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HRP20190807T1 - Miševi koji izražavaju imunoglobulinski hibridni laki lanac s humanom varijabilnom regijom - Google Patents

Miševi koji izražavaju imunoglobulinski hibridni laki lanac s humanom varijabilnom regijom Download PDF

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HRP20190807T1
HRP20190807T1 HRP20190807TT HRP20190807T HRP20190807T1 HR P20190807 T1 HRP20190807 T1 HR P20190807T1 HR P20190807T T HRP20190807T T HR P20190807TT HR P20190807 T HRP20190807 T HR P20190807T HR P20190807 T1 HRP20190807 T1 HR P20190807T1
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Croatia
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gene
mouse
human
light chain
segment
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HRP20190807TT
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Lynn Macdonald
Sean Stevens
Cagan Gurer
Andrew J. Murphy
Karolina A. Hosiawa
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Regeneron Pharmaceuticals, Inc.
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Publication of HRP20190807T1 publication Critical patent/HRP20190807T1/hr

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Claims (19)

1. Miš, koji sadrži: nepreuređen humani varijabilni segment gena imunoglobulinskog lakog lanca (hVH), nepreuređeni humani diverzitetski segment gena imunoglobulinskog teškog lanca (hDH) i nepreuređeni humani vezivni segment gena imunoglobulinskog teškog lanca (hJH) koji su operativno povezani s mišjim konstantnim genom (CH) imunoglobulinskog teškog lanca, i nepreuređeni humani varijabilni segment gena imunoglobulinskog lakog lanca λ (hVλ) i humani vezivni segment gena λ (hJλ) koji su operativni povezani s mišjim konstantnim genom imunoglobulinskog lakog lanca k (Ck) na lokusu endogenog mišjeg imunoglobulinskog lakog lanca k, naznačen time, što se na spomenutom lokusu održava element intronskog pojačivača k uzvodno od segmenta gena Ck (označen kao Eki) i pojačivač 3' k nizvodno od segmenta gena Ck (označen kao Ek3'), pri čemu miš izražava antitijelo koje sadrži teški lanac koji sadrži preuređenu humanu sekvencu VH-DH-JH i mišju sekvencu CH i laki lanac koji sadrži preuređenu humanu sekvencu Vλ-Jλ i mišju sekvencu Ck.
2. Miš prema patentnom zahtjevu 1, naznačen time, što mu nedostaje ili suštinski nedostaje funkcionalni mišji segment gena Vk ili suštinski nedostaje funkcionalni mišji segment gena Jk.
3. Miš prema patentnom zahtjevu 1, koji sadrži više nepreuređenih segmenata gena hVλ.
4. Miš prema patentnom zahtjevu 3, naznačen time, što više nepreuređenih segmenata gena hVλ sadrži: (a) najmanje 12 segmenata gena hVλ; ili (b) od 13 do 28 ili više segmenata gena hVλ.
5. Miš prema patentnom zahtjevu 4, naznačen time, što segmenti gena hVλ uključuju 3-1, 4-3, 2-8, 3-9, 3-10, 2-11 i 3-12.
6. Miš prema patentnom zahtjevu 4, naznačen time, što segmenti gena hVλ uključuju 2-14, 3-16, 2-18, 3-19, 3-21, 3-22, 2-23, 3-25 i 3-27.
7. Miš prema patentnom zahtjevu 1, naznačen time, što humani segment gena Jλ predstavlja humani Jλ1.
8. Miš prema patentnom zahtjevu 1, naznačen time što sadrži četiri humana segmenta gena Jλ, naznačen time, što je poželjno da četiri humana segmenta gena Jλ budu Jλ1, Jλ2, Jλ3 i Jλ7.
9. Miš prema patentnom zahtjevu 1, naznačen time, što je lokus endogenog mišjeg lakog lanca λ izbrisan u potpunosti ili djelomično.
10. Miš prema patentnom zahtjevu 1, naznačen time, što lokus endogenog mišjeg lakog lanca k sadrži a) graničnu sekvencu lokusa humanog lakog lanca λkoja se proteže od hVλ3- 12 do hVλ3-1; b) graničnu sekvencu lokusa humanog lakog lanca λ koja se proteže od hVλ3- 27 do hVλ3-1; ili c) graničnu sekvencu lokusa humanog lakog lanca λ koja se proteže od hVλ5- 52 do hVλ1-40 i graničnu sekvencu lokusa humanog lakog lanca λ koja se proteže od hVλ3-29 do hVλ3-1.
11. Izolirana stanica koja izražava antitijelo koje sadrži teški lanac koji sadrži preuređenu humanu sekvencu Vh-Dh-Jh i mišju sekvencu CH i laki lanac koji sadrži preuređenu humanu sekvencu preuređenu humanu sekvencu Vλ-Jλ i mišju sekvencu Ck, naznačena time, što je stanica iz ili se može dobiti iz miša prema bilo kojem od prethodnih patentnih zahtjeva, i naznačena time, što stanica sadrži: hVH, hDH i hJH koji su operativno povezani s mišjim genom CH, i hVλ i hJλ koji su operativno povezani s mišjim genom Ck na lokusu endogenog mišjeg imunoglobulinskog lakog lanca k, naznačeno time, što se na spomenutom lokusu održava element intronskog pojačivača k uzvodno od gena Ck (označen kao Eki) i pojačivač 3' k nizvodno od gena Ck (označen kao Ek3').
