Therapeutic combinations comprising anti-cd123 immunoconjugates

Patent metadata

Field	Value
Publication number	US-2024033371-A1
Application number	US-202318328288-A
Country	US
Kind code	A1
Filing date	Jun 2, 2023
Priority date	Apr 29, 2019
Publication date	Feb 1, 2024
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 venetoclax, 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, wherein the cytotoxin is a DNA-alkylating agent, and wherein the administering is a front-line therapy.

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 azacitidine, 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, wherein the cytotoxin is a DNA-alkylating agent, and the administering is a front-line therapy.

4 . The method of claim 2 , wherein the method further comprises administering azacitidine.

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 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 - 15 . (canceled)

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

17 - 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 once in the 28-day cycle.

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 . (canceled)

29 . The method of claim 4 , wherein the venetoclax is administered at a dose of 400 mg.

30 - 43 . (canceled)

44 . The method of claim 4 , wherein the azacitidine is administered in a 28-day cycle.

45 - 68 . (canceled)

69 . The method of claim 4 , wherein the hematologic 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 . The method of claim 4 , wherein the hematologic malignancy is AML.

71 . The method of claim 4 , wherein the hematologic malignancy is BPDCN.

72 . (canceled)

73 . The method of claim 4 , wherein the hematologic malignancy is a CD123-expressing hematologic malignancy.

74 - 79 . (canceled)

80 . The method of claim 4 , wherein the hematologic malignancy expresses multidrug resistance 1 (MDR1) and/or expresses P-glycoprotein (P-gp).

81 . (canceled)

82 . The method of claim 4 , wherein the subject has an absolute neutrophil count of greater than 500 neutrophils/μL.

83 - 90 . (canceled)

91 . The method of claim 4 , wherein the subject is human.

92 - 108 . (canceled)

109 . A method for treating an unfit acute myeloid leukemia (AML) or blastic plasmacytoid dendritic cell neoplasm (BPDCN) in a subject comprising administering to said subject in need thereof an immunoconjugate that binds to CD123 and venetoclax, 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, wherein the cytotoxin is a DNA-alkylating agent.

110 . A method for treating an unfit acute myeloid leukemia (AML) or blastic plasmacytoid dendritic cell neoplasm (BPDCN) in a subject comprising administering to said subject in need thereof an immunoconjugate that binds to CD123 and azacitidine, 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, wherein the cytotoxin is a DNA-alkylating agent.

111 . The method of claim 109 , wherein the method further comprises administering azacitidine.

112 . The method of claim 109 , wherein the administering is a front-line therapy.

113 . The method of claim 110 , wherein the administering is a front-line therapy.

114 . The method of claim 2 , wherein the hematologic malignancy is unfit AML.

115 . The method of claim 3 , wherein the hematologic malignancy is unfit AML.

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

• A61K47/6867 Primary

  the tumour determinant being from a cell of a blood cancer · CPC title

• A61K31/635

  having a heterocyclic ring, e.g. sulfadiazine · CPC title