HRP20221459T1 - Miševi koji imaju modificirani lambda laki lanac imunoglobulina i njihove upotrebe - Google Patents
Miševi koji imaju modificirani lambda laki lanac imunoglobulina i njihove upotrebe Download PDFInfo
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- 108060003951 Immunoglobulin Proteins 0.000 title claims 5
- 102000018358 immunoglobulin Human genes 0.000 title claims 5
- 241000699670 Mus sp. Species 0.000 title 1
- 108090000623 proteins and genes Proteins 0.000 claims 51
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 claims 10
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 claims 10
- 241001529936 Murinae Species 0.000 claims 9
- 210000002308 embryonic cell Anatomy 0.000 claims 4
- 102000013463 Immunoglobulin Light Chains Human genes 0.000 claims 3
- 108010065825 Immunoglobulin Light Chains Proteins 0.000 claims 3
- 102100029567 Immunoglobulin kappa light chain Human genes 0.000 claims 3
- 101710189008 Immunoglobulin kappa light chain Proteins 0.000 claims 3
- 108091026890 Coding region Proteins 0.000 claims 2
- 108010008286 DNA nucleotidylexotransferase Proteins 0.000 claims 2
- 102100033215 DNA nucleotidylexotransferase Human genes 0.000 claims 2
- 230000002068 genetic effect Effects 0.000 claims 2
- 108091028043 Nucleic acid sequence Proteins 0.000 claims 1
- 210000003719 b-lymphocyte Anatomy 0.000 claims 1
- 150000007523 nucleic acids Chemical group 0.000 claims 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 claims 1
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- C12N9/1241—Nucleotidyltransferases (2.7.7)
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Claims (16)
1. Genetički modificirani miš, čiji genom embrionalnih stanica obuhvaća:
prvi modificirani endogeni imunoglobulinski k lokus lakog lanca koji sadrži:
(a) jedan ili više segmenata humanog Vλ gena,
(b) jedan ili više segmenata humanog Jλ gena, i
(c) jedan mišji Cλ gen,
pri čemu su jedan ili više segmenata humanog Vλ gena iz (a) i jedan ili više segmenata humanog Jλ gena iz (b) umjesto jednog ili više endogenih segmenata Vκ gena miša i jednog ili više endogenih segmenata Jκ gena miša;
pri čemu su jedan ili više segmenata humanog Vλ gena iz (a) i jedan ili više segmenata humanog Jλ gena iz (b) operativno vezani za jedan mišji Cλ gen iz (c);
pri čemu genetički modificirani miš sadrži populaciju B stanica koje eksprimiraju antitijela, pri čemu antitijela uključuju λ lake lance imunoglobulina od kojih svaki uključuje varijabilni domen λ lakog lanca humanog imunoglobulina; i
pri čemu genetički modificiranom mišu nedostaje mišji Cκ gen na prvom modificiranom endogenom lokusu lakog lanca imunoglobulina κ.
2. Genetički modificirani miš prema zahtjevu 1, pri čemu genetički modificirani miš je homozigotan za prvi modificirani endogeni lokus κ lakog lanca imunoglobulina.
3. Genetički modificirani miš prema zahtjevu 1, pri čemu genetički modificirani miš je heterozigotan za prvi modificirani endogeni lokus κ lakog lanca imunoglobulina.
4. Genetički modificirani miš prema zahtjevu 3, pri čemu genom embrionalnih stanica genetički modificiranog miša sadrži drugi modificirani endogeni lokus κ lakog lanca imunoglobulina koji sadrži:
(a) jedan ili više humanih Vκ segmenata gena, i
(b) jedan ili više humanih Jκ segmenata gena,
pri čemu jedan ili više humanih Vκ segmenata gena i jedan ili više humanih Jκ segmenata gena su operativno povezani s Cκ genom.
5. Genetički modificirani miš prema bilo kojem od prethodnih zahtjeva, pri čemu genom embrionalnih stanica miša dalje sadrži:
modificirani endogeni lokus teškog lanca imunoglobulina, koji sadrži:
(a) jedan ili više humanih VH segmenata gena,
(b) jedan ili više humanih DH segmenata gena, i
(c) jedan ili više humanih JH segmenata gena,
pri čemu jedan ili više humanih VH segmenata gena (a), jedan ili više humanih DH segmenata gena (b), i jedan ili više humanih JH segmenata gena (c) su operativno povezani s jednim ili više mišjim genima konstantne regije teškog lanca imunoglobulina u modificiranom lokusu teškog lanca imunoglobulina.
