BISPECIFIC, BIVALENT ANTI-VEGF/ANTI-ANG-2 ANTIBODIES

• US 20110236388A1
• Filed: 03/24/2011
• Published: 09/29/2011
• Est. Priority Date: 03/26/2010
• Status: Active Grant

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Klein, Christian, Schanzer, Juergen Michael, Baehner, Monika, Kavlie, Anita, Thomas, Markus, Schaefer, Wolfgang, Kettenberger, Hubert, Imhof-Jung, Sabine, Scheuer, Werner, Stubenrauch, Kay-Gunnar, Regula, Joerg Thomas
• Granted Patent: US 8,945,552 B2
• 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: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 16/3015 Breast
• CPC Class Codes: C07K 16/3046 Stomach, Intestines
• CPC Class Codes: C07K 16/468 Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/31 multispecific
• CPC Class Codes: C07K 2317/35 Valency
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/522 CH1 domain
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/66 comprising a swap of domains, e.g. CH3-CH2, VH-CL or VL-CH1
• 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 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present invention relates to bispecific, bivalent antibodies against human vascular endothelial growth factor (VEGF/VEGF-A) and against human angiopoietin-2 (ANG-2), methods for their production, pharmaceutical compositions containing said antibodies, and uses thereof.

Claims

1. A bispecific, bivalent antibody comprising a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2, wherein

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

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

2; and

wherein

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

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

4.

2. The bispecific antibody according to claim 1 comprising

a) a heavy chain and a light chain of a first full length antibody that specifically binds to VEGF;

and

b) a modified heavy chain and a modified light chain of a full length antibody that specifically binds to ANG-2, wherein the constant domains CL and CH₁ are replaced by each other.

3. The bispecific antibody according to claim 2 wherein

a) the heavy chain of the first full length antibody comprises the amino acid sequence of SEQ ID NO:

7, and the light chain of the first full length antibody comprises the amino acid sequence of SEQ ID NO;

5, and wherein

b) the modified heavy chain of the second full length antibody comprises the amino acid sequence of SEQ ID NO;

8, and the modified light chain of the second full length antibody comprises the amino acid sequence of SEQ ID NO;

6.

4. The bispecific antibody according to claim 2 wherein

a) the heavy chain of the first full length antibody comprises the amino acid sequence of SEQ ID NO:

11, and the light chain of the first full length antibody comprises the amino acid sequence of SEQ ID NO;

9, and wherein

b) the modified heavy chain of the second full length antibodycomprises the amino acid sequence of SEQ ID NO;

12, and the modified light chain of the second full length antibodycomprises the amino acid sequence of SEQ ID NO;

10.

5. The bispecific antibody according to claim 2, wherein

a) the heavy chain of the first full length antibodycomprises the amino acid sequence of SEQ ID NO:

15, and the light chain of the first full length antibody comprises the amino acid sequence of SEQ ID NO;

13, and wherein

b) the modified heavy chain of the second full length antibody comprises the amino acid sequence of SEQ ID NO;

16, and the modified light chain of the second full length antibody comprises the amino acid sequence of SEQ ID NO;

14.

6. A pharmaceutical composition comprising the antibody according to any one of claims 1 to 5.

7. A method of treating a patient suffering from cancer, comprising administering to the patient an effective amount of the antibody according to any one of claims 1 to 5.

8. The method of claim 7, wherein the cancer is colorectal cancer, lung cancer, breast cancer, renal cancer, ovarian cancer or glioblastoma.

9. A method of treating a patient suffering from vascular diseases, comprising administering to the patient an effective amount of the antibody according to any one of claims 1 to 5.

10. A method of inhibiting angiogenesis in a patient having a pathological condition associated with angiogenesis, comprising administering to the patient an effective amount of the antibody according to any one of claims 1 to 5.

11. An isolated nucleic acid encoding the bispecific antibody according to any one of claims 1 to 5.

12. An expression vector comprising the nucleic acid according claim 11.

13. A prokaryotic or eukaryotic host cell comprising the nucleic acid according to claim 11.

14. A method for producing the bispecific antibody according to any one of claims 1 to 5, comprising culturing the host cell of claim 13 so that the antibody is produced.

15. The method of claim 14, further comprising recovering said antibody from the host cell.

16. A bispecific antibody obtained by the method of claim 14.

17. A bispecific, bivalent antibody comprising a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2, wherein the antibody comprises the amino acid sequences of SEQ ID NO:

5, SEQ ID NO;

6, SEQ ID NO;

7, and SEQ ID NO;

8.

18. A bispecific, bivalent antibody comprising a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2, wherein the antibody comprises the amino acid sequences of SEQ ID NO:

9, SEQ ID NO;

10, SEQ ID NO;

11, and SEQ ID NO;

12.

19. A bispecific, bivalent antibody comprising a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2, wherein the antibody comprises the amino acid sequences of SEQ ID NO:

13, SEQ ID NO;

14, SEQ ID NO;

15, and SEQ ID NO;

16.