HRP20171761T1 - Genetski modificirani miš s glavnim kompleksom histokompatibilnosti - Google Patents

Genetski modificirani miš s glavnim kompleksom histokompatibilnosti Download PDF

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HRP20171761T1
HRP20171761T1 HRP20171761TT HRP20171761T HRP20171761T1 HR P20171761 T1 HRP20171761 T1 HR P20171761T1 HR P20171761T T HRP20171761T T HR P20171761TT HR P20171761 T HRP20171761 T HR P20171761T HR P20171761 T1 HRP20171761 T1 HR P20171761T1
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mouse
polypeptide
human
rodent
microglobulin
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HRP20171761TT
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Lynn Macdonald
Andrew J. Murphy
Cagan Gurer
John Mcwhirter
Vera VORONINA
Faith HARRIS
Sean Stevens
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Regeneron Pharmaceuticals, Inc.
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    • AHUMAN NECESSITIES
    • A01AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01KANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027New or modified breeds of vertebrates
    • A01K67/0275Genetically modified vertebrates, e.g. transgenic
    • A01K67/0278Knock-in vertebrates, e.g. humanised vertebrates
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503Immunoglobulin superfamily
    • C07K14/70539MHC-molecules, e.g. HLA-molecules
    • AHUMAN NECESSITIES
    • A01AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01KANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00Genetically modified animals
    • A01K2217/07Animals genetically altered by homologous recombination
    • A01K2217/072Animals genetically altered by homologous recombination maintaining or altering function, i.e. knock in
    • AHUMAN NECESSITIES
    • A01AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01KANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00Genetically modified animals
    • A01K2217/15Animals comprising multiple alterations of the genome, by transgenesis or homologous recombination, e.g. obtained by cross-breeding
    • AHUMAN NECESSITIES
    • A01AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01KANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00Animals characterised by species
    • A01K2227/10Mammal
    • A01K2227/105Murine
    • AHUMAN NECESSITIES
    • A01AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01KANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00Animals characterised by purpose
    • A01K2267/03Animal model, e.g. for test or diseases
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2319/00Fusion polypeptide

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Environmental Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Zoology (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Biodiversity & Conservation Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Husbandry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Toxicology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Cell Biology (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Peptides Or Proteins (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Breeding Of Plants And Reproduction By Means Of Culturing (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Claims (38)

