KR102338678B1 - Biomarker for predicting effect of an anti-c-Met antibody - Google Patents

Abstract

A biomarker for predicting anti-c-Met antibody drug efficacy and/or selection of an anti-c-Met antibody application target, a reference marker for comparing gene expression levels, and c-Met comprising measuring the level of the biomarker in a biological sample Provided are a method for predicting antibody efficacy and/or a method for screening a subject to which an anti-c-Met antibody is applied, and a method for preventing and/or treating cancer comprising administering an anti-c-Met antibody to the selected subject.

Description

Biomarker for predicting effect of an anti-c-Met antibody

A biomarker for predicting anti-c-Met antibody drug efficacy and/or selection of an anti-c-Met antibody application target, a reference marker for comparing gene expression levels, and c-Met comprising measuring the level of the biomarker in a biological sample Provided are a method for predicting antibody efficacy and/or a method for screening a subject to which an anti-c-Met antibody is applied, and a method for preventing and/or treating cancer comprising administering an anti-c-Met antibody to the selected subject.

Since Genentech's FDA approval of Herceptin-targeted therapy in 1998, various methods of personalized medicine have been introduced, and attempts to develop a screening marker for patients with indications are increasing. In the case of Herceptin, patients are selected based on the expression level of HER2 growth factor receptor expressed on the cell membrane of cancer cells. After the IHC (immunohistochemistry) test method, ICH techniques such as FISH (fluorescence in situ hybridization) and CISH (chromogenic in situ hybridization) A variety of techniques have been introduced for patient screening, including Subsequently, Erlotinib (Tarceva, Genentech)'s EGFR mutation as a selectable marker for lung & pancreatic cancer, and Vectibix and Erbitux's KRAS mutation as a selectable marker for colorectal cancer were approved, and in 2011, these companion diagnostic devices FDA guidelines for concurrent approval have been published.

For anticancer drugs that target c-Met protein, research on markers for selecting patients who can exhibit good efficacy is currently underway. Among the new c-Met targeting drugs, Genentech's metmab is in clinical phase III, and c-Met protein overexpression was detected using ventana IHC assay (sp44: c-met primary antibody, rabbit monoclonal) as a companion diagnostic method. application is in progress. Using the above diagnostic method, a meaningful difference was obtained for the group of patients administered in combination with erlotinib, and based on this, the Ventana assay is used as a diagnostic tool in phase 3 clinical trials. However, if other samples are tested in this way, accurate results may not be obtained, so there is a limit to being used as a general diagnostic tool.

In addition, the IHC method has a disadvantage in that the result value is not constant depending on individual differences of the experimenter, the lesion site, the tendency of the pathologist, and the like.

In order to further enhance the efficacy of treatment using the c-Met target anticancer agent, the development of a biomarker for predicting the efficacy of the target anticancer agent and/or the selection of a patient suitable for the application of the drug and the development of a drug efficacy prediction technology are required.

An example of the present invention provides a biomarker for predicting the efficacy of an anti-c-Met antibody and/or selecting an application target for the anti-c-Met antibody.

Another example provides a composition and kit for predicting the efficacy of an anti-c-Met antibody and/or selecting a target to which the anti-c-Met antibody is applied, including a means for detecting the biomarker.

Another example provides a reference marker for predicting the efficacy of the anti-c-Met antibody and/or comparing the level of the biomarker for selecting a target for applying the anti-c-Met antibody.

Another example provides a method of predicting the efficacy of an anti-c-Met antibody and/or selecting a subject to which the anti-c-Met antibody is applied, comprising measuring the presence and/or level of the biomarker in a biological sample .

Another example provides a method for preventing and/or treating cancer, comprising administering an anti-c-Met antibody to the selected anti-c-Met antibody-applied subject.

Another example provides a method for inhibiting c-Met comprising administering an anti-c-Met antibody to the selected anti-c-Met antibody-applied subject.

By comparing the gene expression levels of the group showing an effect (efficacy group) and the group showing no effect (non-efficacy group) for the anti-c-Met antibody, genes with large differences are selected, and the selected gene or encoded by it This protein is proposed as a biomarker for predicting the efficacy of anti-c-Met antibody. In addition, when comparing the expression level of the target gene and/or the target protein with the selected gene or the protein encoded by the selected gene or by selecting a gene with little or no difference in expression level in individual cells depending on the cell type or even in the same type of cell It is proposed as a reference marker that can be used as a control of

Specifically, an example is a biomarker for predicting the efficacy of anti-c-Met antibody and/or selecting an application target for anti-c-Met antibody of a gene showing a difference in expression in an efficacious group and a non-effective group for the anti-c-Met antibody. provide use.

In one example, the biomarker may be one or more selected from the group consisting of THSD7A, MET, RAB31, FAM126A, PHC1, CHML, ST8SIA4, and CAV1. The biomarker may be at least one selected from the group consisting of full-length DNA, cDNA, mRNA, and a protein encoded by the above-described gene. Genes that can be used as biomarkers are summarized in Table 1 below:

gene name Entrez Gene Name NCBI Accession No. (mRNA) THSD7A thrombospondin, type I, domain containing 7A NM_015204 MET met proto-oncogene (hepatocyte growth factor receptor) NM_001127500.1, NM_000245.2 RAB31 RAB31, member RAS oncogene family NM_006868.3 FAM126A family with sequence similarity 126, member A NM_032581.3 PHC1 polyhomeotic homolog 1 (Drosophila) NM_004426.2 CHML choroideremia-like (Rab escort protein 2) NM_001821.3 ST8SIA4 ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 4 NM_005668.5 CAV1 caveolin 1, caveolae protein, 22 kDa NM_001753.4, NM_001172895.1, NM_001172896.1, NM_001172897.1

The biomarkers are THSD7A, MET, RAB31, FAM126A, PHC1, CHML, ST8SIA4, and CAV1 if the biomarkers are listed in descending order from the greatest difference in expression in the efficacy group and the non-efficacy group. In order to more accurately predict efficacy or select an application target, a biomarker having a large difference in expression between the efficacious group and the non-effective group may be preferentially selected and used as the biomarker. Accordingly, in one example, the biomarker may further include one or more selected from the group consisting of the remaining genes in addition to the preferentially selected gene.

In one embodiment, the biomarker is

THSD7A;

a combination of THSD7A with one or more selected from the group consisting of MET, RAB31, FAM126A, PHC1, CHML, ST8SIA4, and CAV1;

MET;

a combination of MET with one or more selected from the group consisting of THSD7A, RAB31, FAM126A, PHC1, CHML, ST8SIA4, and CAV1;

combination of THSD7A and MET;

a combination of THSD7A and MET with one or more selected from the group consisting of RAB31, FAM126A, PHC1, CHML, ST8SIA4, and CAV1;

RAB31;

a combination of RAB31 with one or more selected from the group consisting of THSD7A, MET, FAM126A, PHC1, CHML, ST8SIA4, and CAV1;

THSD7A, MET, and two or more selected from the group consisting of RAB31 (in this case, a combination of THSD7A and MET may be excluded);

a combination of two or more selected from the group consisting of THSD7A, MET, and RAB31, and one or more selected from the group consisting of FAM126A, PHC1, CHML, ST8SIA4, and CAV1;

FAM126A;

a combination of FAM126A with one or more selected from the group consisting of THSD7A, MET, RAB31, PHC1, CHML, ST8SIA4, and CAV1;

THSD7A, MET, two or more selected from the group consisting of RAB31 and FAM126A (in this case, two or more selected from the group consisting of THSD7A, MET, and RAB31 may be excluded); or

Combination of two or more selected from the group consisting of THSD7A, MET, RAB31 and FAM126A, and at least one selected from the group consisting of PHC1, CHML, ST8SIA4, and CAV1

may include.

Another example is a comparison standard ( It provides use as a reference marker (control gene) for use as a reference, control). The target gene may be any gene whose expression level is to be measured. For example, the target gene may be a biomarker for predicting the efficacy of the previously selected anti-c-Met antibody and/or selecting an application target for the anti-c-Met antibody. / or it may be used as a comparison standard for measuring the expression level of a target gene when selecting an application target for the anti-c-Met antibody.

In measuring the gene expression level of a target gene, it is difficult to accurately measure the expression level of the target gene if the expression level in each cell is different even if the gene serving as a reference or control is a cell type or the same type of cell. Therefore, it is important to select an appropriate reference marker to accurately measure the expression level of the target gene.

In one example, the reference marker may be selected from endogenous genes essential for cell survival. For example, the reference marker may be one or more selected from the group consisting of EEF1A1, RPL23A, TPT1, HUWE1, MATR3, SRSF3, HNRNPC, SMARCA4, WDR90, and TUT1. In one example, since the expression levels of RPL23A, TPT1, MATR3, SRSF3, and HNRNPC are kept very constant (see Example 1), the reference marker is one selected from the group consisting of RPL23A, TPT1, MATR3, SRSF3, and HNRNPC. Including the above, and optionally may further include one or more selected from the group consisting of EEF1A1, HUWE1, SMARCA4, WDR90, and TUT1. In one embodiment, the reference marker may include RPL23A, TPT1, MATR3, SRSF3, and HNRNPC. In another example, the reference marker may include TPT1, EEF1M, TUT1, MATR3, and SMARCA4.

The reference marker may be one or more selected from the group consisting of full-length DNA, cDNA, mRNA, and a protein encoded by the above-described gene. In this case, the test target cell may be lung cancer cells, for example, lung cancer adenocarcinoma, non-small cell lung cancer, etc., but is not limited thereto. Genes that can be used as reference markers are summarized in Table 2 below:

gene name NCBI Accession No. (mRNA) EEF1A1 NM_001402.5 RPL23A NM_000984.5 TPT1 NM_001286272.1, NM_003295.3, NM_001286273.1 HUWE1 NM_031407.6 MATR3 NM_199189.2, NM_018834.5, NM_001194954.1, NM_001194955.1, NM_001194956.1, NM_001282278.1 SRSF3 NM_003017.4, NR_036610.1 HNRNC NM_031314.2, NM_001077442.1, NM_004500.3, NM_001077443.1 SMARCA4 NM_001128849.1, NM_001128844.1, NM_003072.3, NM_001128845.1, NM_001128846.1, NM_001128847.1, NM_001128848.1 WDR90 NM_145294.4 TUT1 NM_022830.2

Another example provides a method for measuring (evaluating or determining) a target gene expression level, characterized in that the reference marker is used as a comparison standard in the method for measuring the gene expression level. The measurement (evaluation or determination) of the target gene expression level may be performed on a cell or tissue isolated from a living body, or a gene (DNA or RNA) or protein extracted therefrom. The gene expression level can be measured by quantifying the gene itself (eg, full-length DNA, cDNA, mRNA, etc.) or a protein encoded from the gene.

Another example provides a composition for predicting the effect of an anti-c-Met antibody (or sensitivity or reactivity to the anti-c-Met antibody) and/or selecting an application target for the anti-c-Met antibody, comprising a means for detecting the biomarker . The composition for predicting the anti-c-Met antibody effect (or sensitivity or reactivity to the anti-c-Met antibody) and/or selecting the target for application of the anti-c-Met antibody may further include a means for detecting the reference marker. have.

Another example provides a kit for predicting the anti-c-Met antibody effect (or sensitivity or reactivity to the anti-c-Met antibody) and/or selecting a target for applying the anti-c-Met antibody, which includes a means for detecting the biomarker. The anti-c-Met antibody effect (or sensitivity or reactivity to the anti-c-Met antibody) prediction and/or the anti-c-Met antibody application target selection kit may further include a means for detecting the reference marker. .

Another example provides a reference marker composition for measuring the target gene expression level or a kit for measuring the target gene expression level, which includes a means for detecting the reference marker. In one embodiment, when the target gene is the above-described biomarker, anti-c-Met antibody effect (or sensitivity or reactivity to anti-c-Met antibody) prediction and/or anti-c including a means for detecting the reference marker A kit is provided for the selection of an application target of the -Met antibody.

The biomarker detection means or reference marker detection means is the biomarker gene (full-length DNA, cDNA, or mRNA) or reference marker gene (full-length DNA, cDNA, or mRNA) or a protein encoded by these genes. It may be a means used for a phosphorus gene quantification or a protein quantification method. For example, the means for detecting the biomarker or the means for detecting the reference marker include a primer, probe, and/or pressure that specifically binds (hybridizes) to a gene (full-length DNA, cDNA, or mRNA) of the biomarker or reference marker. tamer; or antibodies and/or aptamers that specifically bind to the protein they encode; Or it may be a combination thereof. The primer is the entire gene (full-length DNA, cDNA, or mRNA) of the biomarker gene or reference marker, or 5 to 1000 bp contiguous among the entire gene nucleotide sequence, such as 10 to 500 bp, 20 to 200 bp , or as capable of detecting a gene fragment of 50 to 200 bp, each successive 5 to 100 bp of the 3'-end or 5'-end of the gene fragment, such as 5 to 50 bp, 5 to 30 bp, or 10 to 25 bp The probe may have a nucleotide sequence capable of hybridizing with the site (eg, complementary), and the probe may be 5 to 100 bp continuous among nucleotide sequences of the biomarker gene or reference marker gene (full-length DNA, cDNA, or mRNA), such as, 5 to 50 bp, 5 to 30 bp, or 10 to 25 bp may have a hybridizable (eg, complementary) nucleotide sequence.

In one embodiment, the probes or primers usable for detection of the biomarker or reference marker are shown in Tables 3 to 5 below.

Gene Probe Sequence (5'-3') THSD7A CCTCTTGAACTTGCGTGCCTG (SEQ ID NO: 109) MET CTTCACTTCGCAGGCAGATTCC (SEQ ID NO: 143) RAB31 ATACGCTGAATCCATAGGTGCCA (SEQ ID NO: 155) FAM126A TCTCTGCTGACCTGATTGATGCT (SEQ ID NO: 178) PHC1 ACCTCCTCACCTGTTGTAGCC (SEQ ID NO: 201) ST8SIA4 ACTGCTCTTGACCACTGACACA (SEQ ID NO: 236) CHML CCTCTGGCTGCTTATCATCACC (SEQ ID NO: 213) CAV1 TAGATAACAAGACCTCAGTGCCTTCC (SEQ ID NO: 248) RPL23A ACTGGCTCCTGATTACGATGCTT (SEQ ID NO: 260) TPT1 CATAACTGGCTTCTGCTTGTCATCC (SEQ ID NO: 261) EEF1A1 CCAGCAGCAACAATCAGGACAG (SEQ ID NO: 262) SRSF3 TTCCACTCTTACACGGCAGC (SEQ ID NO: 263) TUT1 CCTGTGGTCAAGTTCTGTCATCG (SEQ ID NO: 264) HNRNC CTGCTGCTCTGCTCCTCTTCT (SEQ ID NO: 265) HUWE1 TCCTCTTCCTCCTCATCCTCACT (SEQ ID NO: 266) WDR90 TGGTCACTCAGCACACGGAA (SEQ ID NO: 267) MATR3 TGACCAGACAGAGGCAGGAACC (SEQ ID NO: 268) SMARCA4 CCTTCCTCATCATCGTGCCTCT (SEQ ID NO: 269)

Gene Probe Sequence(5'-3') THSD7A TTTTTAAGACTTCTTGTCTCTCTCC (SEQ ID NO: 110) AACGAGTCCTCAAGTTCAGTATTTT (SEQ ID NO: 111) TACAATACGTTTCTACTTTCCCTGA (SEQ ID NO: 112) TGATTTTCAAACTGGTTGCCTGCAT (SEQ ID NO: 113) GGAAGGCACATTTTTGCACTATATT (SEQ ID NO: 114) AGTGCAGCACGATAGGCGCTTAACC (SEQ ID NO: 115) TAGGCGCTTAACCAGTATTGCCATA (SEQ ID NO: 116) GTATTGCCATAGAAACTGCCTCTTT (SEQ ID NO: 117) AACTGCCTCTTTTCATGTGGGATGA (SEQ ID NO: 118) GACATTTGCAAGTTCTTGTATCCTG (SEQ ID NO: 119) GCTATTACACCTGCTGTACACACAC (SEQ ID NO: 120) THSD7A ACTTCTCTATTGACACTTTTACCTC (SEQ ID NO: 121) TGACACTTTTACCTCACCGAGGGGG (SEQ ID NO: 122) GAACTGCTGTTCCCTAGAATGAAGG (SEQ ID NO:123) AGAATGAAGGTCTGTTGTTTGGTTT (SEQ ID NO: 124) TTATATGATTTTGCTGGACTATTTC (SEQ ID NO: 125) GGACTATTTCACTAGAAACCACGTA (SEQ ID NO: 126) GAATAGGACTAACTGATCTCTTTTG (SEQ ID NO: 127) AAAGGGGCTGATTTGCTTATTCATC (SEQ ID NO: 128) ATGTGGACAGTAATCTTAATTTCAA (SEQ ID NO: 129) GAGGATACTACGGTGTAGCTTAAGT (SEQ ID NO: 130) AGCACAAATTACTTCTAACAAGGCA (SEQ ID NO: 131) THSD7A GTATTTTCCCCTACGTAATGTACAT (SEQ ID NO: 132) GTACATGTCTTTAGGCCACAGTATT (SEQ ID NO: 133) AGGTGGCAGTGGTCATTGTAGCTTA (SEQ ID NO: 134) TAATCAGACCCCTGTTAAGTTCCTG (SEQ ID NO: 135) CAAGGTAAATTCACGTCTTCCTTCT (SEQ ID NO: 136) AATAGACCTCTCACACACTTATTTA (SEQ ID NO: 137) GTCTCTTTCTACTCTTGACAGCTAT (SEQ ID NO: 138) CTTGACAGCTATTCTTACCTACTTC (SEQ ID NO: 139) TTCCCACTAAACATGCCCAATTTTT (SEQ ID NO: 140) TCCTATATTTCCTTCCCTATTAGAA (SEQ ID NO: 141) GAATCAAAGTGTCACTCACTCAGAG (SEQ ID NO: 142) MET GTTGTCGACACCTACTATGATGATC (SEQ ID NO: 144) CAGCGTCAACAGAGGGACCTGCCAG (SEQ ID NO: 145) TTTCCCCACAATCATACTGCTGACA (SEQ ID NO: 146) AGATAGAAGAGCCCAGCCAGTGTCC (SEQ ID NO: 147) GGAGCCAAAGTCCTTTCATCTGTAA (SEQ ID NO: 148) TAAAGGACCGGTTCATCAACTTCTT (SEQ ID NO: 149) ATTTCCCAGATCATCCATTGCATTC (SEQ ID NO: 150) ACGGACCAGTCCTACATTGATGTTT (SEQ ID NO: 151) GAGTTCAGAGATTCTTACCCCATTA (SEQ ID NO: 152) CTAGATGCTCAGACTTTTCACACAA (SEQ ID NO: 153) ATCAGGTTCTGTTCCATAAACTCTG (SEQ ID NO: 154) RAB31 AACATTGTAATGGCCATCGCTGGAA (SEQ ID NO: 156) GAAACAAGTGCGACCTCTCAGATAT (SEQ ID NO: 157) GGAGGTTCCCCTGAAGGATGCTAAG (SEQ ID NO: 158) TACGCTGAATCCATAGGTGCCATCG (SEQ ID NO: 159) GTGCCATCGTGGTTGAGACAAGTGC (SEQ ID NO: 160) TTCAAGGAATCAGCCGCCAGATCCC (SEQ ID NO: 161) TGAGAAGCCAACCATGCAAGCCAGC (SEQ ID NO: 162) CGTGGTCCACGGTACTTGAAGAAGC (SEQ ID NO: 163) ATCCTGTGCACTGCTGAAGGACCCT (SEQ ID NO: 164) GAGTGAGCACACTGGCTTTGCATCC (SEQ ID NO: 165) ACCACCACAAAAATGGCCTTTAGTGT (SEQ ID NO: 166) RAB31 GAATATGACGTTACCTTGCAGACTA (SEQ ID NO: 167) TTTTTTGTGTGGGCTCCAGTTCTCA (SEQ ID NO: 168) GTTCTGCAATGCTCATGGCAAGTTG (SEQ ID NO: 169) ACCGACTGGGTATCTAGCTTACTGT (SEQ ID NO: 170) ATCATTGTTGAAACCAGACCCTGTA (SEQ ID NO: 171) AGACCCTGTAGTCCAGTGGTGCTGC (SEQ ID NO: 172) TAAAGAGCTTCCATCTGGGCTGGAC (SEQ ID NO: 173) TGGACCCAGTTCTTGCACATACAAG (SEQ ID NO: 174) GCACATACAAGACACCGCTGCAGTC (SEQ ID NO: 175) ACCGCTGCAGTCAGCTAGGACCTTT (SEQ ID NO: 176) GGTTTAACACACACTGATTCATACT (SEQ ID NO: 177) FAM126A GACTTACTTTAACAACCAGCCAATC (SEQ ID NO: 179) AATCCCTACCTAAGCCTAGTAGCCA (SEQ ID NO: 180) GCCATGGTTTGGCTAAGACCGCAGC (SEQ ID NO: 181) GTCAGTGGTGTCACAGTCCCACATA (SEQ ID NO: 182) ACATAACCCGTCATCTGCTGTTGGT (SEQ ID NO: 183) GCCAATAGGTTTTCCGCTTGTAGTC (SEQ ID NO: 184) GCAGAGACCTCCTAGTATTAGCATT (SEQ ID NO: 185) TTTTCTCCCATAACCTAGTGAACCT (SEQ ID NO: 186) GAAAGTACCCTGGGTCTTTCATCCG (SEQ ID NO: 187) CTTTCATCCGTATTCCTGACAGGAG (SEQ ID NO: 188) GGAGCCCTGATGTCTTAAATTCTGA (SEQ ID NO: 189)
FAM126A CCCGGCTCGGAGCAAGCGGTGCAG (SEQ ID NO: 190) GGAGCGATTCCCATTCGAGGAGTTTT (SEQ ID NO: 191) TCTCATTTTAATACAACACCCGCCT (SEQ ID NO: 192) AACACCCGCCTCTTAGAGGCAGCAG (SEQ ID NO: 193) CAGACCAGTCCAGCCAGGTCAAGGT (SEQ ID NO: 194) TGTGGACCGCACAACGGGGTGCACA (SEQ ID NO: 195) TAAACGAGCCCTGGATCTGCAAAGC (SEQ ID NO: 196) GTGATCCCAACCTTAGCAACATAAT (SEQ ID NO: 197) TATATGTCAGGTGCCAGTGCTATGG (SEQ ID NO: 198) ATACCATTTATTACCACTTCTCAGT (SEQ ID NO: 199) GAGGCTGTAACTCTGGTTGTCGAAA (SEQ ID NO: 200) PHC1 TTTCACGTACCTTAATCCAATCTTT (SEQ ID NO: 202) AGAACTAGGACTGCTCAGCCTTATC (SEQ ID NO: 203) GCCCAGGTCTTAATTCTCCAAGAGG (SEQ ID NO: 204) GGTGGAATGTCAGGTTGCCTGCCCA (SEQ ID NO: 205) AGGGTTTTTCTAGCTTGTGTGACAG (SEQ ID NO: 206) TTGTCACTTACTCCCTTGTGATTGA (SEQ ID NO: 207) TGATTGAATTTTTTCTCCTGCATCC (SEQ ID NO: 208) AGAGACTTGGTTGGCATCTTCTGCT (SEQ ID NO: 209) GGCACATGTGGCTTGTTGTCATTCTT (SEQ ID NO: 210) TGTTCCCCTCCAATTTATGTTATTT (SEQ ID NO: 211) GTACCTGCCTTAGGCACTATTCCTT (SEQ ID NO: 212) CHML GCAACTTTGACTTAGTTCATGCTAT (SEQ ID NO: 214) CTGTTTTAATTGCATGTGTCCTTAT (SEQ ID NO: 215) GTGTCCTTATAGCAGGCAGCATTGTG (SEQ ID NO: 216) GCAGCATTGTGTATTAGTAGCCTTT (SEQ ID NO: 217) AGGGCTTTATAACTGATCTTTTGAC (SEQ ID NO: 218) GATCTTTTGACATACTCACTTTGAG (SEQ ID NO: 219) CACTTTGAGTGGCATATGCCCAGGA (SEQ ID NO: 220) AAGTTTTCTAGCAGTTCCACTCAGA (SEQ ID NO: 221) GTTCCACTCAGATAACTTTAAGGGG (SEQ ID NO: 222) TGGTGTATTGCTAGTGCTATCACAG (SEQ ID NO: 223) ATTGTGTTTACTGATACATGTGAAA (SEQ ID NO: 224) FAM126A TCTAGTCCTTTAATGAGCATGAATT (SEQ ID NO: 225) TATACTTCTACATTTGTTGCTTAGT (SEQ ID NO: 226) ATATTGTCTTCTATACTTTGTAACT (SEQ ID NO: 227) ATTTCACGTATTGTTGCTTTCTCTT (SEQ ID NO: 228) GTTGCTTTCTCTTATATGGAACTTA (SEQ ID NO: 229) GGAACTTATTGTGTACCTCTTACCT (SEQ ID NO: 230) GTATTCCTAGAGTTTACATTCCTAA (SEQ ID NO: 231) ACGACGACTTTGGCTATTTTTGTGT (SEQ ID NO: 232) GTTCCCTACCTTCTTAAGGCTATGG (SEQ ID NO: 233) ATTTGTGTAAATGTTCTCCATATGT (SEQ ID NO: 234) CAAGTGTTGCCTCTTGTTTTATTGA (SEQ ID NO: 235) ST8SIA4 TTTATTTTGCACGGCTCTAAACCTC (SEQ ID NO: 237) TAAACCTCCATGTTATTTTCCAGTG (SEQ ID NO: 238) GGTGTAGAAGGTACCAGCTAAAGTG (SEQ ID NO: 239) AGATGTTCCATGTCATCAGAGATGG (SEQ ID NO: 240) GGTACCAAAGATTACACTTGTGTTT (SEQ ID NO: 241) ACTTGTGTTTCTACACAGCAAACCA (SEQ ID NO: 242) GCTATTAATGTGAAAGTTGTCTCTA (SEQ ID NO: 243) ATGTTTTTCACACCTTTTGCATTAC (SEQ ID NO: 244) TTTTCACACCTTTTGCATTACATAA (SEQ ID NO: 245) AATTTTGTGGAAGCATTTTGCCCTT (SEQ ID NO: 246) GGAAGCATTTTGCCCTTTAGAATAA (SEQ ID NO: 247) CAV1 GAATTTCACCTGTAAACCTGAGTCG (SEQ ID NO: 249) CAGAAAGCTGCCTGGTATATCCAAA (SEQ ID NO: 250) TATTCCTCCTGCTCATATTGTGATT (SEQ ID NO: 251) GTCTTCCTGACACTTTAATTACCAA (SEQ ID NO: 252) TACCAACCTGTTACCTACTTTGACT (SEQ ID NO: 253) GTTACCTACTTTGACTTTTTGCATT (SEQ ID NO: 254) ATGTGCTATACTGCATACTTTTTAA (SEQ ID NO: 255) AACTGTGTATTCCAAGACATGTCTG (SEQ ID NO: 256) CATAGATGCTTAGTCCCTCATGCAA (SEQ ID NO: 257) AATTTTTTATCATGCATGTCCTGTA (SEQ ID NO: 258) TAAAGGTTACAAGCCTGCACAATAA (SEQ ID NO: 259)

Gene Sense Primer Anti-sense Primer THSD7A GCCTGTTATGACTGGAAA (SEQ ID NO: 270) CTGTCAACTTCTTCTCCA (SEQ ID NO: 271) MET CCTTGAACAGAATCACTG (SEQ ID NO: 272) CCATGTTTCATGTATGGTA (SEQ ID NO: 273) FAM126A GCTTGTAGTCTCCAAGAA (SEQ ID NO: 274) GGACAGAGTAATGCTAATAC (SEQ ID NO: 275) PHC1 GACAGCACATGTGGTAAA (SEQ ID NO: 276) CACAGACTGCATATAGAAGG (SEQ ID NO: 277) RAB31 CTCAGATATTAGGGAGGTTC (SEQ ID NO: 278) GCTGATTCCTTGAAAGAG (SEQ ID NO: 279) ST8SIA4 GCACAATGTAGAAGGTTG (SEQ ID NO: 280) CAAGCACATAGTGTATGAC (SEQ ID NO: 281) CHML CTCCAAATCCAGAAGACA (SEQ ID NO: 282) GGCCATTACTACATTATTGG (SEQ ID NO: 283) CAV1 CTGTGCCTGAATATTTTGTTA (SEQ ID NO: 284) CTGAGTTAGACCCTATTTGA (SEQ ID NO: 285) RPL23A GAGAGAAGAAGGCATATG (SEQ ID NO: 286) TGGACTCAGTTTAGATGA (SEQ ID NO: 287) TPT1 GGCAATTATTTTGGATCTATC (SEQ ID NO: 288) CAGTCCCATTTGTCTTAA (SEQ ID NO: 289) EEF1A1 CAGGACACAGAGACTTTA (SEQ ID NO: 290) CAGCTTCAAATTCACCAA (SEQ ID NO: 291) SRSF3 CGAGAGCTAGATGGAAGA (SEQ ID NO: 292) GGCCACGATTTCTACTTC (SEQ ID NO: 293) TUT1 GGTGTATCGAGTCCAAAC (SEQ ID NO: 294) CAGGAAACGGGAGTTATG (SEQ ID NO: 295) HNRNC CAAGCAGTAGAGATGAAG (SEQ ID NO: 296) CTCCATCTTCACATTAGTC (SEQ ID NO: 297) HUWE1 CAAGGTCTAATCATGCTG (SEQ ID NO: 298) CTGCTGGGTAGAATTAAAG (SEQ ID NO: 299) WDR90 CTCTGGAGACAAGGATGG (SEQ ID NO: 300) GACACAGATGGTAGAGATTG (SEQ ID NO: 301) MATR3 GGTGAGAAAGACACAAAG (SEQ ID NO: 302) CTGCTTCTTCTTCATCTAC (SEQ ID NO: 303) SMARCA4 GTACCTCATGGAGCACAA (SEQ ID NO: 304) CCTTGTAAGACACCTTCAC (SEQ ID NO: 305)

In one example, the probe usable for detection of the biomarker THSD7A may be at least one selected from the group consisting of SEQ ID NO: 109 to SEQ ID NO: 142, for example, the probe of SEQ ID NO: 109, SEQ ID NO: 110 to SEQ ID NO: 120 It may be at least one selected from the group consisting of a probe set including SEQ ID NO: 121 to SEQ ID NO: 131, and a probe set including SEQ ID NO: 132 to SEQ ID NO: 142. The primers usable for detecting the biomarker THSD7A may be a primer of SEQ ID NO: 270, a primer of SEQ ID NO: 271, or a primer pair including these, but is not limited thereto.

