KR20150115655A - Biomarker for predicting effect of an anti-c-Met antibody - Google Patents

Abstract

Provided are a biomarker for predicting an effect of an anti-c-Met antibody and/or selecting a subject for application of an anti-c-Met antibody, a reference marker for comparison of gene expression levels, a method of predicting an effect of an anti-c-Met antibody and/or selecting a subject for application of an anti-c-Met antibody including a step of measuring a level of the biomarker in a biological sample, and a method of preventing and/or treating a cancer including administering an anti-c-Met antibody to the selected subject.

Description

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

A c-Met assay system comprising a biomarker for the prediction of the anti-c-Met antibody efficacy and / or screening of the anti-c-Met antibody, a fiducial marker for comparing gene expression levels, and a step of measuring the biomarker level in the biological sample. There is provided a method for the prophylaxis and / or treatment of cancer, which comprises a method for predicting the efficacy of an antibody, and / or a method for screening a subject to which an anti-c-Met antibody is applied, and a step of administering the anti-c-Met antibody to the selected subject.

Since the FDA approval of Genentech's Herceptin Target Therapeutics in 1998, various methods of personalized medicine have been introduced, and there are also increasing attempts to develop selectable patient markers. In the case of Herceptin, the amount of expression of the HER2 growth factor receptor expressed on the cancer cell membrane is selected and the ICH technique such as FISH (fluorescence in situ hybridization) and CISH (chromogenic in situ hybridization) is performed after the IHC (immunohistochemistry) Have been introduced in patient screening. Subsequently, EGFR mutation as a selectable marker for lung and pancreatic cancer in Erlotinib (Tarceva, Genentech), KRAS mutation as a selectable marker for Vectibix and Erbitux (colorectal cancer) patients were approved, and in 2011, The FDA's guideline for simultaneous approval has been published.

For anticancer agents targeting c-Met proteins, research is being conducted on markers for screening patients for which efficacy can be demonstrated. In the current phase of the new c-Met targeting drug, Genentech's metmab is undergoing phase III clinical trials with the c-Met protein overexpression using the ventana IHC assay (sp44: c-met primary antibody, rabbit monoclonal) . Using the above diagnostic method, significant differences were observed in patients treated with erlotinib. Ventana assay was used as a diagnostic tool in clinical phase 3. However, if other samples are tested in this way, accurate results may not be obtained, and there is a limit to being used as general diagnostic means.

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

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

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

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

Other examples provide fiducial markers for comparing the levels of biomarkers for predicting efficacy of the anti-c-Met antibodies and / or screening for anti-c-Met antibodies.

Another example provides a method of predicting the efficacy of an anti-c-Met antibody and / or a method of screening against an anti-c-Met antibody comprising the step of 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 the anti-c-Met antibody to the selected anti-c-Met antibody subject.

Another example provides a method of inhibiting c-Met comprising the step of administering the anti-c-Met antibody to the selected anti-c-Met antibody subject.

The gene expression levels of the group exhibiting the effect on the anti-c-Met antibody (efficacy group) and the group showing no effect (non-efficacy group) are compared to select genes having a large difference, As a biomarker for predicting the efficacy of anti-c-Met antibodies. In addition, even if cells of the same kind or the same kind of cells are selected, a gene having no or little difference in expression level in individual cells is selected, and the selected gene or a protein encoded thereby is compared with the expression level of the target gene and / As a reference marker that can be used as a control of the reference marker.

Specifically, one example is a biomarker for predicting the anti-c-Met antibody efficacy of a gene showing a difference in expression between the efficacy group and the non-efficacy group against the anti-c-Met antibody and / It provides usages.

In one example, the biomarker may be at least one 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 proteins encoded by the above-described genes. The genes that can be used as the biomarker 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

When the biomarker is listed in descending order from the one with the greatest difference in expression in the efficacy group and the non-efficacy group, THSD7A, MET, RAB31, FAM126A, PHC1, CHML, ST8SIA4 and CAV1. For the more accurate prediction of efficacy or screening of the application target, the biomarker can be preferentially selected from those having a large difference in expression between the efficacy group and the non-efficacy group. Thus, in one example, the biomarker may further comprise at least one selected from the group consisting of the remaining genes in addition to the preferentially selected gene.

In one embodiment, the biomarker comprises

THSD7A;

A combination of THSD7A and at least one selected from the group consisting of MET, RAB31, FAM126A, PHCl, CHML, ST8SIA4, and CAV1;

MET;

MET and at least one selected from the group consisting of THSD7A, RAB31, FAM126A, PHCl, CHML, ST8SIA4 and CAV1;

A combination of THSD7A and MET;

A combination of THSD7A and MET and a combination of at least one selected from the group consisting of RAB31, FAM126A, PHCl, CHML, ST8SIA4 and CAV1;

RAB31;

A combination of RAB31 and at least one selected from the group consisting of THSD7A, MET, FAM126A, PHCl, CHML, ST8SIA4, and CAV1;

Two or more selected from the group consisting of THSD7A, MET, and RAB31 (wherein the combination of THSD7A and MET may be excluded);

A combination of at least two selected from the group consisting of THSD7A, MET, and RAB31, and at least one selected from the group consisting of FAM126A, PHC1, CHML, ST8SIA4, and CAV1;

FAM126A;

A combination of FAM126A and at least one selected from the group consisting of THSD7A, MET, RAB31, PHC1, CHML, ST8SIA4, and CAV1;

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

A combination of at least two 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

. ≪ / RTI >

Another example is to identify genes having different expression levels in individual cells even when the cell types are different and / or the same kind of cells are different in the expression level, and comparing the expression level of the target gene with the comparison standard reference, control) for use as a control marker. The target gene may be any gene for which the level of expression is to be measured. For example, the target gene may be a biomarker for predicting the anti-c-Met antibody activity and / or screening the anti-c-Met antibody. In this case, / RTI > and / or < RTI ID = 0.0 > anti-c-Met < / RTI >

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

In one example, the fiducial marker can be selected from endogenous gens essential for cell survival. For example, the reference marker may be at least one 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 species selected from the group consisting of RPL23A, TPT1, MATR3, SRSF3, and HNRNPC And optionally one or more selected from the group consisting of EEF1A1, HUWE1, SMARCA4, WDR90, and TUT1. In one embodiment, the fiducial markers may comprise RPL23A, TPT1, MATR3, SRSF3, and HNRNPC. In another example, the fiducial markers may comprise TPT1, EEF1M, TUT1, MATR3, and SMARCA4.

 The reference marker may be at least one selected from the group consisting of the full-length DNA, cDNA, mRNA, and proteins encoded by the above-mentioned genes. The subject cell may be, but is not limited to, lung cancer cells such as lung cancer adenocarcinoma, non-small cell lung cancer, and the like. The genes that can be used as the reference marker 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 HNRNPC 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) the level of expression of a gene in a method for measuring gene expression level, wherein the reference marker is used as a comparison standard. The measurement (evaluation or determination) of the target gene expression level may be performed on a cell, a tissue, or a gene (DNA or RNA) or protein extracted therefrom separated from the living body. The gene expression level can be measured by quantifying the gene itself (e.g., full-length DNA, cDNA, mRNA, etc.) or a protein encoded from the gene.

Another example provides a composition for predicting the anti-c-Met antibody effect (or sensitivity or reactivity to an anti-c-Met antibody) comprising the means for detecting the biomarker and / or the application of the anti-c-Met antibody . The composition for predicting the anti-c-Met antibody effect (or sensitivity or reactivity to the anti-c-Met antibody) and / or screening the application of the anti-c-Met antibody may further comprise 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 an anti-c-Met antibody) comprising the detection means of the biomarker and / or screening for the anti-c-Met antibody. The kit for predicting the anti-c-Met antibody effect (or sensitivity or reactivity to the anti-c-Met antibody) and / or the anti-c-Met antibody screening may further comprise a means for detecting the reference marker .

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

The means for detecting the biomarker or the means for detecting the reference marker may be a conventional marker of the biomarker gene (full-length DNA, cDNA, or mRNA) or a reference marker gene (full-length DNA, cDNA, or mRNA) Or a method used in a method for quantifying a protein. For example, the means for detecting the biomarker or the means for detecting the reference marker may comprise a primer, a probe, and / or a probe capable of specifically binding (hybridizing) to the biomarker or reference marker gene (full-length DNA, cDNA or mRNA) Tamer; Or antibodies and / or platamers that specifically bind to the proteins they encode; Or a combination thereof. The primer may be a complete gene (full length DNA, cDNA, or mRNA) of the biomarker gene or the reference marker or a sequence of 5 to 1000 bp, such as 10 to 500 bp, 20 to 200 bp Or 5 to 50 bp, 5 to 30 bp, or 10 to 25 bp of the 3'-terminal or 5'-terminal of the gene fragment, (Complementary) base sequence with the reference marker gene (full-length DNA, cDNA, or mRNA), and the probe may comprise a sequence of 5 to 100 bp, 5 to 50 bp, 5 to 30 bp, or 10 to 25 bp sites.

