KR101909955B1 - Novel Antibody Against AXL and Pharmaceutical Composition Comprising the Same - Google Patents

Novel Antibody Against AXL and Pharmaceutical Composition Comprising the Same Download PDF

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KR101909955B1
KR101909955B1 KR1020160159104A KR20160159104A KR101909955B1 KR 101909955 B1 KR101909955 B1 KR 101909955B1 KR 1020160159104 A KR1020160159104 A KR 1020160159104A KR 20160159104 A KR20160159104 A KR 20160159104A KR 101909955 B1 KR101909955 B1 KR 101909955B1
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박재찬
김길중
염혜인
임형권
이재철
김기수
김동식
정준홍
허민규
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원종화
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Abstract

본 발명은 에이엑스엘(AXL)에 특이적으로 결합하는 항체, 상기 항체를 코딩하는 핵산, 상기 핵산을 포함하는 벡터 및 숙주세포, 상기 항체의 제조방법 및 상기 항체를 포함하는 암 또는 종양 치료용 약학 조성물에 관한 것이다.
본 발명에 따른 에이엑스엘에 특이적으로 결합하는 항체는 에이엑스엘에 대한 높은 친화력(affinity) 및 특이성(specificity)으로 인해 암 또는 종양, 특히 폐암(lung cancer) 및 대장암(colon cancer)의 치료에 효과적으로 사용될 수 있다.The present invention relates to an antibody specifically binding to AXL, a nucleic acid encoding the antibody, a vector comprising the nucleic acid and a host cell, a method for producing the antibody, and a method for the treatment of cancer or tumor comprising the antibody ≪ / RTI >
Antibodies specifically binding to A [beta] -el according to the present invention are useful for the treatment of cancer or tumors, particularly lung cancer and colon cancer, due to their high affinity and specificity for A [ Can be effectively used for treatment.

Description

신규 항-에이엑스엘 항체 및 이를 포함하는 약학적 조성물 {Novel Antibody Against AXL and Pharmaceutical Composition Comprising the Same}Novel Antibody Against AXL and Pharmaceutical Composition Comprising the Same < RTI ID = 0.0 >

본 발명은 신규 항-에이엑스엘 (AXL) 항체 및 이를 포함하는 다양한 암 또는 암종을 예방 또는 치료할 수 있는 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition capable of preventing or treating a novel anti-A [beta] el (AXL) antibody and various cancers or carcinomas comprising the same.

에이엑스엘(AXL)은 리셉터 타이로신 카이네이즈(Receptor tyrosine kinase)로, 에이엑스엘 및 에이엑스엘의 리간드인 가스6(Gas6)의 조절 이상은 다양한 암에서 나타나는 현상으로 알려지고 있다. 이러한 에이엑스엘은 유방암(breast cancer), 폐암(lung cancer), 전립선암(prostate cancer), 위암(gastric cancer), 대장암(colon cancer), 신장암(renal cancer) 등에서 과발현(overexpression)된다는 사실이 알려지고 있으며, 최근의 연구 결과를 통해 에이엑스엘의 과발현이 이마티닙(imatinib) 등의 chemotherapy에 대한 저항성도 유발하는 것으로 나타나 현재 몇몇 항-에이엑스엘 항체가 임상 진행 중에 있지만, 아직까지 치료효능을 나타낼 수 있는 수준의 항종양 효과, AXL 발현량 저하작용 또는 항암 효과를 갖는 항체에 대한 보고는 되어있지 않다.AXL is a receptor tyrosine kinase. Regulatory abnormalities of AXEL and AXEL's ligand, Gas6, are known to occur in a variety of cancers. The fact that these AXELs are overexpressed in breast cancer, lung cancer, prostate cancer, gastric cancer, colon cancer, renal cancer, Recent studies have shown that overexpression of AXEL also causes resistance to chemotherapy such as imatinib. Although several anti-AXEL antibodies are now in clinical trials, There has been no report on an antibody having a level of antitumor effect, a function of reducing AXL expression level or an anticancer effect.

따라서, 우수한 항종양 효과, AXL 발현량 저하작용, 항암 효과를 가져 치료효능을 나타낼 수 있는 항-에이엑스엘 항체에 대한 필요성이 높은 상황이다.Therefore, there is a high need for an anti-A [beta] 2 antibody which has an excellent antitumor effect, an AXL expression decreasing action, and an anti-cancer effect and can exhibit therapeutic efficacy.

이에, 본 발명자들은, 에이엑스엘에 높은 친화력을 가지고 특이적으로 결합하는 신규 항체를 발명하였으며, 상기 항체의 항암제로서의 가능성을 확인하고, 본 발명을 완성하였다.Thus, the inventors of the present invention invented a novel antibody that specifically binds to A [beta] l with a high affinity and confirmed the possibility of the antibody as an anticancer agent, thereby completing the present invention.

본 발명은 에이엑스엘에 높은 친화력을 가지고 특이적으로 결합하는 항체의 제공을 목적으로 한다.It is an object of the present invention to provide an antibody that specifically binds to A [beta] -el with high affinity.

본 발명은 상기 항체를 코딩하는 핵산의 제공을 목적으로 한다.The present invention is directed to providing a nucleic acid encoding the antibody.

본 발명은 상기 핵산을 포함하는 벡터 및 숙주세포의 제공을 목적으로 한다.The present invention aims at providing a vector containing the nucleic acid and a host cell.

본 발명은 상기 항체, 핵산, 벡터 및 숙주세포의 제조방법의 제공을 목적으로 한다.The present invention aims to provide a method for producing the antibody, the nucleic acid, the vector and the host cell.

본 발명은 우수한 치료효능을 갖는 다양한 암 및 종양 치료용 약학 조성물의 제공을 목적으로 한다.It is an object of the present invention to provide a pharmaceutical composition for treating various cancers and tumors having excellent therapeutic efficacy.

1. 다음의 중쇄 CDR(complementarity determining region)을 포함하는 중쇄 가변영역을 함유하는 항-에이엑스엘 항체:1. An anti-A [beta] antibody comprising a heavy chain variable region comprising the following heavy chain CDR (complementarity determining region):

서열번호 53, 59, 65, 71, 77, 83, 89, 114, 120, 126, 137, 143, 154, 160, 170, 또는 175의 아미노산 서열을 포함하는 중쇄 CDR1;A heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 53, 59, 65, 71, 77, 83, 89, 114, 120, 126, 137, 143, 154, 160, 170,

서열번호 54, 60, 66, 72, 78, 84, 90, 95, 100, 104, 109, 115, 121, 127, 132, 138, 144, 149, 155, 161, 180, 또는 185의 아미노산 서열을 포함하는 중쇄 CDR2; 및The amino acid sequence of SEQ ID NO: 54, 60, 66, 72, 78, 84, 90, 95, 100, 104, 109, 115, 121, 127, 132, 138, 144, 149, 155, 161, 180, A heavy chain CDR2 comprising; And

서열번호 55, 61, 67, 73, 79, 85, 91, 96, 101, 105, 110, 116, 122, 128, 133, 139, 145, 150, 156, 162, 166, 171, 176, 181, 186, 또는 190의 아미노산 서열을 포함하는 중쇄 CDR3.SEQ ID NOS: 55, 61, 67, 73, 79, 85, 91, 96, 101, 105, 110, 116, 122, 128, 133, 139, 145, 150, 156, 162, 166, 171, 176, 181, 186, < / RTI > or 190.

2. 다음의 경쇄 CDR을 포함하는 경쇄 가변영역을 함유하는 항-에이엑스엘 항체:2. Anti-A [beta] antibody containing a light chain variable region comprising the following light chain CDR:

서열번호 56, 62, 68, 74, 80, 86, 92, 97, 102, 106, 111, 117, 123, 129, 134, 140, 146, 151, 157, 163, 167, 172, 177, 182, 187, 또는 191의 아미노산 서열을 포함하는 경쇄 CDR1;SEQ ID NOS: 56, 62, 68, 74, 80, 86, 92, 97, 102, 106, 111, 117, 123, 129, 134, 140, 146, 151, 157, 163, 167, 172, 177, 182, 187, or 191;

서열번호 57, 63, 69, 75, 81, 87, 93, 98, 107, 112, 118, 124, 130, 135, 141, 147, 152, 158, 164, 168, 173, 178, 183, 188, 또는 192의 아미노산 서열을 포함하는 경쇄 CDR2; 및 183, 188, 183, 183, 183, 183, 183, 183, 184, Or a light chain CDR2 comprising an amino acid sequence of 192; And

서열번호 58, 64, 70, 76, 82, 88, 94, 99, 103, 108, 113, 119, 125, 131, 136, 142, 148, 153, 159, 165, 169, 174, 179, 184, 189, 또는 193의 아미노산 서열을 포함하는 경쇄 CDR3.SEQ ID NOS: 58, 64, 70, 76, 82, 88, 94, 99, 103, 108, 113, 119, 125, 131, 136, 142, 148, 153, 159, 165, 169, 174, 179, 184, 189, or 193.

3. 위 1에 있어서, 서열번호 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 또는 51의 아미노산 서열과 80% 이상의 상동성을 가지는 서열을 포함하는, 항-에이엑스엘 항체.3. A pharmaceutical composition according to any one of the above-mentioned 1, wherein the pharmaceutical composition is a pharmaceutical composition comprising at least one compound selected from the group consisting of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, , 43, 45, 47, 49, or 51. The anti-A [beta] -elantibody comprises a sequence having at least 80% homology with the amino acid sequence of SEQ ID NO:

4. 위 2에 있어서, 서열번호 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 또는 52의 아미노산 서열과 80% 이상의 상동성을 가지는 서열을 포함하는, 항-에이엑스엘 항체.4. A pharmaceutical composition according to any one of the above 2, wherein at least one of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, , 44, 46, 48, 50, or 52 amino acid residues.

5. 위 1 내지 4 중 어느 한 항에 따른 항-에이엑스엘 항체와 약물의 접합체.5. A conjugate of a drug with an anti-A [beta] antibody according to any one of claims 1 to 4 above.

6. 위 5에 있어서, 상기 약물은 항암 약물인 접합체.6. The conjugate of 5 above, wherein said drug is an anti-cancer drug.

7. 위 6에 있어서, 상기 항암 약물은 마이크로튜불린(microtubulin) 구조 형성 억제제, 유사분열(meiosis) 억제제, RNA 중합효소 억제제, 토포아이소머라아제(topoisomerase) 억제제, DNA 인터컬레이터(DNA intercalators), DNA 알킬레이터(DNA akylator), 리보솜 억제제, miRNA, shRNA, siRNA, 방사선 동위원소 및 독소로 이루어진 군에서 선택되는 적어도 하나 이상인, 접합체.7. The method of claim 6, wherein the anti-cancer drug is selected from the group consisting of a microtubulin structure formation inhibitor, a meiosis inhibitor, an RNA polymerase inhibitor, a topoisomerase inhibitor, DNA intercalators, , A DNA akylator, a ribosome inhibitor, a miRNA, an shRNA, an siRNA, a radioactive isotope and a toxin.

8. 위 6에 있어서, 상기 항암 약물은 마이탄시노이드, 아우리스타틴, 돌라스타틴, 트리코테센, CC1065(NSC 298223), 칼리케아미신, 에네디인 항생제, 탁산, 안트라시클린, 메토트렉세이트, 아드리아마이신, 빈데신, 빈카 알카로이드, 독소루비신, 멜팔란, 미토마이신 C, 클로람부실, 다우노루비신, 다우노마이신, 에토포시드, 테니포시드, 카르미노마이신, 아미노프테린, 닥티노마이신, 미토마이신류, 블레오마이신류, 에스페라미신류, 5-플루오로우라실, 질소 머스타드, 시스플라틴, 이리노테칸, 파클리탁셀 및 도세탁셀로 이루어진 군에서 선택되는 적어도 하나 이상인, 접합체.8. The anticancer drug according to claim 6, wherein the anticancer drug is selected from the group consisting of mytensinoid, auristatin, dolastatin, tricothecene, CC1065 (NSC 298223), calicheamicin, enedin antibiotics, taxane, anthracycline, methotrexate, But are not limited to, mucin, vindesine, vincica alkaloid, doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin, daunomycin, etoposide, teniposide, Carminomycin, aminopterin, Wherein the conjugate is at least one or more selected from the group consisting of mitoses, bleomycins, esperamicins, 5-fluorouracil, nitrogen mustard, cisplatin, irinotecan, paclitaxel and docetaxel.

9. 위 1 내지 4 중 어느 한 항에 따른 항-에이엑스엘 항체를 포함하는, 이중특이 항체(bispecific antibody).9. A bispecific antibody comprising an anti-A [beta] antibody according to any one of claims 1-4.

10. 위 1 내지 4 중 어느 한 항에 따른 항-에이엑스엘 항체; 및 면역효능세포 특이적 표적분자에 결합능을 가지는 항체로 이루어지는 이중특이 항체.10. An anti-A [beta] -el antibody according to any one of claims 1 to 4; And an antibody capable of binding to an immunocompetent cell-specific target molecule.

11. 위 10에 있어서, 상기 면역효능세포 특이적 표적분자는 TCR/CD3, CD16(FcγRIIIa) CD44, Cd56, CD69, CD64(FcγRI), CD89 및 CD11b/CD18(CR3)로 이루어진 군에서 선택되는 하나인, 이중특이 항체.11. The method of claim 10, wherein said immuno-efficacy cell-specific target molecule is selected from the group consisting of TCR / CD3, CD16 (FcγRIIIa) CD44, Cd56, CD69, CD64 (FcγRI), CD89 and CD11b / CD18 Lt; / RTI > antibody.

12. 위 1 내지 4 중 어느 한 항에 따른 항체 또는 상기 항체의 단편을 포함하는, 암 예방 또는 치료용.12. An agent for the prevention or treatment of cancer, comprising an antibody according to any one of claims 1 to 4 or a fragment thereof.

13. 위 5 내지 8 중 어느 한 항에 따른 접합체를 포함하는, 암 예방 또는 치료용 조성물.13. A composition for preventing or treating cancer, comprising a conjugate according to any one of claims 5 to 8.

14. 위 9 내지 11 중 어느 한 항에 따른 이중특이 항체를 포함하는, 암 예방 또는 치료용 조성물.14. A composition for preventing or treating cancer, comprising a bispecific antibody according to any one of claims 9 to 11.

15. 12 내지 14 중 어느 한 항에 있어서, 상기 암은 간암, 간세포암, 위암, 유방암, 폐암, 난소암, 관지암, 비인두암, 후두암, 췌장암, 방광암, 대장암, 결장암, 이자암, 자궁경부암, 뇌암, 전립선암, 골암, 피부암, 갑상선암, 부갑상선암, 신장암, 식도암, 담도암, 고환암, 직장암, 두경부암, 경추암, 요관암, 골육종, 신경아세포종, 흑색종, 섬유육종, 횡문근육종, 성상세포종, 신경모세포종 및 신경교종으로 이루어진 군에서 선택되는 어느 하나인, 암 예방 또는 치료용 조성물.15. A method according to any one of claims 12 to 14 wherein said cancer is selected from the group consisting of liver cancer, hepatocellular carcinoma, stomach cancer, breast cancer, lung cancer, ovarian cancer, ductal carcinoma, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, Cancer of the head and neck, cervical cancer, cervical cancer, ureteral cancer, osteosarcoma, neuroblastoma, melanoma, fibrosarcoma, rhabdomyosarcoma, ovarian cancer, cervical cancer, brain cancer, brain cancer, prostate cancer, bone cancer, skin cancer, thyroid cancer, , Astrocytoma, neuroblastoma, and glioma. ≪ / RTI >

16. 12 내지 14 중 어느 한 항에 있어서, 상기 암은 간암, 간세포암, 유방암, 난소암, 대장암, 피부암, 담도암 및 폐암으로 이루어진 군에서 선택되는 어느 하나인, 암 예방 또는 치료용 조성물.16. The composition for preventing or treating cancer according to any one of 12 to 14, wherein the cancer is any one selected from the group consisting of liver cancer, hepatocellular carcinoma, breast cancer, ovarian cancer, colon cancer, skin cancer, .

17. 위 1 내지 4 중 어느 한 항에 따른 항-에이엑스엘 항체를 인코딩하는 폴리뉴클레오티드.17. A polynucleotide encoding an anti-A [beta] -el antibody according to any one of claims 1-4.

18. 위 17에 따른 폴리뉴클레오티드를 포함하는 재조합 벡터.18. A recombinant vector comprising the polynucleotide according to 17 above.

19. 위 18에 따른 재조합 발현 벡터로 형질 전환된 숙주세포.19. A host cell transformed with a recombinant expression vector according to 18 above.

20. 위 19에 있어서, 상기 숙주세포는 동물세포, 식물세포, 효모, 대장균 및 곤충세포로 이루어진 군에서 선택되는 적어도 하나인, 숙주세포.20. The host cell according to 19 above, wherein said host cell is at least one selected from the group consisting of animal cells, plant cells, yeast, Escherichia coli and insect cells.

21. 위 19에 있어서, 상기 숙주세포는 원숭이 신장 세포7 세포, NSO 세포, SP2/0 세포, 차이니즈 햄스터 난소 세포, W138, 어린 햄스터 신장 세포, MDCK, 골수종 세포주, HuT 78 세포, HEK293 세포, 대장균, 바실러스 서브틸리스, 스트렙토마이세스 속, 슈도모나스 속, 프로테우스 미라빌리스, 스타필로코쿠스 속, 아스페르길러스 속, 피치아 파스토리스, 사카로마이세스 세레비지애, 쉬조사카로마세스 속 및 뉴로스포라 크라사로 이루어진 군에서 선택되는 적어도 하나인, 숙주세포.21. The method of claim 19, wherein said host cell is selected from the group consisting of monkey kidney cell 7, NSO cell, SP2 / 0 cell, Chinese hamster ovary cell, W138, young hamster kidney cell, MDCK, myeloma cell line, HuT 78 cell, HEK293 cell, , Bacillus subtilis, Streptomyces spp., Pseudomonas spp., Proteus mirabilis spp., Staphylococcus spp., Aspergillus spp., Pichia pastoris, Saccharomyces cerebilias, And neurosporaclasa. ≪ / RTI >

22. 위 19 내지 21 중 어느 한 항에 따른 숙주세포를 배양하는 단계를 포함하는 항-에이엑스엘 항체의 생산 방법.22. A method for producing an anti-A [beta] -elab antibody comprising culturing a host cell according to any one of 19 to 21 above.

본 발명에 따른 항체는 에이엑스엘에 대한 높은 친화도(affinity) 및 특이성(specificity)으로 인해 다양한 암 또는 암종의 예방 또는 치료에 효과적으로 사용될 수 있다.The antibody according to the present invention can be effectively used for the prevention or treatment of various cancers or carcinomas due to its high affinity and specificity for A [beta].

도 1은 각 세포주에서 AXL 발현량 분석 결과를 나타내는 도이다.
도 2는 각 세포주에서 AXL 발현량 분석 결과를 나타내는 도이다.
도 3은 본 발명에 따른 항-에이엑스엘 항체의 AXL을 발현하는 세포주(RKO)에 대한 결합능을 나타내는 도이다.1 is a graph showing the results of analysis of AXL expression level in each cell line.
2 is a graph showing the results of analysis of AXL expression level in each cell line.
FIG. 3 is a graph showing the binding ability of an anti-A [beta] antibody according to the present invention to a cell line (RKO) expressing AXL.

본 발명의 명세서에서 사용되는 용어 " 에이엑스엘 " 또는 "AXL"은 동물, 바람직하게는 인체 내에 존재하는 그대로의 AXL 뿐 아니라, 이의 임의의 변이체, 이소형 및 종 상동체를 통칭한다.The term " AXL "or" AXL "as used in the specification of the present invention collectively refers to any mutant, isoform and species homologue thereof as well as AXL as it exists in an animal, preferably a human body.

본 발명의 명세서에서 사용되는 용어 "인간 AXL"는 인간의 AXL을 의미하며, 바람직하게는 진뱅크(Genbank) 기탁번호 AAH32229.1의 아미노산 서열을 가지지만, 이에 한정되지는 않는다.The term "human AXL " as used herein in the context of the present invention refers to human AXL and preferably has the amino acid sequence of Genbank accession number AAH32229.1, but is not limited thereto.

본 발명의 명세서에서 사용되는 용어 "항체"는 특정 항원과 면역학적으로 반응성이 있는 면역글로블린 분자로, 항원을 특이적으로 인식하는 수용체 역할을 하는 단백질 분자를 의미하며, 그러한 항체의 전체 항체(whole antibody) 및 항체 단편(antibody fragment)을 모두 포함하는 의미로 사용된다.As used herein, the term "antibody" refers to an immunoglobulin molecule that is immunologically reactive with a particular antigen, and refers to a protein molecule that acts as a receptor that specifically recognizes an antigen. The whole antibody antibody " and " antibody fragment ".

