Therapeutic combinations comprising Anti-CD123 immunoconjugates

Abstract

To provide methods of treating hematological malignancies.SOLUTION: Provided is a method of treating a hematologic malignancy in a subject comprising: administering to a subject in need thereof an immunoconjugate that binds to CD123 (e.g., IMGN632) and a BCL-2 inhibitor, a hypomethylating agent (e.g., azacitidine or decitabine), or a combination thereof. Methods of administering the combination 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 are also provided.SELECTED DRAWING: None

Description

[Technical field]

[0001] The field of the invention relates generally to the combination of anti-CD123 immunoconjugates with hypomethylating agents (HMA) and / or B-cell leukemia / lymphoma-2 (BCL-2) antagonists for combined use in the treatment of hematological malignancies. [Background technology]

[0002] Cancer is one of the leading causes of death in developed countries, with more than one million people diagnosed with cancer each year and half a million deaths in the United States alone. Overall, it is estimated that more than one in three people will develop some form of cancer during their lifetime.

[0003] CD123 is the alpha subunit of the interleukin-3 receptor (IL-3Rα). CD123 expression is low in normal hematopoietic stem cells (Testa et al. Biomark Res., 10;2(1):4. (2014); Jordan et al., Leukemia, 14(10):1777-84 (2000)). However, CD123 is overexpressed in multiple hematological malignancies of both myeloid and lymphoid origin, including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), B-cell acute lymphoblastic leukemia (B-ALL), chronic myeloid leukemia in blast crisis / blast crisis phase (BP-CML), and blastic plasmacytoid dendritic cell neoplasm (BPDCN) (Testa 2014). Interleukin-3 is produced by activated T lymphocytes. IL-3, along with other growth factors, stimulates the development and mediates survival of a wide range of hematopoietic cells in the bone marrow (Testa 2014). CD123 levels on normal hematopoietic stem cells are very low, while early common myeloid precursors express higher CD123 levels (Testa 2014, Jordan 2000). Moderate to high expression of CD123 on normal tissues is restricted to rare populations of leukocytes such as plasmacytoid dendritic cells and basophils (Jordan 2000, Testa 2014).

[0004] Acute myeloid leukemia is the most common form of acute leukemia among adults and is responsible for the highest number of leukemia deaths in the United States. In 2017, an estimated 21,380 people will be diagnosed with AML annually, and 10,590 patients will die from the disease (Siegel et al., CA Cancer J Clin. 2017;67(1):7-30(2017)). The median age at diagnosis is 66 years. Frontline chemotherapy in AML has been reported to induce complete responses (CR) in 70%-80% of patients under 60 years of age, and approximately 50% of older patients. "Fit" patients are deemed able to tolerate intensive treatment, are often young (<60 years of age), and typically receive one to two cycles of induction with a "7+3", cytarabine and anthracycline combination, typically daunorubicin. Following this, these fit patients may receive high-dose cytarabine for one or more cycles and undergo stem cell transplantation. Standard induction and post-induction therapy results in a median remission duration of approximately 1 year, and potential cure in 25%-35% of patients. Often older, "unfit" patients typically receive venetoclax, azacitidine, and hypomethylating agents. The majority of patients with AML eventually relapse, and AML salvage regimens provide poor outcomes with significant toxicity. Thus, novel therapies with limited toxicity in this relapsed population are needed.

[0005] Blastic plasmacytoid dendritic cell neoplasms are rare, aggressive hematologic malignancies derived from myeloid dendritic cell precursors and often present with cutaneous involvement in addition to lymph node, blood, and bone marrow involvement. Characterized by expression of CD4, CD56, and CD123, among other markers, BPDCN blasts express high levels of CD123. Unfortunately, there is no standard treatment for BPDCN, and both acute lymphoblastic leukemia (ALL) and AML regimens are used in frontline treatment. Despite CR rates of 47%-86% in frontline disease, median overall survival is approximately 12-16 months. The majority of patients with BPDCN eventually relapse without standard treatment options.

[0006] Acute lymphoblastic leukemia is a rare aggressive hematologic malignancy that originates from lymphoid precursors and often presents with lymph node, blood, and bone marrow involvement. B-cell acute lymphoblastic leukemia and some T-cell acute lymphoblastic leukemia blasts express CD123 at levels similar to AML blasts. Although initial remission rates are high, long-term survival rates for patients younger than 60 years are 35%-40% and for older patients are less than 10% (Goldstone 2008). Patients with relapsed ALL have several chemotherapy options, including immunotherapy with the US Food and Drug Administration-approved anti-CD19 bispecific blinatumomab. However, long-term survival rates for these patients remain low. Given that currently available therapeutic agents are unable to treat many hematologic malignancies, more effective interventions are needed. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Testa et al.Biomark Res.,10;2(1):4.(2014) [Non-Patent Document 2] Jordan et al., Leukemia, 14(10):1777-84(2000) [Non-Patent Document 3] Siegel et al.,CA Cancer J Clin.2017;67(1):7-30(2017) Summary of the Invention [Means for solving the problem]

[0008] Provided herein are combinations of anti-CD123 immunoconjugates (e.g., IMGN632) with BCL-2 inhibitors and / or hypomethylating agents. Also provided herein are methods of treating cancer patients using such combinations.

[0009] In certain instances, a method of treating a hematological malignancy in a subject includes administering to a subject in need thereof an immunoconjugate that binds CD123 (the immunoconjugate comprises an antibody or antigen-binding fragment thereof comprising 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) and a BCL-2 inhibitor, a hypomethylating agent, or a combination thereof. In certain instances, the immunoconjugate is administered in combination with a BCL-2 inhibitor. In certain instances, the immunoconjugate is administered in combination with a hypomethylating agent. In certain instances, the immunoconjugate is administered in combination with a BCL-2 inhibitor and a hypomethylating agent.

[0010] In certain cases, 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. In certain cases, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region and / or a light chain constant region. In certain cases, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 3, and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 4.

[0011] In certain instances, the immunoconjugate comprises a cytotoxin. In certain instances, the cytotoxin is a DNA alkylating agent. In certain instances, the DNA alkylating agent is an indolyltransferase. No-benzodiazepine (IGN) is a DNA alkylating agent. In certain cases, the immunoconjugate comprises a peptide linker. In certain cases, the immunoconjugate is IMGN632. In certain cases, the immunoconjugate is administered in a pharmaceutical composition comprising an immunoconjugate having the following structure: [ka] 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.

[0012] In certain instances, the administration is frontline therapy, hi certain instances, the immunoconjugate is administered intravenously.

