NL2012424C2 - Common light chain mouse. - Google Patents
Common light chain mouse. Download PDFInfo
- Publication number
- NL2012424C2 NL2012424C2 NL2012424A NL2012424A NL2012424C2 NL 2012424 C2 NL2012424 C2 NL 2012424C2 NL 2012424 A NL2012424 A NL 2012424A NL 2012424 A NL2012424 A NL 2012424A NL 2012424 C2 NL2012424 C2 NL 2012424C2
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- human
- mouse
- light chain
- heavy chain
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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Claims (26)
1. Werkwijze voor het vervaardigen van een bispecifiek antigen-bindend eiwit, de werkwijze omvattende: 5 (a) blootstellen van een eerste genetisch gemodificeerde muis aan een eerste antigen dat van belang is, dat een eerste epitoop omvat; (b) blootstellen van dezelfde muis of een tweede muis aan een tweede antigen dat van belang is, dat een tweede epitoop omvat; (c) de eerste muis immuunresponsen laten ontwikkelen op de eerste en tweede 10 antigenen die van belang zijn, of als een eerste en tweede muis gebruikt zijn, de eerste muis immuunresponsen laten ontwikkelen op het eerste antigen en de tweede muis immuunresponsen laten ontwikkelen op het tweede antigen; (d) in de eerste muis identificeren van een eerste antilichaam omvattende een eerste variabel gebied van de humane zware keten die bindt aan het eerste epitoop van het eerste 15 antigen dat van belang is en in dezelfde of de tweede muis identificeren van een tweede antilichaam omvattende een tweede variabel gebied van de humane zware keten die bindt aan het tweede epitoop van het tweede antigen van belang; (e) vervaardigen van een eerste volledig humane zware-keten-gen omvattende een nucleïnezuur sequentie die codeert voor het eerste variabel gebied van de humane zware 20 keten, waarbij de eerste volledig humane zware-keten-gen codeert voor een eerste volledig humane zware keten, en vervaardigen van een tweede volledig humane zware-keten-gen omvattende een nucleïnezuur sequentie die codeert voor het tweede variabel gebied van de humane zware keten , waarbij het tweede volledig humane zware-keten-gen codeert voor een volledig humane zware keten; 25 (f) tot expressie brengen van de eerste volledig humane zware keten en de tweede volledig humane zware keten in een cel die een enkele volledige humane lichte keten tot expressie brengt die afgeleid is van een humaan Vk1-39/Jk voor het vormen van een bispecifiek antigen-bindend eiwit zodat de eerste volledig humane zware keten het eerste epitoop van het eerste antigen dat van belang is bindt en de tweede volledig humane zware 30 keten het tweede epitoop van het tweede antigen dat van belang is bindt; en (g) het isoleren van het bispecifieke antigen-bindend eiwit, waarbij de eerste muis, en indien gebruikt de tweede muis, variabele gebieden van humaan immunoglobine zware en lichte keten tot expressie brengen, en waarbij de eerste muis, en indien gebruikt de tweede muis, verder het kenmerk hebben dat: 35 (i) het variabel gebied van de immunoglobine κ lichte keten repertoire in de muizen tot expressie gebracht wordt van een enkel variabel gebied van een humane lichte keten welke in het kiemcel genoom aanwezig is en een herrangschikt humane Vk1-39/Jk sequentie omvat; en (ii) de muizen B-cellen, pre-immunisatie, omvatten die ten minste één zware- 40 keten-gen tot expressie brengen die voortkomt uit de herrangschikking van niet herrangschikte nurnane Vu, Jh «nu Uh yenseyirienien aanweziy in γίθι Kiernuaan yenoorn, waaruij οθ herrangschikking gekozen is uit de groep omvattende de herrangschikkingen zoals genoemd in Tabel 29 hieronder:
2. De werkwijze volgens conclusie 1, waarbij in stap (e): (a) het eerste volledige humane zware-keten-gen vervaardigd is door het koppelen van de voorde eerste variabel gebied van de humane zware keten coderende sequentie met een voor constant gebied van de humane zware keten coderende sequentie; en (b) het tweede volledige humane zware-keten-gen vervaardigd is door het koppelen van de voorde tweede variabel gebied van de humane zware keten coderende sequentie met een voor het constant gebied van de humane zware keten coderende sequentie.
