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ME02442B - Miševi koji ispoljavaju laki lanac hibridnog imunoglobulina sa promenljivim regionom čovjeka - Google Patents

Miševi koji ispoljavaju laki lanac hibridnog imunoglobulina sa promenljivim regionom čovjeka

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Publication number
ME02442B
ME02442B MEP-2016-119A MEP11916A ME02442B ME 02442 B ME02442 B ME 02442B ME P11916 A MEP11916 A ME P11916A ME 02442 B ME02442 B ME 02442B
Authority
ME
Montenegro
Prior art keywords
gene
mouse
light chain
endogenous
human
Prior art date
Application number
MEP-2016-119A
Other languages
German (de)
English (en)
French (fr)
Inventor
Lynn Macdonald
Sean Stevens
Cagan Gurer
Andrew J Murphy
Karolina A Hosiawa
Original Assignee
Regeneron Pharma
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Regeneron Pharma filed Critical Regeneron Pharma
Publication of ME02442B publication Critical patent/ME02442B/me

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Claims (17)

1.    Miš, koji obuhvata: a)    zamenu jednog ili više promenljivih (VH), raznovrsnih (DH) i spojnih (JH) segmenata gena teškog lanca sa jednim ili više ljudskih VH, DH, i/ili JH segmenata gena na endogenom mišjem lokusu imunoglobulina teškog lanca; i b)    endogeni λ (lambda) alel lakog lanca koji obuhvata nepreraspoređeni ljudski lambda promenljivi (hVλ) i nepreraspoređeni ljudski lambda spojni (hVλ) segment gena, gde mišji obuhvata brisanje prve Vλ-Jλ-Cλ skupine gena pomenutog endogenog mišjeg λ alela lakog lanca i zamenu, u celini ili delimično, Vλ-Jλ, segmenata gena druge skupine gena pomenutog alela sa pomenutim ljudskim Vλ, i Jλ segmentima gena koji su operativno povezani na nedirnuti mišji lambda (Cλ) gen konstantnog regiona pomenute druge Vλ-Jλ-Cλ skupine gena tako da miš ispoljava laki lanac izveden iz, hVλ. hJλ i mišji Cλ gen, i pri čemu se endogeni pojačavači Enh 2. 4, mišji lambda 3' pojačavač (Enh) i Enh 3. 1 održavaju nedirnuti u pomenutom λ alelu lakog lanca.
2.    Miš prema patentnom zahtjevu 1, pri čemu endogeni λ (lambda) alel lakog lanca obuhvata više ljudskih Vλ segmenata gena.
3.    Miš prema bilo kom od prethodnih patentnih zahtjeva, pri čemu endogeni λ (lambda) alel lakog lanca obuhvata: a)    barem 12 nepreraspoređenih ljudskih Vλ segmenata gena; ili b)    13 do 28 nepreraspoređenih ljudskih Vλ segmenata gena.
4.    Miš prema patentnom zahtjevu 3, pri čemu ljudski Vλ segmenati gena obuhvataju: a)    hVλ-1, hVλ4-3, hVλ2-8, hVλ3-8, hVλ-10, hVλ2-ll, i hVλ3-12; ili b)    hVλ2-14, hVλ3-16, hVo2-18, hVλ3-19, hVλ3-21, hVλ3-22, hVλ2-23, hVλ3-25, i hVλ3-27.
5.    Miš prema patentnom zahtevu 1, pri čemu endogeni λ (lambda) alel lakog lanca obuhvata jedan nepreraspoređeni Jλ segmenata gena koji je hJλl.
6.    Miš prema patentnom zahtjevu 1, pri čemu endogeni λ (lambda) alel lakog lanca obuhvata četiri nepreraspoređena ljudska Jλ segmenta gena.
7.    Miš prema patentnom zahtjevu 6, pri čemu četiri nepreraspoređena ljudska Jλ segmenta gena jesu Jλl, Jλ2, Jλ3, i Jλ7.
