HRP20200093T1 - Humanizirane neljudske životinje s ograničenim lokusima imunoglobulinskog teškog lanca - Google Patents

Humanizirane neljudske životinje s ograničenim lokusima imunoglobulinskog teškog lanca Download PDF

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HRP20200093T1
HRP20200093T1 HRP20200093TT HRP20200093T HRP20200093T1 HR P20200093 T1 HRP20200093 T1 HR P20200093T1 HR P20200093T T HRP20200093T T HR P20200093TT HR P20200093 T HRP20200093 T HR P20200093T HR P20200093 T1 HRP20200093 T1 HR P20200093T1
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human
mouse
gene
heavy chain
segment
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Lynn Macdonald
John MCWHIRTHER
Naxin Tu
Sean Stevens
Andrew J. Murphy
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Regeneron Pharmaceuticals, Inc.
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Claims (14)

1. Miš koji u svom genomu sadrži: (a) nepreuređenu humanu genomsku sekvencu koja obuhvaća jedan humani segment gena VH, jedan ili više humanih segmenata gena DH i jedan ili više humanih segmenata gena JH, naznačeno time, što su jedan humani segment gena VH, jedan ili više humanih segmenata gena DH i jedan ili više humanih segmenata gena JH operativno povezani s genom konstantne regije mišjeg imunoglobulinskog teškog lanca i naznačeno time, što jedan humani segment gena VH jest VH1-2, VH1-69, VH2-26, VH2-70 ili njegova polimorfna varijanta; i (b) sekvencu koja šifrira mišji protein ADAM6a ili njegov funkcionalni fragment i sekvencu koja šifrira mišji protein ADAM6b ili njegov funkcionalni fragment, naznačeno time, što su mišji protein ADAM6a ili njegov funkcionalni fragment i mišji protein ADAM6b ili njegov funkcionalni protein funkcionalni u mužjaka miša, naznačeno time, što se predmetne šifrirajuće sekvence nalaze u položaju izvan lokusa ADAM6 miša divljeg tipa tako da, kao odgovor na izlaganje antigenu, B stanice miša izražavaju varijabilne domene humanog teškog lanca izražene iz sekvence varijabilne regije humanog teškog lanca uključujući segment gena VH koji je identičan ili somatski hipermutirana verzija VH1-2, VH1-69, VH2-26, VH2-70 ili njegove polimorfne varijante; naznačeno time, što predmetni miš ne posjeduje funkcionalni endogeni gen ADAM6.
2. Miš prema patentnom zahtjevu 1, naznačen time, što: (I) jedan humani segment gena VH je polimorfna varijanta VH1-2, VH1-69, VH2-26, VH2-70; (II) šifrirajuće sekvence su prisutne na položaju u genomu miša izvan endogenog lokusa imunoglobulinskog teškog lanca; (III) šifrirajuće sekvence su postavljene podređeno ili neposredno uz nepreuređenu humanu genomsku sekvencu; (IV) nepreuređena humana genomska sekvenca nalazi se na endogenom lokusu imunoglobulinskog teškog lanca; (V) nepreuređena humana genomska sekvenca nalazi se na endogenom lokusu imunoglobulinskog lakog lanca, a šifrirajuće sekvence nalaze se na položaju u genomu miša izvan endogenog lokusa imunoglobulinskog teškog lanca; (VI) miš sadrži deleciju svih ili suštinski svih endogenih segmenata gena VH; ili (VII) gen konstantne regije mišjeg imunoglobulinskog lakog lanca se nalazi na endogenom lokusu imunoglobulinskog teškog lanca.
3. Miš prema patentnom zahtjevu 1, naznačen time, što: (I) jedan humani segment gena VH je VH1-69; ili (II) jedan humani segment gena VH je VH1-2.
4. Miš prema patentnom zahtjevu 1, naznačen time, što: (I) nepreuređena humana genomska sekvenca sadrži humani segment gena VH1-69, dvadeset sedam humanih segmenata gena DH i šest humanih segmenata gena JH; ili (II) nepreuređena humana genomska sekvenca sadrži humani segment gena VH1-2, dvadeset sedam humanih segmenata gena DH i šest humanih segmenata gena JH.
5. Miš prema patentnom zahtjevu 1 ili 4, koji dodatno u svom genomu sadrži jedan ili više humanih segmenata gena Vκ i jedan ili više humanih segmenata Jκ, opcionalno naznačeno time, što se jedan ili više humanih segmenata gena Vκ i jedan ili više humanih segmenata gena Jκ nalaze na endogenom lokusu imunoglobulinskog lakog lanca.
6. Miš koji u svom genomu sadrži sekvencu nukleinske kiseline koja sadrži jedan humani segment gena VH, najmanje jedan humani segment gena DH i najmanje jedan humani segment gena JH, naznačeno time, što su jedan humani segment gena VH, jedan ili više humanih segmenata gena DH i jedan ili više humanih segmenata gena JH operativno povezani s genom konstantne regije mišjeg imunoglobulinskog teškog lanca i naznačeno time, što jedan humani segment gena VH jest VH1-2, VH1-69, VH2-26, VH2-70 ili njegova polimorfna varijanta, naznačeno time, što miš ne posjeduje funkcionalni endogeni gen ADAM6 i naznačeno time, što miš sadrži sekvence ektopijskog mišjeg ADAM6 koje šifriraju protein ADAM6a ili njegov funkcionalni fragment i protein ADAM6b ili njegov funkcionalni fragment.