1. Glodavac koji na lokusu endogenog glavnog sustava tkivne podudarnosti (MHC I) ima nukleotidni slijed kojim se kodira kimerni MHC I polipeptid čovjeka/glodavca, pri čemu se ljudski dio kimernog polipeptida sastoji od domena ljudskog MHC I polipeptida α1, α2, i α3, pri čemu se dio glodavca kimernog polipeptida sastoji od transmembranske i citoplazmatske domene endogenog polipeptida glodavca MHC I i pri čemu glodavac izražava kimerni MHC I polipeptid čovjeka/glodavca.
2. U glodavca iz zahtjeva 1. glodavac ne izražava domene α1, α2, i α3 endogenog MHC I polipeptida iz endogenog MHC I lokusa glodavca.
3. Glodavac iz zahtjeva 1. ili zahtjeva 2. pri čemu je nukleotidni slijed operabilno povezan s endogenim regulatornim elementima glodavca.
4. Glodavac iz bilo kojeg od prethodnih zahtjeva, pri čemu se ljudski dio kimernog polipeptida sastoji od vodećeg ljudskog slijeda.
5. Glodavac iz bilo kojeg od prethodnih zahtjeva, pri čemu je ljudski MHC I polipeptid odabran iz grupe koja se sastoji od HLA-A, HLA-B i HLA-C.
6. Glodavac iz bilo kojeg od prethodnih zahtjeva, pri čemu je glodavac miš.
7. Miš iz zahtjeva 6. pri čemu je endogeni lokus mišji lokus H-2K.
8. Miš iz zahtjeva 7. pri čemu je endogeni MHC I polipeptid glodavca H-2K.
9. Miš iz zahtjeva 6. na endogenom lokusu H-2K sadrži nukleotidni slijed kojim se kodira kimerni ljudski/mišji MHC I polipeptid, pri čemu se ljudski dio kimernog polipeptida sastoji od domena α1, α2 i α3 ljudskog polipeptida HLA-A2, a mišji se dio sastoji od transmembranske i citoplazmatske domene mišjeg H-2K polipeptida i pri čemu miš izražava kimerni HLA-A2/H-2K polipeptid.
10. U miša iz zahtjeva 9. miš ne izražava domene α1, α2, i α3 mišjeg H-2K polipeptida iz endogenog H-2K lokusa.
11. Miš iz zahtjeva 9. ili 10. pri čemu se ljudski dio kimernog polipeptida sastoji od vodećeg ljudskog slijeda.
12. Miš iz bilo kojeg zahtjeva 9. – 11. pri čemu je nukleotidni slijed operabilno povezan s endogenim regulatornim elementima miša.
13. Miš iz bilo kojeg zahtjeva 9. – 12. pri čemu je HLA-A2 polipeptid HLA-A2.1 polipeptid.
14. Miš iz bilo kojeg zahtjeva 9. – 13. pri čemu je mišji H-2K lokus H-2Kb lokus.
15. Metoda kojom se izmjenjuje mišji MHC I lokus kako bi se izrazio kimerni ljudski/mišji MHC I polipeptid, pri čemu se metoda sastoji od zamjene nukleotidnog slijeda kojim se kodiraju domene α1, α2 i α3 na endogenom MHC I lokusu mišjeg MHC I polipeptida nukleotidnim slijedom kojim se kodiraju domene α1, α2 i α3 ljudskog MHC I polipeptida, pri čemu miš izražava transmembranske i citoplazmatske domene mišjeg MHC I polipeptida.
16. Metoda iz zahtjeva 15., pri čemu miš ne izražava domene α1, α2, i α3 mišjeg MHC I polipeptida iz endogenog mišjeg MHC I lokusa.
17. Metoda iz zahtjeva 15. ili zahtjeva 16. pri čemu je mišji MHC I lokus H-2K lokus, a mišji MHC I polipeptid H-2K polipeptid.
18. Metoda iz bilo kojeg zahtjeva 15. – 17. pri čemu je ljudski MHC I polipeptid HLA-A polipeptid.
19. Metoda iz bilo kojeg zahtjeva 15. – 18. gdje se zamjena vrši na jednoj ES stanici, a ta se jedna ES stanica uvodi u mišji embrij kako bi nastao miš.
20. Glodavac koji prema bilo kojem od zahtjeva 1. – 14. nadalje na endogenom lokusu β2 mikroglobulina glodavca sadrži nukleotidni slijed kojim se kodira polipeptid koji sadrži ljudski slijed aminokiselina β2 mikroglobulina, pri čemu glodavac izražava ljudski ili humanizirani polipeptid β2 mikroglobulina.
21. U glodavca iz zahtjeva 20. glodavac ne izražava funkcionalni endogeni polipeptid β2 mikroglobulina iz endogenog lokusa β2 mikroglobulina glodavca.
22. Glodavac iz zahtjeva 20. ili zahtjeva 21. pri čemu je nukleotidni slijed operabilno povezan s endogenim regulatornim elementima β2 mikroglobulina glodavca.
23. Glodavac iz bilo kojeg od zahtjeva 20. – 22. pri čemu nukleotidni slijed sadrži nukleotidni slijed koji je izložen od eksona 2. do eksona 4. ljudskog gena β2 mikroglobulina.
24. Glodavac iz bilo kojeg od zahtjeva 20. – 23. pri čemu nukleotidni slijed sadrži nukleotidne sljedove koji su izloženi u eksonima 2., 3. i 4. ljudskog gena β2 mikroglobulina.
