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NZ740900B2 - Mice that make binding proteins comprising vl domains - Google Patents
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NZ740900B2 - Mice that make binding proteins comprising vl domains - Google Patents

Mice that make binding proteins comprising vl domains Download PDF

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Publication number
NZ740900B2
NZ740900B2 NZ740900A NZ74090011A NZ740900B2 NZ 740900 B2 NZ740900 B2 NZ 740900B2 NZ 740900 A NZ740900 A NZ 740900A NZ 74090011 A NZ74090011 A NZ 74090011A NZ 740900 B2 NZ740900 B2 NZ 740900B2
Authority
NZ
New Zealand
Prior art keywords
gene
unrearranged human
heavy chain
targeting vector
human
Prior art date
Application number
NZ740900A
Other versions
NZ740900A (en
Inventor
Cagan Gurer
Lynn Macdonald
Karolina A Meagher
Andrew J Murphy
Sean Stevens
Original Assignee
Regeneron Pharmaceuticals Inc
Filing date
Publication date
Application filed by Regeneron Pharmaceuticals Inc filed Critical Regeneron Pharmaceuticals Inc
Publication of NZ740900A publication Critical patent/NZ740900A/en
Publication of NZ740900B2 publication Critical patent/NZ740900B2/en

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Classifications

    • 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
    • A01K2217/00—Genetically modified animals
    • A01K2217/07—Animals genetically altered by homologous recombination
    • 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
    • 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
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • 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
    • A01K2267/01—Animal expressing industrially exogenous proteins
    • 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
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/081—DNA viruses
    • C07K16/082—Hepadnaviridae (F), e.g. hepatitis B virus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C07K16/461—Igs containing Ig-regions, -domains or -residues form different species
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
    • C07K2317/14—Specific host cells or culture conditions, e.g. components, pH or temperature
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • 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
    • C12N2015/8518—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic expressing industrially exogenous proteins, e.g. for pharmaceutical use, human insulin, blood factors, immunoglobulins, pseudoparticles

Abstract

Disclosed are targeting vectors comprising a first and second targeting arm directing the targeting vector to an endogenous mouse immunoglobulin heavy chain gene locus, and a contiguous sequence comprising unrearranged human VL gene segments, optionally with an unrearranged human JL gene segment; wherein homologous recombination with the targeting vector creates a hybrid immunoglobulin gene locus comprising the unrearranged human VL and optionally JL gene segments operably linked with an endogenous mouse immunoglobulin heavy chain gene locus. Further disclosed are isolated host cells comprising said targeting vectors and methods for making a genetically modified mouse using said targeting vectors.

Claims (13)

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:
1. A targeting vector comprising a) a first targeting arm and a second targeting arm, wherein the first targeting arm and the second targeting arm direct the targeting vector to an endogenous mouse immunoglobulin heavy chain gene locus; and b) a contiguous sequence comprising (i) unrearranged human V gene segments, or (ii) unrearranged human V gene segments and an unrearranged human JL gene segment, wherein homologous recombination with the targeting vector creates a hybrid immunoglobulin gene locus comprising (i) the unrearranged human V gene segments operably linked with an endogenous immunoglobulin heavy chain constant region nucleic acid sequence comprising a CH sequence, at the endogenous mouse immunoglobulin heavy chain gene locus, or (ii) the unrearranged human VL gene segments and the unrearranged human JL gene segment operably linked with an endogenous immunoglobulin heavy chain constant region nucleic acid sequence comprising a CH1 sequence, at the endogenous mouse immunoglobulin heavy chain gene locus.
2. The targeting vector of claim 1, wherein the unrearranged human V gene segments comprise a human ? segment, a human ? segment, or a combination thereof.
3. The targeting vector of claim 1, wherein the endogenous immunoglobulin heavy chain constant region nucleic acid sequence further comprises a sequence selected from the group consisting of a hinge sequence, a CH2 sequence, a CH3 sequence, and a combination thereof.
4. The targeting vector of claim 1, wherein, upon homologous recombination, the unrearranged human VL gene segments and the unrearranged human JL gene segment replace an endogenous mouse heavy chain variable V gene segment and an endogenous mouse heavy chain JH gene segment, respectively, at the endogenous mouse immunoglobulin heavy chain gene locus.
5. The targeting vector of claim 4, wherein the unrearranged human V gene segments and the unrearranged human JL gene segment replace all functional mouse heavy chain V , D , and J gene segments of the endogenous mouse heavy chain H H H gene locus.
6. The targeting vector of claim 1, wherein the unrearranged human VL gene segments comprise only human V ? gene segments and the unrearranged human J gene segment is a human J ? gene segment.
7. The targeting vector of claim 1, wherein the targeting vector comprises at least six or more unrearranged human light chain VL gene segments and at least one unrearranged human JL gene segment.
8. The targeting vector of claim 1, wherein the contiguous sequence is selected from the group consisting of (i) hV ?4-1 through hV ?1-6 and J ?1, (ii) hV ?4-1 through hV ?1-6 and J ?1 through J ?2, (iii) hV ?4-1 through hV ?1-6 and J ?1 through J ?3, (iv) hV ?4-1 through hV ?1-6 and J ?1 through J ?4, (v) hV ?4-1 through hV ?1-6 and J ?1 through J ?5, (vi) hV ?3-7 through hV ?1-16, (vii) hV ?1-17 through hV ?2-30, (viii) hV ?3-31 through hV ?2-40, and (ix) a combination thereof.
9. The targeting vector of claim 1, wherein the hybrid immunoglobulin gene locus lacks any functional heavy chain D segment between the unrearranged human V gene segments and the unrearranged human JL gene segment.
10. The targeting vector of claim 1, wherein each of the unrearranged human VL gene segments and the unrearranged JL gene segment comprises recombination signal sequences that allow the unrearranged human V gene segments and the unrearranged human JL gene segment to recombine to form a rearranged human immunoglobulin light chain variable region (VL/JL) nucleotide sequence linked to the endogenous immunoglobulin heavy chain constant region nucleic acid sequence at an endogenous mouse immunoglobulin heavy chain locus
11. An isolated cell comprising the targeting vector of any one of claims 1-10.
12. A cell according to claim 11, wherein the cell is selected from an embryonic stem (ES) cell, a B cell, and a hybridoma.
13. A method of making a genetically modified mouse comprising in its germline unrearranged human immunoglobulin light chain variable region (VL) gene segments and an unrearranged human immunoglobulin light chain joining (J ) gene segment operably linked with a heavy chain constant region nucleic acid sequence, the method comprising: (a) modifying a totipotent mouse cell to include a targeting vector according to any one of claims 1-10 by homologous recombination such that the totipotent mouse cell comprises a hybrid immunoglobulin locus comprising unrearranged human VL gene segments and an unrearranged human JL gene segment operably linked with an endogenous immunoglobulin heavy chain constant region nucleic acid sequence at the endogenous mouse immunoglobulin heavy chain gene locus; (b) maintaining the totipotent mouse cell under suitable conditions to develop into a genetically modified mouse comprising in its germline the hybrid immunoglobulin locus.
NZ740900A 2011-08-02 Mice that make binding proteins comprising vl domains NZ740900B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US36990910P 2010-08-02 2010-08-02
NZ724003A NZ724003B2 (en) 2010-08-02 2011-08-02 Mice that make binding proteins comprising vl domains

Publications (2)

Publication Number Publication Date
NZ740900A NZ740900A (en) 2023-11-24
NZ740900B2 true NZ740900B2 (en) 2024-02-27

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