Probes usable for detection of the biomarker MET may be at least one selected from the group consisting of SEQ ID NO: 143 to SEQ ID NO: 154, for example, a probe of SEQ ID NO: 143, a probe set comprising SEQ ID NO: 144 to SEQ ID NO: 154; or a combination thereof. The primers usable for the detection of the biomarker MET may be a primer of SEQ ID NO: 272, a primer of SEQ ID NO: 273, or a pair of primers including them, but is not limited thereto.

The probe usable for detection of the biomarker RAB31 may be at least one selected from the group consisting of SEQ ID NO: 155 to SEQ ID NO: 177, for example, a probe of SEQ ID NO: 155, a probe set comprising SEQ ID NO: 156 to SEQ ID NO: 166; and SEQ ID NO: 167 to SEQ ID NO: 177. It may be at least one selected from the group consisting of probe sets. The primers usable for detection of the biomarker RAB31 may be a primer of SEQ ID NO: 278, a primer of SEQ ID NO: 279, or a primer pair including these, but is not limited thereto.

The probe usable for detection of the biomarker FAM126A may be at least one selected from the group consisting of SEQ ID NO: 178 to SEQ ID NO: 200 and SEQ ID NO: 225 to SEQ ID NO: 235, for example, the probe of SEQ ID NO: 178, SEQ ID NO: 179 to sequence It may be at least one selected from the group consisting of a probe set comprising No. 189, a probe set comprising SEQ ID NO: 190 to SEQ ID NO: 200, and a probe set comprising 225 to SEQ ID NO: 235. The primers usable for detection of the biomarker FAM126A may be a primer of SEQ ID NO: 274, a primer of SEQ ID NO: 275, or a primer pair including these, but is not limited thereto.

The probe usable for detection of the biomarker PHC1 may be at least one selected from the group consisting of SEQ ID NO: 201 to SEQ ID NO: 212, for example, a probe of SEQ ID NO: 201, a probe set comprising SEQ ID NO: 202 to SEQ ID NO: 212; or a combination thereof. The primer usable for detecting the biomarker PHC1 may be a primer of SEQ ID NO: 276, a primer of SEQ ID NO: 277, or a pair of primers including these, but is not limited thereto.

The probe usable for detecting the biomarker CHML may be at least one selected from the group consisting of SEQ ID NOs: 213 to SEQ ID NO: 224, for example, a probe of SEQ ID NO: 213, a probe set comprising SEQ ID NOs: 214 to SEQ ID NO: 224; or a combination thereof. The primers usable for detection of the biomarker CHML may be a primer of SEQ ID NO: 282, a primer of SEQ ID NO: 283, or a primer pair including these, but is not limited thereto.

The probe usable for detecting the biomarker ST8SIA4 may be at least one selected from the group consisting of SEQ ID NO: 236 to SEQ ID NO: 247, for example, a probe of SEQ ID NO: 236, a probe set comprising SEQ ID NO: 237 to SEQ ID NO: 247; or a combination thereof. The primer usable for detection of the biomarker ST8SIA4 may be a primer of SEQ ID NO: 280, a primer of SEQ ID NO: 281, or a primer pair including these, but is not limited thereto.

The probe usable for detection of the biomarker CAV1 may be at least one selected from the group consisting of SEQ ID NO: 248 to SEQ ID NO: 259, for example, a probe of SEQ ID NO: 248, a probe set comprising SEQ ID NO: 249 to SEQ ID NO: 259; or a combination thereof. The primer usable for detection of the biomarker CAV1 may be a primer of SEQ ID NO: 284, a primer of SEQ ID NO: 285, or a primer pair including these, but is not limited thereto.

The probe usable for detecting the reference marker EEF1A1 may be a probe of SEQ ID NO: 262, but is not limited thereto. The primer usable for detecting the reference marker EEF1A1 may be a primer of SEQ ID NO: 290, a primer of SEQ ID NO: 291, or a primer pair including these, but is not limited thereto.

The probe usable for detecting the reference marker RPL23A may be a probe of SEQ ID NO: 260, but is not limited thereto. The primer usable for detecting the reference marker RPL23A may be a primer of SEQ ID NO: 286, a primer of SEQ ID NO: 287, or a primer pair including these, but is not limited thereto.

The probe usable for detecting the reference marker TPT1 may be a probe of SEQ ID NO: 261, but is not limited thereto. The primer usable for detecting the reference marker TPT1 may be a primer of SEQ ID NO: 288, a primer of SEQ ID NO: 289, or a primer pair including these, but is not limited thereto.

The probe usable for detecting the reference marker HUWE1 may be a probe of SEQ ID NO: 266, but is not limited thereto. The primer usable for detecting the reference marker HUWE1 may be a primer of SEQ ID NO: 298, a primer of SEQ ID NO: 299, or a primer pair including these, but is not limited thereto.

The probe usable for detecting the reference marker MATR3 may be a probe of SEQ ID NO: 268, but is not limited thereto. The primers usable for detecting the reference marker MATR3 may be a primer of SEQ ID NO: 302, a primer of SEQ ID NO: 303, or a primer pair including these, but is not limited thereto.

The probe usable for detecting the reference marker SRSF3 may be a probe of SEQ ID NO: 263, but is not limited thereto. The primers usable for detecting the reference marker SRSF3 may be a primer of SEQ ID NO: 292, a primer of SEQ ID NO: 293, or a primer pair including these, but is not limited thereto.

The probe usable for detecting the reference marker HNRNPC may be a probe of SEQ ID NO: 265, but is not limited thereto. The primers usable for detection of the reference marker HNRNPC may be a primer of SEQ ID NO: 296, a primer of SEQ ID NO: 297, or a primer pair including these, but is not limited thereto.

The probe usable for detecting the reference marker SMARCA4 may be a probe of SEQ ID NO: 269, but is not limited thereto. The primers usable for detection of the reference marker SMARCA4 may be a primer of SEQ ID NO: 304, a primer of SEQ ID NO: 305, or a primer pair including these, but is not limited thereto.

The probe usable for detecting the reference marker WDR90 may be a probe of SEQ ID NO: 267, but is not limited thereto. The primer usable for detecting the reference marker WDR90 may be a primer of SEQ ID NO: 300, a primer of SEQ ID NO: 301, or a primer pair including these, but is not limited thereto.

The probe usable for detecting the reference marker TUT1 may be a probe of SEQ ID NO: 264, but is not limited thereto. The primer usable for detecting the reference marker TUT1 may be a primer of SEQ ID NO: 294, a primer of SEQ ID NO: 295, or a pair of primers including these, but is not limited thereto.

Another example is a method for predicting the effect of an anti-c-Met antibody (or reactivity or sensitivity to an anti-c-Met antibody) comprising measuring the presence and level of the biomarker in a biological sample, application of an anti-c-Met antibody Methods of screening a subject or providing information for screening a subject for application of an anti-c-Met antibody are provided. In the method, the presence or absence and expression level of the biomarker may be measured using the reference marker as a comparison standard (control). For example, in the case of CAV1, FAM126A, MET, RAB31, ST8SIA4, and/or THSD7A, if the expression level is high, treatment with an anti-c-Met antibody is effective, or it is determined as a suitable subject for applying the anti-c-Met antibody. can In addition, in the case of CMHL and/or PHC1, when the expression level is low, treatment with an anti-c-Met antibody is effective, or it can be determined as a suitable target for applying the anti-c-Met antibody.

The evaluation of the expression level of the biomarker may be performed by comparing the expression level of the reference marker. For example, the evaluation of the expression level of the biomarker and the determination of the efficacy and / or application suitability of the anti-c-Met antibody is a polymerase chain reaction method (PCR; for example, competitive polymerase chain reaction (Competitive PCR), real-time polymerase chain reaction (RT-PCR), etc.) as described in Table 6 below.

gene (biomarker) reference value judgment CAV1, FAM126A, MET, RAB31, ST8SIA4, THSD7A Average of the minimum ΔCt value in the efficacy group and the maximum ΔCt value in the non-efficacy group: [Min(efficacy value (ΔCt))+Max(non-efficacy value (ΔCt))]/2 If the Ct value of the biomarker in the sample is greater than or equal to the reference value, the expression level is evaluated as high → Treatment with the anti-c-Met antibody is effective for the sample or the patient from which the sample was obtained, or suitable for applying the anti-c-Met antibody judge by target
CMHL, PHC1 Average of the minimum ΔCt value in the non-efficacy group and the maximum ΔCt value in the efficacy group: [Min(non-efficacy value (ΔCt))+Max(efficacy value (ΔCt))]/2 If the Ct value of the biomarker in the sample is less than or equal to the reference value, the expression level is evaluated as low → Treatment with the anti-c-Met antibody is effective for the sample or the patient from which the sample was obtained, or suitable for applying the anti-c-Met antibody judge by target

(ΔCt: Ct (threshold cycle) value of the reference marker (If two or more reference markers are used, the average value of the Ct values of these reference markers - Ct value of the corresponding biomarker)

In Table 6, the reference marker refers to one or more selected from the group consisting of EEF1A1, RPL23A, TPT1, HUWE1, MATR3, SRSF3, HNRNPC, SMARCA4, WDR90, and TUT1 described above. The efficacy (or responder) or non-efficacy (or non-responder) group was evaluated in the preceding in vivo test ( in in vivo test; For example, clinical trials) or in vitro tests ( ex in vivo test; For example, it may be a population of individuals in which the effect of the anti-c-Met antibody or the reactivity (sensitivity) to the anti-c-Met antibody has been confirmed by a cell test.

In another example, the evaluation of the expression level of the biomarker may include comparing the expression level of the biomarker in the test subject biological sample with the expression level in the comparative reference sample, so that the expression level of the biomarker in the test subject biological sample is compared If it is higher than the reference sample, it can be determined that "the expression level of the biomarker is high" can judge The comparative reference sample may be any cell or tissue in which the anti-c-Met antibody does not show efficacy or is resistant to the anti-c-Met antibody (eg, anti-c-Met antibody ineffective group (eg, anti-c-Met antibody ratio). Reactive group (insensitive group) or resistant group).For example, this comparative reference sample is cell line H1373 (ATCC, CRL-5866), HCC1806 (ATCC, CRL-2335), Caki-1 (ATCC, HTB-46), SKBR3 (ATCC, HTB-30), BT474 (ATCC, HTB-20), HT-29 (ATCC, HTB-38), LoVo (ATCC, CCL-229), HCT116 (ATCC, CCL-247), SW620 (ATCC, CCL-227), Ls174T (ATCC, CL-188), and one selected from the group consisting of cells acquired resistance to anti-c-Met antibody by repeated and/or continuous administration of anti-c-Met antibody may be more than

Accordingly, the method of predicting efficacy or selecting a patient may further comprise comparing the expression level of a biomarker in a biological sample to be tested (eg, a biological sample isolated from the test subject) with the level of the biomarker in the reference sample for comparison. can In this case, the method may further include measuring the level of the biomarker in the reference sample. The method may include, wherein the expression level of one or more biomarkers selected from the group consisting of CAV1, FAM126A, MET, RAB31, ST8SIA4, and THSD7A in the biological sample to be tested is higher than in the comparative reference sample, or in the biological sample to be tested. If the expression level of the CMHL and/or PHC1 biomarker is lower than in the reference sample, it is determined that the anti-c-Met antibody may work well on the biological sample to be tested or the subject from which the sample was obtained (or the biological sample or the biological sample to be tested). determining that the subject from which the sample was obtained is sensitive or reactive to the anti-c-Met antibody), or determining that the biological sample or the subject from which the sample was obtained is an appropriate application (administration) subject of the anti-c-Met antibody may further include.

The effect (or efficacy) of the anti-c-Met antibody refers to the effect to be obtained by application of the anti-c-Met antibody, and may be, for example, an anti-cancer effect (eg, an inhibitory effect on cancer cell proliferation, an effect of inhibiting cancer metastasis, etc.). .

The target to which the anti-c-Met antibody is applied refers to a patient suitable for treatment using the anti-c-Met antibody, and may be any mammal, such as humans and primates such as monkeys, and rodents such as mice and rats, For example, it may be a cancer patient. The biological sample may be a patient (eg, a mammal including primates such as humans and monkeys, and rodents such as mice and rats), or cells, tissues, and body fluids isolated or artificially cultured from the patient, such as cancer cells or It may be cancer tissue, or DNA or RNA extracted therefrom, or an isolated protein. The biological sample may be an unprocessed sample or a processed sample (eg, a formalin fixed paraffin embedded (RRPE) sample, etc.).

The target of the anti-c-Met antibody may be a cancer patient, and the cancer may be a solid cancer or a hematologic cancer, or a cancer associated with c-Met overexpression or abnormal activation. The cancer may include not only primary cancer but also metastatic cancer. In one embodiment, the target of application of the anti-c-Met antibody is squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung, peritoneal cancer, skin cancer, skin or intraocular melanoma, rectal cancer, anus Peripheral cancer, esophageal cancer, small intestine cancer, endocrine adenocarcinoma, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, chronic or acute leukemia, lymphocyte lymphoma, hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer , liver tumor, breast cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, brain cancer, osteosarcoma, etc. to be selected from one or more cancer patients selected from the group consisting of can In one embodiment, the target to which the anti-c-Met antibody is applied is one or more cancer patients selected from the group consisting of lung cancer (eg, lung cancer adenocarcinoma, non-small cell adenocarcinoma, etc.) can be selected from

The presence or absence of the biomarker and/or the expression level of the reference marker is determined by a conventional gene quantification method, such as a conventional microarray method using a probe or primer hybridizable with the gene, polymerase chain reaction (PCR) , FISH (fluorescent in situ hybridization), etc. may be used, but is not limited thereto. In one embodiment, the presence or absence of the biomarker and/or the expression level of the biomarker and/or the reference marker may be determined by conventional gene quantification by polymerase chain reaction (PCR). In addition, the presence or absence of the biomarker can be confirmed by conventional sequencing. In one embodiment, the primer is a sequence of 5 to 1000 bp, such as 10 to 500 bp, 20 to 200 bp, or 50 to 200 bp of the nucleotide sequence of the biomarker gene (full-length DNA, cDNA, or mRNA). As may be, bases capable of hybridizing (eg, complementary) to a continuous 5 to 100 bp, eg, 5 to 50 bp, 5 to 30 bp, or 10 to 25 bp region of each of the 3'-end and 5'-end of the gene fragment. It may have a sequence. The probe is capable of hybridizing with a continuous 5 to 100 bp, such as 5 to 50 bp, 5 to 30 bp, or 10 to 25 bp region of the nucleotide sequence of the biomarker gene (full-length DNA, cDNA, or mRNA) (e.g., complementary ) may have a nucleotide sequence. Complementary binding is possible by having the 'hybridizable' sequence with the nucleotide sequence of the gene region of 80% or more, such as 90% or more, 95% or more, 98% or more, 99% or more, or 100% sequence complementarity. means

The presence and/or level of the biomarkers can also be measured through quantification of the protein they encode. For example, the quantification of the protein encoded by the biomarker may be performed through a conventional enzymatic reaction using an antibody, aptamer, etc. that specifically binds to the protein, fluorescence, light emission and/or radiation detection, and specifically , Immunochromatography, immunohistochemical staining, enzyme linked immunosorbent assay (ELISA), radioimmunoassay (RIA), enzyme immunoassay (EIA), fluorescence immunoassay ( Floresence immunoassay (FIA), luminescence immunoassay (LIA), Western blotting, microchip, and the like may be performed by a method selected from the group consisting of, but is not limited thereto.

Another example provides a method for inhibiting c-Met, or a method for preventing and/or treating cancer, comprising administering an anti-c-Met antibody to the selected anti-c-Met antibody-applied subject.

The method for inhibiting c-Met or preventing and/or treating cancer may further include the step of identifying the selected anti-c-Met antibody application target prior to the administering step. The confirming step is a step of identifying a biological sample or a patient selected by the method for screening an anti-c-Met antibody application target described above, and is performed by performing the step described in the method for screening an anti-c-Met antibody application target Or, it may be performed by confirming that the anti-c-Met antibody application target selected by the method for screening the anti-c-Met antibody application target based on the given information.

In one embodiment, the method for inhibiting c-Met or preventing and/or treating cancer comprises:

identifying an anti-c-Met antibody application target; and

administering an effective amount of the anti-c-Met antibody to the subject to which the anti-c-Met antibody is applied

may include

In another embodiment, the method for inhibiting c-Met or preventing and/or treating cancer comprises:

selecting an anti-c-Met antibody application target by measuring the presence and/or level of the biomarker in the biological sample;

administering an effective amount of the anti-c-Met antibody to the selected anti-c-Met antibody-applied subject

may include

In one embodiment, the anti-c-Met antibody may be any antibody or antigen-binding fragment thereof that recognizes c-Met as an antigen. For example, the anti-c-Met antibody may be any antibody or antigen-binding fragment thereof that specifically binds to c-Met to induce intracellular migration (internalization) and degradation (degradation). The anti-c-Met antibody may recognize a specific site of c-Met, for example, a specific site within the SEMA domain as an epitope.

In the present specification, unless otherwise specified, the anti-c-Met antibody is used to include not only the complete form of the anti-c-Met antibody, but also the antigen-binding site of the antibody.

The "c-Met protein" refers to a receptor tyrosine kinase that binds to hepatocyte growth factor. The c-Met protein may be derived from any species, for example, from a primate such as human c-Met (eg, NP_000236), monkey c-Met (eg, Macaca mulatta, NP_001162100), or mouse c- Met (eg NP_032617.2), rat c-Met (eg NP_113705.1), etc. from rodents, and the like. The protein comprises, for example, a polypeptide encoded by a nucleotide sequence provided in GenBank Accession Number NM_000245, or a protein encoded by a polypeptide sequence provided in GenBank Accession Number NM_000236, or an extracellular domain thereof. Receptor tyrosine kinase c-Met is involved in several mechanisms such as, for example, cancer development, cancer metastasis, cancer cell migration, cancer cell invasion, and angiogenesis processes.

c-Met, a receptor for hepatocyte growth factor (HGF), is divided into three parts: an extracellular region, a transmembrane region, and an intracellular region. In a linked form, the HGF-binding domain consists of a SEMA domain, a PSI domain (plexin-semaphorins-integrin homology domain), and an IPT domain (immunoglobulin-like fold shared by plexins and transcriptional factors domain). The SEMA domain of the c-Met protein may have the amino acid sequence of SEQ ID NO: 79, and is a domain present in the extracellular region of c-Met and corresponds to a site to which HGF binds. A specific site in the SEMA domain, for example, the region having the amino acid sequence of SEQ ID NO: 71 corresponding to positions 106 to 124 is a loop between propeller domains 2 and 3 among epitopes in the SEMA domain of c-Met protein. Corresponding to the region, it can act as an epitope of the anti-c-Met antibody proposed in the present invention.

The term “epitope” is interpreted to mean a portion of an antigen recognized by an antibody, as an antigenic determinant. According to one embodiment, the epitope is a region comprising 5 or more consecutive amino acids in the SEMA domain of c-Met protein (SEQ ID NO: 79), for example, the 106th position in the SEMA domain of c-Met protein (SEQ ID NO: 79) It may include consecutive 5 to 19 amino acids located within SEQ ID NO: 71 corresponding to the 124th. For example, the epitope may consist of 5 to 19 consecutive amino acids including SEQ ID NO: 73 (EEPSQ) among the amino acid sequence of SEQ ID NO: 71, for example, the amino acid sequence of SEQ ID NO: 71, SEQ ID NO: 72 or SEQ ID NO: 73 It may be a polypeptide having

The epitope having the amino acid sequence of SEQ ID NO: 72 corresponds to the outermost portion of the loop region between the second and third propeller structure domains in the SEMA domain of c-Met protein, and the amino acid sequence of SEQ ID NO: 73 is The epitope having is the site to which the antibody or antigen-binding fragment according to one embodiment most specifically binds.

Accordingly, the anti-c-Met antibody may specifically bind to an epitope comprising 5 to 19 consecutive amino acids including SEQ ID NO: 73 (EEPSQ) among the amino acid sequence of SEQ ID NO: 71, for example, the sequence It may be an antibody or antigen-binding fragment that specifically binds to an epitope having the amino acid sequence of 71, SEQ ID NO: 72, or SEQ ID NO: 73.

According to one embodiment, the anti-c-Met antibody is

CDR-H1 having the amino acid sequence of SEQ ID NO: 4, the amino acid sequence of SEQ ID NO: 5, the amino acid sequence of SEQ ID NO: 2, or consecutive 8 to 19 amino acids comprising the 3rd to 10th amino acids in the amino acid sequence of SEQ ID NO: 2 CDR-H2 having an amino acid sequence consisting of amino acids, and consecutive 6 to at least one heavy chain complementarity determining region (CDR) selected from the group consisting of CDR-H3 having an amino acid sequence consisting of 13 amino acids, or a heavy chain variable region comprising said at least one heavy chain complementarity determining region;

A CDR-L1 having the amino acid sequence of the amino acid sequence of SEQ ID NO: 7, a CDR-L2 having the amino acid sequence of SEQ ID NO: 8, and the amino acid sequence of SEQ ID NO: 9, the amino acid sequence of SEQ ID NO: 15, the amino acid sequence of SEQ ID NO: 86, or At least one light chain complementarity determining region or at least one light chain complementarity determining region selected from the group consisting of CDR-L3 having an amino acid sequence consisting of 9 to 17 amino acids comprising the first to ninth amino acids in the amino acid sequence of SEQ ID NO: 89 a light chain variable region comprising a region;

a combination of the heavy chain complementarity determining region and the light chain complementarity determining region; or

Combination of the heavy chain variable region and the light chain variable region

may include.

SEQ ID NO: 4 to SEQ ID NO: 9 are amino acid sequences represented by the following general formulas I to VI, respectively:

General formula I

Xaa ₁ -Xaa ₂ -Tyr-Tyr-Met-Ser (SEQ ID NO: 4),

General formula II

Arg-Asn-Xaa ₃ -Xaa ₄ -Asn-Gly-Xaa ₅ -Thr (SEQ ID NO: 5),

General formula Ⅲ

Asp-Asn-Trp-Leu-Xaa ₆ -Tyr (SEQ ID NO: 6),

General formula IV

Lys-Ser-Ser-Xaa ₇ -Ser-Leu-Leu-Ala-Xaa ₈ -Gly-Asn-Xaa _{9 -Xaa 10} -Asn-Tyr-Leu-Ala (SEQ ID NO: 7)

General Ⅴ

Trp-Xaa ₁₁ -Ser-Xaa ₁₂ -Arg-Val-Xaa ₁₃ (SEQ ID NO: 8)

General formula Ⅵ

Xaa ₁₄ -Gln-Ser-Tyr-Ser-Xaa ₁₅ -Pro-Xaa ₁₆ -Thr (SEQ ID NO: 9)

In the general formula I, Xaa ₁ is absent or is Pro or Ser, Xaa ₂ is Glu or Asp,

In Formula II, Xaa ₃ is Asn or Lys, Xaa ₄ is Ala or Val, Xaa ₅ is Asn or Thr,

In the general formula III, Xaa ₆ is Ser or Thr,

In the general formula IV, Xaa ₇ is His, Arg, Gln or Lys, Xaa ₈ is Ser or Trp, Xaa ₉ is His or Gln, Xaa ₁₀ is Lys or Asn,

In Formula V, Xaa ₁₁ is Ala or Gly, Xaa ₁₂ is Thr or Lys, Xaa ₁₃ is Ser or Pro,

In Formula VI, Xaa ₁₄ is Gly, Ala or Gin, Xaa ₁₅ is Arg, His, Ser, Ala, Gly or Lys, and Xaa ₁₆ is Leu, Tyr, Phe or Met.

In one embodiment, the CDR-H1 may have an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 24. The CDR-H2 may have an amino acid sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 25, and SEQ ID NO: 26. The CDR-H3 may have an amino acid sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 27, SEQ ID NO: 28, and SEQ ID NO: 85.

The CDR-L1 may have an amino acid sequence selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 106. The CDR-L2 may have an amino acid sequence selected from the group consisting of SEQ ID NO: 11, SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 36. The CDR-L3 may have an amino acid sequence selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 37, SEQ ID NO: 86, and SEQ ID NO: 89.

In one embodiment, the antibody or antigen-binding fragment comprises a polypeptide (CDR-H1) having an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 24, SEQ ID NO: 2, SEQ ID NO: 25, and a polypeptide (CDR-H2) having an amino acid sequence selected from the group consisting of SEQ ID NO: 26, and a poly having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 27, SEQ ID NO: 28, and SEQ ID NO: 85 a heavy chain variable region comprising a peptide (CDR-H3); and a polypeptide (CDR-L1) having an amino acid sequence selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 106, SEQ ID NO: 11, sequence A polypeptide (CDR-L2) having an amino acid sequence selected from the group consisting of SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 36, and SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, sequence It may include a light chain variable region comprising a polypeptide (CDR-L3) having an amino acid sequence selected from the group consisting of No. 37, SEQ ID NO: 86, and SEQ ID NO: 89.

According to one embodiment, in the anti-c-Met antibody or antigen-binding fragment, the heavy chain variable region is SEQ ID NO: 17, SEQ ID NO: 74, SEQ ID NO: 87, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93 or comprising the amino acid sequence of SEQ ID NO: 94, wherein the light chain variable region is SEQ ID NO: 306, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 75, SEQ ID NO: 88, SEQ ID NO: 95, SEQ ID NO: 96 , may include the amino acid sequence of SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99 or SEQ ID NO: 107.

An animal-derived antibody produced by immunizing an animal to be immunized with a desired antigen may cause an immune rejection reaction when administered to a human for therapeutic purposes. A chimeric antibody is obtained by substituting the constant region of an animal-derived antibody that causes an anti-isotype reaction with that of a human antibody by using a genetic engineering method. Chimeric antibodies have significantly improved anti-isotype response compared to animal-derived antibodies, but still have animal-derived amino acids in the variable region, potentially causing side effects on anti-idiotypic responses. are doing A humanized antibody was developed to improve these side effects. This is produced by grafting complementarity determining regions (CDR) regions that play an important role in antigen binding among variable regions of a chimeric antibody into a human antibody framework.

The most important thing in the CDR grafting technology for producing a humanized antibody is to select an optimized human antibody that can best accept the CDR region of an animal-derived antibody. structure analysis, molecular modeling technology, etc. are used. However, even when the CDR regions of an animal-derived antibody are transplanted into the optimized human antibody framework, there are cases in which amino acids that affect antigen binding are present while being located in the framework of the animal-derived antibody, so that antigen-binding ability is not preserved in many cases. Therefore, it can be said that the application of additional antibody engineering technology to restore antigen binding force is essential.

According to one embodiment, the antibody may be a mouse-derived antibody, a mouse-human chimeric antibody, a humanized antibody, or a human-derived antibody. The antibody may be isolated from a living body or may not occur naturally. The antibody may be recombinantly or synthetically produced.

A complete antibody has a structure having two full-length light chains and two full-length heavy chains, and each light chain is linked to a heavy chain by a disulfide bond. The constant region of the antibody is divided into a heavy chain constant region and a light chain constant region, and the heavy chain constant region has gamma (γ), mu (μ), alpha (α), delta (δ) and epsilon (ε) types, subclasses gamma 1 (γ1), gamma 2 (γ2), gamma 3 (γ3), gamma 4 (γ4), alpha 1 (α1) and alpha 2 (α2). The constant region of the light chain has a kappa (κ) and a lambda (λ) type.