본 발명에서는 서열번호 53, 59, 65, 71, 77, 83, 89, 114, 120, 126, 137, 143, 154, 160, 170, 또는 175의 아미노산 서열을 포함하는 중쇄 CDR1;A heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 53, 59, 65, 71, 77, 83, 89, 114, 120, 126, 137, 143, 154, 160, 170 or 175;

서열번호 54, 60, 66, 72, 78, 84, 90, 95, 100, 104, 109, 115, 121, 127, 132, 138, 144, 149, 155, 161, 180, 또는 185의 아미노산 서열을 포함하는 중쇄 CDR2; 및The amino acid sequence of SEQ ID NO: 54, 60, 66, 72, 78, 84, 90, 95, 100, 104, 109, 115, 121, 127, 132, 138, 144, 149, 155, 161, 180, A heavy chain CDR2 comprising; And

서열번호 55, 61, 67, 73, 79, 85, 91, 96, 101, 105, 110, 116, 122, 128, 133, 139, 145, 150, 156, 162, 166, 171, 176, 181, 186, 또는 190의 아미노산 서열을 포함하는 중쇄 CDR3를 포함하는,SEQ ID NOS: 55, 61, 67, 73, 79, 85, 91, 96, 101, 105, 110, 116, 122, 128, 133, 139, 145, 150, 156, 162, 166, 171, 176, 181, 186, or < RTI ID = 0.0 > 190 < / RTI >

중쇄 가변영역을 갖는 항 에이엑스엘 항체를 제공한다.Lt; / RTI > antibody having a heavy chain variable region.

또 하나의 양태로서, 본 발명에서는 서열번호 56, 62, 68, 74, 80, 86, 92, 97, 102, 106, 111, 117, 123, 129, 134, 140, 146, 151, 157, 163, 167, 172, 177, 182, 187, 또는 191의 아미노산 서열을 포함하는 경쇄 CDR1;In another embodiment of the present invention, the nucleotide sequence of SEQ ID NO: 56, 62, 68, 74, 80, 86, 92, 97, 102, 106, 111, 117, 123, 129, 134, 140, 146, , 167, 172, 177, 182, 187, or 191;

서열번호 57, 63, 69, 75, 81, 87, 93, 98, 107, 112, 118, 124, 130, 135, 141, 147, 152, 158, 164, 168, 173, 178, 183, 188, 또는 192의 아미노산 서열을 포함하는 경쇄 CDR2; 및183, 188, 183, 183, 183, 183, 183, 183, 184, Or a light chain CDR2 comprising an amino acid sequence of 192; And

서열번호 58, 64, 70, 76, 82, 88, 94, 99, 103, 108, 113, 119, 125, 131, 136, 142, 148, 153, 159, 165, 169, 174, 179, 184, 189, 또는 193의 아미노산 서열을 포함하는 경쇄 CDR3을 포함하는,SEQ ID NOS: 58, 64, 70, 76, 82, 88, 94, 99, 103, 108, 113, 119, 125, 131, 136, 142, 148, 153, 159, 165, 169, 174, 179, 184, 189, or < RTI ID = 0.0 > 193 < / RTI >

경쇄 가변영역을 갖는 항 에이엑스엘 항체를 제공한다.Lt; / RTI > antibody having a light chain variable region.

바람직하게는 본 발명에서 제공되는 항 에이엑스엘 항체는,Preferably, the anti-A < RTI ID = 0.0 > X-

서열번호 53, 59, 65, 71, 77, 83, 89, 114, 120, 126, 137, 143, 154, 160, 170, 또는 175의 아미노산 서열을 포함하는 중쇄 CDR1;A heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 53, 59, 65, 71, 77, 83, 89, 114, 120, 126, 137, 143, 154, 160, 170,

서열번호 54, 60, 66, 72, 78, 84, 90, 95, 100, 104, 109, 115, 121, 127, 132, 138, 144, 149, 155, 161, 180, 또는 185의 아미노산 서열을 포함하는 중쇄 CDR2; 및The amino acid sequence of SEQ ID NO: 54, 60, 66, 72, 78, 84, 90, 95, 100, 104, 109, 115, 121, 127, 132, 138, 144, 149, 155, 161, 180, A heavy chain CDR2 comprising; And

서열번호 55, 61, 67, 73, 79, 85, 91, 96, 101, 105, 110, 116, 122, 128, 133, 139, 145, 150, 156, 162, 166, 171, 176, 181, 186, 또는 190의 아미노산 서열을 포함하는 중쇄 CDR3을 포함하는 중쇄 가변영역과,SEQ ID NOS: 55, 61, 67, 73, 79, 85, 91, 96, 101, 105, 110, 116, 122, 128, 133, 139, 145, 150, 156, 162, 166, 171, 176, 181, A heavy chain variable region comprising a heavy chain CDR3 comprising an amino acid sequence of SEQ ID NO: 186, or 190,

서열번호 56, 62, 68, 74, 80, 86, 92, 97, 102, 106, 111, 117, 123, 129, 134, 140, 146, 151, 157, 163, 167, 172, 177, 182, 187, 또는 191의 아미노산 서열을 포함하는 경쇄 CDR1;SEQ ID NOS: 56, 62, 68, 74, 80, 86, 92, 97, 102, 106, 111, 117, 123, 129, 134, 140, 146, 151, 157, 163, 167, 172, 177, 182, 187, or 191;

서열번호 57, 63, 69, 75, 81, 87, 93, 98, 107, 112, 118, 124, 130, 135, 141, 147, 152, 158, 164, 168, 173, 178, 183, 188, 또는 192의 아미노산 서열을 포함하는 경쇄 CDR2; 및183, 188, 183, 183, 183, 183, 183, 183, 184, Or a light chain CDR2 comprising an amino acid sequence of 192; And

서열번호 58, 64, 70, 76, 82, 88, 94, 99, 103, 108, 113, 119, 125, 131, 136, 142, 148, 153, 159, 165, 169, 174, 179, 184, 189, 또는 193의 아미노산 서열을 포함하는 경쇄 CDR3을 포함하는 경쇄 가변영역을 가진다.SEQ ID NOS: 58, 64, 70, 76, 82, 88, 94, 99, 103, 108, 113, 119, 125, 131, 136, 142, 148, 153, 159, 165, 169, 174, 179, 184, 189, or 193 of the light chain variable region comprising light chain CDR3 comprising the amino acid sequence.

또 다른 양태에서, 본 발명에서 제공되는 항 에이엑스엘 항체는In another embodiment, the anti-A [beta] 1 antibody provided in the present invention

서열번호 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 또는 51의 아미노산 서열과 80% 이상, 바람직하게는 90% 이상, 더욱 바람직하게는 95% 이상, 가장 바람직하게는 99% 이상의 서열 상동성을 가지는 서열을 포함하는 중쇄 가변영역을 함유할 수 있거나,37, 39, 41, 43, 45, 47, 47, 47, 48, 49, Chain variable region comprising a sequence having at least 80%, preferably at least 90%, more preferably at least 95%, most preferably at least 99% sequence homology with an amino acid sequence of SEQ ID NO: 49, or 51 However,

서열번호 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 또는 52의 아미노산 서열과 80%이상, 바람직하게는 90% 이상, 더욱 바람직하게는 95% 이상, 가장 바람직하게는 99% 이상의 서열 상동성을 가지는 서열을 포함하는 경쇄 가변영역을 함유할 수 있다.SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, A light chain variable region comprising a sequence having at least 80%, preferably at least 90%, more preferably at least 95%, most preferably at least 99% sequence homology with an amino acid sequence of SEQ ID NO: have.

바람직하게는 본 발명에 따른 항 에이엑스엘 항체는Preferably, the anti-AX1 antibody according to the present invention

서열번호 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 또는 51의 아미노산 서열과 80% 이상, 바람직하게는 90% 이상, 더욱 바람직하게는 95% 이상, 가장 바람직하게는 99% 이상의 서열 상동성을 가지는 서열을 포함하는 중쇄 가변영역과,37, 39, 41, 43, 45, 47, 47, 47, 48, 49, A heavy chain variable region comprising a sequence having 80% or more, preferably 90% or more, more preferably 95% or more, and most preferably 99% or more of sequence homology with the amino acid sequence of SEQ ID NO:

서열번호 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 또는 52의 아미노산 서열과 80%이상, 바람직하게는 90% 이상, 더욱 바람직하게는 95% 이상, 가장 바람직하게는 99% 이상의 서열 상동성을 가지는 서열을 포함하는 경쇄 가변영역을 함유할 수 있다.SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, A light chain variable region comprising a sequence having at least 80%, preferably at least 90%, more preferably at least 95%, most preferably at least 99% sequence homology with an amino acid sequence of SEQ ID NO: have.

상기 중쇄 및 경쇄 가변영역에서, 에이엑스엘에 대한 친화도 및 특이성 등 본 발명의 목적에 부합하는 특성이 유지되는 한, 일부 아미노산이 치환, 삽입 및/또는 결실될 수 있다. 예컨대, 상기 중쇄 및 경쇄 가변영역에서는 아미노산의 보존적 치환(conservative substitution)이 일어날 수 있다. 보존적 치환은 원래의 아미노산 서열과 유사한 특성을 가지는 다른 아미노산 잔기로의 치환을 의미하는데, 예를 들어 라이신, 아르기닌, 히스티딘은 염기 곁사슬을 가지고 있어 유사한 특성을 가지고, 아스팔틱산과 글루타믹산은 산 곁사슬을 가진다는 점에서 유사한 특성을 가진다. 또한, 글라이신, 아스파라긴, 글루타민, 세린, 트레오닌, 티로신, 시스테인, 트립토판은 비전하 극성 곁사슬을 가진다는 점에서 특성이 유사하며, 알라닌, 발린, 루신, 트레오닌, 아이소류신, 프롤린, 페닐알라닌, 메티오닌은 비극성 곁사슬을 가지고 있다는 점에서, 티로신, 페닐알라닌, 트립토판, 히스티딘은 방향족 곁사슬을 가지고 있다는 점에서 유사한 특성을 가진다. 따라서, 상기와 같이 유사한 특성을 가지는 그룹 내에서의 아미노산 치환이 일어나더라도 별다른 특성 변화를 보이지 않을 것이라는 점은 통상의 기술자에게는 자명한 것이므로, 본 발명에 따른 항체의 특성이 유지되는 한, 가변영역 내에서의 보존적 치환에 의한 변이가 일어난 항체도 본 발명의 권리범위에 포함된다.Some of the amino acids may be substituted, inserted and / or deleted in the heavy and light chain variable regions, so long as the characteristics consistent with the purposes of the present invention are maintained, such as the affinity and specificity for A [beta]. For example, conservative substitution of amino acids can occur in the heavy and light chain variable regions. Conservative substitutions refer to the substitution of other amino acid residues with similar properties to those of the original amino acid sequence, for example, lysine, arginine, and histidine have similar characteristics with their base side chains, and aspartic acid and glutamic acid are acid They have similar characteristics in that they have side chains. In addition, glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine and tryptophan have similar characteristics in that they have non-negatively polarized side chains, and alanine, valine, leucine, threonine, isoleucine, proline, phenylalanine, In terms of having side chains, tyrosine, phenylalanine, tryptophan, and histidine have similar characteristics in that they have aromatic side chains. Therefore, it is obvious to those of ordinary skill in the art that even when amino acid substitution occurs within the group having similar characteristics as described above, there will be no change in characteristics. Therefore, as long as the characteristics of the antibody according to the present invention are maintained, The present invention also includes an antibody having a mutation caused by conservative substitution in the present invention.

본 발명에서의 항체 단편은 에이엑스엘에 대한 결합 기능을 보유한 단쇄 항체, 디아바디(diabody), 트리아바디(triabody), 테트라바디(tetrabody), Fab 단편, F(ab')2 단편, Fd, scFv, 도메인 항체, 미니바디, 스캡, IgD 항체, IgE 항체, IgM 항체, IgG1 항체, IgG2 항체, IgG3 항체, IgG4 항체, 항체 불변영역의 유도체들, 단백질 스캐폴드(protein scaffolds)에 기초한 인공항체 등이 포함되나, 이에 제한되는 것은 아니며, 에이엑스엘에 대한 결합능이 유지되는 한, 본 발명에 따른 어떠한 형태의 항체의 단편도 본 발명에 따른 항체와 동일한 특성을 나타낼 것이라는 점은 통상의 기술자에게는 자명한 것이다.The antibody fragment in the present invention may be a single chain antibody, diabody, triabody, tetrabody, Fab fragment, F (ab ') 2 fragment, Fd, scFv, domain antibody, minibody, scab, IgD antibody, IgE antibody, IgM antibody, IgG1 antibody, IgG2 antibody, IgG3 antibody, IgG4 antibody, derivatives of antibody constant domain, artificial antibody based on protein scaffolds But it is not limited thereto and it will be apparent to one of ordinary skill in the art that any fragment of an antibody according to the present invention will exhibit the same characteristics as the antibody according to the present invention as long as the binding ability to A [ It is.

한편, 본 발명의 또 다른 양태에서는 본 발명에 따른 항-에이엑스엘 항체에 종양 세포의 증식억제 효능이 있는 항암 약물이 결합된 항체-약물 접합체(ADC : Antibody-Drug Conjugate)를 제공한다.In another aspect of the present invention, there is provided an antibody-drug conjugate (ADC) conjugated with an anti-cancer drug having anti-proliferative activity against tumor cells, the anti-A [beta] antibody according to the present invention.

본 발명에서 용어, "항암" 이란 "예방" 및 "치료"를 포함하며, 여기서 "예방"이란 암을 억제 또는 지연시키는 모든 행위을 의미하고, "치료"란 암의 증세를 호전시키거나 이롭게 변경시키는 모든 행위를 의미한다.As used herein, the term "anti-cancer" includes "prevention" and "treatment ", where" prevention "means all actions that inhibit or delay cancer, and" treatment " It means all acts.

본 발명에 따른 항체-약물 결합체에 사용될 수 있는 약물은 세포독성 또는 세포증식 억제 효과를 갖는 임의의 화합물, 상기 화합물의 부분 또는 작용기를 포함하며, 마이크로튜불린(microtubulin) 구조 형성 억제제, 유사분열(meiosis) 억제제, RNA 중합효소 억제제, 토포아이소머라아제(topoisomerase) 억제제, DNA 인터컬레이터(DNA intercalators), DNA 알킬레이터(DNA akylator), 리보솜 억제제, miRNA, shRNA, siRNA, 방사선 동위원소, 독소 등이 포함되며, 상기 화합물에서 1종 이상이 사용될 수 있다.The drug that can be used in the antibody-drug conjugate according to the present invention includes any compound having a cytotoxic or cell proliferation inhibiting effect, a part or the functional group of the compound, a microtubulin structure formation inhibitor, mitosis ( DNA intercalators, DNA akylators, ribosomal inhibitors, miRNAs, shRNAs, siRNA, radioisotopes, toxins, and the like. And at least one of the above compounds may be used.

상기 약물에는 마이탄시노이드, 아우리스타틴, 돌라스타틴, 트리코테센, CC1065 (NSC 298223), 칼리케아미신, 탁산, 안트라시클린, 메토트렉세이트, 아드리아마이신, 빈데신, 빈카 알카로이드(빈크리스틴, 빈블라스틴, 에토포시드), 독소루비신, 멜팔란, 미토마이신 C, 클로람부실, 다우노루비신, 다우노마이신, 에토포시드, 테니포시드, 카르미노마이신, 아미노프테린, 닥티노마이신, 미토마이신류, 블레오마이신류, 에스페라미신류, 다른 에네디인 항생제, 5-플루오로우라실, 기타 질소 머스타드 및 그의 입체 이성질체, 동배체, 동족체 또는 유도체, 시스-백금 및 시스-백금 동족체, 기타 삽입제인 효소 및 그의 단편, 예를 들어 핵산 분해 효소, 항생제, 독소(세균, 진균, 식물 또는 동물 기원의 효소적 활성 독소 또는 소분자 독소), 시스플라틴, CPT-11, 파클리탁셀 및 도세탁셀 등의 각종 항종양 또는 항암제 등이 포함되나, 이들로 한정되지는 않는다.Such drugs include but are not limited to: mytansinoid, auristatin, dolastatin, tricothecene, CC1065 (NSC 298223), calicheamicin, taxane, anthracycline, methotrexate, adriamycin, vindesine, But are not limited to, doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin, daunomycin, etoposide, teniposide, carminomycin, aminopterin, dactinomycin, mitomycin 5-fluorouracil, other nitrogen mustards and stereoisomers thereof, copper chelates, homologs or derivatives thereof, cis-platinum and cis-platinum analogs, other intercalating agents, such as antibiotics, antibiotics, Enzymes and fragments thereof, such as nucleic acid degrading enzymes, antibiotics, toxins (enzymatically active toxins or small molecule toxins of bacterial, fungal, plant or animal origin), cisplatin, CPT-11, paclitaxel And anticancer agents such as docetaxel, and the like, but are not limited thereto.

또한, 방사선 동위원소(방사선 핵종)에는 3H, 14C, 32P, 35S, 36Cl, 51Cr, 57Co, 58Co, 59Fe, 90Y, 125I, 131I, 186Re 등이 있으며, 특정 암유전자(oncogene)의 발현을 억제시킬 수 있는 마이크로 RNA (miRNA), siRNA 및 shRNA 등도 사용될 수 있다.The radioactive isotope (radionuclide) includes 3H, 14C, 32P, 35S, 36C1, 51Cr, 57Co, 58Co, 59Fe, 90Y, 125I, 131I and 186Re, and inhibits the expression of a specific oncogene MicroRNA (miRNA), siRNA and shRNA that can be used can also be used.

본 발명에서 제공되는 항-에이엑스엘 항체와 약물의 결합은 항체 내의 라이신이나 시스테인과 같은 아미노산 잔기의 티올(thiol)기 등의 기능기를 이용하여 접합되는 것이 바람직하며, 이때, 필요할 경우 통상적으로 사용되는 링커를 이용하여 링커 매개된(linker-mediated) 형태로 접합시키는 것도 가능하며, 말레이미드 또는 요오드아세트아마이드 계열의 링커가 사용되는 것이 바람직하다. 항체 또는 그 단편에 약물을 접합시킬 경우에는 항체 또는 그 단편의 에이엑스엘에 대한 결합능 및 특이성 등에 영향을 감소시키기 위한 측면에서 약물을 항원 결합부위의 반대편인 C-말단 부위에 접합시키는 것이 바람직하며, 단편이 아닌 전항체를 사용할 경우에는 Fc 영역에 접합시키는 것도 바람직하다.The binding between the anti-A [beta] antibody and the drug provided in the present invention is preferably conjugated using a functional group such as a thiol group of an amino acid residue such as lysine or cysteine in the antibody. In this case, It is also possible to use a linker of the maleimide or iodoacetamide series. When a drug is conjugated to an antibody or a fragment thereof, the drug is preferably conjugated to the C-terminal site on the opposite side of the antigen binding site in order to reduce the influence on the binding ability and specificity of the antibody or fragment thereof to the A [ , And when all antibodies other than the fragment are used, it is preferable to be bonded to the Fc region.

또한, 본 발명에서는 본 발명에 따른 항-에이엑스엘 항체를 포함하는 키메라 항원 수용체(Chimeric Antigen Receptor, CAR) 기반 치료제를 제공한다. 이러한 치료제의 예로서는 CAR-T 세포(Chimeric Antigen Receptor T-Cell) 또는 CAR-NK 세포(Chimeric Antigen Receptor Natural Killer Cell) 치료제가 바람직하지만, 이에 한정되는 것은 아니다.In addition, the present invention provides a therapeutic agent based on a chimeric antigen receptor (CAR) comprising an anti-A [beta] antibody according to the present invention. Examples of such therapeutic agents include, but are not limited to, a therapeutic agent for CAR-T cells (Chimeric Antigen Receptor T-Cell) or CAR-NK cells (Chimeric Antigen Receptor Natural Killer Cell).

본 발명의 또 다른 양태에서는 본발명에 따른 항-에이엑스엘을 포함하는 이중특이 항체(bispecific antibody)를 제공한다. 이중특이 항체는 2가지 항원에 동시에 결합할 수 있는 능력을 가진 항체로서, 서로 다른 항원에 결합할 수 있는 능력을 가지는 서로 다른 중쇄 및 경쇄 쌍이 연결된 형태가 가장 일반적인 형태로 이용가능하며, VL과 VH가 짧은 링커 펩타이드(linker peptide)로 연결되어 있는 single-chain antibody fragments (scFv)가 scFv1-scFv2(-Fc) 형태로 연결된 이중특이성 단일사슬 항체(bispecific single chain antibody), 또는 독일 Micromet사의 BiTE 기술(http://www.micromet.de 참조)을 이용한 이중특이 항체의 형태로도 이용 가능하다.Another aspect of the present invention provides a bispecific antibody comprising anti-A [beta] l according to the present invention. Antibodies with the ability to bind to two antigens at the same time are the most common types of antibodies with different heavy and light chain pairs capable of binding to different antigens. VL and VH A bispecific single chain antibody in which single-chain antibody fragments (scFv) linked with short linker peptides are linked in the form of scFv1-scFv2 (-Fc), or BiTE technology (manufactured by Micromet, Germany) See also http://www.micromet.de), which is also available in the form of a bispecific antibody.