In one embodiment, probes or primers that can be used to detect the biomarkers or reference markers 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) HNRNPC CTGCTGCTCTGCTCCTCTTCT (SEQ ID NO: 265) HUWE1 TCCTCTTCCTCCTCATCCTCACT (SEQ ID NO: 266) WDR90 TGGTCACTCAGCACACGGAA (SEQ ID NO: 267) MATR3 TGACCAGACAGAGCAGGAACC (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) GAATAGGACTAACTGATCTCTTTG (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) ACCACCACAAAATGGCCTTTAGTGT (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 CCGCGGCTCGGAGCAAGCGGTGCAG (SEQ ID NO: 190) GGAGCGATTCCCATTCGAGGAGTTT (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) TGATTGAATTTTTCTCCTGCATCC (SEQ ID NO: 208) AGAGACTTGGTTGGCATCTTCTGCT (SEQ ID NO: 209) GGCACATGTGGCTGTTGTCATTCTT (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) GTGTCCTTATAGCAGCAGCATTGTG (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 CTGTGCCTGAATATTTGTTA (SEQ ID NO: 284) CTGAGTTAGACCCTATTTGA (SEQ ID NO: 285) RPL23A GAGAGAAGAAGGCATATG (SEQ ID NO: 286) TGGACTCAGTTTAGATGA (SEQ ID NO: 287) TPT1 GGCAATTATTTGGATCTATC (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) HNRNPC 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 probes usable for the 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, a probe of SEQ ID NO: 109, SEQ ID NO: 110 to SEQ ID NO: 120 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 primer usable for the detection of the biomarker THSD7A may be a primer of SEQ ID NO: 270, a primer of SEQ ID NO: 271, or a pair of primers comprising them, but is not limited thereto.

The probes usable for the 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 containing them, but the present invention is not limited thereto.

The probes usable for the 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: And a probe set comprising SEQ ID NO: 167 to SEQ ID NO: 177. The primers usable for the detection of the biomarker RAB31 may be a primer of SEQ ID NO: 278, a primer of SEQ ID NO: 279, or a pair of primers containing them, but the present invention is not limited thereto.

The probes usable for the 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: A probe set including SEQ ID NO: 190 to SEQ ID NO: 200, and a probe set including 225 to SEQ ID NO: 235. The probe set may be selected from the group consisting of SEQ ID NO: The primers usable for the detection of the biomarker FAM126A may be a primer of SEQ ID NO: 274, a primer of SEQ ID NO: 275, or a pair of primers containing them. However, the present invention is not limited thereto.

The probes usable for the 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 including SEQ ID NO: 202 to SEQ ID NO: 212, Or a combination thereof. The primers usable for the detection of the biomarker PHC1 may be a primer of SEQ ID NO: 276, a primer of SEQ ID NO: 277, or a pair of primers containing them, but the present invention is not limited thereto.

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

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

The probes usable for the 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: Or a combination thereof. The primers usable for the detection of the biomarker CAV1 may be a primer of SEQ ID NO: 284, a primer of SEQ ID NO: 285, or a pair of primers comprising them, but the present invention is not limited thereto.

The probe usable for detection of the reference marker EEF1A1 may be the probe of SEQ ID NO: 262, but is not limited thereto. The primers usable for the detection of the fiducial marker EEF1A1 may be a primer of SEQ ID NO: 290, a primer of SEQ ID NO: 291, or a pair of primers containing them, but the present invention is not limited thereto.

The probe usable for the detection of the reference marker RPL23A may be a probe of SEQ ID NO: 260, but is not limited thereto. The primers usable for the detection of the reference marker RPL23A may be a primer of SEQ ID NO: 286, a primer of SEQ ID NO: 287, or a pair of primers containing them, but the present invention is not limited thereto.

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

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

The probes usable for the detection of the fidelity marker MATR3 may be probes of SEQ ID NO: 268, but are not limited thereto. The primers usable for the detection of the fiducial marker MATR3 may be a primer of SEQ ID NO: 302, a primer of SEQ ID NO: 303, or a pair of primers containing them, but the present invention is not limited thereto.

The probe usable for the detection of the reference marker SRSF3 may be the probe of SEQ ID NO: 263, but is not limited thereto. The primers usable for the detection of the reference marker SRSF3 may be a primer of SEQ ID NO: 292, a primer of SEQ ID NO: 293, or a pair of primers containing them, but the present invention is not limited thereto.

The probes usable for the detection of the reference marker HNRNPC may be probes of SEQ ID NO: 265, but are not limited thereto. The primers usable for the detection of the reference marker HNRNPC may be a primer of SEQ ID NO: 296, a primer of SEQ ID NO: 297, or a pair of primers including them, but the present invention is not limited thereto.

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

The probe usable for detection of the fidelity marker WDR90 may be the probe of SEQ ID NO: 267, but is not limited thereto. The primers usable for the detection of the reference marker WDR90 may be a primer of SEQ ID NO: 300, a primer of SEQ ID NO: 301, or a pair of primers containing them.

The probe usable for the detection of the reference marker TUT1 may be the probe of SEQ ID NO: 264, but is not limited thereto. The primers usable for the detection of 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 comprising them, but the present invention is not limited thereto.

Another example is a method for predicting the effect (or reactivity or sensitivity to an anti-c-Met antibody) of an anti-c-Met antibody, comprising the step of measuring the presence and level of the biomarker in a biological sample, A method of screening a subject or providing information to the screening of anti-c-Met antibodies. In the method, the presence and expression level of the biomarker may be measured using the reference marker as a control. For example, in the case of CAV1, FAM126A, MET, RAB31, ST8SIA4, and / or THSD7A, the treatment with anti-c-Met antibody is effective when the expression level is high or the c- . Also, in the case of CMHL and / or PHC1, treatment with an anti-c-Met antibody is effective when the expression level is low, or can be judged as an object suitable for application of the anti-c-Met antibody.

Evaluation of the expression level of the biomarker can be performed by comparing the expression level of the reference marker. For example, the evaluation of the level of expression of the biomarker and the determination of the efficacy and / or suitability of the anti-c-Met antibody can be carried out by polymerase chain reaction (PCR; for example, competitive PCR, (RT-PCR), etc.) can be performed as described in Table 6 below.

Genes (biomarkers) Reference value judgment CAV1, FAM126A, MET, RAB31, ST8SIA4, THSD7A The 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 higher than the reference value, it is evaluated that the expression level is high. → The sample or the sample obtained from the patient is preferably treated with the anti-c-Met antibody or is suitable for the application of the anti- Judge as a target
CMHL, PHC1 The 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 If the Ct value of the biomarker in the sample is below the reference value, it is evaluated that the expression level is low. → The sample or the sample obtained from the patient is preferably treated with the anti-c-Met antibody or is suitable for the application of the anti- Judge as a target

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

In Table 6, the reference marker means at least one selected from the group consisting of EEF1A1, RPL23A, TPT1, HUWE1, MATR3, SRSF3, HNRNPC, SMARCA4, WDR90 and TUT1. The efficacy group (or reactive group) or non-efficacy group (or a non-reactive group) in vivo test which precedes (in vivo test; Eg clinical trial) or in vitro test ( ex vivo test; For example, the effect of the anti-c-Met antibody or the reactivity (sensitivity) to the anti-c-Met antibody may be confirmed by the test.

In another example, an assessment of the level of expression of the biomarker may be made by comparing the expression level of the biomarker in the biological sample under test with the level of expression in the comparative reference sample to determine whether the level of expression of the biomarker in the biological sample under test When the level of expression of the biomarker is higher than that of the reference sample, it can be judged that the expression level of the biomarker is high. When the expression level of the biomarker in the biological sample to be tested is lower than that of the comparative reference sample, It can be judged. The comparative reference sample may be any cell or tissue that does not exhibit the activity of the anti-c-Met antibody or is resistant to the anti-c-Met antibody (the anti-c-Met antibody ineffectiveness group (ATCC, CRL-2335), Caki-1 (ATCC, HTB-46), SKBR3 (ATCC) (ATCC, CCL-229), HCT116 (ATCC, CCL-247), SW620 (ATCC, HTB-30), BT474 Cells were obtained by repeated administration and / or continuous administration of anti-c-Met antibody to the c-Met antibody, Or more.

Thus, the efficacy prediction or patient selection method further comprises comparing the level of expression of the biomarker in the biological sample being tested (e.g., biological sample separated from the subject) to the biomarker level in the comparison reference sample . In this case, the method may further comprise the step of measuring the level of the biomarker in the comparison reference sample. The method is characterized in that 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 that of the comparative reference sample, When the expression level of the CMHL and / or PHC1 biomarker is lower than that of the comparative reference sample, it is judged that the anti-c-Met antibody can function well on the biological sample to be tested or on the subject from which the sample is obtained Determining whether the subject to be tested is sensitive or reactive to the anti-c-Met antibody, or judging that the subject biological sample or the subject from which the sample is obtained is a suitable subject (subject to administration) of the anti-c-Met antibody . ≪ / RTI >

The effect (or efficacy) of the anti-c-Met antibody means an effect to be obtained by applying the anti-c-Met antibody, for example, it may be an anti-cancer effect (eg, cancer cell proliferation inhibitory effect, .

The subject to which the anti-c-Met antibody is applied refers to a patient suitable for the treatment using the anti-c-Met antibody, and may be any mammal such as a primate such as a human, a monkey, a rodent such as a mouse or a rat, For example, a cancer patient. The biological sample may be a patient (for example, a mammal including a primate such as a human, a monkey, a rodent such as a mouse or a rat), or a cell, a tissue, a body fluid separated or artificially cultured from the patient, Cancer tissue, DNA or RNA extracted therefrom, or isolated proteins. The biological sample may be an unprocessed sample or a processed sample (e.g., a formalin fixed paraffin embedded (RRPE) sample).