_{The term "heavy chain" refers to a variable region domain V H} comprising an amino acid sequence having sufficient variable region sequence to confer specificity to an antigen and three constant region domains C _H1 , C _H2 and C _H3 and a hinge ( hinge) is interpreted as meaning including all the full-length heavy chains and fragments thereof. Further, the term "light chain (light chain)" Both the full-length light chain and fragments thereof containing the variable region domain, V _L, and a constant region domain, C _L comprises an amino acid sequence having sufficient variable region sequence to impart specificity to the antigen interpreted as including

The term “complementarity determining region (CDR)” refers to an amino acid sequence of a hypervariable region of a heavy chain and a light chain of an immunoglobulin. The heavy and light chains may each comprise three CDRs (CDRH1, CDRH2, CDRH3 and CDRL1, CDRL2, CDRL3). The CDRs may provide key contact residues for the binding of an antibody to an antigen or epitope. Meanwhile, in the present specification, the terms "specifically binding" or "specifically recognized" have the same meaning as commonly known to those skilled in the art, and the antigen and the antibody specifically interact to produce an immunological reaction. means that

The term "antigen-binding fragment" refers to a fragment of the entire immunoglobulin structure, and refers to a portion of a polypeptide including a portion capable of binding an antigen. In one embodiment, the antigen-binding fragment may be scFv, (scFv) ₂ , Fab, Fab' or F(ab') ₂ , but is not limited thereto. Among the antigen-binding fragments, Fab has one antigen-binding site in a structure having a light chain and heavy chain variable regions, a light chain constant region and a heavy chain first constant region (C _{H1 ).}

Fab' differs from Fab in that it has a hinge region comprising one or more cysteine residues at the C-terminus of the heavy chain C _{H1 domain.}

The F(ab') ₂ antibody is produced by forming a disulfide bond with a cysteine residue in the hinge region of Fab'. Fv is a minimal antibody fragment having only a heavy chain variable region and a light chain variable region, and a recombinant technique for generating an Fv fragment is well known in the art.

In a double-chain Fv (two-chain Fv), the heavy chain variable region and the light chain variable region are linked by a non-covalent bond, and in single-chain Fv (single-chain Fv), the heavy chain variable region and the single chain variable region are generally shared through a peptide linker. Since they are linked by a bond or are linked directly at the C-terminus, they can form a dimer-like structure like a double-stranded Fv. The peptide linker may be a polypeptide consisting of 1 to 100 or 2 to 50 arbitrary amino acids, and the type of amino acids included is not limited.

The antigen-binding fragment can be obtained using a proteolytic enzyme (for example, by restriction digestion of the entire antibody with papain to obtain Fab, and by digestion with pepsin to obtain a F(ab') ₂ fragment), It can be produced through genetic recombination technology.

The term "hinge region" refers to a region included in the heavy chain of an antibody, which exists between the CH1 and CH2 regions, and functions to provide flexibility of the antigen-binding site in the antibody.

When the animal-derived antibody undergoes chimerization, the animal-derived IgG1 hinge is replaced with a human IgG1 hinge, but the animal-derived IgG1 hinge has a shorter length than that of the human IgG1 hinge, and a disulfide bond between the two heavy chains ( disulfide bond) is reduced from 3 to 2, so that the rigidity of the hinge has different effects. Thus, modification of the hinge region can increase the antigen binding efficiency of humanized antibodies. Methods for deletion, addition or substitution of amino acids for modifying the amino acid sequence of the hinge region are well known to those skilled in the art.

Accordingly, in one embodiment of the present invention, in order to enhance antigen-binding efficiency, the anti-c-Met antibody or antigen-binding fragment includes a hinge region in which one or more amino acids are deleted, added, or substituted and the amino acid sequence is modified. can For example, the antibody comprises a hinge region having the amino acid sequence of SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, or SEQ ID NO: 104, or a hinge region having the amino acid sequence of SEQ ID NO: 105 (unmodified human hinge area) may be included. More specifically, the hinge region may have the amino acid sequence of SEQ ID NO: 100 or SEQ ID NO: 101.

In one embodiment, the anti-c-Met antibody may be a monoclonal antibody that specifically binds to the extracellular region of the c-Met protein, which is produced in hybridoma cells with accession number KCLRF-BP-00220. Yes (refer to Korean Patent Publication No. 2011-0047698; this document is incorporated herein by reference). The anti-c-Met antibody may include all of the antibodies defined in Korean Patent Publication No. 2011-0047698.

All subtypes of immunoglobulins (eg, IgA, IgD, IgE, IgG (eg, IgA, IgD, IgE, IgG) eg, IgG1, IgG2, IgG3, IgG4, etc.), IgM, etc.) may be a region derived from, for example, a light chain constant region and a heavy chain constant region.

According to one embodiment, the anti-c-Met antibody is

The amino acid sequence of SEQ ID NO: 62 (the amino acid sequence of the 1st to the 17th is a signal peptide), the amino acid sequence of the 18th to the 462th of SEQ ID NO: 62, the amino acid sequence of SEQ ID NO: 64 (from the 1st The amino acid sequence up to the 17th is a signal peptide) or the amino acid sequence from the 18th to the 461st of SEQ ID NO: 64, the amino acid sequence of SEQ ID NO: 66 (the amino acid sequence from the 1st to the 17th is a signal peptide), And a heavy chain comprising an amino acid sequence selected from the group consisting of the amino acid sequence from the 18th to the 460th of SEQ ID NO: 66; and

The amino acid sequence of SEQ ID NO: 68 (the amino acid sequence from the 1st to the 20th is a signal peptide), the amino acid sequence from the 21st to the 240th of SEQ ID NO: 68, the amino acid sequence of SEQ ID NO: 70 (from the 1st The 20th amino acid sequence is a signal peptide), a light chain comprising an amino acid sequence selected from the group consisting of the 21st to 240th amino acid sequence of SEQ ID NO: 70, and the amino acid sequence of SEQ ID NO: 108

may include.

For example, the anti-c-Met antibody is

A heavy chain comprising the amino acid sequence of SEQ ID NO: 62 or the amino acid sequence from the 18th to the 462th of SEQ ID NO: 62 and a light chain comprising the amino acid sequence of SEQ ID NO: 68 or the amino acid sequence from the 21st to the 240th of SEQ ID NO: 68 antibodies comprising;

A heavy chain comprising the amino acid sequence of SEQ ID NO: 64 or the amino acid sequence from the 18th to the 461st of SEQ ID NO: 64 and the light chain comprising the amino acid sequence of SEQ ID NO: 68 or the amino acid sequence from the 21st to the 240th of SEQ ID NO: 68 antibodies comprising;

A heavy chain comprising the amino acid sequence of SEQ ID NO: 66 or the amino acid sequence from the 18th to the 460th of SEQ ID NO: 66 and the light chain comprising the amino acid sequence of SEQ ID NO: 68 or the amino acid sequence from the 21st to the 240th of SEQ ID NO: 68 antibodies comprising;

A heavy chain comprising the amino acid sequence of SEQ ID NO: 62 or the amino acid sequence from the 18th to the 462th of SEQ ID NO: 62 and the light chain comprising the amino acid sequence of SEQ ID NO: 70 or the amino acid sequence from the 21st to the 240th of SEQ ID NO: 70 antibodies comprising;

A heavy chain comprising the amino acid sequence of SEQ ID NO: 64 or the amino acid sequence from the 18th to the 461th of SEQ ID NO: 64 and the light chain comprising the amino acid sequence of SEQ ID NO: 70 or the amino acid sequence from the 21st to the 240th of SEQ ID NO: 70 antibodies comprising; or

A heavy chain comprising the amino acid sequence of SEQ ID NO: 66 or the amino acid sequence from the 18th to the 460th of SEQ ID NO: 66 and a light chain comprising the amino acid sequence of the amino acid sequence from the 21st to the 240th of SEQ ID NO: 70 or SEQ ID NO: 70 antibody comprising

an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 62 or the amino acid sequence of positions 18 to 462 of SEQ ID NO: 62 and a light chain comprising the amino acid sequence of SEQ ID NO: 108;

an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 64 or the amino acid sequence of positions 18 to 461 of SEQ ID NO: 64 and a light chain comprising the amino acid sequence of SEQ ID NO: 108; and

An antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 66 or the amino acid sequence of positions 18 to 460 of SEQ ID NO: 66 and a light chain comprising the amino acid sequence of SEQ ID NO: 108

It may be selected from the group consisting of.

On the other hand, the polypeptide having the amino acid sequence of SEQ ID NO: 70 is a light chain consisting of a human kappa constant region, and the polypeptide having the amino acid sequence of SEQ ID NO: 68 is number 36 in the polypeptide having the amino acid sequence of SEQ ID NO: 70 (kabat numbering). Accordingly, the 62nd amino acid position in SEQ ID NO: 68) is a polypeptide in which histidine is substituted with tyrosine. Due to the substitution, the production of the antibody according to one embodiment may be increased. In addition, the polypeptide having the amino acid sequence of SEQ ID NO: 108 is at position 27e by kabat numbering in the polypeptide having the amino acid sequence from the 21st to the 240th except for the signal peptide from the 1st to the 20th among the amino acid sequence of SEQ ID NO: 68 (According to kabat numbering, position 32 in SEQ ID NO: 108; inside CDR-L1) is substituted with tryptophan (Trp) for serine (Ser), due to the substitution, the activity of the antibody according to one embodiment (eg, Binding affinity to c-Met, c-Met degradation activity, Akt phosphorylation inhibitory activity, etc.) may be further enhanced.

The anti-c-Met antibody may be formulated together with a pharmaceutically acceptable carrier, which is commonly used in drug formulation, and is lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia. , calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, It may be at least one selected from the group consisting of mineral oil and the like, but is not limited thereto.

The anti-c-Met antibody may be administered orally or parenterally. In the case of parenteral administration, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, intrapulmonary administration, or rectal administration may be used. Since the protein or peptide is digested upon oral administration, oral compositions should be formulated to coat the active agent or to protect it from degradation in the stomach. In addition, the anti-c-Met antibody may be administered by any device capable of translocating to a target cell.

The anti-c-Met antibody may be used for the prevention and/or treatment of cancer. The cancer may be a solid cancer or a blood cancer, and may be associated with overexpression or activation of c-Met. For example, the cancer includes, but is not limited to, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung, peritoneal cancer, skin cancer, skin or intraocular melanoma, rectal cancer, perianal cancer, Esophageal cancer, small intestine cancer, endocrine adenocarcinoma, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, chronic or acute leukemia, lymphocytic lymphoma, hepatocellular carcinoma, gastrointestinal cancer, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, It may be at least one selected from the group consisting of liver tumor, breast cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, brain cancer, osteosarcoma, and the like.

The cancer prevention and / or therapeutic effect includes not only the effect of inhibiting the growth of cancer cells, but also the effect of inhibiting migration, invasion, metastasis, etc., thereby inhibiting the aggravation of cancer. . Also includes effects on primary cancer as well as metastatic cancer.

By using the biomarker and/or the reference marker proposed in the present invention, patients suitable for the application of the anti-c-Met antibody can be selected with high accuracy, and through this, the efficacy of the anti-c-Met antibody in each patient can be improved. Customized treatment for each patient is possible so that it can be maximized, and it can be usefully used in the clinical diagram of the anti-c-Met antibody.

Figure 1a shows the efficacy group and non-efficacy group judgment results obtained using the Ventana MET IHC method for a mouse xenograft model, and 1b is a graph showing the efficacy group and non-efficacy group judgment results obtained through RT-PCR ( In 1b, X-axis: IHC score, ◆: ineffective group, ●: efficacy group).
Figures 2a and 2b are graphs showing the expression levels of reference markers (control genes).
3A and 3B are graphs showing the results of measuring the expression levels of the control gene (3a) and the selected reference marker (3b) using specific primers.

Hereinafter, the present invention will be described in more detail through Examples and Test Examples. However, these Examples and Test Examples are intended to illustrate the present invention, and should not be construed as limiting the present invention.

Reference example 1: term c- Met production of antibodies

1.1. c- Met mouse antibodies against' AbF46' production of

1.1.1. Immunization of mice

To obtain immunized mice necessary for the development of hybridoma cell lines, 100 μg of human c-Met/Fc fusion protein (R&D Systems) and complete Freund's adjuvant were administered to 5 mice each. was mixed and injected intraperitoneally into 4-6 week old BALB/c mice (Japan SLC, Inc.). Two weeks later, in the same manner as above, 50 μg, which is half of the previously injected amount of the human c-Met/Fc fusion protein used as the antigen, was mixed with the same amount of incomplete Freund's adjuvant, and the mouse was Injected intraperitoneally. After one week, the last boosting (boosting) was performed, and 3 days later, blood was collected from the tail of the mouse to obtain serum, and diluted 1/1000 in PBS to confirm that the titer of the c-Met-recognizing antibody was increased by ELISA. As a result of the above, mice having a sufficient amount of antibody were selected, and the following cell fusion process was performed.

1.1.2. cell fusion and of hybridoma Produce

3 days before the cell fusion experiment, a human c-Met/Fc fusion protein mixture in 50 μg PBS was injected intraperitoneally into BALB/c mice (Japan SLC, Inc.), and the immunized mice were anesthetized and then placed on the left side of the torso. The located spleen was excised. Cells were separated by grinding the extracted spleen with a mesh, and mixed with a culture medium (DMEM, GIBCO, Invitrogen) to make a spleen cell suspension. The suspension was centrifuged to recover the cell layer. The obtained splenocytes 1 x 10 ⁸ and myeloma cells (Sp2/0) 1 x 10 ⁸ were mixed, and then centrifuged to precipitate the cells. The centrifuged precipitate is slowly dispersed, treated with 45% polyethylene glycol (PEG) (1 ml) in a culture medium (DMEM), maintained at 37 ° C. for 1 minute, and culture medium (DMEM) 1 ml was added. Then, 10 ml of a culture medium (DMEM) was added for 1 minute, and the mixture was left in water at 37° C. for 5 minutes, adjusted to 50 ml, and centrifuged again. The cell precipitate was resuspended in a separation medium (HAT medium) at about 1 to 2 × 10 ⁵ /ml, and 0.1 ml each was dispensed in a 96-well plate, and then cultured in a carbon dioxide incubator at 37°C to prepare a hybridoma cell group. did

1.1.3. c- Met producing monoclonal antibodies to proteins hybridoma selection of cells

In order to select hybridoma cells that react specifically only to c-Met protein from the hybridoma cell group prepared in Reference Example 1.1.2, human c-Met/Fc fusion protein and human Fc protein were used as antigens. Screened by ELISA analysis method.

To a microtiter plate, 50 μl (2 ug/ml) of human c-Met/Fc fusion protein was added to each well and adhered to the plate surface, and unreacted antigens were removed by washing. Human Fc protein was attached to the plate surface in the same manner as above in order to select and exclude antibodies that bind to Fc rather than c-Met.

50 μl of the hybridoma cell culture solution obtained in Reference Example 1.1.2 was added to each well prepared above and allowed to react for 1 hour, and then washed sufficiently with phosphate buffer-Tween 20 (TBST) solution to remove unreacted culture solution. did Here, goat anti-mouse IgG-horseradish peroxidase (goat anti-mouse IgG-HRP) was added and reacted at room temperature for 1 hour, and then washed sufficiently with TBST solution. Then, a substrate solution (OPD) of peroxidase was added to react, and the degree of the reaction was confirmed by measuring the absorbance at 450 nm with an ELISA reader.

By confirming the reaction level as described above, hybridoma cell lines secreting an antibody having high binding affinity specifically for human c-Met protein without binding to human Fc were repeatedly selected. The hybridoma cell line obtained through repeated selection was subjected to limiting dilution to finally obtain one clone of the hybridoma cell line producing a monoclonal antibody. The final selected monoclonal antibody-producing hybridomas were deposited with the Korea Cell Line Research Foundation located in Yeongeon-dong, Jongno-gu, Seoul, Korea, an international depository under the Budapest Treaty on October 6, 2009, and were given accession number KCLRF-BP-00220 (Korea). See Patent Publication No. 2011-0047698).

1.1.4. Production and purification of monoclonal antibodies

The hybridoma cells obtained in Reference Example 1.1.3 were cultured in a serum-free medium, and monoclonal antibodies were produced and purified from the culture medium.

First, the hybridoma cells cultured in 50 ml of a culture medium (DMEM) medium containing 10% (v/v) FBS were centrifuged, and the cell precipitate was washed twice or more with 20 ml PBS to remove FBS. , The cell precipitate was resuspended in 50 ml of a culture medium (DMEM) medium, and then cultured in a carbon dioxide incubator at 37° C. for 3 days.

Thereafter, by centrifugation, the antibody-producing cells were removed, and the culture medium in which the antibodies were secreted was separated, and stored at 4° C. or immediately collected and used for separation and purification of the antibody. After pure purification of the antibody from 50 ml to 300 ml of the prepared culture solution using an AKTA purification device (GE Healthcare) equipped with an affinity column (Protein G agarose column; Pharmacia, USA), a filter for protein aggregation (Amicon) was applied. The purified antibody was stored by replacing the supernatant with PBS, and used in subsequent Examples.

1.2. c- Met for chimeric antibody chAbF46 production of

In general, mouse antibodies are highly likely to exhibit immunogenicity when injected into humans for therapeutic purposes. A chimeric antibody chAbF46 was constructed in which the constant region excluding the variable region) was substituted with the sequence of a human IgG1 antibody.

The nucleotide sequence corresponding to the heavy chain is 'EcoRI-signal sequence-VH-NheI-CH-TGA-XhoI' (SEQ ID NO: 38), and the nucleotide sequence corresponding to the light chain is 'EcoRI-signal sequence-VL-BsiWI-CL-TGA -XhoI' (SEQ ID NO: 39) was designed so that each gene was synthesized. Then, a DNA fragment (SEQ ID NO: 38) having a nucleotide sequence corresponding to the heavy chain ^{in the pOptiVEC TM} -TOPO TA Cloning Kit included in Invitrogen's OptiCHO ^TM Antibody Express Kit (Cat no. 12762-019), pcDNA ^TM 3.3 -TOPO By cloning a DNA fragment (SEQ ID NO: 39) having a nucleotide sequence corresponding to the light chain in the TA Cloning Kit (Cat no. 8300-01) using EcoRI (NEB, R0101S) and XhoI (NEB, R0146S) restriction enzymes, respectively , a vector containing a heavy chain and a vector containing a light chain for expression of the chimeric antibody were constructed, respectively.

Each of the constructed vectors was amplified using the Qiagen Maxiprep kit (Cat no. 12662), and the transient expression was performed by Freestyle ^TM MAX 293 Expression System (invitrogen) was used. The cell line used was 293 F cell, and was cultured in a suspension culture method using FreeStyle™ 293 Expression Medium as a medium. One day before the transient expression, ^{cells were prepared at a concentration of 5x10 5} cells/ml, and after 24 hours ^{, when the number of cells reached 1x10 6} cells/ml, temporary expression was performed. Transfection was carried out using the liposomal reagent method using Freestyle ^TM MAX reagent (invitrogen). In a 15ml tube, prepare DNA in a ratio of heavy chain DNA: light chain DNA = 1:1, mix with 2ml of OptiPro™ SFM (invtrogen) ^{(A), mix (B) 100 μl of Freestyle TM} MAX reagent and 2 ml of OptiPro™ SFM in another 15 ml tube, mix (A) and (B) and incubate for 15 minutes, The mixture was slowly mixed. After completion of transduction, incubation was carried out at 37 °C, 80% humidity, 8% CO _{2 ,} 130 rpm incubator for 5 days.

The cultured cells were centrifuged to take 100 ml of each supernatant, and purified using AKTA Prime (GE healthcare). A Protein A column (GE healthcare, 17-0405-03) was installed on AKTA Prime, and the culture medium was flowed at a flow rate of 5 ml/min, and eluted with an IgG elution buffer (Thermo Scientific, 21004). The resulting eluate was exchanged with PBS buffer to finally purify the chimeric antibody AbF46 (hereinafter referred to as chAbF46).

1.3. chimeric antibody chAbF46 Humanized Antibodies from huAbF46 production of

1.3.1. heavy chain humanization ( Heavy chain humanization )

For the design of two types of H1-heavy and H3-heavy, first, the VH gene of the mouse antibody AbF46 purified in Reference Example 1.2 through Ig Blast (http://www.ncbi.nlm.nih.gov/igblast/) and the human germline gene with the highest homology was analyzed. As a result, it was confirmed that VH3-71 had 83% homology at the amino acid level, and the CDR-H1, CDR-H2, and CDR-H3 of the mouse antibody AbF46 were defined by Kabat numbering, and the CDR portion of the mouse antibody AbF46 was It was designed to be introduced into the framework of VH3-71. At this time, amino acids No. 30 (S→T), No. 48 (V→L), No. 73 (D→N), and No. 78 (T→L) were back-mutated to the amino acid sequence of the original mouse AbF46 antibody. Thereafter, H1 was further mutated to amino acids 83 times (R→K) and 84 times (A→T) to finally construct H1-heavy (SEQ ID NO: 40) and H3-heavy (SEQ ID NO: 41).

As a result of finding the framework sequence of the human antibody for the design of H4-heavy, the sequence was very similar to the mouse framework sequence of the AbF46 antibody, and at the same time, it was defined by Kabat numbering using the VH3 subtype, which is known to be the most stable. CDR-H1, CDR-H2, and CDR-H3 of the mouse antibody AbF46 were introduced. Through this, H4-heavy (SEQ ID NO: 42) was constructed.

1.3.2. light chain humanization ( Light chain humanization )

For two designs, H1-light (SEQ ID NO: 43) and H2-light (SEQ ID NO: 44), mouse antibody AbF46 via Ig Blast (http://www.ncbi.nlm.nih.gov/igblast/) The human germline gene with the highest homology to the VL gene of As a result, it was confirmed that VK4-1 had 75% homology at the amino acid level, and the CDR-L1, CDR-L2, and CDR-L3 of the mouse antibody AbF46 were defined by Kabat numbering, and the CDR region of the mouse antibody AbF46 was It was designed to be introduced into the skeleton of VK4-1. At this time, H1-light back-mutated three amino acids 36 (Y → H), 46 (L → M), and 49 (Y → I), and H2-light was 49 amino acids (Y → I). Only one was constructed by back-mutation.

For the design of H3-light (SEQ ID NO: 45), a human germline gene most homologous to the VL gene of the mouse antibody AbF46 was generated through Blast (http://www.ncbi.nlm.nih.gov/igblast/). Among the analysis results, VK2-40 was selected in addition to VK4-1. It was confirmed that the mouse antibodies AbF46 VL and VK2-40 had 61% homology at the amino acid level, and the CDR-L1, CDR-L2, and CDR-L3 of the mouse antibody AbF46 were defined by Kabat numbering, and the CDRs of the mouse antibody AbF46 The portion was designed to be introduced into the skeleton of VK4-1. At this time, H3-light was constructed by back-mutation of 3 amino acids 36 times (Y→H), 46 times (L→M), and 49 times (Y→I).

As a result of finding the framework sequence of the human antibody for the design of H4-light (SEQ ID NO: 46), the CDR-L1 of the mouse antibody AbF46 defined by Kabat numbering using the Vk1 subtype known to be the most stable, CDR-L2 and CDR-L3 were introduced. At this time, H4-light was constructed by further back-mutation of 3 amino acids 36 times (Y→H), 46 times (L→M), and 49 times (Y→I).

Then, a DNA fragment (H1-heavy; SEQ ID NO: 47, H3) having a nucleotide sequence corresponding to the heavy chain ^{in the pOptiVEC TM} -TOPO TA Cloning Kit included in Invitrogen's OptiCHO ^TM Antibody Express Kit (Cat no. 12762-019) -heavy; SEQ ID NO: 48, H4-heavy; SEQ ID NO: 49) to pcDNA ^TM 3.3-TOPO DNA fragments (H1-light; SEQ ID NO: 50, H2-light; SEQ ID NO: 51, H3-light; SEQ ID NO: 52, H4-light; SEQ ID NO: 53) each having a nucleotide sequence corresponding to the light chain in the TA Cloning Kit Using EcoRI (NEB, R0101S) and XhoI (NEB, R0146S) restriction enzymes, a vector for expression of a humanized antibody was constructed by cloning.

Each of the constructed vectors was amplified using the Qiagen Maxiprep kit (Cat no. 12662), and the transient expression was performed by Freestyle ^TM MAX 293 Expression System (invitrogen) was used. The cell line used was 293 F cell, and was cultured in a suspension culture method using FreeStyle™ 293 Expression Medium as a medium. One day before the transient expression, ^{cells were prepared at a concentration of 5x10 5} cells/ml, and after 24 hours ^{, when the number of cells reached 1x10 6} cells/ml, temporary expression was performed. Transfection was carried out using the liposomal reagent method using Freestyle ^TM MAX reagent (invitrogen). In a 15ml tube, prepare DNA in a ratio of heavy chain DNA: light chain DNA = 1:1, mix with 2ml of OptiPro™ SFM (invtrogen) ^{(A), mix (B) 100 μl of Freestyle TM} MAX reagent and 2 ml of OptiPro™ SFM in another 15 ml tube, mix (A) and (B) and incubate for 15 minutes, The mixture was slowly mixed. After completion of transduction, incubation was carried out at 37 °C, 80% humidity, 8% CO _{2 ,} 130 rpm incubator for 5 days.

The cultured cells were centrifuged to take 100 ml of each supernatant, and purified using AKTA Prime (GE healthcare). A Protein A column (GE healthcare, 17-0405-03) was installed on AKTA Prime, and the culture medium was flowed at a flow rate of 5 ml/min, and eluted with an IgG elution buffer (Thermo Scientific, 21004). This was exchanged with PBS buffer to finally purify the humanized antibody AbF46 (hereinafter referred to as huAbF46). On the other hand, the combination of the heavy chain and light chain of the humanized antibody huAbF46 used in the following Examples is H4-heavy (SEQ ID NO: 42) and H4-light (SEQ ID NO: 46).

1.4. huAbF46 antibody scFv library creation

A gene for constructing an scFv of the huAbF46 antibody was designed using the heavy chain variable region and the light chain variable region of the huAbF46 antibody. Each heavy chain variable region and light chain variable region was designed to be in the form of 'VH-linker-VL', and the linker was designed to have an amino acid sequence of 'GLGGLGGGGSGGGGSGGSSGVGS' (SEQ ID NO: 54). The polynucleotide (SEQ ID NO: 55) encoding the scFv of the designed huAbF46 antibody was synthesized by requesting Bioneer, and a vector for expressing it was shown in SEQ ID NO: 56.

Then, expressed from the vector By analyzing the result, it was confirmed that c-Met-specific binding ability was shown.

1.5. affinity maturation ( affinity maturation ) of library genes for

1.5.1. target CDR selection and primer produce

For affinity maturation of the huAbF46 antibody, six complementary determining regions (CDRs) were defined from the prepared mouse antibody AbF46 by 'Kabat numbering', and each CDR is shown in Table 7 below. .

CDR amino acid sequence CDR-H1 DYYMS (SEQ ID NO: 1) CDR-H2 FIRNKANGYTTEYSASVKG (SEQ ID NO: 2) CDR-H3 DNWFAY (SEQ ID NO: 3) CDR-L1 KSSQSLLASGNQNNYLA (SEQ ID NO: 10) CDR-L2 WASTRVS (SEQ ID NO: 11) CDR-L3 QQSYSAPLT (SEQ ID NO: 12)

Primers were prepared as follows to introduce random sequences of antibody CDRs. The conventional random sequence introduction method used the N codon to introduce the same ratio of bases (25% A, 25% G, 25% C, 25% T) to the site to be mutated, but in this example, the huAbF46 antibody To introduce random bases into the CDRs of Among wild-type nucleotides, 85% of the first and second nucleotides were preserved as they were, and the remaining three bases were introduced by 5% each. In addition, the primer was designed so that the third nucleotide was introduced identically (33% G, 33% C, 33% T).

1.5.2. huAbF46 Library construction of antibodies and c- Met check the binding force to

The construction of the antibody library gene through the random sequence introduction of CDRs was performed using the primers prepared in the same manner as in Reference Example 1.5.1. Using a polynucleotide containing the scFv of the huAbF46 antibody as a template, two PCR fragments were prepared as in the method shown in FIG. Libraries targeting each of the six CDRs were constructed by securing the scFv library gene of the mutated huAbF46 antibody.

For the library thus prepared, the binding ability of the wild-type and each library to c-Met was confirmed, and each library showed a tendency to have a lower binding affinity to c-Met compared to the wild-type, but some c-Met binding ability was lower. Retained mutations were identified.

