DK2675271T3 - Humaniserede m-csf-mus - Google Patents

Humaniserede m-csf-mus Download PDF

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DK2675271T3
DK2675271T3 DK12746594.6T DK12746594T DK2675271T3 DK 2675271 T3 DK2675271 T3 DK 2675271T3 DK 12746594 T DK12746594 T DK 12746594T DK 2675271 T3 DK2675271 T3 DK 2675271T3
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mouse
csf
human
cells
mice
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DK12746594.6T
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Andrew J Murphy
Elizabeth Eynon
Markus G Manz
Richard Flavell
George D Yancopoulos
Sean Stevens
Chozhavendan Rathinam
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Regeneron Pharma
Univ Yale
Institute For Res In Biomedicine Irb
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
    • A01K67/0278—Knock-in vertebrates, e.g. humanised vertebrates
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0271—Chimeric vertebrates, e.g. comprising exogenous cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
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    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
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    • A01K2217/00—Genetically modified animals
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    • A01K2217/072—Animals genetically altered by homologous recombination maintaining or altering function, i.e. knock in
    • A—HUMAN NECESSITIES
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    • A01K2217/00—Genetically modified animals
    • A01K2217/15—Animals comprising multiple alterations of the genome, by transgenesis or homologous recombination, e.g. obtained by cross-breeding
    • A—HUMAN NECESSITIES
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    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
    • C12N2015/8527—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic for producing animal models, e.g. for tests or diseases
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    • C12N2800/10—Plasmid DNA
    • C12N2800/106—Plasmid DNA for vertebrates
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    • G01N2500/00—Screening for compounds of potential therapeutic value
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Claims (12)

1. Humaniseret M-CSF-mus, omfattende: et Rag2-gen-knockout; et //.2/p-gen-knockout; og en nukleinsyresekvens, der er inkorporeret i genomet af den humaniserede M-CSF-mus, hvilken sekvens koder for et humant makrofag-kolonistimulerende faktor (hM-CSF)-protein og er funktionsmæssigt forbundet med den endogene promoter af muse-M-CSF-genet ved muse-M-CSF-locuset, hvor musen ek-sprimerer M-CSF-RNA kodet af nukleinsyresekvensen i knoglemarv, milt, blod, lever, hjerne, lunge, testikler og nyre.
2. Humaniseret M-CSF-mus ifølge krav 1, hvor musen omfatter to kopier af nukleinsyresekvensen.
3. Humaniseret M-CSF-mus ifølge krav 1, hvor musen omfatter en nul-mutation i mindst et muse-M-CSF allel.
4. Humaniseret M-CSF-mus ifølge krav 1, hvor musen er homozygotisk nul for Rag2 og IL2rg, og hvor musen omfatter humane celler.
5. Humaniseret M-CSF-mus ifølge krav 4, hvor de humane celler er hæma-topoietiske celler.
6. Humaniseret M-CSF-mus ifølge krav 5, hvor musen er inficeret med et humant patogen.
7. Anvendelse af den humaniserede M-CSF-mus ifølge krav 5 som en musemodel for det humane hæmatopoietiske system.
8. Anvendelse ifølge krav 7, hvor musen omfatter en nul-deletion for muse-M-CSF.
9. Anvendelse ifølge krav 7, hvor musen udviser et eller flere karakteristika udvalgt blandt: a. eksprimerer humant M-CSF i knoglemarv, milt, blod, lever, hjerne, lunge, testikler og nyre på et niveau, der er sammenligneligt med eksprimering af muse-M-CSF i en vildtype-mus; b. udviser en frekvens af hCD14+CD33+-celler af milt, der er 2 til 6 gange højere end hCD14+CD33+ hos en podet mus, der ikke eksprimerer hM-CSF; c. udviser en frekvens af hCD14+CD33+-celler af perifert blod, der er 2 til 8 gange højere end hCD14+CD33+ hos en podet mus, der ikke eksprimerer hM-CSF; d. udviser et niveau af hCD14+CD33+-monocyt/makrofag-afstamningsceller i blod på ca. 15 til ca. 40 %; e. udviser et niveau af hCD14+CD33+-monocyt/makrofag-afstamningsceller i blod på ca. 5 til ca. 15 % i en alder af ca. 20 uger; f. udviser et respons på LPS-injektion, der er ca. 1,5 til ca. 6 gange større i forhold til procentdelen af hCD14+CD33+-celler i lever end mus, der ikke har et humant M-CSF; g. udviser en øget produktion af hCD14+CD33+hCD45+-celler i milt ca. 48 timer efter LPS-injektion, hvor øgningen er ca. 2 til ca. 5 gange større end for en podet mus, der ikke har hM-CSF; h. udviser en øget produktion af human serum-IL-6 som reaktion på LPS, hvor niveauet af hlL-6 ca. 6 timer efter LPS-injektion er øget ca. 2 til ca. 5 gange sammenlignet med en podet mus, der ikke har et hM-CSF; i. udviser in v/fro-sekretion via en monocyt og/eller makrofag efter LPS-stimu-lation, der er ca. 2 til 3 gange højere i forhold til hTNFa end hos en podet mus, der ikke har et hM-CSF-gen; j. udviser in v/fro-sekretion via en monocyt og/eller makrofag efter LPS-stimu-lation, der er ca. 2 til 4 gange højere i forhold til hlL-6 end hos en podet mus, der ikke har et hM-CSF-gen; k. udviser in v/fro-sekretion via en monocyt og/eller makrofag efter poly l:C-stimulation, der er ca. 3 til 6 gange højere i forhold til hIFNa end hos en podet mus, der ikke har et hM-CSF-gen; l. udviser in v/fro-sekretion via en monocyt og/eller makrofag efter poly l:C-stimulation, der er ca. 2 til 3 gange højere i forhold til hIFNp end hos en podet mus, der ikke har et hM-CSF-gen; m. udviser øget fagocytose sammenlignet med en genmodificeret og podet mus, der ikke har et hM-CSF-gen; n. udviser øget kemotaksi in vitro som reaktion på Μίρ3β sammenlignet med en genmodificeret, podet mus, der ikke har et hM-CSF-gen; og o. udviser opregulering in vitro af et co-stimulerende molekyle som reaktion på LPS-stimulation, hvor det co-stimulerende molekyle er udvalgt blandt human CD40, human CD80, human CD86, human HLA-DR og en kombination deraf.
10. Anvendelse af den humaniserede M-CSF-mus ifølge krav 6 som en musemodel for en human patogen infektion.
11. Anvendelse ifølge krav 10, hvor patogenet er udvalgt blandt en virus, en svamp og en bakterie.
12. Anvendelse ifølge krav 11, hvor bakterien er en mykobakterie eller en en-terobakterie.
DK12746594.6T 2011-02-15 2012-02-14 Humaniserede m-csf-mus DK2675271T3 (da)

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US201161442946P 2011-02-15 2011-02-15
PCT/US2012/025040 WO2012112544A2 (en) 2011-02-15 2012-02-14 Humanized m-csf mice

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US (4) US8847004B2 (da)
EP (3) EP3375284B1 (da)
JP (5) JP5834097B2 (da)
KR (6) KR102109172B1 (da)
CN (3) CN105861553B (da)
AU (1) AU2012217836B2 (da)
CA (1) CA2826714C (da)
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FI (1) FI3375284T3 (da)
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