3. De werkwijze volgens conclusie 1 of 2, waarbij de herrangschikte humane Vk1-39/Jk sequentie operabel is gekoppeld met een muis Ck gensegment of een rat Ck gensegment.
4. De werkwijze volgens een der voorgaande conclusies, waarbij de niet herrangschikte humane VH gensegmenten operabel gekoppeld zijn met een muis CH gensegment of een rat CH gensegment.
5. De werkwijze volgens conclusie 4, waarbij de muis een kiembaan heeft welke niet herrangschikte humane JH gensegmenten omvat welke operabel gekoppeld zijn met de humane VH gensegmenten en de humane DH gensegmenten, en zodoende met de muis CH gensegmenten.
5 Tabel 29:
6. De werkwijze volgens een der voorgaande conclusies, waarbij de herrangschikte humane Vk1-39/Jk een humane kiembaan Vk1-39 die herrangschikt is tot humane kiembaan Jk5.
7. De werkwijze volgens een der voorgaande conclusies, waarbij de enige kappa lichte keten die door de B cellen tot expressie gebracht wordt het herrangschikte humane Vk1-39/Jk omvat, welke een herrangschikte humane kiembaan Vk1-39/Jk is of een somatische gemuteerde variant daarop.
8. De werkwijze volgens een der voorgaande conclusies, waarbij de enige lichte keten die door de B cellen tot expressie wordt gebracht een herrangschikt humaan Vk1-39/Jk omvat welke een herrangschikte humane kiembaan Vk1-39/Jk of somatische variant daarop is.
9. De werkwijze volgens een der voorgaande conclusies, waarbij het niet herrangschikte humane VH gensegment het endogene muis VH gensegment vervangen heeft.
10. De werkwijze volgens een der conclusies 1 tot en met 9, waarbij het eerste humane variabel gebied gecodeerd wordt door een variabel gebied van een zware keten welke ontstaat door de herrangschikking van de humane VH, JH en DH gensegmenten gekozen uit de groep omvattende de herrangschikkingen zoals genoemd in Tabel 29.
11. De werkwijze volgens een der voorgaande conclusies, waarbij de muis 12 tot 25 functionele niet herrangschikte humane VH gensegmenten omvat.
12. De werkwijze volgens conclusie 11, waarbij 90-100% van de endogene niet herrangschikte muis VH gensegmenten vervangen zijn met de betreffende 12 tot 25 functionele niet herrangschikte humane VH gensegmenten.
13. Een bispecifiek antigen-bindend eiwit vervaardigd volgens de werkwijze van een der voorgaande conclusies.
14. Werkwijze voor het vervaardigen van een bispecifiek antigen-bindend eiwit, de werkwijze omvattende: (a) blootstellen van een eerste genetisch gemodificeerde muis aan een eerste antigen dat van belang is, dat een eerste epitoop omvat; (b) blootstellen van dezelfde muis of een tweede muis aan een tweede antigen dat van belang is, dat een tweede epitoop omvat; (c) de eerste muis immuunresponsen laten ontwikkelen op de eerste en tweede antigenen die van belang zijn, of als een eerste en tweede muis gebruikt zijn, de eerste muis immuunresponsen laten ontwikkelen op het eerste antigen en de tweede muis immuunresponsen laten ontwikkelen op het tweede antigen; (d) in de eerste muis identificeren van een eerste antilichaam omvattende een eerste variabel gebied van de humane zware keten die bindt aan het eerste epitoop van het eerste antigen dat van belang is en in dezelfde of de tweede muis identificeren van een tweede antilichaam omvattende een tweede variabel gebied van de humane zware keten die bindt aan het tweede epitoop van het tweede antigen van