Monoclonal antibodies with reduced immunogenicity

• US 6,936,698 B2
• Filed: 07/16/2001
• Issued: 08/30/2005
• Est. Priority Date: 04/28/1998
• Status: Expired due to Fees

• Current Assignee: SmithKline Beecham (GSK plc)
• Original Assignee: SmithKline Beecham (GSK plc)
• Inventors: Taylor, Alexander H.
• Primary Examiner(s): HELMS, LARRY RONALD
• Application Number:
  US09/905,243
• Publication Number:
  US 20020062009A1
• Time in Patent Office: 1,506 Days
• Field of Search: 530/387.1, 530/387.3, 424/130.1, 424/133.1
• US Class Current: 530/387.3
• CPC Class Codes: A61P 37/02 Immunomodulators
• 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 16/244 Interleukins [IL]
• CPC Class Codes: C07K 16/2848 against integrin beta3-subunit-containing molecules, e.g. CD41, CD51, CD61
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• 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 2317/567 Framework region [FR]
• CPC Class Codes: C07K 2319/00 Fusion polypeptide

Abstract

Antibodies having reduced immunogenicity and methods for making them are disclosed.

Claims

1. An antibody comprising:

a) a variable region comprising six complementarity determining regions (CDRs) from an antigen-specific donor antibody of a rodent and acceptor framework comprising amino acid residues from an Old World Ape, wherein at least one CDR-contacting amino acid residue from the acceptor framework is replaced with a corresponding residue from the donor framework, and wherein said CDR-contacting residue contacts a CDR residue within said antibody by the group selected from coming within the van der Waals radius of said CDR residue, a salt bridge and a hydrophobic interaction; and

b) at least one constant region from human, and

wherein said antibody has a specific binding avidity that is within about three-fold of the specific binding avidity of said antigen-specific donor antibody.

2. The antibody of claim 1, wherein the rodent is mouse.

3. The antibody of claim 1, wherein the rodent is rat.

4. The antibody of claim 1, wherein the Old World Ape is Pan troglodytes, Pan paniscus or Gorilla gorilla.

5. The antibody of claim 1, wherein the Old World Ape is Pan troglodytes.

6. The antibody of claim 1, wherein the acceptor framework comprises a light (VL) and heavy (VH) chain region each comprising four acceptor framework regions (framework I, II, III, and IV), and wherein the VH acceptor framework I, II, III and IV are from chimpanzee.

7. The antibody of claim 6, wherein the VH acceptor framework I, II and III comprise an amino acid sequence as set forth in SEQ ID NOs:

10, 11, 12, 13, 14, 15, 16, 17 or 18.

8. The antibody of claim 6, wherein the VH acceptor framework IV comprises an amino acid sequence as set forth in SEQ ID NOs:

81, 82, 83, 84 or 85.

9. The antibody of claim 1, wherein VL comprises segments Vκ

and Vλ

, and wherein Vκ

comprises four acceptor framework regions (framework I, II, III, and IV), and wherein Vκ

acceptor framework I, II, III and IV are from chimpanzee.

10. The antibody of claim 9, wherein Vκ

acceptor framework I, II, and III comprise an amino acid sequence as set forth in SEQ ID NOs;

28, 29, 30, 31, 32, 33, 34, 35 or 36.

11. The antibody of claim 9, wherein Vκ

acceptor framework IV comprises an amino acid sequence as set forth in SEQ ID NOs;

86 or 87.

12. The antibody of claim 1, wherein the amino acid sequence of the complete light chain is set forth in SEQ ID NO:

68 and the amino acid sequences of the heavy chain is set forth in SEQ ID NO;

70.

13. The antibody of claim 1, wherein the amino acid sequence of the complete light chain is set forth in SEQ ID NO:

73 and the amino acid sequences of the heavy chain is set forth in SEQ ID NO;

74.

14. The antibody of claim 1, wherein the amino acid sequence of the complete light chain is set forth in SEQ ID NO:

77 and the amino acid sequences of the heavy chain is set forth in SEQ ID NO;

78.