본 발명에 따른 이중특이항체는 본 발명에 따른 항-에이엑스엘 항체가 면역효능세포-특이적 표적분자에 대한 결합능을 가지는 항체 또는 그 단편과 결합된 형태가 바람직하다. 면역효능세포 특이적 표적 분자는 TCR/CD3, CD16(FcγRIIIa), CD44, CD56, CD69, CD64(FcγRI), CD89 및 CD11b/CD18(CR3)에서 선택되는 것이 바람직하지만 이에 한정되는 것은 아니다.The bispecific antibody according to the present invention is preferably a form in which the anti-A [beta] antibody according to the present invention is bound to an antibody or fragment thereof capable of binding to an immuno-efficient cell-specific target molecule. Preferably, the immunocompetent target molecule is selected from TCR / CD3, CD16 (FcγRIIIa), CD44, CD56, CD69, CD64 (FcγRI), CD89 and CD11b / CD18 (CR3).

또한, 본 발명에서는 본 발명에 따른 항-에이엑스엘 항체의 가변영역을 인코딩하는 유전자 및 이를 포함하는 재조합 벡터를 제공한다. 본 발명에 따른 항체 또는 그 단편의 경쇄 및/또는 중쇄 가변영역을 코딩하는 폴리뉴클레오티드, 즉 유전자는 본 발명에서 제공되는 항-에이엑스엘 항체의 아미노산 서열로부터 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자라면 용이하게 도출 가능하다.In addition, the present invention provides a gene encoding a variable region of the anti-A [beta] 2 antibody according to the present invention and a recombinant vector comprising the same. The polynucleotide, that is, the gene encoding the light chain and / or heavy chain variable region of the antibody or fragment thereof according to the present invention can be obtained from the amino acid sequence of the anti-A [beta] 1 antibody provided in the present invention by conventional knowledge in the art to which the present invention belongs It can be easily derived.

본 발명에서 용어, "재조합 벡터"란 적당한 숙주세포에서 목적 단백질을 발현할 수 있는 발현 벡터로서, 유전자 삽입물이 발현되도록 작동가능하게 연결된 필수적인 조절 요소를 포함하는 유전자 작제물을 말한다. 본 발명에 따른 항-에이엑스엘 항체를 코딩하는 유전자는 별개의 벡터에 삽입될 수도 있고, 하나의 벡터에 삽입된 형태로 이용될 수도 있다.As used herein, the term "recombinant vector" refers to an expression vector capable of expressing a desired protein in a suitable host cell, including a necessary regulatory element operatively linked to the expression of the gene insert. The gene encoding the anti-A [beta] 1 antibody according to the present invention may be inserted into a separate vector or inserted into a single vector.

구체적으로, 본 발명에서 제공되는 항-에이엑스엘 항체의 아미노산 서열을 인코딩하는 폴리뉴클레오티드가 각각 별개 또는 하나의 벡터에 삽입된 형태로 이용될 수 있으며, 중쇄 및 경쇄, 또는 그 가변영역 등을 코딩하는 폴리뉴클레오티드가 각각 별개 또는 하나의 벡터에 삽입된 형태로 이용될 수 있다.Specifically, the polynucleotides encoding the amino acid sequences of the anti-A [beta] 2 antibody provided in the present invention may be used individually or in a form inserted into one vector, and the heavy and light chains, Polynucleotides < / RTI > may be used separately or in a form inserted into one vector.

본 발명에서 "작동 가능하게 연결된 (operably linked)"은 목적하는 기능을 수행하도록 핵산 발현조절 서열과 목적하는 단백질을 코딩하는 핵산 서열이 기능적으로 연결되어 있는 것을 말한다. 재조합 벡터와의 작동 가능한 연결은 당해 기술분야에서 잘 알려진 유전자 재조합 기술을 이용하여 제조할 수 있으며, 부위 특이적 DNA 절단 및 연결은 당해 기술 분야에서 일반적으로 알려진 효소 등을 사용하여 용이하게 할 수 있다.In the present invention, "operably linked" refers to a functional linkage between a nucleic acid expression control sequence and a nucleic acid sequence encoding a desired protein to perform the desired function. Operational linkages with recombinant vectors can be made using genetic recombination techniques well known in the art, and site specific DNA cleavage and linkage can be facilitated using enzymes generally known in the art .

본 발명에 따른 항-에이엑스엘 항체의 생산에 적합한 발현 벡터는 프로모터, 개시코돈, 종결코돈, 폴리아데닐화 시그널 및 인핸서 같은 발현 조절 엘리먼트 외에도 막 표적화 또는 분비를 위한 시그널 서열을 포함할 수 있다. 개시 코돈 및 종결 코돈은 일반적으로 면역원성 표적 단백질을 코딩하는 뉴클레오타이드 서열의 일부로 간주되며, 유전자 작제물이 투여되었을 때 개체에서 반드시 작용을 나타내야 하며 코딩 서열과 인프레임(in frame)에 있어야 한다. 일반 프로모터는 구성적 또는 유도성일 수 있다. 프로모터로는 lac, tac, T3, 및 T7의 원핵 세포, 원숭이 바이러스 40(SV40), 마우스 유방 종양 바이러스(MMTV) 프로모터, 사람 면역 결핍 바이러스(HIV), 예를 들면 HIV의 긴 말단 반복부(LTR) 프로모터, 몰로니 바이러스, 시토메갈로바이러스(CMV), 엡스타인 바 바이러스(EBV), 로우스 사코마 바이러스(RSV) 프로모터뿐만 아니라, β-액틴 프로모터, 사람 헤로글로빈, 사람 근육 크레아틴, 사람 메탈로티오네인 유래의 진핵세포 프로모터 등을 들 수 있으나, 이들로 제한되지 않는다.Expression vectors suitable for the production of anti-A [beta] 2 antibodies according to the present invention may include signal sequence for membrane targeting or secretion in addition to expression control elements such as promoter, initiation codon, termination codon, polyadenylation signal and enhancer. The initiation codon and termination codon are generally considered to be part of the nucleotide sequence encoding the immunogenic target protein and must be operative in the subject when the gene construct is administered and in the coding sequence and in frame. Generic promoters may be constitutive or inducible. Promoters include the prokaryotic cells lac, tac, T3, and T7, the monkey virus 40 (SV40), the mouse mammary tumor virus (MMTV) promoter, the human immunodeficiency virus (HIV) But are not limited to, the promoter, the Moloney virus, the cytomegalovirus (CMV), the Epstein-Barr virus (EBV), the Roussacomavirus (RSV) promoter, as well as the? -Actin promoter, human heparobin, human muscle creatine, Derived eukaryotic cell promoter, and the like.

상기 발현 벡터는 벡터를 함유하는 숙주 세포를 선택하기 위한 선택성 마커를 포함할 수 있다. 선택성 마커는 벡터로 형질 전환된 세포를 선별하기 위한 것으로, 약물 내성, 영양 요구성, 세포 독성제에 대한 내성 또는 표면 단백질의 발현과 같은 선택 가능한 표현형을 부여하는 마커들이 사용될 수 있다. 선택제 (selective agent)가 처리된 환경에서는 선별 마커를 발현하는 세포만 생존하므로 형질 전환된 세포의 선별 가능하다. 또한, 벡터는 복제 가능한 발현벡터인 경우, 복제가 개시되는 특정 핵산 서열인 복제원점 (replication origin)을 포함할 수 있다.The expression vector may comprise a selectable marker for selecting a host cell containing the vector. Selectivity markers are for selecting cells transfected with a vector and markers conferring selectable phenotypes such as drug resistance, nutritional requirement, tolerance to cytotoxic agents or expression of surface proteins may be used. In the environment treated with the selective agent, only the cells expressing the selection marker survive, so that the transformed cells can be selected. In addition, if the vector is a replicable expression vector, it may contain a replication origin which is a specific nucleic acid sequence at which replication is initiated.

외래 유전자를 삽입하기 위한 재조합 발현 벡터로는 플라스미드, 바이러스, 코즈미드 등 다양한 형태의 벡터를 사용할 수 있다. 재조합 벡터의 종류는 원핵세포 및/또는 진핵세포의 각종 숙주세포에서 원하는 유전자를 발현하고 원하는 단백질을 생산하는 기능을 하는 한 특별히 한정되지 않지만, 강력한 활성을 나타내는 프로모터와 강한 발현력을 보유하면서 자연 상태와 유사한 형태의 외래 단백질을 대량으로 생산할 수 있는 벡터가 바람직하다.As the recombinant expression vector for inserting the foreign gene, various types of vectors such as plasmids, viruses, and cosmids can be used. The type of the recombinant vector is not particularly limited as long as it expresses a desired gene in various host cells of prokaryotic and / or eukaryotic cells and produces a desired protein. However, the recombinant vector has a promoter exhibiting strong activity and a promoter A vector capable of producing a large amount of exogenous protein in a form similar to that of the wild type.

본 발명에 따른 항-에이엑스엘 항체를 발현시키기 위해 다양한 발현 숙주/벡터 조합이 이용될 수 있다. 진핵숙주에 적합한 발현 벡터로는 SV40, 소 유두종바이러스, 아네노바이러스, 아데노-연관 바이러스(adeno-associated virus), 시토메갈로바이러스 및 레트로바이러스로부터 유래된 발현 조절 서열 등이 있으나, 이로 한정되지 않는다. 세균 숙주에 사용할 수 있는 발현 벡터에는 pET, pRSET, pBluescript, pGEX2T, pUC벡터, colE1, pCR1, pBR322, pMB9, 및 이들의 유도체와 같이 대장균(Escherichia coli)에서 얻어지는 세균성 플라스미드, RP4와 같이 보다 넓은 숙주 범위를 갖는 플라스미드, λgt10과 λgt11, NM989와 같은 매우 다양한 파지 람다(phage lambda) 유도체로 예시될 수 있는 파지 DNA, 및 M13과 필라멘트성 단일가닥의 DNA 파지와 같은 기타 다른 DNA 파지가 포함된다. 효모 세포에 유용한 발현 벡터는 2 micron 플라스미드 및 그의 유도체이다. 곤충 세포에 유용한 벡터는 pVL941이다.A variety of expression host / vector combinations may be used to express the anti-A [beta] 1 antibody according to the invention. Suitable expression vectors for eukaryotic hosts include, but are not limited to, SV40, bovine papilloma virus, anenovirus, adeno-associated virus, cytomegalovirus and retrovirus-derived expression control sequences. Expression vectors that can be used for bacterial hosts include Escherichia coli such as pET, pRSET, pBluescript, pGEX2T, pUC vector, colE1, pCR1, pBR322, pMB9, plasmids obtained from E. coli , plasmids with a broader host range such as RP4, phage DNAs which can be exemplified by a wide variety of phage lambda derivatives such as lambda gt10 and lambda gt11, NM989, and M13 and filamentous single strands And other DNA fingerprints such as DNA fingerprints. A useful expression vector for yeast cells is a 2 micron plasmid and its derivatives. The vector useful for insect cells is pVL941.

다른 하나의 양태로서, 본 발명은 상기 재조합 벡터로 형질 전환된 숙주세포를 제공한다. 상기 재조합 벡터는 숙주세포에 삽입되어 형질 전환체를 형성한다. 상기 벡터의 적합한 숙주세포는 대장균, 바실러스 서브틸리스(Bacillus subtilis), 스트렙토마이세스 속 (Streptomyces sp.), 슈도모나스 속(Pseudomonas sp.), 프로테우스 미라빌리스(Proteus mirabilis) 또는 스타필로코쿠스 속(Staphylococcus sp.)과 같은 원핵 세포일 수 있다. 또한, 아스페르길러스 속(Aspergillus sp.)과 같은 진균, 피치아 파스토리스(Pichia pastoris), 사카로마이세스 세레비지애(Saccharomyces cerevisiae), 쉬조사카로마세스 속(Schizosaccharomyces sp.) 및 뉴로스포라 크라사(Neurospora crassa)와 같은 효모, 그 밖의 하등진핵 세포, 및 곤충으로부터의 세포와 같은 고등 진핵생물의 세포와 같은 진핵 세포일 수 있다. 또한 식물, 포유동물로부터 유래할 수 있다. 바람직하게는, 원숭이 신장 세포7(COS7 : monkey kidney cells)세포, NSO 세포(마우스 기원의 골수종 세포), SP2/0 세포(마우스 기원의 골수종 세포), 기타 골수종 세포주, 차이니즈 햄스터 난소(CHO:chinese hamster ovary) 세포, W138 세포(diploid human cell culture), 어린 햄스터 신장(BHK:baby hamster kidney)세포, MDCK, HuT 78 세포 및 HEK293 세포 등이 이용 가능하지만 이에 한정되지 않는다. 특히 바람직하게는 CHO 세포이다.In another embodiment, the present invention provides a host cell transformed with the recombinant vector. The recombinant vector is inserted into a host cell to form a transformant. A suitable host cell of the vector is E. coli, Bacillus subtilis (Bacillus subtilis), genus Streptomyces (Streptomyces sp.), Pseudomonas species (Pseudomonas sp.), Proteus ( Proteus mirabilis , or Staphylococcus sp.). In addition, the genus Aspergillus sp.), fungi such as Pichia pastoris , Saccharomyces cerevisiae , Schizosaccharomyces, eukaryotic cells such as yeast such as Neurospora crassa , other lower eukaryotic cells, and cells of higher eukaryotes such as cells from insects. It can also be derived from plants and mammals. Preferably, monkey kidney cells (COS7), NSO cells (myeloma cells of mouse origin), SP2 / 0 cells (myeloma cells of mouse origin), other myeloma cell lines, Chinese hamster ovary (CHO: chinese hamster ovary cells, diploid human cell cultures, baby hamster kidney (BHK) cells, MDCK, HuT 78 cells and HEK293 cells, but are not limited thereto. Particularly preferably, it is a CHO cell.

본 발명에서 "숙주세포로의 형질 전환"은 핵산을 유기체, 세포, 조직 또는 기관에 도입하는 어떤 방법도 포함되며 당 분야에서 공지된 바와 같이 숙주 세포에 따라 적합한 표준 기술을 선택하여 수행할 수 있다. 이런 방법에는 전기천공법(electroporation), 원형질 융합, 인산 칼슘(CaPO4) 침전, 염화 칼슘(CaCl2) 침전, 실리콘 카바이드 섬유 이용한 교반, 아그로 박테리아 매개된 형질 전환, PEG, 덱스트란 설페이트, 리포펙타민 및 건조/억제 매개된 형질 전환 방법 등이 포함되나 이로 제한되지 않는다.In the present invention, "transformation into a host cell " includes any method of introducing a nucleic acid into an organism, cell, tissue or organ, and can be carried out by selecting a suitable standard technique depending on the host cell as is known in the art . Such methods include electroporation, protoplast fusion, calcium phosphate (CaPO 4 ) precipitation, calcium chloride (CaCl 2 ) precipitation, agitation with silicon carbide fibers, Agrobacterium mediated transformation, PEG, dextran sulfate, Thymine and dry / suppressed mediated transformation methods, and the like.

다른 하나의 양태로서, 본 발명은 상기 재조합 벡터로 형질 전환된 숙주세포를 배양하여 본 발명에 따른 항-에이엑스엘 항체를 제조하는 방법을 제공한다.In another aspect, the present invention provides a method for producing an anti-A [beta] antibody according to the present invention by culturing a host cell transformed with the recombinant vector.

상기 인간화 항체의 제조방법은 본 발명의 항-에이엑스엘 항체를 코딩하는 뉴클레오타이드 서열을 벡터에 삽입하여 재조합 벡터를 제조하는 단계; 상기 재조합 벡터를 숙주세포에 형질 전환시켜 배양하는 단계; 상기 배양된 형질 전환체로부터 인간화 항체를 분리, 정제하는 단계를 포함할 수 있다.The method for producing the humanized antibody comprises the steps of: preparing a recombinant vector by inserting a nucleotide sequence encoding the anti-A [beta] antibody of the present invention into a vector; Transforming the recombinant vector into a host cell and culturing it; And separating and purifying the humanized antibody from the cultured transformant.

구체적으로, 재조합 벡터가 발현되는 형질 전환체를 영양배지에서 배양함으로써 본 발명에 따른 인간화 항체를 대량으로 생산할 수 있으며, 배지와 배양조건은 숙주 세포에 따라 관용되는 것을 적당히 선택 및/또는 이용할 수 있다. 배양시 세포의 생육과 단백질의 대량 생산에 적합하도록 온도, 배지의 pH 및 배양시간 등의 조건들을 적절하게 조절할 수 있다.Specifically, a humanized antibody according to the present invention can be produced in large quantities by culturing the transformant expressing the recombinant vector in a nutrient medium, and the medium and culturing conditions can be suitably selected and / or used according to the host cell . The conditions such as the temperature, the pH of the medium and the incubation time can be appropriately adjusted so as to be suitable for cell growth and mass production of the protein at the time of culturing.

상기와 같이 재조합으로 생산된 항-에이엑스엘 항체는 배지 또는 세포 분해물로부터 회수될 수 있다. 막 결합형인 경우, 적합한 계면활성제 용액(예, 트리톤-X 100)을 사용하거나 또는 효소적 절단에 의해 막으로부터 유리될 수 있다. 인간화 항체 발현에 사용된 세포는 동결-해동 순화, 음파처리, 기계적 파괴 또는 세포 분해제와 같은 다양한 물질적 또는 화학적 수단에 의해 파괴될 수 있으며, 통상적인 생화학 분리 기술에 의해서 분리, 정제가 가능하다. 전기영동, 원심분리, 겔여과, 침전, 투석, 크로마토그래피(이온교환 크로마토그래피, 친화성 크로마토그래피, 면역흡착 크로마토그래피, 크기 배제 크로마토그래피 등), 등전점 포커싱 및 이의 다양한 변화 및 복합 방법 등이 이용 가능하지만 이에 한정되지 않는다.The recombinantly produced anti-A [beta] 1 antibody as described above can be recovered from the medium or the cell lysate. If membrane bound, it can be liberated from the membrane by using a suitable surfactant solution (e.g., Triton-X 100) or by enzymatic cleavage. Cells used for humanized antibody expression can be destroyed by various physical or chemical means such as freeze-thawing, sonication, mechanical destruction or cell disintegration, and can be isolated and purified by conventional biochemical separation techniques. Electrophoresis, centrifugation, gel filtration, precipitation, dialysis, chromatography (ion exchange chromatography, affinity chromatography, immuno adsorption chromatography, size exclusion chromatography, etc.), isoelectric focusing and various variations and combinations thereof But are not so limited.

또 다른 양태로서, 본 발명은 본 발명에 따른 항-에이엑스엘 항체, 상기 항체의 단편, 접합체 및/또는 이중특이 항체를 포함하는 암 예방 또는 치료용 조성물을 제공한다.In another aspect, the present invention provides a composition for preventing or treating cancer, comprising an anti-A [beta] -el antibody, a fragment, conjugate and / or a bispecific antibody of the antibody according to the present invention.

본 발명의 조성물로 치료할 수 있는 암 또는 암종은 특별히 제한되지 않으며, 고형암 및 혈액암을 모두 포함할 수 있다. 바람직하게는 에이엑스엘이 발현되는 모든 암을 포함하며, 보다 바람직하게 간암, 간세포암(hepatocellular carcinoma), 간세포성암, 위암, 유방암, 폐암, 난소암, 기관지암, 비인두암, 후두암, 췌장암, 방광암, 대장암, 결장암, 이자암, 자궁경부암, 뇌암, 전립선암, 골암, 피부암, 갑상선암, 부갑상선암, 신장암, 식도암, 담도암, 고환암, 직장암, 두경부암, 경추암, 요관암, 골육종, 신경아세포종, 흑색종, 섬유육종, 횡문근육종, 성상세포종, 신경모세포종 및 신경교종으로 이루어진 군에서 선택될 수 있다. 가장 바람직한 본 발명의 조성물로 치료할 수 있는 암은 폐암, 특히 소세포폐암일 수 있다.The cancer or carcinoma that can be treated with the composition of the present invention is not particularly limited and may include both solid cancer and blood cancer. Preferably all of the cancers in which the AXEL is expressed, and more preferably all of the cancers including hepatocellular carcinoma, hepatocellular carcinoma, hepatocellular carcinoma, gastric cancer, breast cancer, lung cancer, ovarian cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, , Cancer of the colon, cancer of the colon, cancer of the cervix, cancer of the cervix, brain cancer, prostate cancer, bone cancer, skin cancer, thyroid cancer, parathyroid cancer, kidney cancer, esophageal cancer, biliary cancer, testicular cancer, rectal cancer, head and neck cancer, cervical cancer, Sarcoma, melanoma, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, and glioma. The cancer which can be treated with the most preferred composition of the present invention may be lung cancer, particularly small cell lung cancer.

