ala Asn Ser Val 50 55 60 Lys Ser Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ala Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 113 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 113 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 Thr Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Ser Gly Ser Gly Gly Ser Thr Leu Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Ser Ala Thr Trp Ala Phe Asp Leu Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 114 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 114 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 Thr Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ser Ile Tyr Tyr Ser Gly Tyr Thr His Tyr Asn Pro Ser Leu Glu 50 55 60 Ser Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr Met 65 70 75 80 Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Tyr Ser Gly Trp Met Asp Val Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 115 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 115 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 Asn Phe 20 25 30 Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Pro Gly Ser Ile Thr Ser Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Val Gly Asp Val Leu Asp Tyr Trp Gly Gin Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 116 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 116 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Trp Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Glu Ile Ser Pro Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr Met 65 70 75 80 Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu Val Gly Asp Leu Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 117 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 117 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Thr Ile Ser Gly Ser Gly Gly Gln Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Arg Ser Ile Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 118 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 118 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Thr Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Lys Ser Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 119 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 119 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ala Tyr 20 25 30 Tyr Met Ile Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ile Thr Asn Pro Ser Gly Gly Val Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Gly Gly Arg Gly Phe Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 120 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 120 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Asn Pro Arg Gly Gly Ser Thr Ser Tyr Ala Glu Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Asn Leu Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 121 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 121 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Ser Gly Ser Gly Thr Ser Ile Tyr Tyr Ala Asn Ser Val 50 55 60 Lys Ser Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ala Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 122 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 122 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Ser Gly Ser Gly Gly Ser Thr Leu Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Ser Ala Thr Trp Ala Phe Asp Leu Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 123 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 123 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ser Ile Tyr Tyr Ser Gly Tyr Thr His Tyr Asn Pro Ser Leu Glu 50 55 60 Ser Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr Met 65 70 75 80 Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Tyr Ser Gly Trp Met Asp Val Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 124 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 124 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Phe 20 25 30 Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Pro Gly Ser Ile Thr Ser Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Val Gly Asp Val Leu Asp Tyr Trp Gly Gin Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 125 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 125 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Trp Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Glu Ile Ser Pro Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr Met 65 70 75 80 Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu Val Gly Asp Leu Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 126 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 126 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Thr Ile Ser Gly Ser Gly Gly Gln Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Arg Ser Ile Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 127 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 127 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Lys Ser Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 128 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 128 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ala Tyr 20 25 30 Tyr Met Ile Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ile Thr Asn Pro Ser Gly Gly Val Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln 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 Val Gly Gly Arg Gly Phe Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 129 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 129 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ile Ile Asn Pro Arg Gly Gly Ser Thr Ser Tyr Ala Glu Lys Phe 50 55 60 Gln 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 Trp Asn Leu Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 130 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 130 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Thr Ser Ile Tyr Tyr Ala Asn Ser Val 50 55 60 Lys Ser 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 Gly Ala Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 131 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 131 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 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 Ala Ile Ser Gly Ser Gly Gly Ser Thr Leu Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Ser Ala Thr Trp Ala Phe Asp Leu Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 132 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 132 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Tyr Tyr Ser Gly Tyr Thr His Tyr Asn Pro Ser Leu Glu 50 55 60 Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Tyr Ser Gly Trp Met Asp Val Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 133 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 133 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30 Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Trp Ile Asn Pro Pro Gly Ser Ile Thr Ser Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Val Gly Asp Val Leu Asp Tyr Trp Gly Gin Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 134 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 134 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Glu Ile Ser Pro Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu Val Gly Asp Leu Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 135 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 135 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Gly Ser Gly Gly Gln Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Arg Ser Ile Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 136 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 136 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asp 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 Tyr Lys Ser Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 137 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 137 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ala Tyr 20 25 30 Tyr Met Ile Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ile Thr Asn Pro Ser Gly Gly Val Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asp 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 Val Gly Gly Arg Gly Phe Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 138 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 138 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ile Ile Asn Pro Arg Gly Gly Ser Thr Ser Tyr Ala Glu Lys Phe 50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asp 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 Trp Asn Leu Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 139 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 139 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Thr Ser Ile Tyr Tyr Ala Asn Ser Val 50 55 60 Lys Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asp 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 Gly Ala Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 140 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 140 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 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 Ala Ile Ser Gly Ser Gly Gly Ser Thr Leu Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asp 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 Gly Gly Ser Ala Thr Trp Ala Phe Asp Leu Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 141 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 141 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Tyr Tyr Ser Gly Tyr Thr His Tyr Asn Pro Ser Leu Glu 50 55 60 Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asp Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Tyr Ser Gly Trp Met Asp Val Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 142 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 142 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30 Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Trp Ile Asn Pro Pro Gly Ser Ile Thr Ser Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asp 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 Glu Val Gly Asp Val Leu Asp Tyr Trp Gly Gin Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 143 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 143 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Glu Ile Ser Pro Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asp Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu Val Gly Asp Leu Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 144 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 144 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Gly Ser Gly Gly Gln Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asp 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 Trp Arg Ser Ile Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 145 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 145 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Ser 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Lys Ser Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 146 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 146 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Ser 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ala Tyr 20 25 30 Tyr Met Ile Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ile Thr Asn Pro Ser Gly Gly Val Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln 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 Val Gly Gly Arg Gly Phe Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 147 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 147 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Ser 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ile Ile Asn Pro Arg Gly Gly Ser Thr Ser Tyr Ala Glu Lys Phe 50 55 60 Gln 