Production of humanized antibodies in transgenic animals

• US 20070092505A1
• Filed: 10/20/2006
• Published: 04/26/2007
• Est. Priority Date: 08/03/2000
• Status: Abandoned Application

• Current Assignee: Jens-Ulrich Buelow, Josef Platzer, Roland Buelow, Wim Schooten
• Original Assignee: Jens-Ulrich Buelow, Josef Platzer, Roland Buelow, Wim Schooten
• Inventors: Buelow, Roland, Platzer, Josef, Buelow, Jens-Ulrich, Schooten, Wim
• Application Number:
  US11/584,187
• Publication Number:
  US 20070092505A1
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A01K 2207/15 Humanized animals
• CPC Class Codes: A01K 2217/00 Genetically modified animals
• CPC Class Codes: A01K 2217/20 Animal model comprising regulated expression system
• CPC Class Codes: A01K 2227/107 Rabbit
• CPC Class Codes: A01K 2227/30 Bird
• CPC Class Codes: A01K 2267/01 Animal expressing industrially exogenous proteins
• CPC Class Codes: A01K 67/0273 Cloned vertebrates
• CPC Class Codes: A01K 67/0278 Knock-in vertebrates, e.g. humanised vertebrates
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 16/082 Hepadnaviridae, e.g. hepatitis B virus
• CPC Class Codes: C07K 16/1271 from Micrococcaceae (F), e.g. Staphylococcus
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/734 Complement-dependent cytotoxicity [CDC]
• CPC Class Codes: C12N 15/8509 for producing genetically modified animals, e.g. transgenic
• CPC Class Codes: C12N 2800/30 Vector systems comprising sequences for excision in presence of a recombinase, e.g. loxP or FRT

Abstract

This invention relates to humanized antibodies and antibody preparations produced from transgenic non-human animals. The non-human animals are genetically engineered to contain one or more humanized immunoglobulin loci which are capable of undergoing gene rearrangement and gene conversion in the transgenic non-human animals to produce diversified humanized immunoglobulins. The present invention further relates to novel sequences, recombination vectors and transgenic vectors useful for making these transgenic animals. The humanized antibodies of the present invention have minimal immunogenicity to humans and are appropriate for use in the therapeutic treatment of human subjects.

Claims

1. A humanized immunoglobulin molecule comprising at least a portion of a human immunoglobulin heavy chain constant (C) region, and variable region amino acids sequences encoded by more than one immunoglobulin variable (V) gene segment.

2. The humanized immunoglobulin molecule of claim 1 which is derived from a nonhuman transgenic animal relying primarily on gene conversion and/or somatic hypermutation to generate antibody diversity.

3. The humanized immunoglobulin molecule of claim 2 wherein said transgenic animal is a rabbit, chicken, sheep or cow.

4. The humanized immunoglobulin molecule of claim 1 wherein said human immunoglobulin heavy chain C region sequence is a C_γ

, C_κ

, or C_λ

sequence.

5. The humanized immunoglobulin molecule of any one of claims 1-4, which is specific for an antigen.

6. The humanized immunoglobulin molecule of claim 5, wherein said antigen is a microorganism selected from bacterium, fungus, or virus;

an antigenic portion of said organism;

an antigenic molecule derived from said microorganism;

or a tumor-associated antigen.

7. The humanized immunoglobulin molecule of claim 6, wherein said bacterium is selected from S. aureus, Pseudomonas aeruginosa, enterococcus, enterobacter, and Klebsiella pneumoniae.

8. The humanized immunoglobulin molecule of claim 6, wherein said fungus is selected from Candida albicans, Candida parapsilosis, Candida tropicalis, and Cryptococcus neoformans.

9. The humanized immunoglobulin molecule of claim 6, wherein said virus is selected from respiratory synctial virus (RSV), Hepatitis C virus (HCV), Hepatitis virus (HBV), cytomegalovirus (CMV), EBV, and HSV.

10. The humanized immunoglobulin molecule of claim 6, wherein said antigen is selected from Her-2-neu antigen, CD20, CD22, CD53, prostate specific membrane antigen (PMSA), and 17-1A molecule.

11. A monoclonal antibody preparation comprising a humanized immunoglobulin molecule of claim 5.

12. A monoclonal antibody preparation comprising a humanized immunoglobulin molecule of any one of claims 6-10.

13. The monoclonal antibody preparation of claim 11 which is substantially non-immunogenic to human.

14. The monoclonal antibody preparation of claim 12 which is substantially non-immunogenic to human.

15. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and the monoclonal antibody preparation of claim 11.

16. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and the monoclonal antibody preparation of claim 12.

17. A method of treating a disease in a human subject comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition of claim 15.

18. The method of claim 17 wherein said disease is caused by bacterial, fungal or viral infection, or said disease is a cancer.