The object of application of the anti-c-Met antibody may be a cancer patient, which may be a solid cancer or a blood cancer, and may be a cancer associated with overexpression or abnormal activation of c-Met. The cancer may include a primary cancer as well as a metastatic cancer. In one embodiment, the subject of the anti-c-Met antibody is selected from the group consisting of squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal carcinoma, skin cancer or skin or intraocular melanoma, rectal cancer, Cancer, ovarian cancer, liver cancer, bladder cancer, endometrioid cancer, endometrioid cancer, pituitary cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, chronic or acute leukemia, lymphocytic lymphoma, hepatocellular carcinoma, gastric cancer, pancreatic cancer, A cancer patient selected from the group consisting of one or more cancer patients selected from the group consisting of hepatoma, breast cancer, breast cancer, colon cancer, endometrial or uterine cancer, salivary cancer, kidney cancer, prostate cancer, mucin cancer, thyroid cancer, head and neck cancer, brain cancer, . In one embodiment, the object to which the anti-c-Met antibody is applied is one or more cancer patients selected from the group consisting of lung cancer (e.g., lung cancer adenocarcinoma, non-small cell adenocarcinoma, etc.) ≪ / RTI >

The presence or absence of the biomarker and / or the expression level of the reference marker can be determined by a conventional gene quantification method, for example, a conventional microarray method using a probe or a primer capable of hybridizing with the gene, a polymerase chain reaction (PCR) , Fluorescent in situ hybridization (FISH), and the like, but the present invention is not limited thereto. In one embodiment, the presence of the biomarker and / or the level of expression of the biomarker and / or the reference marker can be determined by conventional polymerase chain reaction (PCR). In addition, the presence or absence of the biomarker can be confirmed by conventional sequencing. In one embodiment, the primer detects a 5 to 1000 bp sequential 5 to 1000 bp, for example, 10 to 500 bp, 20 to 200 bp, or 50 to 200 bp gene fragment in the nucleotide sequence of the biomarker gene (full-length DNA, cDNA or mRNA) (E. G., Complementary) to a consecutive 5-100 bp, such as 5 to 50 bp, 5 to 30 bp, or 10 to 25 bp sites of each of the 3'-terminal and 5'- Sequence. ≪ / RTI > The probe is capable of hybridizing with a consecutive 5 to 100 bp, such as 5 to 50 bp, 5 to 30 bp, or 10 to 25 bp sites in the nucleotide sequence of the biomarker gene (full-length DNA, cDNA or mRNA) ) ≪ / RTI > base sequence. The 'hybridization possible' means complementary binding by having 80% or more, such as 90% or more, 95% or more, 98% or more, 99% or more, or 100% sequence complementarity with the nucleotide sequence of the gene site. .

The presence and / or level of the biomarker can also be measured through quantification of the proteins they encode. For example, the quantification of the protein encoded by the biomarker can be performed by a conventional enzyme reaction, fluorescence, luminescence, and / or radiation detection using an antibody, aptamer or the like that specifically binds to the protein. Specifically, Immunochromatography, immunohistochemical staining, enzyme linked immunosorbent assay (ELISA), radioimmunoassay (RIA), enzyme immunoassay (EIA), fluorescent immunoassay But are not limited to, fluorescence immunoassay (FIA), luminescence immunoassay (LIA), Western blotting, microchip, and the like.

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

The method for inhibiting c-Met or the method for preventing and / or treating cancer may further include the step of confirming the selected anti-c-Met antibody before the administration step. The identifying step may include identifying a biological sample or a patient selected by the selection method of the anti-c-Met antibody to which the anti-c-Met antibody is applied, by performing the steps described in the method for selecting the anti-c- Or by confirming that the selected anti-c-Met antibody is the subject of selection by the method of selecting the subject of the anti-c-Met antibody according to the given information.

In one embodiment, the method of c-Met inhibition or the method of preventing and /

Identifying the subject to which the anti-c-Met antibody is to be applied; And

Administering an effective amount of an anti-c-Met antibody to said anti-c-Met antibody subject

. ≪ / RTI >

In another embodiment, the c-Met inhibition method or the method of preventing and /

Measuring the presence and / or the level of the biomarker in the biological sample to select an object to which the anti-c-Met antibody is applied;

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

. ≪ / RTI >

In one embodiment, the anti-c-Met antibody can 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 c-Met to induce internalization and degradation. The anti-c-Met antibody may be one that recognizes a specific site of c-Met, such as a specific site in the SEMA domain, as an epitope.

In this specification, unless stated otherwise, the anti-c-Met antibody is used to include the full-form anti-c-Met antibody as well as the antigen binding site of the antibody.

The "c-Met protein" means a receptor tyrosine kinase that binds hepatocyte growth factor. The c-Met protein may be derived from any species and may be derived from primates such as human c-Met (e.g., NP_000236), monkey c-Met (e.g., Macaca mulatta, NP_001162100) Derived from rodents such as Met (e.g., NP_032617.2), rat c-Met (e.g., NP_113705.1), and the like. Such a protein includes, for example, a polypeptide encoded by the nucleotide sequence provided in GenBank Aceession Number NM_000245, or a protein encoded by the polypeptide sequence provided in GenBank Aceession Number NM_000236, or an extracellular domain thereof. The receptor tyrosine kinase c-Met is involved in various mechanisms such as, for example, cancer development, cancer metastasis, cancer cell migration, cancer cell infiltration, and neovascularization process.

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

The term "epitope" is an antigenic determinant and is understood to mean a portion of an antigen recognized by an antibody. According to one embodiment, the epitope is located at a site comprising at least five contiguous amino acids in the SEMA domain (SEQ ID NO: 79) of the c-Met protein, such as at position 106 in the SEMA domain of the c- To SEQ ID NO: 71 corresponding to SEQ ID NO: 71 to SEQ ID NO: 71. For example, the epitope may consist of 5 to 19 consecutive amino acids including SEQ ID NO: 73 (EEPSQ) in the amino acid sequence of SEQ ID NO: 71, for example, an amino acid sequence of SEQ ID NO: 71, SEQ ID NO: 72 or SEQ ID NO: ≪ / RTI >

The epitope having the amino acid sequence of SEQ ID NO: 72 corresponds to the outermost position of the loop region between the domains 2 and 3 of the propeller structure in the SEMA domain of the c-Met protein, and the amino acid sequence of SEQ ID NO: Is an antibody or antigen binding fragment according to one embodiment most specifically binds to a site.

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

According to one embodiment, the anti-c-

A CDR-H1 having the amino acid sequence of SEQ ID NO: 4, an amino acid sequence of SEQ ID NO: 5, an amino acid sequence of SEQ ID NO: 2, or a sequence of 8 to 19 consecutive amino acids including the third to tenth amino acids in the amino acid sequence of SEQ ID NO: CDR-H2 having an amino acid sequence consisting of the amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 85, or SEQ ID NO: 85, or a sequence of six to six consecutive amino acids comprising the amino acid sequence of SEQ ID NO: 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 the at least one heavy chain complementarity determining region;

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

A combination of the heavy chain complementary crystal region and the light chain complementarity determining region; or

The combination of the heavy chain variable region and the light chain variable region

. ≪ / RTI >

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

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),

The 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)

Formula V

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

The general formula VI

Xaa ₁₄ -Gln-Ser-Tyr-Ser-Xaa ₁₅ -Pro-Xaa _16- Thr (SEQ ID NO: 9)

Wherein Xaa ₁ is absent or Pro or Ser, Xaa ₂ is Glu or Asp,

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

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

Xaa ₇ is He, Arg, Gln or Lys, Xaa ₈ is Ser or Trp, Xaa ₉ is His or Gln, Xaa ₁₀ is Lys or Asn,

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

Wherein Xaa ₁₄ is Gly, Ala or Gln, 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: 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:

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: 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: The CDR-L3 may have an amino acid sequence selected from the group consisting of SEQ ID NO: 12, 13, 14, 15, 16, 37, 88,

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, (CDR-H2) having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 25, and SEQ ID NO: 26 and a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: A heavy chain variable region comprising a peptide (CDR-H3); (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: (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 a polypeptide having the amino acid sequence selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: A light chain variable region comprising a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 37, SEQ ID NO: 86, and SEQ ID NO: 89 (CDR-L3).

According to one embodiment, in the anti-c-Met antibody or antigen-binding fragment, the heavy chain variable region is selected from the group consisting of SEQ ID NO: 17, SEQ ID NO: 74, SEQ ID NO: 87, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, The light chain variable region comprises an amino acid sequence of SEQ ID NO: 94, wherein the light chain variable region comprises 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: , SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99 or SEQ ID NO: 107.

An animal-derived antibody that produces a desired antigen by immunizing an immunized animal generally has immunomodulation upon administration to a human for therapeutic purposes, and a chimeric antibody has been developed in order to suppress such immune rejection. The chimeric antibody uses a genetic engineering method to replace the constant region of the animal-derived antibody, which is responsible for the anti-isotype reaction, with the constant region of the human antibody. Chimeric antibodies have improved substantially in the anti-isotype response compared to animal-derived antibodies, but still have adverse effects on potential anti-idiotypic responses due to the presence of animal-derived amino acids in variable regions . Humanized antibodies have been developed to improve these side effects. This is made by grafting complementarity determining regions (CDRs), which play an important role in the binding of the antigen among the variable regions of the chimeric antibody, to the human antibody framework.

The most important of the CDR grafting techniques for making humanized antibodies is to select an optimized human antibody that can best accommodate the CDR region of the animal-derived antibody. For this purpose, use of the antibody database, crystal structure structure analysis, and molecular modeling techniques. However, even if the CDR region of the animal-derived antibody is transplanted into the optimized human antibody backbone, the amino acid that affects the antigen binding may exist in the skeleton of the animal-derived antibody, The application of additional antibody engineering techniques to restore antigen binding 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 the living body or not naturally occurring. The antibody may be recombinantly or synthetically prepared.