[0013] In certain cases, administration of an immunoconjugate with a BCL-2 inhibitor, a hypomethylating agent, or a combination thereof produces a synergistic effect. In certain cases, administration of an immunoconjugate and a BCL-2 inhibitor does not result in more toxicity than administration of an immunoconjugate alone or a BCL-2 inhibitor alone. In certain cases, administration of an immunoconjugate and a hypomethylating agent does not result in more toxicity than administration of an immunoconjugate alone or a hypomethylating agent alone. In certain cases, administration of an immunoconjugate, a BCL-2 inhibitor, and a hypomethylating agent does not result in more toxicity than administration of an immunoconjugate, a BCL-2 inhibitor, and / or a hypomethylating agent.

[0014] In certain cases, the immunoconjugate is administered once every 21 day cycle. In certain cases, the immunoconjugate is administered once every 21 day cycle at a dose of about 0.015 mg / kg to about 0.09 mg / kg. In certain cases, the immunoconjugate is administered once every 21 day cycle at a dose of about 0.015 mg / kg to about 0.135 mg / kg. In certain cases, the dose is about 0.015 mg / kg, about 0.045 mg / kg, or about 0.09 mg / kg. In certain cases, the dose is about 0.015 mg / kg, about 0.045 mg / kg, or about 0.135 mg / kg. In certain cases, the dose is about 0.045 mg / kg. In certain cases, the dose is about 0.03 mg / kg.

[0015] In certain cases, the immunoconjugate is administered three times in a 21-day cycle. In certain cases, the total amount of the immunoconjugate administered in a 21-day cycle is about 0.045 mg / kg, about 0.09 mg / kg, or about 0.18 mg / kg. In certain cases, the total amount of the immunoconjugate administered in a 21-day cycle is about 0.135 mg / kg. In certain cases, about 0.015 mg / kg to about 0.06 mg / kg of the immunoconjugate is administered three times in a 21-day cycle. In certain cases, about 0.015 mg / kg, about 0.03 mg / kg, or about 0.06 mg / kg is administered three times in a 21-day cycle. In certain cases, about 0.045 mg / kg is administered three times in a 21-day cycle. In certain cases, the first administration of the immunoconjugate is on the seventh day of the 21-day cycle. In certain instances, the second administration of the immunoconjugate is on day 10 of a 21 day cycle. In certain instances, the third administration is on day 14 of a 21 day cycle. In certain instances, the first, second, and third administrations are on days 7, 10, and 14, respectively, of a 21-day cycle.

[0016] In certain instances, the BCL-2 inhibitor is venetoclax. In certain instances, the BCL-2 inhibitor is administered at a dose of 400 mg. In certain instances, the BCL-2 inhibitor is venetoclax. In certain instances, the BCL-2 inhibitor is administered at a dose of 200 mg.

[0017] In certain cases, the BCL-2 inhibitor is administered daily in a 21-day cycle. In certain cases, the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of the 21-day cycle, at a dose of 200 mg on day 2 of the 21-day cycle, and at a dose of 400 mg on days 3-21 of the 21-day cycle. In certain cases, the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of the 21-day cycle, at a dose of 200 mg on day 2 of the 21-day cycle, and at a dose of 400 mg on days 3-7 or 3-14 of the 21-day cycle. In certain cases, the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of the 21-day cycle, and at a dose of 200 mg on days 2-21, 2-14, or 2-7 of the 21-day cycle. In certain cases, the BCL-2 inhibitor is administered on days 1-7 of the 21-day cycle. In certain cases, the BCL-2 inhibitor is administered on days 1-8 of a 21 day cycle. In certain cases, the BCL-2 inhibitor is administered on days 1-14 of a 21 day cycle. In certain cases, the BCL-2 inhibitor is administered on days 1-18 of a 21 day cycle. In certain cases, the BCL-2 inhibitor is administered on days 1-21 of a 21 day cycle. In certain cases, the BCL-2 inhibitor is administered orally.

[0018] In certain instances, administration of the immunoconjugate begins 6 days after the initiation of administration of the BCL-2 inhibitor.

[0019] In certain cases, the immunoconjugate is administered once every 28 day cycle. In certain cases, the immunoconjugate is administered once every 28 day cycle at a dose of about 0.015 mg / kg to about 0.09 mg / kg. In certain cases, the immunoconjugate is administered once every 28 day cycle at a dose of about 0.015 mg / kg to about 0.135 mg / kg. In certain cases, the dose is about 0.015 mg / kg, about 0.045 mg / kg, or about 0.09 mg / kg. In certain cases, the dose is about 0.015 mg / kg, about 0.045 mg / kg, or about 0.135 mg / kg. In certain cases, the dose is about 0.045 mg / kg. In certain cases, the dose is about 0.03 mg / kg.

[0020] In certain cases, the immunoconjugate is administered three times in a 28-day cycle. In certain cases, the total amount of the immunoconjugate administered in a 28-day cycle is about 0.045 mg / kg, about 0.09 mg / kg, or about 0.18 mg / kg. In certain cases, the total amount of the immunoconjugate administered in a 28-day cycle is about 0.135 mg / kg. In certain cases, about 0.015 mg / kg to about 0.06 mg / kg of the immunoconjugate is administered three times in a 28-day cycle. In certain cases, about 0.015 mg / kg, about 0.03 mg / kg, or about 0.06 mg / kg of the immunoconjugate is administered three times in a 28-day cycle. In certain cases, about 0.135 mg / kg of the immunoconjugate is administered three times in a 28-day cycle. In certain cases, the first administration of the immunoconjugate is on the seventh day of the 28-day cycle. In certain instances, the second administration of the immunoconjugate is on day 10 of a 28 day cycle. In certain instances, the third administration of the immunoconjugate is on day 14 of a 28 day cycle. In certain instances, the first, second, and third administrations of the immunoconjugate are on days 7, 10, and 14, respectively, of a 28 day cycle.

[0021] In certain instances, the BCL-2 inhibitor is venetoclax. In certain instances, the BCL-2 inhibitor is administered at a dose of 400 mg. In certain instances, the BCL-2 inhibitor is administered at a dose of 200 mg.