7. Miš prema patentnom zahtjevu 6, naznačen time, što: (I) sekvence ektopijskog mišjeg ADAM6 se nalaze na endogenom imunoglobulinskom lokusu; Ili (II) sekvence ektopijskog mišjeg ADAM6 se nalaze u genomu miša na položaju izvan endogenog imunoglobulinskog lokusa.
8. Stanica ili tkivo dobiveno iz miša prema bilo kojem od prethodnih patentnih zahtjeva, naznačeno time, što stanica ili miš sadrži (a) nepreuređenu humanu genomsku sekvencu koja sadrži jedan humani segment gena VH, jedan ili više humanih segmenata gena DH i jedan ili više humanih segmenata gena JH, naznačeno time, što su jedan humani segment gena VH, jedan ili više humanih segmenata gena DH i jedan ili više humanih segmenata gena JH operativno povezani s genom konstantne regije mišjeg imunoglobulinskog teškog lanca i naznačeno time, što jedan humani segment gena VH jest VH1-2, VH1-69, VH2-26, VH2-70 ili njegova polimorfna varijanta; i (b) sekvencu koja šifrira mišji protein ADAM6a ili njegov funkcionalni fragment i sekvencu koja šifrira mišji protein ADAM6b ili njegov funkcionalni fragment, naznačeno time, što su mišji protein ADAM6a ili njegov funkcionalni fragment i mišji protein ADAM6b ili njegov funkcionalni protein funkcionalni u mužjaka miša, naznačeno time, što se predmetne šifrirajuće sekvence nalaze u položaju izvan lokusa ADAM6 miša divljeg tipa
9. Metoda za proizvodnju humanog antitijela koje sadrži imunoglobulinski teški lanac dobiven iz jednog humanog segmenta gena VH, pri čemu se metoda sastoji od (a) imunizacije miša prema bilo kojem patentnom zahtjevu od 1 do 7 pomoću interesnog antigena; (b) omogućavanja predmetnom mišu da razvije imunološki odgovor na interesni antigen; i (c) identifikacije ili izolacije sekvence varijabilne regije imunoglobulinskog teškog lanca koja šifrira varijabilnu domenu imunoglobulinskog teškog lanca antitijela koje stvara miš, naznačeno time, što se antitijelo vezuje za interesni antigen.
10. Metoda prema patentnom zahtjevu 9, naznačena time, što: (I) varijabilna domena imunoglobulinskog teškog lanca je najmanje 75 %, najmanje 80 %, najmanje 85 %, najmanje 95 % ili najmanje 98 % identična SEQ ID NO: 5; (II) varijabilna domena imunoglobulinskog teškog lanca sadrži SEQ ID NO: 5; (III) varijabilna domena imunoglobulinskog teškog lanca je najmanje 75 %, najmanje 80 %, najmanje 85 %, najmanje 95 % ili najmanje 98 % identična SEQ ID NO: 64; (IV) varijabilna domena imunoglobulinskog teškog lanca sadrži SEQ ID NO: 64.
11. Metoda za modifikaciju mišjeg lokusa imunoglobulinskog teškog lanca radi dobivanja miša čiji genom sadrži lokus imunoglobulinskog teškog lanca uključujući jedan humani segment VH, pri čemu se metoda sastoji od: (a) postizanja prve modifikacije lokusa mišjeg imunoglobulinskog teškog lanca koja uključuje umetanje jednog humanog segmenta VH i dovodi do smanjenja ili eliminacije aktivnosti endogenog mišjeg ADAM6 kod mužjaka miša, naznačeno time, što jedan humani segment gena VH jest VH1-2, VH1-69, VH2-26, VH2-70 ili njegova polimorfna varijanta; i (b) postizanja druge modifikacija miša radi vraćanja aktivnosti ADAM6 kod miša, koje se sastoji od izražavanja sekvence koja šifrira mišji protein ADAM6a ili njegov funkcionalni fragment naznačeno time, što su mišji protein ADAM6a ili njegov funkcionalni fragment i mišji protein ADAM6b ili njegov funkcionalni fragment funkcionalni kod mužjaka miša.
12. Metoda za dobivanje antitijela koje specifično djeluje protiv antigena, pri čemu se metoda sastoji od sljedećih koraka: (a) imunizacije miša prema bilo kojem patentnom zahtjevu od 1 do 7 pomoću antigena; (b) izolacije najmanje jedne stanice iz miša koja proizvodi antitijelo koje specifično djeluje protiv antigena; i (c) uzgajanja najmanje jedne stanice koja proizvodi antitijelo iz koraka (b) i dobivanja predmetnog antitijela.
13. Metoda prema patentnom zahtjevu 12, naznačena time, što: (I) uzgajanje iz koraka (c) se obavlja na najmanje jednoj hibridoma stanici proizvedenoj iz najmanje jedne stanice dobivene u koraku (b); (II) najmanje jedna stanica dobivena u koraku (b) se dobiva iz slezene, limfnog čvora ili koštane srži miša iz koraka (a); Ili (III) imunizacija pomoću antigena iz koraka (a) obavlja se pomoću proteina, DNK, kombinacije DNK i proteina ili stanica koje izražavaju antigen.
14. Upotreba miša prema bilo kojem patentnom zahtjevu od 1 do 7, radi dobivanja sekvence nukleinske kiseline koja šifrira varijabilnu domenu humanog imunoglobulinskog teškog lanca.
HRP20200093TT 2012-06-12 2013-03-07 Humanizirane neljudske životinje s ograničenim lokusima imunoglobulinskog teškog lanca HRP20200093T1 (hr)

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US201261658466P 2012-06-12 2012-06-12
US201261663131P 2012-06-22 2012-06-22
PCT/US2013/029624 WO2013187953A1 (en) 2012-06-12 2013-03-07 Humanized non-human animals with restricted immunoglobulin heavy chain loci
EP13710268.7A EP2858487B1 (en) 2012-06-12 2013-03-07 Humanized non-human animals with restricted immunoglobulin heavy chain loci

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