Transgenic non-human animals for producing heterologous antibodies

• US 5,625,126 A
• Filed: 12/07/1994
• Issued: 04/29/1997
• Est. Priority Date: 08/29/1990
• Status: Expired due to Term

• Current Assignee: Genpharm International Inc (Bristol-Myers Squibb Company)
• Original Assignee: Genpharm International Inc (Bristol-Myers Squibb Company)
• Inventors: Kay, Robert M., Lonberg, Nils
• Primary Examiner(s): Ziska, Suzanne E.
• Application Number:
  US08/352,322
• Time in Patent Office: 874 Days
• Field of Search: 800/2, 435/172.3, 435/172.2, 536/23.1
• US Class Current: 800/18
• CPC Class Codes: A01K 2207/15 Humanized animals
• CPC Class Codes: A01K 2217/00 Genetically modified animals
• CPC Class Codes: A01K 2217/05 Animals comprising random inserted nucleic acids (transgenic)
• CPC Class Codes: A01K 2217/072 maintaining or altering function, i.e. knock in
• CPC Class Codes: A01K 2217/075 inducing loss of function, i.e. knock out
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/01 Animal expressing industrially exogenous proteins
• CPC Class Codes: A01K 67/0275 Genetically modified vertebrates, e.g. transgenic
• CPC Class Codes: A01K 67/0276 Knock-out vertebrates
• CPC Class Codes: A01K 67/0278 Knock-in vertebrates, e.g. humanised vertebrates
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 14/7051 T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/2812 against CD4
• CPC Class Codes: C07K 16/3007 Carcino-embryonic Antigens
• CPC Class Codes: C07K 16/4266 against anti-tumor receptor Ig
• CPC Class Codes: C07K 16/4291 against IgE
• CPC Class Codes: C07K 16/44 against material not provided for elsewhere , e.g. haptens, metals, DNA, RNA, amino acids
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/52 : Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C12N 15/00 : Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor mutants or genetically engineered microorganisms, per se C12N1/00, C12N5/00, C12N7/00; new plants per se A01H; plant reproduction by tissue culture techniques A01H4/00; new animals per se A01K67/00; use of medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases, gene therapy A61K48/00
• CPC Class Codes: C12N 15/85 : for animal cells
• CPC Class Codes: C12N 15/8509 : for producing genetically modified animals, e.g. transgenic
• CPC Class Codes: C12N 15/87 : Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
• CPC Class Codes: C12N 15/90 : Stable introduction of foreign DNA into chromosome
• CPC Class Codes: C12N 15/907 : in mammalian cells
• CPC Class Codes: C12N 2800/206 : of yeast origin, e.g. YAC, 2u
• CPC Class Codes: C12N 2800/70 : Vectors containing special elements for cloning, e.g. topoisomerase, adaptor sites
• CPC Class Codes: C12N 2830/30 : being an enhancer not forming part of the promoter region
• CPC Class Codes: C12N 2830/36 : being a transcription termination element
• CPC Class Codes: C12N 2830/85 : mammalian
• CPC Class Codes: C12N 5/163 : one of the fusion partners being a B or a T lymphocyte

Abstract

The invention relates to transgenic non-human animals capable of producing heterologous antibodies and methods for producing human sequence antibodies which bind to human antigens with substantial affinity.

Claims

1. A transgenic mouse containing in its genome a transgene comprising in operable linkage a plurality of human V genes, a plurality of human D genes, a plurality of human J genes, a human μ

C_H gene, at least two different non-μ

human C_H genes and associated isotype switching sequences, wherein human μ and

human γ

switch sequences are located in closer proximity to each other than in the naturally occurring human immunoglobulin locus; and

wherein in lymphocytes of said mouse the transgene undergoes productive VDJ rearrangement and μ

to γ

isotype switching by recombination between the human μ and

human γ

switch sequences such that the mouse produces a serum containing immunoglobulins of at least three human heavy chain isotypes in response to antigenic stimulation.

2. A transgenic mouse of claim 1, wherein the lymphocytes further have integrated a human light chain transgene.

3. A transgenic mouse of claim 2, wherein the serum comprises a population of IgG comprising a subpopulation of IgG composed of human γ

1and human κ and

a subpopulation of IgG composed of human γ

3 and human κ

.

4. The transgenic mouse of claim 1, wherein the human γ

switch sequences is contained within an approximately 5.3 kb HindIII fragment.

5. The transgenic mouse of claim 1, wherein the human γ

switch sequences is contained within an approximately 4 kb HindIII fragment.