NZ765428B2 - Non-human animals having a humanized programmed cell death 1 gene - Google Patents

Non-human animals having a humanized programmed cell death 1 gene Download PDF

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Publication number
NZ765428B2
NZ765428B2 NZ765428A NZ76542815A NZ765428B2 NZ 765428 B2 NZ765428 B2 NZ 765428B2 NZ 765428 A NZ765428 A NZ 765428A NZ 76542815 A NZ76542815 A NZ 76542815A NZ 765428 B2 NZ765428 B2 NZ 765428B2
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New Zealand
Prior art keywords
humanized
human
exon
polypeptide
mouse
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NZ765428A
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NZ765428A (en
Inventor
Elena Burova
Ka Man Venus Lai
Alexander O Mujica
Andrew J Murphy
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Regeneron Pharmaceuticals Inc
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Publication date
Application filed by Regeneron Pharmaceuticals Inc filed Critical Regeneron Pharmaceuticals Inc
Publication of NZ765428A publication Critical patent/NZ765428A/en
Publication of NZ765428B2 publication Critical patent/NZ765428B2/en

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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
    • A01K2207/00—Modified animals
    • A01K2207/15—Humanized animals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01K2217/00—Genetically modified animals
    • A01K2217/07—Animals genetically altered by homologous recombination
    • A01K2217/072—Animals genetically altered by homologous recombination maintaining or altering function, i.e. knock in
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01K2227/10—Mammal
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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Abstract

Non-human animals, and methods and compositions for making and using the same, are provided, wherein said non-human animals comprise a humanization of a Programmed cell death 1 (Pdcd1) gene. Said non-human animals may be described, in some embodiments, as having a genetic modification to an endogenous Pdcd1 gene so that said non-human animals express a PD-1 polypeptide that includes a human portion and an endogenous portion (e.g., a non-human portion).

Claims (16)