12. Izolirana stanica prema patentnom zahtjevu 11, naznačena time, što je spomenuta stanica B stanica.
13. Izolirana mišja embrionalna matična (ES) stanica koja sadrži: nepreuređen humani varijabilni segment gena imunoglobulinskog lakog lanca (hVH), nepreuređeni humani diverzitetski segment gena imunoglobulinskog teškog lanca (hDH) i nepreuređeni humani vezivni segment gena imunoglobulinskog teškog lanca (hJH) koji su operativno povezani s mišjim konstantnim genom (CH) imunoglobulinskog teškog lanca, i nepreuređeni humani varijabilni segment gena imunoglobulinskog lakog lanca λ (hVλ) i humani vezivni segment gena λ (hJλ) koji su operativni povezani s mišjim konstantnim genom imunoglobulinskog lakog lanca k (Ck) na lokusu endogenog mišjeg imunoglobulinskog lakog lanca k, naznačeno time, što se na spomenutom lokusu održava element intronskog pojačivača k uzvodno od gena Ck (označen kao Eki) i pojačivač 3' k nizvodno od gena Ck (označen kao Ek3').
14. Mišji embrio koji se sastoji od, sačinjen je od ili se može dobiti iz mišje embrionalne matične stanice prema patentnom zahtjevu 13, naznačen time, što spomenuti mišji embrio sadrži: nepreuređen humani varijabilni segment gena imunoglobulinskog lakog lanca (hVH), nepreuređeni humani diverzitetski segment gena imunoglobulinskog teškog lanca (hDH) i nepreuređeni humani vezivni segment gena imunoglobulinskog teškog lanca (hJH) koji su operativno povezani s mišjim konstantnim genom (CH) imunoglobulinskog teškog lanca, i nepreuređeni humani varijabilni segment gena imunoglobulinskog lakog lanca λ (hVλ) i humani vezivni segment gena λ (hJλ) koji su operativni povezani s mišjim konstantnim genom imunoglobulinskog lakog lanca k (Ck) na lokusu endogenog mišjeg imunoglobulinskog lakog lanca k, naznačeno time, što se na spomenutom lokusu održava element intronskog pojačivača k uzvodno od segmenta gena Ck (označen kao Eki) i pojačivač 3' k nizvodno od segmenta gena Ck (označen kao Ek3').
15. Hibridom koji sadrži preuređenu sekvencu gena imunoglobulinskog lakog lanca dobivenu iz miša prema patentnom zahtjevu 1, preuređenu sekvencu koja sadrži segment gena hVλ, segment gena hJλ i mišji gen Ck na lokusu endogenog mišjeg imunoglobulinskog lakog lanca k, naznačen time, što se na spomenutom lokusu održava element intronskog pojačivača k uzvodno od gena Ck (označen kao Eki) i pojačivač 3' k nizvodno od gena Ck (označen kao Ek3'), pri čemu hibridom izražava antitijelo koje sadrži laki lanac koji sadrži preuređenu humanu sekvencu Vλ-Jλ i mišju sekvencu Ck.
16. Primjena B stanice prema patentnom zahtjevu 12 za dobivanje hibridoma koji sadrži preuređenu sekvencu gena imunoglobulinskog lakog lanca dobivenu iz miša prema patentnom zahtjevu 1, preuređenu sekvencu koja sadrži segment gena hVλ, segment gena hJλ i mišji gen Ck na lokusu endogenog mišjeg imunoglobulinskog lakog lanca k, naznačeno time, što se na spomenutom lokusu održava element intronskog pojačivača k uzvodno od gena Ck (označen kao Eki) i pojačivač 3' k nizvodno od gena Ck (označen kao Ek3'), pri čemu hibridom izražava antitijelo koje sadrži laki lanac koji sadrži preuređenu humanu sekvencu Vλ-Jλ i mišju sekvencu Ck.
17. Miš prema patentnom zahtjevu 1, naznačen time, što miš sadrži: od 12 do 40 nepreuređenih segmenata gena varijabilne regije humanog imunoglobulinskog lakog lanca λ (hVλ) i najmanje jedan humani segment gena Jλ (hJλ); i humanu međugensku sekvencu nukleinske kiseline Vk-Jk smještenu između 12 do 40 segmenata gena varijabilne regije humanog imunoglobulinskog lakog lanca i najmanje jedne sekvence nukleinske kiseline Jλ.
18. Miš prema patentnom zahtjevu 1, naznačen time, što miš sadrži (a) 12 humanih segmenata gena Vλ; ili (b) 28 ili više humanih segmenata gena Vλ.
19. Postupak za dobivanje antitijela u mišu, koji se sastoji od (a) izlaganja miša antigenu prema bilo kojem patentnom zahtjevu od 1 do 10 ili 17; (b) puštanja miša da razvije imunološki odgovor na antigen; i (c) izoliranja iz miša prema (b) antitijela koje specifično prepoznaje antigen, ili izoliranja iz miša prema (b) stanice koja sadrži imunoglobulinsku domenu koja specifično prepoznaje antigen, naznačeno time, što antitijelo sadrži teški lanac dobiven iz humanog segmenta gena Vh, humanog segmenta gena Dh, humanog segmenta gena JH i mišjeg gena CH te laki lanac dobiven iz humanog segmenta gena Vλ, humanog segmenta gena Jλ i mišjeg gena Ck.
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