A complete antibody is a structure with two full length light chains and two full length heavy chains, each light chain linked by a heavy chain and 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 a gamma (gamma), mu (mu), alpha (alpha), delta (delta) and epsilon Gamma 1, gamma 2, gamma 3, gamma 4, alpha 1, and alpha 2, respectively. The constant region of the light chain has kappa (kappa) and lambda (lambda) types.

The term "heavy chain" refers to a variable region domain V _H comprising an amino acid sequence having a variable region sequence sufficient to confer antigen specificity, and three constant region domains C _H1 , C _H2 and C _H3 and a hinge hinge < / RTI > and fragments thereof. The term "light chain" also encompasses both the light chain light chain comprising the variable region domain V _L and the constant region domain C _L comprising the amino acid sequence having sufficient variable region sequences to confer specificity to the antigen, and fragments thereof Is interpreted to mean inclusive.

The term "CDR (complementarity determining region)" refers to the amino acid sequence of the heavy chain of the immunoglobulin and the hypervariable region of the light chain. The heavy and light chains may each contain three CDRs (CDRH1, CDRH2, CDRH3 and CDRL1, CDRL2, CDRL3). The CDRs may provide the major contact residues for binding of the antibody to the antigen or epitope. In the present specification, the terms "specifically binding" or "specifically recognizing" are the same as those conventionally known to those skilled in the art, and the antigen and the antibody specifically interact to effect an immunological reaction .

The term "antigen binding fragment" refers to a fragment of a polypeptide comprising an immunoglobulin entire structure and a portion to which an antigen can bind. In one embodiment, the antigen binding fragment may be, but is not limited to, scFv, (scFv) ₂ , Fab, Fab 'or F (ab') ₂ . Among the antigen-binding fragments, Fab has one antigen-binding site with a variable region of a light chain and a heavy chain, a constant region of a light chain, and a first constant region (C _H1 ) of a heavy chain.

Fab 'differs from Fab in that it has a hinge region that contains at least one cysteine residue at the C-terminus of the heavy chain C _H1 domain.

The F (ab ') ₂ antibody is produced when the cysteine residue of the hinge region of the Fab' forms a disulfide bond. Recombinant techniques for generating Fv fragments with minimal antibody fragments having only a heavy chain variable region and a light chain variable region are well known in the art.

The double-chain Fv is a non-covalent bond, and the variable region of the heavy chain and the light chain variable region are connected to each other. The single-chain Fv generally shares the variable region of the heavy chain and the variable region of the short chain through the peptide linker Or directly connected at the C-terminus to form a dimer-like structure like the 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 the amino acid contained therein is not limited.

The antigen-binding fragment can be obtained using a protein hydrolyzing enzyme (for example, when the whole antibody is restricted to papain, a Fab can be obtained and when cut with pepsin, an F (ab ') ₂ fragment can be obtained) Can be produced through recombinant DNA technology.

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

When the animal-derived antibody is subjected to a chimerization process, the animal-derived IgG1 hinge is replaced with a human IgG1 hinge. However, the animal-derived IgG1 hinge is shorter in length than the human IgG1 hinge, and the disulfide bond disulfide bond decreases from 3 to 2, and the rigidity of the hinge is different from each other. Thus, modification of the hinge region can increase the antigen binding efficiency of the humanized antibody. Methods of deletion, addition, or substitution of amino acids to modify 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 the antigen binding efficiency, the anti-c-Met antibody or antigen-binding fragment is one comprising at least one amino acid deletion, addition or substitution, . For example, the antibody may comprise a hinge region having an 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 an amino acid sequence of SEQ ID NO: Region). ≪ / RTI > More specifically, the hinge region may have an amino acid sequence of SEQ ID NO: 100 or SEQ ID NO: 101.

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

The light chain constant region and the heavy chain constant region except for the above defined CDR region or light chain variable region and the heavy chain variable region of the anti-c-Met antibody are all subtypes of immunoglobulins (e.g., IgA, IgD, IgE, IgG IgG1, IgG2, IgG3, IgG4, etc.), IgM, etc.), such as a light chain constant region and a heavy chain constant region.

According to one embodiment, the anti-c-

The amino acid sequence of SEQ ID NO: 62 (the first to seventh amino acid sequences are signal peptides), the 18th to 462th amino acid sequences of SEQ ID NO: 62, the amino acid sequence of SEQ ID NO: 64 The amino acid sequence of SEQ ID NO: 66 is a signal peptide), or the 18th to 461th amino acid sequence of SEQ ID NO: 64, the amino acid sequence of SEQ ID NO: 66 (wherein the amino acid sequence of the 1st to 17th is a signal peptide) And an amino acid sequence selected from the group consisting of amino acids 18 to 460 of SEQ ID NO: 66; And

The amino acid sequence of SEQ ID NO: 68 (wherein the first to 20th amino acid sequences are signal peptides), the 21st to 240th amino acid sequences of SEQ ID NO: 68, the amino acid sequence of SEQ ID NO: 70 20 th amino acid sequence is a signal peptide), an amino acid sequence from position 21 to position 240 of SEQ ID NO: 70, and an amino acid sequence from SEQ ID NO: 108,

. ≪ / RTI >

For example, the anti-c-

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

A heavy chain comprising the amino acid sequence of SEQ ID NO: 64 or an 18th to 461th amino acid sequence of SEQ ID NO: 64 and a light chain comprising the amino acid sequence of SEQ ID NO: 68 or the 21st to 240th amino acids of SEQ ID NO: 68 An antibody comprising;

The light chain comprising the amino acid sequence of SEQ ID NO: 66 or the 18th to 460th amino acids of SEQ ID NO: 66 and the light chain comprising the amino acid sequence of SEQ ID NO: 68 or the 21st to 240th amino acids of SEQ ID NO: 68 An antibody comprising;

The light chain comprising the amino acid sequence of SEQ ID NO: 62 or the 18th to 462th amino acid sequence of SEQ ID NO: 62 and the light chain comprising the amino acid sequence of SEQ ID NO: 70 or the 21st to 240th amino acid sequence of SEQ ID NO: 70 An antibody comprising;

The light chain comprising the amino acid sequence of SEQ ID NO: 64 or the 18th to 461th amino acid sequence of SEQ ID NO: 64 and the light chain comprising the amino acid sequence of SEQ ID NO: 70 or the 21st to 240th amino acid sequence of SEQ ID NO: 70 An antibody comprising; or

The heavy chain comprising the amino acid sequence of SEQ ID NO: 66 or the 18th to 460th amino acids of SEQ ID NO: 66, and the light chain comprising the amino acid sequence of the 21st to 240th amino acids of SEQ ID NO: 70 or SEQ ID NO: 70 Antibodies included

An antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 62 or an 18th to 462th amino acid sequence 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 an 18th to 461th amino acid sequence of SEQ ID NO: 64 and a light chain comprising the amino acid sequence of SEQ ID NO: 108; And

The heavy chain comprising the amino acid sequence of SEQ ID NO: 66 or the 18th to 460th amino acids of SEQ ID NO: 66 and the light chain comprising the amino acid sequence of SEQ ID NO: 108

≪ / RTI >

In the meantime, the polypeptide having the amino acid sequence of SEQ ID NO: 70 is a light chain consisting of the kappa constant region of human, and the polypeptide having the amino acid sequence of SEQ ID NO: 68 has the amino acid sequence of SEQ ID NO: The amino acid position 62 of SEQ ID NO: 68) is a polypeptide in which histidine is substituted with tyrosine. Due to this substitution, the yield of antibody according to one embodiment can be increased. In addition, the polypeptide having the amino acid sequence of SEQ ID NO: 108 is a polypeptide having the amino acid sequence of the 21st to 240th amino acid except for the 1st to 20th signal peptides in the amino acid sequence of SEQ ID NO: 68, (Ser) in the CDR-L1 is substituted with tryptophan (Trp) according to the Kabat numbering, the 32nd position in SEQ ID NO: 108; the activity of the antibody according to one embodiment (e.g., binding affinity for c-Met, c-Met degrading activity, and Akt phosphorylation-inhibiting activity, etc.) can be further enhanced.

The anti-c-Met antibody can be formulated together with a pharmaceutically acceptable carrier, which is commonly used in the formulation of drugs, including lactose, dextrose, sucrose, sorbitol, mannitol, starch, , Calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, Mineral oil, and the like, but the present invention is not limited thereto.

The anti-c-Met antibody can be administered orally or parenterally. In the case of parenteral administration, it can be administered by intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, intrapulmonary administration or rectal administration. When administered orally, the protein or peptide is extinguished and the oral composition should be formulated to coat the active agent or protect it from degradation from above. In addition, the anti-c-Met antibody can be administered by any device capable of migrating to a target cell.

The anti-c-Met antibody can be used for the prevention and / or treatment of cancer. The cancer may be a solid tumor or hematoma and may be associated with overexpression or activation of c-Met. For example, the cancer may be, but is not limited to, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell carcinoma of the lung, peritoneal cancer, skin cancer, skin or intraocular melanoma, rectal cancer, Cancer of the stomach, cancer of the esophagus, cancer of the esophagus, cancer of the endocrine system, cancer of the parathyroid gland, adenocarcinoma, soft tissue sarcoma, urethral cancer, chronic or acute leukemia, lymphocytic lymphoma, hepatocellular carcinoma, gastric cancer, gastric cancer, pancreatic cancer, The present invention may be at least one selected from the group consisting of liver cancer, breast cancer, colon cancer, colon cancer, endometrial or uterine cancer, salivary cancer, renal cancer, prostate cancer, mucin cancer, thyroid cancer, head and neck cancer, brain cancer,

The preventive and / or therapeutic effect of the cancer includes not only an effect of inhibiting the growth of cancer cells but also an effect of inhibiting migration, invasion, metastasis, . It also includes effects on metastatic cancer as well as primary cancer.