8.    Miš prema patentnom zahtjevu 1, pri čemu endogeni λ (lambda) alel lakog lanca nema endogeni Vλ segment gena.
9.    Miš prema bilo kom od patentnih zahtjeva 1 do 3, 5 i 8, pri čemu se endogeni κ(kappa) alel lakog lanca briše.
10.    Miš prema patentnom zahtjevu 1, pri čemu endogeni mišji λ alel lakog lanca obuhvata: a)    dodirunu sekvencu ljudskog λ lokusa lakog lanca koja ima raspon od Vλ3-12 do Vλ.3-1; b)    dodirunu sekvencu ljudskog λ lokusa lakog lanca koja ima raspon od Vλ3-29 do Vλ.3-1; ili sekvencu ljudskog λ lokusa lakog lanca koja ima raspon od Vλ5-52 do Vλl-40.
11.    Izolovana ćelija koja ispoljava laki lanac izveden iz hVλ, hJλ i mišjeg Cλ gena, pri čemu je ćelija iz, ili može se dobiti iz, miša prema bilo kom od prethodnih patentnih zahteva, i pri čemu ćelija obuhvata: a)    zamenu jednog ili više promenljivih (VH), raznovrsnih (DH) i spojnih (JH) segmenata    gena teškog lanca sa jednim ili više ljudskih Vh/ Dh, i Jh segmenata gena na endogenom mišjem    lokusu imunoglobulina teškog lanca; i b)    endogeni λ (lambda) alel lakog lanca koji obuhvata preraspoređeni ljudski promenljivi lambda (hVλ) i preraspoređeni ljudski spojni lambda (hJλ) segment gena, i brisanje prve Vλ-Jλ- Cλ skupine gena pomenutog endogenog mišjeg λ alela lakog lanca i zamenu, u celini ili delimično, Vλ-Jλ segmenata gena druge Vλ-Jλ-Cλ skupine gena pomenutog alela sa pomenutim ljudskim Vλ i Jλ segmentima gena koji su operativno povezani na nedirnuti mišji Cλ konstantni region gena pomenute druge Vλ-Jλ-Cλ skupine gena, i pri čemu se endogeni pojačavači Enh 2.4, mišji lambda 3' pojačavač (Enh) i Enh 3.1 održavaju nedirnuti u pomenutom λ alelu lakog lanca.
12.    Izolovana ćelija prema patentnom zahtjevu 11, pri čemu ćelija jeste B ćelija.
13.    Izolovana mišja embrionska matična (ES) ćelija obuhvata: a)    zamenu jednog ili više promenljivih (VH), raznovrsnih (DH) i spojnih (JH) segmenata gena teškog lanca sa jednim ili više ljudskih VH, DH, i JHsegmenata gena na endogenom mišjem lokusu imunoglobulina teškog lanca; i b)    endogenom λ (lambda) alelu lakog lanca koji obuhvata nepreraspoređeni ljudski lambda promenljivi (hVλ) i nepreraspoređeni ljudski lambda spojni (hJλ) segment gena, i brisanje prve Vλ-Jλ-Cλ skupine gena pomenutog endogenog mišjeg λ alela lakog lanca i zamenu, u celini ili delimično, Vλ-Jλ segmenata gena druge Vλ-Jλ-Cλ skupine gena pomenutog alela sa pomenutim ljudskim Vλ i Jλ segmentima gena koji su operativno povezani na nedirnuti mišji Cλ konstantni region gena pomenute druge Vλ-Jλ-Jλ skupine gena, pri čemu se endogeni pojačavači Enh 2.4, mišji lambda 3' pojačavač (Enh) i Enh 3.1 održavaju nedirnuti u pomenutom λ alelu lakog lanca.
