ANTI-CD79b ANTIBODIES AND METHODS OF USE

• US 20160159906A1
• Filed: 12/04/2015
• Published: 06/09/2016
• Est. Priority Date: 12/05/2014
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: SUN, Liping L., Chen, Yvonne Man-yee, Dennis, Mark S., Ebens, Jr., Allen J., Polson, Andrew
• Granted Patent: US 9,975,949 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• 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 2317/24 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 2317/34 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 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The invention provides anti-CD79b antibodies and methods of using the same.

Claims

1. An isolated anti-CD79b antibody, wherein the antibody comprises a CD79b binding domain comprising the following six hypervariable regions (HVRs):

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

5;

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

8;

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

9;

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

10;

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

11; and

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

12.

2. The anti-CD79b antibody of claim 1, wherein the CD79b binding domain comprises the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

3;

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

6;

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

9;

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

10;

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

11; and

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

12.

3. The anti-CD79b antibody of claim 1, wherein the CD79b binding domain comprises the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

4;

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

7;

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

9;

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

10;

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

11; and

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

12.

4. The anti-CD79b antibody of claim 2, comprising (a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:

17, 21, 23, 25, 27 or 29;

(b) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

18, 22, 24, 26, 28, or 30;

or (c) a VH sequence as in (a) and a VL sequence as in (b).

5. The anti-CD79b antibody of claim 3 comprising a VH sequence of SEQ ID NO:

17, 21, 23, 25, 27 or 29.

6. The anti-CD79b antibody of claim 3 comprising a VL sequence of SEQ ID NO:

18, 22, 24, 26, 28, or 30.

7. The anti-CD79b antibody of claim 3, comprising (a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:

19;

(b) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

20;

or (c) a VH sequence as in (a) and a VL sequence as in (b).

8. The anti-CD79b antibody of claim 3, comprising a VH sequence of SEQ ID NO:

19.

9. The anti-CD79b antibody of claim 8, comprising a VL sequence of SEQ ID NO:

20.

10. The anti-CD79b antibody of claim 1, wherein the CD79b binding domain binds to SEQ ID NO:

63.

11. The anti-CD79b antibody of claim 10, wherein the CD79b binding domain binds human CD79b with a Kd of less than about 25 nM as a dual arm, bivalent IgG antibody, e.g., less than about any of 10 nM or 5 nM.

12. The antibody of claim 11, wherein the CD79b binding domain binds human CD79b binds a B cell at an EC₅₀ of less than about 1.5 ug/mL in a monovalent format, e.g., less than about 1 ug/mL, 0.75 ug/mL, 0.5 ug/mL or less than 0.25 ug/mL.

13. The anti-CD79b antibody of claim 1, wherein the anti-CD79b antibody is a monoclonal, human, humanized, or chimeric antibody.

14. The anti-CD79b antibody of claim 1, wherein the anti-CD79b antibody is an IgG antibody.

15. The anti-CD79b antibody of claim 1, wherein the anti-CD79b antibody is an antibody fragment that binds CD79b.

16. The anti-CD79b antibody of claim 15, wherein the anti-CD79b antibody fragment is a Fab, Fab′

-SH, Fv, scFv, and/or (Fab′

)₂ fragment.

17. The anti-CD79b antibody of claim 1, wherein the anti-CD79b antibody is a full-length antibody.

18. The anti-CD79b antibody of claim 1, wherein the anti-CD79b antibody comprises an aglycosylation site mutation.

19. The anti-CD79b antibody of claim 18, wherein the aglycosylation site mutation is a substitution mutation.

20. The anti-CD79b antibody of claim 1, wherein the anti-CD79b antibody comprises reduced effector function.

21. The anti-CD79b antibody of claim 1, wherein the anti-CD79b antibody comprises a substitution mutation is at amino acid residue N297, L234, L235, and/or D265 according to EU numbering.

22. The anti-CD79b antibody of claim 21, wherein the substitution mutation is selected from the group consisting of N297G, N297A, L234A, L235A, and D265A according to EU numbering.

23. The anti-CD79b antibody of claim 21, wherein the antibody comprises an N297G substitution mutation at amino acid residue 297 according to EU numbering.

24. The anti-CD79b antibody of claim 1, wherein the anti-CD79b antibody is a monospecific antibody (e.g., bivalent, dual arm antibody).