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 Trp Asn Leu Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 148 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 148 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Ser 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Thr Ser Ile Tyr Tyr Ala Asn Ser Val 50 55 60 Lys Ser 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 Gly Ala Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 149 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 149 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Ser 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 Ala Ile Ser Gly Ser Gly Gly Ser Thr Leu Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Ser Ala Thr Trp Ala Phe Asp Leu Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 150 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 150 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Ser 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Tyr Tyr Ser Gly Tyr Thr His Tyr Asn Pro Ser Leu Glu 50 55 60 Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Tyr Ser Gly Trp Met Asp Val Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 151 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 151 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Ser 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe 20 25 30 Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Trp Ile Asn Pro Pro Gly Ser Ile Thr Ser Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Val Gly Asp Val Leu Asp Tyr Trp Gly Gin Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 152 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 152 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Ser 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Glu Ile Ser Pro Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu Val Gly Asp Leu Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 153 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 153 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Ser 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Gly Ser Gly Gly Gln Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Arg Ser Ile Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 154 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 154 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 Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Lys Ser Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 155 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 155 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 Ala Tyr 20 25 30 Tyr Met Ile Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ile Thr Asn Pro Ser Gly Gly Val Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Gly Gly Arg Gly Phe Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 156 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 156 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 Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ile Ile Asn Pro Arg Gly Gly Ser Thr Ser Tyr Ala Glu Lys Phe 50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Asn Leu Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 157 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 157 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 Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Thr Ser Ile Tyr Tyr Ala Asn Ser Val 50 55 60 Lys Ser Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ala Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 158 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 158 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 Ala Ile Ser Gly Ser Gly Gly Ser Thr Leu Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Ser Ala Thr Trp Ala Phe Asp Leu Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 159 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 159 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 Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Tyr Tyr Ser Gly Tyr Thr His Tyr Asn Pro Ser Leu Glu 50 55 60 Ser Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Tyr Ser Gly Trp Met Asp Val Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 160 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 160 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 Asn Phe 20 25 30 Trp Ile Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Trp Ile Asn Pro Pro Gly Ser Ile Thr Ser Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Val Gly Asp Val Leu Asp Tyr Trp Gly Gin Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 161 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 161 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 Ser Tyr 20 25 30 Trp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Glu Ile Ser Pro Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu Val Gly Asp Leu Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 162 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 162 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 Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Gly Ser Gly Gly Gln Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Arg Ser Ile Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 163 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 163 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 Val Tyr Gly Gly Ser Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Thr Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Lys Ser Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 164 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 164 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 Val Tyr Gly Gly Ser Phe Ser Ala Tyr 20 25 30 Tyr Met Ile Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Thr Asn Pro Ser Gly Gly Val Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Gly Gly Arg Gly Phe Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 165 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 165 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 Val Tyr Gly Gly Ser Phe Ser Thr Tyr 20 25 30 Tyr Met Thr Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Asn Pro Arg Gly Gly Ser Thr Ser Tyr Ala Glu Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Asn Leu Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 166 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 166 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 Val Tyr Gly Gly Ser Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Ser Gly Ser Gly Thr Ser Ile Tyr Tyr Ala Asn Ser Val 50 55 60 Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ala Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 167 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 167 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 Val Tyr Gly Gly Ser Phe Ser Thr Tyr 20 25 30 Ala Met Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Ser Gly Ser Gly Gly Ser Thr Leu Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Ser Ala Thr Trp Ala Phe Asp Leu Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 168 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 168 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 Val Tyr Gly Gly Ser Phe Ser Thr Tyr 20 25 30 Ala Ile Ser Trp Ile Arg Gln Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Tyr Ser Gly Tyr Thr His Tyr Asn Pro Ser Leu Glu 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Tyr Ser Gly Trp Met Asp Val Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 169 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 169 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 Val Tyr Gly Gly Ser Phe Ser Asn Phe 20 25 30 Trp Ile Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Asn Pro Pro Gly Ser Ile Thr Ser Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Val Gly Asp Val Leu Asp Tyr Trp Gly Gin Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 170 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 170 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 Val Tyr Gly Gly Ser Phe Ser Ser Tyr 20 25 30 Trp Ile Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Ser Pro Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu Val Gly Asp Leu Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 171 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 171 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 Val Tyr Gly Gly Ser Phe Ser Ser Tyr 20 25 30 Ala Met Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Thr Ile Ser Gly Ser Gly Gly Gln Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Arg Ser Ile Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 172 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 172 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 Ala Met Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Thr Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Lys Ser Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 173 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 173 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 Ala Tyr 20 25 30 Tyr Met Ile Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Thr Asn Pro Ser Gly Gly Val Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Gly Gly Arg Gly Phe Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 174 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 174 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 Thr Tyr 20 25 30 Tyr Met Thr Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Asn Pro Arg Gly Gly Ser Thr Ser Tyr Ala Glu Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Asn Leu Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 175 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 175 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 Gly Met His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Ser Gly Ser Gly Thr Ser Ile Tyr Tyr Ala Asn Ser Val 50 55 60 Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ala Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 176 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 176 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 Thr Tyr 20 25 30 Ala Met Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Ser Gly Ser Gly Gly Ser Thr Leu Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Ser Ala Thr Trp Ala Phe Asp Leu Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 177 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 177 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 Thr Tyr 20 25 30 Ala Ile Ser Trp Ile Arg Gln Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Tyr Ser Gly Tyr Thr His Tyr Asn Pro Ser Leu Glu 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Tyr Ser Gly Trp Met Asp Val Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 178 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 178 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 Asn Phe 20 25 30 Trp Ile Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Asn Pro Pro Gly Ser Ile Thr Ser Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Val Gly Asp Val Leu Asp Tyr Trp Gly Gin Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 179 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 179 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 Trp Ile Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Ser Pro Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu Val Gly Asp Leu Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 180 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 180 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 Ala Met Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Thr Ile Ser Gly Ser Gly Gly Gln Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Arg Ser Ile Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 