The biomarkers and / or reference markers proposed in the present invention can be used to select patients that are suitable for the application of anti-c-Met antibodies with high accuracy, thereby enabling the efficacy of the anti-c-Met antibodies in individual patients It is possible to customize the treatment according to the patient to maximize the use and can be usefully used for the resolution of the anti-c-Met antibody.

FIG. 1A shows the results of judging the efficacy group and the non-efficacy group obtained using the Ventana MET IHC method for the mouse xenograft model, and 1b is a graph showing the results of judging the efficacy group and the non-efficacy group obtained through RT-PCR 1b, X axis: IHC score, ◆: non-potency group, ●: potency group).
Figures 2a and 2b are graphs showing the expression levels of control genes.
3A and 3B are graphs showing the results of measurement of 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 with reference to Examples and Test Examples. However, these examples and test examples are for the purpose of illustrating the present invention and should not be construed as limiting the present invention.

Reference example  1: The term c- Met  Production of antibodies

1.1. c- Met ≪ / RTI > AbF46 ' Production of

1.1.1. Immunization of mice

To obtain immunized mice required for the development of hybridoma cell lines, 5 mice were immunized with 100 ug of human c-Met / Fc fusion protein (R & D Systems) in equal amounts of Freund ' s adjuvant Were mixed and injected into the abdominal cavity of 4-6 week old BALB / c mice (Japan SLC, Inc.). After 2 weeks, 50 [mu] g 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, Were injected intraperitoneally. Three days after the last boosting was performed, the blood was collected from the tail of the mouse to obtain serum. After dilution with PBS at 1/1000, the antibody titer of c-Met 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 Hybrid  Produce

Three days before the cell fusion experiment, human c-Met / Fc fusion protein mixture was injected into the abdominal cavity of BALB / c mice (Japan SLC, Inc.) in 50 μg of PBS, The spleen was removed. The extracted spleen was grinded with a mesh to separate cells and mixed with a culture medium (DMEM, GIBCO, Invitrogen) to prepare a spleen cell suspension. The suspension was centrifuged to recover the cell layer. A mixture of the resulting spleen cells, 1 x 10 ⁸ dogs and myeloma cells (Sp2 / 0) 1 x 10 8 gae precipitate the following, the cells by centrifugation. The centrifuged precipitate was slowly dispersed and treated with 45% polyethylene glycol (PEG) (1 ml) in a culture medium (DMEM), maintained at 37 ° C for 1 minute, and then 1 ml of culture medium (DMEM) Was added. Then, 10 ml of the culture medium (DMEM) was added for 1 minute, allowed to stand in water at 37 ° C for 5 minutes, and then centrifuged again to 50 ml. The cell precipitate was resuspended in a separation medium (HAT medium) at a concentration of 1 to 2 × 10 ⁵ / ml, and 0.1 ml of each of the cells was dispensed into a 96-well plate and cultured in a 37 ° C. carbon dioxide incubator to prepare a hybridoma cell group Respectively.

1.1.3. c- Met  To produce a monoclonal antibody to a protein Hybridoma  Cell sorting

Among the hybridoma cell groups prepared in Reference Example 1.1.2, human c-Met / Fc fusion proteins and human Fc proteins were used as antigens in order to select hybridoma cells that specifically react only with c-Met protein ELISA assay.

The human c-Met / Fc fusion protein was added to the microtiter plate in an amount of 50 μl (2 μg / ml) per well, and the unreacted antigen was washed away. To selectively exclude antibodies that bind to Fc other than c-Met, human Fc proteins were attached to the plate surface in the same manner as above.

The culture of the hybridoma cells obtained in Reference Example 1.1.2 was added to each of the prepared wells in an amount of 50 μl each, reacted for 1 hour, and sufficiently washed with a phosphate buffer solution-Tween 20 (TBST) to remove unreacted culture medium Respectively. Mouse IgG-horseradish peroxidase (goat anti-mouse IgG-HRP) was added thereto, followed by reaction at room temperature for 1 hour, followed by washing with TBST solution. Subsequently, a peroxidase substrate solution (OPD) was added and reacted. The degree of the reaction was confirmed by measuring the absorbance at 450 nm using an ELISA reader.

Hybridoma cell lines secreting an antibody having a high binding force specifically to human c-Met protein but not binding to human Fc were repeatedly selected by confirming the above reaction degree. One clone of hybridoma cell line producing a monoclonal antibody by limiting dilution of the hybridoma cell line obtained through repeated selection was finally obtained. The final screened monoclonal antibody-producing hybridoma was deposited with the Korean Cell Line Research Foundation, located in Yeongeon-dong, Jongno-gu, Seoul, Korea, on October 6, 2009 under the Budapest Treaty, and granted accession number KCLRF-BP-00220 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 purified from the culture medium.

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 with 20 ml of PBS twice or more to remove FBS , The cell pellet was resuspended in 50 ml of culture medium (DMEM) medium, and then cultured in a 37 ° C carbon dioxide incubator for 3 days.

Thereafter, the cells producing the antibody 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. The antibody was pure purified from 50 ml to 300 ml of the prepared culture medium using an AKTA purification apparatus (GE Healthcare) equipped with an affinity column (Protein G agarose column; Pharmacia, USA), and then a protein aggregation filter (Amicon) The purified antibody was stored by substituting the supernatant with PBS and used in the following examples.

1.2. c- Met For Chimeric  Antibody chAbF46 Production

In general, mouse antibodies are highly likely to show immunogenicity when they are injected into humans for therapeutic purposes. Therefore, in order to solve this problem, it has been found from mouse antibody AbF46 prepared in Example 1 that mutation regions related to antigen binding chAbF46, a chimeric antibody that substitutes a constant region of a human IgG1 antibody, except the variable region, was prepared.

The nucleotide sequence corresponding to the heavy chain was designated as EcoRI-signal sequence-VL-BsiWI-CL-TGA (SEQ ID NO: -XhoI '(SEQ ID NO: 39), respectively. Since, DNA fragments in pOptiVEC ^TM -TOPO TA Cloning Kit that is included in the Invitrogen Corporation ^{OptiCHO TM Antibody Express Kit (Cat no} . 12762-019) having a nucleotide sequence corresponding to the heavy chain (SEQ ID NO: 38) for, pcDNA ^TM 3.3 -TOPO (SEQ ID NO: 39) having the nucleotide sequence corresponding to the light chain was cloned into the TA Cloning Kit (Cat No. 8300-01) using restriction enzymes EcoRI (NEB, R0101S) and XhoI (NEB, R0146S) , A vector containing a heavy chain for expression of a chimeric antibody, and a vector containing a light chain, respectively.

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

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

1.3. Chimeric  Antibody chAbF46 From a humanized antibody huAbF46 Production

1.3.1. Heavy chain  Humanization Heavy chain humanization )

For the design of the two H1-heavy and H3-heavy species, the VH gene of the mouse antibody AbF46 purified in Reference Example 1.2 was firstly introduced into Ig Blast (http://www.ncbi.nlm.nih.gov/igblast/) And the most homologous human germline genes were analyzed. As a result, it was confirmed that VH3-71 had a homology of 83% at amino acid level. CDR-H1, CDR-H2 and CDR-H3 of mouse antibody AbF46 were defined as Kabat numbering and CDR part of mouse antibody AbF46 Lt; RTI ID = 0.0 > VH3-71. ≪ / RTI > At this time, the amino acids 30 (S → T), 48 (V → L), 73 (D → N) and 78 (T → L) originally backmutated with the amino acid sequence of mouse AbF46 antibody. Subsequently, H1 further mutated to amino acids 83 (R? K) and 84 (A? T) to finally construct H1-heavy (SEQ ID NO: 40) and H3-heavy (SEQ ID NO: 41).

For the design of H4-heavy, the framework sequences of human antibodies were found to be similar to the mouse framework sequences of AbF46 antibody and to be defined as Kabat numbering using the most stable known VH3 subtypes CDR-Hl, CDR-H2, and CDR-H3 of the mouse antibody AbF46. Thereby constructing H4-heavy (SEQ ID NO: 42).

1.3.2. Light chain  Humanization Light chain humanization )

For the design of two types of H1-light (SEQ ID NO: 43) and H2-light (SEQ ID NO: 44), the mouse antibody AbF46 (SEQ ID NO: The most homologous to the VL gene of the human germline gene was analyzed. As a result, it was confirmed that VK4-1 had a homology of 75% at the amino acid level. CDR-L1, CDR-L2 and CDR-L3 of mouse antibody AbF46 were defined as Kabat numbering and CDR part of mouse antibody AbF46 It was designed to be introduced into the skeleton of VK4-1. H1-light back-mutated 36 amino acids (Y → H), 46 amino acids (L → M) and 49 amino acids (Y → I) Only one back-mutation was constructed.

For the design of H3-light (SEQ ID NO: 45), the human germline gene, which is most homologous to the VL gene of mouse antibody AbF46 through Blast (http://www.ncbi.nlm.nih.gov/igblast/) Of the analyzed results, VK2-40 was selected in addition to VK4-1. The mouse antibodies AbF46 VL and VK2-40 were found to have a homology of 61% at the amino acid level. CDR-L1, CDR-L2 and CDR-L3 of mouse antibody AbF46 were defined as Kabat numbering and CDR Was introduced into the skeleton of VK4-1. At this time, H3-light was constructed by back-mutating 36 amino acids (Y → H), 46 amino acids (L → M), and 49 amino acids (Y → I).