[0022] In certain cases, the BCL-2 inhibitor is administered daily in a 28 day cycle. In certain cases, the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of a 28 day cycle, at a dose of 200 mg on day 2 of a 28 day cycle, and at a dose of 400 mg on days 3-28 of a 28 day cycle. In certain cases, the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of a 28 day cycle, at a dose of 200 mg on day 2 of a 28 day cycle, and at a dose of 400 mg on days 3-7 or 3-14 of a 28 day cycle. In certain cases, the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of a 28 day cycle, and at a dose of 200 mg on days 2-28, 2-14, or 2-7 of a 28 day cycle. In certain cases, the BCL-2 inhibitor is administered on days 1-7 of a 28 day cycle. In certain cases, the BCL-2 inhibitor is administered on days 1-8 of a 28 day cycle. In certain cases, the BCL-2 inhibitor is administered on days 1-14 of a 28 day cycle. In certain cases, the BCL-2 inhibitor is administered on days 1-18 of a 28 day cycle. In certain cases, the BCL-2 inhibitor is administered on days 1-21 of a 28 day cycle. In certain cases, the BCL-2 inhibitor is administered on days 1-28 of a 21 day cycle.

[0023] In certain instances, the BCL-2 inhibitor is administered orally. In certain instances, administration of the immunoconjugate begins 6 days after the initiation of administration of the BCL-2 inhibitor.

[0024] In certain cases, the hypomethylating agent is azacitidine. In certain cases, the azacitidine is administered in a 28 day cycle. In certain cases, the azacitidine is administered once daily on days 1-7 of a 28 day cycle. In certain cases, the azacitidine is administered once daily on days 3-7 of a 28 day cycle. In certain cases, the azacitidine is administered once daily on days 1-5 of a 28 day cycle. In certain cases, the azacitidine is administered at a dose of about 75 mg / m 2 In certain instances, azacitidine is administered subcutaneously. In certain instances, azacitidine is administered intravenously.

[0025] In certain instances, the hypomethylating agent is decitabine. In certain instances, decitabine is administered intravenously.

[0026] In certain cases, the hematological malignancy is present in the subject as minimal residual disease (MRD).

[0027] In certain cases, a method for treating a hematological malignancy present as minimal residual disease in a human subject includes administering to the subject an anti-CD123 immunoconjugate comprising an anti-CD123 antibody or antigen-binding fragment thereof linked to a cytotoxic agent. In certain cases, the immunoconjugate is administered at a dose of about 0.045 mg / kg to about 0.18 mg / kg. In certain cases, about 0.045 mg / kg, about 0.09 mg / kg, about 0.135 mg / kg, or about 0.18 mg / kg is administered to the subject. In certain cases, about 0.045 mg / kg is administered to the subject. In certain cases, about 0.03 mg / kg is administered to the subject. In certain cases, the immunoconjugate is administered intravenously. In certain cases, the hematological malignancy is leukemia. In certain cases, the immunoconjugate is administered to the subject once every 21-day cycle.

[0028] In certain cases, the administration is for one cycle. In certain cases, the administration is for two or more cycles. In certain cases, the administration is for at least two cycles, at least three cycles, The administration may be for at least 2 to 4 cycles, at least 2 to 6 cycles, at least 2 to 8 cycles, at least 2 to 10 cycles, or at least 10 cycles. In certain cases, the administration is for about 2 to 4 cycles, about 2 to 6 cycles, about 2 to 8 cycles, about 2 to 10 cycles, or about 2 to 12 cycles.

[0029] In certain instances, the method further comprises administering a reduced dose of the immunoconjugate after dose-limiting toxicity occurs in the subject and is reduced to baseline or grade 2 or below.

[0030] In certain cases, the immunoconjugate is further administered as a maintenance therapy.

[0031] In certain cases, the maintenance therapy includes administering the immunoconjugate once every 21 day cycle. In certain cases, the maintenance therapy includes administering the immunoconjugate at a dose of about 0.015 mg / kg to about 0.09 mg / kg once every 21 day cycle. In certain cases, the maintenance therapy includes administering the immunoconjugate at a dose of about 0.015 mg / kg to about 0.135 mg / kg once every 21 day cycle. In certain cases, the maintenance therapy includes administering the immunoconjugate at a dose of 0.015 mg / kg once every 21 day cycle. In certain cases, the maintenance therapy includes administering the immunoconjugate at a dose of about 0.045 mg / kg once every 21 day cycle. In certain cases, the maintenance therapy includes administering the immunoconjugate at a dose of about 0.03 mg / kg once every 21 day cycle. In certain cases, the maintenance therapy includes administering the immunoconjugate at a dose of about 0.09 mg / kg once every 21-day cycle. In certain cases, the maintenance therapy includes administering the immunoconjugate at a dose of about 0.135 mg / kg once every 21-day cycle. In certain cases, the maintenance therapy includes administering the immunoconjugate three times every 21-day cycle. In certain cases, the total amount of the immunoconjugate administered during the 21-day cycle during the maintenance therapy is about 0.045 mg / kg, about 0.09 mg / kg, or about 0.18 mg / kg. In certain cases, the total amount of the immunoconjugate administered during the 21-day cycle during the maintenance therapy is about 0.135 mg / kg. In certain cases, about 0.015 mg / kg to about 0.06 mg / kg of the immunoconjugate is administered each of the three times during the 21-day cycle during the maintenance therapy. In certain cases, during maintenance therapy, about 0.015 mg / kg of the immunoconjugate is administered each of three times during a 21-day cycle. In certain cases, during maintenance therapy, about 0.03 mg / kg of the immunoconjugate is administered each of three times during a 21-day cycle. In certain cases, during maintenance therapy, about 0.045 mg / kg of the immunoconjugate is administered each of three times during a 21-day cycle. In certain cases, during maintenance therapy, about 0.06 mg / kg of the immunoconjugate is administered each of three times during a 21-day cycle.

[0032] In certain cases, the hematological malignancy is a relapsed hematological malignancy. In certain cases, the hematological malignancy is a refractory hematological malignancy. In certain cases, the hematological malignancy is acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), B-cell acute lymphoblastic leukemia (B-ALL), blast crisis / chronic myeloid leukemia in blast crisis phase (BP-CML), and blastic plasmacytoid dendritic cell neoplasm (BPDCN). In certain cases, the hematological malignancy is AML. In certain cases, the AML is relapsed AML. In certain cases, the AML is refractory AML. In certain cases, the hematological malignancy is BPDCN. In certain cases, the BPDCN is relapsed BPDCN. In certain cases, the BPDCN is relapsed BPDCN. In certain cases, the hematological malignancy is ALL. In certain cases, the ALL is relapsed ALL. In certain cases, the ALL is refractory ALL. In certain cases, the hematological malignancy is chronic myelomonocytic leukemia (CMML). In certain cases, the CMML is relapsed CMML. In certain cases, the CMML is refractory CMML. In certain cases, the hematological malignancy is myelofibrosis (MF). In certain cases, the MF is relapsed MF. In certain cases, the MF is refractory MF. In certain cases, the hematological malignancy is myelodysplastic syndrome (MDS). In certain cases, the MDS is relapsed MDS. In certain cases, the MDS is refractory MDS.

