Anti-HER2 antibodies and immunoconjugates

• US 9,518,118 B2
• Filed: 09/11/2015
• Issued: 12/13/2016
• Est. Priority Date: 09/12/2014
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Chen, Xiaocheng, Dennis, Mark, Junutula, Jagath Reddy, Phillips, Gail Lewis, Pillow, Thomas Harden, Sliwkowski, Mark X.
• Primary Examiner(s): Duffy, Brad
• Assistant Examiner(s): Moseley, II, Nelson B
• Application Number:
  US14/851,001
• Publication Number:
  US 20160096893A1
• Time in Patent Office: 459 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/5517 condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 47/68 the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
• CPC Class Codes: A61K 47/6809 Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6855 the tumour determinant being from breast cancer cell
• CPC Class Codes: A61K 47/6863 the tumour determinant being from stomach or intestines cancer cell
• CPC Class Codes: A61K 49/00 Preparations for testing in vivo
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/3015 Breast
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 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 2317/51 Complete heavy chain or Fd fragment, i.e. VH + CH1
• CPC Class Codes: C07K 2317/515 Complete light chain, i.e. VL + CL
• 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 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: G01N 2333/82 : Translation products from oncogenes
• CPC Class Codes: G01N 33/57415 : of breast
• CPC Class Codes: G01N 33/57446 : of stomach or intestine
• CPC Class Codes: G01N 33/57492 : involving compounds localized on the membrane of tumor or cancer cells

Abstract

The invention provides anti-HER2 antibodies and immunoconjugates and methods of using the same.

Claims

1. An isolated antibody that binds to HER2, wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:

15;

(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO;

16;

(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO;

17;

(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO;

12;

(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO;

13; and

(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO;

14.

2. The antibody of claim 1, wherein the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO:

11 and a light chain variable region comprising the sequence of SEQ ID NO;

10.

3. The antibody of claim 1, which is a monoclonal antibody.

4. The antibody of claim 1, which is a humanized or chimeric antibody.

5. The antibody of claim 1, which is an antibody fragment that binds HER2.

6. The antibody of claim 1, wherein HER2 is human HER2 comprising amino acids 23 to 1255 of SEQ ID NO:

1.

7. The antibody of claim 1, wherein the antibody binds to extracellular domain I of HER2.

8. The antibody of claim 7, wherein extracellular domain I of HER2 has the sequence of SEQ ID NO:

35.

9. The antibody of claim 1, which is an IgG1, IgG2a or IgG2b antibody.

10. The antibody of claim 1, wherein the antibody comprises at least one mutation in the heavy chain constant region selected from A118C and S400C.

11. The antibody of claim 1, wherein the antibody comprises at least one mutation in the light chain constant region selected from K149C and V205C.

12. The antibody of claim 1, wherein the antibody comprises:

a) a heavy chain comprising the sequence of SEQ ID NO;

19 and a light chain comprising the sequence of SEQ ID NO;

18;

or

b) a heavy chain comprising the sequence of SEQ ID NO;

19 and a light chain comprising the sequence of SEQ ID NO;

23;

or

c) a heavy chain comprising the sequence of SEQ ID NO;

24 and a light chain comprising the sequence of SEQ ID NO;

18.

13. The antibody of claim 1, wherein the antibody comprises the heavy chain constant region of SEQ ID NO:

28.

14. The antibody of claim 1, wherein the antibody comprises the light chain constant region of SEQ ID NO:

25.

17. An immunoconjugate comprising the antibody of claim 1 and a cytotoxic agent.

18. The antibody of claim 1 conjugated to a label.

19. The antibody of claim 18, wherein the label is a positron emitter.

20. The antibody of claim 19, wherein the positron emitter is ⁸⁹Zr.

21. The antibody of claim 1, wherein the antibody comprises a heavy chain variable region comprising a sequence at least 95% identical to the sequence of SEQ ID NO:

11 and a light chain variable region comprising a sequence at least 95% identical to the sequence of SEQ ID NO;

10.

22. The antibody of claim 2, which is an IgG1, IgG2a or IgG2b antibody.

23. The antibody of claim 22, wherein the antibody comprises at least one mutation in the heavy chain constant region selected from A118C and S400C.

24. The antibody of claim 22, wherein the antibody comprises at least one mutation in the light chain constant region selected from K149C and V205C.

25. The antibody of claim 22, wherein the antibody comprises a K149C mutation in the light chain constant region.

26. The antibody of claim 21, which is an IgG1, IgG2a or IgG2b antibody.

27. The antibody of claim 26, wherein the antibody comprises at least one mutation in the heavy chain constant region selected from A118C and S400C.

28. The antibody of claim 26, wherein the antibody comprises at least one mutation in the light chain constant region selected from K149C and V205C.

29. The antibody of claim 26, wherein the antibody comprises a K149C mutation in the light chain constant region.

15. An isolated antibody that binds to HER2, wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO:

19 and a light chain comprising the sequence of SEQ ID NO;

23.

16. An isolated antibody that binds to HER2, wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO:

24 and a light chain comprising the sequence of SEQ ID NO;

18.