1.6. from the created library. friendliness Selection of improved antibodies

After improving the binding ability of the library to c-Met from the constructed library, the gene sequence of scFv was analyzed from each individual clone. The secured gene sequences are shown in Table 8, respectively, and they were converted into IgG form. Among the clones below, four types of antibodies produced from L3-1, L3-2, L3-3, and L3-5 were selected and subsequent experiments were performed .

clone name derived library CDR sequence H11-4 CDR-H1 PEYYMS (SEQ ID NO: 22) YC151 CDR-H1 PDYYMS (SEQ ID NO:23) YC193 CDR-H1 SDYYMS (SEQ ID NO: 24) YC244 CDR-H2 RNNANGNT (SEQ ID NO: 25) YC321 CDR-H2 RNKVNGYT (SEQ ID NO: 26) YC354 CDR-H3 DNWLSY (SEQ ID NO: 27) YC374 CDR-H3 DNWLTY (SEQ ID NO: 28) L1-1 CDR-L1 KSSHSLLASGNQNNYLA (SEQ ID NO: 29) L1-3 CDR-L1 KSSRSLLSSGNHKNYLA (SEQ ID NO: 30) L1-4 CDR-L1 KSSKSLLASGNQNNYLA (SEQ ID NO: 31) L1-12 CDR-L1 KSSRSLLASGNQNNYLA (SEQ ID NO: 32) L1-22 CDR-L1 KSSHSLLASGNQNNYLA (SEQ ID NO: 33) L2-9 CDR-L2 WASKRVS (SEQ ID NO: 34) L2-12 CDR-L2 WGSTRVS (SEQ ID NO: 35) L2-16 CDR-L2 WGSTRVP (SEQ ID NO: 36) L3-1 CDR-L3 QQSYSRPYT (SEQ ID NO: 13) L3-2 CDR-L3 GQSYSRPLT (SEQ ID NO: 14) L3-3 CDR-L3 AQSYSHPFS (SEQ ID NO: 15) L3-5 CDR-L3 QQSYSRPFT (SEQ ID NO: 16) L3-32 CDR-L3 QQSYSKPFT (SEQ ID NO: 37)

1.7. of the selected antibody IgG conversion to

The polynucleotide encoding the heavy chains of the four selected antibodies is composed of 'EcoRI-signal sequence-VH-NheI-CH-XhoI' (SEQ ID NO: 38), and in the case of heavy chains, the amino acid of the antibody is not changed after affinity maturation. Therefore, the heavy chain of the huAbF46 antibody was used as it was. However, the hinge region was substituted with the U6-HC7 hinge (SEQ ID NO: 57), not the hinge of human IgG1. The light chain was designed to consist of 'EcoRI-signal sequence-VL-BsiWI-CL-XhoI' and genes were synthesized, and a polynucleotide (sequence No. 58 to SEQ ID NO: 61) were synthesized by requesting Bioneer. Then, a DNA fragment (SEQ ID NO: 38) having a nucleotide sequence corresponding to the heavy chain ^{in the pOptiVEC TM} -TOPO TA Cloning Kit included in Invitrogen's OptiCHO ^TM Antibody Express Kit (Cat no. 12762-019), pcDNA ^TM 3.3 -TOPO A DNA fragment having a nucleotide sequence corresponding to the light chain in the TA Cloning Kit (Cat no. 8300-01) (DNA fragment including CDR-L3 derived from L3-1: SEQ ID NO: 58, CDR-L3 derived from L3-2 included DNA fragment comprising: SEQ ID NO: 59, a DNA fragment comprising CDR-L3 derived from L3-3: DNA fragment comprising SEQ ID NO: 60, CDR-L3 derived from L3-5: SEQ ID NO: 61) to EcoRI (NEB, R0101S), respectively and XhoI (NEB, R0146S) restriction enzymes were used to construct a vector for expression of the antibody matured by cloning.

Each of the constructed vectors was amplified using the Qiagen Maxiprep kit (Cat no. 12662), and the transient expression was performed by Freestyle ^TM MAX 293 Expression System (invitrogen) was used. The cell line used was 293 F cell, and was cultured in a suspension culture method using FreeStyle™ 293 Expression Medium as a medium. One day before the transient expression, ^{cells were prepared at a concentration of 5x10 5} cells/ml, and after 24 hours ^{, when the number of cells reached 1x10 6} cells/ml, temporary expression was performed. Transfection was carried out using the liposomal reagent method using Freestyle ^TM MAX reagent (invitrogen). In a 15ml tube, prepare DNA in a ratio of heavy chain DNA: light chain DNA = 1:1, mix with 2ml of OptiPro™ SFM (invtrogen) ^{(A), mix (B) 100 μl of Freestyle TM} MAX reagent and 2 ml of OptiPro™ SFM in another 15 ml tube, mix (A) and (B) and incubate for 15 minutes, The mixture was slowly mixed. After completion of transduction, incubation was carried out at 37 °C, 80% humidity, 8% CO _{2 ,} 130 rpm incubator for 5 days.

The cultured cells were centrifuged to take 100 ml of each supernatant, and purified using AKTA Prime (GE healthcare). A Protein A column (GE healthcare, 17-0405-03) was installed on AKTA Prime, and the culture medium was flowed at a flow rate of 5 ml/min, and eluted with an IgG elution buffer (Thermo Scientific, 21004). These were exchanged with PBS buffer and finally affinity matured 4 antibodies (hereinafter, huAbF46-H4-A1 (derived from L3-1), huAbF46-H4-A2 (derived from L3-2), huAbF46-H4-A3 (L3- 3), and named huAbF46-H4-A5 (derived from L3-5)) were purified.

1.8. constant region and/or the hinge area substituted huAbF46 - H4 Preparation of -A1

Among the four antibodies selected in Reference Example 1.7, huAbF46-H4-A1, which had the highest c-Met binding affinity and the lowest degree of Akt phosphorylation and c-Met differentiation, was tested in the hinge region. Alternatively, an antibody in which the constant region and the hinge region are substituted was prepared.

An antibody consisting of a heavy chain consisting of a heavy chain variable region of huAbF46-H4-A1, a U6-HC7 hinge, and a human IgG1 constant region, and a light chain consisting of a light chain variable region of huAbF46-H4-A1 and a human kappa constant region, was prepared using the huAbF46 antibody. as -H4-A1(U6-HC7); An antibody consisting of a heavy chain consisting of a heavy chain variable region of huAbF46-H4-A1, a human IgG2 hinge and a human IgG1 constant region, and a light chain consisting of a light chain variable region of huAbF46-H4-A1 and a human kappa constant region were prepared using huAbF46-H4- with A1 (IgG2 hinge); An antibody consisting of a heavy chain consisting of a heavy chain variable region of huAbF46-H4-A1, a human IgG2 hinge and a human IgG2 constant region, and a light chain consisting of a light chain variable region of huAbF46-H4-A1 and a human kappa constant region was prepared using huAbF46-H4- Each was named A1 (IgG2 Fc). On the other hand, in the three types of antibodies, all of histidine (histidine) of the light chain consisting of the human kappa constant region was substituted with tyrosine in order to increase production.

In order to construct the above three types of antibodies, a polynucleotide (SEQ ID NO: 63) encoding a polypeptide (SEQ ID NO: 62) consisting of a heavy chain variable region of huAbF46-H4-A1, a U6-HC7 hinge and a human IgG1 constant region (SEQ ID NO: 63), huAbF46- Polynucleotide (SEQ ID NO: 65) encoding a polypeptide (SEQ ID NO: 64) comprising a heavy chain variable region of H4-A1, a human IgG2 hinge and a human IgG1 constant region, heavy chain variable region of huAbF46-H4-A1, human IgG2 A polynucleotide (SEQ ID NO: 67) encoding a polypeptide (SEQ ID NO: 66) consisting of a hinge and a human IgG2 constant region, a light chain variable region of huAbF46-H4-A1 in which histine 36 is substituted with tyrosine, and a human kappa constant region A polynucleotide (SEQ ID NO: 69) encoding a polypeptide consisting of (SEQ ID NO: 68) was synthesized by requesting Bioneer. Then, a DNA fragment having a nucleotide sequence corresponding to the heavy chain was ^{added to the pOptiVEC TM} -TOPO TA Cloning Kit included in Invitrogen's OptiCHO ^TM Antibody Express Kit (Cat no. 12762-019), pcDNA ^TM 3.3-TOPO A vector for expression of the antibody was constructed by inserting a DNA fragment having a nucleotide sequence corresponding to the light chain into the TA Cloning Kit (Cat no. 8300-01).

Each of the constructed vectors was amplified using the Qiagen Maxiprep kit (Cat no. 12662), and the transient expression was performed by Freestyle ^TM MAX 293 Expression System (invitrogen) was used. The cell line used was 293 F cell, and was cultured in a suspension culture method using FreeStyle™ 293 Expression Medium as a medium. One day before the transient expression, ^{cells were prepared at a concentration of 5x10 5} cells/ml, and after 24 hours ^{, when the number of cells reached 1x10 6} cells/ml, temporary expression was performed. Transfection was carried out using the liposomal reagent method using Freestyle ^TM MAX reagent (invitrogen). In a 15ml tube, prepare DNA in a ratio of heavy chain DNA: light chain DNA = 1:1, mix with 2ml of OptiPro™ SFM (invtrogen) ^{(A), mix (B) 100 μl of Freestyle TM} MAX reagent and 2 ml of OptiPro™ SFM in another 15 ml tube, mix (A) and (B) and incubate for 15 minutes, The mixture was slowly mixed. After completion of transduction, incubation was carried out at 37 °C, 80% humidity, 8% CO _{2 ,} 130 rpm incubator for 5 days.

The cultured cells were centrifuged to take 100 ml of each supernatant, and purified using AKTA Prime (GE healthcare). A Protein A column (GE healthcare, 17-0405-03) was installed on AKTA Prime, and the culture medium was flowed at a flow rate of 5 ml/min, and eluted with an IgG elution buffer (Thermo Scientific, 21004). This was exchanged with PBS buffer and finally three types of antibodies (huAbF46-H4-A1 (U6-HC7), huAbF46-H4-A1 (IgG2 hinge), huAbF46-H4-A1 (IgG2 Fc)) were purified. Among them, huAbF46-H4-A1 (IgG2 Fc) was selected to represent the anti-c-Met antibody according to the present invention and used in the following examples, and for convenience, the antibody was named anti-c-Met antibody L3-1Y/IgG2 did

Reference example 2. Xenograft Model and Test Sample Preparation

14 types of mouse xenograft models in which patient driven tumor tissues (Non-small cell lung cancer: NSCLC) were intraperitoneally transplanted were obtained from Oncotest (Germany).

The candidate drug final form (L3-1Y/IgG2; number of each model (n) = 10) and empty vehicle (control; number of individuals of each model (n) = 10) were administered to the 14 mouse xenograft models, and tumor Reactivity to the antibody was measured by measuring the size of the tissue.

L3-1Y/IgG2 (PBS buffer in case of control) was administered at an amount of 5 mg/kg once a week from the time when the tumor size in the mouse xenograft model ^{grew to 500 mm 3 or more, and the experiment was carried out for a total of 6 weeks.} and the experiment was stopped when the tumor size was ^{greater than 2000 mm 3 .}

The tumor size (mm ³ ) was calculated by volume using the formula of major axis*minor axis*minor axis*1/2, and the discrimination of efficacy groups was performed by rejecting only hypotheses with a p-value of 0.05 or less through ANOVA analysis. That is, the hypothesis that the size distribution of tumors did not change in the group to which the drug was administered compared to the group in which the drug was not administered was tested by ANOVA, and a group with a p-value of 0.05 or less was classified as an ineffective group and a group exceeding it as an efficacy group.

Table 9 below shows the results of the reactivity of the obtained selected samples to L3-1Y/IgG2 treatment:

Responder (Efficacy Group) Non-responder group (non-effective group) sample name LXFA1647, LXFA2158, LXFA526, LXFA623 LXFA1041, LXFA162, LXFA1848, LXFA2201, LXFA289, LXFA297, LXFA400, LXFA749, LXFA923, LXFA983

After completing the experiment, the tumor tissue of the mouse was extracted, and some FFPE (Formalin Fixed Paraffin Embedded) blocks were produced, and the rest were obtained from the tumor tissue using Qiagen RNeasy Mini Kit (Cat. No. 74104), total according to the manufacturer's protocol. RNA was extracted.

The prepared FFPE block is used to measure the surface expression c-MET according to the standard protocol provided by the manufacturer using Ventana MET IHC (immunohistochemistry) (Roche; see US2013089541 A1), and the extracted total RNA is Real Time PCR (RT-PCR) was used for c-MET mRNA expression experiment (MET sense primer: CCTTGAACAGAATCACTG (SEQ ID NO: 272); MET anti-sense primer: CCATGTTTCATGTATGGTA (SEQ ID NO: 273)).

The results obtained using the obtained Ventana MET IHC method are shown in Figure 1a. According to this method, if the IHC score is 2-3, it can be judged as an efficacy group. However, as confirmed in Figure 1a, LXFA297, LXFA983, and LXFA1041 classified as ineffective group also appeared to have an IHC score of 2 to 3, indicating that the selection accuracy of the effective group and the non-effective group was not high by the IHC method. possible (accuracy: about 50%).

On the other hand, RT-PCR results obtained for the six models (LXFA297, LXFA983, LXFA1041, LXFA623, LXFA526, and LXFA1647) shown as the efficacy group in FIG. 1A are shown in FIG. 1B. In Figure 1b, the Y-axis is the Ct value measured by RT-PCR, the X-axis is the obtained IHC score, ◆ indicates the ineffective group, ● indicates the efficacy group. As can be seen in FIG. 1b , according to the RT-PCR results, all of the non-effective groups had a Ct value of 0 or higher, whereas all of the efficacy groups had a Ct value lower than 0. Therefore, it can be seen that the RT-PCR result enables a more accurate distinction between the efficacious group and the non-effective group compared to the case by the conventional IHC method (accuracy: about 71% to about 93%), here If the IHC score is supplementally applied to , more accurate discrimination is possible (eg, when the Ct value of RT-PCR is lower than 0 and the IHC score is 2 to 3, it is selected as an efficacy group).

Example One: of biomarkers Selection

Using the xenograft sample for drug efficacy test for the anti-c-Met antibody L3-1Y/IgG2 prepared in Reference Example 1 (xenograft sample; 15 types of preclinical samples; Reference Example 2), the anti-c-Met antibody L3- For 1Y/IgG2, the gene expression levels of the effective and non-effective groups were measured, and the gene expression difference (Δ log2(exp)) between each group was measured using the obtained results, and genes with many differences were selected.

The gene expression difference was measured using the Affymatrix human u133 plus 2.0 microarray experiment raw data cell file, and using the microarray analysis console provided by the manufacturer, the log2 (probe intensity) value for each probe was measured as a reference. . The probes used at this time are as shown in Table 10:

Gene Probe Sequence(5'-3') Probe Interrogation Target Strandedness THSD7A (213894_at) TTTTTAAGACTTCTTGTCTCTCTCC (SEQ ID NO: 110) 4486 Antisense AACGAGTCCTCAAGTTCAGTATTTT (SEQ ID NO: 111) 4549 Antisense TACAATACGTTTCTACTTTCCCTGA (SEQ ID NO: 112) 4614 Antisense TGATTTTCAAACTGGTTGCCTGCAT (SEQ ID NO: 113) 4636 Antisense GGAAGGCACATTTTTGCACTATATT (SEQ ID NO: 114) 4675 Antisense AGTGCAGCACGATAGGCGCTTAACC (SEQ ID NO: 115) 4700 Antisense TAGGCGCTTAACCAGTATTGCCATA (SEQ ID NO: 116) 4712 Antisense GTATTGCCATAGAAACTGCCTCTTT (SEQ ID NO: 117) 4726 Antisense AACTGCCTCTTTTCATGTGGGATGA (SEQ ID NO: 118) 4739 Antisense GACATTTGCAAGTTCTTGTATCCTG (SEQ ID NO: 119) 4791 Antisense GCTATTACACCTGCTGTACACACAC (SEQ ID NO: 120) 4858 Antisense THSD7A (214920_at) ACTTCTCTATTGACACTTTTACCTC (SEQ ID NO: 121) 2072 Antisense TGACACTTTTACCTCACCGAGGGGG (SEQ ID NO: 122) 2082 Antisense GAACTGCTGTTCCCTAGAATGAAGG (SEQ ID NO:123) 2118 Antisense AGAATGAAGGTCTGTTGTTTGGTTT (SEQ ID NO: 124) 2133 Antisense TTATATGATTTTGCTGGACTATTTC (SEQ ID NO: 125) 2194 Antisense GGACTATTTCACTAGAAACCACGTA (SEQ ID NO: 126) 2209 Antisense GAATAGGACTAACTGATCTCTTTTG (SEQ ID NO: 127) 2234 Antisense AAAGGGGCTGATTTGCTTATTCATC (SEQ ID NO: 128) 2259 Antisense ATGTGGACAGTAATCTTAATTTCAA (SEQ ID NO: 129) 2299 Antisense GAGGATACTACGGTGTAGCTTAAGT (SEQ ID NO: 130) 2334 Antisense AGCACAAATTACTTCTAACAAGGCA (SEQ ID NO: 131) 2407 Antisense THSD7A (230008_at) GTATTTTCCCCTACGTAATGTACAT (SEQ ID NO: 132) 177 Antisense GTACATGTCTTTAGGCCACAGTATT (SEQ ID NO: 133) 196 Antisense AGGTGGCAGTGGTCATTGTAGCTTA (SEQ ID NO: 134) 255 Antisense TAATCAGACCCCTGTTAAGTTCCTG (SEQ ID NO: 135) 278 Antisense CAAGGTAAATTCACGTCTTCCTTCT (SEQ ID NO: 136) 310 Antisense AATAGACCTCTCACACACTTATTTA (SEQ ID NO: 137) 346 Antisense GTCTCTTTCTACTCTTGACAGCTAT (SEQ ID NO: 138) 420 Antisense CTTGACAGCTATTCTTACCTACTTC (SEQ ID NO: 139) 433 Antisense TTCCCACTAAACATGCCCAATTTTT (SEQ ID NO: 140) 455 Antisense TCCTATATTTCCTTCCCTATTAGAA (SEQ ID NO: 141) 499 Antisense GAATCAAAGTGTCACTCACTCAGAG (SEQ ID NO: 142) 521 Antisense MET (213816_s_at) GTTGTCGACACCTACTATGATGATC (SEQ ID NO: 144) 567 Antisense CAGCGTCAACAGAGGGACCTGCCAG (SEQ ID NO: 145) 608 Antisense TTTCCCCACAATCATACTGCTGACA (SEQ ID NO: 146) 642 Antisense AGATAGAAGAGCCCAGCCAGTGTCC (SEQ ID NO: 147) 700 Antisense GGAGCCAAAGTCCTTTCATCTGTAA (SEQ ID NO: 148) 747 Antisense TAAAGGACCGGTTCATCAACTTCTT (SEQ ID NO: 149) 769 Antisense ATTTCCCAGATCATCCATTGCATTC (SEQ ID NO: 150) 820 Antisense ACGGACCAGTCCTACATTGATGTTT (SEQ ID NO: 151) 894 Antisense GAGTTCAGAGATTCTTACCCCATTA (SEQ ID NO: 152) 924 Antisense CTAGATGCTCAGACTTTTCACACAA (SEQ ID NO: 153) 1011 Antisense ATCAGGTTCTGTTCCATAAACTCTG (SEQ ID NO: 154) 1041 Antisense RAB31 (217763_s_at) AACATTGTAATGGCCATCGCTGGAA (SEQ ID NO: 156) 400 Antisense GAAACAAGTGCGACCTCTCAGATAT (SEQ ID NO: 157) 422 Antisense GGAGGTTCCCCTGAAGGATGCTAAG (SEQ ID NO: 158) 450 Antisense TACGCTGAATCCATAGGTGCCATCG (SEQ ID NO: 159) 478 Antisense GTGCCATCGTGGTTGAGACAAGTGC (SEQ ID NO: 160) 494 Antisense TTCAAGGAATCAGCCGCCAGATCCC (SEQ ID NO: 161) 548 Antisense TGAGAAGCCAACCATGCAAGCCAGC (SEQ ID NO: 162) 618 Antisense CGTGGTCCACGGTACTTGAAGAAGC (SEQ ID NO: 163) 666 Antisense ATCCTGTGCACTGCTGAAGGACCCT (SEQ ID NO: 164) 701 Antisense GAGTGAGCACACTGGCTTTGCATCC (SEQ ID NO: 165) 758 Antisense ACCACCACAAAAATGGCCTTTAGTGT (SEQ ID NO: 166) 856 Antisense RAB31 (217764_s_at) GAATATGACGTTACCTTGCAGACTA (SEQ ID NO: 167) 3398 Antisense TTTTTTGTGTGGGCTCCAGTTCTCA (SEQ ID NO: 168) 3570 Antisense GTTCTGCAATGCTCATGGCAAGTTG (SEQ ID NO: 169) 3597 Antisense ACCGACTGGGTATCTAGCTTACTGT (SEQ ID NO: 170) 3668 Antisense ATCATTGTTGAAACCAGACCCTGTA (SEQ ID NO: 171) 3699 Antisense AGACCCTGTAGTCCAGTGGTGCTGC (SEQ ID NO: 172) 3714 Antisense TAAAGAGCTTCCATCTGGGCTGGAC (SEQ ID NO: 173) 3776 Antisense TGGACCCAGTTCTTGCACATACAAG (SEQ ID NO: 174) 3796 Antisense GCACATACAAGACACCGCTGCAGTC (SEQ ID NO: 175) 3810 Antisense ACCGCTGCAGTCAGCTAGGACCTTT (SEQ ID NO: 176) 3823 Antisense GGTTTAACACACACTGATTCATACT (SEQ ID NO: 177) 3915 Antisense FAM126A (223625_at) GACTTACTTTAACAACCAGCCAATC (SEQ ID NO: 179) 1447 Antisense AATCCCTACCTAAGCCTAGTAGCCA (SEQ ID NO: 180) 1468 Antisense GCCATGGTTTGGCTAAGACCGCAGC (SEQ ID NO: 181) 1489 Antisense GTCAGTGGTGTCACAGTCCCACATA (SEQ ID NO: 182) 1542 Antisense ACATAACCCGTCATCTGCTGTTGGT (SEQ ID NO: 183) 1562 Antisense GCCAATAGGTTTTCCGCTTGTAGTC (SEQ ID NO: 184) 1605 Antisense GCAGAGACCTCCTAGTATTAGCATT (SEQ ID NO: 185) 1697 Antisense TTTTCTCCCATAACCTAGTGAACCT (SEQ ID NO: 186) 1752 Antisense GAAAGTACCCTGGGTCTTTCATCCG (SEQ ID NO: 187) 1801 Antisense CTTTCATCCGTATTCCTGACAGGAG (SEQ ID NO: 188) 1816 Antisense GGAGCCCTGATGTCTTAAATTCTGA (SEQ ID NO: 189) 1837 Antisense FAM126A CCCGGCTCGGAGCAAGCGGTGCAG (SEQ ID NO: 190) 33 Antisense GGAGCGATTCCCATTCGAGGAGTTTT (SEQ ID NO: 191) 63 Antisense TCTCATTTTAATACAACACCCGCCT (SEQ ID NO: 192) 92 Antisense AACACCCGCCTCTTAGAGGCAGCAG (SEQ ID NO: 193) 106 Antisense CAGACCAGTCCAGCCAGGTCAAGGT (SEQ ID NO: 194) 128 Antisense TGTGGACCGCACAACGGGGTGCACA (SEQ ID NO: 195) 152 Antisense TAAACGAGCCCTGGATCTGCAAAGC (SEQ ID NO: 196) 214 Antisense GTGATCCCAACCTTAGCAACATAAT (SEQ ID NO: 197) 263 Antisense TATATGTCAGGTGCCAGTGCTATGG (SEQ ID NO: 198) 434 Antisense ATACCATTTATTACCACTTCTCAGT (SEQ ID NO: 199) 480 Antisense GAGGCTGTAACTCTGGTTGTCGAAA (SEQ ID NO: 200) 511 Antisense PHC1 (218338_at) TTTCACGTACCTTAATCCAATCTTT (SEQ ID NO: 202) 3474 Antisense AGAACTAGGACTGCTCAGCCTTATC (SEQ ID NO: 203) 3517 Antisense GCCCAGGTCTTAATTCTCCAAGAGG (SEQ ID NO: 204) 3559 Antisense GGTGGAATGTCAGGTTGCCTGCCCA (SEQ ID NO: 205) 3616 Antisense AGGGTTTTTCTAGCTTGTGTGACAG (SEQ ID NO: 206) 3652 Antisense TTGTCACTTACTCCCTTGTGATTGA (SEQ ID NO: 207) 3740 Antisense TGATTGAATTTTTTCTCCTGCATCC (SEQ ID NO: 208) 3758 Antisense AGAGACTTGGTTGGCATCTTCTGCT (SEQ ID NO: 209) 3806 Antisense GGCACATGTGGCTTGTTGTCATTCTT (SEQ ID NO: 210) 3856 Antisense TGTTCCCCTCCAATTTATGTTATTT (SEQ ID NO: 211) 3893 Antisense GTACCTGCCTTAGGCACTATTCCTT (SEQ ID NO: 212) 4002 Antisense CHML (226350_at) GCAACTTTGACTTAGTTCATGCTAT (SEQ ID NO: 214) 2504 Antisense CTGTTTTAATTGCATGTGTCCTTAT (SEQ ID NO: 215) 2542 Antisense GTGTCCTTATAGCAGGCAGCATTGTG (SEQ ID NO: 216) 2557 Antisense GCAGCATTGTGTATTAGTAGCCTTT (SEQ ID NO: 217) 2571 Antisense AGGGCTTTATAACTGATCTTTTGAC (SEQ ID NO: 218) 2624 Antisense GATCTTTTGACATACTCACTTTGAG (SEQ ID NO: 219) 2638 Antisense CACTTTGAGTGGCATATGCCCAGGA (SEQ ID NO: 220) 2654 Antisense AAGTTTTCTAGCAGTTCCACTCAGA (SEQ ID NO: 221) 2712 Antisense GTTCCACTCAGATAACTTTAAGGGG (SEQ ID NO: 222) 2725 Antisense TGGTGTATTGCTAGTGCTATCACAG (SEQ ID NO: 223) 2788 Antisense ATTGTGTTTACTGATACATGTGAAA (SEQ ID NO: 224) 2898 Antisense FAM126A (227239_at) TCTAGTCCTTTAATGAGCATGAATT (SEQ ID NO: 225) 1179 Antisense TATACTTCTACATTTGTTGCTTAGT (SEQ ID NO: 226) 1204 Antisense ATATTGTCTTCTATACTTTGTAACT (SEQ ID NO: 227) 1304 Antisense ATTTCACGTATTGTTGCTTTCTCTT (SEQ ID NO: 228) 1449 Antisense GTTGCTTTCTCTTATATGGAACTTA (SEQ ID NO: 229) 1461 Antisense GGAACTTATTGTGTACCTCTTACCT (SEQ ID NO: 230) 1478 Antisense GTATTCCTAGAGTTTACATTCCTAA (SEQ ID NO: 231) 1562 Antisense ACGACGACTTTGGCTATTTTTGTGT (SEQ ID NO: 232) 1594 Antisense GTTCCCTACCTTCTTAAGGCTATGG (SEQ ID NO: 233) 1619 Antisense ATTTGTGTAAATGTTCTCCATATGT (SEQ ID NO: 234) 1680 Antisense CAAGTGTTGCCTCTTGTTTTATTGA (SEQ ID NO: 235) 1721 Antisense ST8SIA4 (242943_at) TTTATTTTGCACGGCTCTAAACCTC (SEQ ID NO: 237) 302 Antisense TAAACCTCCATGTTATTTTCCAGTG (SEQ ID NO: 238) 319 Antisense GGTGTAGAAGGTACCAGCTAAAGTG (SEQ ID NO: 239) 343 Antisense AGATGTTCCATGTCATCAGAGATGG (SEQ ID NO: 240) 402 Antisense GGTACCAAAGATTACACTTGTGTTT (SEQ ID NO: 241) 455 Antisense ACTTGTGTTTCTACACAGCAAACCA (SEQ ID NO: 242) 470 Antisense GCTATTAATGTGAAAGTTGTCTCTA (SEQ ID NO: 243) 543 Antisense ATGTTTTTCACACCTTTTGCATTAC (SEQ ID NO: 244) 611 Antisense TTTTCACACCTTTTGCATTACATAA (SEQ ID NO: 245) 615 Antisense AATTTTGTGGAAGCATTTTGCCCTT (SEQ ID NO: 246) 641 Antisense GGAAGCATTTTGCCCTTTAGAATAA (SEQ ID NO: 247) 649 Antisense CAV1 (212097_at) GAATTTCACCTGTAAACCTGAGTCG (SEQ ID NO: 249) 1175 Antisense CAGAAAGCTGCCTGGTATATCCAAA (SEQ ID NO: 250) 1202 Antisense TATTCCTCCTGCTCATATTGTGATT (SEQ ID NO: 251) 1235 Antisense GTCTTCCTGACACTTTAATTACCAA (SEQ ID NO: 252) 1353 Antisense TACCAACCTGTTACCTACTTTGACT (SEQ ID NO: 253) 1372 Antisense GTTACCTACTTTGACTTTTTGCATT (SEQ ID NO: 254) 1381 Antisense ATGTGCTATACTGCATACTTTTTAA (SEQ ID NO: 255) 1463 Antisense AACTGTGTATTCCAAGACATGTCTG (SEQ ID NO: 256) 1556 Antisense CATAGATGCTTAGTCCCTCATGCAA (SEQ ID NO: 257) 1586 Antisense AATTTTTTATCATGCATGTCCTGTA (SEQ ID NO: 258) 1668 Antisense TAAAGGTTACAAGCCTGCACAATAA (SEQ ID NO: 259) 1691 Antisense

Based on the difference between the effective group and the non-effective group, the differences were sorted in order from the largest difference to selection.

The obtained results are shown in Table 11 below (in the table below, the larger the delta expFold, the greater the difference in expression between the effective group and the non-effective group):

As can be seen in Table 11, the expression difference between the efficacious group and the non-effective group was shown in the order of THSD7A, MET, RAB31, FAM126A, PHC1, CHML, ST8SIA4, and CAV1.

These 8 genes were selected as biomarkers for the detection of anti-c-Met antibody efficacy.

Example 2: Standard marker's Selection

A total of 120 Lung cancer adenocarcinoma microarray data (public DB - GEO: gene expression omnibus; http://www.ncbi.nlm.nih.gov/geo/) were used to select genes with less variation in gene expression levels. .