[0033] In certain cases, the hematological malignancy is a hematological malignancy that expresses CD123.In certain cases, CD123 is detected in a sample obtained from the hematological malignancy before administration.In certain cases, CD123 is detected using flow cytometry.In certain cases, the method further comprises detecting CD123 in a sample obtained from the hematological malignancy before administration.

[0034] In certain cases, at least 80% of cells in the hematological malignancy express CD123. In certain cases, CD123 is detected in at least 80% of cells in a sample obtained from the hematological malignancy before administration. In certain cases, the method further comprises detecting CD123 in at least 80% of cells in a sample obtained from the hematological malignancy before administration.

[0035] In certain cases, the hematological malignancies are resistant to IMGN632.

[0036] In certain cases, the hematological malignancy expresses multidrug resistance 1 (MDR1). In certain cases, the hematological malignancy expresses P-glycoprotein (P-gp). In certain cases, the subject has an absolute neutrophil count of greater than 500 / μL.

[0037] In certain cases, the subject has had at least one prior therapy. In certain cases, the subject has had at least two prior therapies. In certain cases, the subject has had at least three prior therapies. In certain cases, the cancer has been previously treated with venetoclax. In certain cases, the cancer has not been previously treated with venetoclax. In certain cases, the cancer has been previously treated with a hypomethylating agent. In certain cases, the cancer has not been previously treated with a hypomethylating agent.

[0038] In certain cases, the subject is pretreated with a corticosteroid prior to administration of the immunoconjugate. In some cases, the method further comprises pretreating the subject with a corticosteroid prior to administration of the immunoconjugate. In certain cases, the corticosteroid is diphenhydramine, acetaminophen, paracetamol, dexamethasone, or a combination thereof.

[0039] In certain cases, the immunoconjugate and the BCL-2 inhibitor, hypomethylating agent, or a combination thereof, are administered in separate pharmaceutical compositions.

[0040] In certain cases, the immunoconjugate and the BCL-2 inhibitor, hypomethylating agent, or a combination thereof, are administered in separate pharmaceutical compositions.

[0041] In certain instances, the subject is a human.

[0042] In certain instances, a method for treating a hematological malignancy in a human subject includes administering to a subject in need thereof IMGN632 and venetoclax in a 21 day cycle, where IMGN632 is administered intravenously at a dose of about 0.015 mg / kg to about 0.09 mg / kg on day 7 of the cycle (optionally, the dose is about 0.015 mg / kg, about 0.045 mg / kg, or about 0.09 mg / kg), and venetoclax is administered orally at a dose of 100 mg on day 1 of the cycle, at a dose of 200 mg on day 2 of the cycle, and at a dose of 400 mg on days 3-21 of the cycle.

[0043] In certain instances, a method for treating a hematological malignancy in a human subject includes administering to a subject in need thereof IMGN632 and venetoclax in a 21 day cycle, where IMGN632 is administered intravenously at a dose of about 0.015 mg / kg to about 0.135 mg / kg on day 7 of the cycle (optionally, the dose is about 0.135 mg / kg), and venetoclax is administered orally at a dose of 100 mg on day 1 of the cycle, at a dose of 200 mg on day 2 of the cycle, and at a dose of 400 mg on days 3-21 of the cycle.

[0044] In certain instances, a method for treating a hematological malignancy in a human subject includes administering to a subject in need thereof IMGN632 and venetoclax in a 21 day cycle, where IMGN632 is administered intravenously on day 7 of the cycle at a dose of about 0.015 mg / kg to about 0.09 mg / kg (optionally, the dose is about 0.015 mg / kg, about 0.045 mg / kg, or about 0.09 mg / kg), and venetoclax is administered at an oral daily dose of 400 mg.

[0045] In certain instances, a method for treating a hematological malignancy in a human subject includes administering to a subject in need thereof IMGN632 and venetoclax in a 21 day cycle, where IMGN632 is administered intravenously at a dose of about 0.015 mg / kg to about 0.09 mg / kg on day 7 of the cycle, and venetoclax is administered at an oral daily dose of 400 mg. In certain instances, venetoclax is administered on days 1-7 of the 21 day cycle. In certain instances, venetoclax is administered on days 1-8 of the 21 day cycle. In certain instances, venetoclax is administered on days 1-14 of the 21 day cycle. In certain instances, venetoclax is administered on days 1-18 of the 21 day cycle. In certain instances, venetoclax is administered on days 1-21 of the 21 day cycle. In certain cases, IMGN632 is administered at a dose of about 0.045 mg / kg. In certain cases, IMGN632 is administered at a dose of about 0.03 mg / kg. In certain cases, IMGN632 is administered at a dose of about 0.015 mg / kg.

[0046] In certain instances, a method for treating a hematological malignancy in a human subject includes administering to a subject in need thereof IMGN632 and venetoclax in a 21 day cycle, where IMGN632 is administered intravenously at a dose of about 0.015 mg / kg to about 0.135 mg / kg on day 7 of the cycle (optionally, the dose is about 0.135 mg / kg) and venetoclax is administered at an oral daily dose of 400 mg.

[0047] In certain instances, a method for treating a hematological malignancy in a human subject includes administering to a subject in need thereof IMGN632 and venetoclax in a 21 day cycle, where IMGN632 is administered intravenously at a dose of about 0.015 mg / kg to about 0.06 mg / kg on days 7, 10, and 14 of the cycle (optionally, the dose is about 0.015 mg / kg, about 0.03 mg / kg, or about 0.06 mg / kg), and venetoclax is administered orally at a dose of 100 mg on day 1 of the cycle, at a dose of 200 mg on day 2 of the cycle, and at a dose of 400 mg on days 3-21 of the cycle.

[0048] In certain instances, a method for treating a hematological malignancy in a human subject includes administering to a subject in need thereof IMGN632 and venetoclax in a 21 day cycle, where IMGN632 is administered intravenously at a dose of about 0.015 mg / kg to about 0.06 mg / kg on days 7, 10, and 14 of the cycle (optionally, the dose is about 0.015 mg / kg, about 0.03 mg / kg, or about 0.06 mg / kg), and venetoclax is administered at an oral daily dose of 400 mg.