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

Since, Invitrogen Corporation OptiCHO ^TM Antibody Express Kit pOptiVEC contained in ^{(Cat no 12762-019.) TM -TOPO} TA Cloning Kit wherein the heavy chain DNA fragments (H1-heavy with a nucleotide sequence in a; SEQ ID NO: 47, H3 -heavy; SEQ ID NO: 48, H4-heavy; SEQ ID NO .: 49) pcDNA ^TM 3.3-TOPO (H1-light; SEQ ID NO: 51; H3-light; SEQ ID NO: 52; H4-light; SEQ ID NO: 53) having the nucleotide sequence corresponding to the light chain was inserted into the TA Cloning Kit A vector for the expression of humanized antibodies was constructed by cloning using EcoRI (NEB, R0101S) and XhoI (NEB, R0146S) restriction enzymes.

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

The cultured cells were centrifuged and 100 ml of each supernatant was collected and purified using AKTA Prime (GE healthcare). Protein A column (GE healthcare, 17-0405-03) was installed on AKTA Prime, and the culture solution was flowed at a flow rate of 5 ml / min and then 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). The heavy and light chain combinations of the humanized antibody huAbF46 used in the following Examples are H4-heavy (SEQ ID NO: 42) and H4-light (SEQ ID NO: 46).

1.4. huAbF46  Antibody scFv  Library production

A gene was designed to construct the scFv of the huAbF46 antibody 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 in the form of 'VH-Linker-VL', and the linker was designed to have the amino acid sequence of 'GLGGLGGGGSGGGGSGGSSGVGS' (SEQ ID NO: 54). The polynucleotide encoding the scFv of the huAbF46 antibody thus designed (SEQ ID NO: 55) was synthesized by biona, and the vector for expressing it was shown in SEQ ID NO: 56.

Thereafter, expression from said vector The results were analyzed and it was confirmed that c-Met had specific binding ability.

1.5. Affinity maturation ( affinity maturation Generation of library genes for

1.5.1. Target CDR And primer  making

For affinity maturation of huAbF46 antibody, six complementary determining regions (CDRs) were defined by 'Kabat numbering' from the prepared mouse antibody AbF46, and the respective CDRs were as 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 for the random introduction of antibody CDRs. In the conventional random sequence introduction method, the N codon was used to introduce the same ratio of the base (25% A, 25% G, 25% C, 25% T) to the site to be mutated. In this example, the huAbF46 antibody To introduce a random base into the CDRs of the three CDRs, three 85% of the first and second nucleotides of the wild-type nucleotides were retained and 5% of the remaining three bases were introduced. In addition, the primer was designed so that the third nucleotide was equally introduced (33% G, 33% C, 33% T).

1.5.2. huAbF46  Libraries of antibodies and c- Met Confirmation of bond strength to

The construction of the antibody library gene by randomly introducing CDRs was carried out using primers prepared in the same manner as in Reference Example 1.5.1. Using the polynucleotide containing the scFv of the huAbF46 antibody as a template, two PCR fragments were prepared as in the method shown in Fig. 1, and the PCR fragments were subjected to overlapping PCR using only the desired CDRs The scFv library gene of the mutated huAbF46 antibody was constructed and libraries were constructed targeting each of the six CDRs produced.

The library thus constructed showed the binding ability of wild type and each library to c-Met, and each library tended to have a lower binding force to c-Met than wild type, but the binding strength to some c-Met Mutations that were maintained were identified.

1.6. From the library produced Affinity  Screening of Improved Antibodies

After enhancing the binding capacity of the library to c-Met from the constructed library, the gene sequence of scFv was analyzed from each individual clone. The obtained gene sequences are shown in Table 8, respectively, and they are converted into IgG form. In the following clones, four kinds of antibodies produced from L3-1, L3-2, L3-3 and L3-5 were selected to carry out subsequent experiments .

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 antibodies IgG Conversion to

The polynucleotide encoding the heavy chain of the four selected antibodies consists of the EcoRI-signal sequence-VH-NheI-CH-XhoI '(SEQ ID NO: 38) and the amino acid of the antibody is changed after affinity maturation , The heavy chain of the huAbF46 antibody was used as it was. However, the hinge region was replaced by the U6-HC7 hinge (SEQ ID NO: 57), not the hinge of human IgG1. The light chain was designed to be composed of the EcoRI-signal sequence-VL-BsiWI-CL-XhoI, respectively, and a polynucleotide encoding a light chain variable region of the above-mentioned four kinds of antibodies selected after affinity maturation SEQ ID NO: 58 to SEQ ID NO: 61) was synthesized with reference to bionan. Since, DNA fragments in pOptiVEC ^TM -TOPO TA Cloning Kit that is included in the Invitrogen Corporation ^{OptiCHO TM Antibody Express Kit (Cat no} . 12762-019) having a nucleotide sequence corresponding to the heavy chain (SEQ ID NO: 38) for, pcDNA ^TM 3.3 -TOPO (DNA fragment containing CDR-L3 derived from L3-1: SEQ ID NO: 58, CDR-L3 derived from L3-2) in the TA Cloning Kit (Cat No. 8300-01) containing the nucleotide sequence corresponding to the light chain (NEB, R0101S), which is a DNA fragment comprising SEQ ID NO: 59 and L3-3-derived CDR-L3: SEQ ID NO: 60 and L3-5-derived CDR- And XhoI (NEB, R0146S) restriction enzymes to construct vectors for the expression of affinity matured antibodies.

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

The cultured cells were centrifuged and 100 ml of each supernatant was collected and purified using AKTA Prime (GE healthcare). Protein A column (GE healthcare, 17-0405-03) was installed on AKTA Prime, and the culture solution was flowed at a flow rate of 5 ml / min and then eluted with an IgG elution buffer (Thermo Scientific, 21004). (Hereinafter referred to as huAbF46-H4-A1 (derived from L3-1), huAbF46-H4-A2 (derived from L3-2) and huAbF46-H4-A3 3), and huAbF46-H4-A5 (derived from L3-5).

1.8. Constant region and / or The hinge region  Substituted huAbF46 - H4 Manufacturing of -A1

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

The antibody consisting of the heavy chain consisting of the heavy chain variable region of huAbF46-H4-A1, the U6-HC7 hinge and the human IgG1 constant region and the light chain consisting of the light chain variable region of huAbF46-H4-A1 and the human kappa constant region was designated huAbF46 -H4-A1 (U6-HC7); The antibody consisting of the heavy chain consisting of the heavy chain variable region of huAbF46-H4-A1, the human IgG2 hinge and the human IgG1 constant region and the light chain consisting of the light chain variable region of huAbF46-H4-A1 and the human kappa constant region was designated huAbF46- A1 (IgG2 hinge); The heavy chain consisting of the heavy chain variable region of huAbF46-H4-A1, the human IgG2 hinge and the human IgG2 constant region, and the light chain consisting of the light chain variable region of huAbF46-H4-A1 and the human kappa constant region was designated huAbF46- A1 (IgG2 Fc), respectively. On the other hand, in order to increase the production amount of the three kinds of antibodies, all of the light chain histidine of the human kappa constant region was substituted with tyrosine.

(SEQ ID NO: 63), huAbF46-H4-A1, which comprises a heavy chain variable region of huAbF46-H4-A1, a U6-HC7 hinge and a human IgG1 constant region, A polynucleotide (SEQ ID NO: 65) encoding a polypeptide consisting of the heavy chain variable region of H4-A1, the human IgG2 hinge and the human IgGl constant region (SEQ ID NO: 64), the heavy chain variable region of huAbF46-H4- A polynucleotide (SEQ ID NO: 67) encoding a polypeptide consisting of a hinge and a human IgG2 constant region (SEQ ID NO: 66), a light chain variable region of huAbF46-H4-A1 substituted with 36 histidine-tyrosine and a human kappa constant region (SEQ ID NO: 69) encoding a polypeptide (SEQ ID NO: 68) was synthesized with reference to Bioneer. Then, a DNA fragment having a base sequence corresponding to the heavy chain to pOptiVEC ^TM -TOPO TA Cloning Kit that is included in the Invitrogen Corporation ^{OptiCHO TM Antibody Express Kit (Cat no} . 12762-019), pcDNA TM 3.3-TOPO A DNA fragment having the nucleotide sequence corresponding to the light chain was inserted into the TA Cloning Kit (Cat No. 8300-01) to construct a vector for expression of the antibody.

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

The cultured cells were centrifuged and 100 ml of each supernatant was collected and purified using AKTA Prime (GE healthcare). Protein A column (GE healthcare, 17-0405-03) was installed on AKTA Prime, and the culture solution was flowed at a flow rate of 5 ml / min and then eluted with an IgG elution buffer (Thermo Scientific, 21004). (HUAbF46-H4-A1 (U6-HC7), huAbF46-H4-A1 (IgG2 hinge) and huAbF46-H4-A1 (IgG2 Fc)) were finally purified by exchanging them with PBS buffer. Among them, huAbF46-H4-A1 (IgG2 Fc) was selected as the representative anti-c-Met antibody according to the present invention and used for the following examples. For convenience, the antibody was named anti-c-Met antibody L3-1Y / IgG2 Respectively.

Reference example  2. Xenotransplantation model and test sample preparation

Fourteen mouse xenograft models were obtained from Oncotest (Germany) in which patient-derived tumor tissues (non-small cell lung cancer: NSCLC) were transplanted intraperitoneally.

The 14 species of mouse xenografts were injected with the candidate drug final form (L3-1Y / IgG2; n = 10) and empty vehicle (control; n = 10) The size of the tissue was measured to determine the reactivity to the antibody.