For NSCLC tumor driven total RNA obtained from GEO, log2(int) value for each probe was obtained using affymetrix U133 plus2.0 microarray raw data (cell file), and the gene with the least coefficient of variation (CV) between 120 samples are listed, and a gene having a log2 (int) value similar to the distribution of the target gene (eight biomarkers selected in Example 1) was selected. The primers used at this time are summarized in Table 12 below:

Gene Sense Primer Position Tm Anti-sense Primer Position Tm RPL23A GAGAGAAGAAGGCATATG (SEQ ID NO: 286) 419 57.9 TGGACTCAGTTTAGATGA (SEQ ID NO: 287) 505 58.2 TPT1 GGCAATTATTTTGGATCTATC (SEQ ID NO: 288) 620 58.7 CAGTCCCATTTGTCTTAA (SEQ ID NO: 289) 707 57.9 EEF1A1 CAGGACACAGAGACTTTA (SEQ ID NO: 290) 341 59.3 CAGCTTCAAATTCACCAA (SEQ ID NO: 291) 439 59.6 SRSF3 CGAGAGCTAGATGGAAGA (SEQ ID NO: 292) 361 61.3 GGCCACGATTTCTACTTC (SEQ ID NO: 293) 445 61.6 TUT1 GGTGTATCGAGTCCAAAC (SEQ ID NO: 294) 1214 61.2 CAGGAAACGGGAGTTATG (SEQ ID NO: 295) 1340 61.2 HNRNC CAAGCAGTAGAGATGAAG (SEQ ID NO: 296) 914 58.2 CTCCATCTTCACATTAGTC (SEQ ID NO: 297) 1000 58.5 HUWE1 CAAGGTCTAATCATGCTG (SEQ ID NO: 298) 2499 58.9 CTGCTGGGTAGAATTAAAG (SEQ ID NO: 299) 2590 59.1 WDR90 CTCTGGAGACAAGGATGG (SEQ ID NO: 300) 4677 62.6 GACACAGATGGTAGAGATTG (SEQ ID NO: 301) 4782 61.3 MATR3 GGTGAGAAAGACACAAAG (SEQ ID NO: 302) 2681 59.3 CTGCTTCTTCTTCATCTAC (SEQ ID NO: 303) 2774 58.8 SMARCA4 GTACCTCATGGAGCACAA (SEQ ID NO: 304) 2456 62.9 CCTTGTAAGACACCTTCAC (SEQ ID NO: 305) 2580 61.6

The obtained results are shown in FIGS. 2A and 2B. As shown in Figure 2a, 10 genes with low gene expression fluctuations, namely, EEF1A1, RPL23A, TPT1, HUWE1, MATR3, SRSF3, HNRNPC, SMARCA4, WDR90, and TUT1 were selected as reference markers.

For the 10 selected reference markers, variance and classification performance differences were measured compared to the existing control gene (Oncotype DX ^{TM; see FIG. 2B).}

The probes and primers used for the 10 selected reference markers are summarized in Tables 13 and 14 below, respectively:

Gene Probe Sequence (5'-3') Position Tm RPL23A ACTGGCTCCTGATTACGATGCTT (SEQ ID NO: 260) 441 69.1 TPT1 CATAACTGGCTTCTGCTTGTCATCC (SEQ ID NO: 261) 650 69 EEF1A1 CCAGCAGCAACAATCAGGACAG (SEQ ID NO: 262) 419 69.1 SRSF3 TTCCACTCTTACACGGCAGC (SEQ ID NO: 263) 408 67.6 TUT1 CCTGTGGTCAAGTTCTGTCATCG (SEQ ID NO: 264) 1251 68.3 HNRNC CTGCTGCTCTGCTCCTCTTCT (SEQ ID NO: 265) 963 69.1 HUWE1 TCCTCTTCCTCCTCATCCTCACT (SEQ ID NO: 266) 2553 69 WDR90 TGGTCACTCAGCACACGGAA (SEQ ID NO: 267) 4751 69.1 MATR3 TGACCAGACAGAGGCAGGAACC (SEQ ID NO: 268) 2701 69 SMARCA4 CCTTCCTCATCATCGTGCCTCT (SEQ ID NO: 269) 2488 69

Gene Sense Primer Position Tm Anti-sense Primer Position Tm RPL23A GAGAGAAGAAGGCATATG (SEQ ID NO: 286) 419 57.9 TGGACTCAGTTTAGATGA (SEQ ID NO: 287) 505 58.2 TPT1 GGCAATTATTTTGGATCTATC (SEQ ID NO: 288) 620 58.7 CAGTCCCATTTGTCTTAA (SEQ ID NO: 289) 707 57.9 EEF1A1 CAGGACACAGAGACTTTA (SEQ ID NO: 290) 341 59.3 CAGCTTCAAATTCACCAA (SEQ ID NO: 291) 439 59.6 SRSF3 CGAGAGCTAGATGGAAGA (SEQ ID NO: 292) 361 61.3 GGCCACGATTTCTACTTC (SEQ ID NO: 293) 445 61.6 TUT1 GGTGTATCGAGTCCAAAC (SEQ ID NO: 294) 1214 61.2 CAGGAAACGGGAGTTATG (SEQ ID NO: 295) 1340 61.2 HNRNC CAAGCAGTAGAGATGAAG (SEQ ID NO: 296) 914 58.2 CTCCATCTTCACATTAGTC (SEQ ID NO: 297) 1000 58.5 HUWE1 CAAGGTCTAATCATGCTG (SEQ ID NO: 298) 2499 58.9 CTGCTGGGTAGAATTAAAG (SEQ ID NO: 299) 2590 59.1 WDR90 CTCTGGAGACAAGGATGG (SEQ ID NO: 300) 4677 62.6 GACACAGATGGTAGAGATTG (SEQ ID NO: 301) 4782 61.3 MATR3 GGTGAGAAAGACACAAAG (SEQ ID NO: 302) 2681 59.3 CTGCTTCTTCTTCATCTAC (SEQ ID NO: 303) 2774 58.8 SMARCA4 GTACCTCATGGAGCACAA (SEQ ID NO: 304) 2456 62.9 CCTTGTAAGACACCTTCAC (SEQ ID NO: 305) 2580 61.6

Using the 14 NSCLC mRNA samples prepared in Reference Example 2, the variance of the ct values was measured for the 10 selected reference markers and the existing control gene by the above method.

The obtained results are shown in FIGS. 3a (control gene) and 3b (selected reference markers). As shown in FIGS. 3A and 3B , the average CV (Coefficient of Variation) value of the 10 reference markers selected in the present invention was about 11.770, which was ^{significantly reduced compared to the existing control gene (Oncotype DX TM} ) (average CV=15.40335). It can be confirmed that, among the 10 reference markers, 5 genes of RPL23A, TPT1, MATR3, SRSF3, and HNRNPC had very small expression level fluctuations (average CV of 5 genes = 8.39).

Example 3: selected biomarker and standard marker term c- Met antibody Efficacy group Selection

The selected biomarkers and reference markers were applied to the mouse xenograft model prepared in Reference Example 1, and their efficacy/non-efficacy group selection accuracy was tested.

To this end, PCR was performed under the conditions of Table 17 using the probes in Table 15 and the primers in Table 16 below for total RNA extracted from the tumor tissue of the mouse xenograft model, and the 8 biomarkers and 5 types Ct values of reference markers (TPT1, EEF1M, TUT1, MATR3, and SMARCA4) were obtained.

Gene Probe Sequence (5'-3') Position Tm THSD7A CCTCTTGAACTTGCGTGCCTG (SEQ ID NO: 109) 2,053 69.1 MET CTTCACTTCGCAGGCAGATTCC (SEQ ID NO: 143) 3,692 68.8 RAB31 ATACGCTGAATCCATAGGTGCCA (SEQ ID NO: 155) 583 69 FAM126A TCTCTGCTGACCTGATTGATGCT (SEQ ID NO: 178) 1,785 68.8 PHC1 ACCTCCTCACCTGTTGTAGCC (SEQ ID NO: 201) 1987 68.8 ST8SIA4 ACTGCTCTTGACCACTGACACA (SEQ ID NO: 236) 631 69 CHML CCTCTGGCTGCTTATCATCACC (SEQ ID NO: 213) 2,043 67.9 CAV1 TAGATAACAAGACCTCAGTGCCTTCC (SEQ ID NO: 248) 1,453 68.9 RPL23A ACTGGCTCCTGATTACGATGCTT (SEQ ID NO: 260) 441 69.1 TPT1 CATAACTGGCTTCTGCTTGTCATCC (SEQ ID NO: 261) 650 69 EEF1A1 CCAGCAGCAACAATCAGGACAG (SEQ ID NO: 262) 419 69.1 SRSF3 TTCCACTCTTACACGGCAGC (SEQ ID NO: 263) 408 67.6 TUT1 CCTGTGGTCAAGTTCTGTCATCG (SEQ ID NO: 264) 1251 68.3 HNRNC CTGCTGCTCTGCTCCTCTTCT (SEQ ID NO: 265) 963 69.1 HUWE1 TCCTCTTCCTCCTCATCCTCACT (SEQ ID NO: 266) 2553 69 WDR90 TGGTCACTCAGCACACGGAA (SEQ ID NO: 267) 4751 69.1 MATR3 TGACCAGACAGAGGCAGGAACC (SEQ ID NO: 268) 2701 69 SMARCA4 CCTTCCTCATCATCGTGCCTCT (SEQ ID NO: 269) 2488 69

Gene Sense Primer Position Tm Anti-sense Primer Position Tm THSD7A GCCTGTTATGACTGGAAA (SEQ ID NO: 270) 1,966 60.7 CTGTCAACTTCTTCTCCA (SEQ ID NO: 271) 2,090 59.9 MET CCTTGAACAGAATCACTG (SEQ ID NO: 272) 3,573 59 CCATGTTTCATGTATGGTA (SEQ ID NO: 273) 3,729 58.4 FAM126A GCTTGTAGTCTCCAAGAA (SEQ ID NO: 274) 1,702 60 GGACAGAGTAATGCTAATAC (SEQ ID NO: 275) 1,812 58.9 PHC1 GACAGCACATGTGGTAAA (SEQ ID NO: 276) 1,956 61.4 CACAGACTGCATATAGAAGG (SEQ ID NO: 277) 2,040 61.4 RAB31 CTCAGATATTAGGGAGGTTC (SEQ ID NO: 278) 544 60.2 GCTGATTCCTTGAAAGAG (SEQ ID NO: 279) 667 59.1 ST8SIA4 GCACAATGTAGAAGGTTG (SEQ ID NO: 280) 523 59.8 CAAGCACATAGTGTATGAC (SEQ ID NO: 281) 665 59.5 CHML CTCCAAATCCAGAAGACA (SEQ ID NO: 282) 1,993 60 GGCCATTACTACATTATTGG (SEQ ID NO: 283) 2,072 59.9 CAV1 CTGTGCCTGAATATTTTGTTA (SEQ ID NO: 284) 1,431 59.7 CTGAGTTAGACCCTATTTGA (SEQ ID NO: 285) 1,518 59.9 RPL23A GAGAGAAGAAGGCATATG (SEQ ID NO: 286) 419 57.9 TGGACTCAGTTTAGATGA (SEQ ID NO: 287) 505 58.2 TPT1 GGCAATTATTTTGGATCTATC (SEQ ID NO: 288) 620 58.7 CAGTCCCATTTGTCTTAA (SEQ ID NO: 289) 707 57.9 EEF1A1 CAGGACACAGAGACTTTA (SEQ ID NO: 290) 341 59.3 CAGCTTCAAATTCACCAA (SEQ ID NO: 291) 439 59.6 SRSF3 CGAGAGCTAGATGGAAGA (SEQ ID NO: 292) 361 61.3 GGCCACGATTTCTACTTC (SEQ ID NO: 293) 445 61.6 TUT1 GGTGTATCGAGTCCAAAC (SEQ ID NO: 294) 1214 61.2 CAGGAAACGGGAGTTATG (SEQ ID NO: 295) 1340 61.2 HNRNC CAAGCAGTAGAGATGAAG (SEQ ID NO: 296) 914 58.2 CTCCATCTTCACATTAGTC (SEQ ID NO: 297) 1000 58.5 HUWE1 CAAGGTCTAATCATGCTG (SEQ ID NO: 298) 2499 58.9 CTGCTGGGTAGAATTAAAG (SEQ ID NO: 299) 2590 59.1 WDR90 CTCTGGAGACAAGGATGG (SEQ ID NO: 300) 4677 62.6 GACACAGATGGTAGAGATTG (SEQ ID NO: 301) 4782 61.3 MATR3 GGTGAGAAAGACACAAAG (SEQ ID NO: 302) 2681 59.3 CTGCTTCTTCTTCATCTAC (SEQ ID NO: 303) 2774 58.8 SMARCA4 GTACCTCATGGAGCACAA (SEQ ID NO: 304) 2456 62.9 CCTTGTAAGACACCTTCAC (SEQ ID NO: 305) 2580 61.6

At this time, the judgment of the effective group and the non-effective group was performed as shown in Table 18 below:

Gene Value classifier Judgment CAV1 2.4641667 up efficacy CMHL 5.0303333 down efficacy FAM126A 7.0321667 up efficacy MET 4.9 up efficacy PHC1 8.4125 down efficacy RAB31 4.8678333 up efficacy ST8SIA4 12.038833 up efficacy THSD7A 8.3295 up efficacy

(Value:

[Min(efficacy value (ΔCt)) + Max(non-efficacy value (ΔCt))]/2 (for CAV1, FAM126A, MET, RAB31, RAB31, ST8SIA4, and THSD7A),

[Min(non-efficacy value (ΔCt)) + Max(efficacy value (ΔCt))]/2 (for CMHL and PHC1);

ΔCt: mean Ct of 5 reference markers (TPT1, EEF1M, TUT1, MATR3, and SMARCA4) - Ct of the corresponding biomarker;

Min(efficacy value (ΔCt)): the minimum ΔCt value in the efficacy group;

Max(non-efficacy value (ΔCt)): the maximum ΔCt value of the non-efficacy group;

Min(non-efficacy value (ΔCt)): the minimum ΔCt value of the non-efficacy group; and

Max(efficacy value (ΔCt)): the maximum ΔCt value of the efficacy group)

ΔCt calculated for each biomarker was compared with the values in Table 17, and in the case of CAV1, FAM126A, MET, RAB31, RAB31, ST8SIA4, and THSD7A, efficacy when the ΔCt value for each gene is higher than the value in Table 17 It was determined as a group, and in the case of CMHL and PHC1, when the ΔCt value for each gene was lower than the value in Table 17, it was determined as an efficacy group.

Table 19 below shows the accuracy and “ΔFold” value for determining the efficacy and non-efficacy groups for the 14 mouse xenograft models prepared in Reference Example 2 in the same manner as described above.

ID Accuracy Δ Fold THSD7A 0.86 0.49 MET 0.86 0.79 RAB31 0.79 0.53 FAM126A 0.64 0.82 PHC1 0.93 0.33 CHML 0.93 0.27 ST8SIA4 0.93 1.36 CAV1 0.79 1.96

Accuracy: The closer to 1 (corresponding to 100%), the higher the accuracy is, and it can be obtained by the following formula:

Accuracy={(TP+TN)/14}

(TP: the number of samples that showed positive (with drug) efficacy in both the predicted results using the biomarker and the actual test results treated with L3-1Y/IgG2 (see Table 9))

(TN: the number of samples that showed negative efficacy (no efficacy) in both the predicted results using the corresponding biomarker and the actual test results treated with L3-1Y/IgG2 (see Table 9);

ΔFold: delta Ct (control gene (reference marker) Ct (average of reference marker Ct values when two or more reference markers are used) - target gene (biomarker) Ct) difference between responder and non-responder group, response Indicates the range of mRNA expression values that can be divided into group and non-responder)

As shown in Table 13, by using the biomarkers and reference markers selected in the present invention, the efficacy and ineffective groups of the anti-c-Met antibody can be determined with an accuracy of about 60% or more, for example, about 80% or more.