14.    Mišji embrion obuhvata, napravljen iz, ili koji se može dobiti iz, pomenute mišje ES ćelije prema patentnom zahtevu 13, pri čemu mišji embrion obuhvata: a)    zamenu jednog ili više promenljivih (VH), raznovrsnih (DH) i spojnih (JH) segmenata gena teškog lanca sa jednim ili više ljudskih VH, DH, i JH segmenata gena na endogenom mišjem lokusu imunoglobulina teškog lanca; i b)    endogeni λ (lambda) alel lakog lanca koji obuhvata nepreraspoređeni ljudski lambda promenljivi (hVλ) i nepreraspoređeni ljudski lambda spojni (hJλ) segment gena, i brisanje prve Vλ-Jλ-Cλ skupine gena pomenutog endogenog mišjeg λ alela lakog lanca i zamenu, u celini ili delimično, Vλ-Jλ segmenata gena druge Vλ-Jλ-Cλ skupine gena pomenutog alela sa pomenutim ljudskim Vλ i Jλ segmentima gena koji su operativno povezani na nedirnuti mišji Cλ konstantni region gena pomenute druge Vλ-Jλ-Cλ skupine gena, i pri čemu se endogeni pojačivači Enh 2.4, mišji lambda 3' pojačivač (Enh) i Enh 3.1 održavaju nedirnuti u pomenutomλalelu lakog lanca.
15. Upotreba B ćelije prema patentnom zahtjevu 12 da se napravi hibridom koji ispoljava laki a)    zamenu jednog ili više promenljivih (VH), raznovrsnih (DH) i spojnih (JH) segmenata gena teškog lanca sa jednim ili više ljudskih VH, DH, i JH segmenata gena na endogenom mišjem lokusu imunoglobulina teškog lanca; i b)    endogeni λ (lambda) alel lakog lanca koji obuhvata preraspoređeni ljudski lambda promenljivi (hVλ) i preraspoređeni ljudski lambda spojni (hJλ) segment gena, i brisanje prve Vλ-Jλ- Cλ skupine gena pomenutog endogenog mišjeg λ alela lakog lanca i zamenu, u celini ili delimično, Vλ-Jλ segmenata gena druge Vλ-Jλ-Cλ skupine gena pomenutog alela sa pomenutim ljudskim Vλ i Jλ segmentima gena koji su operativno povezani na nedirnuti mišji Cλ konstantni region gena pomenute druge Vλ-Jλ-Cλ skupine gena i pri čemu endogeni pojačavači Enh 2.4, mišji lambda 3' pojačavač (Enh) i Enh 3.1 održavaju nedirnuti u pomenutom λ alelu lakog lanca.
16.    Hibridom koji ispoljava laki lanac izveden iz hVλ, hJλ i mišjeg Cλ gena pri čemu je hibridom iz, ili se može dobiti iz miša prema bilo kom od patentnih zahteva 1 do 10, pri čemu ćelija obuhvata: a) zamenu jednog ili više promenljivih (VH), raznovrsnih (DH) i spojnih (JH) segmenata gena teškog lanca sa jednim ili više ljudskih VH, DH, i JH segmenata gena na endogenom mišjem lokusu imunoglobulina teškog lanca; i b)    endogeni λ (lambda) alel lakog lanca koji obuhvata preraspoređeni ljudski lambda promenljivi (hVλ) i preraspoređeni ljudski lambda spojni (hJλ) segment gena, i brisanje prve Vλ-Jλ- Cλ skupine gena pomenutog endogenog mišjeg λ alela lakog lanca i zamenu, u celini ili delimično, Vλ-Jλ segmenata gena druge Vλ-Jλ-Cλ skupine gena pomenutog alela sa pomenutim ljudskim Vλ i Jλ segmentima gena koji su operativno povezani na nedirnuti mišji Cλ konstantni region gena pomenute druge Vλ-Jλ-Cλ skupine gena i pri čemu endogeni pojačavači Enh 2.4, mišji lambda 3' pojačavač (Enh) i Enh 3.1 održavaju nedirnuti u pomenutom λ alelu lakog lanca.
17.    Postupak za pravljenje antitela kod miša koji obuhvata: a)    izlaganje miša prema patentnom zahtevu 1 antigenu; b)    omogućavanje mišu da razvije imuni odgovor na antigen; i c)    izolovanje iz miša (b) antitela koje specifično prepoznaje antigen, ili izolovanje iz miša (b) ćelije koja obuhvata domen imunoglobulina koji specifično prepoznaje antigen, ili identifikovanje kod miša (b) sekvence nukleinske kiseline koja kodira promenljivi domen teškog i/ili lakog lanca koji vezuje antigen, pri čemu antitijelo obuhvata laki lanac izveden iz hVλ, hJλ i mišjeg Cλ gena.
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