belang; (e) vervaardigen van een eerste volledig humane zware-keten-gen omvattende een nucleïnezuur sequentie die codeert voor het eerste variabel gebied van de humane zware keten, waarbij de eerste volledig humane zware-keten-gen codeert voor een eerste volledig humane zware keten, en vervaardigen van een tweede volledig humane zware-keten-gen omvattende een nucleïnezuur sequentie die codeert voor het tweede variabel gebied van de humane zware keten , waarbij het tweede volledig humane zware-keten-gen codeert voor een volledig humane zware keten; (f) tot expressie brengen van de eerste volledig humane zware keten en de tweede volledig humane zware keten in een cel die een enkele volledige humane lichte keten tot expressie brengt die afgeleid is van een humaan Vk1-39/Jk voor het vormen van een bispecifiek antigen-bindend eiwit zodat de eerste volledig humane zware keten het eerste epitoop van het eerste antigen dat van belang is bindt en de tweede volledig humane zware keten het tweede epitoop van het tweede antigen dat van belang is bindt; en (g) het isoleren van het bispecifieke antigen-bindend eiwit, waarbij de eerste muis, en indien gebruikt de tweede muis, variabele gebieden van humaan immunoglobine zware en lichte keten tot expressie brengen, en waarbij de eerste muis, en indien gebruikt de tweede muis, verder het kenmerk hebben dat: (i) het variabel gebied van de immunoglobine κ lichte keten repertoire in de muizen tot expressie gebracht wordt van een enkel variabel gebied van een humane lichte keten welke in het kiemcel genoom aanwezig is en een herrangschikt humane Vk1-39/Jk sequentie omvat; en (ii) de muizen B-cellen, pre-immunisatie, omvatten die ten minste één zware-keten-gen tot expressie brengen die voortkomt uit de herrangschikking van niet herrangschikte humane VH, JH and DH gensegmenten aanwezig in het kiembaan genoom, waarbij de herrangschikking gekozen is uit de groep omvattende de herrangschikkingen zoals genoemd in Tabel 30 hieronder: Tabel 30
IUHV2-5 IUHJ4 IUHD4-1 ί IGHV3-15 IGHJ4 IGHD1-26 IGHV3-15 IGHJ4 IGHD1-7 IGHV3-23 IGHJ5 IGHD3-9 IGHV3-23 IGHJ6 IGHD6-6 IGHV3-30 IGHJ3 IGHD3-16 IGHV4-39 IGHJ3 IGHD1-7 IGHV4-59 IGHJ4 IGHD2-15 IGHV1-24 IGHJ4 IGHD5-18 IGHV2-5 IGHJ5 IGHD3-10 IGHV3-23 IGHJ2 IGHD6-6 IGHV3-23 IGHJ3 IGHD1-26 IGHV3-23 IGHJ5 IGHD1-7 IGHV3-33 IGHJ4 IGHD6-13 IGHV4-39 IGHJ4 IGHD7-27 IGHV4-59 IGHJ3 IGHD1-1 IGHV1-69 IGHJ5 IGHD3-10 IGHV2-5 IGHJ4 IGHD2-2 IGHV3-23 IGHJ6 IGHD7-27 IGHV4-59 IGHJ4 IGHD1-7 IGHV1-69 IGHJ6 IGHD7-27 IGHV2-5 IGHJ4 IGHD1-20 IGHV3-21 IGHJ2 IGHD3-22 IGHV3-23 IGHJ3 IGHD3-16 IGHV3-23 IGHJ3 IGHD3-9 IGHV3-23 IGHJ4 IGHD5-18 IGHV4-39 IGHJ2 IGHD7-27 IGHV4-39 IGHJ4 IGHD6-6 IGHV4-59 IGHJ3 IGHD4-17 IGHV4-59 IGHJ4 IGHD3-9 IGHV4-59 IGHJ5 IGHD6-13 IGHV4-59 IGHJ6 IGHD3-10 IGHV2-5 IGHJ4 IGHD1-1 IGHV3-15 IGHJ4 IGHD3-22 IGHV3-21 IGHJ4 IGHD1-26
15. De werkwijze volgens conclusie 14, waarbij in stap (e): (a) het eerste volledige humane zware-keten-gen vervaardigd is door het koppelen van de voorde eerste variabel gebied van de humane zware keten coderende sequentie met een voor humaan constant gebied van de zware keten coderende sequentie; en (b) het tweede volledige humane zware-keten-gen vervaardigd is door het koppelen van de voorde tweede variabel gebied van de humane zware keten coderende sequentie met een voor het constant gebied van de humane zware keten coderende sequentie.
