Humanized anti-CD3 antibodies

• US 7,994,289 B2
• Filed: 06/18/2003
• Issued: 08/09/2011
• Est. Priority Date: 07/21/1998
• Status: Expired due to Fees

• Current Assignee: BTG International Limited (Boston Scientific Corporation)
• Original Assignee: BTG International Limited (Boston Scientific Corporation)
• Inventors: Frewin, Mark, Waldmann, Herman
• Primary Examiner(s): Blanchard; David J.
• Application Number:
  US10/463,442
• Publication Number:
  US 20040006216A1
• Time in Patent Office: 2,974 Days
• Field of Search: 424/133.1, 424/154.1, 530/387.1, 530/388.2, 530/387.3, 530/388.75
• US Class Current: 530/387.3
• 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: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 16/2809 against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/41 Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2319/00 Fusion polypeptide

Abstract

An IgG antibody is provided having a binding affinity for the CD3 antigen complex in which in the heavy chain has a variable region framework together with at least one CDR selected from the amino acid sequences of SEQ ID No 2, 4 and 6 and respective conservatively modified variants thereof and the light chain has a variable region framework together with at least one CDR selected from the amino acid sequences of SEQ ID No 8, 10 and 12 and respective conservatively modified variants thereof characterised in that the heavy chain variable region framework corresponds in sequence to the human type sequence and the light chain variable region framework includes one or more of the specific amino acids characteristic of the rodent type sequence. The novel antibody is capable of being expressed by mammalian cell expression systems at enhanced yields.

Claims

1. An IgG antibody having a binding affinity for the CD3 antigen complex comprising:

a heavy chain having the amino acid sequence SEQ ID NO;

20;

a human lambda light chain constant region; and

a light chain variable domain comprising three CDRs having the amino acid sequences SEQ ID NOS;

8, 10, and 12, and four framework regions having the amino acid sequences SEQ ID NOS;

35, 26, 27, and 28,

wherein alanine at amino acid 7 of SEQ ID NO;

35 is replaced with proline.

8. The antibody of claim 1, wherein the antibody is monovalent.

10. The antibody of claim 1, wherein the antibody is aglycosylated by replacing the amino acid corresponding to Asn 297 of the constant region heavy chain with an alternative amino acid residue.

11. The antibody of claim 10, wherein Asn 297 is replaced with an alanine.

12. The antibody of claim 1, in which the heavy chain constant region is of an IgG1 isotype.

14. The antibody of claim 1, wherein said antibody is in the form of a pharmaceutical composition comprising a physiologically acceptable diluent or carrier.

2. An IgG antibody having a binding affinity for the CD3 antigen complex comprising:

a heavy chain having the amino acid sequence SEQ ID NO;

20;

a human lambda light chain constant region; and

a light chain variable domain comprising three CDRs having the amino acid sequences SEQ ID NOS;

8, 10, and 12, and four framework regions having the amino acid sequences SEQ ID NOS;

25, 26, 27, and 28.

3. The antibody of claim 2, wherein the amino acid sequence of the light chain variable domain is SEQ ID NO:

14.

4. The antibody of claim 3, wherein the amino acid sequence of the light chain is SEQ ID NO:

18.

5. The antibody of claim 2, wherein the antibody is aglycosylated by replacing the amino acid corresponding to Asn 297 of the constant region heavy chain with an alternative amino acid residue.

6. The antibody of claim 5, wherein Asn 297 is replaced with an alanine.

7. The antibody of claim 2, in which the heavy chain constant region is of an IgG1 isotype.

9. The antibody of claim 2, wherein said antibody is in the form of a pharmaceutical composition comprising a physiologically acceptable diluent or carrier.

13. The antibody of claim 2, wherein the antibody is monovalent.