[0049] In certain cases, the method of treating a hematological malignancy in a human subject in need thereof includes The method includes administering to a subject IMGN632 and azacitidine in a 28 day cycle, where IMGN632 is administered intravenously at a dose of about 0.015 mg / kg to about 0.09 mg / kg on day 7 of the cycle (optionally, the dose is about 0.015 mg / kg, about 0.045 mg / kg, or about 0.09 mg / kg), and azacitidine is administered intravenously at a dose of 75 mg / m on days 1-7 of the cycle. 2 It is administered subcutaneously or intravenously at a dose of

[0050] In certain instances, a method of treating a hematological malignancy in a human subject includes administering to a subject in need thereof IMGN632 and azacitidine in a 28 day cycle, where IMGN632 is administered intravenously on day 7 of the cycle at a dose of about 0.015 mg / kg to about 0.09 mg / kg (optionally, the dose is about 0.015 mg / kg, about 0.03 mg / kg, about 0.045 mg / kg, or about 0.09 mg / kg) and azacitidine is administered intravenously at a dose of 75 mg / m 2 In certain cases, azacytidine is administered subcutaneously or intravenously at a dose of about 0.045 mg / kg. In certain cases, IMGN632 is administered at a dose of about 0.03 mg / kg. In certain cases, azacytidine is administered on days 1-7 of the cycle. In certain cases, azacytidine is administered on days 1-5 of the cycle. In certain cases, IMGN632 is administered at a dose of about 0.045 mg / kg. In certain cases, IMGN632 is administered at a dose of about 0.03 mg / kg.

[0051] In certain instances, a method for treating a hematological malignancy in a human subject includes administering to a subject in need thereof IMGN632 and azacitidine in a 28 day cycle, where IMGN632 is administered intravenously at a dose of about 0.015 mg / kg to about 0.135 mg / kg on day 7 of the cycle (optionally, the dose is about 0.135 mg / kg) and azacitidine is administered intravenously at a dose of 75 mg / m on days 1 to 7 of the cycle. 2 It is administered subcutaneously or intravenously at a dose of

[0052] In certain instances, a method of treating a hematological malignancy in a human subject includes administering to a subject in need thereof IMGN632 and azacitidine in a 28 day cycle, where IMGN632 is administered intravenously at a dose of about 0.015 mg / kg to about 0.06 mg / kg on days 7, 10, and 14 of the cycle (optionally, the dose is about 0.015 mg / kg, about 0.03 mg / kg, or about 0.06 mg / kg), and azacitidine is administered intravenously at a dose of 75 mg / m on days 1-7 of the cycle. 2 It is administered subcutaneously or intravenously at a dose of

[0053] In certain instances, a method for treating a hematological malignancy in a human subject includes administering to a subject in need thereof IMGN632 and azacitidine in a 28 day cycle, where IMGN632 is administered intravenously at a dose of about 0.015 mg / kg to about 0.06 mg / kg on days 7, 10, and 14 of the cycle, and the azacitidine .... 2 In certain cases, azacytidine is administered subcutaneously or intravenously at a dose of about 0.045 mg / kg. In certain cases, IMGN632 is administered at a dose of about 0.03 mg / kg. In certain cases, azacytidine is administered on days 1-7 of the cycle. In certain cases, azacytidine is administered on days 1-5 of the cycle. In certain cases, IMGN632 is administered at a dose of about 0.045 mg / kg. In certain cases, IMGN632 is administered at a dose of about 0.03 mg / kg.

[0054] In certain cases, the method further includes administering venetoclax. In certain cases, venetoclax is administered on days 1-7 of a 28 day cycle. In certain cases, venetoclax is administered on days 1-8 of a 28 day cycle. In certain cases, venetoclax is administered on days 1-14 of a 28 day cycle. In certain cases, venetoclax is administered on days 1-18 of a 28 day cycle. In certain cases, venetoclax is administered on days 1-21 of a 28 day cycle. In certain cases, venetoclax is administered on days 1-28 of a 28 day cycle.

[0055] In certain instances, the method includes administering 100 mg of ribavirin on day 1 of the cycle at a dose of 100 mg on day 2 of the cycle. The method further includes orally administering venetoclax at a dose of 200 mg on day 2 and at a dose of 400 mg on days 3-28 of the cycle. In certain instances, the method further includes administering venetoclax at an oral daily dose of 400 mg.

[0056] In certain cases, the hematological malignancy is AML. In certain cases, the hematological malignancy is BPDCN. In certain cases, the hematological malignancy is ALL. In certain cases, the hematological malignancy is chronic myelomonocytic leukemia (CMML). In certain cases, the hematological malignancy is myelofibrosis (MF). In certain cases, the hematological malignancy is myelodysplastic syndrome (MDS). [Brief description of the drawings]