본 발명의 암 예방 또는 치료용 조성물은 약학적으로 허용되는 담체를 추가로 포함할 수 있다. 경구 투여시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등을 사용할 수 있으며, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등을 혼합하여 사용할 수 있으며, 국소 투여용의 경우에는 기제, 부형제, 윤활제, 보존제 등을 사용할 수 있다. 본 발명의 약제학적 조성물의 제형은 상술한 바와 같은 약제학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구 투여시에는 정제, 트로키, 캡슐, 엘릴시르, 서스펜션, 시럽, 웨이퍼 등의 형태로 제조할 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수회 투약 형태로 제조할 수 있다. 또한, 상기 암 예방 또는 치료용 조성물은 전형적으로 막을 통과한 이동을 용이하게 하는 계면활성제를 포함할 수 있다. 이러한 계면활성제는 스테로이드에서 유도된 것이거나 N-[1-(2,3-디올레오일)프로필-N,N,N-트리메틸암모늄클로라이드(DOTMA) 등의 양이온성 지질, 또는 콜레스테롤 헤미숙시네이트, 포스파티딜 글리세롤 등의 각종 화합물 등이 있다.The composition for preventing or treating cancer of the present invention may further comprise a pharmaceutically acceptable carrier. In the case of oral administration, a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a pigment and a flavoring agent may be used. , A stabilizer, and the like. In case of topical administration, a base, an excipient, a lubricant, a preservative, etc. may be used. Formulations of the pharmaceutical compositions of the present invention may be prepared in a variety of ways by mixing with pharmaceutically acceptable carriers as described above. For example, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like in the case of oral administration, and in the case of injections, unit dosage ampoules or a plurality of dosage forms. In addition, the composition for preventing or treating cancer may include a surfactant, which typically facilitates migration through the membrane. Such surfactants are those derived from steroids or cationic lipids such as N- [1- (2,3-dioloyl) propyl-N, N, N-trimethylammonium chloride (DOTMA), or cholesterol hemi- , Phosphatidylglycerol, and the like.

또 다른 양태로서, 본 발명은 본 발명에 따른 조성물을 개체에 투여하여 암을 치료하거나 암의 성장을 억제하는 방법을 제공한다. 본 발명에 따른 항-에이엑스엘 항체를 포함하는 조성물은 암세포 또는 그들의 전이를 치료하기 위하여, 또는 암의 성장을 억제하기 위하여 약학적으로 효과적인 양으로 투여될 수 있다. 암 종류, 환자의 연령, 체중, 증상의 특성 및 정도, 현재 치료법의 종류, 치료 회수, 투여 형태 및 경로 등 다양한 요인에 따라 달라질 수 있으며, 해당 분야의 전문가들에 의해 용이하게 결정될 수 있다. 본 발명의 조성물은 상기한 약리학적 또는 생리학적 성분을 함께 투여하거나 순차적으로 투여할 수 있으며, 또한 추가의 종래의 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다. 이러한 투여는 단일 또는 다중 투여일 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다.In another aspect, the present invention provides a method for treating cancer or inhibiting cancer growth by administering a composition according to the present invention to a subject. A composition comprising an anti-A [beta] 2 antibody according to the present invention may be administered in a pharmaceutically effective amount to treat cancer cells or their metastasis, or to inhibit cancer growth. The type of cancer, the age and weight of the patient, the nature and severity of symptoms, the type of current treatment, the number of treatments, the route and route of administration, and can be readily determined by those skilled in the art. The composition of the present invention may be administered together with the above-described pharmacological or physiological components or may be administered sequentially, or may be administered in combination with additional conventional therapeutic agents, and administered sequentially or concurrently with conventional therapeutic agents. Such administration may be single or multiple administrations. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without adverse effect, and can be easily determined by those skilled in the art.

본 발명에서, "개체"는 본 발명에 따른 조성물을 투여하여 경감, 억제 또는 치료될 수 있는 상태 또는 질환을 앓고 있거나 그러한 위험이 있는 포유동물을 의미하며, 바람직하게 사람을 의미한다.In the present invention, "individual" means a mammal suffering from or at risk for a condition or disease that can be alleviated, suppressed or treated by administering the composition according to the present invention, preferably means a human.

본 발명에서, "투여"는 어떠한 적절한 방법으로 개체에게 소정의 물질을 도입하는 것을 의미하며, 본 발명에 따른 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 이러한 투여 방법으로 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 경구 투여, 국소 투여, 비내 투여, 폐내 투여 또는 직장내 투여 등을 들 수 있으나, 이에 제한되지는 않는다. 그러나 경구 투여시, 단백질은 소화가 되기 때문에 경구용 조성물은 활성 약제를 코팅하거나 위에서의 분해로부터 보호되도록 제형화 하는 것이 바람직하다. 또한, 제약 조성물은 활성 물질이 표적 세포로 이동할 수 있도록 임의의 장치에 의해 투여될 수 있다.In the present invention, "administration" means introducing a predetermined substance into a subject by any suitable method, and the administration route of the composition according to the present invention can be administered through any conventional route so long as it can reach the target tissue . Such administration methods include, but are not limited to intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intravenous administration, intrapulmonary administration or rectal administration. However, at the time of oral administration, since the protein is digested, it is preferable to formulate the oral composition so as to coat the active agent or protect it from decomposition at the top. In addition, the pharmaceutical composition can be administered by any device so that the active substance can migrate to the target cell.

이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위를 제한하는 것이 아님은 당연하다.Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are for illustrative purposes only and do not limit the scope of the present invention.

실시예Example 1: 항- 1: anti- AXLAXL 항체의 제조 Preparation of antibodies

1-1 : 파지 디스플레이(Phage display)를 이용한 항-인간 1-1: Anti-human using phage display AXLAXL scFvscFv 항체선별 Antibody screening

대장균(E. coli)에 기생하는 박테리오 파지(Bacteriophage)에 유전자 재조합 기술로 발현시키려는 DNA 서열을 박테리오 파지의 게놈(genome)에 삽입하고 삽입된 단백질이 파지의 coat protein 중 하나와 융합된 형태로 파지의 표면에 발현시키는 파지 디스플레이(phage display) 기술을 이용하여 항체 선별 작업을 하였다. 1차 패닝(panning)은 1013이상의 라이브러리 스톡(library stock) 1ml을 AXL이 코팅된 고체상 폴리스티렌(Solid phase polystyrene) 튜브(Nunc, 444202)에서 37℃ 2시간 동안 반응시켰다. 이와 동시에 XLI-Blue Electroporation-Competent Cell (Stratagene) 10μl를 SB(Smith-Baskerville medium) 10ml/tetracycline 10μl에서 inoculation시켜 OD600 값이 0.8 내지 1.0이 되도록 배양하였다. 37℃ 2시간 동안 반응시켰던 것을 0.05% Tween 20/PBS 5ml로 4회 washing하고 2차 panning부터 panning 횟수 증가에 따라 0.05% Tween 20/PBS 5ml의 washing 횟수를 증가시켰다. 이후 1% BSA/0.1M Glycine pH2.0으로 상온에서 10분간 배양하여 phagemid를 정제하였다. 정제한 것을 50ml 튜브에 옮기고 2M Tris 70μl로 중화시켰다. XLI-Blue Electroporation-Competent Cell(Stratagene) 9ml을 처리하고 1ml은 세척된 튜브에 처리하였다. 상온에서 30분간 감염시킨 후 SB 10ml, tetracycline 20μl, carbencillin 10μl를 첨가하여 37℃ 220rpm으로 1시간 동안 현탁 배양시켰다. 이후 VCS M13 helper phage 1ml(1011 pfu)을 처리한 후 1시간 동안 37℃ 220rpm 에서 현탁 배양 한 후 SB 80ml, kanamycin 100μl, carbencillin 100μl를 처리하고 37℃ 220rpm으로 12시간이상 배양하였다. 12시간이상 배양한 것을 3500rpm 4℃, 10min으로 원심분리 한 후 상등액을 새로운 튜브로 옮겨 20% PEG/15% NaCl 20ml을 첨가하여 잘 섞은 후 ice에서 30분간 반응하였다. 이후 8000 rpm 4℃ 30min으로 상등액을 버리고 pellet을 모아서 1% BSA/PBS 2ml로 재현탁시켜 15000 rpm 4℃ 10분간 원심분리시켰다. 이때 모인 pellet은 버리고 상등액 2 ml중 1 ml은 -20℃에 보관하고 1ml은 다음 차수 panning 에 이용하였다.A DNA sequence to be expressed by a recombinant technique is inserted into a bacteriophage parasitic on E. coli into a genome of a bacteriophage and the inserted protein is fused with one of the coat proteins of the phage The antibody was screened using a phage display technique for expressing the antibody on the surface of the antibody. For primary panning, 1 ml of a library stock of 10 13 or more was reacted in an AXL-coated solid phase polystyrene tube (Nunc, 444202) for 2 hours at 37 ° C. At the same time, 10 μl of XLI-Blue Electroporation-Competent Cell (Stratagene) was inoculated in 10 μl of Smith-Baskerville medium (SB) / 10 μl of tetracycline and cultured to an OD 600 value of 0.8-1.0. After washing for 2 hours at 37 ° C, the cells were washed 4 times with 5 ml of 0.05% Tween 20 / PBS. From the second panning, the number of washing cycles was increased to 5 ml with 0.05% Tween 20 / PBS. Then, phagemid was purified by culturing in 1% BSA / 0.1 M Glycine pH 2.0 at room temperature for 10 minutes. The purified product was transferred to a 50 ml tube and neutralized with 70 μl of 2 M Tris. 9 ml of XLI-Blue Electroporation-Competent Cell (Stratagene) was treated and 1 ml was treated in a washed tube. After incubation at room temperature for 30 min, 10 ml of SB, 20 μl of tetracycline, and 10 μl of carbencillin were added and suspension culture was carried out at 37 ° C and 220 rpm for 1 hour. Then, 1 ml (10 11 pfu) of VCS M13 helper phage was treated and suspension cultured at 37 ° C and 220 rpm for 1 hour. Then, 80 ml of SB, 100 μl of kanamycin and 100 μl of carbencillin were treated and cultured at 37 ° C and 220 rpm for over 12 hours. After incubation for more than 12 hours, the mixture was centrifuged at 3500 rpm at 4 ° C for 10 min. The supernatant was transferred to a new tube, and 20 ml of 20% PEG / 15% NaCl was added thereto. The supernatant was discarded at 8000 rpm and 4 ° C for 30 min. The pellet was collected, resuspended in 2 ml of 1% BSA / PBS, and centrifuged at 15000 rpm at 4 ° C for 10 minutes. The pellet was discarded and 1 ml of the supernatant was stored at -20 ° C and 1 ml was used for next order panning.

1-One- 2 : ELISA방식의2: ELISA 개별 클론 확보 Securing individual clones

Phage display 합성 scFv 라이브러리 최종 증폭집단의 단일 콜로니를 채취한 다음 SB/carbenicillin 1.5 mL에서 OD600 값이 0.8 내지 1.0 정도까지 되도록 37℃ 220rpm으로 배양한 후 1mM IPTG, 30℃ 200rpm으로 12시간 이상 배양시켰다. 이 반응물을 5500rpm, 5분간 원심 분리한 후 각각의 상층액만을 AXL 항원이 깔려있는 ELISA plate에 첨가한 후 2시간 동안 상온에서 반응시킨 다음 PBST(1XPBS, 0.05% tween 20)로 4회 세척 후 HRP/Anti-hFab-HRP conjugate를 1% BSA/1XPBS로 1/5000로 희석한 것을 첨가한 후 1시간 동안 상온에서 반응한 후 다시 PBST (1XPBS, 0.05% tween 20)로 4회 세척 한 후 TMB solution 첨가한 후 5 내지 10분간 반응한 후에 TMB stop solution 첨가한 후 TECAN사의 Sunrise를 이용하여 450nm 측정 파장에서 그 값을 읽고 높은 O.D 값을 갖는 클론을 개별클론으로 확보하였다.Phage display Synthetic scFv library After collecting a single colony of the final amplification population, 1.5 mL of SB / carbenicillin was cultured at 37 ° C and 220 rpm at an OD600 of 0.8 to 1.0, followed by 1 mM IPTG and 30 rpm at 200 rpm for more than 12 hours. The reaction mixture was centrifuged at 5500 rpm for 5 minutes, and then the supernatant was added to the ELISA plate containing the AXL antigen. The reaction mixture was reacted at room temperature for 2 hours, washed 4 times with PBST (1XPBS, 0.05% tween 20) / Anti-hFab-HRP conjugate was diluted 1/5000 with 1% BSA / 1XPBS. After 1 hour of reaction at room temperature, the cells were washed 4 times with PBST (1XPBS, 0.05% tween 20) After the addition, the reaction was continued for 5 to 10 minutes. Then, TMB stop solution was added, and the value was read at a measurement wavelength of 450 nm using Sunrise of TECAN Co., and clones having a high OD value were obtained as individual clones.

그 결과, 인간 AXL에 특이적으로 결합하는 26개의 클론을 선별할 수 있었고, 이들의 아미노산 서열을 확인하였다. 선별된 클론들은 각각 클론 L1, 클론 L2, 클론 L3, 클론 L4, 클론 L5, 클론 L6, 클론 L7, 클론 L8, 클론 L9, 클론 L10, 클론 L11, 클론 L12, 클론 L13, 클론 L14, 클론 L15, 클론 L16, 클론 L17, 클론 L18, 클론 L19, 클론 L20, 클론 L21, 클론 K1, 클론 K2, 클론 K3, 클론 K4 및 클론 K5로 명명되었으며, 각 클론들의 가변영역 서열을 첨부된 서열목록에 기재된 바와 같이 확인할 수 있었고, 각 클론들의 가변 영역 내의 CDR 아미노산 서열을 첨부된 서열목록에 기재된 바와 같이 Kabat numbering 기준으로 확인하였다.As a result, 26 clones that specifically bind to human AXL could be selected and their amino acid sequences were confirmed. The selected clones are clone L1, clone L2, clone L3, clone L4, clone L5, clone L6, clone L7, clone L8, clone L9, clone L10, clone L11, clone L12, clone L13, clone L14, clone L15, Clone L16, clone L17, clone L18, clone L19, clone L20, clone L21, clone K1, clone K2, clone K3, clone K4 and clone K5. The variable region sequences of each clone were named as described in the attached sequence listing And the amino acid sequences of the CDRs within the variable regions of each of the clones were confirmed by Kabat numbering as described in the attached sequence listing.

1-3 : 항-1-3: anti- AXLAXL 항체의 항원에 대한 정량적인 결합력 측정 Quantitative binding assay of antibodies against antigen

정제된 항-AXL 항체인 L4, L15, L18 클론 항체의 재조합 인간 AXL (Recombinant human AXL)에 대한 정량적인 결합력(친화도, Affinity)을 Biacore T-200(GE Healthcare, 미국) 바이오센서를 이용하여 측정하였다. HEK293 세포로부터 정제된 AXL(Cat.No10279-H08H, Sino Biological)을 아민-카르복실 반응을 이용하여 CM5칩(GE Healthcare)에 200 Rmax가 되도록 고정시킨 다음, HBS-EP 완충용액(10mM HEPES, pH7.4, 150mM NaCl, 3mM EDTA, 0.005% surfactant P20)에 순차적으로 희석한 L4, L15 또는 L18 항체를 0.078nM 내지 5nM 농도 범위에서 120초 동안 결합(association)시키고, 1800초간 유속 30μL/분으로 흘려주어 해리(dissociation)시켰다. 10mM Glycine-HCl pH1.5를 30초 동안 유속 30μL/분으로 흘려줌으로써 AXL에 결합된 항체의 해리를 유도하였다(표 1). Biacore T-200 evaluation software를 이용하여 친화도를 운동속도상수(Kon 및 Koff)와 평형해리상수(KD)로 얻었다(표 2).The quantitative binding affinity (affinity) of the purified anti-AXL antibodies L4, L15, and L18 clones to recombinant human AXL was determined using a Biacore T-200 (GE Healthcare, USA) biosensor Respectively. AXL (Cat.No10279-H08H, Sino Biological) purified from HEK293 cells was immobilized on a CM5 chip (GE Healthcare) using an amine-carboxyl reaction to 200 Rmax and then diluted with HBS-EP buffer (10 mM HEPES, L15, or L18 antibody diluted sequentially in a concentration range of 0.078 nM to 5 nM for 120 seconds and flowed at a flow rate of 30 μL / min for 1800 seconds Subject to dissociation. The dissociation of AXL-bound antibody was induced by flowing 10 mM Glycine-HCl pH 1.5 at a flow rate of 30 μL / min for 30 seconds (Table 1). Affinity was obtained with kinetic rate constants (K on and K off ) and equilibrium dissociation constant (K D ) using Biacore T-200 evaluation software (Table 2).

SPRSPR Biacore T200Biacore T200 칩(Chip)Chip CM5CM5 러닝버퍼 (Running Buffer)Running Buffer HBS-EP pH7.4HBS-EP pH 7.4 유속률 (Flow rate)Flow rate 30㎕/분30 μl / min 결합 (Association) /
해리 (dissociation time)Association /
Dissociation time 120초 / 600초120 seconds / 600 seconds IgG 농도IgG concentration 0.078~5nM, 1/2 계단희석
(serial dilution)0.078 to 5 nM, 1/2 step dilution
(serial dilution) 재생 (Regeneration)Regeneration 10mM Glycine-HCl pH1.5, 30초10 mM Glycine-HCl pH 1.5, 30 seconds

Kon K on Koff K off KD K D L4L4 2.8X106 2.8X10 6 2.3X10-4 2.3X10 -4 8.2X10-11 8.2X10 -11 L5L5 1.2X106 1.2X10 6 3.5X10-4 3.5X10 -4 3.0 X10-10 3.0 X10 -10 L18L18 8.3X105 8.3X10 5 7.0X10-5 7.0X10 -5 8.5 X10-11 8.5 X10 -11

실시예 2 : AXL 발현 암세포에 대한 항- AXL 항체의 결합에 대한 FACS 분석 합성 라이브러리로부터 도출된 항-AXL 항체가 AXL을 발현하는 세포에 선택적으로 결합하는지 평가하기 위해 암세포주에서 AXL의 발현양을 측정하고 항체의 결합을 FACS 실험으로 확인하였다(표 3). Example 2 FACS Analysis of Binding of Anti- AXL Antibodies to AXL Expressing Cancer Cells To evaluate whether anti- AXL antibodies derived from synthetic libraries selectively bind to AXL expressing cells, the expression level of AXL in cancer cell lines was determined And the binding of the antibody was confirmed by FACS experiments (Table 3).