L3-1Y / IgG2 (PBS buffer for control) was administered at a dose of 5 mg / kg once a week from the time when the tumor size of the mouse xenograft model grew over 500 mm ³ , and the experiment was performed for a total of 6 weeks And the experiment was stopped when the tumor size reached 2000 mm ³ or more.

Tumor size (mm ³ ) was calculated using the formula of long diameter * short axis * short axis * 1/2, and discrimination of efficacy group was performed by rejection of hypothesis with p-value less than 0.05 through ANOVA analysis. In other words, the hypothesis that the size distribution of the tumor was not changed compared with the group not administered the drug was tested by ANOVA, and the group with the p-value of less than 0.05 was judged to be ineffective and the group exceeding the efficacy.

The reactivity results for the L3-1Y / IgG2 treatment of the obtained sorted samples are shown in Table 9 below:

Reactive group (efficacy group) Non-responders (non-responders) Sample name LXFA1647, LXFA2158, LXFA526, LXFA623 LXFA1041, LXFA162, LXFA1848, LXFA2201, LXFA289, LXFA297, LXFA400, LXFA749, LXFA923, LXFA983

The tumor tissues of the mice that had undergone the experiment were extracted, and FFPE (Formalin Fixed Paraffin Embedded) block was prepared. The rest of the tumor tissues were collected using Qiagen RNeasy Mini Kit (Cat. No. 74104) RNA was extracted.

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

The results obtained using the obtained Ventana MET IHC method are shown in FIG. 1A. According to this method, if the IHC score is 2 ~ 3, it can be judged as an efficacy group. However, as shown in Fig. 1A, LXFA297, LXFA983, and LXFA1041 classified as ineffective group also showed IHC score of 2 to 3, and the IHC method showed that the screening accuracy of the efficacy group and the non-efficacy group was not high (Accuracy: about 50%).

On the other hand, RT-PCR results obtained for six models (LXFA297, LXFA983, LXFA1041, LXFA623, LXFA526, and LXFA1647) shown in the efficacy group in FIG. 1A are shown in FIG. In FIG. 1B, the Y-axis is the Ct value measured by RT-PCR, and the X-axis is the obtained IHC score, and ◆ represents the non-potency group and ● represents the potency group. As shown in FIG. 1B, according to RT-PCR results, all of the non-potency group had a Ct value of 0 or more, whereas all the potency groups showed a Ct value of less than zero. Therefore, it can be seen that the result of RT-PCR makes it possible to discriminate between the more effective group and the less effective group (accuracy: about 71% to about 93%) compared with the case of the conventional IHC method, (For example, 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: Biomarker  Selection

The anti-c-Met antibody L3-1Y / IgG2 was prepared using the xenograft sample (15 kinds of pre-clinical samples; Reference Example 2) for drug efficacy test for the anti-c-Met antibody L3-1Y / IgG2 prepared in Reference Example 1, 1Y / IgG2. The gene expression level (Δ log2 (exp)) between the groups was measured using the obtained results, and genes with large differences were selected.

The difference in gene expression was measured using a raw data cell file of Affymatrix human u133 plus 2.0 microarray, and the log2 (probe intensity) value of each probe was measured using a microarray analysis console provided by the manufacturer . 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 GAATAGGACTAACTGATCTCTTTG (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 ACCACCACAAAATGGCCTTTAGTGT (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 CCGCGGCTCGGAGCAAGCGGTGCAG (SEQ ID NO: 190) 33 Antisense GGAGCGATTCCCATTCGAGGAGTTT (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 TGATTGAATTTTTCTCCTGCATCC (SEQ ID NO: 208) 3758 Antisense AGAGACTTGGTTGGCATCTTCTGCT (SEQ ID NO: 209) 3806 Antisense GGCACATGTGGCTGTTGTCATTCTT (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 GTGTCCTTATAGCAGCAGCATTGTG (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 efficacy group and the non-efficacy group, they were selected in descending order of the difference.

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

As shown in Table 11, the differences in expression between the potency group and the non potency group were in the order of THSD7A, MET, RAB31, FAM126A, PHCl, CHML, ST8SIA4 and CAV1.

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

Example  2: Criteria Marker  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 little variation in gene expression level .

The log2 (int) value of each probe was obtained by using affymetrix U133 plus2.0 microarray raw data (cell file) for NSCLC tumor driven total RNA obtained from GEO, and the gene with the lowest coefficient of variation (CV) And a gene whose log2 (int) value is similar to the target gene (8 kinds of 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 GGCAATTATTTGGATCTATC (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 HNRNPC 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 FIG. 2A, 10 genes with low gene expression fluctuation, namely EEF1A1, RPL23A, TPT1, HUWE1, MATR3, SRSF3, HNRNPC, SMARCA4, WDR90 and TUT1 were selected as reference markers.

The variance and classification performance difference of the 10 selected reference markers with respect to the conventional control gene (Oncotype DX ^TM ; see FIG. 2b) was measured

The probes and primers used for the 10 types of selected reference markers are listed 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 HNRNPC 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 TGACCAGACAGAGCAGGAACC (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 GGCAATTATTTGGATCTATC (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 HNRNPC 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 value was measured for the 10 selected reference markers and the existing control genes by the method described above.

The results obtained are shown in FIG. 3A (control gene) and 3b (selected reference marker). As shown in FIGS. 3A and 3B, the average coefficient of variation (CV) of the 10 kinds of reference markers selected in the present invention is 11.770, which is significantly reduced from the conventional control gene (Oncotype DX ^TM ) (mean CV = 15.40335) Among the 10 reference markers, the five kinds of genes of RPL23A, TPT1, MATR3, SRSF3, and HNRNPC showed particularly small variation in the expression amount (5 species average CV = 8.39).

Example  3: Selected Biomarker  And The fiducial marker  The anti-c- Met  Antibody Efficacy group  Selection

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

For this, total RNA extracted from the tumor tissues of the mouse xenograft model was subjected to PCR under the conditions of Table 17 using the probes shown in Table 15 and the primers shown in Table 16, and the 8 kinds of biomarkers and 5 kinds Ct values of the 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) 1,987 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 HNRNPC 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 TGACCAGACAGAGCAGGAACC (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 CTGTGCCTGAATATTTGTTA (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 GGCAATTATTTGGATCTATC (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 HNRNPC 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 efficacy group and the non-efficacy group was carried out 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:

(In the case of CAV1, FAM126A, MET, RAB31, RAB31, ST8SIA4, and THSD7A), [Min (efficacy value (Ct)

[Min (non-efficacy value (? Ct)) + Max (efficacy value (? Ct))] / 2 (in the case of CMHL and PHC1);

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

Min (efficacy value (? Ct)): minimum ΔCt value of potency group;

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

Min (non-efficacy value (ΔCt)): minimum ΔCt value of ineffective group; And

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

In the case of CAV1, FAM126A, MET, RAB31, RAB31, ST8SIA4, and THSD7A, the calculated ΔCt for each biomarker was compared with the value in Table 17. When the ΔCt value for each gene was higher than the value in Table 17, And in the case of CMHL and PHC1, it was judged to be an efficacy group when the ΔCt value for each gene was lower than the value in Table 17.

The accuracy and "ΔFold" value of the efficacy group and the non-efficacy group for the 14 kinds of mouse xenotransplantation models prepared in Reference Example 2 as described above are shown in Table 19 below.

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 accuracy of the predictive effect when the candidate marker is used, which is closer to 1 (corresponding to 100%), indicates higher accuracy and can be obtained by the following equation:

Accuracy = {(TP + TN) / 14}

(TP: the number of specimens showing efficacy (efficacy) in both the predicted results using the biomarkers and the actual test results (see Table 9) treated with L3-1Y / IgG2)

(TN: the number of samples in which the efficacy was negative (no drug efficacy) in both the predicted results using the biomarkers and the actual test results of L3-1Y / IgG2 treatment (see Table 9));

ΔFold: the difference in delta Ct (control gene (reference marker) Ct (average of the reference marker Ct values when two or more reference markers are used) - target gene (biomarker) Ct) between the reaction group and the non-reaction group, MRNA expression levels that can be divided into non-responsive and non-responsive groups)

