JP2016047845A5 - - Google Patents
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- JP2016047845A5 JP2016047845A5 JP2015247222A JP2015247222A JP2016047845A5 JP 2016047845 A5 JP2016047845 A5 JP 2016047845A5 JP 2015247222 A JP2015247222 A JP 2015247222A JP 2015247222 A JP2015247222 A JP 2015247222A JP 2016047845 A5 JP2016047845 A5 JP 2016047845A5
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- 210000004027 cell Anatomy 0.000 claims description 59
- 150000007523 nucleic acids Chemical group 0.000 claims description 43
- 102100038449 Claudin-6 Human genes 0.000 claims description 41
- 101000882898 Homo sapiens Claudin-6 Proteins 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 18
- 101100112922 Candida albicans CDR3 gene Proteins 0.000 claims description 17
- 108020004707 nucleic acids Proteins 0.000 claims description 17
- 102000039446 nucleic acids Human genes 0.000 claims description 17
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 12
- 239000000427 antigen Substances 0.000 claims description 8
- 102000036639 antigens Human genes 0.000 claims description 8
- 108091007433 antigens Proteins 0.000 claims description 8
- 239000012634 fragment Substances 0.000 claims description 7
- 108091028043 Nucleic acid sequence Proteins 0.000 claims 25
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 claims 16
- 102100035361 Cerebellar degeneration-related protein 2 Human genes 0.000 claims 16
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims 16
- 101000737793 Homo sapiens Cerebellar degeneration-related antigen 1 Proteins 0.000 claims 16
- 101000737796 Homo sapiens Cerebellar degeneration-related protein 2 Proteins 0.000 claims 16
- 239000013604 expression vector Substances 0.000 claims 4
- 210000003527 eukaryotic cell Anatomy 0.000 claims 3
- 241000238631 Hexapoda Species 0.000 claims 2
- 210000003719 b-lymphocyte Anatomy 0.000 claims 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 claims 2
- 210000004443 dendritic cell Anatomy 0.000 claims 2
- 230000002538 fungal effect Effects 0.000 claims 2
- 210000004698 lymphocyte Anatomy 0.000 claims 2
- 210000005253 yeast cell Anatomy 0.000 claims 2
- 101100370002 Mus musculus Tnfsf14 gene Proteins 0.000 claims 1
- 210000000628 antibody-producing cell Anatomy 0.000 claims 1
- 238000012258 culturing Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000008488 polyadenylation Effects 0.000 claims 1
- 210000001236 prokaryotic cell Anatomy 0.000 claims 1
- 230000005030 transcription termination Effects 0.000 claims 1
- 230000001131 transforming effect Effects 0.000 claims 1
- 230000014621 translational initiation Effects 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 description 18
- 201000011510 cancer Diseases 0.000 description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 230000001605 fetal effect Effects 0.000 description 6
- 102100026097 Claudin-9 Human genes 0.000 description 4
- 208000030808 Clear cell renal carcinoma Diseases 0.000 description 4
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- 208000000587 small cell lung carcinoma Diseases 0.000 description 4
- 230000002381 testicular Effects 0.000 description 4
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 4
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 3
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 3
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- 239000012642 immune effector Substances 0.000 description 3
- 229940121354 immunomodulator Drugs 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 2
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 2
- 208000036832 Adenocarcinoma of ovary Diseases 0.000 description 2
- 206010004146 Basal cell carcinoma Diseases 0.000 description 2