2-1: 2-1: AXLAXL 발현 종양 세포주에서  In expression tumor cell lines AXLAXL 발현량 확인 Check the expression level

폐암 세포주 6종(H358, HCC827, A549, HCC44, H1299, 및 Calu-1), 대장암 세포주 6종(DLD1, SW48, HCT8, HCT15, LS513, 및 RKO), 신장암 세포주 2종(A498, 및 786O) 그리고 유방암 세포주 10종(BT-20, DU4475, HCC1143, Hs578t, MDA-MB-231, MDA-MB-361, MDA-MB-453, MDA-MB-468, HCC1395, 및 T47D)에서 FACS 실험법으로 세포 표면의 AXL의 발현을 확인했다. 배양접시에서 키우고 있는 분석할 세포들을 Tryple Express 용액을 가하여 떼어낸 후 50 mL 튜브에 담아 1500 rpm에서 5분간 상온에서 원심분리하여 배양액을 따라버리고 PBS로 1회 세척하였다. FACS buffer로 부유화 시킨 뒤에 둥근 바닥 튜브로 옮기고 1500 rpm에서 5분간 상온에서 원심 분리하였다. 상층액을 버리고 FACS buffer로 5x105개/100μL이 되도록 잘 풀어주었다. 그리고 4℃에서 AXL에 대한 FACS 분석항체로 마우스 anti-AXL 항체(R&D systems)를 사용하였고, isotope 대조군으로는 Human IgG1(R&D systems)를 1μg씩 사용하였다. 30분 후에 FACS buffer로 2회 세척하고, anti-Human IgG antibody, PE conjugated를 sample 당 0.5μL를 넣고 4℃에서 30분동안 결합시켰다. 1500rpm에서 5분 동안 원심 분리하여 세포를 수거한 뒤 Fixation buffer를 300μL 넣고 세포를 재부유시킨 뒤 FACS fortessa로 측정하였다. (도 1 및 도 2)(DL5), HCC827, A549, HCC44, H1299 and Calu-1), six colorectal cancer cell lines (DLD1, SW48, HCT8, HCT15, LS513 and RKO), two kidney cancer cell lines (A498, 786O) and 10 kinds of breast cancer cell lines (BT-20, DU4475, HCC1143, Hs578t, MDA-MB-231, MDA-MB-361, MDA-MB-453, MDA-MB-468, HCC1395 and T47D) To confirm the expression of AXL on the cell surface. The cells to be analyzed were washed with Tryple Express solution and centrifuged at room temperature for 5 minutes at 1500 rpm in a 50-mL tube. The cells were washed with PBS and washed once with PBS. After floatation with FACS buffer, it was transferred to a round bottom tube and centrifuged at 1500 rpm for 5 minutes at room temperature. Discard the supernatant was released well to the dogs 5x10 5 / 100μL with FACS buffer. A mouse anti-AXL antibody (R & D systems) was used as a FACS analysis antibody against AXL at 4 ° C, and 1 μg of human IgG1 (R & D systems) was used as an isotope control. After 30 minutes, the cells were washed twice with FACS buffer, and 0.5 μL of anti-human IgG antibody and PE conjugated per sample were added and incubated at 4 ° C. for 30 minutes. Cells were harvested by centrifugation at 1500 rpm for 5 minutes, 300 μL of fixation buffer was added, and the cells were resuspended and counted with FACS fortessa. (Figures 1 and 2)

그 결과, 도 1에 나타난 바와 같이 폐암 세포주에서는 A549, HCC44, H1299, 및 Calu-1에서 AXL 발현이 확인 되었고, Calu-1에서의 AXL 발현이 가장 많은 것으로 확인되었다. 대장암 세포주에서는 LS513과 RKO에서 AXL 발현이 확인됐고, RKO에서의 AXL의 발현이 가장 높았다. 또한, 도 2에 나타난 바와 같이 신장암 세포주에서는 A498과 786O에서 모두 AXL 발현이 되었다. 그리고 유방암 세포주에서는 HCC1143, Hs578t, MDA-MB-231, 및 HCC1395에서 AXL 발현이 확인되었다.As a result, as shown in Fig. 1, AXL expression was confirmed in A549, HCC44, H1299, and Calu-1 in lung cancer cell lines and it was confirmed that AXL expression was the highest in Calu-1. Expression of AXL in LS513 and RKO was confirmed in colorectal cancer cell line, and expression of AXL in RKO was the highest. As shown in Fig. 2, AXL expression was also found in A498 and 786O in kidney cancer cell lines. And AXL expression was confirmed in HCC1143, Hs578t, MDA-MB-231, and HCC1395 in breast cancer cell lines.

2-2: 항-2-2: anti- AXLAXL 항체의  Antibody AXLAXL 발현 암 세포주에 대한 선택적 결합 분석 Selective Binding Assay for Expression Cancer Cell Lines

AXL을 발현하고 있는 대장암 세포주 RKO에서 항-AXL 항체가 선택적으로 결합하는지를 FACS 시험으로 측정하였다. 선택적 결합 분석에 대한 FACS스크리닝에 사용한 항체 클론을 하기 표 3에 나타냈다.In the colon cancer cell line RKO expressing AXL, whether anti -AXL antibody selectively binds was measured by FACS test. Antibody clones used for FACS screening for selective binding assays are shown in Table 3 below.

SourceSource NumberNumber ClonesClones 합성 라이브러리Synthetic library 2727 L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14, L15, L16, L17, L18, L19, L20, L21, L22, K1, K2, K3, K4, K5L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14, L15, L16, L17, L18, L19, L20, L21, L22, K4, K5

배양접시에서 키우고 있는 RKO 세포들에 Tryple Express 용액을 가하여 떼어낸 후 50 mL 튜브에 담아 1500rpm에서 5분간 상온에서 원심분리하여 배양액을 따라버리고 PBS로 1회 세척하였다. FACS buffer로 부유시킨 뒤에 둥근 바닥 튜브로 옮기고 1500rpm에서 5분간 상온에서 원심 분리하였다. 상층액을 버리고 FACS buffer로 5x105개/100μL이 되도록 잘 풀어준 뒤, 4℃에서 후보 항체 1μg을 첨가하였고, 동위원소 (isotope) 비교군은 후보 항체 대신 인간 IgG (Sigma)를 1μg 첨가하였다. 1시간 후에 FACS buffer로 2회 세척하고, PE가 연결된 염소 (Goat) anti-human IgG 항체를 sample 당 0.5μL를 넣고 4℃에서 30분동안 결합시켰다. 1500 rpm에서 5분 동안 원심 분리하여 세포를 수거한 뒤 Fixation buffer를 300μL 넣고 세포를 재부유시킨 뒤 FACS fortessa로 측정하여 도 3에 나타냈다. 도 3의 (A) 그래프는 오른쪽에서 왼쪽 방향으로 차례대로 RKO.L2.007.fcs, RKO.L1.006.fcs, RKO.L3.003.fcs, RKO.L4.009.fcs, RKO.L6.010.fcs, RKO.L7.011.fcs, RKO.L8.012.fcs, RKO.L11.013.fcs, RKO.L12.014.fcs, RKO.L13.015.fcs, RKO.L14.016.fcs, RKO.L15.017.fcs, RKO.L18.018.fcs, RKO.L19.019.fcs, RKO.L20.020.fcs, RKO.L21.021.fcs, RKO.L22.022.fcs, RKO.YW327.6S2.003.fcs, 그리고 RKO.ISO.002.fcs를 나타내는 것이고, 해당 값을 (A) 그래프 아래 (B) 표에 나타냈다. (C) 표는 L3, L4, L12, L15, L18 및 YW237.6S2형광 강도의 평균을 나타냈다.The RKO cells grown in the culture dish were removed by adding Tryple Express solution, and then centrifuged at room temperature for 5 minutes at 1500 rpm in a 50-mL tube. After floating with FACS buffer, it was transferred to a round bottom tube and centrifuged at 1500 rpm for 5 minutes at room temperature. The supernatant was discarded, and 5 μl / 100 μl of the supernatant was discarded, and 1 μg of the candidate antibody was added at 4 ° C. In the isotope comparison group, 1 μg of human IgG (Sigma) was added instead of the candidate antibody. After 1 hour, the cells were washed twice with FACS buffer, and 0.5 μL of goat anti-human IgG antibody conjugated with PE was added thereto at 4 ° C. for 30 minutes. Cells were collected by centrifugation at 1500 rpm for 5 minutes, 300 μL of Fixation buffer was added, and the cells were resuspended and measured by FACS fortessa. The graph of FIG. 3 (A) shows RKO.L2.007.fcs, RKO.L1.006.fcs, RKO.L3.003.fcs, RKO.L4.009.fcs, RKO.L6 .010.fcs, RKO.L7.011.fcs, RKO.L8.012.fcs, RKO.L11.013.fcs, RKO.L12.014.fcs, RKO.L13.015.fcs, RKO.L14.016 .fcs, RKO.L15.017.fcs, RKO.L18.018.fcs, RKO.L19.019.fcs, RKO.L20.020.fcs, RKO.L21.021.fcs, RKO.L22.022.fcs , RKO.YW327.6S2.003.fcs, and RKO.ISO.002.fcs, and the corresponding values are shown in Table (B) below the graph (A). Table (C) shows the average of L3, L4, L12, L15, L18 and YW237.6S2 fluorescence intensities.

분석한 후보 항체 간 결합력을 비교하기 위해 각 분석 별로 기준 항체를 설정하여 MFI 값의 비율로 비교하였다. 항-에이엑스엘 항체의 선택적 결합 분석 결과를 하기 표 4에 나타내었다.In order to compare the binding strength between the candidate antibodies, the reference antibody was set for each assay and compared with the ratio of MFI values. The results of selective binding analysis of anti-A [beta] -el antibody are shown in Table 4 below.

Figure 112016116111518-pat00001
Figure 112016116111518-pat00001

그 결과, AXL 발현이 높은 RKO 세포주에 우수한 결합력을 보인 항체는 L4, L15 및 L18 클론으로 확인하였다. 결합능력을 비교항체의 MFI 대비 값으로 보자면 L4, L18, L15 클론의 순서로 AXL에 결합을 더 잘 하는 것으로 확인되었다.As a result, L4, L15 and L18 clones were found to show excellent binding ability to RKO cell line with high expression of AXL. In terms of MFI of the comparative antibody, the binding ability was confirmed to be better in binding to AXL in the order of L4, L18 and L15 clones.