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:
1. A humanized Programmed cell death 1 (Pdcd1) gene for expressing a humanized PD- 1 polypeptide in a rodent, wherein the humanized Pdcd1 gene encodes the humanized PD-1 polypeptide, and ses exon 2 and a portion of exon 3 of a human Pdcd1 gene, wherein the humanized PD-1 polypeptide comprises a human portion and a rodent portion, wherein the human portion comprises amino acids 26-169 of a human PD-1 polypeptide, and is encoded by exon 2 and the portion of exon 3 of the human Pdcd1 gene, n the rodent portion comprises the intracellular portion of a rodent PD-1 polypeptide, and wherein the rodent is a mouse or a rat.
2. The humanized Pdcd1 gene of claim 1, n the zed PD-1 polypeptide comprises the transmembrane portion of the rodent PD-1 polypeptide.
3. The humanized Pdcd1 gene according to claim 1 or 2, wherein the humanized Pdcd1 gene comprises exons 1, 4 and 5 of a rodent Pdcd1 gene.
4. The humanized Pdcd1 gene of claim 3, wherein the humanized Pdcd1 gene comprises a portion of exon 3 of the rodent Pdcd1 gene.
5. The humanized Pdcd1 gene according to any one of claims 1-4, operably linked to a rodent Pdcd1 promoter.
6. A targeting c acid vector, comprising a 5’ homology arm, which comprises a nucleotide sequence upstream of exon 2 of a mouse Pdcd1 gene, a genomic DNA fragment of a human Pdcd1 gene, which comprises exon 2 and a portion of exon 3 of the human Pdcd1 gene and s amino acids 26-169 of the human PD-1 ptide encoded by the human Pdcd1 gene, and a 3’ homology arm, which comprises a n of exon 3, exon 4 and exon 5 of the mouse Pdcd1 gene, wherein the portion of exon 3 encodes amino acids of the transmembrane portion of the mouse PD-1 polypeptide encoded by the mouse Pdcd1 gene.
7. A humanized PD-1 polypeptide, comprising a human portion and a rodent portion, wherein the human portion comprises amino acids 26-169 of a human PD-1 polypeptide, and is encoded by exon 2 and a portion of exon 3 of a human Pdcd1 gene, wherein the rodent portion comprises the intracellular portion of a rodent PD-1 polypeptide, and wherein the rodent is a mouse or a rat.
8. The humanized PD-1 polypeptide of claim 7, wherein the humanized PD-1 polypeptide comprises the transmembrane portion of the rodent PD-1 ptide.
9. A method of assessing the properties of a drug targeting human PD-1, the method comprising the steps of stering the drug to a mouse whose genome comprises a humanized Pdcd1 gene at an endogenous mouse Pdcd1 locus, operably linked to a mouse Pdcd1 promoter, wherein the humanized Pdcd1 gene encodes a humanized PD-1 ptide, and comprises exon 2 and a portion of exon 3 of a human Pdcd1 gene, wherein the humanized PD-1 polypeptide comprises a human portion and an nous portion, wherein the human portion comprises amino acids 26-169 of a human PD-1 polypeptide, and is encoded by exon 2 and the portion of exon 3 of the human Pdcd1 gene, wherein the endogenous portion comprises the intracellular portion of an nous mouse PD-1 polypeptide; and monitoring the mouse to determine the properties of the drug.
10. The method of claim 9, wherein the drug targeting human PD-1 is a PD-1 antagonist.
11. The method of claim 9, wherein the drug targeting human PD-1 is an uman PD- 1 antibody.
12. The method of claim 9, wherein the mouse comprises a tumor, wherein said properties of the drug comprise an anti-tumor effect of the drug, and wherein said monitoring ses monitoring the mouse to determine the effect of the drug on the tumor.
13. The method of claim 9, wherein the humanized PD-1 ptide is translated in a cell of the mouse with a mouse signal peptide.
14. The method of claim 9, wherein the humanized PD-1 polypeptide comprises the transmembrane portion of the endogenous mouse PD-1 ptide.
15. The method of claim 9, wherein the humanized Pdcd1 gene comprises endogenous mouse Pdcd1 exons 1, 4 and 5.
16. The method of claim 15, wherein the humanized Pdcd1 gene comprises a portion of an endogenous Pdcd1 exon 3. ?ab“ m qoxm y., m _.s,:z?mwm%mmmmm..... N 85% Qoxm soxm m ...... ...... 1‘ .......... ,,,,,,5:111 .................... ................... ?g ? 256m ;; MHD?m coxm 3:02 5&9st m??g -mmmm EB gem ............... 5% lmwmm _m 823 3508 5on @559 , SE 5M .m @853 ............................................ ................... 828 2 ”NUQZ 3538 ..... ‘ mg m E mm ________________ oéw 0mm I Eoz @2600 Dug; D/rA 9 SEE: 0% N $502 Egaw? ........ an <75 E mww ............. #38:: Esw? ‘ 60$me ........ 852 n3 ?x»: g A: 09% mww MED Eam- OMm WU .................................... S02 mxg 9 a ............ gm 0% ?OZ «m ..... A: ........ TE 0mm ............... 9308 mm omzmo-m§m EM 828-8% l @258 I ..... 5.3 83 ........ 2 5.3 Eé .......... 2 lllll Qrwcog Coxm @238: m N 83mg E. Dr: :vo?nw M ??o??w MHDhm :0me @mSOE CMESE Tmm Th3 umsoa..ug< sma??é?x m3 S i3 v2 «or van Em Suopw m3 HA<-m_n_v «8 K<.m_n_v 0 0 oow ow 8 9» ON o Dow cm co 0v ON o w.W m, % mW m, % ‘‘‘‘‘ mg m3 93mg a: «3 FDA 51 m: ”Adrmmv m8 v NS N3 633585 o 0 80:5 oer ow 8 CV ON o car om om av ON 0 wop??—Emmg w.W w % mW w % ..... SEE ..\\\
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