DK2967013T3 - Mus, der udtrykker et begrænset immunoglobulin-letkæde-repertoire - Google Patents
Mus, der udtrykker et begrænset immunoglobulin-letkæde-repertoire Download PDFInfo
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- DK2967013T3 DK2967013T3 DK14717331.4T DK14717331T DK2967013T3 DK 2967013 T3 DK2967013 T3 DK 2967013T3 DK 14717331 T DK14717331 T DK 14717331T DK 2967013 T3 DK2967013 T3 DK 2967013T3
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Classifications
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/46—Hybrid immunoglobulins
- C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
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- A—HUMAN NECESSITIES
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- C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
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Claims (14)
1. Mus, der i sit kimbanegenom omfatter: to humane immunoglobulin VK-gensegmenter og fem humane immunoglobulin jK-gensegmenter, der er operativt forbundet med en konstant immunoglobulin-letkæde-region fra mus eller rotte, hvor de to humane immunoglobulin VK-gensegmenter er et humant Vk1-39 og et humant Vk3-20, og de fem humane immunoglobulin JK-gensegmenter er humant Jk1, humant Jk2, humant Jk3, humant Jk4 og humant Jk5; og ét eller flere humane immunoglobulin Vn-gensegmenter, ét eller flere humane immunoglobulin Dn-gensegmenter og ét eller flere humane immunoglobulin JH-gensegmenter, der er operativt forbundet med en sekvens af en konstant immunoglobulin-region fra mus eller rotte; hvor de humane immunoglobulin-gensegmenter er i stand til at omarrangere og kode for humane variable immunoglobulin-domæner af et antistof, og endvidere hvor musen ikke omfatter et endogent immunoglobulin Vl-gensegment, der er i stand til at omarrangere, for at danne en sekvens af en variabel immunoglobulin-letkæde-region.
2. Mus ifølge krav 1, hvor (a) de to humane VK-gensegmenter og de fem humane JK-gensegmenter er operativt forbundet med en konstant immunoglobulin-letkæde-region fra mus eller rotte, der er (i) en CK-region fra rotte eller (ii) en CK-region fra mus; og/eller (b) de to humane Vk gensegmenter og fem humane Jk- gensegmenter er til stede ved et endogent immunoglobulin-letkædelocus; og/eller (c) det ene eller flere humane VH-gensegmenter, ene eller flere humane Dn-gensegmenter og ene eller flere humane JH-gensegmenter er operativt forbundet med en sekvens afen konstant region fra mus; og/eller (d) de to humane Vk gensegmenter og fem humane JK-gensegmenter er operativt forbundet med en sekvens af en konstant immunoglobulin-letkæde-region fra mus eller rotte og er til stede ved et locus, der i rækkefølge omfatter: det humane νκΙ-39-gensegment, det humane VK3-20-gensegment, et humant Jk1 , et humant Jk2, et humant Jk3, et humant Jk4 og et humant Jk5; og/eller (e) musen omfatter et letkædelocus, der i rækkefølge omfatter: det humane νκΙ-39-gensegment, det humane VK3-20-gensegment, et humant Jk1, et humant Jk2, et humant Jk3, et humant Jk4 og et humant Jk5, og hvor letkædelocusset omfatter en hVK/hJK/mCK-samlingssekvens valgt fra SEQ ID NO: 38-49; og/eller (f) musen er blevet immuniseret
3. Mus ifølge krav 1 eller 2, hvor musen omfatter et funktionelt eller ikke-funktionelt λ letkædelocus.
4. Isoleret celle fra musen ifølge et hvilket som helst af de foregående krav, hvor: (a) cellen er en embryostam- (ES) celle; eller (b) cellen er en B-celle.
5. Museembryo, der omfatter ES-cellen ifølge krav 4(a).
6. Hybridom frembragt med B-cellen ifølge krav 4(b).
7. Anvendelse af en mus ifølge et hvilket som helst af kravene 1 til 3 til at: (a) generere et antistof; og/eller (b) identificere en nukleinsyresekvens, der koder for et humant variabelt immunoglobulin-tungkæde-domæne og/eller (c) frembringe et humant bispecifikt antistof; og/eller (d) vælge et gensegment af en humant variabel immunoglobulin-tungkæde-region.
8. Fremgangsmåde til frembringelse af et antistof, der binder et antigen af interesse, hvilken fremgangsmåde omfatter immunisering af en mus ifølge et hvilket som helst af kravene 1 til 3 med et antigen af interesse, opnåelse af en sekvens af en variabel immunoglobulin-region fra musen og anvendelse af sekvensen af den variable immunoglobulin-region til at producere et antistof, der binder antigenet, fortrinsvis hvor fremgangsmåden endvidere omfatter: ekspression i en enkelt celle af: (a) en første human sekvens af en variabel immunoglobulin-tungkæde-region fra musen ifølge et hvilket som helst af kravene 1 til 3, der er blevet immuniseret, hvor den humane sekvens af en variabel immunoglobulin-tungkæde-region kondenseres med en human Cn-gensekvens; og (b) en human sekvens af en variabel immunoglobulin-letkæde-region, hvor den humane sekvens af en variabel immunoglobulin-letkæde-region kondenseres med en human sekvens af en konstant immunoglobulin-letkæde-region; bevaring af cellen under forhold, der er tilstrækkelige til at udtrykke et fuldt humant antistof; og isolering af antistoffet fra cellen.