181 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 181 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Thr Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Tyr Lys Ser Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 182 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 182 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ala Tyr 20 25 30 Tyr Met Ile Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Ile Thr Asn Pro Ser Gly Gly Val Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Val Gly Gly Arg Gly Phe Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 183 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 183 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Asn Pro Arg Gly Gly Ser Thr Ser Tyr Ala Glu Lys Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Trp Asn Leu Gly Met Asp Val Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 184 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 184 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Ser Gly Ser Gly Thr Ser Ile Tyr Tyr Ala Asn Ser Val 50 55 60 Lys Ser Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Gly Ala Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 185 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 185 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Ala Ile Ser Gly Ser Gly Gly Ser Thr Leu Tyr Ala Asp Ser Val 50 55 60 Lys Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Ser Ala Thr Trp Ala Phe Asp Leu Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 186 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 186 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Ser Ile Tyr Tyr Ser Gly Tyr Thr His Tyr Asn Pro Ser Leu Glu 50 55 60 Ser Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 65 70 75 80 Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Arg Gly Tyr Ser Gly Trp Met Asp Val Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 187 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 187 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Phe 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Pro Gly Ser Ile Thr Ser Tyr Ala Asp Ser Val 50 55 60 Lys Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Glu Val Gly Asp Val Leu Asp Tyr Trp Gly Gin Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 188 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 188 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Ser Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Glu Ile Ser Pro Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 65 70 75 80 Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Arg Glu Val Gly Asp Leu Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 189 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 189 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Thr Ile Ser Gly Ser Gly Gly Gln Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Trp Arg Ser Ile Trp Ala Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 190 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 190 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Tyr 20 25 30 Ala Met Ser Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu 35 40 45 Trp Leu Gly Thr Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Gly Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn Gln 65 70 75 80 Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Tyr Lys Ser Gly Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 191 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 191 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ala Tyr 20 25 30 Tyr Met Ile Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu 35 40 45 Trp Leu Gly Ile Thr Asn Pro Ser Gly Gly Val Thr Ser Tyr Ala Gln 50 55 60 Lys Phe Gln Gly Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn Gln 65 70 75 80 Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Val Gly Gly Arg Gly Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 192 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 192 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Thr Tyr 20 25 30 Tyr Met Thr Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu 35 40 45 Trp Leu Gly Ile Ile Asn Pro Arg Gly Gly Ser Thr Ser Tyr Ala Glu 50 55 60 Lys Phe Gln Gly Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn Gln 65 70 75 80 Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Trp Asn Leu Gly Met Asp Val Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 193 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 193 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Tyr 20 25 30 Gly Met His Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu 35 40 45 Trp Leu Gly Ala Ile Ser Gly Ser Gly Thr Ser Ile Tyr Tyr Ala Asn 50 55 60 Ser Val Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn Gln 65 70 75 80 Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Gly Ala Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 194 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 194 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Thr Tyr 20 25 30 Ala Met Ser Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu 35 40 45 Trp Leu Gly Ala Ile Ser Gly Ser Gly Gly Ser Thr Leu Tyr Ala Asp 50 55 60 Ser Val Lys Gly Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn Gln 65 70 75 80 Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Gly Gly Ser Ala Thr Trp Ala Phe Asp Leu Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 195 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 195 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Thr Tyr 20 25 30 Ala Ile Ser Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu 35 40 45 Trp Leu Gly Ser Ile Tyr Tyr Ser Gly Tyr Thr His Tyr Asn Pro Ser 50 55 60 Leu Glu Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Gly Tyr Ser Gly Trp Met Asp Val Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 196 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 196 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Tyr 20 25 30 Ala Met Asn Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu 35 40 45 Trp Leu Gly Thr Ile Ser Gly Ser Gly Gly Gin Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Gly Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn Gln 65 70 75 80 Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Trp Arg Ser Ile Trp Ala Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 197 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 197 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Tyr 20 25 30 Trp Ile Ser Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu 35 40 45 Trp Leu Gly Glu Ile Ser Pro Ser Gly Asn Thr Asn Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Val Gly Asp Leu Leu Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 198 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 198 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Tyr 20 25 30 Ala Met Asn Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu 35 40 45 Trp Leu Gly Thr Ile Ser Gly Ser Gly Gly Gin Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Gly Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn Gln 65 70 75 80 Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Trp Arg Ser Ile Trp Ala Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 199 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 199 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Gly Ile Gly Asn Tyr Leu 20 25 30 Gly Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Thr Ala Ser Ser Leu Gln Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gly Tyr Ser Thr Pro Ser Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 200 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 200 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys His Ala Ser Gln Gly Ile Ser Asn Tyr Val 20 25 30 Ala Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Ala Ser Asn Arg Ala Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Leu Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 201 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 201 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Arg Val Ser Gln Ser Ile Ser Ser Ser Tyr Leu 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Ala Ser His Arg Ala Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gln Tyr Tyr Ala Pro Ser Val Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 202 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 202 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Thr Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Gly Lys Asn Ile Arg Pro Asn Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu 85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 203 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 203 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 204 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 204 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val 20 25 30 His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn Val 85 90 95 Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 205 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 205 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Arg Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Arg Asn Thr Gln Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu 65 70 75 80 Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser 85 90 95 Leu Asn Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 206 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 206 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Asn Ile Gly Asn Asn Tyr Val 20 25 30 Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Gln Asp Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Leu Val Trp Asp Arg Ser Ser Asp His 85 90 95 Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 207 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 207 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Asp Asn Asn Ile Gly Ser Lys Ser Val 20 25 30 His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Asp Ser Leu Ser Gly 85 90 95 Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 208 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 208 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Gly Ile Gly Asn Tyr Leu 20 25 30 Gly Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Thr Ala Ser Ser Leu Gln Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu His Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gly Tyr Ser Thr Pro Ser Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 209 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 209 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys His Ala Ser Gln Gly Ile Ser Asn Tyr Val 20 25 30 Ala Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Ala Ser Asn Arg Ala Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu His Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Leu Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 210 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 210 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Arg Val Ser Gln Ser Ile Ser Ser Ser Tyr Leu 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Ala Ser His Arg Ala Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu His Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gln Tyr Tyr Ala Pro Ser Val Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 211 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 211 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Thr Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Gly Lys Asn Ile Arg Pro Asn Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu His 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu 85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 212 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 212 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu His 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 213 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 213 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val 20 25 30 His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu His Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn Val 85 90 95 Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 214 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 214 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Arg Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Arg Asn Thr Gln Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu 65 70 75 80 His Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser 85 90 95 Leu Asn Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 215 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 215 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Asn Ile Gly Asn Asn Tyr Val 20 25 30 Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Gln Asp Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu His Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Leu Val Trp Asp Arg Ser Ser Asp His 85 90 95 Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 216 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 216 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Asn Ile Gly Asn Asn Tyr Val 20 25 30 Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Gln Asp Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu His Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Leu Val Trp Asp Arg Ser Ser Asp His 85 90 95 Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 217 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 217 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Arg Val Ser Gln Ser Ile Ser Ser Ser Tyr Leu 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Ala Ser His Arg Ala Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gln Tyr Tyr Ala Pro Ser Val Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 218 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 218 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys His Ala Ser Gln Gly Ile Ser Asn Tyr Val 20 25 30 Ala Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Ala Ser Asn Arg Ala Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Leu Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 219 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 219 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Arg Val Ser Gln Ser Ile Ser Ser Ser Tyr Leu 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Ala Ser His Arg Ala Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gln Tyr Tyr Ala Pro Ser Val Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 220 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 220 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Thr Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Gly Lys Asn Ile Arg Pro Asn Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu 85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 221 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 221 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 222 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 222 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val 20 25 30 His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn Val 85 90 95 Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 223 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 223 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Arg Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Arg Asn Thr Gln Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu 65 70 75 80 Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser 85 90 95 Leu Asn Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 224 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 224 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Asn Ile Gly Asn Asn Tyr Val 20 25 30 Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Gln Asp Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Leu Val Trp Asp Arg Ser Ser Asp His 85 90 95 Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 225 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 225 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Asp Asn Asn Ile Gly Ser Lys Ser Val 20 25 30 His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Asp Ser Leu Ser Gly 85 90 95 Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 226 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 226 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Gly Ile Gly Asn Tyr Leu 20 25 30 Gly Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Thr Ala Ser Ser Leu Gln Ser Gly Val Pro Asn Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gly Tyr Ser Thr Pro Ser Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 227 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 227 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys His Ala Ser Gln Gly Ile Ser Asn Tyr Val 20 25 30 Ala Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Ala Ser Asn Arg Ala Thr Gly Val Pro Asn Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Leu Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 228 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 228 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Arg Val Ser Gln Ser Ile Ser Ser Ser Tyr Leu 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Ala Ser His Arg Ala Thr Gly Val Pro Asn Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gln Tyr Tyr Ala Pro Ser Val Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 229 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 229 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Thr Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Gly Lys Asn Ile Arg Pro Asn Gly Val Pro Asn Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu 85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 230 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 230 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asn Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 231 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 231 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val 20 25 30 His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Asn Asn Lys Arg Pro Ser Gly Val Pro Asn Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn Val 85 90 95 Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 232 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 232 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Arg Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Arg Asn Thr Gln Arg Pro Ser Gly Val Pro Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu 65 70 75 80 Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser 85 90 95 Leu Asn Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 233 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 233 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Asn Ile Gly Asn Asn Tyr Val 20 25 30 Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Gln Asp Ser Lys Arg Pro Ser Gly Val Pro Asn Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Leu Val Trp Asp Arg Ser Ser Asp His 85 90 95 Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 234 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 234 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Asp Asn Asn Ile Gly Ser Lys Ser Val 20 25 30 His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Asn Asn Lys Arg Pro Ser Gly Val Pro Asn Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Asp Ser Leu Ser Gly 85 90 95 Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 235 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 235 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Arg Ala Ser Gln Gly Ile Gly Asn Tyr Leu 20 25 30 Gly Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Thr Ala Ser Ser Leu Gln Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln Thr Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gly Tyr Ser Thr Pro Ser Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 236 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 236 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys His Ala Ser Gln Gly Ile Ser Asn Tyr Val 20 25 30 Ala Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln Thr Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Leu Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 237 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 237 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Arg Val Ser Gln Ser Ile Ser Ser Ser Tyr Leu 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Ala Ser His Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln Thr Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gln Tyr Tyr Ala Pro Ser Val Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 238 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 238 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Thr Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Gly Lys Asn Ile Arg Pro Asn Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu 85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 239 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 239 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 240 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 240 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val 20 25 30 His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln Thr Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn Val 85 90 95 Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 241 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 241 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Arg Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Arg Asn Thr Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu 65 70 75 80 Gln Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser 85 90 95 Leu Asn Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 242 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 242 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Asn Ile Gly Asn Asn Tyr Val 20 25 30 Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Gln Asp Ser Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln Thr Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Leu Val Trp Asp Arg Ser Ser Asp His 85 90 95 Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 243 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 243 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Asp Asn Asn Ile Gly Ser Lys Ser Val 20 25 30 His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln Thr Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Asp Ser Leu Ser Gly 85 90 95 Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 244 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 244 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Arg Ala Ser Gln Gly Ile Gly Asn Tyr Leu 20 25 30 Gly Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 35 40 45 Thr Ala Ser Ser Leu Gln Ser Gly Val Ser Asn Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gly Tyr Ser Thr Pro Ser Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 245 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 245 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys His Ala Ser Gln Gly Ile Ser Asn Tyr Val 20 25 30 Ala Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 35 40 45 Asp Ala Ser Asn Arg Ala Thr Gly Val Ser Asn Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Leu Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 