Korea Cell Line Research Foundation KCLRFBP00220 20091006

<110> Samsung Electronics Co. Ltd <120> Biomarker for predicting effect of an anti-c-Met antibody <130> DPP20151569KR <140> KR <141> 2014-04-03 <150> KR10-2014-0040146 <151> 2014-04-03 <160> 306 <170> KopatentIn 1.71 <210> 1 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> heavy chain CDR1 of AbF46 <400> 1 Asp Tyr Tyr Met Ser 1 5 <210> 2 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> heavy chain CDR2 of AbF46 <400> 2 Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala Ser 1 5 10 15 Val Lys Gly <210> 3 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> heavy chain CDR3 of AbF46 <400> 3 Asp Asn Trp Phe Ala Tyr 1 5 <210> 4 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> heavy chain CDR1 of c-Met antibody <220> <221> MOD_RES <222> (1) <223> X is Pro or Ser or absent <220> <221> MOD_RES <222> (2) <223> X is Glu or Asp <400> 4 Xaa Xaa Tyr Tyr Met Ser 1 5 <210> 5 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> heavy chain CDR2 of c-Met antibody <220> <221> MOD_RES <222> (3) <223> X is Asn or Lys <220> <221> MOD_RES <222> (4) <223> X is Ala or Val <220> <221> MOD_RES <222> (7) <223> X is Asn or Thr <400> 5 Arg Asn Xaa Xaa Asn Gly Xaa Thr 1 5 <210> 6 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> heavy chain CDR3 of c-Met antibody <220> <221> MOD_RES <222> (5) <223> X is Ser or Thr <400> 6 Asp Asn Trp Leu Xaa Tyr 1 5 <210> 7 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> light chain CDR1 of c-Met antibody <220> <221> MOD_RES <222> (4) <223> X is His, Arg, Gln or Lys <220> <221> MOD_RES <222> (12) <223> X is His or Gln <220> <221> MOD_RES <222> (13) <223> X is Lys or Asn <220> <221> MOD_RES <222> (9) <223> X is Ser or Trp <400> 7 Lys Ser Ser Xaa Ser Leu Leu Ala Xaa Gly Asn Xaa Xaa Asn Tyr Leu 1 5 10 15 Ala <210> 8 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> light chain CDR2 of c-Met antibody <220> <221> MOD_RES <222> (2) <223> X is Ala or Gly <220> <221> MOD_RES <222> (4) <223> X is Thr or Lys <220> <221> MOD_RES <222> (7) <223> X is Ser or Pro <400> 8 Trp Xaa Ser Xaa Arg Val Xaa 1 5 <210> 9 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> light chain CDR3 of c-Met antibody <220> <221> MOD_RES <222> (1) <223> X is Gly, Ala or Gln <220> <221> MOD_RES <222> (6) <223> X is Arg, His, Ser, Ala, Gly or Lys <220> <221> MOD_RES <222> (8) <223> X is Leu, Tyr, Phe or Met <400> 9 Xaa Gln Ser Tyr Ser Xaa Pro Xaa Thr 1 5 <210> 10 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> light chain CDR1 of AbF46 <400> 10 Lys Ser Ser Gln Ser Leu Leu Ala Ser Gly Asn Gln Asn Asn Tyr Leu 1 5 10 15 Ala <210> 11 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> light chain CDR2 of AbF46 <400> 11 Trp Ala Ser Thr Arg Val Ser 1 5 <210> 12 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> light chain CDR3 of AbF46 <400> 12 Gln Gln Ser Tyr Ser Ala Pro Leu Thr 1 5 <210> 13 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 derived from L3-1 clone <400> 13 Gln Gln Ser Tyr Ser Arg Pro Tyr Thr 1 5 <210> 14 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 derived from L3-2 clone <400> 14 Gly Gln Ser Tyr Ser Arg Pro Leu Thr 1 5 <210> 15 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 derived from L3-3 clone <400> 15 Ala Gln Ser Tyr Ser His Pro Phe Ser 1 5 <210> 16 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 derived from L3-5 clone <400> 16 Gln Gln Ser Tyr Ser Arg Pro Phe Thr 1 5 <210> 17 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> heavy chain variable region of anti c-Met humanized antibody (huAbF46-H4) <400> 17 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 Thr Asp Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 18 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of anti c-Met humanized antibody (huAbF46-H4) <400> 18 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 Lys Ser Ser Gln Ser Leu Leu Ala Ser 20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys 35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val 50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 85 90 95 Ser Tyr Ser Arg Pro Tyr Thr Phe Gly Gin Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg <210> 19 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of anti c-Met humanized antibody (huAbF46-H4) <400> 19 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 Lys Ser Ser Gln Ser Leu Leu Ala Ser 20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys 35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val 50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gln 85 90 95 Ser Tyr Ser Arg Pro Leu Thr Phe Gly Gin Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg <210> 20 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of anti c-Met humanized antibody (huAbF46-H4) <400> 20 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser 20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys 35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val 50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln 85 90 95 Ser Tyr Ser His Pro Phe Ser Phe Gly Gin Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg <210> 21 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of anti c-Met humanized antibody (huAbF46-H4) <400> 21 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 Lys Ser Ser Gln Ser Leu Leu Ala Ser 20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys 35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val 50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 85 90 95 Ser Tyr Ser Arg Pro Phe Thr Phe Gly Gin Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg <210> 22 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 derived from H11-4 clone <400> 22 Pro Glu Tyr Tyr Met Ser 1 5 <210> 23 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 derived from YC151 clone <400> 23 Pro Asp Tyr Tyr Met Ser 1 5 <210> 24 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 derived from YC193 clone <400> 24 Ser Asp Tyr Tyr Met Ser 1 5 <210> 25 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 derived from YC244 clone <400> 25 Arg Asn Asn Ala Asn Gly Asn Thr 1 5 <210> 26 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 derived from YC321 clone <400> 26 Arg Asn Lys Val Asn Gly Tyr Thr 1 5 <210> 27 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3 derived from YC354 clone <400> 27 Asp Asn Trp Leu Ser Tyr 1 5 <210> 28 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3 derived from YC374 clone <400> 28 Asp Asn Trp Leu Thr Tyr 1 5 <210> 29 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 derived from L1-1 clone <400> 29 Lys Ser Ser His Ser Leu Leu Ala Ser Gly Asn Gln Asn Asn Tyr Leu 1 5 10 15 Ala <210> 30 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 derived from L1-3 clone <400> 30 Lys Ser Ser Arg Ser Leu Leu Ser Ser Ser Gly Asn His Lys Asn Tyr Leu 1 5 10 15 Ala <210> 31 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 derived from L1-4 clone <400> 31 Lys Ser Ser Lys Ser Leu Leu Ala Ser Gly Asn Gln Asn Asn Tyr Leu 1 5 10 15 Ala <210> 32 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 derived from L1-12 clone <400> 32 Lys Ser Ser Arg Ser Leu Leu Ala Ser Gly Asn Gln Asn Asn Tyr Leu 1 5 10 15 Ala <210> 33 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 derived from L1-22 clone <400> 33 Lys Ser Ser His Ser Leu Leu Ala Ser Gly Asn Gln Asn Asn Tyr Leu 1 5 10 15 Ala <210> 34 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 derived from L2-9 clone <400> 34 Trp Ala Ser Lys Arg Val Ser 1 5 <210> 35 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 derived from L2-12 clone <400> 35 Trp Gly Ser Thr Arg Val Ser 1 5 <210> 36 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2 derived from L2-16 clone <400> 36 Trp Gly Ser Thr Arg Val Pro 1 5 <210> 37 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3 derived from L3-32 clone <400> 37 Gln Gln Ser Tyr Ser Lys Pro Phe Thr 1 5 <210> 38 <211> 1416 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of heavy chain of chAbF46 <220> <221> misc_feature <222> (1)..(6) <223> EcoRI restriction site <220> <221> misc_feature <222> (7)..(66) <223> signal sequence <220> <221> misc_feature <222> (67)..(417) <223> VH - heavy chain variable region <220> <221> misc_feature <222> (418)..(423) <223> NdeI restriction site <220> <221> misc_feature <222> (418)..(1407) <223> CH - heavy chain constant region <220> <221> misc_feature <222> (1408)..(1410) <223> TGA - stop codon <220> <221> misc_feature <222> (1411)..(1416) <223> XhoI restriction site <400> 38 gaattcgccg ccaccatgga atggagctgg gtttttctcg taacactttt aaatggtatc 60 cagtgtgagg tgaagctggt ggagtctgga ggaggcttgg tacagcctgg gggttctctg 120 agactctcct gtgcaacttc tgggttcacc ttcactgatt actacatgag ctgggtccgc 180 cagcctccag gaaaggcact tgagtggttg ggttttatta gaaacaaagc taatggttac 240 acaacagagt acagtgcatc tgtgaagggt cggttcacca tctccagaga taattcccaa 300 agcatcctct atcttcaaat ggacaccctg agagctgagg acagtgccac ttattactgt 360 gcaagagata actggtttgc ttactggggc caagggactc tggtcactgt ctctgcagct 420 agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 480 acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540 aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 600 ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 660 atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 720 tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 780 tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 840 gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 900 gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 960 acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 1020 tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1080 gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggaggagatg 1140 accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1200 gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1260 gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1320 caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1380 aagagcctct ccctgtctcc gggtaaatga ctcgag 1416 <210> 39 <211> 759 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of light chain of chAbF46 <220> <221> misc_difference <222> (1)..(6) <223> EcoRI restriction site <220> <221> misc_difference <222> (7)..(90) <223> signal sequence <220> <221> misc_difference <222> (91)..(432) <223> VL - light chain variable region <220> <221> misc_difference <222> (430)..(435) <223> BsiWI restriction site <220> <221> misc_difference <222> (433)..(750) <223> CL - light chain constant region <220> <221> misc_difference <222> (751)..(753) <223> stop codon <220> <221> misc_difference <222> (754)..(759) <223> XhoI restriction site <400> 39 gaattcacta gtgattaatt cgccgccacc atggattcac aggcccaggt cctcatgttg 60 ctgctgctat cggtatctgg tacctgtgga gacattttga tgacccagtc tccatcctcc 120 ctgactgtgt cagcaggaga gaaggtcact atgagctgca agtccagtca gagtctttta 180 gctagtggca accaaaataa ctacttggcc tggcaccagc agaaaccagg acgatctcct 240 aaaatgctga taatttgggc atccactagg gtatctggag tccctgatcg cttcataggc 300 agtggatctg ggacggattt cactctgacc atcaacagtg tgcaggctga agatctggct 360 gtttattact gtcagcagtc ctacagcgct ccgctcacgt tcggtgctgg gaccaagctg 420 gagctgaaac gtacggtggc tgcaccatct gtcttcatct tcccgccatc tgatgagcag 480 ttgaaatctg gaactgcctc tgttgtgtgc ctgctgaata acttctatcc cagagaggcc 540 aaagtacagt ggaaggtgga taacgccctc caatcgggta actcccagga gagtgtcaca 600 gagcaggaca gcaaggacag cacctacagc ctcagcagca ccctgacgct gagcaaagca 660 gactacgaga aacacaaagt ctacgcctgc gaagtcaccc atcagggcct gagctcgccc 720 gtcacaaaga gcttcaacag gggagagtgt tgactcgag 759 <210> 40 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of H1-heavy <400> 40 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 Thr Asp Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 41 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of H3-heavy <400> 41 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 Thr Asp Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 42 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of H4-heavy <400> 42 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 Thr Asp Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 43 <211> 220 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of H1-light <400> 43 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 Lys Ser Ser Gln Ser Leu Leu Ala Ser 20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Met Leu Ile Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 44 <211> 220 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of H2-light <400> 44 Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser 20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Leu Gln Lys Pro Gly Gln 35 40 45 Ser Pro Gln Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys 65 70 75 80 Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gln Gln 85 90 95 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Leu 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 45 <211> 220 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of H3-light <400> 45 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 Lys Ser Ser Gln Ser Leu Leu Ala Ser 20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 46 <211> 219 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of H4-light <400> 46 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 Lys Ser Ser Gln Ser Leu Leu Ala Ser 20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys 35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val 50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 85 90 95 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Gin Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu 210 215 <210> 47 <211> 1350 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of H1-heavy <400> 47 gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggagggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcact gactactaca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg gttgggcttt attagaaaca aagctaacgg ttacaccaca 180 gaatacagtg cgtctgtgaa aggcagattc accatctcaa gagataattc aaagaactca 240 ctgtatctgc aaatgaacag cctgaaaacc gaggacacgg ccgtgtatta ctgtgctaga 300 gataactggt ttgcttactg gggtcaagga accctggtca ccgtctcctc ggctagcacc 360 aagggcccat cggtcttccc cctggcaccc tcctccaaga gcacctctgg gggcacagcg 420 gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 480 ggcgccctga ccagcggcgt gcacaccttc ccggctgtcc tacagtcctc aggactctac 540 tccctcagca gcgtggtgac cgtgccctcc agcagcttgg gcacccagac ctacatctgc 600 aacgtgaatc acaagcccag caacaccaag gtggacaaga aagttgagcc caaatcttgt 660 gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 720 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 780 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 960 tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1260 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1320 ctctccctgt ctccgggtaa atgactcgag 1350 <210> 48 <211> 1350 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of H3-heavy <400> 48 gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggagggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcact gactactaca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg gttgggcttt attagaaaca aagctaacgg ttacaccaca 180 gaatacagtg cgtctgtgaa aggcagattc accatctcaa gagataattc aaagaactca 240 ctgtatctgc aaatgaacag cctgcgtgct gaggacacgg ccgtgtatta ctgtgctaga 300 gataactggt ttgcttactg gggtcaagga accctggtca ccgtctcctc ggctagcacc 360 aagggcccat cggtcttccc cctggcaccc tcctccaaga gcacctctgg gggcacagcg 420 gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 480 ggcgccctga ccagcggcgt gcacaccttc ccggctgtcc tacagtcctc aggactctac 540 tccctcagca gcgtggtgac cgtgccctcc agcagcttgg gcacccagac ctacatctgc 600 aacgtgaatc acaagcccag caacaccaag gtggacaaga aagttgagcc caaatcttgt 660 gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 720 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 780 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 960 tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1260 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1320 ctctccctgt ctccgggtaa atgactcgag 1350 <210> 49 <211> 1350 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of H4-heavy <400> 49 gaggttcagc tggtggagtc tggcggtggc ctggtgcagc cagggggctc actccgtttg 60 tcctgtgcag cttctggctt caccttcact gattactaca tgagctgggt gcgtcaggcc 120 ccgggtaagg gcctggaatg gttgggtttt attagaaaca aagctaatgg ttacacaaca 180 gagtacagtg catctgtgaa gggtcgtttc actataagca gagataattc caaaaacaca 240 ctgtacctgc agatgaacag cctgcgtgct gaggacactg ccgtctatta ttgtgctaga 300 gataactggt ttgcttactg gggccaaggg actctggtca ccgtctcctc ggctagcacc 360 aagggcccat cggtcttccc cctggcaccc tcctccaaga gcacctctgg gggcacagcg 420 gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 480 ggcgccctga ccagcggcgt gcacaccttc ccggctgtcc tacagtcctc aggactctac 540 tccctcagca gcgtggtgac cgtgccctcc agcagcttgg gcacccagac ctacatctgc 600 aacgtgaatc acaagcccag caacaccaag gtggacaaga aagttgagcc caaatcttgt 660 gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 720 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 780 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 960 tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1260 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1320 ctctccctgt ctccgggtaa atgactcgag 1350 <210> 50 <211> 669 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of H1-light <400> 50 gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60 atcaactgca agtccagcca gagtctttta gctagcggca accaaaataa ctacttagct 120 tggcaccagc agaaaccagg acagcctcct aagatgctca ttatttgggc atctacccgg 180 gtatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240 atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaatc ctatagtgct 300 cctctcacgt tcggaggcgg taccaaggtg gagatcaaac gtacggtggc tgcaccatct 360 gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420 ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480 caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540 ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600 gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660 tgactcgag 669 <210> 51 <211> 669 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of H2-light <400> 51 gatattgtga tgacccagac tccactctcc ctgcccgtca cccctggaga gccggcctcc 60 atctcctgca agtccagtca gagtctttta gctagtggca accaaaataa ctacttggcc 120 tggcacctgc agaagccagg gcagtctcca cagatgctga tcatttgggc atccactagg 180 gtatctggag tcccagacag gttcagtggc agtgggtcag gcactgattt cacactgaaa 240 atcagcaggg tggaggctga ggatgttgga gtttattact gccagcagtc ctacagcgct 300 ccgctcacgt tcggacaggg taccaagctg gagctcaaac gtacggtggc tgcaccatct 360 gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420 ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480 caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540 ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600 gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660 tgactcgag 669 <210> 52 <211> 669 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of H3-light <400> 52 gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60 atcaactgca agtccagcca gagtctttta gctagcggca accaaaataa ctacttagct 120 tggtaccagc agaaaccagg acagcctcct aagctgctca ttatttgggc atctacccgg 180 gtatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240 atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaatc ctatagtgct 300 cctctcacgt tcggaggcgg taccaaggtg gagatcaaac gtacggtggc tgcaccatct 360 gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420 ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480 caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540 ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600 gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660 tgactcgag 669 <210> 53 <211> 669 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of H4-light <400> 53 gatatccaga tgacccagtc cccgagctcc ctgtccgcct ctgtgggcga tagggtcacc 60 atcacctgca agtccagtca gagtctttta gctagtggca accaaaataa ctacttggcc 120 tggcaccaac agaaaccagg aaaagctccg aaaatgctga ttatttgggc atccactagg 180 gtatctggag tcccttctcg cttctctgga tccgggtctg ggacggattt cactctgacc 240 atcagcagtc tgcagccgga agacttcgca acttattact gtcagcagtc ctacagcgct 300 ccgctcacgt tcggacaggg taccaaggtg gagatcaaac gtacggtggc tgcaccatct 360 gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420 ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480 caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540 ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600 gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660 tgactcgag 669 <210> 54 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> linker between VH and VL <400> 54 Gly Leu Gly Gly Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser Gly 1 5 10 15 Gly Ser Ser Gly Val Gly Ser 20 <210> 55 <211> 1088 <212> DNA <213> Artificial Sequence <220> <223> polynucleotide encoding scFv of huAbF46 antibody <400> 55 gctagcgttt tagcagaagt tcaattggtt gaatctggtg gtggtttggt tcaaccaggt 60 ggttctttga gattgtcttg tgctgcttct ggttttactt tcaccgatta ttacatgtcc 120 tgggttagac aagctccagg taaaggtttg gaatggttgg gtttcattag aaacaaggct 180 aacggttaca ctaccgaata ttctgcttct gttaagggta gattcaccat ttctagagac 240 aactctaaga acaccttgta cttgcaaatg aactccttga gagctgaaga tactgctgtt 300 tattactgcg ctagagataa ttggtttgct tattggggtc aaggtacttt ggttactgtt 360 tcttctggcc tcggggggcct cggaggagga ggtagtggcg gaggaggctc cggtggatcc 420 agcggtgtgg gttccgatat tcaaatgacc caatctccat cttctttgtc tgcttcagtt 480 ggtgatagag ttaccattac ttgtaagtcc tcccaatctt tgttggcttc tggtaatcag 540 aacaattact tggcttggca tcaacaaaaa ccaggtaaag ctccaaagat gttgattatt 600 tgggcttcta ccagagtttc tggtgttcca tctagatttt ctggttctgg ttccggtact 660 gattttactt tgaccatttc atccttgcaa ccagaagatt tcgctactta ctactgtcaa 720 caatcttact ctgctccatt gacttttggt caaggtacaa aggtcgaaat caagagagaa 780 ttcggtaagc ctatccctaa ccctctcctc ggtctcgatt ctacgggtgg tggtggatct 840 ggtggtggtg gttctggtgg tggtggttct caggaactga caactatatg cgagcaaatc 900 ccctcaccaa ctttagaatc gacgccgtac tctttgtcaa cgactactat tttggccaac 960 gggaaggcaa tgcaaggagt ttttgaatat tacaaatcag taacgtttgt cagtaattgc 1020 ggttctcacc cctcaacaac tagcaaaggc agccccataa acacacagta tgttttttga 1080 gtttaaac 1088 <210> 56 <211> 5597 <212> DNA <213> Artificial Sequence <220> <223> expression vector including polynucleotide encoding scFv of huAbF46 antibody <220> <221> misc_difference <222> (573)..(578) <223> NheI restriction site <220> <221> misc_difference <222> (588)..(938) <223> huAbF46 VH <220> <221> misc_difference <222> (939)..(1007) <223> linker <220> <221> misc_difference <222> (1008)..(1349) <223> huAbF46 VL <220> <221> misc_difference <222> (1350)..(1355) <223> EcoRI restriction site <220> <221> misc_difference <222> (1356)..(1397) <223> V5 epitope <220> <221> misc_difference <222> (1398)..(1442) <223> (G4S)3 linker <220> <221> misc_difference <222> (1443)..(1649) <223> Aga2 <220> <221> misc_difference <222> (1650)..(1652) <223> TGA (stop codon) <220> <221> misc_difference <222> (1653)..(1660) <223> PmeI restriction site <400> 56 acggattaga agccgccgag cgggtgacag ccctccgaag gaagactctc ctccgtgcgt 60 cctcgtcttc accggtcgcg ttcctgaaac gcagatgtgc ctcgcgccgc actgctccga 120 acaataaaga ttctacaata ctagctttta tggttatgaa gaggaaaaat tggcagtaac 180 ctggccccac aaaccttcaa atgaacgaat caaattaaca accataggat gataatgcga 240 ttagtttttt agccttattt ctggggtaat taatcagcga agcgatgatt tttgatctat 300 taacagatat ataaatgcaa aaactgcata accactttaa ctaatacttt caacattttc 360 ggtttgtatt acttcttatt caaatgtaat aaaagtatca acaaaaaatt gttaatatac 420 ctctatactt taacgtcaag gagaaaaaac cccggatcgg actactagca gctgtaatac 480 gactcactat agggaatatt aagctaattc tacttcatac attttcaatt aagatgcagt 540 tacttcgctg tttttcaata ttttctgtta ttgctagcgt tttagcagaa gttcaattgg 600 ttgaatctgg tggtggtttg gttcaaccag gtggttcttt gagattgtct tgtgctgctt 660 ctggttttac tttcaccgat tattacatgt cctgggttag acaagctcca ggtaaaggtt 720 tggaatggtt gggtttcatt agaaacaagg ctaacggtta cactaccgaa tattctgctt 780 ctgttaaggg tagattcacc atttctagag acaactctaa gaacaccttg tacttgcaaa 840 tgaactcctt gagagctgaa gatactgctg tttattactg cgctagagat aattggtttg 900 cttattgggg tcaaggtact ttggttactg tttcttctgg cctcgggggc ctcggaggag 960 gaggtagtgg cggaggaggc tccggtggat ccagcggtgt gggttccgat attcaaatga 1020 cccaatctcc atcttctttg tctgcttcag ttggtgatag agttaccatt acttgtaagt 1080 cctcccaatc tttgttggct tctggtaatc agaacaatta cttggcttgg catcaacaaa 1140 aaccaggtaa agctccaaag atgttgatta tttgggcttc taccagagtt tctggtgttc 1200 catctagatt ttctggttct ggttccggta ctgattttac tttgaccatt tcatccttgc 1260 aaccagaaga tttcgctact tactactgtc aacaatctta ctctgctcca ttgacttttg 1320 gtcaaggtac aaaggtcgaa atcaagagag aattcggtaa gcctatccct aaccctctcc 1380 tcggtctcga ttctacgggt ggtggtggat ctggtggtgg tggttctggt ggtggtggtt 1440 ctcaggaact gacaactata tgcgagcaaa tcccctcacc aactttagaa tcgacgccgt 1500 actctttgtc aacgactact attttggcca acgggaaggc aatgcaagga gtttttgaat 1560 attacaaatc agtaacgttt gtcagtaatt gcggttctca cccctcaaca actagcaaag 1620 gcagccccat aaacacacag tatgtttttt gagtttaaac ccgctgatct gataacaaca 1680 gtgtagatgt aacaaaatcg actttgttcc cactgtactt ttagctcgta caaaatacaa 1740 tatacttttc atttctccgt aaacaacatg ttttcccatg taatatcctt ttctattttt 1800 cgttccgtta ccaactttac acatacttta tatagctatt cacttctata cactaaaaaa 1860 ctaagacaat tttaattttg ctgcctgcca tatttcaatt tgttataaat tcctataatt 1920 tatcctatta gtagctaaaa aaagatgaat gtgaatcgaa tcctaagaga attgggcaag 1980 tgcacaaaca atacttaaat aaatactact cagtaataac ctatttctta gcatttttga 2040 cgaaatttgc tattttgtta gagtctttta caccatttgt ctccacacct ccgcttacat 2100 caacaccaat aacgccattt aatctaagcg catcaccaac attttctggc gtcagtccac 2160 cagctaacat aaaatgtaag ctctcggggc tctcttgcct tccaacccag tcagaaatcg 2220 agttccaatc caaaagttca cctgtcccac ctgcttctga atcaaacaag ggaataaacg 2280 aatgaggttt ctgtgaagct gcactgagta gtatgttgca gtcttttgga aatacgagtc 2340 ttttaataac tggcaaaccg aggaactctt ggtattcttg ccacgactca tctccgtgca 2400 gttggacgat atcaatgccg taatcattga ccagagccaa aacatcctcc ttaggttgat 2460 tacgaaacac gccaaccaag tatttcggag tgcctgaact atttttatat gcttttacaa 2520 gacttgaaat tttccttgca ataaccgggt caattgttct ctttctattg ggcacacata 2580 taatacccag caagtcagca tcggaatcta gagcacattc tgcggcctct gtgctctgca 2640 agccgcaaac tttcaccaat ggaccagaac tacctgtgaa attaataaca gacatactcc 2700 aagctgcctt tgtgtgctta atcacgtata ctcacgtgct caatagtcac caatgccctc 2760 cctcttggcc ctctcctttt cttttttcga ccgaatttct tgaagacgaa agggcctcgt 2820 gatacgccta tttttatagg ttaatgtcat gataataatg gtttcttagg acggatcgct 2880 tgcctgtaac tacacgcgc ctcgtatctt ttaatgatgg aataatttgg gaatttactc 2940 tgtgtttatt tatttttatg ttttgtattt ggattttaga aagtaaataa agaaggtaga 3000 agagttacgg aatgaagaaa aaaaaataaa caaaggttta aaaaatttca acaaaaagcg 3060 tactttacat atatatttat tagacaagaa aagcagatta aatagatata cattcgatta 3120 acgataagta aaatgtaaaa tcacaggatt ttcgtgtgtg gtcttctaca cagacaagat 3180 gaaacaattc ggcattaata cctgagagca ggaagagcaa gataaaaggt agtatttgtt 3240 ggcgatcccc ctagagtctt ttacatcttc ggaaaacaaa aactattttt tctttaattt 3300 ctttttttac tttctatttt taatttatat atttatatta aaaaatttaa attataatta 3360 tttttatagc acgtgatgaa aaggacccag gtggcacttt tcggggaaat gtgcgcggaa 3420 cccctatttg tttatttttc taaatacatt caaatatgta tccgctcatg agacaataac 3480 cctgataaat gcttcaataa tattgaaaaa ggaagagtat gagtattcaa catttccgtg 3540 tcgcccttat tccctttttt gcggcatttt gccttcctgt ttttgctcac ccagaaacgc 3600 tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg agtgggttac atcgaactgg 3660 atctcaacag cggtaagatc cttgagagtt ttcgccccga agaacgtttt ccaatgatga 3720 gcacttttaa agttctgcta tgtggcgcgg tattatcccg tgttgacgcc gggcaagagc 3780 aactcggtcg ccgcatacac tattctcaga atgacttggt tgagtactca ccagtcacag 3840 aaaagcatct tacggatggc atgacagtaa gagaattatg cagtgctgcc ataaccatga 3900 gtgataacac tgcggccaac ttacttctga caacgatcgg aggaccgaag gagctaaccg 3960 cttttttgca caacatgggg gatcatgtaa ctcgccttga tcgttgggaa ccggagctga 4020 atgaagccat accaaacgac gagcgtgaca ccacgatgcc tgtagcaatg gcaacaacgt 4080 tgcgcaaact attaactggc gaactactta ctctagcttc ccggcaacaa ttaatagact 4140 ggatggaggc ggataaagtt gcaggaccac ttctgcgctc ggcccttccg gctggctggt 4200 ttattgctga taaatctgga gccggtgagc gtgggtctcg cggtatcatt gcagcactgg 4260 ggccagatgg taagccctcc cgtatcgtag ttatctacac gacgggcagt caggcaacta 4320 tggatgaacg aaatagacag atcgctgaga taggtgcctc actgattaag cattggtaac 4380 tgtcagacca agtttactca tatatacttt agattgattt aaaacttcat ttttaattta 4440 aaaggatcta ggtgaagatc ctttttgata atctcatgac caaaatccct taacgtgagt 4500 tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa aggatcttct tgagatcctt 4560 tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc accgctacca gcggtggttt 4620 gtttgccgga tcaagagcta ccaactcttt ttccgaaggt aactggcttc agcagagcgc 4680 agataccaaa tactgtcctt ctagtgtagc cgtagttagg ccaccacttc aagaactctg 4740 tagcaccgcc tacatacctc gctctgctaa tcctgttacc agtggctgct gccagtggcg 4800 ataagtcgtg tcttaccggg ttggactcaa gacgatagtt accggataag gcgcagcggt 4860 cgggctgaac ggggggttcg tgcacacagc ccagcttgga gcgaacgacc tacaccgaac 4920 tgagatacct acagcgtgag cattgagaaa gcgccacgct tcccgaaggg agaaaggcgg 4980 acaggtatcc ggtaagcggc agggtcggaa caggagagcg cacgagggag cttccagggg 5040 ggaacgcctg gtatctttat agtcctgtcg ggtttcgcca cctctgactt gagcgtcgat 5100 ttttgtgatg ctcgtcaggg gggccgagcc tatggaaaaa cgccagcaac gcggcctttt 5160 tacggttcct ggccttttgc tggccttttg ctcacatgtt ctttcctgcg ttatcccctg 5220 attctgtgga taaccgtatt accgcctttg agtgagctga taccgctcgc cgcagccgaa 5280 cgaccgagcg cagcgagtca gtgagcgagg aagcggaaga gcgcccaata cgcaaaccgc 5340 ctctccccgc gcgttggccg attcattaat gcagctggca cgacaggttt cccgactgga 5400 aagcgggcag tgagcgcaac gcaattaatg tgagttacct cactcattag gcaccccagg 5460 ctttacactt tatgcttccg gctcctatgt tgtgtggaat tgtgagcgga taacaatttc 5520 acacaggaaa cagctatgac catgattacg ccaagctcgg aattaaccct cactaaaggg 5580 aacaaaagct ggctagt 5597 <210> 57 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> U6-HC7 hinge <400> 57 Glu Pro Lys Ser Cys Asp Cys His Cys Pro Pro Cys Pro 1 5 10 <210> 58 <211> 435 <212> DNA <213> Artificial Sequence <220> <223> polynucleotide encoding CDR-L3 derived from L3-1 clone <400> 58 gaattcacta gtgattaatt cgccgccacc atggattcac aggcccaggt cctcatgttg 60 ctgctgctat cggtatctgg tacctgtgga gatatccaga tgacccagtc cccgagctcc 120 ctgtccgcct ctgtgggcga tagggtcacc atcacctgca agtccagtca gagtctttta 180 gctagtggca accaaaataa ctacttggcc tggcaccaac agaaaccagg aaaagctccg 240 aaaatgctga ttatttgggc atccactagg gtatctggag tcccttctcg cttctctgga 300 tccgggtctg ggacggattt cactctgacc atcagcagtc tgcagccgga agacttcgca 360 acttattact gtcagcagtc ctacagccgc ccgtacacgt tcggacaggg taccaaggtg 420 gagatcaaac gtacg 435 <210> 59 <211> 435 <212> DNA <213> Artificial Sequence <220> <223> polynucleotide encoding CDR-L3 derived from L3-2 clone <400> 59 gaattcacta gtgattaatt cgccgccacc atggattcac aggcccaggt cctcatgttg 60 ctgctgctat cggtatctgg tacctgtgga gatatccaga tgacccagtc cccgagctcc 120 ctgtccgcct ctgtgggcga tagggtcacc atcacctgca agtccagtca gagtctttta 180 gctagtggca accaaaataa ctacttggcc tggcaccaac agaaaccagg aaaagctccg 240 aaaatgctga ttatttgggc atccactagg gtatctggag tcccttctcg cttctctgga 300 tccgggtctg ggacggattt cactctgacc atcagcagtc tgcagccgga agacttcgca 360 acttattact gtgggcagtc ctacagccgt ccgctcacgt tcggacaggg taccaaggtg 420 gagatcaaac gtacg 435 <210> 60 <211> 435 <212> DNA <213> Artificial Sequence <220> <223> polynucleotide encoding CDR-L3 derived from L3-3 clone <400> 60 gaattcacta gtgattaatt cgccgccacc atggattcac aggcccaggt cctcatgttg 60 ctgctgctat cggtatctgg tacctgtgga gatatccaga tgacccagtc cccgagctcc 120 ctgtccgcct ctgtgggcga tagggtcacc atcacctgca agtccagtca gagtctttta 180 gctagtggca accaaaataa ctacttggcc tggcaccaac agaaaccagg aaaagctccg 240 aaaatgctga ttatttgggc atccactagg gtatctggag tcccttctcg cttctctgga 300 tccgggtctg ggacggattt cactctgacc atcagcagtc tgcagccgga agacttcgca 360 acttattact gtgcacagtc ctacagccat ccgttctctt tcggacaggg taccaaggtg 420 gagatcaaac gtacg 435 <210> 61 <211> 435 <212> DNA <213> Artificial Sequence <220> <223> polynucleotide encoding CDR-L3 derived from L3-5 clone <400> 61 gaattcacta gtgattaatt cgccgccacc atggattcac aggcccaggt cctcatgttg 60 ctgctgctat cggtatctgg tacctgtgga gatatccaga tgacccagtc cccgagctcc 120 ctgtccgcct ctgtgggcga tagggtcacc atcacctgca agtccagtca gagtctttta 180 gctagtggca accaaaataa ctacttggcc tggcaccaac agaaaccagg aaaagctccg 240 aaaatgctga ttatttgggc atccactagg gtatctggag tcccttctcg cttctctgga 300 tccgggtctg ggacggattt cactctgacc atcagcagtc tgcagccgga agacttcgca 360 acttattact gtcagcagtc ctacagccgc ccgtttacgt tcggacaggg taccaaggtg 420 gagatcaaac gtacg 435 <210> 62 <211> 462 <212> PRT <213> Artificial Sequence <220> <223> polypeptide consisting of heavy chain of huAbF46-H4-A1, U6-HC7 hinge and constant region of human IgG1 <400> 62 Met Glu Trp Ser Trp Val Phe Leu Val Thr Leu Leu Asn Gly Ile Gln 1 5 10 15 Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly 20 25 30 Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp 35 40 45 Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 50 55 60 Leu Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser 65 70 75 80 Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr 115 120 125 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 130 135 140 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 145 150 155 160 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 165 170 175 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 180 185 190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 195 200 205 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 210 215 220 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Cys His 225 230 235 240 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 245 250 255 Leu Phe Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 260 265 270 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 275 280 285 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 290 295 300 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 305 310 315 320 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 325 330 335 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 340 345 350 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 355 360 365 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 370 375 380 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 385 390 395 400 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Val Leu Asp Ser Asp 405 410 415 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 420 425 430 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 435 440 445 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210> 63 <211> 1410 <212> DNA <213> Artificial Sequence <220> <223> polynucleotide encoding polypeptide consisting of heavy chain of huAbF46-H4-A1, U6-HC7 hinge and constant region of human IgG1 <400> 63 gaattcgccg ccaccatgga atggagctgg gtttttctcg taacactttt aaatggtatc 60 cagtgtgagg ttcagctggt ggagtctggc ggtggcctgg tgcagccagg gggctcactc 120 cgtttgtcct gtgcagcttc tggcttcacc ttcactgatt actacatgag ctgggtgcgt 180 caggccccgg gtaagggcct ggaatggttg ggttttatta gaaacaaagc taatggttac 240 acaacagagt acagtgcatc tgtgaagggt cgtttcacta taagcagaga taattccaaa 300 aacacactgt acctgcagat gaacagcctg cgtgctgagg acactgccgt ctattattgt 360 gctagagata actggtttgc ttactggggc caagggactc tggtcaccgt ctcctcggct 420 agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 480 acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540 aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 600 ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 660 atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 720 agctgcgatt gccactgtcc tccatgtcca gcacctgaac tcctgggggg accgtcagtc 780 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 840 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 900 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 960 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 1020 tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 1080 gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 1140 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1200 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1260 gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1320 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1380 ctctccctgt ctccgggtaa atgactcgag 1410 <210> 64 <211> 461 <212> PRT <213> Artificial Sequence <220> <223> polypeptide consisting of heavy chain of huAbF46-H4-A1, human IgG2 hinge and constant region of human IgG1 <400> 64 Met Glu Trp Ser Trp Val Phe Leu Val Thr Leu Leu Asn Gly Ile Gln 1 5 10 15 Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly 20 25 30 Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp 35 40 45 Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 50 55 60 Leu Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser 65 70 75 80 Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr 115 120 125 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 130 135 140 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 145 150 155 160 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 165 170 175 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 180 185 190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 195 200 205 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 210 215 220 Asn Thr Lys Val Asp Lys Lys Val Glu Arg Lys Cys Cys Val Glu Cys 225 230 235 240 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 245 250 255 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 260 265 270 Val Thr Cys Val Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 275 280 285 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 290 295 300 Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 305 310 315 320 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 325 330 335 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 340 345 350 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 355 360 365 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 370 375 380 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 385 390 395 400 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 405 410 415 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 420 425 430 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 435 440 445 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210> 65 <211> 1407 <212> DNA <213> Artificial Sequence <220> <223> polynucleotide encoding polypeptide consisting of heavy chain of huAbF46-H4-A1, human IgG2 hinge and constant region of human IgG1 <400> 65 gaattcgccg ccaccatgga atggagctgg gtttttctcg taacactttt aaatggtatc 60 cagtgtgagg ttcagctggt ggagtctggc ggtggcctgg tgcagccagg gggctcactc 120 cgtttgtcct gtgcagcttc tggcttcacc ttcactgatt actacatgag ctgggtgcgt 180 caggccccgg gtaagggcct ggaatggttg ggttttatta gaaacaaagc taatggttac 240 acaacagagt acagtgcatc tgtgaagggt cgtttcacta taagcagaga taattccaaa 300 aacacactgt acctgcagat gaacagcctg cgtgctgagg acactgccgt ctattattgt 360 gctagagata actggtttgc ttactggggc caagggactc tggtcaccgt ctcctcggct 420 agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 480 acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540 aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 600 ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 660 atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagaggaag 720 tgctgtgtgg agtgcccccc ctgcccagca cctgaactcc tggggggacc gtcagtcttc 780 ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 840 gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 900 gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 960 gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 1020 aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1080 cagccccgag aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac 1140 caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1200 gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1260 ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1320 gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1380 tccctgtctc cgggtaaatg actcgag 1407 <210> 66 <211> 460 <212> PRT <213> Artificial Sequence <220> <223> polypeptide consisting of heavy chain of huAbF46-H4-A1, human IgG2 hinge and constant region of human IgG2 <400> 66 Met Glu Trp Ser Trp Val Phe Leu Val Thr Leu Leu Asn Gly Ile Gln 1 5 10 15 Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly 20 25 30 Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp 35 40 45 Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 50 55 60 Leu Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser 65 70 75 80 Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr 115 120 125 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 130 135 140 Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 145 150 155 160 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 165 170 175 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 180 185 190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 195 200 205 Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser 210 215 220 Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys 225 230 235 240 Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe 245 250 255 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 260 265 270 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe 275 280 285 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 290 295 300 Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr 305 310 315 320 Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 325 330 335 Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr 340 345 350 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 355 360 365 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 370 375 380 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 385 390 395 400 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser 405 410 415 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 420 425 430 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 435 440 445 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210> 67 <211> 1404 <212> DNA <213> Artificial Sequence <220> <223> polynucleotide encoding polypeptide consisting of heavy chain of huAbF46-H4-A1, human IgG2 hinge and constant region of human IgG2 <400> 67 gaattcgccg ccaccatgga atggagctgg gtttttctcg taacactttt aaatggtatc 60 cagtgtgagg ttcagctggt ggagtctggc ggtggcctgg tgcagccagg gggctcactc 120 cgtttgtcct gtgcagcttc tggcttcacc ttcactgatt actacatgag ctgggtgcgt 180 caggccccgg gtaagggcct ggaatggttg ggttttatta gaaacaaagc taatggttac 240 acaacagagt acagtgcatc tgtgaagggt cgtttcacta taagcagaga taattccaaa 300 aacacactgt acctgcagat gaacagcctg cgtgctgagg acactgccgt ctattattgt 360 gctagagata actggtttgc ttactggggc caagggactc tggtcaccgt ctcctcggct 420 agcaccaagg gcccatcggt cttccccctg gcgccctgct ccaggagcac ctccgagagc 480 acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540 aactcaggcg ctctgaccag cggcgtgcac accttcccag ctgtcctaca gtcctcagga 600 ctctactccc tcagcagcgt ggtgaccgtg ccctccagca acttcggcac ccagacctac 660 acctgcaacg tagatcacaa gcccagcaac accaaggtgg acaagacagt tgagcgcaaa 720 tgttgtgtcg agtgcccacc gtgcccagca ccacctgtgg caggaccgtc agtcttcctc 780 ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacgtgcgtg 840 gtggtggacg tgagccacga agaccccgag gtccagttca actggtacgt ggacggcgtg 900 gaggtgcata atgccaagac aaagccacgg gaggagcagt tcaacagcac gttccgtgtg 960 gtcagcgtcc tcaccgttgt gcaccaggac tggctgaacg gcaaggagta caagtgcaag 1020 gtctccaaca aaggcctccc agcccccatc gagaaaacca tctccaaaac caaagggcag 1080 ccccgagaac cacaggtgta caccctgccc ccatccggg aggagatgac caagaaccag 1140 gtcagcctga cctgcctggt caaaggcttc taccccagcg acatcgccgt ggagtgggag 1200 agcaatgggc agccggagaa caactacaag accacgcctc ccatgctgga ctccgacggc 1260 tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1320 ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1380 ctgtctccgg gtaaatgact cgag 1404 <210> 68 <211> 240 <212> PRT <213> Artificial Sequence <220> <223> polypeptide consisting of light chain of huAbF46-H4-A1(H36Y) and human kappa constant region <400> 68 Met Asp Ser Gln Ala Gln Val Leu Met Leu Leu Leu Leu Leu Ser Val Ser 1 5 10 15 Gly Thr Cys Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser 20 25 30 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser 35 40 45 Leu Leu Ala Ser Gly Asn Gln Asn Asn Tyr Leu Ala Trp Tyr Gln Gln 50 55 60 Lys Pro Gly Lys Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg 65 70 75 80 Val Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 85 90 95 Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr 100 105 110 Tyr Cys Gln Gln Ser Tyr Ser Arg Pro Tyr Thr Phe Gly Gln Gly Thr 115 120 125 Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 130 135 140 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 145 150 155 160 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 165 170 175 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 180 185 190 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 195 200 205 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 210 215 220 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 240 <210> 69 <211> 758 <212> DNA <213> Artificial Sequence <220> <223> polynucleotide encoding polypeptide consisting of light chain of huAbF46-H4-A1(H36Y) and human kappa constant region <400> 69 aattcactag tgattaattc gccgccacca tggattcaca ggcccaggtc ctcatgttgc 60 tgctgctatc ggtatctggt acctgtggag atatccagat gacccagtcc ccgagctccc 120 tgtccgcctc tgtgggcgat agggtcacca tcacctgcaa gtccagtcag agtcttttag 180 ctagtggcaa ccaaaataac tacttggcct ggtaccaaca gaaaccagga aaagctccga 240 aaatgctgat tatttgggca tccactaggg tatctggagt cccttctcgc ttctctggat 300 ccgggtctgg gacggatttc actctgacca tcagcagtct gcagccggaa gacttcgcaa 360 cttattactg tcagcagtcc tacagccgcc cgtacacgtt cggacagggt accaaggtgg 420 agatcaaacg tacggtggct gcaccatctg tcttcatctt cccgccatct gatgagcagt 480 tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc agagaggcca 540 aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag agtgtcacag 600 agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg agcaaagcag 660 actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg agctcgcccg 720 tcacaaagag cttcaacagg ggagagtgtt gactcgag 758 <210> 70 <211> 240 <212> PRT <213> Artificial Sequence <220> <223> polypeptide consisting of light chain of huAbF46-H4-A1 and human kappa constant region <400> 70 Met Asp Ser Gln Ala Gln Val Leu Met Leu Leu Leu Leu Leu Ser Val Ser 1 5 10 15 Gly Thr Cys Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser 20 25 30 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser 35 40 45 Leu Leu Ala Ser Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln 50 55 60 Lys Pro Gly Lys Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg 65 70 75 80 Val Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 85 90 95 Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr 100 105 110 Tyr Cys Gln Gln Ser Tyr Ser Arg Pro Tyr Thr Phe Gly Gln Gly Thr 115 120 125 Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 130 135 140 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys 145 150 155 160 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 165 170 175 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 180 185 190 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 195 200 205 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His 210 215 220 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 240 <210> 71 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> epitope in SEMA domain of c-Met <400> 71 Phe Ser Pro Gln Ile Glu Glu Pro Ser Gln Cys Pro Asp Cys Val Val 1 5 10 15 Ser Ala Leu <210> 72 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> epitope in SEMA domain of c-Met <400> 72 Pro Gln Ile Glu Glu Pro Ser Gln Cys Pro 1 5 10 <210> 73 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> epitope in SEMA domain of c-Met <400> 73 Glu Glu Pro Ser Gln 1 5 <210> 74 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> heavy chain variable region of anti-c-Met antibody (AbF46 or huAbF46-H1) <400> 74 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 Thr Asp Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 75 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of anti-c-Met antibody (AbF46 or huAbF46-H1) <400> 75 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 Lys Ser Ser Gln Ser Leu Leu Ala Ser 20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Met Leu Ile Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg <210> 76 <211> 1416 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of heavy chain of anti-c-Met antibody (AbF46 or huAbF46-H1) <220> <221> misc_feature <222> (1)..