- 206010004593 Bile duct cancer Diseases 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 201000000274 Carcinosarcoma Diseases 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 102100038423 Claudin-3 Human genes 0.000 description 2
- 102100038447 Claudin-4 Human genes 0.000 description 2
- 208000019487 Clear cell papillary renal cell carcinoma Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000032320 Germ cell tumor of testis Diseases 0.000 description 2
- 101000882908 Homo sapiens Claudin-3 Proteins 0.000 description 2
- 101000882890 Homo sapiens Claudin-4 Proteins 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061328 Ovarian epithelial cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 description 2
- 208000033133 Testicular seminomatous germ cell tumor Diseases 0.000 description 2
- 206010057644 Testis cancer Diseases 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- -1 aromatic amino acid Chemical class 0.000 description 2
- 210000000270 basal cell Anatomy 0.000 description 2
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- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 210000004408 hybridoma Anatomy 0.000 description 2
- 201000002312 ileal neoplasm Diseases 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
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- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 201000005249 lung adenocarcinoma Diseases 0.000 description 2
- 230000036244 malformation Effects 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 208000013371 ovarian adenocarcinoma Diseases 0.000 description 2
- 201000006588 ovary adenocarcinoma Diseases 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 208000004333 pleomorphic adenoma Diseases 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 206010073373 small intestine adenocarcinoma Diseases 0.000 description 2
- 201000002314 small intestine cancer Diseases 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 206010042863 synovial sarcoma Diseases 0.000 description 2
- 208000001608 teratocarcinoma Diseases 0.000 description 2
- 201000003120 testicular cancer Diseases 0.000 description 2
- 208000002918 testicular germ cell tumor Diseases 0.000 description 2
- 208000024662 testicular seminoma Diseases 0.000 description 2
- 208000004238 testicular teratoma Diseases 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 206010044412 transitional cell carcinoma Diseases 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- 206010046766 uterine cancer Diseases 0.000 description 2
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 210000004252 chorionic villi Anatomy 0.000 description 1
- 230000005757 colony formation Effects 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 210000002445 nipple Anatomy 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US26020209P | 2009-11-11 | 2009-11-11 | |
| EP09014136A EP2322555A1 (en) | 2009-11-11 | 2009-11-11 | Antibodies specific for claudin 6 (CLDN6) |
| US61/260,202 | 2009-11-11 | ||
| EP09014136.7 | 2009-11-11 | ||
| US36161810P | 2010-07-06 | 2010-07-06 | |
| EP10006956.6 | 2010-07-06 | ||
| EP10006956 | 2010-07-06 | ||
| US61/361,618 | 2010-07-06 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2012538239A Division JP5889196B2 (ja) | 2009-11-11 | 2010-11-11 | クローディン６（ｃｌｄｎ６）に特異的な抗体 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2017075017A Division JP6502992B2 (ja) | 2009-11-11 | 2017-04-05 | クローディン６（ｃｌｄｎ６）に特異的な抗体 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2016047845A JP2016047845A (ja) | 2016-04-07 |
| JP2016047845A5 true JP2016047845A5 (enExample) | 2016-06-23 |
| JP6125604B2 JP6125604B2 (ja) | 2017-05-10 |
Family
ID=43480734
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2012538239A Active JP5889196B2 (ja) | 2009-11-11 | 2010-11-11 | クローディン６（ｃｌｄｎ６）に特異的な抗体 |