246 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 246 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Arg Val Ser Gln Ser Ile Ser Ser Ser Tyr Leu 20 25 30 Asn Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 35 40 45 Asp Ala Ser His Arg Ala Thr Gly Val Ser Asn Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gln Tyr Tyr Ala Pro Ser Val Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 247 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 247 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Ser Gly Ser Thr Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met 35 40 45 Ile Tyr Gly Lys Asn Ile Arg Pro Asn Gly Val Ser Asn Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu 85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 248 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 248 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met 35 40 45 Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Ser Asn Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 249 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 249 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val 20 25 30 His Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 35 40 45 Asp Asn Asn Lys Arg Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn Val 85 90 95 Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 250 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 250 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Arg Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Arg Asn Thr Gln Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser 85 90 95 Leu Asn Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 251 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 251 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Ser Gly Ser Asn Ile Gly Asn Asn Tyr Val 20 25 30 Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 35 40 45 Gln Asp Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Leu Val Trp Asp Arg Ser Ser Asp His 85 90 95 Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 252 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 252 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Ser Asp Asn Asn Ile Gly Ser Lys Ser Val 20 25 30 His Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 35 40 45 Asp Asn Asn Lys Arg Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Asp Ser Leu Ser Gly 85 90 95 Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 253 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 253 Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Arg Ala Ser Gln Gly Ile Gly Asn Tyr Leu 20 25 30 Gly Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 35 40 45 Thr Ala Ser Ser Leu Gln Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gly Tyr Ser Thr Pro Ser Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 254 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 254 Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys His Ala Ser Gln Gly Ile Ser Asn Tyr Val 20 25 30 Ala Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 35 40 45 Asp Ala Ser Asn Arg Ala Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Leu Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 255 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 255 Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Arg Val Ser Gln Ser Ile Ser Ser Ser Tyr Leu 20 25 30 Asn Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 35 40 45 Asp Ala Ser His Arg Ala Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gln Tyr Tyr Ala Pro Ser Val Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 256 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 256 Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Ser Gly Ser Thr Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met 35 40 45 Ile Tyr Gly Lys Asn Ile Arg Pro Asn Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu 85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 257 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 257 Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met 35 40 45 Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 258 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 258 Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val 20 25 30 His Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 35 40 45 Asp Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn Val 85 90 95 Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 259 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 259 Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Arg Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Arg Asn Thr Gln Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser 85 90 95 Leu Asn Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 260 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 260 Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Ser Gly Ser Asn Ile Gly Asn Asn Tyr Val 20 25 30 Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 35 40 45 Gln Asp Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Leu Val Trp Asp Arg Ser Ser Asp His 85 90 95 Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 261 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 261 Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Ser Asp Asn Asn Ile Gly Ser Lys Ser Val 20 25 30 His Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr 35 40 45 Asp Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Asp Ser Leu Ser Gly 85 90 95 Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 262 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 262 Ser Tyr Glu Leu Thr Gln Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Ser Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Asn Tyr Leu 20 25 30 Gly Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr 35 40 45 Thr Ala Ser Ser Leu Gln Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gly Tyr Ser Thr Pro Ser Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 263 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 263 Ser Tyr Glu Leu Thr Gln Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Ser Ile Thr Cys His Ala Ser Gln Gly Ile Ser Asn Tyr Val 20 25 30 Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr 35 40 45 Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Leu Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 264 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 264 Ser Tyr Glu Leu Thr Gln Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Ser Ile Thr Cys Arg Val Ser Gln Ser Ile Ser Ser Ser Tyr Leu 20 25 30 Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr 35 40 45 Asp Ala Ser His Arg Ala Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Gln Tyr Tyr Ala Pro Ser Val Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 265 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 265 Ser Tyr Glu Leu Thr Gln Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Ser Ile Thr Cys Ser Gly Ser Thr Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val 35 40 45 Ile Tyr Gly Lys Asn Ile Arg Pro Asn Gly Ile Pro Glu Arg Phe Ser 50 55 60 Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln 65 70 75 80 Ala Met Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu 85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 266 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 266 Ser Tyr Glu Leu Thr Gln Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Ser Ile Thr Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val 35 40 45 Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser 50 55 60 Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln 65 70 75 80 Ala Met Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 267 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 267 Ser Tyr Glu Leu Thr Gln Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Ser Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr 35 40 45 Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn Val 85 90 95 Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 268 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 268 Ser Tyr Glu Leu Thr Gln Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Ser Ile Thr Cys Thr Gly Thr Ser Ser Asp Ile Gly Arg Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu 35 40 45 Val Ile Tyr Arg Asn Thr Gln Arg Pro Ser Gly Ile Pro Glu Arg Phe 50 55 60 Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr 65 70 75 80 Gln Ala Met Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser 85 90 95 Leu Asn Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 269 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 269 Ser Tyr Glu Leu Thr Gln Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Ser Ile Thr Cys Ser Gly Ser Asn Ile Gly Asn Asn Tyr Val 20 25 30 Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr 35 40 45 Gln Asp Ser Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Leu Val Trp Asp Arg Ser Ser Asp His 85 90 95 Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 270 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 270 Ser Tyr Glu Leu Thr Gln Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Ser Ile Thr Cys Ser Asp Asn Asn Ile Gly Ser Lys Ser Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr 35 40 45 Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Asp Ser Leu Ser Gly 85 90 95 Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 271 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 271 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 Gly Asn Tyr 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Thr 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 Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ser Thr Pro Ser 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 272 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 272 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 His Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 273 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 273 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 Val Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser His Arg Ala Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ala Pro Ser Val 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 274 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 274 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 Ser Gly Ser Thr Ser Asn Ile Gly Ser 20 25 30 Asn Thr Val Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Lys Asn Ile Arg Pro Asn Gly Val Pro Ser Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu 65 70 75 80 Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 275 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 275 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 Ser Gly Ser Ser Ser Asn Ile Gly Ser 20 25 30 Asn Tyr Val Tyr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Ser Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu 65 70 75 80 Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gly Thr Trp Asp Ser Ser 85 90 95 Leu Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 276 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 276 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 Gly Gly Asn Asn Ile Gly Ser Lys Ser 20 25 30 Val His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Asn Asn Lys Arg Pro Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn 85 90 95 Val Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 277 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 277 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 Thr Gly Thr Ser Ser Asp Ile Gly Arg 20 25 30 Tyr Asn Tyr Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys 35 40 45 Leu Leu Ile Tyr Arg Asn Thr Gln Arg Pro Ser Gly Val Pro Ser Arg 50 55 60 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser 65 70 75 80 Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gly Thr Trp Asp Ser 85 90 95 Ser Leu Asn Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 278 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 278 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 Ser Gly Ser Asn Ile Gly Asn Asn Tyr 20 25 30 Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Gln Asp Ser Lys Arg Pro Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Val Trp Asp Arg Ser Ser Asp 85 90 95 His Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 279 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 279 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 Ser Asp Asn Asn Ile Gly Ser Lys Ser 20 25 30 Val His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Asn Asn Lys Arg Pro Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gly Thr Trp Asp Asp Ser Leu Ser 85 90 95 Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 280 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 280 Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Asn Tyr 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Thr Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ser Thr Pro Ser 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 281 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 281 Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys His Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 282 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 282 Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Val Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser His Arg Ala Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ala Pro Ser Val 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 283 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 283 Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Gly Ser Thr Ser Asn Ile Gly Ser 20 25 30 Asn Thr Val Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Lys Asn Ile Arg Pro Asn Gly Val Pro Ser Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 65 70 75 80 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 284 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 284 Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser 20 25 30 Asn Tyr Val Tyr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Ser Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 65 70 75 80 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Thr Trp Asp Ser Ser 85 90 95 Leu Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 285 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 285 Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser 20 25 30 Val His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Asn Asn Lys Arg Pro Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn 85 90 95 Val Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 286 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 286 Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Thr Gly Thr Ser Ser Asp Ile Gly Arg 20 25 30 Tyr Asn Tyr Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys 35 40 45 Leu Leu Ile Tyr Arg Asn Thr Gln Arg Pro Ser Gly Val Pro Ser Arg 50 55 60 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser 65 70 75 80 Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Thr Trp Asp Ser 85 90 95 Ser Leu Asn Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 287 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 287 Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Gly Ser Asn Ile Gly Asn Asn Tyr 20 25 30 Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Gln Asp Ser Lys Arg Pro Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Val Trp Asp Arg Ser Ser Asp 85 90 95 His Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 288 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 288 Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Asp Asn Asn Ile Gly Ser Lys Ser 20 25 30 Val His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Asn Asn Lys Arg Pro Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Thr Trp Asp Asp Ser Leu Ser 85 90 95 Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 289 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 289 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ala Ser Gln Gly Ile Gly Asn Tyr 20 25 30 Leu Gly Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile 35 40 45 Tyr Thr Ala Ser Ser Leu Gln Ser Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala 65 70 75 80 Glu Asp Val Gly Val Tyr Tyr Cys Gln Gin Gly Tyr Ser Thr Pro Ser 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 290 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 290 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys His Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30 Val Ala Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala 65 70 75 80 Glu Asp Val Gly Val Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 291 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 291 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Val Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile 35 40 45 Tyr Asp Ala Ser His Arg Ala Thr Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala 65 70 75 80 Glu Asp Val Gly Val Tyr Tyr Cys Gln Gln Tyr Tyr Ala Pro Ser Val 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 292 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 292 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Ser Gly Ser Thr Ser Asn Ile Gly Ser 20 25 30 Asn Thr Val Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu 35 40 45 Leu Ile Tyr Gly Lys Asn Ile Arg Pro Asn Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val 65 70 75 80 Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 293 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 293 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser 20 25 30 Asn Tyr Val Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu 35 40 45 Leu Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val 65 70 75 80 Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Thr Trp Asp Ser Ser 85 90 95 Leu Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 294 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 294 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser 20 25 30 Val His Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile 35 40 45 Tyr Asp Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala 65 70 75 80 Glu Asp Val Gly Val Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn 85 90 95 Val Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 295 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 295 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Arg 20 25 30 Tyr Asn Tyr Val Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln 35 40 45 Leu Leu Ile Tyr Arg Asn Thr Gln Arg Pro Ser Gly Val Pro Asp Arg 50 55 60 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg 65 70 75 80 Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gly Thr Trp Asp Ser 85 90 95 Ser Leu Asn Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 296 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 296 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Ser Gly Ser Asn Ile Gly Asn Asn Tyr 20 25 30 Val Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile 35 40 45 Tyr Gln Asp Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala 65 70 75 80 Glu Asp Val Gly Val Tyr Tyr Cys Leu Val Trp Asp Arg Ser Ser Asp 85 90 95 His Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 297 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 297 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Ser Asp Asn Asn Ile Gly Ser Lys Ser 20 25 30 Val His Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile 35 40 45 Tyr Asp Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala 65 70 75 80 Glu Asp Val Gly Val Tyr Tyr Cys Gly Thr Trp Asp Asp Ser Leu Ser 85 90 95 Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 298 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 298 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Gly Ile Gly Asn Tyr 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Thr Ala Ser Ser Leu Gln Ser Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Tyr Ser Thr Pro Ser 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 299 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 299 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys His Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30 Val 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 Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 300 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 300 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Val Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser His Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr Ala Pro Ser Val 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 301 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 301 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Ser Gly Ser Thr Ser Asn Ile Gly Ser 20 25 30 Asn Thr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu 35 40 45 Leu Ile Tyr Gly Lys Asn Ile Arg Pro Asn Gly Ile Pro Ala Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu 65 70 75 80 Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 302 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 302 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser 20 25 30 Asn Tyr Val Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu 35 40 45 Leu Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Ile Pro Ala Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu 65 70 75 80 Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gly Thr Trp Asp Ser Ser 85 90 95 Leu Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 303 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 303 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser 20 25 30 Val His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn 85 90 95 Val Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 304 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 304 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Arg 20 25 30 Tyr Asn Tyr Val Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg 35 40 45 Leu Leu Ile Tyr Arg Asn Thr Gln Arg Pro Ser Gly Ile Pro Ala Arg 50 55 60 Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser 65 70 75 80 Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gly Thr Trp Asp Ser 85 90 95 Ser Leu Asn Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 305 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 305 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Ser Gly Ser Asn Ile Gly Asn Asn Tyr 20 25 30 Val Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gln Asp Ser Lys Arg Pro Ser Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Leu Val Trp Asp Arg Ser Ser Asp 85 90 95 His Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 306 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 306 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Ser Asp Asn Asn Ile Gly Ser Lys Ser 20 25 30 Val His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gly Thr Trp Asp Asp Ser Leu Ser 85 90 95 Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 307 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 307 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 Gly Ile Gly Asn Tyr 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Thr Ala Ser Ser Leu Gln Ser Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Tyr