As shown in Table 13, using the biomarkers and reference markers selected in the present invention, the efficacy group and the non-efficacy group of the anti-c-Met antibody can be judged 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> DPP20151569 <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 <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) &Lt; 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> &Lt; 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> &Lt; 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 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 Gln 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 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 Gln 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 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 Gln 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 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 Gln 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> &Lt; 223 > CDR-L1 derived from L1-3 clone <400> 30 Lys Ser Ser Arg Ser Leu Leu 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> &Lt; 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 &Lt; 222 > (67) .. (417) <223> VH - heavy chain variable region <220> <221> misc_feature <222> (418). (423) <223> NdeI restriction site <220> <221> misc_feature &Lt; 222 > (418) .. (1407) <223> CH - heavy chain constant region <220> <221> misc_feature (1408). (1410) <223> TGA - stop codon <220> <221> misc_feature (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 &Lt; 222 > (7) <223> signal sequence <220> <221> misc_difference &Lt; 222 > (91) <223> VL - light chain variable region <220> <221> misc_difference &Lt; 222 > 430 (430) <223> BsiWI restriction site <220> <221> misc_difference &Lt; 222 > (433) .. (750) <223> CL - light chain constant region <220> <221> misc_difference &Lt; 222 > (751) .. (753) <223> stop codon <220> <221> misc_difference &Lt; 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 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 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 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 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 Ser Ser Ser Ser Thr Ser Ser Ser Ser Thr Leu             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 Ser Ser Ser Ser Thr Ser Ser Ser Ser Thr Leu             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 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 Ser Ser Ser Ser Thr Ser Ser Ser Ser Thr Leu             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 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 Gln 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 Ser Ser Ser Ser Thr Ser Ser Ser Ser Thr Leu             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 gagaccaca 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 gagaccaca 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 gagaccaca 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 Gly Ser 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 tcgggggcct 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 &Lt; 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 (1350). (1355) <223> EcoRI restriction site <220> <221> misc_difference &Lt; 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 &Lt; 222 > (1650) .. (1652) <223> TGA (stop codon) <220> <221> misc_difference &Lt; 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 gggtagtgg 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 ttacacgcgc 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> A polypeptide consisting of heavy chains 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 Ser 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 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 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 Val Ser 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 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 chain of heavy chain          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 gagaccaca 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> &Lt; 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 Ser 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 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 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 Val Ser 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 chain of heavy chain          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 gactggctta 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> &Lt; 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 Ser 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 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 chain of heavy chain          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 ccatcccggg 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> The polypeptide chain 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 Ser Val Ser   1 5 10 15 Gly Thr Cys Gly Asp Ile Gln Met Thr Gln Ser Ser 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 Ser Ser 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 a polypeptide consisting of light chains 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> A polypeptide consisting of light chains of huAbF46-H4-A1 and human          kappa constant region <400> 70 Met Asp Ser Gln Ala Gln Val Leu Met Leu Leu Leu Leu Ser Val Ser   1 5 10 15 Gly Thr Cys Gly Asp Ile Gln Met Thr Gln Ser Ser 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 Ser Ser 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> The epitope in the 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> The epitope in the 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> The epitope in the 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> The 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 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 &Lt; 222 > (67) .. (417) <223> VH - heavy chain variable region <220> <221> misc_feature <222> (418). (423) <223> NdeI restriction site <220> <221> misc_feature &Lt; 222 > (418) .. (1407) <223> CH - heavy chain constant region <220> <221> misc_feature (1408). (1410) <223> TGA - stop codon <220> <221> misc_feature (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 &Lt; 222 > (7) <223> signal sequence <220> <221> misc_difference &Lt; 222 > (91) <223> VL - light chain variable region <220> <221> misc_difference &Lt; 222 > 430 (430) <223> BsiWI restriction site <220> <221> misc_difference &Lt; 222 > (433) .. (750) <223> CL - light chain constant region <220> <221> misc_difference &Lt; 222 > (751) .. (753) <223> stop codon <220> <221> misc_difference &Lt; 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 cacattttcc 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 acattctcct 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 ggattggt 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 cccctaaag 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 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 Ser Ser 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 Ser 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 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 Ser 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 acattctcct 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 ttcakhga 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 ggagctgatg 600 acaagaggag ccccacctta tcctgacgta aacacctttg atataactgt ttacttgttg 660 caagggagaa gactcctaca acccgaatac tgcccagacc ccttatatga agtaatgcta 720 aaatgctggc accctaaagc cgaaatgcgc ccatcctttt ctgaactggt gtcccggata 780 tcagcgatct tctctacttt cattggggag cactatgtcc atgtgaacgc tacttatgtg 840 aacgtaaaat gtgtcgctcc gtatccttct ctgttgtcat cagaagataa cgctgatgat 900 gaggtggaca 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 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 Ser Ser Ser 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 Ser Ser Ser 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 Ser Ser Ser 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 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 Gln 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 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 Gln 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 Ser Ser Ser Ser Ser Ser 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 Gln 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 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 Gln 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 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 Gln Gly Thr Lys Leu Glu Ile             100 105 110 Lys     <210> 100 <211> 13 <212> PRT <213> Artificial Sequence <220> The 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> The 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> 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> The 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> The 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 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 Gln 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 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 Gln 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 Ser Ser Ser Ser Thr Ser Ser Ser Ser Thr Leu             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 cagaccagtc 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 appointed 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 ttagatga 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 gtagagattg 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 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 and level of expression of a biomarker for selection of an anti-c-Met antibody subject in a biological sample,
Wherein the biomarker is at least one selected from the group consisting of THSD7A, MET, RAB31, FAM126A, PHC1, CHML, ST8SIA4, and CAV1.
Methods for screening for anti-c-Met antibodies. The biomarker of claim 1,
THSD7A, or
A combination of THSD7A and at least one selected from the group consisting of MET, RAB31, FAM126A, PHC1, CHML, ST8SIA4, and CAV1
&Lt; / RTI &gt;
Methods for screening for anti-c-Met antibodies. The biomarker of claim 1,
MET; or
MET and a combination of at least one selected from the group consisting of THSD7A, RAB31, FAM126A, PHCl, CHML, ST8SIA4, and CAV1
&Lt; / RTI &gt;
Methods for screening for anti-c-Met antibodies. The biomarker of claim 1,
RAB31; or
RAB31 and at least one selected from the group consisting of THSD7A, MET, FAM126A, PHC1, CHML, ST8SIA4 and CAV1
&Lt; / RTI &gt;
Methods for screening for anti-c-Met antibodies. The biomarker of claim 1,
FAM126A; or
A combination of FAM126A and at least one selected from the group consisting of THSD7A, MET, RAB31, PHC1, CHML, ST8SIA4, and CAV1;
&Lt; / RTI &gt;
Methods for screening for anti-c-Met antibodies. The method according to claim 1, wherein the biomarker comprises two or more selected from the group consisting of THSD7A, MET, RAB31 and FAM126A. The method according to claim 1, wherein the presence and expression level of the biomarker is measured by measuring at least one selected from the group consisting of EEF1A1, RPL23A, TPT1, HUWE1, MATR3, SRSF3, HNRNPC, SMARCA4, WDR90, Wherein the reference marker is performed on a comparison basis.
Methods for screening for anti-c-Met antibodies. The method according to any one of claims 1 to 7,
A CDR-H1 having the amino acid sequence of SEQ ID NO: 4, an amino acid sequence of SEQ ID NO: 5, an amino acid sequence of SEQ ID NO: 2, or a sequence of 8 to 19 consecutive amino acids including the third to tenth amino acids in the amino acid sequence of SEQ ID NO: CDR-H2 having an amino acid sequence consisting of the amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 85, or SEQ ID NO: 85, or a sequence of six to six consecutive amino acids comprising the amino acid sequence of SEQ ID NO: 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 the at least one heavy chain complementarity determining region;
CDR-L1 having the amino acid sequence of SEQ ID NO: 7, CDR-L2 having the amino acid sequence of SEQ ID NO: 8, and amino acid sequence of SEQ ID NO: 9, SEQ ID NO: 15, SEQ ID NO: 86, CDR-L3 having an amino acid sequence consisting of 9 to 17 amino acids including the first to ninth amino acids in the amino acid sequence of SEQ ID NO: 89; or one or more light chain complementarity determining regions selected from the group consisting of the one or more light chain complementarity determining regions A light chain variable region comprising a region;
A combination of the heavy chain complementary crystal region and the light chain complementarity determining region; or
The combination of the heavy chain variable region and the light chain variable region
Or an antigen-binding fragment thereof,
Methods for screening for anti-c-Met antibodies. METHODS FOR DETECTION OF BIOMARKERS FOR SELECTION OF AN APPLICATION OF AN ANTI-c-MET ANTIBODY SELECTED FROM THEMATIC ANTIBODIES, THSD7A, MET, RAB31, FAM126A, PHC1, CHML, ST8SIA4 and CAV1 Target selection kit. The method according to 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, Applicable screening kit. 11. The method of claim 9 or 10, wherein the means for detecting the biomarker or the fiducial marker comprises a primer or probe capable of hybridizing with the biomarker or the fiducial marker, an antibody or an antibody that specifically binds to the protein , Or a combination thereof. 12. The method according to any one of claims 9 to 11,
A CDR-H1 having the amino acid sequence of SEQ ID NO: 4, an amino acid sequence of SEQ ID NO: 5, an amino acid sequence of SEQ ID NO: 2, or a sequence of 8 to 19 consecutive amino acids including the third to tenth amino acids in the amino acid sequence of SEQ ID NO: CDR-H2 having an amino acid sequence consisting of the amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 85, or SEQ ID NO: 85, or a sequence of six to six consecutive amino acids comprising the amino acid sequence of SEQ ID NO: 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 the at least one heavy chain complementarity determining region;
CDR-L1 having the amino acid sequence of SEQ ID NO: 7, CDR-L2 having the amino acid sequence of SEQ ID NO: 8, and amino acid sequence of SEQ ID NO: 9, SEQ ID NO: 15, SEQ ID NO: 86, CDR-L3 having an amino acid sequence consisting of 9 to 17 amino acids including the first to ninth amino acids in the amino acid sequence of SEQ ID NO: 89; or one or more light chain complementarity determining regions selected from the group consisting of the one or more light chain complementarity determining regions A light chain variable region comprising a region;
A combination of the heavy chain complementary crystal region and the light chain complementarity determining region; or
The combination of the heavy chain variable region and the light chain variable region
Or an antigen-binding fragment thereof, wherein the anti-c-Met antibody is an antibody or an antigen-binding fragment thereof. Wherein at least one reference marker selected from the group consisting of EEF1A1, RPL23A, TPT1, HUWE1, MATR3, SRSF3, HNRNPC, SMARCA4, WDR90 and TUT1 is used as a comparison standard. A kit for measuring gene expression level 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. 15. The method of claim 14, wherein the means for detecting the fiducial markers comprises a primer that hybridizes with the fiducial markers, an antibody that specifically binds to a probe, or a protein that they encode, an aptamer, Kits.

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