<110> Mogam Institute for Biomedical Research <120> Novel Antibody Against AXL and Pharmaceutical Composition Comprising the Same <130> 16P10049 <160> 193 <170> KoPatentIn 3.0 <210> 1 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> L1 heavy chain variable region <400> 1 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 Ala Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Ser Ser Gly Ser His Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu His Val Gly Gly Ser Asp Ala Phe Gly His Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 2 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L1 light chain variable region <400> 2 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Val Glu Lys Tyr 20 25 30 Thr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Gly Asn Asn Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp Asp Ser Leu 85 90 95 Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 3 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> L2 heavy chain variable region <400> 3 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 Gly Tyr 20 25 30 Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Tyr Gly Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Lys Ser Ser Leu Tyr Ile Pro Asn Ser Tyr Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 4 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L2 light chain variable region <400> 4 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Gly Arg Ser Asn Val Glu Asn Asn 20 25 30 Phe Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Lys Asp Gly Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Asp Ala Leu 85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 5 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> L3 heavy chain variable region <400> 5 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 Thr Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Lys Trp Val 35 40 45 Ser Ala Ile Ser Ser Asp Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Phe Thr Lys Gly Trp Val Asp Leu Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 6 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> L3 light chain variable region <400> 6 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Val Glu Ser Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Phe Asp Asn Ile Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln Thr 65 70 75 80 Gly Asp Glu Ala Asp Tyr Tyr Cys Ser Thr Trp Asp Ser Ser Leu Thr 85 90 95 Ala Pro Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 7 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> L4 heavy chain variable region <400> 7 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 Asn Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Cys Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Leu Gln Gly Ser Asp Ala Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 8 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L4 light chain variable region <400> 8 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Thr Thr Ser Asn Val Glu Lys Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ala Asn Asn Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Asp Ser Ser Leu 85 90 95 Ser Ala Val Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 9 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> L5 heavy chain variable region <400> 9 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 Thr Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Tyr Asp Ser Ser Ala Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Asn Ala Ser Asp Ser Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 10 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L5 light chain variable region <400> 10 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Thr Ser Asn Val Glu Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ser Asn Thr Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ala Val Trp Asp Asp Ser Leu 85 90 95 Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 11 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> L6 heavy chain variable region <400> 11 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 Asn Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Ser Ser Gly Ser Thr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Val Ile Gly Lys Asn Tyr Gly Arg Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 12 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L6 light chain variable region <400> 12 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Val Glu Thr Gln 20 25 30 Asp Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Gly Asn His Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Ser Ser Leu 85 90 95 Asn Ser Met Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 13 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> L7 heavy chain variable region <400> 13 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 Asn Tyr 20 25 30 Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Ser Ser Ser Gly Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Asn His Gly Val Leu His Tyr Lys Arg Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 14 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L7 light chain variable region <400> 14 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Val Glu Asn Asn 20 25 30 Ser Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Ser Asp Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Thr Trp Asp Asn Ser Ser 85 90 95 Asn Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 15 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> L8 heavy chain variable region <400> 15 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 Thr Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Asp Ser Ser Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Ile Ile Ser Gly Ser Asp Gly Leu Asp Val Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 16 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L8 light chain variable region <400> 16 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Val Glu Thr Asn 20 25 30 Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Gly Asn Val Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ala Ile Trp Asp Ser Ser Leu 85 90 95 Asn Gln Met Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 17 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> L9 heavy chain variable region <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 Asn Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Ser Ser Ser Ser Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Met Lys Gly Gly Trp Asn Val Leu Gly Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 18 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L9 light chain variable region <400> 18 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Thr Ser Asn Val Gly His His 20 25 30 Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ala Asn Asn Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Thr Trp Asp Asn Ser Leu 85 90 95 Lys Ala Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 19 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> L10 heavy chain variable region <400> 19 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 Asn Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Ser Gly Ser Ser Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Leu Tyr Ser Gly Phe Gly Leu Asp Leu Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 20 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L10 light chain variable region <400> 20 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Gly Ser Ser Asn Val Glu Glu Phe 20 25 30 Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Ser Arg Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ala Val Trp Asp Ser Ser Ser 85 90 95 Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 21 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> L11 heavy chain variable region <400> 21 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 Asn Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Ser Asp Ser Gly Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Ser Leu Gly Trp Gly Pro Arg Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 22 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L11 light chain variable region <400> 22 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Thr Ser Ser Asn Val Glu Asn Tyr 20 25 30 Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asn Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Ser Ser Leu 85 90 95 Asp Gly Trp Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 23 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> L12 heavy chain variable region <400> 23 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 Asn Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Ser Lys Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Ile Asp His Ile Tyr Arg Ser Asp Pro Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 24 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L12 light chain variable region <400> 24 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Val Glu Asn Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ser Asn Thr Glu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Tyr Asp Ser Ser Leu 85 90 95 Asp Glu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 25 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> L13 heavy chain variable region <400> 25 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 Ser Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Ser Ser Ala Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Tyr Met Ser Trp Pro Leu Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 26 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L13 light chain variable region <400> 26 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Thr Ser Asn Val Gly Asp Ser 20 25 30 Tyr Val Ala Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Glu Asp Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Trp Asp Gly Ser Leu 85 90 95 Ser Gly Leu Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 27 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> L14 heavy chain variable region <400> 27 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 Asn Tyr 20 25 30 Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Ser Gly Ser Ser Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Thr Leu Gly Ser Gly Gly Arg Asp His Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 28 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L14 light chain variable region <400> 28 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Val Glu Ser Asn 20 25 30 Ala Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ala Asn Asn Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Tyr Asp Lys Ser Ile 85 90 95 Asn Ser Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 29 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> L15 heavy chain variable region <400> 29 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 Thr Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Ser Ser Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly His Tyr Ser Phe Tyr Tyr Trp Pro Asn Ile Arg Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 30 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L15 light chain variable region <400> 30 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Val Glu Lys Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Thr Asn Asn Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Asp Ser Arg Leu 85 90 95 Asp His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 31 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> L16 heavy chain variable region <400> 31 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 Ser Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Tyr Asp Gly Ser Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Lys Glu Leu Trp Phe Ile Pro Thr Leu Gly Ser Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 32 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L16 light chain variable region <400> 32 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Ile Glu Thr Asn 20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asp Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp Asp Ala Leu 85 90 95 Asp His Trp Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 33 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> L17 heavy chain variable region <400> 33 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 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Tyr Asp Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Leu Asp Gln Leu Ser Arg Phe Arg Leu Leu Gly Ser Arg 100 105 110 Tyr Thr Val Thr Val Ser Ser 115 <210> 34 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L17 light chain variable region <400> 34 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Val Glu Ser Asn 20 25 30 Ala Val Gln Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asn Asn Thr Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Thr Trp Asp Ser Ser Leu 85 90 95 Asn Gly Trp Met Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 35 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> L18 heavy chain variable region <400> 35 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 Asn Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Ser Ser Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Pro Leu Ser Ser Trp Gly Trp Leu Asn Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 36 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L18 light chain variable region <400> 36 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Thr Ser Asn Ile Glu Ser Tyr 20 25 30 Asp Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Leu Gly Asn Ser Val Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Gly Trp Asp Asn Ser Leu 85 90 95 Asn Thr Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 37 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> L19 heavy chain variable region <400> 37 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 Ser Tyr 20 25 30 Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Ser Asp Ser Ser Thr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Met Gly Ala Tyr Xaa Asn Thr Leu Gly Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 38 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L19 light chain variable region <400> 38 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Val Gly Arg Asn 20 25 30 His Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Phe Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Asp Asp Ser Leu 85 90 95 Asn Gly Tyr Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 39 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> L20 heavy chain variable region <400> 39 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 Asp Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Ser Asp Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Arg Val Val His Gly Phe Tyr Leu Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 40 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L20 light chain variable region <400> 40 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Val Glu Val His 20 25 30 Thr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Ala Trp Asp Ser Ser Ile 85 90 95 Thr Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 41 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> L21 heavy chain variable region <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 Leu Thr Phe Ser Asn Tyr 20 25 30 Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Ser Ser Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Tyr Gly Val Asp Gly Leu Asp Phe Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 42 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L21 light chain variable region <400> 42 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Val Glu Tyr Asn 20 25 30 Ser Val Ala Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Phe Gly Asn Asn Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Asp Ser Asn Leu 85 90 95 Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 43 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> K1 heavy chain variable region <400> 43 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 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Ser Ser Gly Ser Thr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Pro Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Trp Lys Trp Pro Glu Thr Tyr Tyr Pro Asp Asp Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 44 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> K1 light chain variable region <400> 44 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Arg Ser Val Ser Ser Trp 20 25 30 Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Glu Ala Asn Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Arg Gln Ser Tyr Ser Phe Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 45 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> K2 heavy chain variable region <400> 45 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 Val 35 40 45 Ser Ala Ile Ser Ser Gly Ser Ser Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Thr Leu Asn Thr Gly Leu Gly Arg Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 46 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> K2 light chain variable region <400> 46 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Arg Ala Val Ser Thr His 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ser Asn Thr Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asp Ser Tyr Pro Gly 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 47 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> K3 heavy chain variable region <400> 47 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 Asn Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Tyr Gly Ser Gly Thr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Pro Leu Met Gln Ala Ile Leu Asp Val Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 48 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> K3 light chain variable region <400> 48 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Gly Val Ser Thr Ser 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Glu Ala Asn Lys Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Arg Gln Tyr Asp Asn Ala Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 49 <211> 123 <212> PRT <213> Artificial Sequence <220> <223> K4 heavy chain variable region <400> 49 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 Asn Tyr 20 25 30 Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Gly Gly Gly Lys Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Pro Tyr Ser Lys Gln Ser Lys Pro Asn Trp Val Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 50 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> K4 light chain variable region <400> 50 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Arg Ser Val Ser Asn Asp 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Asn Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Arg Gln His Phe Ser Ala Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 51 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> K5 heavy chain variable region <400> 51 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asn Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Ser Ser Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Trp Asp Trp Thr Ser Ala Gly Gln Asn Trp Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 52 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> K5 light chain variable region <400> 52 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Arg Ser Val Ser Asn Ser 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Gly Ala Asn Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Lys Ser Leu Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 53 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L1 heavy chain CDR1 <400> 53 Ala Tyr Tyr Met Ser 1 5 <210> 54 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L1 heavy chain CDR2 <400> 54 Ile Ser Ser Ser Gly Ser His Thr 1 5 <210> 55 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L1 heavy chain CDR3 <400> 55 Glu His Val Gly Gly Ser Asp Ala Phe Gly His 1 5 10 <210> 56 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L1 light chain CDR1 <400> 56 Ser Gly Ser Asn Ser Asn Val Glu Lys Tyr Thr Val Ser 1 5 10 <210> 57 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L1 light chain CDR2 <400> 57 Tyr Gly Asn Asn Gln Arg Pro Ser 1 5 <210> 58 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L1 light chain CDR3 <400> 58 Gln Ala Trp Asp Asp Ser Leu Asn Gly Tyr Val 1 5 10 <210> 59 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L2 heavy chain CDR1 <400> 59 Gly Tyr Ser Met Ser 1 5 <210> 60 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L2 heavy chain CDR2 <400> 60 Ile Ser Tyr Gly Gly Ser Asn Thr 1 5 <210> 61 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L2 heavy chain CDR3 <400> 61 Ser Lys Ser Ser Leu Tyr Ile Pro Asn Ser Tyr Asp Tyr 1 5 10 <210> 62 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L2 light chain CDR1 <400> 62 Ser Gly Gly Arg Ser Asn Val Glu Asn Asn Phe Val Asn 1 5 10 <210> 63 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L2 light chain CDR2 <400> 63 Tyr Lys Asp Gly Leu Arg Pro Ser 1 5 <210> 64 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L2 light chain CDR3 <400> 64 Gln Val Trp Asp Asp Ala Leu Ser Gly Trp Val 1 5 10 <210> 65 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L3 heavy chain CDR1 <400> 65 Thr Tyr Ala Met Ser 1 5 <210> 66 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L3 heavy chain CDR2 <400> 66 Ile Ser Ser Asp Gly Ser Ser Thr 1 5 <210> 67 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> L3 heavy chain CDR3 <400> 67 Asp Phe Thr Lys Gly Trp Val Asp Leu Phe Asp Val 1 5 10 <210> 68 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L3 light chain CDR1 <400> 68 Ser Gly Ser Ser Ser Asn Val Glu Ser Asn Tyr Val Ser 1 5 10 <210> 69 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> L3 light chain CDR2 <400> 69 Phe Asp Asn Ile Arg Pro Ser 1 5 <210> 70 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L3 light chain CDR3 <400> 70 Ser Thr Trp Asp Ser Ser Leu Thr Ala Pro Leu 1 5 10 <210> 71 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L4 heavy chain CDR1 <400> 71 Asn Tyr Ala Met Ser 1 5 <210> 72 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L4 heavy chain CDR2 <400> 72 Ile Ser Ser Ser Gly Gly Ser Thr 1 5 <210> 73 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L4 heavy chain CDR3 <400> 73 Glu Trp Leu Gln Gly Ser Asp Ala Phe Asp Tyr 1 5 10 <210> 74 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L4 light chain CDR1 <400> 74 Ser Gly Thr Thr Ser Asn Val Glu Lys Asn Thr Val Asn 1 5 10 <210> 75 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L4 light chain CDR2 <400> 75 Tyr Ala Asn Asn Leu Arg Pro Ser 1 5 <210> 76 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L4 light chain CDR3 <400> 76 Ala Ser Trp Asp Ser Ser Leu Ser Ala Val Leu 1 5 10 <210> 77 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L5 heavy chain CDR1 <400> 77 Thr Tyr Asp Met Ser 1 5 <210> 78 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L5 heavy chain CDR2 <400> 78 Ile Ser Tyr Asp Ser Ser Ala Thr 1 5 <210> 79 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> L5 heavy chain CDR3 <400> 79 Ala Gly Asn Ala Ser Asp Ser Phe Asp Tyr 1 5 10 <210> 80 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L5 light chain CDR1 <400> 80 Ser Gly Ser Thr Ser Asn Val Glu Asn Asn Tyr Val Ser 1 5 10 <210> 81 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L5 light chain CDR2 <400> 81 Tyr Ser Asn Thr Lys Arg Pro Ser 1 5 <210> 82 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L5 light chain CDR3 <400> 82 Ala Val Trp Asp Asp Ser Leu Asn Gly Tyr Val 1 5 10 <210> 83 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L6 heavy chain CDR1 <400> 83 Asn Tyr Tyr Met Ser 1 5 <210> 84 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L6 heavy chain CDR2 <400> 84 Ile Ser Ser Ser Gly Ser Thr Thr 1 5 <210> 85 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L6 heavy chain CDR3 <400> 85 Glu Val Ile Gly Lys Asn Tyr Gly Arg Asp Tyr 1 5 10 <210> 86 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L6 light chain CDR1 <400> 86 Ser Gly Ser Asn Ser Asn Val Glu Thr Gln Asp Val Ser 1 5 10 <210> 87 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L6 light chain CDR2 <400> 87 Tyr Gly Asn His Gln Arg Pro Ser 1 5 <210> 88 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L6 light chain CDR3 <400> 88 Gly Ser Trp Asp Ser Ser Leu Asn Ser Met Val 1 5 10 <210> 89 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L7 heavy chain CDR1 <400> 89 Asn Tyr Ser Met Ser 1 5 <210> 90 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L7 heavy chain CDR2 <400> 90 Ile Ser Ser Ser Ser Gly Asn Thr 1 5 <210> 91 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> L7 heavy chain CDR3 <400> 91 Gly Asn His Gly Val Leu His Tyr Lys Arg Asp Tyr 1 5 10 <210> 92 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L7 light chain CDR1 <400> 92 Ser Gly Ser Asn Ser Asn Val Glu Asn Asn Ser Val Asn 1 5 10 <210> 93 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L7 light chain CDR2 <400> 93 Tyr Asp Ser Asp Gln Arg Pro Ser 1 5 <210> 94 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L7 light chain CDR3 <400> 94 Gln Thr Trp Asp Asn Ser Ser Asn Gly Trp Val 1 5 10 <210> 95 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L8 heavy chain CDR2 <400> 95 Ile Ser Gly Asp Ser Ser Ser Thr 1 5 <210> 96 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L8 heavy chain CDR3 <400> 96 Glu Ile Ile Ser Gly Ser Asp Gly Leu Asp Val 1 5 10 <210> 97 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L8 light chain CDR1 <400> 97 Ser Gly Ser Ser Ser Asn Val Glu Thr Asn Ser Val Ser 1 5 10 <210> 98 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L8 light chain CDR2 <400> 98 Tyr Gly Asn Val Leu Arg Pro Ser 1 5 <210> 99 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L8 light chain CDR3 <400> 99 Ala Ile Trp Asp Ser Ser Leu Asn Gln Met Val 1 5 10 <210> 100 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L9 heavy chain CDR2 <400> 100 Ile Ser Ser Ser Ser Ser Asn Thr 1 5 <210> 101 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> L9 heavy chain CDR3 <400> 101 Asp Leu Met Lys Gly Gly Trp Asn Val Leu Gly Tyr 1 5 10 <210> 102 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L9 light chain CDR1 <400> 102 Ser Gly Ser Thr Ser Asn Val Gly His His Tyr Val Asn 1 5 10 <210> 103 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L9 light chain CDR3 <400> 103 Gln Thr Trp Asp Asn Ser Leu Lys Ala Val Val 1 5 10 <210> 104 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L10 heavy chain CDR2 <400> 104 Ile Ser Ser Gly Ser Ser Asn Thr 1 5 <210> 105 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> L10 heavy chain CDR3 <400> 105 Glu Leu Tyr Ser Gly Phe Gly Leu Asp Leu 1 5 10 <210> 106 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L10 light chain CDR1 <400> 106 Ser Gly Gly Ser Ser Asn Val Glu Glu Phe Tyr Val Asn 1 5 10 <210> 107 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L10 light chain CDR2 <400> 107 Ser Arg Asn Asn Lys Arg Pro Ser 1 5 <210> 108 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L10 light chain CDR3 <400> 108 Ala Val Trp Asp Ser Ser Ser Ser Gly Tyr Val 1 5 10 <210> 109 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L11 heavy chain CDR2 <400> 109 Ile Ser Ser Asp Ser Gly Asn Thr 1 5 <210> 110 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> L11 heavy chain CDR3 <400> 110 Glu Ser Leu Gly Trp Gly Pro Arg Asp Tyr 1 5 10 <210> 111 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L11 light chain CDR1 <400> 111 Ser Gly Thr Ser Ser Asn Val Glu Asn Tyr Tyr Val Asn 1 5 10 <210> 112 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L11 light chain CDR2 <400> 112 Tyr Tyr Asp Asn Gln Arg Pro Ser 1 5 <210> 113 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L11 light chain CDR3 <400> 113 Ala Thr Trp Asp Ser Ser Leu Asp Gly Trp Leu 1 5 10 <210> 114 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L12 heavy chain CDR1 <400> 114 Asn Tyr Asp Met Ser 1 5 <210> 115 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L12 heavy chain CDR2 <400> 115 Ile Ser Gly Ser Gly Ser Lys Thr 1 5 <210> 116 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> L12 heavy chain CDR3 <400> 116 Leu Ile Asp His Ile Tyr Arg Ser Asp Pro 1 5 10 <210> 117 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L12 light chain CDR1 <400> 117 Ser Gly Ser Ser Ser Asn Val Glu Asn Asn Thr Val Asn 1 5 10 <210> 118 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L12 light chain CDR2 <400> 118 Tyr Ser Asn Thr Glu Arg Pro Ser 1 5 <210> 119 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L12 light chain CDR3 <400> 119 Ala Ser Tyr Asp Ser Ser Leu Asp Glu Trp Val 1 5 10 <210> 120 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L13 heavy chain CDR1 <400> 120 Ser Tyr Asp Met Ser 1 5 <210> 121 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L13 heavy chain CDR2 <400> 121 Ile Ser Gly Ser Ser Ser Ala Thr 1 5 <210> 122 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> L13 heavy chain CDR3 <400> 122 Ala Tyr Met Ser Trp Pro Leu Met Asp Tyr 1 5 10 <210> 123 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L13 light chain CDR1 <400> 123 Ser Gly Ser Thr Ser Asn Val Gly Asp Ser Tyr Val Ala 1 5 10 <210> 124 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L13 light chain CDR2 <400> 124 Tyr Glu Asp Asn Lys Arg Pro Ser 1 5 <210> 125 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L13 light chain CDR3 <400> 125 Ser Ser Trp Asp Gly Ser Leu Ser Gly Leu Leu 1 5 10 <210> 126 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L14 heavy chain CDR1 <400> 126 Asn Tyr Val Met Ser 1 5 <210> 127 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L14 heavy chain CDR2 <400> 127 Ile Ser Ser Gly Ser Ser Ser Thr 1 5 <210> 128 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> L14 heavy chain CDR3 <400> 128 Glu Thr Leu Gly Ser Gly Gly Arg Asp His 1 5 10 <210> 129 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L14 light chain CDR1 <400> 129 Ser Gly Ser Ser Ser Asn Val Glu Ser Asn Ala Val Asn 1 5 10 <210> 130 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L14 light chain CDR2 <400> 130 Tyr Ala Asn Asn Gln Arg Pro Ser 1 5 <210> 131 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L14 light chain CDR3 <400> 131 Gln Ala Tyr Asp Lys Ser Ile Asn Ser Trp Val 1 5 10 <210> 132 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L15 heavy chain CDR2 <400> 132 Ile Ser Ser Ser Gly Ser Asn Thr 1 5 <210> 133 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L15 heavy chain CDR3 <400> 133 Gly His Tyr Ser Phe Tyr Tyr Trp Pro Asn Ile 1 5 10 <210> 134 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L15 light chain CDR1 <400> 134 Ser Gly Ser Asn Ser Asn Val Glu Lys Asn Thr Val Asn 1 5 10 <210> 135 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L15 light chain CDR2 <400> 135 Tyr Thr Asn Asn Leu Arg Pro Ser 1 5 <210> 136 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L15 light chain CDR3 <400> 136 Ala Ser Trp Asp Ser Arg Leu Asp His Trp Val 1 5 10 <210> 137 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L16 heavy chain CDR1 <400> 137 Ser Tyr Tyr Met Ser 1 5 <210> 138 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L16 heavy chain CDR2 <400> 138 Ile Ser Tyr Asp Gly Ser Tyr Thr 1 5 <210> 139 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> L16 heavy chain CDR3 <400> 139 Arg Lys Glu Leu Trp Phe Ile Pro Thr Leu Gly Ser 1 5 10 <210> 140 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L16 light chain CDR1 <400> 140 Ser Gly Ser Asn Ser Asn Ile Glu Thr Asn Thr Val Asn 1 5 10 <210> 141 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L16 light chain CDR2 <400> 141 Tyr Asp Asp Asn Asn Arg Pro Ser 1 5 <210> 142 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L16 light chain CDR3 <400> 142 Gln Ala Trp Asp Asp Ala Leu Asp His Trp Ile 1 5 10 <210> 143 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L17 heavy chain CDR1 <400> 143 Asp Tyr Ala Met Ser 1 5 <210> 144 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L17 heavy chain CDR2 <400> 144 Ile Ser Tyr Asp Gly Ser Asn Thr 1 5 <210> 145 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> L17 heavy chain CDR3 <400> 145 Gly Leu Asp Gln Leu Ser Arg Phe Arg Leu 1 5 10 <210> 146 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L17 light chain CDR1 <400> 146 Ser Gly Ser Asn Ser Asn Val Glu Ser Asn Ala Val Gln 1 5 10 <210> 147 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L17 light chain CDR2 <400> 147 Tyr Asn Asn Thr Gln Arg Pro Ser 1 5 <210> 148 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L17 light chain CDR3 <400> 148 Gln Thr Trp Asp Ser Ser Leu Asn Gly Trp Met 1 5 10 <210> 149 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L18 heavy chain CDR2 <400> 149 Ile Ser Ser Ser Gly Ser Ser Thr 1 5 <210> 150 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> L18 heavy chain CDR3 <400> 150 Asp Leu Pro Leu Ser Ser Trp Gly Trp Leu Asn Tyr 1 5 10 <210> 151 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L18 light chain CDR1 <400> 151 Ser Gly Ser Thr Ser Asn Ile Glu Ser Tyr Asp Val Asn 1 5 10 <210> 152 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L18 light chain CDR2 <400> 152 Leu Gly Asn Ser Val Arg Pro Ser 1 5 <210> 153 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L18 light chain CDR3 <400> 153 Gly Gly Trp Asp Asn Ser Leu Asn Thr Leu Val 1 5 10 <210> 154 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L19 heavy chain CDR1 <400> 154 Ser Tyr Ser Met Ser 1 5 <210> 155 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L19 heavy chain CDR2 <400> 155 Ile Ser Ser Asp Ser Ser Thr Thr 1 5 <210> 156 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L19 heavy chain CDR3 <400> 156 Asp Met Gly Ala Tyr Xaa Asn Thr Leu Gly Tyr 1 5 10 <210> 157 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L19 light chain CDR1 <400> 157 Ser Gly Ser Ser Ser Asn Val Gly Arg Asn His Val Ser 1 5 10 <210> 158 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L19 light chain CDR2 <400> 158 Phe Asp Asn Asn Lys Arg Pro Ser 1 5 <210> 159 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L19 light chain CDR3 <400> 159 Ala Ser Trp Asp Asp Ser Leu Asn Gly Tyr Leu 1 5 10 <210> 160 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L20 heavy chain CDR1 <400> 160 Ser Tyr Ala Met Ser 1 5 <210> 161 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L20 heavy chain CDR2 <400> 161 Ile Ser Ser Asp Gly Ser Asn Thr 1 5 <210> 162 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L20 heavy chain CDR3 <400> 162 Glu Arg Val Val His Gly Phe Tyr Leu Asp Tyr 1 5 10 <210> 163 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L20 light chain CDR1 <400> 163 Ser Gly Ser Ser Ser Asn Val Glu Val His Thr Val Ser 1 5 10 <210> 164 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L20 light chain CDR2 <400> 164 Tyr Arg Asn Asn Gln Arg Pro Ser 1 5 <210> 165 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L20 light chain CDR3 <400> 165 Gly Ala Trp Asp Ser Ser Ile Thr Gly Pro Val 1 5 10 <210> 166 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> L21 heavy chain CDR3 <400> 166 Asp Ser Tyr Gly Val Asp Gly Leu Asp Phe 1 5 10 <210> 167 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L21 light chain CDR1 <400> 167 Ser Gly Ser Asn Ser Asn Val Glu Tyr Asn Ser Val Ala 1 5 10 <210> 168 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L21 light chain CDR2 <400> 168 Phe Gly Asn Asn Leu Arg Pro Ser 1 5 <210> 169 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L21 light chain CDR3 <400> 169 Ala Ser Trp Asp Ser Asn Leu Asn Gly Tyr Val 1 5 10 <210> 170 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> K1 heavy chain CDR1 <400> 170 Asp Tyr Asp Met Ser 1 5 <210> 171 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> K1 heavy chain CDR3 <400> 171 Gly Trp Lys Trp Pro Glu Thr Tyr Tyr Pro Asp Asp 1 5 10 <210> 172 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> K1 light chain CDR1 <400> 172 Ser Ala Ser Arg Ser Val Ser Ser Trp Leu Asp 1 5 10 <210> 173 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> K1 light chain CDR2 <400> 173 Glu Ala Asn Ser Leu Ala Asp 1 5 <210> 174 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> K1 light chain CDR3 <400> 174 Arg Gln Ser Tyr Ser Phe Pro Tyr 1 5 <210> 175 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> K2 heavy chain CDR1 <400> 175 Asp Tyr Tyr Met Ser 1 5 <210> 176 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> K2 heavy chain CDR3 <400> 176 Glu Thr Leu Asn Thr Gly Leu Gly Arg Asp Tyr 1 5 10 <210> 177 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> K2 light chain CDR1 <400> 177 Ser Ala Ser Arg Ala Val Ser Thr His Leu Ala 1 5 10 <210> 178 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> K2 light chain CDR2 <400> 178 Asp Ser Asn Thr Leu His Ser 1 5 <210> 179 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> K2 light chain CDR3 <400> 179 Leu Gln His Asp Ser Tyr Pro Gly 1 5 <210> 180 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> K3 heavy chain CDR2 <400> 180 Ile Ser Tyr Gly Ser Gly Thr Thr 1 5 <210> 181 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> K3 heavy chain CDR3 <400> 181 Leu Pro Leu Met Gln Ala Ile Leu Asp Val 1 5 10 <210> 182 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> K3 light chain CDR1 <400> 182 Ser Ala Ser Gln Gly Val Ser Thr Ser Leu Ser 1 5 10 <210> 183 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> K3 light chain CDR2 <400> 183 Glu Ala Asn Lys Leu Glu Ser 1 5 <210> 184 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> K3 light chain CDR3 <400> 184 Arg Gln Tyr Asp Asn Ala Pro Tyr 1 5 <210> 185 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> K4 heavy chain CDR2 <400> 185 Ile Ser Gly Gly Gly Gly Lys Thr 1 5 <210> 186 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> K4 heavy chain CDR3 <400> 186 Pro Tyr Ser Lys Gln Ser Lys Pro Asn Trp Val Phe Asp Tyr 1 5 10 <210> 187 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> K4 light chain CDR1 <400> 187 Ser Ala Ser Arg Ser Val Ser Asn Asp Leu Asn 1 5 10 <210> 188 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> K4 light chain CDR2 <400> 188 Ala Ala Asn Thr Leu Gln Ser 1 5 <210> 189 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> K4 light chain CDR3 <400> 189 Arg Gln His Phe Ser Ala Pro Leu 1 5 <210> 190 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> K5 heavy chain CDR3 <400> 190 Gly Trp Asp Trp Thr Ser Ala Gly Gln Asn 1 5 10 <210> 191 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> K5 light chain CDR1 <400> 191 Ser Ala Ser Arg Ser Val Ser Asn Ser Leu Asn 1 5 10 <210> 192 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> K5 light chain CDR2 <400> 192 Gly Ala Asn Asn Leu Glu Ser 1 5 <210> 193 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> K5 light chain CDR3 <400> 193 Leu Gln Tyr Lys Ser Leu Pro Leu 1 5 <110> Mogam Institute for Biomedical Research <120> Novel Antibody Against AXL and Pharmaceutical Composition          Comprising the Same <130> 16P10049 <160> 193 <170> KoPatentin 3.0 <210> 1 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> L1 heavy chain variable region <400> 1 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 Ala Tyr              20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Ser Ser Gly Ser His Thr Tyr Tyr Ala Asp Ser Val      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Glu His Val Gly Gly Ser Asp Ala Phe Gly His Trp Gly Gln             100 105 110 Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 2 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L1 light chain variable region <400> 2 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Val Glu Lys Tyr              20 25 30 Thr Val Ser Trp Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Gly Asn Asn Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser      50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln  65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp Asp Ser Leu                  85 90 95 Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 3 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> L2 heavy chain variable region <400> 3 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 Gly Tyr              20 25 30 Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Tyr Gly Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Ser Ser Ser Ser Leu Tyr Ile Pro Asn Ser Tyr Asp Tyr Trp             100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 4 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L2 light chain variable region <400> 4 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Gly Arg Ser Ser Val Val Glu Asn Asn              20 25 30 Phe Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Lys Asp Gly Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser      50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln  65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Asp Ala Leu                  85 90 95 Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 5 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> L3 heavy chain variable region <400> 5 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 Thr Tyr              20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Lys Trp Val          35 40 45 Ser Ala Ile Ser Ser Asp Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Asp Phe Thr Lys Gly Trp Val Asp Leu Phe Asp Val Trp Gly             100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 6 <211> 110 <212> PRT <213> Artificial Sequence <220> <223> L3 light chain variable region <400> 6 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Val Glu Ser Asn              20 25 30 Tyr Val Ser Trp Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Phe Asp Asn Ile Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly      50 55 60 Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln Thr  65 70 75 80 Gly Asp Glu Ala Asp Tyr Tyr Cys Ser Thr Trp Asp Ser Ser Leu Thr                  85 90 95 Ala Pro Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 7 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> L4 heavy chain variable region <400> 7 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 Asn Tyr              