Ser Thr Pro Ser 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 308 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 308 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 His Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30 Val 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 Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 309 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 309 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 Val Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser His Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr Ala Pro Ser Val 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 310 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 310 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 Ser Gly Ser Thr Ser Asn Ile Gly Ser 20 25 30 Asn Thr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu 35 40 45 Leu Ile Tyr Gly Lys Asn Ile Arg Pro Asn Gly Ile Pro Asp Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu 65 70 75 80 Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 311 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 311 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 Ser Gly Ser Ser Ser Asn Ile Gly Ser 20 25 30 Asn Tyr Val Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu 35 40 45 Leu Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu 65 70 75 80 Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gly Thr Trp Asp Ser Ser 85 90 95 Leu Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 312 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 312 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 Gly Gly Asn Asn Ile Gly Ser Lys Ser 20 25 30 Val His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn 85 90 95 Val Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 313 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 313 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 Thr Gly Thr Ser Ser Asp Ile Gly Arg 20 25 30 Tyr Asn Tyr Val Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg 35 40 45 Leu Leu Ile Tyr Arg Asn Thr Gln Arg Pro Ser Gly Ile Pro Asp Arg 50 55 60 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg 65 70 75 80 Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gly Thr Trp Asp Ser 85 90 95 Ser Leu Asn Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 314 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 314 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 Ser Gly Ser Asn Ile Gly Asn Asn Tyr 20 25 30 Val Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gln Asp Ser Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Leu Val Trp Asp Arg Ser Ser Asp 85 90 95 His Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 315 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 315 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 Ser Asp Asn Asn Ile Gly Ser Lys Ser 20 25 30 Val His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gly Thr Trp Asp Asp Ser Leu Ser 85 90 95 Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 316 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 316 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 Gly Ile Gly Asn Tyr 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Thr Ala Ser Ser Leu Gln Ser Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser His Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Tyr Ser Thr Pro Ser 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 317 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 317 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 His Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30 Val 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 Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser His Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 318 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 318 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 Val Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser His Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser His Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr Ala Pro Ser Val 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 319 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 319 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 Ser Gly Ser Thr Ser Asn Ile Gly Ser 20 25 30 Asn Thr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu 35 40 45 Leu Ile Tyr Gly Lys Asn Ile Arg Pro Asn Gly Ile Pro Asp Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser His Leu 65 70 75 80 Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 320 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 320 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 Ser Gly Ser Ser Ser Asn Ile Gly Ser 20 25 30 Asn Tyr Val Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu 35 40 45 Leu Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser His Leu 65 70 75 80 Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gly Thr Trp Asp Ser Ser 85 90 95 Leu Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 321 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 321 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 Gly Gly Asn Asn Ile Gly Ser Lys Ser 20 25 30 Val His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser His Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn 85 90 95 Val Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 322 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 322 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 Thr Gly Thr Ser Ser Asp Ile Gly Arg 20 25 30 Tyr Asn Tyr Val Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg 35 40 45 Leu Leu Ile Tyr Arg Asn Thr Gln Arg Pro Ser Gly Ile Pro Asp Arg 50 55 60 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser His 65 70 75 80 Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gly Thr Trp Asp Ser 85 90 95 Ser Leu Asn Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 323 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 323 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 Ser Gly Ser Asn Ile Gly Asn Asn Tyr 20 25 30 Val Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gln Asp Ser Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser His Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Leu Val Trp Asp Arg Ser Ser Asp 85 90 95 His Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 324 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 324 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 Ser Asp Asn Asn Ile Gly Ser Lys Ser 20 25 30 Val His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser His Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gly Thr Trp Asp Asp Ser Leu Ser 85 90 95 Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 325 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 325 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Gln Gly Ile Gly Asn Tyr 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Thr Ala Ser Ser Leu Gln Ser Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 65 70 75 80 Glu Asp Val Ala Val Tyr Tyr Cys Gln Gly Tyr Ser Thr Pro Ser 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 326 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 326 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys His Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 65 70 75 80 Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Leu Leu 85 90 95 Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys 100 105 <210> 327 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 327 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Arg Val Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser His Arg Ala Thr Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 65 70 75 80 Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr Ala Pro Ser Val 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 328 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 328 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Ser Gly Ser Thr Ser Asn Ile Gly Ser 20 25 30 Asn Thr Val Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Lys Asn Ile Arg Pro Asn Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 65 70 75 80 Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 329 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 329 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser 20 25 30 Asn Tyr Val Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu 35 40 45 Leu Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 65 70 75 80 Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gly Thr Trp Asp Ser Ser 85 90 95 Leu Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 330 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 330 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser 20 25 30 Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 65 70 75 80 Glu Asp Val Ala Val Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn 85 90 95 Val Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 331 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 331 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Thr Gly Thr Ser Ser Asp Ile Gly Arg 20 25 30 Tyr Asn Tyr Val Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys 35 40 45 Leu Leu Ile Tyr Arg Asn Thr Gln Arg Pro Ser Gly Val Pro Asp Arg 50 55 60 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser 65 70 75 80 Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gly Thr Trp Asp Ser 85 90 95 Ser Leu Asn Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <210> 332 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 332 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Ser Gly Ser Asn Ile Gly Asn Asn Tyr 20 25 30 Val Ser Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Gln Asp Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 65 70 75 80 Glu Asp Val Ala Val Tyr Tyr Cys Leu Val Trp Asp Arg Ser Ser Asp 85 90 95 His Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 333 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 333 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Ser Asp Asn Asn Ile Gly Ser Lys Ser 20 25 30 Val His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 65 70 75 80 Glu Asp Val Ala Val Tyr Tyr Cys Gly Thr Trp Asp Asp Ser Leu Ser 85 90 95 Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 334 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> VH_FR4 <400> 334 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> 335 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> VL_FR4 <400> 335 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 1 5 10 <210> 336 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> VL_FR4 <400> 336 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 1 5 10

Claims (15)

B7-H3 antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising the following HCDR and a light chain variable region comprising the following LCDR:
(a) HCDRs of SEQ ID NOs: 1, 10 and 19 and LCDRs of SEQ ID NOs: 28, 37 and 45;
(b) HCDRs of SEQ ID NOs: 2, 11 and 20 and LCDRs of SEQ ID NOs: 29, 38 and 46;
(c) the HCDRs of SEQ ID NOs: 3, 12 and 21 and the LCDRs of SEQ ID NOs: 30, 39 and 47;
(d) HCDRs of SEQ ID NOs: 4, 13 and 22 and LCDRs of SEQ ID NOs: 31, 40 and 48;
(e) HCDRs of SEQ ID NOs: 5, 14 and 23 and LCDRs of SEQ ID NOs: 32, 41 and 49;
(f) HCDRs of SEQ ID NOs: 6, 15 and 24 and LCDRs of SEQ ID NOs: 33, 42 and 50;
(g) HCDRs of SEQ ID NOs: 7, 16 and 25 and LCDRs of SEQ ID NOs: 34, 43 and 51;
(h) HCDRs of SEQ ID NOs: 8, 17 and 26 and LCDRs of SEQ ID NOs: 35, 44 and 52; or
(i) HCDRs of SEQ ID NOs: 9, 18 and 27 and LCDRs of SEQ ID NOs: 36, 42 and 53.
