Anti-CD3 antibodies and methods of use thereof

• US 7,728,114 B2
• Filed: 06/03/2005
• Issued: 06/01/2010
• Est. Priority Date: 06/03/2004
• Status: Active Grant

• Current Assignee: Novimmune SA (Light Chain Bioscience AG)
• Original Assignee: Novimmune SA (Light Chain Bioscience AG)
• Inventors: Mach, Bernard, Leger, Olivier, Kosco-Vilbois, Marie, Fischer, Nicolas, Elson, Greg, Dean, Yann
• Primary Examiner(s): Shukla; Ram R
• Assistant Examiner(s): Skelding; Zachary
• Application Number:
  US11/145,131
• Publication Number:
  US 20060177896A1
• Time in Patent Office: 1,824 Days
• Field of Search: None
• US Class Current: 530/388.15
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/16 for decreasing, blocking or antagonising the activity of the thyroid hormones
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/2809 : against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• 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: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/74 : Inducing cell proliferation

Abstract

The present invention is related to antibodies directed to the antigen CD3 and uses of such antibodies. In particular, the present invention provides fully human monoclonal antibodies directed to CD3. Nucleotide sequences encoding, and amino acid sequences comprising, heavy and light chain immunoglobulin molecules, particularly sequences corresponding to contiguous heavy and light chain sequences spanning the framework regions and/or complementarity determining regions (CDR'"'"'s), specifically from FR1 through FR4 or CDR1 through CDR3, are provided. Hybridomas or other cell lines expressing such immunoglobulin molecules and monoclonal antibodies are also provided.

Claims

1. An isolated fully human monoclonal antibody, wherein said antibody has a heavy chain with three complementarity determining regions (CDRs), comprising a VH CDR1 comprising the amino acid sequence GYGMH (SEQ ID NO:

27);

a VH CDR2 comprising the amino acid sequence of VIWYDGSKKYYVDSVKG (SEQ ID NO;

28); and

a VH CDR3 comprising the amino acid sequence of QMGYWHFDL (SEQ ID NO;

29) and a light chain with three CDRs, comprising a VL CDR1 comprising the amino acid sequence of RASQSVSSYLA (SEQ ID NO;

30);

a VL CDR2 comprising the amino acid sequence of DASNRAT (SEQ ID NO;

31); and

a VL CDR3 comprising the amino acid sequence of QQRSNWPPLT (SEQ ID NO;

32), wherein said antibody binds CD3.

4. The antibody of claim 1, wherein said antibody includes a mutation in the heavy chain at an amino acid residue at position 234, 235, 265, or 297 or combinations thereof, and reduces the release of cytokines from a T cell, wherein the amino acid residue positions are numbered according to Kabat.

5. The antibody of claim 4, wherein said mutation results in an alanine or glutamic acid residue at said position.

6. The antibody of claim 1, wherein said antibody is an IgG1 isotype and contains at least a first mutation at position 234 and a second mutation at position 235, wherein said first mutation results in an alanine residue at position 234 and said second mutation results in a glutamic acid residue at position 235, wherein the amino acid residue positions are numbered according to Kabat.

7. The antibody of claim 1, wherein said antibody comprises a heavy chain variable amino acid sequence selected from the group consisting of SEQ ID NOS:

2 and 6.

8. The antibody of claim 1, wherein said antibody comprises the light chain variable amino acid sequence of SEQ ID NO:

4.

9. The antibody of claim 1, wherein the antibody comprises the heavy chain variable amino acid sequence of SEQ ID NO:

2 and the light chain variable amino acid sequence of SEQ ID NO;

4.

10. The antibody of claim 1, wherein the antibody comprises the heavy chain variable amino acid sequence of SEQ ID NO:

6 and the light chain variable amino acid sequence of SEQ ID NO;

8.

11. The antibody of claim 1, wherein said antibody is an IgG1 isotype.

2. An isolated fully human monoclonal antibody, wherein said antibody comprises a heavy chain variable amino acid sequence selected from the group consisting of SEQ ID NOS:

2 and 6, wherein said antibody binds CD3.

12. The antibody of claim 2, wherein said antibody includes a mutation in the heavy chain at an amino acid residue at position 234, 235, 265, or 297 or combinations thereof, and reduces the release of cytokines from a T cell, wherein the amino acid residue positions are numbered according to Kabat.

13. The antibody of claim 12, wherein said mutation results in an alanine or glutamic acid residue at said position.

14. The antibody of claim 2, wherein said antibody is an IgG1 isotype and contains at least a first mutation at position 234 and a second mutation at position 235, wherein said first mutation results in an alanine residue at position 234 and said second mutation results in a glutamic acid residue at position 235, wherein the amino acid residue positions are numbered according to Kabat.

15. The antibody of claim 2, wherein said antibody further comprises the light chain variable amino acid sequence of SEQ ID NO:

4.

16. The antibody of claim 2, wherein the antibody comprises the heavy chain variable amino acid sequence of SEQ ID NO:

2 and the light chain variable amino acid sequence of SEQ ID NO;

4.

17. The antibody of claim 2, wherein the antibody comprises the heavy chain variable amino acid sequence of SEQ ID NO:

6 and the light chain variable amino acid sequence of SEQ ID NO;

4.

18. The antibody of claim 2, wherein said antibody is an IgG1 isotype.

3. An isolated fully human monoclonal antibody, wherein said antibody comprises the light chain variable amino acid sequence of SEQ ID NO:

4, wherein said antibody binds CD3.

19. The antibody of claim 3, wherein said antibody includes a mutation in the heavy chain at an amino acid residue at position 234, 235, 265, or 297 or combinations thereof, and reduces the release of cytokines from a T cell, wherein the amino acid residue positions are numbered according to Kabat.

20. The antibody of claim 19, wherein said mutation results in an alanine or glutamic acid residue at said position.

21. The antibody of claim 3, wherein said antibody is an IgG1 isotype and contains at least a first mutation at position 234 and a second mutation at position 235, wherein said first mutation results in an alanine residue at position 234 and said second mutation results in a glutamic acid residue at position 235, wherein the amino acid residue positions are numbered according to Kabat.

22. The antibody of claim 3, wherein said antibody further comprises a heavy chain variable amino acid sequence selected from the group consisting of SEQ ID NOS:

2 and 6.

23. The antibody of claim 3, wherein the antibody comprises the heavy chain variable amino acid sequence of SEQ ID NO:

2 and the light chain variable amino acid sequence of SEQ ID NO;

4.

24. The antibody of claim 3, wherein the antibody comprises the heavy chain variable amino acid sequence of SEQ ID NO:

6 and the light chain variable amino acid sequence of SEQ ID NO;

4.

25. The antibody of claim 3, wherein said antibody is an IgG1 isotype.