20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Cys Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Glu Trp Leu Gln Gly Ser Asp Ala Phe Asp Tyr Trp Gly Gln             100 105 110 Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 8 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L4 light chain variable region <400> 8 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Thr Thr Ser Asn Val Glu Lys Asn              20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Ala Asn Asn Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser      50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln  65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Asp Ser Ser Leu                  85 90 95 Ser Ala Val Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 9 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> L5 heavy chain variable region <400> 9 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 Thr Tyr              20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Tyr Asp Ser Ser Ala      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Ala Gly Asn Ala Ser Asp Ser Phe Asp Tyr Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 10 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L5 light chain variable region <400> 10 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Thr Ser Asn Val Glu Asn Asn              20 25 30 Tyr Val Ser Trp Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Ser Asn Thr Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser      50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln  65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ala Val Trp Asp Asp Ser Leu                  85 90 95 Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 11 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> L6 heavy chain variable region <400> 11 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 Asn Tyr              20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Ser Ser Ser Ser Thr Thr Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Glu Val Ile Gly Lys Asn Tyr Gly Arg Asp Tyr Trp Gly Gln             100 105 110 Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 12 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L6 light chain variable region <400> 12 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Val Glu Thr Gln              20 25 30 Asp Val Ser Trp Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Gly Asn His Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser      50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln  65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Ser Ser Leu                  85 90 95 Asn Ser Met Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 13 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> L7 heavy chain variable region <400> 13 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 Asn Tyr              20 25 30 Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Ser Ser Gly Asn Thr Tyr Tyr Ala Asp Ser Val      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Gly Asn His Gly Val Leu His Tyr Lys Arg Asp Tyr Trp Gly             100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 14 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L7 light chain variable region <400> 14 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Val Glu Asn Asn              20 25 30 Ser Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Asp Ser Asp Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser      50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln  65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Thr Trp Asp Ser Ser Ser                  85 90 95 Asn Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 15 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> L8 heavy chain variable region <400> 15 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 Thr Tyr              20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Gly Asp Ser Ser Ser Thr Tyr Tyr Ala Asp Ser Val      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Glu Ile Ile Ser Gly Ser Asp Gly Leu Asp Val Trp Gly Gln             100 105 110 Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 16 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L8 light chain variable region <400> 16 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Val Glu Thr Asn              20 25 30 Ser Val Ser Trp Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Gly Asn Val Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser      50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln  65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ala Ile Trp Asp Ser Ser Leu                  85 90 95 Asn Gln Met Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 17 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> L9 heavy chain variable region <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 Asn Tyr              20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Ser Ser Ser Asn Thr Tyr      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Asp Leu Met Lys Gly Gly Trp Asn Val Leu Gly Tyr Trp Gly             100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 18 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L9 light chain variable region <400> 18 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Thr Ser Asn Val Gly His His              20 25 30 Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Ala Asn Asn Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser      50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln  65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Thr Trp Asp Asn Ser Leu                  85 90 95 Lys Ala Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 19 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> L10 heavy chain variable region <400> 19 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 Asn Tyr              20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Ser Gly Ser Ser Asn Thr Tyr Tyr Ala Asp Ser Val      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Glu Leu Tyr Ser Gly Phe Gly Leu Asp Leu Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 20 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L10 light chain variable region <400> 20 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Gly Ser Ser Asn Val Glu Glu Phe              20 25 30 Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Ser Arg Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser      50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln  65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ala Val Trp Asp Ser Ser Ser                  85 90 95 Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 21 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> L11 heavy chain variable region <400> 21 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 Asn Tyr              20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Ser Asp Ser Gly Asn Thr Tyr Tyr Ala Asp Ser Val      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Glu Ser Leu Gly Trp Gly Pro Arg Asp Tyr Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 22 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L11 light chain variable region <400> 22 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Thr Ser Ser Asn Val Glu Asn Tyr              20 25 30 Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Tyr Asp Asn Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser      50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln  65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Ser Seru                  85 90 95 Asp Gly Trp Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 23 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> L12 heavy chain variable region <400> 23 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 Asn Tyr              20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Leu Ile Asp His Ile Tyr Arg Ser Asp Pro Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 24 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L12 light chain variable region <400> 24 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Val Glu Asn Asn              20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Ser Asn Thr Glu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser      50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln  65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Tyr Asp Ser Ser Leu                  85 90 95 Asp Glu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 25 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> L13 heavy chain variable region <400> 25 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 Ser Tyr              20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ala      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Ala Tyr Met Ser Trp Pro Leu Met Asp Tyr Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 26 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L13 light chain variable region <400> 26 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Thr Ser Asn Val Gly Asp Ser              20 25 30 Tyr Val Ala Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Glu Asp Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser      50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln  65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Trp Asp Gly Ser Leu                  85 90 95 Ser Gly Leu Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 27 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> L14 heavy chain variable region <400> 27 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 Asn Tyr              20 25 30 Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Tyr      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Glu Thr Leu Gly Ser Gly Gly Arg Asp His Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 28 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L14 light chain variable region <400> 28 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Val Glu Ser Asn              20 25 30 Ala Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Ala Asn Asn Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser      50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln  65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Tyr Asp Lys Ser Ile                  85 90 95 Asn Ser Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 29 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> L15 heavy chain variable region <400> 29 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 Thr Tyr              20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Ser Ser Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Gly His Tyr Ser Phe Tyr Tyr Trp Pro Asn Ile Arg Gly Gln             100 105 110 Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 30 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L15 light chain variable region <400> 30 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Val Glu Lys Asn              20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Thr Asn Asn Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser      50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln  65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Asp Ser Arg Leu                  85 90 95 Asp His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 31 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> L16 heavy chain variable region <400> 31 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 Ser Tyr              20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Tyr Asp Gly Ser Tyr Thr Tyr Tyr Ala Asp Ser Val      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Arg Lys Glu Leu Trp Phe Ile Pro Thr Leu Gly Ser Trp Gly             100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 32 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L16 light chain variable region <400> 32 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Ile Glu Thr Asn              20 25 30 Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Asp Asp Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser      50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln  65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp Asp Ala Leu                  85 90 95 Asp His Trp Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 33 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> L17 heavy chain variable region <400> 33 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 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Tyr Asp Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Gly Leu Asp Gln Leu Ser Arg Phe Arg Leu Leu Gly Ser Arg             100 105 110 Tyr Thr Val Thr Val Ser Ser         115 <210> 34 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L17 light chain variable region <400> 34 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Val Glu Ser Asn              20 25 30 Ala Val Gln Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Asn Asn Thr Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser      50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln  65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Thr Trp Asp Ser Ser Leu                  85 90 95 Asn Gly Trp Met Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 35 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> L18 heavy chain variable region <400> 35 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 Asn Tyr              20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Ser Ser Ser Ser Thr Ser Ser Ser Ser Tyr      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Asp Leu Pro Leu Ser Ser Trp Gly Trp Leu Asn Tyr Trp Gly             100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 36 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L18 light chain variable region <400> 36 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Thr Ser Asn Ile Glu Ser Tyr              20 25 30 Asp Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Leu Gly Asn Ser Val Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser      50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln  65 70 75 80 Thr Gly Asp Gly Ala Asp Tyr Tyr Cys Gly Gly Trp Asp Asn Ser Leu                  85 90 95 Asn Thr Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 37 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> L19 heavy chain variable region <400> 37 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 Ser Tyr              20 25 30 Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Ser As Ser Ser Thr Thr Tyr Tyr Ala Asp Ser Val      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Asp Met Gly Ala Tyr Xaa Asn Thr Leu Gly Tyr Trp Gly Gln             100 105 110 Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 38 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L19 light chain variable region <400> 38 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Val Gly Arg Asn              20 25 30 His Val Ser Trp Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Phe Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser      50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln  65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Asp Asp Ser Leu                  85 90 95 Asn Gly Tyr Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 39 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> L20 heavy chain variable region <400> 39 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 Asp Phe Thr Phe Ser Ser Tyr              20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ser Ser Asp Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Glu Arg Val Val His Gly Phe Tyr Leu Asp Tyr Trp Gly Gln             100 105 110 Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 40 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L20 light chain variable region <400> 40 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Val Glu Val His              20 25 30 Thr Val Ser Trp Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser      50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln  65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Ala Trp Asp Ser Ser Ile                  85 90 95 Thr Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 41 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> L21 heavy chain variable region <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 Leu Thr Phe Ser Asn Tyr              20 25 30 Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Ser Ser Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Asp Ser Tyr Gly Val Asp Gly Leu Asp Phe Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 42 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> L21 light chain variable region <400> 42 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Pro Gly Gln   1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Val Glu Tyr Asn              20 25 30 Ser Val Ala Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu          35 40 45 Ile Phe Gly Asn Asn Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser      50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln  65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Asp Ser Asn Leu                  85 90 95 Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly             100 105 110 <210> 43 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> K1 heavy chain variable region <400> 43 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 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Ser Ser Ser Ser Thr Thr Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Pro Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Gly Trp Lys Trp Pro Glu Thr Tyr Tyr Pro Asp Asp Trp Gly             100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 44 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> K1 light chain variable region <400> 44 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 Ser Ala Ser Arg Ser Val Ser Ser Trp              20 25 30 Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile          35 40 45 Tyr Glu Ala Asn Ser Leu Ala Asp Gly Val Ser Ser Arg Phe Ser Gly      50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro  65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Arg Gln Ser Tyr Ser Phe Pro Tyr                  85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg             100 105 <210> 45 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> K2 heavy chain variable region <400> 45 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 Val          35 40 45 Ser Ala Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Tyr      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Glu Thr Leu Asn Thr Gly Leu Gly Arg Asp Tyr Trp Gly Gln             100 105 110 Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 46 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> K2 light chain variable region <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 Ser Ala Ser Arg Ala Val Ser Thr His              20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile          35 40 45 Tyr Asp Ser Asn Thr Leu His Ser Gly Val Ser Ser Arg Phe Ser Gly      50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro  65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asp Ser Tyr Pro Gly                  85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg             100 105 <210> 47 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> K3 heavy chain variable region <400> 47 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 Asn Tyr              20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Tyr Gly Ser Gly Thr Thr Tyr Tyr Ala Asp Ser Val      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Leu Pro Leu Met Gln Ala Ile Leu Asp Val Trp Gly Gln Gly             100 105 110 Thr Leu Val Thr Val Ser Ser         115 <210> 48 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> K3 light chain variable region <400> 48 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 Ser Ala Ser Gln Gly Val Ser Thr Ser              20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile          35 40 45 Tyr Glu Ala Asn Lys Leu Glu Ser Gly Val Ser Ser Phe Ser Gly      50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro  65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Arg Gln Tyr Asp Asn Ala Pro Tyr                  85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg             100 105 <210> 49 <211> 123 <212> PRT <213> Artificial Sequence <220> <223> K4 heavy chain variable region <400> 49 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 Asn Tyr              20 25 30 Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Gly Gly Gly Gly Lys Thr Tyr Tyr Ala Asp Ser Val      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Pro Tyr Ser Lys Gln Ser Lys Pro Asn Trp Val Phe Asp Tyr             100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser         115 120 <210> 50 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> K4 light chain variable region <400> 50 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 Ser Ala Ser Arg Ser Val Ser Asn Asp              20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile          35 40 45 Tyr Ala Ala Asn Thr Leu Gln Ser Gly Val Ser Ser Arg Phe Ser Gly      50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro  65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Arg Gln His Phe Ser Ala Pro Leu                  85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg             100 105 <210> 51 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> K5 heavy chain variable region <400> 51 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly   1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asn Tyr              20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val          35 40 45 Ser Ala Ile Ser Ser Ser Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val      50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr  65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                  85 90 95 Ala Arg Gly Trp Asp Trp Thr Ser Ala Gly Gln Asn Trp Gln Gly Thr             100 105 110 Leu Val Thr Val Ser Ser         115 <210> 52 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> K5 light chain variable region <400> 52 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 Ser Ala Ser Arg Ser Val Ser Asn Ser              20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile          35 40 45 Tyr Gly Ala Asn Asn Leu Glu Ser Gly Val Ser Ser Phe Ser Gly      50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro  65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Lys Ser Leu Pro Leu                  85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg             100 105 <210> 53 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L1 heavy chain CDR1 <400> 53 Ala Tyr Tyr Met Ser   1 5 <210> 54 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L1 heavy chain CDR2 <400> 54 Ile Ser Ser Ser Gly Ser His Thr   1 5 <210> 55 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L1 heavy chain CDR3 <400> 55 Glu His Val Gly Gly Ser Asp Ala Phe Gly His   1 5 10 <210> 56 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L1 light chain CDR1 <400> 56 Ser Gly Ser Asn Ser Asn Val Glu Lys Tyr Thr Val Ser   1 5 10 <210> 57 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L1 light chain CDR2 <400> 57 Tyr Gly Asn Asn Gln Arg Pro Ser   1 5 <210> 58 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L1 light chain CDR3 <400> 58 Gln Ala Trp Asp Asp Ser Leu Asn Gly Tyr Val   1 5 10 <210> 59 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L2 heavy chain CDR1 <400> 59 Gly Tyr Ser Met Ser   1 5 <210> 60 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L2 heavy chain CDR2 <400> 60 Ile Ser Tyr Gly Gly Ser Asn Thr   1 5 <210> 61 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L2 heavy chain CDR3 <400> 61 Ser Lys Ser Ser Leu Tyr Ile Pro Asn Ser Tyr Asp Tyr   1 5 10 <210> 62 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L2 light chain CDR1 <400> 62 Ser Gly Gly Arg Ser Ser Val Val Glu Asn Asn Phe Val Asn   1 5 10 <210> 63 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L2 light chain CDR2 <400> 63 Tyr Lys Asp Gly Leu Arg Pro Ser   1 5 <210> 64 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L2 light chain CDR3 <400> 64 Gln Val Trp Asp Asp Ala Leu Ser Gly Trp Val   1 5 10 <210> 65 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L3 heavy chain CDR1 <400> 65 Thr Tyr Ala Met Ser   1 5 <210> 66 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L3 heavy chain CDR2 <400> 66 Ile Ser Ser Asp Gly Ser Ser Thr   1 5 <210> 67 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> L3 heavy chain CDR3 <400> 67 Asp Phe Thr Lys Gly Trp Val Asp Leu Phe Asp Val   1 5 10 <210> 68 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L3 light chain CDR1 <400> 68 Ser Gly Ser Ser Ser Asn Val Glu Ser Asn Tyr Val Ser   1 5 10 <210> 69 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> L3 light chain CDR2 <400> 69 Phe Asp Asn Ile Arg Pro Ser   1 5 <210> 70 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L3 light chain CDR3 <400> 70 Ser Thr Trp Asp Ser Ser Leu Thr Ala Pro Leu   1 5 10 <210> 71 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L4 heavy chain CDR1 <400> 71 Asn Tyr Ala Met Ser   1 5 <210> 72 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L4 heavy chain CDR2 <400> 72 Ile Ser Ser Ser Gly Gly Ser Thr   1 5 <210> 73 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L4 heavy chain CDR3 <400> 73 Glu Trp Leu Gln Gly Ser Asp Ala Phe Asp Tyr   1 5 10 <210> 74 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L4 light chain CDR1 <400> 74 Ser Gly Thr Thr Ser Asn Val Glu Lys Asn Thr Val Asn   1 5 10 <210> 75 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L4 light chain CDR2 <400> 75 Tyr Ala Asn Asn Leu Arg Pro Ser   1 5 <210> 76 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L4 light chain CDR3 <400> 76 Ala Ser Trp Asp Ser Ser Leu Ser Ala Val Leu   1 5 10 <210> 77 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L5 heavy chain CDR1 <400> 77 Thr Tyr Asp Met Ser   1 5 <210> 78 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L5 heavy chain CDR2 <400> 78 Ile Ser Tyr Asp Ser Ser Ala Thr   1 5 <210> 79 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> L5 heavy chain CDR3 <400> 79 Ala Gly Asn Ala Ser Asp Ser Phe Asp Tyr   1 5 10 <210> 80 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L5 light chain CDR1 <400> 80 Ser Gly Ser Thr Ser Asn Val Glu Asn Asn Tyr Val Ser   1 5 10 <210> 81 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L5 light chain CDR2 <400> 81 Tyr Ser Asn Thr Lys Arg Pro Ser   1 5 <210> 82 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L5 light chain CDR3 <400> 82 Ala Val Trp Asp Asp Ser Leu Asn Gly Tyr Val   1 5 10 <210> 83 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L6 heavy chain CDR1 <400> 83 Asn Tyr Tyr Met Ser   1 5 <210> 84 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L6 heavy chain CDR2 <400> 84 Ile Ser Ser Ser Gly Ser Thr Thr   1 5 <210> 85 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L6 heavy chain CDR3 <400> 85 Glu Val Ile Gly Lys Asn Tyr Gly Arg Asp Tyr   1 5 10 <210> 86 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L6 light chain CDR1 <400> 86 Ser Gn Ser Ser Ser Val Ser Ser Val Ser Ser Val Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser   1 5 10 <210> 87 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L6 light chain CDR2 <400> 87 Tyr Gly Asn His Gln Arg Pro Ser   1 5 <210> 88 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L6 light chain CDR3 <400> 88 Gly Ser Trp Asp Ser Ser Leu Asn Ser Ser Val   1 5 10 <210> 89 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L7 heavy chain CDR1 <400> 89 Asn Tyr Ser Met Ser   1 5 <210> 90 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L7 heavy chain CDR2 <400> 90 Ile Ser Ser Ser Ser Gly Asn Thr   1 5 <210> 91 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> L7 heavy chain CDR3 <400> 91 Gly Asn His Gly Val Leu His Tyr Lys Arg Asp Tyr   1 5 10 <210> 92 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L7 light chain CDR1 <400> 92 Ser Gly Ser Asn Ser Asn Val Glu Asn Asn Ser Val Asn   1 5 10 <210> 93 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L7 light chain CDR2 <400> 93 Tyr Asp Ser Asp Gln Arg Pro Ser   1 5 <210> 94 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L7 light chain CDR3 <400> 94 Gln Thr Trp Asp Asn Ser Ser Asn Gly Trp Val   1 5 10 <210> 95 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L8 heavy chain CDR2 <400> 95 Ile Ser Gly Asp Ser Ser Ser Thr   1 5 <210> 96 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L8 heavy chain CDR3 <400> 96 Glu Ile Ile Ser Gly Ser Asp Gly Leu Asp Val   1 5 10 <210> 97 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L8 light chain CDR1 <400> 97 Ser Gly Ser Ser Ser Asn Val Glu Thr Asn Ser Val Ser   1 5 10 <210> 98 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L8 light chain CDR2 <400> 98 Tyr Gly Asn Val Leu Arg Pro Ser   1 5 <210> 99 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L8 light chain CDR3 <400> 99 Ala Ile Trp Asp Ser Ser Leu Asn Gln Met Val   1 5 10 <210> 100 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L9 heavy chain CDR2 <400> 100 Ile Ser Ser Ser Ser Asn Thr   1 5 <210> 101 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> L9 heavy chain CDR3 <400> 101 Asp Leu Met Lys Gly Gly Trp Asn Val Leu Gly Tyr   1 5 10 <210> 102 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L9 light chain CDR1 <400> 102 Ser Gly Ser Thr Ser Asn Val Gly His His Tyr Val Asn   1 5 10 <210> 103 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L9 light chain CDR3 <400> 103 Gln Thr Trp Asp Asn Ser Leu Lys Ala Val Val   1 5 10 <210> 104 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L10 heavy chain CDR2 <400> 104 Ile Ser Ser Gly Ser Ser Asn Thr   1 5 <210> 105 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> L10 heavy chain CDR3 <400> 105 Glu Leu Tyr Ser Gly Phe Gly Leu Asp Leu   1 5 10 <210> 106 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L10 light chain CDR1 <400> 106 Ser Gly Gly Ser Ser Asn Val Glu Glu Phe Tyr Val Asn   1 5 10 <210> 107 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L10 light chain CDR2 <400> 107 Ser Arg Asn Asn Lys Arg Pro Ser   1 5 <210> 108 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L10 light chain CDR3 <400> 108 Ala Val Trp Asp Ser Ser Ser Ser Gly Tyr Val   1 5 10 <210> 109 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L11 heavy chain CDR2 <400> 109 Ile Ser Ser Asp Ser Gly Asn Thr   1 5 <210> 110 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> L11 heavy chain CDR3 <400> 110 Glu Ser Leu Gly Trp Gly Pro Arg Asp Tyr   1 5 10 <210> 111 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L11 light chain CDR1 <400> 111 Ser Gly Thr Ser Ser Asn Val Glu Asn Tyr Tyr Val Asn   1 5 10 <210> 112 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L11 light chain CDR2 <400> 112 Tyr Tyr Asp Asn Gln Arg Pro Ser   1 5 <210> 113 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L11 light chain CDR3 <400> 113 Ala Thr Trp Asp Ser Ser Leu Asp Gly Trp Leu   1 5 10 <210> 114 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L12 heavy chain CDR1 <400> 114 Asn Tyr Asp Met Ser   1 5 <210> 115 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L12 heavy chain CDR2 <400> 115 Ile Ser Gly Ser Gly Ser Lys Thr   1 5 <210> 116 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> L12 heavy chain CDR3 <400> 116 Leu Ile Asp His Ile Tyr Arg Ser Asp Pro   1 5 10 <210> 117 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L12 light chain CDR1 <400> 117 Ser Gly Ser Ser Ser Asn Val Glu Asn Asn Thr Val Asn   1 5 10 <210> 118 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L12 light chain CDR2 <400> 118 Tyr Ser Asn Thr Glu Arg Pro Ser   1 5 <210> 119 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L12 light chain CDR3 <400> 119 Ala Ser Tyr Asp Ser Ser Leu Asp Glu Trp Val   1 5 10 <210> 120 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L13 heavy chain CDR1 <400> 120 Ser Tyr Asp Met Ser   1 5 <210> 121 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L13 heavy chain CDR2 <400> 121 Ile Ser Gly Ser Ser Ser Ala Thr   1 5 <210> 122 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> L13 heavy chain CDR3 <400> 122 Ala Tyr Met Ser Trp Pro Leu Met Asp Tyr   1 5 10 <210> 123 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L13 light chain CDR1 <400> 123 Ser Gly Ser Thr Ser Asn Val Gly Asp Ser Tyr Val Ala   1 5 10 <210> 124 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L13 light chain CDR2 <400> 124 Tyr Glu Asp Asn Lys Arg Pro Ser   1 5 <210> 125 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L13 light chain CDR3 <400> 125 Ser Ser Trp Asp Gly Ser Leu Ser Gly Leu Leu   1 5 10 <210> 126 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L14 heavy chain CDR1 <400> 126 Asn Tyr Val Met Ser   1 5 <210> 127 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L14 heavy chain CDR2 <400> 127 Ile Ser Ser Gly Ser Ser Ser Thr   1 5 <210> 128 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> L14 heavy chain CDR3 <400> 128 Glu Thr Leu Gly Ser Gly Gly Arg Asp His   1 5 10 <210> 129 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L14 light chain CDR1 <400> 129 Ser Gly Ser Ser Ser Asn Val Glu Ser Asn Ala Val Asn   1 5 10 <210> 130 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L14 light chain CDR2 <400> 130 Tyr Ala Asn Asn Gln Arg Pro Ser   1 5 <210> 131 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L14 light chain CDR3 <400> 131 Gln Ala Tyr Asp Lys Ser Ile Asn Ser Trp Val   1 5 10 <210> 132 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L15 heavy chain CDR2 <400> 132 Ile Ser Ser Ser Gly Ser Asn Thr   1 5 <210> 133 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L15 heavy chain CDR3 <400> 133 Gly His Tyr Ser Phe Tyr Tyr Trp Pro Asn Ile   1 5 10 <210> 134 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L15 light chain CDR1 <400> 134 Ser Gly Ser Asn Ser Asn Val Glu Lys Asn Thr Val Asn   1 5 10 <210> 135 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L15 light chain CDR2 <400> 135 Tyr Thr Asn Asn Leu Arg Pro Ser   1 5 <210> 136 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L15 light chain CDR3 <400> 136 Ala Ser Trp Asp Ser Arg Leu Asp His Trp Val   1 5 10 <210> 137 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L16 heavy chain CDR1 <400> 137 Ser Tyr Tyr Met Ser   1 5 <210> 138 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L16 heavy chain CDR2 <400> 138 Ile Ser Tyr Asp Gly Ser Tyr Thr   1 5 <210> 139 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> L16 heavy chain CDR3 <400> 139 Arg Lys Glu Leu Trp Phe Ile Pro Thr Leu Gly Ser   1 5 10 <210> 140 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L16 light chain CDR1 <400> 140 Ser Gly Ser Asn Ser Asn Ile Glu Thr Asn Thr Val Asn   1 5 10 <210> 141 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L16 light chain CDR2 <400> 141 Tyr Asp Asp Asn Asn Arg Pro Ser   1 5 <210> 142 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L16 light chain CDR3 <400> 142 Gln Ala Trp Asp Asp Ala Leu Asp His Trp Ile   1 5 10 <210> 143 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L17 heavy chain CDR1 <400> 143 Asp Tyr Ala Met Ser   1 5 <210> 144 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L17 heavy chain CDR2 <400> 144 Ile Ser Tyr Asp Gly Ser Asn Thr   1 5 <210> 145 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> L17 heavy chain CDR3 <400> 145 Gly Leu Asp Gln Leu Ser Arg Phe Arg Leu   1 5 10 <210> 146 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L17 light chain CDR1 <400> 146 Ser Gly Ser Asn Ser Asn Val Glu Ser Asn Ala Val Gln   1 5 10 <210> 147 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L17 light chain CDR2 <400> 147 Tyr Asn Asn Thr Gln Arg Pro Ser   1 5 <210> 148 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L17 light chain CDR3 <400> 148 Gln Thr Trp Asp Ser Ser Leu Asn Gly Trp Met   1 5 10 <210> 149 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L18 heavy chain CDR2 <400> 149 Ile Ser Ser Ser Gly Ser Ser Thr   1 5 <210> 150 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> L18 heavy chain CDR3 <400> 150 Asp Leu Pro Leu Ser Ser Trp Gly Trp Leu Asn Tyr   1 5 10 <210> 151 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L18 light chain CDR1 <400> 151 Ser Gly Ser Thr Ser Asn Ile Glu Ser Tyr Asp Val Asn   1 5 10 <210> 152 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L18 light chain CDR2 <400> 152 Leu Gly Asn Ser Val Arg Pro Ser   1 5 <210> 153 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L18 light chain CDR3 <400> 153 Gly Gly Trp Asp Asn Ser Leu Asn Thr Leu Val   1 5 10 <210> 154 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L19 heavy chain CDR1 <400> 154 Ser Tyr Ser Met Ser   1 5 <210> 155 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L19 heavy chain CDR2 <400> 155 Ile Ser Ser Asp Ser Ser Thr Thr   1 5 <210> 156 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L19 heavy chain CDR3 <400> 156 Asp Met Gly Ala Tyr Xaa Asn Thr Leu Gly Tyr   1 5 10 <210> 157 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L19 light chain CDR1 <400> 157 Ser Gly Ser Ser Ser Asn Val Gly Arg Asn His Val Ser   1 5 10 <210> 158 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L19 light chain CDR2 <400> 158 Phe Asp Asn Asn Lys Arg Pro Ser   1 5 <210> 159 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L19 light chain CDR3 <400> 159 Ala Ser Trp Asp Ser Ser Leu Asn Gly Tyr Leu   1 5 10 <210> 160 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> L20 heavy chain CDR1 <400> 160 Ser Tyr Ala Met Ser   1 5 <210> 161 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L20 heavy chain CDR2 <400> 161 Ile Ser Ser Asp Gly Ser Asn Thr   1 5 <210> 162 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L20 heavy chain CDR3 <400> 162 Glu Arg Val Val His Gly Phe Tyr Leu Asp Tyr   1 5 10 <210> 163 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L20 light chain CDR1 <400> 163 Ser Gly Ser Ser Ser Asn Val Glu Val His Thr Val Ser   1 5 10 <210> 164 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L20 light chain CDR2 <400> 164 Tyr Arg Asn Asn Gln Arg Pro Ser   1 5 <210> 165 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L20 light chain CDR3 <400> 165 Gly Ala Trp Asp Ser Ser Ile Thr Gly Pro Val   1 5 10 <210> 166 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> L21 heavy chain CDR3 <400> 166 Asp Ser Tyr Gly Val Asp Gly Leu Asp Phe   1 5 10 <210> 167 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> L21 light chain CDR1 <400> 167 Ser Gly Ser Asn Ser Asn Val Glu Tyr Asn Ser Val Ala   1 5 10 <210> 168 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> L21 light chain CDR2 <400> 168 Phe Gly Asn Asn Leu Arg Pro Ser   1 5 <210> 169 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> L21 light chain CDR3 <400> 169 Ala Ser Trp Asp Ser Asn Leu Asn Gly Tyr Val   1 5 10 <210> 170 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> K1 heavy chain CDR1 <400> 170 Asp Tyr Asp Met Ser   1 5 <210> 171 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> K1 heavy chain CDR3 <400> 171 Gly Trp Lys Trp Pro Glu Thr Tyr Tyr Pro Asp Asp   1 5 10 <210> 172 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> K1 light chain CDR1 <400> 172 Ser Ala Ser Arg Ser Ser Ser Ser Trp Leu Asp   1 5 10 <210> 173 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> K1 light chain CDR2 <400> 173 Glu Ala Asn Ser Leu Ala Asp   1 5 <210> 174 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> K1 light chain CDR3 <400> 174 Arg Gln Ser Tyr Ser Phe Pro Tyr   1 5 <210> 175 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> K2 heavy chain CDR1 <400> 175 Asp Tyr Tyr Met Ser   1 5 <210> 176 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> K2 heavy chain CDR3 <400> 176 Glu Thr Leu Asn Thr Gly Leu Gly Arg Asp Tyr   1 5 10 <210> 177 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> K2 light chain CDR1 <400> 177 Ser Ala Ser Ala Val Ser Thr His Leu Ala   1 5 10 <210> 178 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> K2 light chain CDR2 <400> 178 Asp Ser Asn Thr Leu His Ser   1 5 <210> 179 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> K2 light chain CDR3 <400> 179 Leu Gln His Asp Ser Tyr Pro Gly   1 5 <210> 180 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> K3 heavy chain CDR2 <400> 180 Ile Ser Tyr Gly Ser Gly Thr Thr   1 5 <210> 181 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> K3 heavy chain CDR3 <400> 181 Leu Pro Leu Met Gln Ala Ile Leu Asp Val   1 5 10 <210> 182 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> K3 light chain CDR1 <400> 182 Ser Ala Ser Gln Gly Val Ser Thr Ser Leu Ser   1 5 10 <210> 183 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> K3 light chain CDR2 <400> 183 Glu Ala Asn Lys Leu Glu Ser   1 5 <210> 184 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> K3 light chain CDR3 <400> 184 Arg Gln Tyr Asp Asn Ala Pro Tyr   1 5 <210> 185 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> K4 heavy chain CDR2 <400> 185 Ile Ser Gly Gly Gly Gly Lys Thr   1 5 <210> 186 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> K4 heavy chain CDR3 <400> 186 Pro Tyr Ser Lys Gln Ser Lys Pro Asn Trp Val Phe Asp Tyr   1 5 10 <210> 187 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> K4 light chain CDR1 <400> 187 Ser Ala Ser Arg Ser Val Ser Asn Asp Leu Asn   1 5 10 <210> 188 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> K4 light chain CDR2 <400> 188 Ala Ala Asn Thr Leu Gln Ser   1 5 <210> 189 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> K4 light chain CDR3 <400> 189 Arg Gln His Phe Ser Ala Pro Leu   1 5 <210> 190 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> K5 heavy chain CDR3 <400> 190 Gly Trp Asp Trp Thr Ser Ala Gly Gln Asn   1 5 10 <210> 191 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> K5 light chain CDR1 <400> 191 Ser Ala Ser Arg Ser Val Ser Asn Ser Leu Asn   1 5 10 <210> 192 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> K5 light chain CDR2 <400> 192 Gly Ala Asn Asn Leu Glu Ser   1 5 <210> 193 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> K5 light chain CDR3 <400> 193 Leu Gln Tyr Lys Ser Leu Pro Leu   1 5

