Therapeutic combinations comprising anti-cd123 immunoconjugates

Patent metadata

Field	Value
Publication number	US-2021023237-A1
Application number	US-202016862358-A
Country	US
Kind code	A1
Filing date	Apr 29, 2020
Priority date	Apr 29, 2019
Publication date	Jan 28, 2021
Grant date	—

Abstract

Therapeutic combinations of immunoconjugates that bind to CD123 (e.g., IMGN632) with BCL-2 inhibitors (e.g., venetoclax), and/or a hypomethylating agent (e.g., azacitidine or decitabine) are provided. Methods of administering the combinations to treat hematological malignancies with clinical efficacy and/or decreased toxicity are also provided. Methods of treating hematological malignances present as minimal residual disease using immunoconjugates that bind to CD123 (e.g., IMGN632) are also provided.

First claim

1 . (canceled)

2 . A method for treating a hematologic malignancy in a subject comprising administering to said subject in need thereof an immunoconjugate that binds to CD123 and a BCL-2 inhibitor, wherein the immunoconjugate comprises an antibody or antigen-binding fragment linked to a cytotoxin and wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 5; a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 6; and a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 7; and a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 8; a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 9; and a light chain variable region CDR3 comprising the amino acid sequence of: SEQ ID NO: 10.

3 . A method for treating a hematologic malignancy in a subject comprising administering to said subject in need thereof an immunoconjugate that binds to CD123 and a hypomethylating agent, wherein the immunoconjugate comprises an antibody or antigen-binding fragment linked to a cytotoxin and wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 5; a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 6; and a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 7; and a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 8; a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 9; and a light chain variable region CDR3 comprising the amino acid sequence of: SEQ ID NO: 10.

4 . A method for treating a hematologic malignancy in a subject comprising administering to said subject in need thereof an immunoconjugate that binds to CD123, a BCL-2 inhibitor and a hypomethylating agent, wherein the immunoconjugate comprises an antibody or antigen-binding fragment linked to a cytotoxin and wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 5; a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 6; and a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 7; and a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 8; a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 9; and a light chain variable region CDR3 comprising the amino acid sequence of: SEQ ID NO: 10.

5 . The method of claim 4 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:1 and/or a VL comprising the amino acid sequence set forth in SEQ ID NO: 2.

6 . (canceled)

7 . The method of claim 4 , wherein the cytotoxin is a DNA-alkylating agent, optionally wherein the DNA-alkylating agent is indolino-benzodiazepine (IGN) DNA-alkylator.

8 . (canceled)

9 . The method of claim 4 , wherein the immunoconjugate is administered in a pharmaceutical composition comprising immunoconjugates with the following structure:

wherein G4723A comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:3 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:4.

10 . (canceled)

11 . (canceled)

12 . (canceled)

13 . (canceled)

14 . (canceled)

15 . (canceled)

16 . The method of claim 4 , wherein the immunoconjugate is administered once in a 21-day cycle.

17 . (canceled)

18 . (canceled)

19 . (canceled)

20 . (canceled)

21 . (canceled)

22 . (canceled)

23 . (canceled)

24 . The method of claim 4 , wherein the immunoconjugate is administered once in a 28-day cycle.

25 . The method of claim 24 , wherein the immunoconjugate is administered at a dose of about 0.015 mg/kg.

26 . (canceled)

27 . The method of claim 24 , wherein the immunoconjugate is administered at a dose of about 0.045 mg/kg once in the 28-day cycle.

28 . The method of claim 4 , wherein the BCL-2 inhibitor is venetoclax.

29 . The method of claim 28 , wherein the BCL-2 inhibitor is administered at a dose of 400 mg on days 1-8 of a 28-day cycle.

30 . (canceled)

31 . (canceled)

32 . (canceled)

33 . (canceled)

34 . (canceled)

35 . (canceled)

36 . (canceled)

37 . (canceled)

38 . (canceled)

39 . (canceled)

40 . (canceled)

41 . (canceled)

42 . (canceled)

43 . The method of claim 4 , wherein the hypomethylating agent is azacitidine.

44 . The method of claim 43 , wherein the azacitidine is administered in a 28-day cycle.

45 . (canceled)

46 . (canceled)

47 . (canceled)

48 . (canceled)

49 . (canceled)

50 . The method of claim 4 , wherein the hypomethylating agent is decitabine.

51 . (canceled)

52 . The method of claim 4 , wherein the hematological malignancy is present in the subject as minimal residual disease (MRD).

53 . A method for treating a hematologic malignancy present as a minimal residual disease in a human subject, the method comprising administering to the subject an anti-CD123 immunoconjugate comprising an anti-CD123 antibody or antigen-binding fragment thereof linked to a cytotoxic agent.

54 . (canceled)

55 . (canceled)

56 . (canceled)

57 . (canceled)

58 . (canceled)

59 . (canceled)

60 . (canceled)

61 . (canceled)

62 . (canceled)

63 . The method of claim 4 , wherein the immunoconjugate is further administered as a maintenance therapy.

64 . (canceled)

65 . (canceled)

66 . (canceled)

67 . The method of claim 4 , wherein the hematological malignancy is a relapsed and/or refractory hematological malignancy.

68 . (canceled)

69 . The method of claim 4 , wherein the hematological malignancy is acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), B-cell acute lymphoblastic leukemia (B-ALL), chronic myeloid leukemia in blast crisis/phase (BP-CML), and blastic plasmacytoid dendritic cell neoplasm (BPDCN).

70 . (canceled)

71 . (canceled)

72 . The method of claim 4 , wherein the hematological malignancy is ALL.

73 . (canceled)

74 . (canceled)

75 . (canceled)

76 . (canceled)

Assignees

• Immunogen Inc

Inventors

• Adams Sharlene
• Sloss Callum M
• Zweidler-Mckay Patrick

Classifications

• A61K47/68035

  the drug being a pyrrolobenzodiazepine · CPC title

• A61K47/6849 Primary

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title

• C07K16/2866 Primary

  against receptors for cytokines, lymphokines, interferons · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61K31/706

  containing six-membered rings with nitrogen as a ring hetero atom · CPC title