Bispecific Anti ErbB3 / Anti cMet Antibodies

• US 20100256339A1
• Filed: 04/01/2010
• Published: 10/07/2010
• Est. Priority Date: 04/07/2009
• Status: Abandoned Application

• Current Assignee: Roche Glycart AG (Roche Holding AG)
• Original Assignee: Roche Glycart AG (Roche Holding AG)
• Inventors: Umana, Pablo, Klein, Christian, Brinkmann, Ulrich, Niederfellner, Gerhard, Bossenmaier, Birgit, Hoffmann, Eike, Stracke, Jan Olaf, Schanzer, Juergen Michael, Sustmann, Claudio, Dormeyer, Wilma
• Application Number:
  US12/752,196
• Publication Number:
  US 20100256339A1
• Time in Patent Office: Days
• US Class Current: 530/387.300
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 16/468 Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 multispecific
• CPC Class Codes: C07K 2317/41 Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/77 Internalization into the cell
• CPC Class Codes: C07K 2319/00 Fusion polypeptide

Abstract

The present invention relates to bispecific antibodies against human ErbB-3 and against human c-Met, methods for their production, pharmaceutical compositions containing the antibodies, and uses thereof.

Claims

1. A bispecific antibody that specifically binds to human ErbB-3 and human c-Met comprising a first antigen-binding site that specifically binds to human ErbB-3 and a second antigen-binding site that specifically binds to human c-Met, wherein the bispecific antibody causes increase in internalization of ErbB-3 on A431 cells of no more than 15% when measured after 2 hours of A431 cell-antibody incubation as measured by a flow cytometry assay, as compared to internalization of ErbB-3 on A431 cells in the absence of antibody.

2. The antibody according to claim 1, wherein the antibody is a bivalent or trivalent bispecific antibody that specifically binds to human ErbB-3 and human c-Met, wherein the antibody comprises one or two antigen-binding sites that specifically bind to human ErbB-3 and one antigen-binding site that specifically binds to human c-Met.

3. The antibody according to claim 1 wherein the antibody is a trivalent, bispecific antibody that specifically binds to human ErbB-3 and human c-Met, wherein the antibody comprises two antigen-binding sites that specifically bind to human ErbB-3 and a third antigen-binding site that specifically binds to human c-Met.

4. The antibody according to claim 1 wherein the antibody is a bivalent, bispecific antibody that specifically binds to human ErbB-3 and human c-Met, wherein the antibody comprises one antigen-binding site that specifically binds to human ErbB-3 and a second antigen-binding site that specifically binds to human c-Met.

8. The bispecific antibody according to claim 1, wherein the antibody comprises a constant region with the amino acid sequence of IgG1 or IgG3 subclass.

9. The bispecific antibody according to claim 1, wherein the antibody is glycosylated with a sugar chain at Asn297 and wherein the amount of fucose within the sugar chain is 65% or lower.

10. A nucleic acid encoding a bispecific antibody according to claim 1.

13. A pharmaceutical composition comprising a bispecific antibody according to claim 1.

5. A bispecific antibody that specifically binds to human ErbB-3 and human c-Met, wherein the antibody comprises a first antigen-binding site that specifically binds to human ErbB-3 and a second antigen-binding site that specifically binds to human c-Met, wherein

i) the first antigen-binding site comprises in the heavy chain variable domain a CDR3H region with the amino acid sequence of SEQ ID NO:

53, a CDR2H region with the amino acid sequence of SEQ ID NO;

54, and a CDR1H region with the amino acid sequence of SEQ ID NO;

55, and in the light chain variable domain a CDR3L region with the amino acid sequence of SEQ ID NO;

56, a CDR2L region with the amino acid sequence of SEQ ID NO;

57, and a CDR1L region with the amino acid sequence of SEQ ID NO;

58 or a CDR1L region with the amino acid sequence of SEQ ID NO;

59; and

the second antigen-binding site comprises in the heavy chain variable domain a CDR3H region with the amino acid sequence of SEQ ID NO;

66, a CDR2H region with the amino acid sequence of SEQ ID NO;

67, and a CDR1H region with the amino acid sequence of SEQ ID NO;