Claims (22)

서열번호 71의 아미노산 서열을 포함하는 중쇄 CDR1, 서열번호 72의 아미노산 서열을 포함하는 중쇄 CDR2, 서열번호 73의 아미노산 서열을 포함하는 중쇄 CDR3를 포함하는 중쇄 가변 영역 및 서열번호 74의 아미노산 서열을 포함하는 경쇄 CDR1, 서열번호 75의 아미노산 서열을 포함하는 경쇄 CDR2, 서열번호 76의 아미노산 서열을 포함하는 경쇄 CDR3를 포함하는 경쇄 가변 영역;
서열번호 65의 아미노산 서열을 포함하는 중쇄 CDR1, 서열번호 132의 아미노산 서열을 포함하는 중쇄 CDR2, 서열번호 133의 아미노산 서열을 포함하는 중쇄 CDR3를 포함하는 중쇄 가변 영역 및 서열번호 134의 아미노산 서열을 포함하는 경쇄 CDR1, 서열번호 135의 아미노산 서열을 포함하는 경쇄 CDR2, 서열번호 136의 아미노산 서열을 포함하는 경쇄 CDR3를 포함하는 경쇄 가변 영역; 또는
서열번호 83의 아미노산 서열을 포함하는 중쇄 CDR1, 서열번호 149의 아미노산 서열을 포함하는 중쇄 CDR2, 서열번호 150의 아미노산 서열을 포함하는 중쇄 CDR3를 포함하는 중쇄 가변 영역 및 서열번호 151의 아미노산 서열을 포함하는 경쇄 CDR1, 서열번호 152의 아미노산 서열을 포함하는 경쇄 CDR2, 서열번호 153의 아미노산 서열을 포함하는 경쇄 CDR3를 포함하는 경쇄 가변 영역;을 포함하는 항-에이엑스엘 항체.
A heavy chain variable region comprising the heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 73, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 74, wherein the heavy chain variable region comprises the heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: Light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 75, light chain variable region comprising the light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 76;
A heavy chain variable region comprising the heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 133, a heavy chain variable region comprising the heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 133, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: Light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 135; light chain variable region comprising the light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 136; or
A heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 83, a heavy chain variable region comprising the heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 150, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 151 A light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 152, and a light chain variable region comprising the light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 153.
삭제delete 삭제delete 삭제delete 제1항에 따른 항-에이엑스엘 항체와 약물의 접합체.
A conjugate of the anti-A [beta] 1 antibody and the drug according to claim 1.
제5항에 있어서,
상기 약물은 항암 약물인 접합체.
6. The method of claim 5,
Wherein said drug is an anti-cancer drug.
제6항에 있어서,
상기 항암 약물은 마이크로튜불린 구조 형성 억제제, 유사분열 억제제, RNA 중합효소 억제제, 토포아이소머라아제 억제제, DNA 인터컬레이터, DNA 알킬레이터, 리보솜 억제제, miRNA, shRNA, siRNA, 방사선 동위원소 및 독소로 이루어진 군에서 선택되는 적어도 하나인, 접합체.
The method according to claim 6,
The anticancer drug may be selected from the group consisting of a microtubulin structure formation inhibitor, a mitotic inhibitor, an RNA polymerase inhibitor, a topoisomerase inhibitor, a DNA intercalator, a DNA alkylator, a ribosome inhibitor, a miRNA, a shRNA, a siRNA, a radioactive isotope and a toxin Lt; RTI ID = 0.0 &gt; of: &lt; / RTI &gt;
제6항에 있어서,
상기 항암 약물은 마이탄시노이드, 아우리스타틴, 돌라스타틴, 트리코테센, CC1065(NSC 298223), 칼리케아미신, 에네디인 항생제, 탁산, 안트라시클린, 메토트렉세이트, 아드리아마이신, 빈데신, 빈카 알카로이드, 독소루비신, 멜팔란, 미토마이신 C, 클로람부실, 다우노루비신, 다우노마이신, 에토포시드, 테니포시드, 카르미노마이신, 아미노프테린, 닥티노마이신, 미토마이신류, 블레오마이신류, 에스페라미신류, 5-플루오로우라실, 질소 머스타드, 시스플라틴, 이리노테칸, 파클리탁셀 및 도세탁셀로 이루어진 군에서 선택되는 적어도 하나인, 접합체.
The method according to claim 6,
The anticancer drug may be selected from the group consisting of mytensinoid, auristatin, dolastatin, tricothecene, CC1065 (NSC 298223), calicheamicin, enediyne antibiotic, taxane, anthracycline, methotrexate, adriamycin, vindesine, , Doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin, daunomycin, etoposide, tenifoside, carminomycin, aminopterin, dactinomycin, mitomycins, bleomycins, Which is at least one selected from the group consisting of esperamicins, 5-fluorouracil, nitrogen mustard, cisplatin, irinotecan, paclitaxel and docetaxel.
제1항에 따른 항-에이엑스엘 항체를 포함하는 이중특이 항체.
A bispecific antibody comprising the anti-A [beta] -el antibody according to claim 1.
제1항에 따른 항-에이엑스엘 항체; 및
면역효능세포 특이적 표적분자에 결합능을 가지는 항체로 이루어지는 이중특이 항체.
An anti-A [beta] -el antibody according to claim 1; And
Immune Efficacy A bispecific antibody consisting of an antibody capable of binding to a cell-specific target molecule.
제10항에 있어서,
상기 면역효능세포 특이적 표적분자는 TCR/CD3, CD16(FcγRIIIa), CD44, CD56, CD69, CD64(FcγRI), CD89, 및 CD11b/CD18(CR3)로 이루어진 군에서 선택되는 적어도 어느 하나인, 이중특이 항체.
11. The method of claim 10,
Wherein the immunoreactor cell-specific target molecule is at least one selected from the group consisting of TCR / CD3, CD16 (Fc? RIIIa), CD44, CD56, CD69, CD64 (Fc? RI), CD89, and CD11b / CD18 Specific antibody.
삭제delete 제5항 내지 제8항 중 어느 한 항에 따른 접합체를 포함하는 암 예방 또는 치료용 조성물.
9. A composition for preventing or treating cancer comprising the conjugate according to any one of claims 5 to 8.
삭제delete 제13항에 있어서,
상기 암은 간암, 간세포암, 위암, 유방암, 폐암, 난소암, 관지암, 비인두암, 후두암, 췌장암, 방광암, 대장암, 결장암, 이자암, 자궁경부암, 뇌암, 전립선암, 골암, 피부암, 갑상선암, 부갑상선암, 신장암, 식도암, 담도암, 고환암, 직장암, 두경부암, 경추암, 요관암, 골육종, 신경아세포종, 흑색종, 섬유육종, 횡문근육종, 성상세포종, 신경모세포종 및 신경교종으로 이루어진 군에서 선택되는 어느 하나인, 암 예방 또는 치료용 조성물.
14. The method of claim 13,
The cancer may be selected from the group consisting of liver cancer, hepatocellular carcinoma, stomach cancer, breast cancer, lung cancer, ovarian cancer, ductal carcinoma, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, colon carcinoma, cervical cancer, brain cancer, prostate cancer, Neuroblastoma, neuroblastoma, neuroblastoma, osteosarcoma, neuroblastoma, melanoma, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, and glioma Or a pharmaceutically acceptable salt thereof.
제13항에 있어서,
상기 암은 간암, 간세포암, 유방암, 난소암, 대장암, 피부암, 담도암 및 폐암으로 이루어진 군에서 선택되는 어느 하나인, 암 예방 또는 치료용 조성물.
14. The method of claim 13,
Wherein the cancer is any one selected from the group consisting of liver cancer, hepatocellular carcinoma, breast cancer, ovarian cancer, colon cancer, skin cancer, biliary cancer and lung cancer.
제1항에 따른 항-에이엑스엘 항체를 인코딩하는 폴리뉴클레오티드.
A polynucleotide encoding the anti-A [beta] -el antibody according to claim 1.
제17항에 따른 폴리뉴클레오티드를 포함하는 재조합 벡터.
18. A recombinant vector comprising a polynucleotide according to claim 17.
제18항에 따른 재조합 발현 벡터로 형질 전환된 숙주세포.
18. A host cell transformed with a recombinant expression vector according to claim 18.
제19항에 있어서,
상기 숙주세포는 동물세포, 식물세포, 효모, 대장균 및 곤충세포로 이루어진 군에서 선택되는 적어도 하나인, 숙주세포.
20. The method of claim 19,
Wherein the host cell is at least one selected from the group consisting of animal cells, plant cells, yeast, E. coli, and insect cells.
제19항에 있어서,
원숭이 신장 세포7 세포, NSO 세포, SP2/0 세포, 차이니즈 햄스터 난소 세포, W138 세포, 어린 햄스터 신장 세포, MDCK, 골수종 세포주, HuT 78 세포, HEK293 세포, 대장균, 바실러스 서브틸리스, 스트렙토마이세스 속, 슈도모나스 속, 프로테우스 미라빌리스, 스타필로코쿠스 속, 아스페르길러스 속, 피치아 파스토리스, 사카로마이세스 세레비지애, 쉬조사카로마세스 속 및 뉴로스포라 크라사로 이루어진 군에서 선택되는 적어도 하나인, 숙주세포.
20. The method of claim 19,
Monkey kidney cell 7, NSO cell, SP2 / 0 cell, Chinese hamster ovary cell, W138 cell, young hamster kidney cell, MDCK, myeloma cell line, HuT 78 cell, HEK293 cell, Escherichia coli, Bacillus subtilis, Streptomyces sp. , Pseudomonas sp., Proteus sp. Mirabilis, Staphylococcus sp., Aspergillus sp., Pichia pastoris, Saccharomyces cerevisiae, Shiros caramaceus spp., And Neurosporacla sp. At least one host cell.
제19항 내지 제21항 중 어느 한 항에 따른 숙주세포를 배양하는 단계를 포함하는 항-에이엑스엘 항체의 생산 방법.22. A method for producing an anti-A [beta] antibody comprising culturing a host cell according to any one of claims 19 to 21.
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WO2013064685A1 (en) * 2011-11-03 2013-05-10 Pierre Fabre Medicament Antigen binding protein and its use as addressing product for the treatment cancer
WO2016187354A1 (en) * 2015-05-18 2016-11-24 Agensys, Inc. Antibodies that bind to axl proteins

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US20120121587A1 (en) * 2009-05-15 2012-05-17 Chugai Seiyaku Kabushiki Kaisha Anti-axl antibody
WO2013064685A1 (en) * 2011-11-03 2013-05-10 Pierre Fabre Medicament Antigen binding protein and its use as addressing product for the treatment cancer
WO2016187354A1 (en) * 2015-05-18 2016-11-24 Agensys, Inc. Antibodies that bind to axl proteins

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