[0057] [Figure 1A] 1 shows the chemical structure of IMGN632. IMGN632 is a composition that includes an immunoconjugate containing an anti-CD123 G4723A antibody linked to the cytotoxic payload DGN549-C in sodium bisulfite. The majority of the immunoconjugate in the composition is the sulfonated version shown in FIG. 1A. [Figure 1B] 1 shows the non-sulfonated form of an immunoconjugate containing an anti-CD123 G4723A antibody linked to the cytotoxic payload DGN549-C (monoimine structure), which may also be present in the IMGN632 composition. [Figure 2A] Figure 1 shows the antitumor activity of IMGN632 over a wide dose range against three acute myeloid leukemia (AML) cell lines (EOL-1, MV4-11, KG-1). [Figure 2B] Shows the antitumor activity of venetoclax over a wide dose range against three AML (EOL-1, MV4-11, KG-1) cell lines. [Figure 2C] 1 shows the antitumor activity of IMGN632 over a narrower dose range against four AML (EOL-1, MV4-11, KG-1, Molm-13) cell lines. [Figure 2D] Shows the antitumor activity of a narrower dose range of venetoclax against four AML (EOL-1, MV4-11, KG-1, Molm-13) cell lines. [Figure 3A] Antitumor activity of IMGN632 and escalating doses of venetoclax (0.625 nM, 1.25 nM, 2.5 nM, 5 nM, 10 nM, 20 nM) against EOL-1 cell line is shown. [Figure 3B] Shows the antitumor activity of IMGN632 and escalating doses of venetoclax (0.625 nM, 1.25 nM, 2.5 nM, 5 nM, 10 nM, 20 nM) in the MV4-11 cell line. [Figure 3C] Shows the antitumor activity of IMGN632 and escalating doses of venetoclax (0.625 nM, 1.25 nM, 2.5 nM, 5 nM, 10 nM, 20 nM) in KG-1 cell line. [Figure 3D] Antitumor activity of IMGN632 and escalating doses of venetoclax (0.625 nM, 1.25 nM, 2.5 nM, 5 nM, 10 nM, 20 nM) in Molm-13 cell line is shown. [Figure 4A] Shows the combined efficacy readout of the combination of IMGN632 and venetoclax as a function of dose in the EOL-1 cell line. [Figure 4B] 1 shows the combined efficacy readout of the combination of IMGN632 and venetoclax as a function of treatment effect in the EOL-1 cell line. [Figure 4C] Shows the combined efficacy readout of the combination of IMGN632 and venetoclax compared to the expected dose effect on a normalized scale in the EOL-1 cell line. [Figure 4D] Shows the combined efficacy readout of the combination of IMGN632 and venetoclax as a function of dose in the MV4-11 cell line. [Figure 4E] Shows the combined efficacy readout of the combination of IMGN632 and venetoclax as a function of treatment effect in the MV4-11 cell line. [Figure 4F] Shows the combined efficacy readout of the combination of IMGN632 and venetoclax compared to the expected dose effect on a normalized scale in the MV4-11 cell line. [Figure 4G] Shows the combined efficacy readout of the combination of IMGN632 and venetoclax as a function of dose in the KG-1 cell line. [Figure 4H]1 shows the combined efficacy readout of the combination of IMGN632 and venetoclax as a function of treatment effect in the KG-1 cell line. [Figure 4I] Shows the combined efficacy readout of the combination of IMGN632 and venetoclax compared to the expected dose effect on a normalized scale in the KG-1 cell line. [Figure 4J] Shows the combined efficacy readout of the combination of IMGN632 and venetoclax as a function of dose in the Molm-13 cell line. [Figure 4K] 1 shows the combined efficacy readout of the combination of IMGN632 and venetoclax as a function of treatment effect in the Molm-13 cell line. [Figure 4L] Shows the combined efficacy readout of the combination of IMGN632 and venetoclax compared to the expected dose effect on a normalized scale in the Molm-13 cell line. [Diagram 5] The in vivo efficacy of single doses of IMGN632 alone (1 μg / kg or 0.5 μg / kg), venetoclax alone (QD×28, 100 mg / kg), and the combination of IMGN632 (1 μg / kg or 0.5 μg / kg) and venetoclax (QD×28, 100 mg / kg) is shown by plotting median tumor volume (mm3) as a function of days after inoculation of the EOL-1 cell line. [Figure 6] The in vivo efficacy of IMGN632 alone (QW x 3, 3 μg / kg or 10 μg / kg), venetoclax alone (QD x 28, 100 mg / kg), and the combination of IMGN632 (QW x 3, 3 μg / kg or 10 μg / kg) and venetoclax (QD x 28, 100 mg / kg) is shown by plotting median tumor volume (mm3) as a function of days after inoculation of the KG-1 cell line. [Figure 7]Mouse survival is shown as a function of time after Molm-3 tumor cell inoculation. Mice received IMGN632 alone (QWx3, 0.3 μg / kg), azacitidine alone (QDx5, 3.5 mg / kg), or a combination of IMGN632 (QWx3, 0.3 μg / kg) and azacitidine (QDx5, 3.5 mg / kg) according to three different dosing schedules. [Figure 8] Survival of mice is shown as a function of time after Molm-3 tumor cell inoculation. Mice received IMGN632 alone (QWx3, 0.3 μg / kg), decitabine alone (QDx5, 0.75 mg / kg), or a combination of IMGN632 (QWx3, 0.3 μg / kg) and decitabine (QDx5, 0.75 mg / kg) according to three different dosing schedules. [Figure 9] The in vivo efficacy of single doses of IMGN632 alone (1 μg / kg), venetoclax (QD×28, 100 mg / kg), and azacitidine (QD×5, 3 mg / kg), or IMGN632 (1 μg / kg) in combination with venetoclax (QD×28, 100 mg / kg) and azacitidine (QD×5, 3 mg / kg) is shown by plotting median tumor volume (mm3) as a function of days after inoculation of the EOL-1 cell line. [Figure 10A] Mouse survival is shown as a function of time after Molm-3 tumor cell inoculation. Mice received IMGN632 alone (QW×3), venetoclax (QD×28) and azacitidine (QD×5), or IMGN632 (QW×3) in combination with venetoclax (QD×28) and azacitidine (QD×5). [Figure 10B] Mouse survival is shown as a function of time after Molm-3 tumor cell inoculation. Mice received IMGN632 alone (QW×3), venetoclax (QD×28) and azacitidine (QD×5), or IMGN632 (QW×3) in combination with venetoclax (QD×28) and azacitidine (QD×5). [Figure 11]Mouse survival is shown as a function of time after MV4-11 tumor cell inoculation. Mice received IMGN632 alone (QW×3), venetoclax (QD×28) and azacitidine (QD×5), or IMGN632 (QW×3) in combination with venetoclax (QD×28) and azacitidine (QD×5). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0058] The present invention provides combinations of anti-CD123 immunoconjugates with hypomethylating agents (HMA) and / or B-cell leukemia / lymphoma-2 (BCL-2) antagonists, and the use of the combinations in the treatment of hematological malignancies. The present invention also provides anti-CD123 immunoconjugates, optionally in combination with HMA and / or BCL-2 antagonists, for the treatment of hematological malignancies presenting as minimal residual disease.

[0059] I. Definition To facilitate the understanding of this invention, several terms and phrases are defined below.