9. Fremgangsmåde ifølge krav 8, hvor cellen omfatter en anden human sekvens af en variabel immunoglobulin-tungkæde-region fra en mus ifølge et hvilket som helst af kravene 1 til 3, der er blevet immuniseret, hvor den anden humane sekvens af en variabel immunoglobulin-tungkæde-region kondenseres med en human sekvens af en konstant immunoglobulin-tungkæde-region, hvor den første humane sekvens af en variabel immunoglobulin-tungkæde-region koder for et første humant domæne af en immunoglobulin-tungkæde, der genkender en første epitop, og den anden human sekvens af en variabel immunoglobulin-tungkæde-region koder for et andet humant variabelt domæne af en immunoglobulin-tungkæde, der genkender en anden epitop, hvor den første epitop og den anden epitop ikke er identiske, og hvor det første og det andet humane variable domæne af immunoglobulin-tungkæden interagerer med det humane variable domæne af immunoglobulin-letkæden kodet for af den humane sekvens af en variabel immunoglobulin-letkæde-region.
10. Fremgangsmåde til frembringelse af et humant bispecifikt antistof, hvor fremgangsmåden omfatter immunisering af en mus ifølge et hvilket som helst af kravene 1 til 3 og frembringelse af det bispecifikke antistof ved anvendelse af humane sekvenser af en variabel immunoglobulin-region af B-celler fra musen, fortrinsvis hvor fremgangsmåden endvidere omfatter: (a) identificering af en klonisk udvalgt lymfocyt fra musen ifølge et hvilket som helst af kravene 1 til 3, hvor musen er blevet immuniseret og har fået mulighed for at udvikle et immunrespons på et antigen af interesse, hvor lymfocytten udtrykker et antistof, der specifikt binder antigenet af interesse; (b) opnåelse af lymfocytten eller antistoffet af en nukleotidsekvens, der koder for et humant variabelt domæne af en immunoglobulin-tungkæde, der specifikt binder antigenet af interesse; og (c) anvendelse af nukleotidsekvensen fra (b) til frembringelse af et bispecifikt antistof.
11. Fremgangsmåde ifølge krav 10, hvor trin (a) til og med (c) først udføres for et første antigen af interesse for at generere en første human sekvens af en variabel immunoglobulin-tungkæde-region, og trin (a) til og med (c) udføres derefter for et andet antigen af interesse for at generere en anden human sekvens af en variabel immunoglobulin-tungkæde-region, og hvor den første humane sekvens af den variable immunoglobulin-tungkæde-region udtrykkes med en første human sekvens af den konstante immunoglobulin-tungkæde-region for at danne en første human immunoglobulin-tungkæde, den anden humane sekvens af en variabel immunoglobulin-tungkæde-region udtrykkes med en anden human sekvens af en konstant immunoglobulin-tungkæde-region for at danne en anden human immunoglobulin-tungkæde, hvor den første og den anden humane immunoglobulin-tungkæde udtrykkes i nærvær af en enkelt human immunoglobulin-letkæde, der omfatter en human V|_.region afledt af en omarrangeret human letkædesekvens, der omfatter et humant Vk1-39-gensegment eller et humant VK3-20-gensegment.
12. Fremgangsmåde ifølge krav 11, hvor fremgangsmåden omfatter: (a) kloning af humane sekvenser af variable immunoglobulin-tungkæde-regioner fra B-celler fra: (i) musen ifølge et hvilket som helst af kravene 1 til 3, der er blevet immuniseret med et første immunogen; og (ii) den samme mus, eller en anden mus, der genetisk er den samme, der er blevet immuniseret med et andet immunogen; (b) ekspression i en celle af den humane sekvens af variable immunoglobulin-tungkæde-regioner fra (a) med en human sekvens af en konstant immunoglobulin-tungkæde-region og den samme immunoglobulin-letkæde for at frembringe et bispecifikt antistof, fortrinsvis hvor den første humane immunoglobulin-tungkæde omfatter en modifikation, der eliminerer eller i alt væsentligt reducerer affiniteten for det første humane immunoglobulin-tungkæde til protein A, og den anden human immunoglobulin-tungkæde bevarer evnen til at binde protein A, hvor modifikationen, der eliminerer eller i alt væsentligt reducerer affinitet for den første humane immunoglobulin-tungkæde til protein A, er valgt fra: 95R (EU 435R), 96F (EU 436F), og en kombination deraf.