(6) <223> EcoRI restriction site <220> <221> misc_feature <222> (7)..(66) <223> signal sequence <220> <221> misc_feature <222> (67)..(417) <223> VH - heavy chain variable region <220> <221> misc_feature <222> (418)..(423) <223> NdeI restriction site <220> <221> misc_feature <222> (418)..(1407) <223> CH - heavy chain constant region <220> <221> misc_feature <222> (1408)..(1410) <223> TGA - stop codon <220> <221> misc_feature <222> (1411)..(1416) <223> XhoI restriction site <400> 76 gaattcgccg ccaccatgga atggagctgg gtttttctcg taacactttt aaatggtatc 60 cagtgtgagg tgaagctggt ggagtctgga ggaggcttgg tacagcctgg gggttctctg 120 agactctcct gtgcaacttc tgggttcacc ttcactgatt actacatgag ctgggtccgc 180 cagcctccag gaaaggcact tgagtggttg ggttttatta gaaacaaagc taatggttac 240 acaacagagt acagtgcatc tgtgaagggt cggttcacca tctccagaga taattcccaa 300 agcatcctct atcttcaaat ggacaccctg agagctgagg acagtgccac ttattactgt 360 gcaagagata actggtttgc ttactggggc caagggactc tggtcactgt ctctgcagct 420 agcaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 480 acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540 aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 600 ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 660 atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 720 tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 780 tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 840 gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 900 gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 960 acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 1020 tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1080 gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggaggagatg 1140 accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1200 gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1260 gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1320 caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1380 aagagcctct ccctgtctcc gggtaaatga ctcgag 1416 <210> 77 <211> 759 <212> DNA <213> Artificial Sequence <220> <223> nucleotide sequence of light chain of anti-c-Met antibody (AbF46 or huAbF46-H1) <220> <221> misc_difference <222> (1)..(6) <223> EcoRI restriction site <220> <221> misc_difference <222> (7)..(90) <223> signal sequence <220> <221> misc_difference <222> (91)..(432) <223> VL - light chain variable region <220> <221> misc_difference <222> (430)..(435) <223> BsiWI restriction site <220> <221> misc_difference <222> (433)..(750) <223> CL - light chain constant region <220> <221> misc_difference <222> (751)..(753) <223> stop codon <220> <221> misc_difference <222> (754)..(759) <223> XhoI restriction site <400> 77 gaattcacta gtgattaatt cgccgccacc atggattcac aggcccaggt cctcatgttg 60 ctgctgctat cggtatctgg tacctgtgga gacattttga tgacccagtc tccatcctcc 120 ctgactgtgt cagcaggaga gaaggtcact atgagctgca agtccagtca gagtctttta 180 gctagtggca accaaaataa ctacttggcc tggcaccagc agaaaccagg acgatctcct 240 aaaatgctga taatttgggc atccactagg gtatctggag tccctgatcg cttcataggc 300 agtggatctg ggacggattt cactctgacc atcaacagtg tgcaggctga agatctggct 360 gtttattact gtcagcagtc ctacagcgct ccgctcacgt tcggtgctgg gaccaagctg 420 gagctgaaac gtacggtggc tgcaccatct gtcttcatct tcccgccatc tgatgagcag 480 ttgaaatctg gaactgcctc tgttgtgtgc ctgctgaata acttctatcc cagagaggcc 540 aaagtacagt ggaaggtgga taacgccctc caatcgggta actcccagga gagtgtcaca 600 gagcaggaca gcaaggacag cacctacagc ctcagcagca ccctgacgct gagcaaagca 660 gactacgaga aacacaaagt ctacgcctgc gaagtcaccc atcagggcct gagctcgccc 720 gtcacaaaga gcttcaacag gggagagtgt tgactcgag 759 <210> 78 <211> 4170 <212> DNA <213> Artificial Sequence <220> <223> polynucleotide encoding c-Met protein <400> 78 atgaaggccc ccgctgtgct tgcacctggc atcctcgtgc tcctgtttac cttggtgcag 60 aggagcaatg gggagtgtaa agaggcacta gcaaagtccg agatgaatgt gaatatgaag 120 tatcagcttc ccaacttcac cgcggaaaca cccatccaga atgtcattct acatgagcat 180 cacatttcc ttggtgccac taactacatt tatgttttaa atgaggaaga ccttcagaag 240 gttgctgagt acaagactgg gcctgtgctg gaacacccag attgtttccc atgtcaggac 300 tgcagcagca aagccaattt atcaggaggt gtttggaaag ataacatcaa catggctcta 360 gttgtcgaca cctactatga tgatcaactc attagctgtg gcagcgtcaa cagagggacc 420 tgccagcgac atgtctttcc ccacaatcat actgctgaca tacagtcgga ggttcactgc 480 atattctccc cacagataga agagcccagc cagtgtcctg actgtgtggt gagcgccctg 540 ggagccaaag tcctttcatc tgtaaaggac cggttcatca acttctttgt aggcaatacc 600 ataaattctt cttatttccc agatcatcca ttgcattcga tatcagtgag aaggctaaag 660 gaaacgaaag atggttttat gtttttgacg gaccagtcct acattgatgt tttacctgag 720 ttcagagatt cttaccccat taagtatgtc catgcctttg aaagcaacaa ttttatttac 780 ttcttgacgg tccaaaggga aactctagat gctcagactt ttcacacaag aataatcagg 840 ttctgttcca taaactctgg attgcattcc tacatggaaa tgcctctgga gtgtattctc 900 acagaaaaga gaaaaaagag atccacaaag aaggaagtgt ttaatatact tcaggctgcg 960 tatgtcagca agcctggggc ccagcttgct agacaaatag gagccagcct gaatgatgac 1020 attcttttcg gggtgttcgc acaaagcaag ccagattctg ccgaaccaat ggatcgatct 1080 gccatgtgtg cattccctat caaatatgtc aacgacttct tcaacaagat cgtcaacaaa 1140 aacaatgtga gatgtctcca gcatttttac ggacccaatc atgagcactg ctttaatagg 1200 acacttctga gaaattcatc aggctgtgaa gcgcgccgtg atgaatatcg aacagagttt 1260 accacagctt tgcagcgcgt tgacttattc atgggtcaat tcagcgaagt cctcttaaca 1320 tctatatcca ccttcattaa aggagacctc accatagcta atcttgggac atcagagggt 1380 cgcttcatgc aggttgtggt ttctcgatca ggaccatcaa cccctcatgt gaattttctc 1440 ctggactccc atccagtgtc tccagaagtg attgtggagc atacattaaa ccaaaatggc 1500 tacacactgg ttatcactgg gaagaagatc acgaagatcc cattgaatgg cttgggctgc 1560 agacatttcc agtcctgcag tcaatgcctc tctgccccac cctttgttca gtgtggctgg 1620 tgccacgaca aatgtgtgcg atcggaggaa tgcctgagcg ggacatggac tcaacagatc 1680 tgtctgcctg caatctacaa ggttttccca aatagtgcac cccttgaagg agggacaagg 1740 ctgaccatat gtggctggga ctttggattt cggaggaata ataaatttga tttaaagaaa 1800 actagagttc tccttggaaa tgagagctgc accttgactt taagtgagag cacgatgaat 1860 acattgaaat gcacagttgg tcctgccatg aataagcatt tcaatatgtc cataattatt 1920 tcaaatggcc acgggacaac acaatacagt acatctcct atgtggatcc tgtaataaca 1980 agtatttcgc cgaaatacgg tcctatggct ggtggcactt tacttacttt aactggaaat 2040 tacctaaaca gtgggaattc tagacacatt tcaattggtg gaaaaacatg tactttaaaa 2100 agtgtgtcaa acagtattct tgaatgttat accccagccc aaaccatttc aactgagttt 2160 gctgttaaat tgaaaattga cttagccaac cgagagacaa gcatcttcag ttaccgtgaa 2220 gatcccattg tctatgaaat tcatccaacc aaatctttta ttagtggtgg gagcacaata 2280 acaggtgttg ggaaaaacct gaattcagtt agtgtcccga gaatggtcat aaatgtgcat 2340 gaagcaggaa ggaactttac agtggcatgt caacatcgct ctaattcaga gataatctgt 2400 tgtaccactc cttccctgca acagctgaat ctgcaactcc ccctgaaaac caaagccttt 2460 ttcatgttag atgggatcct ttccaaatac tttgatctca tttatgtaca taatcctgtg 2520 tttaagcctt ttgaaaagcc agtgatgatc tcaatgggca atgaaaatgt actggaaatt 2580 aagggaaatg atattgaccc tgaagcagtt aaaggtgaag tgttaaaagt tggaaataag 2640 agctgtgaga atatacactt acattctgaa gccgttttat gcacggtccc caatgacctg 2700 ctgaaattga acagcgagct aaatatagag tggaagcaag caatttcttc aaccgtcctt 2760 ggaaaagtaa tagttcaacc agatcagaat ttcacaggat tgattgctgg tgttgtctca 2820 atatcaacag cactgttatt actacttggg tttttcctgt ggctgaaaaa gagaaagcaa 2880 attaaagatc tgggcagtga attagttcgc tacgatgcaa gagtacacac tcctcatttg 2940 gataggcttg taagtgcccg aagtgtaagc ccaactacag aaatggtttc aaatgaatct 3000 gtagactacc gagctacttt tccagaagat cagtttccta attcatctca gaacggttca 3060 tgccgacaag tgcagtatcc tctgacagac atgtccccca tcctaactag tggggactct 3120 gatatatcca gtccattact gcaaaatact gtccacattg acctcagtgc tctaaatcca 3180 gagctggtcc aggcagtgca gcatgtagtg attgggccca gtagcctgat tgtgcatttc 3240 aatgaagtca taggaagagg gcattttggt tgtgtatatc atgggacttt gttggacaat 3300 gatggcaaga aaattcactg tgctgtgaaa tccttgaaca gaatcactga cataggagaa 3360 gtttcccaat ttctgaccga gggaatcatc atgaaagatt ttagtcatcc caatgtcctc 3420 tcgctcctgg gaatctgcct gcgaagtgaa gggtctccgc tggtggtcct accatacatg 3480 aaacatggag atcttcgaaa tttcattcga aatgagactc ataatccaac tgtaaaagat 3540 cttattggct ttggtcttca agtagccaaa ggcatgaaat atcttgcaag caaaaagttt 3600 gtccacagag acttggctgc aagaaactgt atgctggatg aaaaattcac agtcaaggtt 3660 gctgattttg gtcttgccag agacatgtat gataaagaat actatagtgt acacaacaaa 3720 acaggtgcaa agctgccagt gaagtggatg gctttggaaa gtctgcaaac tcaaaagttt 3780 accaccaagt cagatgtgtg gtcctttggc gtgctcctct gggagctgat gacaagagga 3840 gccccacctt atcctgacgt aaacaccttt gatataactg tttacttgtt gcaagggaga 3900 agactcctac aacccgaata ctgcccagac cccttatatg aagtaatgct aaaatgctgg 3960 caccctaaag ccgaaatgcg cccatccttt tctgaactgg tgtcccggat atcagcgatc 4020 ttctctactt tcattgggga gcactatgtc catgtgaacg ctacttatgt gaacgtaaaa 4080 tgtgtcgctc cgtatccttc tctgttgtca tcagaagata acgctgatga tgaggtggac 4140 acacgaccag cctccttctg ggagacatca 4170 <210> 79 <211> 444 <212> PRT <213> Artificial Sequence <220> <223> SEMA domain of c-Met <400> 79 Leu His Glu His His Ile Phe Leu Gly Ala Thr Asn Tyr Ile Tyr Val 1 5 10 15 Leu Asn Glu Glu Asp Leu Gln Lys Val Ala Glu Tyr Lys Thr Gly Pro 20 25 30 Val Leu Glu His Pro Asp Cys Phe Pro Cys Gln Asp Cys Ser Ser Lys 35 40 45 Ala Asn Leu Ser Gly Gly Val Trp Lys Asp Asn Ile Asn Met Ala Leu 50 55 60 Val Val Asp Thr Tyr Tyr Asp Asp Gln Leu Ile Ser Cys Gly Ser Val 65 70 75 80 Asn Arg Gly Thr Cys Gln Arg His Val Phe Pro His Asn His Thr Ala 85 90 95 Asp Ile Gln Ser Glu Val His Cys Ile Phe Ser Pro Gln Ile Glu Glu 100 105 110 Pro Ser Gln Cys Pro Asp Cys Val Val Ser Ala Leu Gly Ala Lys Val 115 120 125 Leu Ser Ser Val Lys Asp Arg Phe Ile Asn Phe Phe Val Gly Asn Thr 130 135 140 Ile Asn Ser Ser Tyr Phe Pro Asp His Pro Leu His Ser Ile Ser Val 145 150 155 160 Arg Arg Leu Lys Glu Thr Lys Asp Gly Phe Met Phe Leu Thr Asp Gln 165 170 175 Ser Tyr Ile Asp Val Leu Pro Glu Phe Arg Asp Ser Tyr Pro Ile Lys 180 185 190 Tyr Val His Ala Phe Glu Ser Asn Asn Phe Ile Tyr Phe Leu Thr Val 195 200 205 Gln Arg Glu Thr Leu Asp Ala Gln Thr Phe His Thr Arg Ile Ile Arg 210 215 220 Phe Cys Ser Ile Asn Ser Gly Leu His Ser Tyr Met Glu Met Pro Leu 225 230 235 240 Glu Cys Ile Leu Thr Glu Lys Arg Lys Lys Arg Ser Thr Lys Lys Glu 245 250 255 Val Phe Asn Ile Leu Gln Ala Ala Tyr Val Ser Lys Pro Gly Ala Gln 260 265 270 Leu Ala Arg Gln Ile Gly Ala Ser Leu Asn Asp Asp Ile Leu Phe Gly 275 280 285 Val Phe Ala Gln Ser Lys Pro Asp Ser Ala Glu Pro Met Asp Arg Ser 290 295 300 Ala Met Cys Ala Phe Pro Ile Lys Tyr Val Asn Asp Phe Phe Asn Lys 305 310 315 320 Ile Val Asn Lys Asn Asn Val Arg Cys Leu Gln His Phe Tyr Gly Pro 325 330 335 Asn His Glu His Cys Phe Asn Arg Thr Leu Leu Arg Asn Ser Ser Gly 340 345 350 Cys Glu Ala Arg Arg Asp Glu Tyr Arg Thr Glu Phe Thr Thr Ala Leu 355 360 365 Gln Arg Val Asp Leu Phe Met Gly Gln Phe Ser Glu Val Leu Leu Thr 370 375 380 Ser Ile Ser Thr Phe Ile Lys Gly Asp Leu Thr Ile Ala Asn Leu Gly 385 390 395 400 Thr Ser Glu Gly Arg Phe Met Gln Val Val Val Ser Arg Ser Gly Pro 405 410 415 Ser Thr Pro His Val Asn Phe Leu Leu Asp Ser His Pro Val Ser Pro 420 425 430 Glu Val Ile Val Glu His Thr Leu Asn Gln Asn Gly 435 440 <210> 80 <211> 451 <212> PRT <213> Artificial Sequence <220> <223> PSI-IPT domain of c-Met <400> 80 Tyr Thr Leu Val Ile Thr Gly Lys Lys Ile Thr Lys Ile Pro Leu Asn 1 5 10 15 Gly Leu Gly Cys Arg His Phe Gln Ser Cys Ser Gln Cys Leu Ser Ala 20 25 30 Pro Pro Phe Val Gln Cys Gly Trp Cys His Asp Lys Cys Val Arg Ser 35 40 45 Glu Glu Cys Leu Ser Gly Thr Trp Thr Gln Gln Ile Cys Leu Pro Ala 50 55 60 Ile Tyr Lys Val Phe Pro Asn Ser Ala Pro Leu Glu Gly Gly Thr Arg 65 70 75 80 Leu Thr Ile Cys Gly Trp Asp Phe Gly Phe Arg Arg Asn Asn Lys Phe 85 90 95 Asp Leu Lys Lys Thr Arg Val Leu Leu Gly Asn Glu Ser Cys Thr Leu 100 105 110 Thr Leu Ser Glu Ser Thr Met Asn Thr Leu Lys Cys Thr Val Gly Pro 115 120 125 Ala Met Asn Lys His Phe Asn Met Ser Ile Ile Ile Ile Ser Asn Gly His 130 135 140 Gly Thr Thr Gln Tyr Ser Thr Phe Ser Tyr Val Asp Pro Val Ile Thr 145 150 155 160 Ser Ile Ser Pro Lys Tyr Gly Pro Met Ala Gly Gly Thr Leu Leu Thr 165 170 175 Leu Thr Gly Asn Tyr Leu Asn Ser Gly Asn Ser Arg His Ile Ser Ile 180 185 190 Gly Gly Lys Thr Cys Thr Leu Lys Ser Val Ser Asn Ser Ile Leu Glu 195 200 205 Cys Tyr Thr Pro Ala Gln Thr Ile Ser Thr Glu Phe Ala Val Lys Leu 210 215 220 Lys Ile Asp Leu Ala Asn Arg Glu Thr Ser Ile Phe Ser Tyr Arg Glu 225 230 235 240 Asp Pro Ile Val Tyr Glu Ile His Pro Thr Lys Ser Phe Ile Ser Thr 245 250 255 Trp Trp Lys Glu Pro Leu Asn Ile Val Ser Phe Leu Phe Cys Phe Ala 260 265 270 Ser Gly Gly Ser Thr Ile Thr Gly Val Gly Lys Asn Leu Asn Ser Val 275 280 285 Ser Val Pro Arg Met Val Ile Asn Val His Glu Ala Gly Arg Asn Phe 290 295 300 Thr Val Ala Cys Gln His Arg Ser Asn Ser Glu Ile Ile Cys Cys Thr 305 310 315 320 Thr Pro Ser Leu Gln Gln Leu Asn Leu Gln Leu Pro Leu Lys Thr Lys 325 330 335 Ala Phe Phe Met Leu Asp Gly Ile Leu Ser Lys Tyr Phe Asp Leu Ile 340 345 350 Tyr Val His Asn Pro Val Phe Lys Pro Phe Glu Lys Pro Val Met Ile 355 360 365 Ser Met Gly Asn Glu Asn Val Leu Glu Ile Lys Gly Asn Asp Ile Asp 370 375 380 Pro Glu Ala Val Lys Gly Glu Val Leu Lys Val Gly Asn Lys Ser Cys 385 390 395 400 Glu Asn Ile His Leu His Ser Glu Ala Val Leu Cys Thr Val Pro Asn 405 410 415 Asp Leu Leu Lys Leu Asn Ser Glu Leu Asn Ile Glu Trp Lys Gln Ala 420 425 430 Ile Ser Ser Thr Val Leu Gly Lys Val Ile Val Gln Pro Asp Gln Asn 435 440 445 Phe Thr Gly 450 <210> 81 <211> 313 <212> PRT <213> Artificial Sequence <220> <223> TyrKc domain of c-Met <400> 81 Val His Phe Asn Glu Val Ile Gly Arg Gly His Phe Gly Cys Val Tyr 1 5 10 15 His Gly Thr Leu Leu Asp Asn Asp Gly Lys Lys Ile His Cys Ala Val 20 25 30 Lys Ser Leu Asn Arg Ile Thr Asp Ile Gly Glu Val Ser Gln Phe Leu 35 40 45 Thr Glu Gly Ile Ile Met Lys Asp Phe Ser His Pro Asn Val Leu Ser 50 55 60 Leu Leu Gly Ile Cys Leu Arg Ser Glu Gly Ser Pro Leu Val Val Leu 65 70 75 80 Pro Tyr Met Lys His Gly Asp Leu Arg Asn Phe Ile Arg Asn Glu Thr 85 90 95 His Asn Pro Thr Val Lys Asp Leu Ile Gly Phe Gly Leu Gln Val Ala 100 105 110 Lys Gly Met Lys Tyr Leu Ala Ser Lys Lys Phe Val His Arg Asp Leu 115 120 125 Ala Ala Arg Asn Cys Met Leu Asp Glu Lys Phe Thr Val Lys Val Ala 130 135 140 Asp Phe Gly Leu Ala Arg Asp Met Tyr Asp Lys Glu Tyr Tyr Ser Val 145 150 155 160 His Asn Lys Thr Gly Ala Lys Leu Pro Val Lys Trp Met Ala Leu Glu 165 170 175 Ser Leu Gln Thr Gln Lys Phe Thr Thr Lys Ser Asp Val Trp Ser Phe 180 185 190 Gly Val Leu Leu Trp Glu Leu Met Thr Arg Gly Ala Pro Pro Tyr Pro 195 200 205 Asp Val Asn Thr Phe Asp Ile Thr Val Tyr Leu Leu Gln Gly Arg Arg 210 215 220 Leu Leu Gln Pro Glu Tyr Cys Pro Asp Pro Leu Tyr Glu Val Met Leu 225 230 235 240 Lys Cys Trp His Pro Lys Ala Glu Met Arg Pro Ser Phe Ser Glu Leu 245 250 255 Val Ser Arg Ile Ser Ala Ile Phe Ser Thr Phe Ile Gly Glu His Tyr 260 265 270 Val His Val Asn Ala Thr Tyr Val Asn Val Lys Cys Val Ala Pro Tyr 275 280 285 Pro Ser Leu Leu Ser Ser Glu Asp Asn Ala Asp Asp Glu Val Asp Thr 290 295 300 Arg Pro Ala Ser Phe Trp Glu Thr Ser 305 310 <210> 82 <211> 1332 <212> DNA <213> Artificial Sequence <220> <223> polynucleotide encoding SEMA domain of c-Met <400> 82 ctacatgagc atcacatttt ccttggtgcc actaactaca tttatgtttt aaatgaggaa 60 gaccttcaga aggttgctga gtacaagact gggcctgtgc tggaacaccc agattgtttc 120 ccatgtcagg actgcagcag caaagccaat ttatcaggag gtgtttggaa agataacatc 180 aacatggctc tagttgtcga cacctactat gatgatcaac tcattagctg tggcagcgtc 240 aacagaggga cctgccagcg acatgtcttt ccccacaatc atactgctga catacagtcg 300 gaggttcact gcatattctc cccacagata gaagagccca gccagtgtcc tgactgtgtg 360 gtgagcgccc tgggagccaa agtcctttca tctgtaaagg accggttcat caacttcttt 420 gtaggcaata ccataaattc ttcttatttc ccagatcatc cattgcattc gatatcagtg 480 agaaggctaa aggaaacgaa agatggtttt atgtttttga cggaccagtc ctacattgat 540 gttttacctg agttcagaga ttcttacccc attaagtatg tccatgcctt tgaaagcaac 600 aattttattt acttcttgac ggtccaaagg gaaactctag atgctcagac ttttcacaca 660 agaataatca ggttctgttc cataaactct ggattgcatt cctacatgga aatgcctctg 720 gagtgtattc tcacagaaaa gagaaaaaag agatccacaa agaaggaagt gtttaatata 780 cttcaggctg cgtatgtcag caagcctggg gcccagcttg ctagacaaat aggagccagc 840 ctgaatgatg acattctttt cggggtgttc gcacaaagca agccagattc tgccgaacca 900 atggatcgat ctgccatgtg tgcattccct atcaaatatg tcaacgactt cttcaacaag 960 atcgtcaaca aaaacaatgt gagatgtctc cagcattttt acggacccaa tcatgagcac 1020 tgctttaata ggacacttct gagaaattca tcaggctgtg aagcgcgccg tgatgaatat 1080 cgaacagagt ttaccacagc tttgcagcgc gttgacttat tcatgggtca attcagcgaa 1140 gtcctcttaa catctatatc caccttcatt aaaggagacc tcaccatagc taatcttggg 1200 acatcagagg gtcgcttcat gcaggttgtg gtttctcgat caggaccatc aacccctcat 1260 gtgaattttc tcctggactc ccatccagtg tctccagaag tgattgtgga gcatacatta 1320 aaccaaaatg gc 1332 <210> 83 <211> 1299 <212> DNA <213> Artificial Sequence <220> <223> polynucleotide encoding PSI-IPT domain of c-Met <400> 83 tacacactgg ttatcactgg gaagaagatc acgaagatcc cattgaatgg cttgggctgc 60 agacatttcc agtcctgcag tcaatgcctc tctgccccac cctttgttca gtgtggctgg 120 tgccacgaca aatgtgtgcg atcggaggaa tgcctgagcg ggacatggac tcaacagatc 180 tgtctgcctg caatctacaa ggttttccca aatagtgcac cccttgaagg agggacaagg 240 ctgaccatat gtggctggga ctttggattt cggaggaata ataaatttga tttaaagaaa 300 actagagttc tccttggaaa tgagagctgc accttgactt taagtgagag cacgatgaat 360 acattgaaat gcacagttgg tcctgccatg aataagcatt tcaatatgtc cataattatt 420 tcaaatggcc acgggacaac acaatacagt acatctcct atgtggatcc tgtaataaca 480 agtatttcgc cgaaatacgg tcctatggct ggtggcactt tacttacttt aactggaaat 540 tacctaaaca gtgggaattc tagacacatt tcaattggtg gaaaaacatg tactttaaaa 600 agtgtgtcaa acagtattct tgaatgttat accccagccc aaaccatttc aactgagttt 660 gctgttaaat tgaaaattga cttagccaac cgagagacaa gcatcttcag ttaccgtgaa 720 gatcccattg tctatgaaat tcatccaacc aaatctttta ttagtggtgg gagcacaata 780 acaggtgttg ggaaaaacct gaattcagtt agtgtcccga gaatggtcat aaatgtgcat 840 gaagcaggaa ggaactttac agtggcatgt caacatcgct ctaattcaga gataatctgt 900 tgtaccactc cttccctgca acagctgaat ctgcaactcc ccctgaaaac caaagccttt 960 ttcatgttag atgggatcct ttccaaatac tttgatctca tttatgtaca taatcctgtg 1020 tttaagcctt ttgaaaagcc agtgatgatc tcaatgggca atgaaaatgt actggaaatt 1080 aagggaaatg atattgaccc tgaagcagtt aaaggtgaag tgttaaaagt tggaaataag 1140 agctgtgaga atatacactt acattctgaa gccgttttat gcacggtccc caatgacctg 1200 ctgaaattga acagcgagct aaatatagag tggaagcaag caatttcttc aaccgtcctt 1260 ggaaaagtaa tagttcaacc agatcagaat ttcacagga 1299 <210> 84 <211> 939 <212> DNA <213> Artificial Sequence <220> <223> polynucleotide encoding TyrKc domain of c-Met <400> 84 gtgcatttca atgaagtcat aggaagaggg cattttggtt gtgtatatca tgggactttg 60 ttggacaatg atggcaagaa aattcactgt gctgtgaaat ccttgaacag aatcactgac 120 ataggagaag tttcccaatt tctgaccgag ggaatcatca tgaaagattt tagtcatccc 180 aatgtcctct cgctcctggg aatctgcctg cgaagtgaag ggtctccgct ggtggtccta 240 ccatacatga aacatggaga tcttcgaaat ttcattcgaa atgagactca taatccaact 300 gtaaaagatc ttattggctt tggtcttcaa gtagccaaag gcatgaaata tcttgcaagc 360 aaaaagtttg tccacagaga cttggctgca agaaactgta tgctggatga aaaattcaca 420 gtcaaggttg ctgattttgg tcttgccaga gacatgtatg ataaagaata ctatagtgta 480 cacaacaaaa caggtgcaaa gctgccagtg aagtggatgg ctttggaaag tctgcaaact 540 caaaagttta ccaccaagtc agatgtgtgg tcctttggcg tgctcctctg ggagctgatg 600 acaagaggag ccccacctta tcctgacgta aacacctttg atataactgt ttacttgttg 660 caagggagaa gactcctaca acccgaatac tgcccagacc ccttatatga agtaatgcta 720 aaatgctggc accctaaagc cgaaatgcgc ccatcctttt ctgaactggt gtccccggata 780 tcagcgatct tctctacttt cattggggag cactatgtcc atgtgaacgc tacttatgtg 840 aacgtaaaat gtgtcgctcc gtatccttct ctgttgtcat cagaagataa cgctgatgat 900 gagtggaca cacgaccagc ctccttctgg gagacatca 939 <210> 85 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> heavy chain CDR3 of anti-c-Met antibody <400> 85 Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val 1 5 10 <210> 86 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> light chain CDR3 of anti-c-Met antibody <400> 86 Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu 1 5 10 <210> 87 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> heavy chain variable region of monoclonal antibody AbF46 <400> 87 Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asp Thr Leu Arg Ala Glu Asp Ser Ala Thr Tyr 85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala 115 <210> 88 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of anti-c-Met antibody <400> 88 Asp Ile Leu Met Thr Gln Ser Pro Ser Ser Leu Thr Val Ser Ala Gly 1 5 10 15 Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser 20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Arg 35 40 45 Ser Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val 50 55 60 Pro Asp Arg Phe Ile Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Asn Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu 100 105 110 Lys Arg <210> 89 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> light chain CDR3 of anti-c-Met antibody <400> 89 Gln Gln Ser Tyr Ser Ala Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu 1 5 10 15 Glu <210> 90 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> heavy chain variable region of AT-VH1 <400> 90 Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Ser Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ser Ala Thr Tyr 85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 91 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> heavy chain variable region of AT-VH2 <400> 91 Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Ser Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr 85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 92 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> heavy chain variable region of AT-VH3 <400> 92 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 Thr Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Ser Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr 85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 93 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> heavy chain variable region of AT-VH4 <400> 93 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 Thr Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr 85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 94 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> heavy chain variable region of AT-VH5 <400> 94 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 Thr Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Phe Ile Arg Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg Asp Asn Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 95 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of anti c-Met humanized antibody (huAbF46-H4) <400> 95 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 Lys Ser Ser Gln Ser Leu Leu Ala Ser 20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys 35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val 50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 85 90 95 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Gin Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg <210> 96 <211> 113 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of AT-Vk1 <400> 96 Asp Ile Leu Met Thr Gln Ser Pro Ser Ser Leu Thr Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Met Thr Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser 20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys 35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val 50 55 60 Pro Asp Arg Phe Ile Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Gin Gly Thr Lys Leu Glu Ile 100 105 110 Lys <210> 97 <211> 113 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of AT-Vk2 <400> 97 Asp Ile Leu Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Ala Ser 20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys 35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val 50 55 60 Pro Asp Arg Phe Ile Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Gin Gly Thr Lys Leu Glu Ile 100 105 110 Lys <210> 98 <211> 113 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of AT-Vk3 <400> 98 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 Lys Ser Ser Gln Ser Leu Leu Ala Ser 20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys 35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val 50 55 60 Pro Asp Arg Phe Ile Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Gin Gly Thr Lys Leu Glu Ile 100 105 110 Lys <210> 99 <211> 113 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of AT-Vk4 <400> 99 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 Lys Ser Ser Gln Ser Leu Leu Ala Ser 20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp His Gln Gln Lys Pro Gly Lys 35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Ser Tyr Ser Ala Pro Leu Thr Phe Gly Gin Gly Thr Lys Leu Glu Ile 100 105 110 Lys <210> 100 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> modified hinge region (U7-HC6) <400> 100 Glu Pro Ser Cys Asp Lys His Cys Cys Pro Pro Cys Pro 1 5 10 <210> 101 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> modified hinge region (U6-HC7) <400> 101 Glu Pro Lys Ser Cys Asp Cys His Cys Pro Pro Cys Pro 1 5 10 <210> 102 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> modified hinge region (U3-HC9) <400> 102 Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 1 5 10 <210> 103 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> modified hinge region (U6-HC8) <400> 103 Glu Pro Arg Asp Cys Gly Cys Lys Pro Cys Pro Pro Cys Pro 1 5 10 <210> 104 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> modified hinge region (U8-HC5) <400> 104 Glu Lys Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 1 5 10 <210> 105 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> human hinge region <400> 105 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 1 5 10 15 <210> 106 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1 of antibody L3-11Y <400> 106 Lys Ser Ser Gln Ser Leu Leu Ala Trp Gly Asn Gln Asn Asn Tyr Leu 1 5 10 15 Ala <210> 107 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of light chain variable region of antibody L3-11Y <400> 107 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 Lys Ser Ser Gln Ser Leu Leu Ala Trp 20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys 35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val 50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 85 90 95 Ser Tyr Ser Arg Pro Tyr Thr Phe Gly Gin Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg <210> 108 <211> 220 <212> PRT <213> Artificial Sequence <220> <223> amino acid sequence of light chain of antibody L3-11Y <400> 108 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 Lys Ser Ser Gln Ser Leu Leu Ala Trp 20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys 35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val 50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 85 90 95 Ser Tyr Ser Arg Pro Tyr Thr Phe Gly Gin Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 109 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 109 cctcttgaac ttgcgtgcct g 21 <210> 110 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 110 tttttaagac ttcttgtctc tctcc 25 <210> 111 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 111 aacgagtcct caagttcagt atttt 25 <210> 112 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 112 tacaatacgt ttctactttc cctga 25 <210> 113 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 113 tgattttcaa actggttgcc tgcat 25 <210> 114 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 114 ggaaggcaca tttttgcact atatt 25 <210> 115 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 115 agtgcagcac gataggcgct taacc 25 <210> 116 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 116 taggcgctta accagtattg ccata 25 <210> 117 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 117 gtattgccat agaaactgcc tcttt 25 <210> 118 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 118 aactgcctct tttcatgtgg gatga 25 <210> 119 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 119 gacatttgca agttcttgta tcctg 25 <210> 120 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 120 gctattacac ctgctgtaca cacac 25 <210> 121 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 121 acttctctat tgacactttt acctc 25 <210> 122 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 122 tgacactttt acctcaccga ggggg 25 <210> 123 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 123 gaactgctgt tccctagaat gaagg 25 <210> 124 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 124 agaatgaagg tctgttgttt ggttt 25 <210> 125 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 125 ttatatgatt ttgctggact atttc 25 <210> 126 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 126 ggactatttc actagaaacc acgta 25 <210> 127 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 127 gaataggact aactgatctc ttttg 25 <210> 128 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 128 aaaggggctg atttgcttat tcatc 25 <210> 129 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 129 atgtggacag taatcttaat ttcaa 25 <210> 130 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 130 gaggatacta cggtgtagct taagt 25 <210> 131 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 131 agcacaaatt acttctaaca aggca 25 <210> 132 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 132 gtattttccc ctacgtaatg tacat 25 <210> 133 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 133 gtacatgtct ttaggccaca gtatt 25 <210> 134 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 134 aggtggcagt ggtcattgta gctta 25 <210> 135 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 135 taatcagacc cctgttaagt tcctg 25 <210> 136 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 136 caaggtaaat tcacgtcttc cttct 25 <210> 137 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 137 aatagacctc tcacacactt attta 25 <210> 138 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 138 gtctctttct actcttgaca gctat 25 <210> 139 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 139 cttgacagct attcttacct acttc 25 <210> 140 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 140 ttcccactaa acatgcccaa ttttt 25 <210> 141 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 141 tcctatattt ccttccctat tagaa 25 <210> 142 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for THSD7A <400> 142 gaatcaaagt gtcactcact cagag 25 <210> 143 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for MET <400> 143 cttcacttcg caggcagatt cc 22 <210> 144 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for MET <400> 144 gttgtcgaca cctactatga tgatc 25 <210> 145 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for MET <400> 145 cagcgtcaac agagggacct gccag 25 <210> 146 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for MET <400> 146 tttccccaca atcatactgc tgaca 25 <210> 147 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for MET <400> 147 agatagaaga gcccagccag tgtcc 25 <210> 148 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for MET <400> 148 ggagccaaag tcctttcatc tgtaa 25 <210> 149 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for MET <400> 149 taaaggaccg gttcatcaac ttctt 25 <210> 150 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for MET <400> 150 atttcccaga tcatccattg cattc 25 <210> 151 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for MET <400> 151 acggaccagt cctacattga tgttt 25 <210> 152 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for MET <400> 152 gagttcagag attcttaccc catta 25 <210> 153 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for MET <400> 153 ctagatgctc agacttttca cacaa 25 <210> 154 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for MET <400> 154 atcaggttct gttccataaa ctctg 25 <210> 155 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 155 atacgctgaa tccataggtg cca 23 <210> 156 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 156 aacattgtaa tggccatcgc tggaa 25 <210> 157 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 157 gaaacaagtg cgacctctca gatat 25 <210> 158 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 158 ggaggttccc ctgaaggatg ctaag 25 <210> 159 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 159 tacgctgaat ccataggtgc catcg 25 <210> 160 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 160 gtgccatcgt ggttgagaca agtgc 25 <210> 161 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 161 ttcaaggaat cagccgccag atccc 25 <210> 162 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 162 tgagaagcca accatgcaag ccagc 25 <210> 163 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 163 cgtggtccac ggtacttgaa gaagc 25 <210> 164 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 164 atcctgtgca ctgctgaagg accct 25 <210> 165 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 165 gagtgagcac actggctttg catcc 25 <210> 166 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 166 accaccacaa aatggccttt agtgt 25 <210> 167 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 167 gaatatgacg ttaccttgca gacta 25 <210> 168 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 168 ttttttgtgt gggctccagt tctca 25 <210> 169 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 169 gttctgcaat gctcatggca agttg 25 <210> 170 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 170 accgactggg tatctagctt actgt 25 <210> 171 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 171 atcattgttg aaaccagacc ctgta 25 <210> 172 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 172 agaccctgta gtccagtggt gctgc 25 <210> 173 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 173 taaagagctt ccatctgggc tggac 25 <210> 174 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 174 tggacccagt tcttgcacat acaag 25 <210> 175 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 175 gcacatacaa gacaccgctg cagtc 25 <210> 176 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 176 accgctgcag tcagctagga ccttt 25 <210> 177 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RAB31 <400> 177 ggtttaacac acactgattc atact 25 <210> 178 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 178 tctctgctga cctgattgat gct 23 <210> 179 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 179 gacttacttt aacaaccagc caatc 25 <210> 180 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 180 aatccctacc taagcctagt agcca 25 <210> 181 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 181 gccatggttt ggctaagacc gcagc 25 <210> 182 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 182 gtcagtggtg tcacagtccc acata 25 <210> 183 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 183 acataacccg tcatctgctg ttggt 25 <210> 184 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 184 gccaataggt tttccgcttg tagtc 25 <210> 185 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 185 gcagagacct cctagtatta gcatt 25 <210> 186 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 186 ttttctccca taacctagtg aacct 25 <210> 187 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 187 gaaagtaccc tgggtctttc atccg 25 <210> 188 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 188 ctttcatccg tattcctgac aggag 25 <210> 189 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 189 ggagccctga tgtcttaaat tctga 25 <210> 190 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 190 ccgcggctcg gagcaagcgg tgcag 25 <210> 191 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 191 ggagcgattc ccattcgagg agttt 25 <210> 192 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 192 tctcatttta atacaacacc cgcct 25 <210> 193 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 193 aacacccgcc tcttagaggc agcag 25 <210> 194 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 194 cagccagtc cagccaggtc aaggt 25 <210> 195 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 195 tgtggaccgc acaacggggt gcaca 25 <210> 196 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 196 taaacgagcc ctggatctgc aaagc 25 <210> 197 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 197 gtgatcccaa ccttagcaac ataat 25 <210> 198 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 198 tatatgtcag gtgccagtgc tatgg 25 <210> 199 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 199 ataccattta ttaccacttc tcagt 25 <210> 200 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 200 gaggctgtaa ctctggttgt cgaaa 25 <210> 201 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for PHC1 <400> 201 acctcctcac ctgttgtagc c 21 <210> 202 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for PHC1 <400> 202 tttcacgtac cttaatccaa tcttt 25 <210> 203 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for PHC1 <400> 203 agaactagga ctgctcagcc ttatc 25 <210> 204 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for PHC1 <400> 204 gcccaggtct taattctcca agagg 25 <210> 205 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for PHC1 <400> 205 ggtggaatgt caggttgcct gccca 25 <210> 206 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for PHC1 <400> 206 agggtttttc tagcttgtgt gacag 25 <210> 207 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for PHC1 <400> 207 ttgtcactta ctcccttgtg attga 25 <210> 208 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for PHC1 <400> 208 tgattgaatt ttttctcctg catcc 25 <210> 209 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for PHC1 <400> 209 agagacttgg ttggcatctt ctgct 25 <210> 210 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for PHC1 <400> 210 ggcacatgtg gctgttgtca ttctt 25 <210> 211 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for PHC1 <400> 211 tgttcccctc caatttatgt tattt 25 <210> 212 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for PHC1 <400> 212 gtacctgcct taggcactat tcctt 25 <210> 213 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CHML <400> 213 cctctggctg cttatcatca cc 22 <210> 214 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CHML <400> 214 gcaactttga cttagttcat gctat 25 <210> 215 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CHML <400> 215 ctgttttaat tgcatgtgtc cttat 25 <210> 216 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CHML <400> 216 gtgtccttat agcagcagca ttgtg 25 <210> 217 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CHML <400> 217 gcagcattgt gtattagtag ccttt 25 <210> 218 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CHML <400> 218 agggctttat aactgatctt ttgac 25 <210> 219 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CHML <400> 219 gatcttttga catactcact ttgag 25 <210> 220 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CHML <400> 220 cactttgagt ggcatatgcc cagga 25 <210> 221 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CHML <400> 221 aagttttcta gcagttccac tcaga 25 <210> 222 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CHML <400> 222 gttccactca gataacttta agggg 25 <210> 223 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CHML <400> 223 tggtgtattg ctagtgctat cacag 25 <210> 224 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CHML <400> 224 attgtgttta ctgatacatg tgaaa 25 <210> 225 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 225 tctagtcctt taatgagcat gaatt 25 <210> 226 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 226 tatacttcta catttgttgc ttagt 25 <210> 227 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 227 atattgtctt ctatactttg taact 25 <210> 228 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 228 atttcacgta ttgttgcttt ctctt 25 <210> 229 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 229 gttgctttct cttatatgga actta 25 <210> 230 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 230 ggaacttatt gtgtacctct tacct 25 <210> 231 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 231 gtattcctag agtttacatt cctaa 25 <210> 232 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 232 acgacgactt tggctatttt tgtgt 25 <210> 233 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 233 gttccctacc ttcttaaggc tatgg 25 <210> 234 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 234 atttgtgtaa atgttctcca tatgt 25 <210> 235 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for FAM126A <400> 235 caagtgttgc ctcttgtttt attga 25 <210> 236 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for ST8SIA4 <400> 236 actgctcttg accactgaca ca 22 <210> 237 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for ST8SIA4 <400> 237 tttattttgc acggctctaa acctc 25 <210> 238 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for ST8SIA4 <400> 238 taaacctcca tgttattttc cagtg 25 <210> 239 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for ST8SIA4 <400> 239 ggtgtagaag gtaccagcta aagtg 25 <210> 240 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for ST8SIA4 <400> 240 agatgttcca tgtcatcaga gatgg 25 <210> 241 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for ST8SIA4 <400> 241 ggtaccaaag attacacttg tgttt 25 <210> 242 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for ST8SIA4 <400> 242 acttgtgttt ctacacagca aacca 25 <210> 243 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for ST8SIA4 <400> 243 gctattaatg tgaaagttgt ctcta 25 <210> 244 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for ST8SIA4 <400> 244 atgtttttca caccttttgc attac 25 <210> 245 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for ST8SIA4 <400> 245 ttttcacacc ttttgcatta cataa 25 <210> 246 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for ST8SIA4 <400> 246 aattttgtgg aagcattttg ccctt 25 <210> 247 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for ST8SIA4 <400> 247 ggaagcattt tgccctttag aataa 25 <210> 248 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CAV1 <400> 248 tagataacaa gacctcagtg ccttcc 26 <210> 249 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CAV1 <400> 249 gaatttcacc tgtaaacctg agtcg 25 <210> 250 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CAV1 <400> 250 cagaaagctg cctggtatat ccaaa 25 <210> 251 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CAV1 <400> 251 tattcctcct gctcatattg tgatt 25 <210> 252 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CAV1 <400> 252 gtcttcctga cactttaatt accaa 25 <210> 253 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CAV1 <400> 253 taccaacctg ttacctactt tgact 25 <210> 254 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CAV1 <400> 254 gttacctact ttgacttttt gcatt 25 <210> 255 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CAV1 <400> 255 atgtgctata ctgcatactt tttaa 25 <210> 256 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CAV1 <400> 256 aactgtgtat tccaagacat gtctg 25 <210> 257 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CAV1 <400> 257 catagatgct tagtccctca tgcaa 25 <210> 258 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CAV1 <400> 258 aattttttat catgcatgtc ctgta 25 <210> 259 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for CAV1 <400> 259 taaaggttac aagcctgcac aataa 25 <210> 260 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for RPL23A <400> 260 actggctcct gattacgatg ctt 23 <210> 261 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for TPT1 <400> 261 cataactggc ttctgcttgt catcc 25 <210> 262 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for EEF1A1 <400> 262 ccagcagcaa caatcaggac ag 22 <210> 263 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for SRSF3 <400> 263 ttccactctt acacggcagc 20 <210> 264 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for TUT1 <400> 264 cctgtggtca agttctgtca tcg 23 <210> 265 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for HNRNPC <400> 265 ctgctgctct gctcctcttc t 21 <210> 266 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for HUWE1 <400> 266 tcctcttcct cctcatcctc act 23 <210> 267 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for WDR90 <400> 267 tggtcactca gcacacggaa 20 <210> 268 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for MATR3 <400> 268 tgaccagaca gagcaggaac c 21 <210> 269 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Probe Sequence for SMARCA4 <400> 269 ccttcctcat catcgtgcct ct 22 <210> 270 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Sense Primer for THSD7A <400> 270 gcctgttatg actggaaa 18 <210> 271 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Anti-sense Primer for THSD7A <400> 271 ctgtcaactt cttctcca 18 <210> 272 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Sense Primer for MET <400> 272 ccttgaacag aatcactg 18 <210> 273 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Anti-sense Primer for MET <400> 273 ccatgtttca tgtatggta 19 <210> 274 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Sense Primer for FAM126A <400> 274 gcttgtagtc tccaagaa 18 <210> 275 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Anti-sense Primer for FAM126A <400> 275 ggacagagta atgctaatac 20 <210> 276 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Sense Primer for PHC1 <400> 276 gacagcacat gtggtaaa 18 <210> 277 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Anti-sense Primer for PHC1 <400> 277 cacagactgc atatagaagg 20 <210> 278 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Sense Primer for RAB31 <400> 278 ctcagatatt agggaggttc 20 <210> 279 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Anti-sense Primer for RAB31 <400> 279 gctgattcct tgaaagag 18 <210> 280 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Sense Primer for ST8SIA4 <400> 280 gcacaatgta gaaggttg 18 <210> 281 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Anti-sense Primer for ST8SIA4 <400> 281 caagcacata gtgtatgac 19 <210> 282 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Sense Primer for CHML <400> 282 ctccaaatcc agaagaca 18 <210> 283 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Anti-sense Primer for CHML <400> 283 ggccattact acattattgg 20 <210> 284 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Sense Primer for CAV1 <400> 284 ctgtgcctga atatttgtta 20 <210> 285 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Anti-sense Primer for CAV1 <400> 285 ctgagttaga ccctatttga 20 <210> 286 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Sense Primer for RPL23A <400> 286 gagagaagaa ggcatatg 18 <210> 287 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Anti-sense Primer for RPL23A <400> 287 tggactcagt tagatga 18 <210> 288 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Sense Primer for TPT1 <400> 288 ggcaattatt ttggatctat c 21 <210> 289 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Anti-sense Primer for TPT1 <400> 289 cagtcccatt tgtcttaa 18 <210> 290 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Sense Primer for EEF1A1 <400> 290 caggacacag agacttta 18 <210> 291 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Anti-sense Primer for EEF1A1 <400> 291 cagcttcaaa ttcaccaa 18 <210> 292 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Sense Primer for SRSF3 <400> 292 cgagagctag atggaaga 18 <210> 293 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Anti-sense Primer for SRSF3 <400> 293 ggccacgatt tctacttc 18 <210> 294 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Sense Primer for TUT1 <400> 294 ggtgtatcga gtccaaac 18 <210> 295 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Anti-sense Primer for TUT1 <400> 295 caggaaacgg gagttatg 18 <210> 296 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Sense Primer for HNRNPC <400> 296 caagcagtag agatgaag 18 <210> 297 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Anti-sense Primer for HNRNPC <400> 297 ctccatcttc acattagtc 19 <210> 298 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Sense Primer for HUWE1 <400> 298 caaggtctaa tcatgctg 18 <210> 299 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Anti-sense Primer for HUWE1 <400> 299 ctgctgggta gaattaaag 19 <210> 300 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Sense Primer for WDR90 <400> 300 ctctggagac aaggatgg 18 <210> 301 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Anti-sense Primer for WDR90 <400> 301 gacacagatg gtagagatg 20 <210> 302 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Sense Primer for MATR3 <400> 302 ggtgagaaag acacaaag 18 <210> 303 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Anti-sense Primer for MATR3 <400> 303 ctgcttcttc ttcatctac 19 <210> 304 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Sense Primer for SMARCA4 <400> 304 gtacctcatg gagcacaa 18 <210> 305 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Anti-sense Primer for SMARCA4 <400> 305 ccttgtaaga caccttcac 19 <210> 306 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> light chain variable region of anti c-Met antibody <400> 306 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 Lys Ser Ser Gln Ser Leu Leu Ala Ser 20 25 30 Gly Asn Gln Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys 35 40 45 Ala Pro Lys Met Leu Ile Ile Trp Ala Ser Thr Arg Val Ser Gly Val 50 55 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 85 90 95 Ser Tyr Ser Arg Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg

Claims (15)

Measuring the presence or expression level of a biomarker for selection of an anti-c-Met antibody application target in a biological sample,
The anti-c-Met antibody is applied to lung cancer patients,
The biomarker is
THSD7A, or
Combination of THSD7A with one or more selected from the group consisting of MET, RAB31, FAM126A, PHC1, CHML, ST8SIA4, and CAV1
which includes,
A method for screening a subject for application of an anti-c-Met antibody. According to claim 1, wherein the biomarker,
THSD7A;
a combination of THSD7A with one or more selected from the group consisting of MET, RAB31, and FAM126A; or
Combination of THSD7A with at least one member selected from the group consisting of MET, RAB31, and FAM126A, and at least one member selected from the group consisting of PHC1, CHML, ST8SIA4, and CAV1
which includes,
A method for screening a subject for application of an anti-c-Met antibody. According to claim 1, wherein the biomarker,
Which includes THSD7A and MET,
A method for screening a subject for application of an anti-c-Met antibody. According to claim 1, wherein the biomarker,
which comprises THSD7A and RAB31,
A method for screening a subject for application of an anti-c-Met antibody. According to claim 1, wherein the biomarker,
which comprises THSD7A and FAM126A,
A method for screening a subject for application of an anti-c-Met antibody. The method of claim 1, wherein the biomarkers include THSD7A, MET, RAB31 and FAM126A. The method according to claim 1, wherein the measuring of the presence or absence of the biomarker comprises at least one selected from the group consisting of EEF1A1, RPL23A, TPT1, HUWE1, MATR3, SRSF3, HNRNPC, SMARCA4, WDR90, and TUT1. which is performed with reference to a reference marker as a comparative reference,
A method for screening a subject for application of an anti-c-Met antibody. The method according to any one of claims 1 to 7, wherein the c-Met antibody is
CDR-H1 having the amino acid sequence of SEQ ID NO: 4, the amino acid sequence of SEQ ID NO: 5, the amino acid sequence of SEQ ID NO: 2, or consecutive 8 to 19 amino acids comprising the 3rd to 10th amino acids in the amino acid sequence of SEQ ID NO: 2 CDR-H2 having an amino acid sequence consisting of amino acids, and consecutive 6 to at least one heavy chain complementarity determining region (CDR) selected from the group consisting of CDR-H3 having an amino acid sequence consisting of 13 amino acids, or a heavy chain variable region comprising said at least one heavy chain complementarity determining region;
A CDR-L1 having the amino acid sequence of the amino acid sequence of SEQ ID NO: 7, a CDR-L2 having the amino acid sequence of SEQ ID NO: 8, and the amino acid sequence of SEQ ID NO: 9, the amino acid sequence of SEQ ID NO: 15, the amino acid sequence of SEQ ID NO: 86, or At least one light chain complementarity determining region or at least one light chain complementarity determining region selected from the group consisting of CDR-L3 having an amino acid sequence consisting of 9 to 17 amino acids comprising the first to ninth amino acids in the amino acid sequence of SEQ ID NO: 89 a light chain variable region comprising a region;
a combination of the heavy chain complementarity determining region and the light chain complementarity determining region; or
Combination of the heavy chain variable region and the light chain variable region
An antibody or antigen-binding fragment thereof comprising a,
A method for screening a subject for application of an anti-c-Met antibody. A means for detecting a biomarker for selection of an anti-c-Met antibody application target;
The anti-c-Met antibody is applied to lung cancer patients,
The biomarker is
THSD7A, or
Combination of THSD7A with one or more selected from the group consisting of MET, RAB31, FAM126A, PHC1, CHML, ST8SIA4, and CAV1
which includes,
Anti-c-Met antibody application target selection kit. 10. The anti-c-Met antibody of claim 9, further comprising means for detecting one or more reference markers selected from the group consisting of EEF1A1, RPL23A, TPT1, HUWE1, MATR3, SRSF3, HNRNPC, SMARCA4, WDR90, and TUT1. Kits for screening applications. The anti-c-Met antibody according to claim 9, wherein the means for detecting the biomarker is a primer or probe capable of hybridizing with the biomarker, an antibody or aptamer that specifically binds to the protein they encode, or a combination thereof. Kits for screening applications. 11. The method of claim 9 or 10, wherein the c-Met antibody,
CDR-H1 having the amino acid sequence of SEQ ID NO: 4, the amino acid sequence of SEQ ID NO: 5, the amino acid sequence of SEQ ID NO: 2, or consecutive 8 to 19 amino acids comprising the 3rd to 10th amino acids in the amino acid sequence of SEQ ID NO: 2 CDR-H2 having an amino acid sequence consisting of amino acids, and consecutive 6 to at least one heavy chain complementarity determining region (CDR) selected from the group consisting of CDR-H3 having an amino acid sequence consisting of 13 amino acids, or a heavy chain variable region comprising said at least one heavy chain complementarity determining region;
A CDR-L1 having the amino acid sequence of the amino acid sequence of SEQ ID NO: 7, a CDR-L2 having the amino acid sequence of SEQ ID NO: 8, and the amino acid sequence of SEQ ID NO: 9, the amino acid sequence of SEQ ID NO: 15, the amino acid sequence of SEQ ID NO: 86, or At least one light chain complementarity determining region or at least one light chain complementarity determining region selected from the group consisting of CDR-L3 having an amino acid sequence consisting of 9 to 17 amino acids comprising the first to ninth amino acids in the amino acid sequence of SEQ ID NO: 89 a light chain variable region comprising a region;
a combination of the heavy chain complementarity determining region and the light chain complementarity determining region; or
Combination of the heavy chain variable region and the light chain variable region
An antibody or antigen-binding fragment thereof comprising a, anti-c-Met antibody application target selection kit. delete delete delete

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