[0060] The terms "IL-3Rα", "interleukin-3 receptor α", and "CD123", as used interchangeably herein, refer to mammalian CD123 polypeptides, including, but not limited to, naturally occurring CD123 polypeptides and isoforms of CD123 polypeptides, unless otherwise indicated. These terms encompass "full-length" unprocessed CD123 polypeptides, and any form of CD123 polypeptide resulting from processing within a cell. The terms also encompass naturally occurring variants of CD123, such as those encoded by splice variants and allelic variants. The CD123 polypeptides described herein can be isolated from a variety of sources, such as human tissue types or another source, or can be prepared by recombinant or synthetic methods. Where specifically indicated, "CD123" can be used to refer to a nucleic acid encoding a CD123 polypeptide. Human CD123 sequences are known and include, for example, sequences associated with NCBI reference numbers NP_002174 and NM_002183 (protein and nucleic acid sequences of human CD123 variant 1), and NP_001254642 and NM_001267713 (protein and nucleic acid sequences of human CD123 variant 2). As used herein, the term "human CD123" refers to CD123 comprising the sequence of SEQ ID NO:11 or SEQ ID NO:12. MVLLWLTLLL IALPCLLQTK EDPNPPITNL RMKAKAQQLT WDLNRNVTDI ECVKDADYSM PAVNNSYCQF GAISLCEVTN YTVRVANPPF STWILFPENS GKPWAGAENL TCWIHDVDFL SCSWAVGPGA PADVQYDLYL NVANRRQQYE CLHYKTDAQG TRIGCRFDDI SRLSSGSQSS HILVRGRSAA FGIPCTDKFV VFSQIEILTP PNMTAKCNKT HSFMHWKMRS HFNRKFRYEL QIQKRMQPVI TEQVRDRTSF QLLNPGTYTV QIRARERVYE FLSAWSTPQR FECDQEEGAN TRAWRTSLLI ALGTLLALVC VFVICRRYLV MQRLFPRIPH MKDPIGDSFQ NDKLVVWEAG KAGLEECLVT EVQVVQKT(SEQ ID NO: 11) MVLLWLTLLL IALPCLLQTK EGGKPWAGAE NLTCWIHDVD FLSCSWAVGP GAPADVQYDL YLNVANRRQQ YECLHYKTDA QGTRIGCRFD DISRLSSGSQ SSHILVRGRS AAFGIPCTDK FVVFSQIEIL TPPNMTAKCN KTHSFMHWKM RSHFNRKFRY ELQIQKRMQP VITEQVRDRT SFQLLNPGTY TVQIRARERV YEFLSAWSTP QRFECDQEEG ANTRAWRTSL LIALGTLLAL VCVFVICRRY LVMQRLFPRI PHMKDPIGDS FQNDKLVVWE AGKAGLEECL V TEVQVVQKT(SEQ ID NO: 12)

[0061] The term "antibody" refers to an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or a combination of the foregoing, through at least one antigen recognition site within the variable region of the immunoglobulin molecule. As used herein, the term "antibody" encompasses intact polyclonal antibodies, intact monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins containing antibodies, and any other modified immunoglobulin molecule, so long as the antibodies exhibit the desired biological activity. Antibodies can be any of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), based on the identity of their heavy chain constant domains, designated α, δ, ε, γ, and μ, respectively. Different classes of immunoglobulins have different well-known subunit structures and three-dimensional configurations. Antibodies can be naked or can be conjugated to other molecules, such as toxins, radioisotopes, etc.

[0062] The term "anti-CD123 antibody" or "antibody that binds CD123" refers to an antibody that can bind CD123 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting CD123 (e.g., the antibody in IMGN632). The extent of binding of an anti-CD123 antibody to unrelated, non-CD123 proteins can be less than about 10% of the binding of the antibody to CD123 as measured, for example, by radioimmunoassay (RIA).

[0063] The term "antibody fragment" refers to a portion of an intact antibody that has sufficient positive charge to bind to a cation exchange resin. An "antigen-binding fragment" refers to a portion of an intact antibody that binds to an antigen and has sufficient positive charge to bind to a cation exchange resin. An antigen-binding fragment can contain the antigen-determining variable region of an intact antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, and single-chain antibodies.

[0064] The term "cysteine ​​engineered" antibody or antigen-binding fragment thereof includes an antibody or antigen-binding fragment thereof having at least one cysteine ​​("Cys") not normally present at a given residue in the light or heavy chain of the antibody or antigen-binding fragment thereof. Such a Cys, which may also be referred to as an "engineered Cys", may be engineered using any conventional molecular biology or recombinant technique (e.g., by replacing the coding sequence of a non-Cys residue at the target residue with the coding sequence of Cys). For example, if the original residue is Ser with a coding sequence of 5'-UCU-3', the coding sequence can be mutated (e.g., by site-directed mutagenesis) to 5'-UGU-3', which codes for Cys. In certain embodiments, a Cys-engineered antibody or antigen-binding fragment thereof has an engineered Cys in the heavy chain. In certain embodiments, the engineered Cys is in or near the CH3 domain of the heavy chain. In certain embodiments, the engineered Cys is at residue 442 of the heavy chain (EU / OU numbering; EU index, Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed., NIH publication No. 91-3242, 1991, the entire contents of which are incorporated herein by reference). In certain embodiments, the Fc region comprises a cysteine ​​at one or more of positions 239, 282, 289, 297, 312, 324, 330, 335, 337, 339, 356, 359, 361, 383, 384, 398, 400, 440, 422, and 442, as numbered by the EU index. In certain embodiments, any one or more of the following residues may be substituted with a cysteine: V205 (Kabat numbering) of the light chain, A118 (EU numbering) of the heavy chain, and S400 (EU numbering) of the heavy chain Fc region. In certain embodiments, for example, the variable light domain of an scFv has a cysteine ​​at Kabat position 100. In certain embodiments, for example, the variable heavy domain of an scFv has a cysteine ​​at Kabat position 44. Cysteine ​​engineered antibodies may be generated as described, for example, in U.S. Pat. No. 7,521,541, U.S. Pat. No. 7,855,275, U.S. Published Application No. 2011 / 0033378, and WO2011 / 005481.

[0065] A "monoclonal" antibody or antigen-binding fragment thereof refers to a homogeneous antibody or antigen-binding fragment population that is involved in highly specific recognition and binding of a single antigenic determinant, or epitope. This is in contrast to a polyclonal antibody, which typically contains different antibodies directed against different antigenic determinants. The term "monoclonal" antibody or antigen-binding fragment thereof encompasses both intact and full-length monoclonal antibodies, as well as antibody fragments (e.g., Fab, Fab', F(ab')2, Fv), single-chain (scFv) variants, fusion proteins containing an antibody portion, and any other modified immunoglobulin molecule that contains an antigen recognition site. Furthermore, a "monoclonal" antibody or antigen-binding fragment thereof refers to such antibodies and antigen-binding fragments thereof produced in any number of ways, including, but not limited to, hybridoma, phage selection, recombinant expression, and transgenic animals.

