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DK2564695T3 - Dyremodeller og terapeutiske molekyler - Google Patents

Dyremodeller og terapeutiske molekyler Download PDF

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Publication number
DK2564695T3
DK2564695T3 DK12194970.5T DK12194970T DK2564695T3 DK 2564695 T3 DK2564695 T3 DK 2564695T3 DK 12194970 T DK12194970 T DK 12194970T DK 2564695 T3 DK2564695 T3 DK 2564695T3
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human
regions
dna
mouse
region
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DK12194970.5T
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Allan Bradley
E-Chiang Lee
Qi Liang
Wei Wang
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Kymab Ltd
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Priority claimed from GBGB0911846.4A external-priority patent/GB0911846D0/en
Priority claimed from GB0913102A external-priority patent/GB0913102D0/en
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Claims (16)

1. Fremgangsmåde til fremstilling af en muse-ES-celle omfattende humane VDJ-regioner, hvilken fremgangsmåde omfatter indsætning i et muse-ES-cellegenom (a) (i) en initierings-kassette omfattende en BAC DNA-backbone-sekvens der tjener som et target- sted til indsætning af en homolog sekvens og (ii) en sekvens der er homolog til det ønskede indsætningssted af target-stedet i IgH-locuset af muse-genomet, hvor backbone-sekvensen er indsat ved homolog rekombination af sekvensen der er homolog til det ønskede indsætningssted med den musehomologe sekvens i ES-cellegenomet, og (b) en flerhed af humane IgH V-regioner, én eller flere humane D-regioner og én eller flere humane J-regioner indsat i muse-IgH-locuset opstrøms for en musekonstant region; hvor IgH-regionerne fra trin (b) er i en vektor-backbone-sekvens fra en vektor, idet backbone-sekvensen er den samme backbone-sekvens som initierings-kassetten og hvor IgH-regionerne er indsat ved rekombination af vektoren med target-stedet fra trin (a), idet indsætningen udføres på en trinvis måde under anvendelse af 2 eller flere separate indsætninger og indsætningen af IgH-regionerne resulterer i et funktionelt arrangement med den muse-konstante region til antistof- eller antistofkædeproduktion og hvor processen til indsætning begynder på et sted hvor initierings-kassetten er blevet indsat i genomet af ES-cellen, tilvejebringende en unik target-region.
2. Fremgangsmåden ifølge krav 1, hvor 800-1000KB af den humane IgH VDJ-region indsættes i muse-IgH-locuset.
3. Fremgangsmåden ifølge krav 2, hvor den indsatte IgH region omfatter baserne 105,400,051 to 106,368,585 fra humant kromosom 14 (NCBI36 for det humane genom, ENSEMBL Release 54).
4. Fremgangsmåde til fremstilling af en muse-ES-celle omfattende humane VJ-regioner, fremgangsmåden omfattende indsætning i et muse-ES-cellegenom (a) (i) en initierings-kassette omfattende en BAC DNA-backbone-sekvens der tjener som et target-sted til indsætning af en homolog sekvens og (ii) en sekvens der er homolog til det ønskede indsætningssted af target-stedet i Ig-let-kæde-locuset af muse-genomet, hvor backbone-sekvensen er indsat ved homolog rekombination af sekvensen der er homolog til det ønskede indsætningssted med den musehomologe sekvens i ES-cellegenomet, og (b) en flerhed af humane Ig-let-kæde-kappa V-regioner og én eller flere humane Ig-let-kæde-kappa J-regioner indsat i muse-Ig-let-kæde-locuset opstrøms og i funktionelt arrangement med en muse-kappa- eller lambda-konstantregion og/eller en flerhed af humane Ig-let-kæde-lambda V-regioner og én eller flere humane Ig-let-kæde-lambda-J-regioner indsat i muse-Ig-let-kæde-locuset opstrøms fra en muse-lambda- eller kappa-konstantregion; hvor let-kæde-regioner fra trin (b) er i en vektor-backbone-sekvens fra en vektor, backbone-sekvensen er den samme backbone-sekvens som initierings-kassetten og hvor the let-kæde-regioner er indsat ved rekombination fra en vektor backbone omfattende det human DNA fra trin (b) med target-stedet fra trin (a), indsætningen udføres på en trinvis måde under anvendelse af 2 eller flere separate indsætninger og indsætningen af let-kæde-regionerne resulterer i et funktionelt arrangement med den muse-konstante region til antistof- eller antistofkædeproduktion og hvor processen til indsætning begynder på et sted hvor initierings-kassetten er blevet indsat i genomet af ES-cellen, tilvejebringende en unik target-region.
5. Fremgangsmåden ifølge krav 4, hvor den indsatte VJ region omfatter baserne 88,940,356 til 89,857,000 fra humant kromosom 2 (NCBI36 for det humane genom, ENSEMBL Release 54).
6. Fremgangsmåde ifølge et hvilket som helst af de foregående krav, hvor indsætningen af target-stedet er ved homolog rekombination eller site -specifik rekombination.
7. Fremgangsmåde ifølge et hvilket som helst af de foregående krav omfattende 3, 4, 5, 6, 7. 8, 9, 10, 11, 12, 13, 14, 15, 20 eller flere separate indsætninger.
8. Fremgangsmåden ifølge et hvilket som helst af de foregående krav, hvor flere DNA-fragmenter fra Ig-regionerne indsættes i DNA-target'et.
9. Fremgangsmåden ifølge et hvilket som helst af de foregående krav, hvor 5'-enden af den humane indsætning er forøget i længde.
10. Fremgangsmåden ifølge krav 8 eller 9, hvor flere DNA-fragmenter fra Ig-regionerne indsættes ved 5'-enden af det tidligere indsatte fragment og vektor-DNA der adskiller de indsatte humane DNA-sekvenser slettes in vivo ved transposase medieret DNA-excision for at danne en sammenhængende indsætning i hvilken de indsatte fragmenter af Ig-regionerne samles sammen direkte uden mellemliggende vektor DNA-sekvenser.
11. Fremgangsmåden ifølge et hvilket som helst af de foregående krav, hvor de humane VDJ- eller VJ-insertioner udføres ved homolog rekombination eller ved site-specifik rekombination.
12. Fremgangsmåden ifølge et hvilket som helst af de foregående krav, hvor indsætning af BAC-DNA-backbone-sekvensen ifølge (a) er ved homolog rekombination og hvor indsætning af (a) efterfølges af indsætning ved RMCE af de humane VDJ eller VJ-regioner fra (b) i et afsnit af target-stedet.
13. Fremgangsmåden ifølge et hvilket som helst af de foregående krav, hvor the BAC DNA-backbone-sekvens omfatter rekombinase-targetsekvenser og efterfølgende indsætning af et fragment af de humane VDJ eller VJ-regioner, idet backbone-sekvensen slettes ved rekombination mellem rekombinase-targetsekvenserne.
14. Fremgangsmåden ifølge et hvilket som helst af de foregående krav, hvor BAC-DNA-sekvensen benyttes til at ramme indsætningen af et fragment af de humane VDJ eller VJ-regioner.
15. Fremgangsmåden ifølge et hvilket som helst af de foregående krav, hvor indsætningen omfatter en indsætning af DNA omfattende et fragment af VDJ eller VJ på over 100KB.
16. Fremgangsmåden ifølge et hvilket som helst af de foregående krav, hvor 3'-enden af det sidste humane J-gen der skal indsættes er mindre end 2KB, eventuelt mindre end 1 KB, fra human-mus-samleregionen.
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