Bispecific Anti ErbB1 / Anti cMet Antibodies

• US 20130156772A1
• Filed: 02/22/2013
• Published: 06/20/2013
• 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: Bossenmaier, Birgit, Brinkmann, Ulrich, Klein, Christian, Niederfellner, Gerhard, Schaefer, Wolfgang, Schanzer, Juergen Michael, Sustmann, Claudio, Umana, Pablo
• Application Number:
  US13/774,192
• Publication Number:
  US 20130156772A1
• Time in Patent Office: Days
• US Class Current: 424/136.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• 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 2317/55 Fab or Fab'
• 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 2317/622 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 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2319/00 Fusion polypeptide

Abstract

The present invention relates to bispecific antibodies against human ErbB-1 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-1 and human c-Met comprising a first antigen-binding site that specifically binds to human ErbB-1 and a second antigen-binding site that specifically binds to human c-Met, wherein the bispecific antibody causes an increase in internalization of c-Met on OVCAR-8 cells of no more than 15% when measured after 2 hours of OVCAR-8 cell-antibody incubation as measured by a flow cytometry assay as compared to internalization of c-Met on OVCAR-8 cells in the absence of the bispecific antibody.

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

3. The antibody according to claim 2 comprising

a) a full length antibody that specifically binds to ErbB-1 consisting of two antibody heavy chains and two antibody light chains;

and

b) one single chain Fab fragment that specifically binds to human c-Met,

wherein the single chain Fab fragment under b) is fused to the full length antibody under a) via a peptide connector to the C- or N-terminus of the heavy or light chain of the full length antibody.

6. The bispecific antibody according to claim 1 wherein the antibody comprises a constant region of IgG1 or IgG3 subclass.

8. The bispecific antibody according to claim 1 wherein the antibody is glycosylated with a sugar chain at Asn297 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.

12. A method of treatment of a patient suffering from cancer by administering an effective amount of a bispecific antibody according to claim 1 to a patient in the need of such treatment.

4. A bispecific antibody that specifically binds to human ErbB-1 and human c-Met comprising a first antigen-binding site that specifically binds to human ErbB-1 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 CDR3 region with the amino acid sequence of SEQ ID NO:

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

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

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

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

21, 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;

22; 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;

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

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

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

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

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

35.

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;

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

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

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

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

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

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

29; 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;

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

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

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

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

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

35.

5. The bispecific antibody according to claim 4 characterized in that

i) the first antigen-binding site specifically binding to ErbB-1 comprises as heavy chain variable domain the sequence of SEQ ID NO:

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

2; and

the second antigen-binding site specifically binding to c-Met comprises as heavy chain variable domain the sequence of SEQ ID NO;

5, and as light chain variable domain the sequence of SEQ ID NO;

6;

or

ii) the first antigen-binding site specifically binding to ErbB-1 comprises as heavy chain variable domain the sequence of SEQ ID NO;

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

4; and

the second antigen-binding site specifically binding to c-Met comprises as heavy chain variable domain the sequence of SEQ ID NO;

5, and as light chain variable domain the sequence of SEQ ID NO;

6.

7. The bispecific antibody according to claim 5 wherein the antibody comprises a constant region of IgG1 or IgG3 subclass.

9. The bispecific antibody according to claim 5 wherein the antibody is glycosylated with a sugar chain at Asn297 wherein the amount of fucose within the sugar chain is 65% or lower.

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

13. A method of treatment of a patient suffering from cancer by administering an effective amount of a bispecific antibody according to claim 5 to a patient in the need of such treatment.