16. De werkwijze volgens conclusie 14 of 15, waarbij de herrangschikte humane Vk1-39/Jk sequentie operabel is gekoppeld met een muis Ck gensegment of een rat Ck gensegment.
17. De werkwijze volgens een der conclusies 14 tot en met 16, waarbij de niet herrangschikte humane VH gensegmenten operabel gekoppeld zijn met een muis CH gensegment of een rat CH gensegment.
18. De werkwijze volgens conclusie 17, waarbij de muis een kiembaan heeft welke niet herrangschikte humane JH gensegmenten omvat welke operabel gekoppeld zijn met de humane VH gensegmenten en de humane DH gensegmenten, en zodoende met de muis CH gensegmenten.
19. De werkwijze volgens een der conclusies 14 tot en met 18, waarbij de herrangschikte humane Vk1-39/Jk een humane kiembaan Vk1-39 die herrangschikt is tot humane kiembaan Jk5.
20. De werkwijze volgens een der conclusies 14 tot en met 19, waarbij de enige kappa lichte keten die door de B cellen tot expressie gebracht wordt het herrangschikte humane Vk1-39/Jk omvat, welke een herrangschikte humane kiembaan Vk1-39/Jk is of een somatische gemuteerde variant daarop.
21. De werkwijze volgens een der conclusies 14 tot en met 20, waarbij de enige lichte keten die door de B cellen tot expressie wordt gebracht een herrangschikt humaan Vk1-39/Jk omvat welke een herrangschikte humane kiembaan Vk1-39/Jk of somatische variant daarop is.
22. De werkwijze volgens een der conclusies 14 tot en met 21, waarbij het niet herrangschikte humane VH gensegment het endogene muis VH gensegment vervangen heeft.
23. De werkwijze volgens een der conclusies 14 tot en met 22, waarbij het eerste humane variabel gebied gecodeerd wordt door een variabel gebied van een zware keten welke ontstaat door de herrangschikking van de humane VH, JH en DH gensegmenten gekozen uit de groep omvattende de herrangschikkingen zoals genoemd in Tabel 29.
24. De werkwijze volgens een der conclusies 14 tot en met 23, waarbij de muis 12 tot 25 functionele niet herrangschikte humane VH gensegmenten omvat.
25. De werkwijze volgens conclusie 24, waarbij 90-100% van de endogene niet herrangschikte muis VH gensegmenten vervangen zijn met de betreffende 12 tot 25 functionele niet herrangschikte humane VH gensegmenten.
26. Een bispecifiek antigen-bindend eiwit vervaardigd volgens de werkwijze van een der conclusies 14 tot en met 25.
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| US20130045492A1 (en) | 2010-02-08 | 2013-02-21 | Regeneron Pharmaceuticals, Inc. | Methods For Making Fully Human Bispecific Antibodies Using A Common Light Chain |
| ES2547142T5 (es) | 2010-02-08 | 2021-12-09 | Regeneron Pharma | Cadena ligera común de ratón |
| US9796788B2 (en) | 2010-02-08 | 2017-10-24 | Regeneron Pharmaceuticals, Inc. | Mice expressing a limited immunoglobulin light chain repertoire |
| PL3572517T3 (pl) | 2011-08-05 | 2021-10-04 | Regeneron Pharmaceuticals, Inc. | Myszy z humanizowanym uniwersalnym łańcuchem lekkim |
| KR20210088756A (ko) | 2014-03-21 | 2021-07-14 | 리제너론 파마슈티칼스 인코포레이티드 | 단일 도메인 결합 단백질을 생산하는 비-인간 동물 |
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| GB201710984D0 (en) | 2017-07-07 | 2017-08-23 | Kymab Ltd | Cells, vertebrates, populations & methods |