25. Glodavac iz bilo kojeg od zahtjeva 20. – 24. pri čemu nukleotidni slijed nadalje sadrži nukleotidni slijed koji je izložen u eksonu 1. gena β2 mikroglobulina glodavca.
26. Glodavac iz bilo kojeg od zahtjeva 20. – 25., pri čemu je glodavac miš.
27. Metoda prema bilo kojem od zahtjeva 15. – 19., pri čemu metoda dodatno sadrži izmjenu mišjeg lokusa β2 mikroglobulina kako bi izražavao ljudski ili humanizirani polipeptid β2 mikroglobulina tako da se na endogenom mišjem lokusu β2 mikroglobulina nukleotidni slijed kojim se kodira mišji polipeptid β2 mikroglobulina zamijeni nukleotidnim slijedom kojim se kodira ljudski ili humanizirani polipeptid β2 mikroglobulina.
28. Metoda iz zahtjeva 27. pri čemu miš ne izražava funkcionalni mišji polipeptid β2 mikroglobulina iz endogenog lokusa β2 mikroglobulina.
29. Metoda iz zahtjeva 27. ili 28. pri čemu nukleotidni slijed kojim se kodira ljudski ili humanizirani polipeptid β2 mikroglobulina sadrži nukleotidni slijed koji je izložen od eksona 2. do eksona 4. ljudskog gena β2 mikroglobulina.
30. Metoda iz bilo kojeg zahtjeva 27. – 29. pri čemu nukleotidni slijed kojim se kodira ljudski ili humanizirani polipeptid β2 mikroglobulina sadrži nukleotidne sljedove koji su izloženi u eksonima 2., 3. i 4. ljudskog gena β2 mikroglobulina.
31. Metoda iz bilo kojeg od zahtjeva 27. – 30. pri čemu izmijenjeni lokus zadržava nukleotidni slijed eksona 1. mišjeg gena β2 mikroglobulina.
32. Metoda iz bilo kojeg zahtjeva 27. – 31. gdje se zamjena vrši na jednoj ES stanici, a ta se jedna ES stanica uvodi u mišji embrij kako bi nastao miš.
33. Genom miša iz zahtjeva 9. sastoji se od: prvog nukleotidnog slijeda kojim se kodira kimerni ljudski/mišji MHC I polipeptid, pri čemu se ljudski dio kimernog polipeptida sastoji od domena α1, α2 i α3 ljudskog HLA-A2, a mišji se dio sastoji od transmembranske i citoplazmatske domene mišjeg H-2K, i drugog nukleotidnog slijeda kojim se kodira ljudski ili humanizirani polipeptid β2 mikroglobulina, pri čemu se prvi nukleotidni slijed nalazi na endogenom H-2K lokus, a drugi se nukleotidni slijed nalazi na endogenom mišjem lokusu β2 mikroglobulina te pri čemu miš izražava kimerni ljudski/mišji MHC I polipeptid i ljudski ili humanizirani polipeptid β2 mikroglobulina.
34. Miš iz zahtjeva 33. pri čemu miš ne izražava endogene mišje polipeptide H-2K i β2 mikroglobulina iz njihovih endogenih lokusa.
35. Miš iz zahtjeva 33. i 34., pri čemu je prvi nukleotidni slijed operabilno povezan s endogenim mišjim H-2K regulatornim elementima, a drugi je nukleotidni slijed operabilno povezan s endogenim mišjim regulatornim elementima β2 mikroglobulina.
36. Miš iz bilo kojeg od zahtjeva 33. – 35. pri čemu drugi nukleotidni slijed sadrži nukleotidni slijed koji je izložen od eksona 2. do eksona 4. ljudskog gena β2 mikroglobulina.
37. Miš iz bilo kojeg od zahtjeva 33. – 36. pri čemu drugi nukleotidni slijed sadrži nukleotidne sljedove koji su izloženi u eksonima 2., 3. i 4. ljudskog gena β2 mikroglobulina.
38. Miš iz bilo kojeg od zahtjeva 33. – 37. pri čemu se u izražavanju ljudskog ili humaniziranog polipeptida β2 mikroglobulina povećava izražavanje kimernog ljudskog/mišjeg MHC I polipeptida u usporedbi s izražavanjem kimernog ljudskog/mišjeg MHC I polipeptida gdje ne dolazi do izražavanja ljudskog ili humaniziranog polipeptida β2 mikroglobulina.
HRP20171761TT 2011-10-28 2017-11-15 Genetski modificirani miš s glavnim kompleksom histokompatibilnosti HRP20171761T1 (hr)

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US201161552587P 2011-10-28 2011-10-28
US201161552582P 2011-10-28 2011-10-28
US201261700908P 2012-09-14 2012-09-14
EP12787255.4A EP2770821B1 (en) 2011-10-28 2012-10-26 Genetically modified major histocompatibility complex mice
PCT/US2012/062042 WO2013063346A1 (en) 2011-10-28 2012-10-26 Genetically modified major histocompatibility complex mice

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US (3) US9615550B2 (hr)
EP (4) EP3563680B1 (hr)
JP (4) JP6154391B2 (hr)
KR (3) KR101921126B1 (hr)
CN (3) CN104039132B9 (hr)
AU (3) AU2012324016C1 (hr)
BR (1) BR112014009259A2 (hr)
CA (2) CA2850387A1 (hr)
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