6. Genetički modificirani miš prema zahtjevu 5, pri čemu jedan ili više humanih VH segmenata gena (a), jedan ili više humanih DH segmenata gena (b), i jedan ili više humanih JH segmenata gena (c) su umjesto jednog ili više mišjih VH segmenata gena, jednog ili više mišjih DH segmenata gena, jednog ili više mišjih JH segmenata gena, ili njihove kombinacije.
7. Genetički modificirani miš prema zahtjevu 5 ili 6, pri čemu modificirani endogeni lokus teškog lanca imunoglobulina dalje sadrži:
(i) jednu ili više humanih VH nekodirajućih sekvenci, od kojih je svaka u blizini s barem jednim od jednog ili više humanih VH segmenata gena, pri čemu svaka od jedne ili više VH nekodirajućih sekvenci prirodno se nalazi u blizini u odnosu na humani VH segment gena u endogenom lokusu humanog teškog lanca imunoglobulina;
(ii) jednu ili više humanih DH nekodirajućih sekvenci, od kojih je svaka u blizini s barem jednim od jednog ili više humanih DH segmenata gena, pri čemu svaka od jedne ili više DH nekodirajućih sekvenci prirodno se nalazi u blizini u odnosu na humani DH segment gena u endogenom lokusu humanog teškog lanca imunoglobulina;
(iii) jednu ili više humanih JH nekodirajućih sekvenci, od kojih je svaka u blizini s barem jednim od jednog ili više humanih JH segmenata gena, pri čemu svaka od jedne ili više JH nekodirajućih sekvenci prirodno se nalazi u blizini u odnosu na humani JH segment gena u endogenom lokusu humanog teškog lanca imunoglobulina; ili
(iv) bilo koju njihovu kombinaciju.
8. Genetički modificirani miš prema bilo kojem od zahtjeva 5 do 7, pri čemu jedan ili više gena konstantne regije mišjeg teškog lanca imunoglobulina su jedan ili više endogenih gena mišje konstantne regije teškog lanca imunoglobulina.
9. Genetički modificirani miš prema bilo kojem od zahtjeva 5 do 8, pri čemu:
(i) jedan ili više humanih VH segmenata gena sadrže VH3-74, VH3-73, VH3-72, VH2-70, VH1-69, VH3-66, VH3-64, VH4-61, VH4-59, VH1-58, VH3-53, VH5-51, VH3-49, VH3-48, VH1-46, VH1-45, VH3-43, VH4-39, VH4-34, VH3-33, VH4-31, VH3-30, VH4-28, VH2-26, VH1-24, VH3-23, VH3-21, VH3-20, VH1-18, VH3-15, VH3-13, VH3-11, VH3-9, VH1-8, VH3-7, VH2-5, VH7-4-1, VH4-4, VH1-3, VH1-2, VH6-1, ili njihovu kombinaciju,
(ii) jedan ili više humanih DH genetičkih segmenata sadrže DH1-1, DH2-2, DH3-3, DH4-4, DH5-5, DH6-6, DH1-7, DH2-8, DH3-9, DH3-10, DH5-12, DH6-13, DH2-15, DH3-16, DH4-17, DH6-19, DH1-20, DH2-21, DH3-22, DH6-25, DH1-26, DH7-27, ili njihovu kombinaciju, i
(iii) jedan ili više humanih JH segmenata gena sadrže JH1, JH2, JH3, JH4, JH5, JH6, ili njihovu kombinaciju.
10. Genetički modificirani miš prema bilo kojem od zahtjeva 5 do 9, pri čemu genetički modificirani miš je homozigotan za modificirani endogeni lokus teškog lanca imunoglobulina.
11. Genetički modificirani miš prema bilo kojem od prethodnih zahtjeva, pri čemu jedan ili više humanih Vλ genetičkih segmenata pod (a) i jedan ili više humanih Jλ segmenata gena pod (b) zamjenjuju jedan ili više mišjih Vκ segmenata gena, jedan ili više mišjih Jκ segmenata gena, ili njihovu kombinaciju.