68, and in the light chain variable domain a CDR3L region with the amino acid sequence of SEQ ID NO;

69, a CDR2L region with the amino acid sequence of SEQ ID NO;

70, and a CDR1L region with the amino acid sequence of SEQ ID NO;

71.

ii) the first antigen-binding site comprises in the heavy chain variable domain a CDR3H region with the amino acid sequence of SEQ ID NO;

60, a CDR2H region with the amino acid sequence of SEQ ID NO;

61, and a CDR1H region with the amino acid sequence of SEQ ID NO;

62, and in the light chain variable domain a CDR3L region with the amino acid sequence of SEQ ID NO;

63, a CDR2L region with the amino acid sequence of SEQ ID NO;

64, and a CDR1L region with the amino acid sequence of SEQ ID NO;

65 or a CDR1L region with the amino acid sequence of SEQ ID NO;

66; and

the second antigen-binding site comprises in the heavy chain variable domain a CDR3H region with the amino acid sequence of SEQ ID NO;

66, a CDR2H region with the amino acid sequence of, SEQ ID NO;

67, and a CDR1H region with the amino acid sequence of SEQ ID NO;

68, and in the light chain variable domain a CDR3L region with the amino acid sequence of SEQ ID NO;

69, a CDR2L region with the amino acid sequence of SEQ ID NO;

70, and a CDR1L region with the amino acid sequence of SEQ ID NO;

71.

6. The bispecific antibody according to claim 5, selected from the group of bispecific antibodies wherein

i) the first antigen-binding site comprises as heavy chain variable domain the amino acid sequence of SEQ ID NO:

47, and as light chain variable domain the amino acid sequence of SEQ ID NO;

48, and the second antigen-binding site comprises as heavy chain variable domain the amino acid sequence of SEQ ID NO;

3, and as light chain variable domain the amino acid sequence of SEQ ID NO;

4;

ii) the first antigen-binding site comprises as heavy chain variable domain the amino acid sequence of SEQ ID NO;

49, and as light chain variable domain the amino acid sequence of SEQ ID NO;

50, and the second antigen-binding site comprises as heavy chain variable domain the amino acid sequence of SEQ ID NO;

3, and as light chain variable domain the amino acid sequence of SEQ ID NO;

4;

iii) the first antigen-binding site comprises as heavy chain variable domain the amino acid sequence of SEQ ID NO;

49, and as light chain variable domain the amino acid sequence of SEQ ID NO;

51, and the second antigen-binding site comprises as heavy chain variable domain the amino acid sequence of SEQ ID NO;

3, and as light chain variable domain the amino acid sequence of SEQ ID NO;

4;

iv) the first antigen-binding site comprises as heavy chain variable domain the amino acid sequence of SEQ ID NO;

49, and as light chain variable domain the amino acid sequence of SEQ ID NO;

52, and the second antigen-binding site comprises as heavy chain variable domain the amino acid sequence of SEQ ID NO;

3, and as light chain variable domain the amino acid sequence of SEQ ID NO;

4;

or

v) the first antigen-binding site comprises as heavy chain variable domain the amino acid sequence of SEQ ID NO;

1, and as light chain variable domain the amino acid sequence of SEQ ID NO;

2, and the second antigen-binding site comprises as heavy chain variable domain the amino acid sequence of SEQ ID NO;

3, and as light chain variable domain the amino acid sequence of SEQ ID NO;

4;

or

7. The bispecific antibody according to claim 5, wherein

the first antigen-binding site comprises as heavy chain variable domain the amino acid sequence of SEQ ID NO:

49, and as light chain variable domain the amino acid sequence of SEQ ID NO;

51, and the second antigen-binding site comprises as heavy chain variable domain the amino acid sequence of SEQ ID NO;

3, and as light chain variable domain the amino acid sequence of a SEQ ID NO;

4;

11. A nucleic acid encoding a bispecific antibody according to claim 5.

12. A nucleic acid encoding a bispecific antibody according to claim 6,

14. A pharmaceutical composition comprising a bispecific antibody according to claim 5.

15. A pharmaceutical composition comprising a bispecific antibody according to claim 6.