| JP2015247222A Active JP6125604B2 (ja) | 2009-11-11 | 2015-12-18 | クローディン６（ｃｌｄｎ６）に特異的な抗体 |
| JP2017075017A Active JP6502992B2 (ja) | 2009-11-11 | 2017-04-05 | クローディン６（ｃｌｄｎ６）に特異的な抗体 |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2012538239A Active JP5889196B2 (ja) | 2009-11-11 | 2010-11-11 | クローディン６（ｃｌｄｎ６）に特異的な抗体 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2017075017A Active JP6502992B2 (ja) | 2009-11-11 | 2017-04-05 | クローディン６（ｃｌｄｎ６）に特異的な抗体 |
Country Status (29)
| Country | Link |
|---|---|
| US (5) | US9487584B2 (enExample) |
| EP (4) | EP4461354A3 (enExample) |
| JP (3) | JP5889196B2 (enExample) |
| KR (4) | KR101960509B1 (enExample) |
| CN (4) | CN111875703B (enExample) |
| AU (3) | AU2010318316B2 (enExample) |
| BR (1) | BR112012011143B1 (enExample) |
| CA (2) | CA3050655A1 (enExample) |
| CY (2) | CY1120300T1 (enExample) |
| DK (2) | DK2499161T3 (enExample) |
| ES (3) | ES2649389T3 (enExample) |
| HR (2) | HRP20171749T1 (enExample) |
| HU (2) | HUE035516T2 (enExample) |
| IL (2) | IL218628B (enExample) |
| LT (2) | LT3305813T (enExample) |
| ME (1) | ME02943B (enExample) |
| MX (3) | MX347150B (enExample) |
| NO (1) | NO2499161T3 (enExample) |
| NZ (2) | NZ734307A (enExample) |
| PL (3) | PL3305813T3 (enExample) |
| PT (2) | PT2499161T (enExample) |
| RS (2) | RS60168B1 (enExample) |
| RU (1) | RU2675997C2 (enExample) |
| SG (2) | SG10202110692WA (enExample) |
| SI (2) | SI2499161T1 (enExample) |
| SM (1) | SMT201700566T1 (enExample) |
| UA (2) | UA117799C2 (enExample) |
| WO (1) | WO2011057788A1 (enExample) |
| ZA (1) | ZA201202418B (enExample) |
Families Citing this family (47)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6358588A (ja) * | 1986-08-29 | 1988-03-14 | Toshiba Corp | バ−コ−ド読取装置 |
| DE10254601A1 (de) | 2002-11-22 | 2004-06-03 | Ganymed Pharmaceuticals Ag | Differentiell in Tumoren exprimierte Genprodukte und deren Verwendung |
| US12492253B1 (en) * | 2008-02-25 | 2025-12-09 | Xencor, Inc. | Anti-human C5 antibodies |
| DK2398902T3 (da) | 2009-02-20 | 2023-12-04 | Astellas Pharma Inc | Fremgangsmåder og sammensætninger til diagnosticering og behandling af cancer |
| SG10202110692WA (en) | 2009-11-11 | 2021-12-30 | Ganymed Pharmaceuticals Gmbh | Antibodies specific for claudin 6 (cldn6) |
| EP2404936A1 (en) | 2010-07-06 | 2012-01-11 | Ganymed Pharmaceuticals AG | Cancer therapy using CLDN6 target-directed antibodies in vivo |
| EP4279513A3 (en) | 2010-11-30 | 2024-02-28 | Chugai Seiyaku Kabushiki Kaisha | Cytotoxicity-inducing therapeutic agent |
| MX341147B (es) | 2011-05-13 | 2016-08-09 | Ganymed Pharmaceuticals Ag | Anticuerpos para el tratamiento del cáncer que expresa cldn6. |
| SG10201911551RA (en) * | 2011-05-13 | 2020-02-27 | Ganymed Pharmaceuticals Gmbh | Antibodies for treatment of cancer expressing claudin 6 |
| CN103320381B (zh) * | 2012-03-23 | 2015-04-15 | 上海市儿童医院 | 一种多能干细胞表面标志物及其用途 |
| CN104662044B (zh) | 2012-08-24 | 2018-10-30 | 加利福尼亚大学董事会 | 用于治疗ror1癌症并抑制转移的抗体和疫苗 |
| EP3766903A3 (en) * | 2012-11-13 | 2021-02-17 | BioNTech SE | Bispecific anti claudin xcd3 antibodies for treatment of claudin expressing cancer diseases |
| KR102643443B1 (ko) * | 2012-11-13 | 2024-03-06 | 비온테크 에스이 | 클라우딘 발현 암 질환의 치료제 |
| WO2015014376A1 (en) * | 2013-07-31 | 2015-02-05 | Biontech Ag | Diagnosis and therapy of cancer involving cancer stem cells |
| EP3747465A1 (en) * | 2013-07-31 | 2020-12-09 | BioNTech AG | Diagnosis and therapy of cancer involving cancer stem cells |
| US10053511B2 (en) * | 2013-11-06 | 2018-08-21 | Abbvie Stemcentrx Llc | Anti-claudin antibodies and methods of use |
| CN105940107B (zh) | 2013-11-11 | 2021-06-15 | 中外制药株式会社 | 含有改变了抗体可变区的抗原结合分子 |
| SI3126381T2 (sl) | 2014-04-01 | 2022-05-31 | Biontech Cell&Gene Therapies Gmbh | Claudin-6-specifični imunoreceptorji in t-celični epitopi |