13. Fremgangsmåde til fremstilling af et antistof, der omfatter immunisering af en mus ifølge et hvilket som helst af kravene 1 til 3 med et antigen og opnåelse af en human aminosyresekvens af et variabelt immunoglobulin-tungkæde-domæne, eller kodning for nukleotidsekvens, fra et resulterende antistof produceret af musen mod antigenet, og anvendelse af den humane aminosyresekvens af et variabelt immunoglobulin-tungkæde-domæne eller kodning for nukleinsyresekvens ved frembringelse af et antistof, fortrinsvis hvor fremgangsmåden endvidere omfatter: (a) identificering af den humane aminosyresekvens af et variabelt immunoglobulin-tungkæde-domæne, eller kodning for nukleotidsekvens, fra to forskellige antistoffer mod forskellige epitoper af det antigen, som musen er blevet immuniseret med; eller (b) immunisering af den samme mus, eller en yderligere mus ifølge et hvilket som helst af kravene 1 til 3, med et andet antigen, derefter identificering af en human aminosyresekvens af et variabelt immunoglobulin-tungkæde-domæne, eller kodning for nukleotidsekvens, fra et antistof produceret af musen, der er specifikt for det andet antigen, hvor fremgangsmåden endvidere omfatter anvendelse af de to forskellige humane aminosyresekvenser af et variabelt immunoglobulin-tungkæde-domæne, eller kodning for nukleotidsekvenser, for at generere et bispecifikt antistof.
14. Fremgangsmåde ifølge krav 13, hvor fremgangsmåden endvidere omfatter (a) identificering af den humane aminosyresekvens af et variabelt immunoglobulin-letkæde-domæne, eller kodning for nukleotidsekvens, fra antistoffet eller to antistoffer; og/eller (b) anvendelse af den humane aminosyresekvens af et variabelt immunoglobulin-letkæde-domæne og/eller de humane aminosyresekvenser af et variabelt immunoglobulin-tungkæde-domæne identificeret i antistoffet produceret ved hjælp af fremgangsmåden til at generere et bispecifikt antistof.
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| US13/798,455 US9796788B2 (en) | 2010-02-08 | 2013-03-13 | Mice expressing a limited immunoglobulin light chain repertoire |
| PCT/US2014/026040 WO2014160202A1 (en) | 2013-03-13 | 2014-03-13 | Mice expressing a limited immunoglobulin light chain repertoire |
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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 |
| ES2728942T3 (es) | 2010-02-08 | 2019-10-29 | 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 |
| BR112014002713B1 (pt) | 2011-08-05 | 2023-01-17 | Regeneron Pharmaceuticals, Inc | Métodos para produzir camundongos geneticamente modificados, uso dos referidos camundongos e uso de uma sequência de ácido nucleico produzida pelos referidos camundongos |
| MX355062B (es) | 2011-10-17 | 2018-04-03 | Regeneron Pharma | Ratones con cadena pesada de inmunoglobulina restringida. |
| KR20150027793A (ko) | 2012-06-12 | 2015-03-12 | 리제너론 파마슈티칼스 인코포레이티드 | 제한된 면역글로불린 중쇄 유전자좌를 가지는 인간화된 비-인간 동물 |
| US20140245468A1 (en) * | 2013-02-20 | 2014-08-28 | Regeneron Pharmaceuticals, Inc. | Non-human animals with modified immunoglobulin heavy chain sequences |
| EP3119194B1 (en) | 2014-03-21 | 2021-04-28 | Regeneron Pharmaceuticals, Inc. | Non-human animals that make single domain binding proteins |
| EP3271403A1 (en) | 2015-03-19 | 2018-01-24 | Regeneron Pharmaceuticals, Inc. | Non-human animals that select for light chain variable regions that bind antigen |
| SG10201914034WA (en) | 2016-01-13 | 2020-03-30 | Regeneron Pharma | Rodents having an engineered heavy chain diversity region |
| BR112020004977A2 (pt) * | 2017-09-29 | 2020-10-06 | Regeneron Pharmaceuticals, Inc. | moléculas de ligação de antígenos biespecíficas que ligam antígeno alvo de staphyocococcus e componente de complemento e usos dos mesmos |
| IL318469A (en) | 2018-06-14 | 2025-03-01 | Regeneron Pharma | Non-human animals capable of reorganizing transgenic DH-DH, and their uses |
| EP3897117A1 (en) * | 2018-12-21 | 2021-10-27 | Compass Therapeutics LLC | Transgenic mouse expressing common human light chain |
| CN117099741A (zh) | 2019-02-18 | 2023-11-24 | 百奥赛图(北京)医药科技股份有限公司 | 具有人源化免疫球蛋白基因座的经遗传修饰的非人动物 |
| US11464217B2 (en) | 2019-02-22 | 2022-10-11 | Regeneron Pharmaceuticals, Inc. | Rodents having genetically modified sodium channels and methods of use 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 |
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