| KR102617284B1 (ko) | 2018-06-14 | 2023-12-27 | 리제너론 파마슈티칼스 인코포레이티드 | 면역글로불린 중쇄 암호화 서열에서 dh-dh 재배열 가능한 비인간 동물 |
| EP3927153A1 (en) | 2019-02-22 | 2021-12-29 | Regeneron Pharmaceuticals, Inc. | Rodents having genetically modified sodium channels and methods of use thereof |
| AU2020289554A1 (en) * | 2019-06-05 | 2021-11-18 | Regeneron Pharmaceuticals, Inc. | Non-human animals having a limited lambda light chain repertoire expressed from the kappa locus and uses thereof |
| KR20210095781A (ko) | 2020-01-24 | 2021-08-03 | 주식회사 에이프릴바이오 | 항원결합 단편 및 생리활성 이펙터 모이어티로 구성된 융합 컨스트럭트를 포함하는 다중결합항체 및 이를 포함하는 약학조성물 |
| CA3187680A1 (en) | 2020-09-11 | 2022-03-17 | Yashu Liu | Identification and production of antigen-specific antibodies |
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| TW202242114A (zh) | 2020-12-23 | 2022-11-01 | 美商再生元醫藥公司 | 用於獲得結合至跨膜蛋白之抗體以及抗體生成細胞的方法 |
| US20220195014A1 (en) | 2020-12-23 | 2022-06-23 | Regeneron Pharmaceuticals, Inc. | Nucleic acids encoding anchor modified antibodies and uses thereof |
| GB202107372D0 (en) | 2021-05-24 | 2021-07-07 | Petmedix Ltd | Animal models and therapeutics molecules |
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| GB202216503D0 (en) | 2022-11-05 | 2022-12-21 | Quadrucept Bio Ltd | Non-human vertebrates & cells |
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| US6737056B1 (en) | 1999-01-15 | 2004-05-18 | Genentech, Inc. | Polypeptide variants with altered effector function |
| US6596541B2 (en) | 2000-10-31 | 2003-07-22 | Regeneron Pharmaceuticals, Inc. | Methods of modifying eukaryotic cells |
| US6586251B2 (en) | 2000-10-31 | 2003-07-01 | Regeneron Pharmaceuticals, Inc. | Methods of modifying eukaryotic cells |
| US7105348B2 (en) | 2000-10-31 | 2006-09-12 | Regeneron Pharmaceuticals, Inc. | Methods of modifying eukaryotic cells |
| JP4836451B2 (ja) * | 2002-07-18 | 2011-12-14 | メルス ベー ヴェー | 抗体混合物の組換え生産 |
| US7217797B2 (en) | 2002-10-15 | 2007-05-15 | Pdl Biopharma, Inc. | Alteration of FcRn binding affinities or serum half-lives of antibodies by mutagenesis |
| CN1852925A (zh) * | 2003-07-15 | 2006-10-25 | 人类多克隆治疗公司 | 人源化免疫球蛋白基因座 |
| PT1802193E (pt) | 2004-10-19 | 2014-06-23 | Regeneron Pharma | Método para gerar um murganho homozigótico para uma modificação genética |
| ES2398076T3 (es) | 2006-06-02 | 2013-03-13 | Regeneron Pharmaceuticals, Inc. | Anticuerpos de alta afinidad contra el receptor de IL-6 humano |
| MX2011014008A (es) | 2009-06-26 | 2012-06-01 | Regeneron Pharma | Anticuerpos biespecificos facilmente aislados con formato de inmunoglobulina original. |
| ES2547142T5 (es) * | 2010-02-08 | 2021-12-09 | Regeneron Pharma | Cadena ligera común de ratón |
| US20120021409A1 (en) * | 2010-02-08 | 2012-01-26 | Regeneron Pharmaceuticals, Inc. | Common Light Chain Mouse |
| US20130045492A1 (en) * | 2010-02-08 | 2013-02-21 | Regeneron Pharmaceuticals, Inc. | Methods For Making Fully Human Bispecific Antibodies Using A Common Light Chain |
| JP2015509380A (ja) * | 2012-03-06 | 2015-03-30 | リジェネロン・ファーマシューティカルズ・インコーポレイテッドＲｅｇｅｎｅｒｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． | 共通の軽鎖のマウス |
| CN104582476B (zh) * | 2012-06-05 | 2017-03-08 | 瑞泽恩制药公司 | 使用共同轻链制备完全人双特异性抗体的方法 |
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