25. The anti-CD79b antibody of claim 1, wherein the anti-CD79b antibody is a multispecific antibody.

26. The anti-CD79b antibody of claim 25, wherein the multispecific antibody comprises a CD3 binding domain.

27. The anti-CD79b antibody of claim 26, wherein the CD3 binding domain binds to a human CD3 polypeptide or a cynomolgus monkey (cyno) CD3 polypeptide.

28. The anti-CD79b antibody of claim 27, wherein the human CD3 polypeptide or the cyno CD3 polypeptide is a human CDR polypeptide or a cyno CDR polypeptide, respectively.

29. The anti-CD79b antibody of claim 27, wherein the human CD3 polypeptide or the cyno CD3 polypeptide is a human CD3y polypeptide or a cyno CD3y polypeptide, respectively.

30. The anti-CD79b antibody of claim 26, wherein the CD3 binding domain comprises the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

45;

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

46;

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

47;

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

48;

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

49; and

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

50.

31. The anti-CD79b antibody of claim 26, wherein the CD3 binding domain comprises (a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:

59;

(b) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

60;

or (c) a VH sequence as in (a) and a VL sequence as in (b).

32. The anti-CD79b antibody of claim 26, wherein the CD3 binding domain comprises a VH sequence of SEQ ID NO:

59.

33. The anti-CD79b antibody of claim 32, wherein the CD3 binding domain comprises a VL sequence of SEQ ID NO:

60.

34. The anti-CD79b antibody of claim 26, wherein the CD3 binding domain comprises the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

39;

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

40;

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

41;

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

42;

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

43; and

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

44.

35. The anti-CD79b antibody of claim 26, wherein the CD3 binding domain comprises (a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:

57;

(b) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

58;

or (c) a VH sequence as in (a) and a VL sequence as in (b).

36. The anti-CD79b antibody of claim 26, wherein the CD3 binding domain comprises a VH sequence of SEQ ID NO:

57.

37. The anti-CD79b antibody claim 36, wherein the CD3 binding domain comprises a VL sequence of SEQ ID NO:

58.

38. The anti-CD79b antibody of claim 26, wherein the CD3 binding domain comprises the following six HVRs:

(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO;

51;

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

52;

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

53;

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

54;

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

55; and

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

56.

39. The anti-CD79b antibody of claim 26, wherein the CD3 binding domain comprises (a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:

61;

(b) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

62;

or (c) a VH sequence as in (a) and a VL sequence as in (b).

40. The anti-CD79b antibody of claim 26, wherein the CD3 binding domain comprises a VH sequence of SEQ ID NO:

61.

41. The anti-CD79b antibody claim 40, wherein the CD3 binding domain comprises a VL sequence of SEQ ID NO:

62.

42. The anti-CD79b antibody of claim 26, wherein the multispecific antibody is a bispecific antibody.

43. The anti-CD79b antibody of claim 26, wherein the anti-CD79b antibody has a B cell killing EC₅₀ of less than about 100 ng/mL.

44. The anti-CD79b antibody of claim 43, wherein the B cell killing is endogenous B cell killing or cell line B cell killing, e.g., BJAB cell line, WSU-CLCL2 cell line, OCI-Ly-19 cell line.

45. The anti-CD79b antibody of claim 26, wherein the anti-CD79b antibody has a cytotoxic T cell activation EC₅₀ is less than about any of 50 ng/mL.

46. The anti-CD79b antibody of claim 26, wherein (a) the CD3 binding domain comprises a Fc domain, wherein the Fc domain comprises T366S, L368A, Y407V, and N297G substitution mutations according EU numbering and (b) the CD79b binding domain comprises a Fc domain, wherein the Fc domain comprises T366W and N297G substitution mutations according EU numbering.

47. An isolated nucleic acid encoding the anti-CD79b antibody of claim 1.

48. A vector comprising the isolated nucleic acid of claim 47.

49. A host cell comprising the vector of claim 48.

50. A method of producing the anti-CD79b antibody of claim 1, the method comprising culturing the host cell of claim 49 in a culture medium.

51. An immunoconjugate comprising the anti-CD79b antibody of claim 1 and a cytotoxic agent.

52. A pharmaceutical composition comprising the anti-CD79b antibody of claim1.

62. A method of treating or delaying the progression of a cell proliferative disorder or an autoimmune disorder in a subject in need thereof, the method comprising administering to the subject the anti-CD79b antibody of claim 1.

63. A method of enhancing immune function in a subject having a cell proliferative disorder or an autoimmune disorder, the method comprising administering to the subject an effective amount of the anti-CD79b antibody of claim 1.

53-61. -61 (canceled)

64-69. -69. (canceled)