The method according to claim 1, wherein the heavy chain variable region comprises any one framework sequence selected from the group consisting of the following HFR, B7-H3 antibody or antigen-binding fragment thereof:
(hf1) HFRs of SEQ ID NOs: 54, 63, 68 and 334;
(hf2) HFRs of SEQ ID NOs: 55, 63, 69 and 334;
(hf3) HFRs of SEQ ID NOs: 56, 64, 70 and 334;
(hf4) HFRs of SEQ ID NOs: 56, 64, 71 and 334;
(hf5) HFRs of SEQ ID NOs: 57, 64, 70 and 334;
(hf6) HFRs of SEQ ID NOs: 58, 64, 72 and 334;
(hf7) HFRs of SEQ ID NOs: 59, 65, 73 and 334;
(hf8) HFRs of SEQ ID NOs: 60, 65, 73 and 334;
(hf9) HFRs of SEQ ID NOs: 61, 66, 74 and 334; and
(hf10) HFRs of SEQ ID NOs: 62, 67, 75 and 334.
The method according to claim 1, wherein the light chain variable region comprises any one framework sequence selected from the group consisting of the following LFR, B7-H3 antibody or antigen-binding fragment thereof:
(lf1) LFR of SEQ ID NOs: 76, 82, 86 and 335;
(lf2) LFR of SEQ ID NOs: 77, 82, 87 and 335;
(lf3) LFR of SEQ ID NOs: 78, 83, 88 and 335;
(lf4) LFR of SEQ ID NOs: 79, 84, 89 and 335;
(lf5) LFR of SEQ ID NOs: 80, 84, 90 and 335;
(lf6) LFR of SEQ ID NOs: 80, 84, 91 and 335;
(lf7) LFR of SEQ ID NOs: 81, 85, 92 and 335;
(lf8) LFR of SEQ ID NOs: 93, 98, 101 and 336;
(lf9) LFR of SEQ ID NOs: 93, 98, 102 and 336;
(lf10) LFR of SEQ ID NOs: 93, 98, 103 and 336;
(lf11) LFR of SEQ ID NOs: 93, 98, 104 and 336;
(lf12) LFR of SEQ ID NOs: 94, 98, 105 and 336;
(lf13) LFR of SEQ ID NOs: 95, 99, 106 and 336;
(lf14) LFR of SEQ ID NOs: 96, 99, 107 and 336; and
(lf15) LFR of SEQ ID NOs: 97, 100, 108 and 336.
The method according to claim 1, wherein the heavy chain variable region is any one selected from the group consisting of SEQ ID NOs: 127, 128, 129, 130, 131, 132, 135, 142 and 152 B7-H3 antibody or antigen-binding fragment thereof.
The method according to claim 1, wherein the light chain variable region is any one selected from the group consisting of SEQ ID NOs: 211, 221, 223, 224, 225, 231, 307, 309 and 317 B7-H3 antibody or antigen-binding fragment thereof.
A gene encoding the B7-H3 antibody or antigen-binding fragment thereof according to any one of claims 1 to 5.
A cell into which the vector into which the gene of claim 6 is inserted has been introduced.
A method for producing a B7-H3 antibody or antigen-binding fragment thereof comprising culturing the cell of claim 7.
A pharmaceutical composition for the treatment or prevention of cancer comprising the B7-H3 antibody or antigen-binding fragment thereof of any one of claims 1 to 5.
The method according to claim 9, wherein the cancer is lung cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, glioma, neuroblastoma, prostate cancer, pancreatic cancer, colorectal cancer, colon cancer, head and neck cancer, leukemia, lymphoma, kidney cancer, bladder cancer, stomach cancer, Liver cancer, skin cancer, brain tumor, cerebrospinal cancer, adrenal tumor, melanoma, sarcoma, multiple myeloma, neuroendocrine tumor, peripheral nerve sheath tumor and any one selected from the group consisting of small cell tumor, a pharmaceutical composition for the treatment or prevention of cancer .
A method of treating cancer comprising administering to a subject the B7-H3 antibody or antigen-binding fragment thereof of any one of claims 1 to 5, or a gene encoding the same.
The method according to claim 11, wherein the cancer is lung cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, glioma, neuroblastoma, prostate cancer, pancreatic cancer, colorectal cancer, colon cancer, head and neck cancer, leukemia, lymphoma, kidney cancer, bladder cancer, stomach cancer, A method of treating cancer, which is any one selected from the group consisting of liver cancer, skin cancer, brain tumor, cerebrospinal cancer, adrenal tumor, melanoma, sarcoma, multiple myeloma, neuroendocrine tumor, peripheral nerve sheath tumor, and small cell tumor.
The B7-H3 antibody or antigen-binding fragment thereof according to any one of claims 1 to 5 for use as a medicament.
The method according to claim 13, wherein the drug is an anti-cancer agent according to any one of claims 1 to 5, B7-H3 antibody or antigen-binding fragment thereof.
The method according to claim 13, wherein the cancer is lung cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, glioma, neuroblastoma, prostate cancer, pancreatic cancer, colorectal cancer, colon cancer, head and neck cancer, leukemia, lymphoma, kidney cancer, bladder cancer, stomach cancer, Any one selected from the group consisting of liver cancer, skin cancer, brain tumor, cerebrospinal cancer, adrenal tumor, melanoma, sarcoma, multiple myeloma, nervous system endocrine tumor, peripheral nerve sheath tumor, and small cell tumor of any one of claims 1 to 5 B7-H3 antibody or antigen-binding fragment thereof.

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