| MA40921A (fr) * | 2014-11-05 | 2017-09-12 | Abbvie Stemcentrx Llc | Récepteurs antigéniques chimériques anti-cldn et procédés d'utilisation |
| WO2016076345A1 (ja) | 2014-11-11 | 2016-05-19 | 中外製薬株式会社 | 改変された抗体可変領域を含む抗原結合分子のライブラリ |
| KR20240113990A (ko) | 2016-06-27 | 2024-07-23 | 더 리젠츠 오브 더 유니버시티 오브 캘리포니아 | 암 치료 조합 |
| WO2018105560A1 (ja) * | 2016-12-07 | 2018-06-14 | 国立大学法人大阪大学 | Ｃｌａｕｄｉｎ ５抗体、及びその抗体を含有する医薬 |
| WO2018207638A1 (ja) * | 2017-05-08 | 2018-11-15 | 国立大学法人大阪大学 | 抗ｃｌｄｎ－５抗体、及びその抗体を含有する医薬 |
| WO2019048040A1 (en) * | 2017-09-06 | 2019-03-14 | Ganymed Pharmaceuticals Gmbh | ANTIBODIES USEFUL IN THE DIAGNOSIS OF CANCER |
| JP7273716B2 (ja) | 2017-09-29 | 2023-05-15 | 第一三共株式会社 | 抗体－ピロロベンゾジアゼピン誘導体コンジュゲート |
| JP7357616B2 (ja) | 2017-12-05 | 2023-10-06 | 中外製薬株式会社 | Ｃｄ３およびｃｄ１３７に結合する改変された抗体可変領域を含む抗原結合分子 |
| JP2021510064A (ja) * | 2018-01-05 | 2021-04-15 | 中外製薬株式会社 | 細胞傷害誘導治療剤 |
| WO2020075325A1 (ja) * | 2018-10-09 | 2020-04-16 | 公立大学法人福島県立医科大学 | 子宮体癌患者の予後予測バイオマーカー |
| KR20210128443A (ko) * | 2019-02-15 | 2021-10-26 | 인테그럴 몰큘러 인코포레이티드 | 클라우딘 6 항체 및 이의 용도 |
| ES3017207T3 (en) | 2019-03-20 | 2025-05-12 | Univ California | Claudin-6 antibodies and drug conjugates |
| EP3950061A4 (en) | 2019-03-25 | 2022-11-16 | Daiichi Sankyo Company, Limited | ANTIBODY PYRROLOBENZODIAZEPINE DERIVATIVE CONJUGATE |
| PH12021552960A1 (en) | 2019-07-10 | 2022-07-25 | Chugai Pharmaceutical Co Ltd | Claudin-6 binding molecules and uses thereof |
| CN111087465B (zh) * | 2019-12-24 | 2020-12-08 | 广州医科大学 | 一种针对密蛋白6的抗体偶联药物及应用 |
| CA3174094A1 (en) | 2020-03-31 | 2021-10-07 | Shinya Ishii | Claudin-6 targeting multispecific antigen-binding molecules and uses thereof |
| CA3212530A1 (en) * | 2021-03-05 | 2022-09-09 | Shanghai GenBase Biotechnology Co., Ltd. | Anti-cldn6 antibody and use thereof |
| CA3212665A1 (en) | 2021-03-09 | 2022-09-15 | Xencor, Inc. | Heterodimeric antibodies that bind cd3 and cldn6 |
| JPWO2023053282A1 (enExample) | 2021-09-29 | 2023-04-06 | ||
| WO2024022512A1 (en) * | 2022-07-29 | 2024-02-01 | Nanjing Legend Biotech Co., Ltd. | Claudin-6 binding moieties and uses thereof |
| WO2024095964A1 (ja) | 2022-10-31 | 2024-05-10 | アステラス製薬株式会社 | Ｔｏｌｌ様受容体７／８デュアルアゴニスト化合物を含む抗体薬物複合体 |
| CN120282987A (zh) | 2022-11-30 | 2025-07-08 | 因特格尔莫来库乐有限公司 | 包括双特异性型式的针对紧密连接蛋白6的抗体 |
| CN116064622B (zh) * | 2023-02-13 | 2023-10-13 | 优睿赛思(武汉)生物科技有限公司 | Claudin6-mCherry报告基因CHO-K1稳转细胞株制备及应用 |
| WO2024235175A1 (zh) * | 2023-05-12 | 2024-11-21 | 智泽童康(广州)生物科技有限公司 | 抗cldn6抗体及其用途 |
| US12403202B2 (en) | 2023-05-25 | 2025-09-02 | The Regents Of The University Of California | Dosage of claudin-6 conjugates for cancer treatment |
| WO2025149667A1 (en) | 2024-01-12 | 2025-07-17 | Pheon Therapeutics Ltd | Antibody drug conjugates and uses thereof |
| CN118754987B (zh) * | 2024-08-21 | 2025-02-11 | 广州百吉生物制药有限公司 | 一种紧密连接蛋白抗体h04及其应用 |
| CN119320451B (zh) * | 2024-08-21 | 2025-05-16 | 百吉生物医药(广州)股份有限公司 | 一种紧密连接蛋白抗体d03及其应用 |
| CN119371534B (zh) * | 2024-08-21 | 2025-05-27 | 百吉生物医药(广州)股份有限公司 | 一种紧密连接蛋白抗体e02及其应用 |
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| GB8601597D0 (en) | 1986-01-23 | 1986-02-26 | Wilson R H | Nucleotide sequences |
| US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
| EP0307434B2 (en) | 1987-03-18 | 1998-07-29 | Scotgen Biopharmaceuticals, Inc. | Altered antibodies |
| GB8717430D0 (en) | 1987-07-23 | 1987-08-26 | Celltech Ltd | Recombinant dna product |
| GB8809129D0 (en) | 1988-04-18 | 1988-05-18 | Celltech Ltd | Recombinant dna methods vectors and host cells |
| US6255458B1 (en) | 1990-08-29 | 2001-07-03 | Genpharm International | High affinity human antibodies and human antibodies against digoxin |
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