Therapeutic combinations comprising anti-cd123 immunoconjugates

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.

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.