12. Genetički modificirani miš prema bilo kojem od prethodnih zahtjeva, pri čemu prvi modificirani endogeni lokus κ lakog lanca imunoglobulina dalje sadrži nekodirajuću sekvencu κ lakog lanca između jednog ili više humanih Vλ segmenata gena i jedan ili više humanih Jλ segmenata gena.
13. Genetički modificirani miš prema zahtjevu 12, pri čemu κ laki lanac nekodirajuće sekvence ima sekvencu koja se prirodno nalazi između humanog Vκ4-1 genskog segmenta i humanog Jκ1 genskog segmenta u endogenom humanom lokusu κ lakog lanca imunoglobulina.
14. Genetički modificirani miš prema bilo kojem od prethodnih zahtjeva, pri čemu endogeni Vλ segmenti gena, endogeni Jλ segmenti gena, i endogeni Cλ geni su uklonjeni u cjelini ili dijelom.
15. Genetički modificirani miš prema bilo kojem od prethodnih zahtjeva, pri čemu svaki varijabilni domen humanog λ lakog lanca imunoglobulina je kodiran s preuređenom sekvencom varijabilne regije humanog λ lakog lanca imunoglobulina koja sadrži (i) jedan od jednog ili više humanih Vλ genskih segmenata pod (a) ili njegova somatski hipermutirana varijanta, i (ii) jedan od jednog ili više humanih Jλ genskih segmenata pod (b) ili njegova somatski hipermutirana varijanta.
16. Genetički modificirani miš prema bilo kojem od prethodnih zahtjeva, pri čemu genom embrionalnih stanica dalje obuhvaća sekvencu nukleinske kiseline koja kodira egzogenu terminalnu deoksinukleotidiltransferazu (TdT) koja je operativno povezana s transkripcijskim kontrolnim elementom.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201762594944P | 2017-12-05 | 2017-12-05 | |
| US201762594946P | 2017-12-05 | 2017-12-05 | |
| US201762609241P | 2017-12-21 | 2017-12-21 | |
| US201762609251P | 2017-12-21 | 2017-12-21 | |
| PCT/US2018/063841 WO2019113065A1 (en) | 2017-12-05 | 2018-12-04 | Non-human animals having an engineered immunoglobulin lambda light chain and uses thereof |
| EP18821945.5A EP3720279B1 (en) | 2017-12-05 | 2018-12-04 | Mice having an engineered immunoglobulin lambda light chain and uses thereof |
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| HRP20221459T1 true HRP20221459T1 (hr) | 2023-01-20 |
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| US (3) | US20210345591A1 (hr) |
| EP (2) | EP3720279B1 (hr) |
| JP (2) | JP7430636B2 (hr) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017095939A1 (en) | 2015-12-03 | 2017-06-08 | Trianni, Inc. | Enhanced immunoglobulin diversity |
| CN111432635B (zh) | 2017-12-05 | 2022-10-21 | 瑞泽恩制药公司 | 具有经工程改造的免疫球蛋白λ轻链的非人动物以及所述非人动物的用途 |
| US20190380316A1 (en) | 2018-06-14 | 2019-12-19 | Regeneron Pharmaceuticals, Inc. | Non-human animals capable of engineered dh-dh rearrangement and uses thereof |
| WO2020172505A1 (en) | 2019-02-22 | 2020-08-27 | Regeneron Pharmaceuticals, Inc. | Rodents having genetically modified sodium channels and methods of use thereof |
| JP2022538885A (ja) * | 2019-07-01 | 2022-09-06 | トリアニ・インコーポレイテッド | トランスジェニック哺乳動物およびその使用法 |
| IL301137A (en) | 2020-09-11 | 2023-05-01 | Regeneron Pharma | Identification and production of antigen-specific antibodies |
| KR20230147048A (ko) | 2020-12-16 | 2023-10-20 | 리제너론 파마슈티칼스 인코포레이티드 | 인간화 Fc 알파 수용체를 발현하는 마우스 |
| CN116635413A (zh) | 2020-12-23 | 2023-08-22 | 再生元制药公司 | 用于获得结合跨膜蛋白的抗体的方法和生产所述抗体的细胞 |
| EP4051700A1 (en) | 2020-12-23 | 2022-09-07 | Regeneron Pharmaceuticals, Inc. | Nucleic acids encoding anchor modified antibodies and uses thereof |
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