[0066] The term "humanized" antibody or antigen-binding fragment thereof refers to forms of non-human (e.g., murine) antibodies or antigen-binding fragments that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human (e.g., murine) sequences. Typically, humanized antibodies or antigen-binding fragments thereof are human immunoglobulins in which residues from the complementarity determining regions (CDRs) are replaced by residues from the CDRs of a non-human species (e.g., mouse, rat, rabbit, hamster) that has the desired specificity, affinity, and capacity ("grafted CDRs") (Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Verhoeyen et al., Science 239:1534-1536 (1988)). In some cases, Fv framework region (FR) residues of a human immunoglobulin are replaced by corresponding residues in an antibody or fragment from a non-human species having the desired specificity, affinity, and capacity. The humanized antibody or antigen-binding fragment thereof can be further modified by substitution of additional residues either within the Fv framework regions and / or within the substituted non-human residues to refine and optimize the specificity, affinity, and / or capacity of the antibody or antigen-binding fragment thereof. Generally, a humanized antibody or antigen-binding fragment thereof will comprise substantially all of at least one, and typically two or three, variable domains including all or substantially all of the CDR regions corresponding to a non-human immunoglobulin, while all or substantially all of the FR regions are of a human immunoglobulin consensus sequence. The humanized antibody or antigen-binding fragment thereof can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. Examples of methods used to generate humanized antibodies are described in U.S. Patent No. 5,225,539, Roguska et al., Proc. Natl. Acad. Sci., USA, 91(3):969-973 (1994), and Roguska et al., Protein Eng. 9(10):895-904 (1996). In some embodiments, a "humanized antibody" is a resurfaced antibody.

[0067] The "variable region" of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. The heavy and light chain variable regions each consist of four framework regions (FRs) connected by three complementarity determining regions (CDRs), also known as hypervariable regions. The CDRs in each chain are held together in close proximity by the FRs and, together with the CDRs from the other chain, contribute to the formation of the antigen-binding site of antibodies. At least one of the following sequences is used to determine the CDRs: There are two techniques for determining CDRs: (1) an approach based on interspecies sequence variability (i.e., Kabat et al., Sequences of Proteins of Immunological Interest, (5th ed., 1991, National Institutes of Health, Bethesda Md.), "Kabat"), and (2) an approach based on crystallographic studies of antigen-antibody complexes (Al-lazikani et al, J. Molec. Biol. 273:927-948(1997)). In addition, a combination of these two approaches may be used in the art to determine CDRs.

[0068] The Kabat numbering system is commonly used to refer to residues within the variable domain (approximately residues 1-107 in the light chain and residues 1-113 in the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. (5th Ed., 1991, National Institutes of Health, Bethesda, Md.) ("Kabat").

[0069] Kabat amino acid position numbering refers to the numbering system used for the heavy or light chain variable domains of the compilation of antibodies in Kabat et al. (Sequences of Immunological Interest. (5th Ed., 1991, National Institutes of Health, Bethesda, Md.), "Kabat"). Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to shortening or insertion of a FR or CDR of the variable domain. For example, a heavy chain variable domain may contain a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat) and inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c, etc. according to Kabat). The Kabat numbering of residues can be determined for a given antibody by alignment of the antibody's sequence with the "standard" Kabat numbering sequence at the region of homology. Instead, Chothia refers to the location of the structural loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). The end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34, depending on the length of the loop (this is because the Kabat numbering scheme places the insertion at H35A and H35B. If neither 35A nor 35B is present, the loop ends at 32. If only 35A is present, the loop ends at 33. If both 35A and 35B are present, the loop ends at 34). The AbM hypervariable regions represent a compromise between the Kabat CDRs and the Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software. [Table A]

[0070] The term "human" antibody or antigen-binding fragment thereof means an antibody or antigen-binding fragment thereof produced by a human, or an antibody or antigen-binding fragment thereof having an amino acid sequence that corresponds to an antibody or antigen-binding fragment thereof produced by a human, made using any technique known in the art. This definition of a human antibody or antigen-binding fragment thereof includes intact or full-length antibodies and fragments thereof.

[0071] The term "chimeric" antibody or antigen-binding fragment thereof refers to an antibody or antigen-binding fragment thereof whose amino acid sequences are derived from two or more species. Typically, the variable regions of both the light and heavy chains correspond to the variable regions of an antibody or antigen-binding fragment thereof from one species of mammal (e.g., mouse, rat, rabbit, etc.) having the desired specificity, affinity, and capacity, while the constant regions are homologous to sequences of an antibody or antigen-binding fragment thereof from another species (usually human) and do not elicit an immune response in that species.

[0072] The terms "epitope" or "antigenic determinant" are used interchangeably herein and refer to a portion of an antigen that can be recognized and specifically bound by a particular antibody. When the antigen is a polypeptide, epitopes can be formed from both contiguous and non-contiguous amino acids juxtaposed by tertiary folding of the protein. Epitopes formed from contiguous amino acids are typically retained upon protein denaturation, whereas epitopes formed by tertiary folding are typically lost upon protein denaturation. An epitope typically contains at least 3, more usually at least 5 or 8-10 amino acids in a unique spatial conformation.

[0073] "Binding affinity" generally refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y can generally be represented by a dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Low affinity antibodies generally bind antigens slowly and tend to dissociate easily, whereas high affinity antibodies generally bind antigens faster and tend to remain bound longer. Various methods of measuring binding affinity are known in the art, any of which can be used for the purposes of the present disclosure. Specific exemplary embodiments are described below.

[0074] "Or better" as used herein to refer to binding affinity refers to stronger binding between a molecule and its binding partner. "Or better" as used herein refers to stronger binding, represented by a smaller numerical Kd value. For example, an antibody having an affinity for an antigen of "0.6nM or greater", where the affinity of the antibody for the antigen is less than 0.6nM, i.e., 0.59nM, 0.58nM, 0.57nM, etc., or any value less than 0.6nM.

[0075] "Specifically bind" generally means that an antibody binds to an epitope through its antigen-binding domain, and that the binding involves a degree of complementarity between the antigen-binding domain and the epitope. According to this definition, an antibody is said to "specifically bind" to an epitope when it binds to the epitope through its antigen-binding domain more readily than it binds to a random, unrelated epitope. The term "specificity" is used herein to modify the relative affinity with which a particular antibody binds to a particular epitope. For example, antibody "A" may be considered to have a higher specificity for a given epitope than antibody "B", or antibody "A" may be more specific to a related epitope "D". It can be said to bind epitope "C" with high specificity.

[0076] "Preferentially binds" means that the antibody specifically binds to an epitope more readily than it binds to a related, similar, homologous, or analogous epitope. Thus, an antibody that "preferentially binds" to a given epitope will be more likely to bind to that epitope than to a related epitope, although such an antibody may cross-react with the related epitope.

[0077] The terms "polypeptide", "peptide" and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. The polymers may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acids. These terms also encompass amino acid polymers that are modified naturally or by intervention, for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. The definition also includes, for example, polypeptides that contain one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), as well as other modifications known in the art. Because the polypeptides of the present disclosure are based on antibodies, it is understood that in certain embodiments, the polypeptides can occur as single chains or associated chains.

[0078] As used herein, the term "immunoconjugate" or "conjugate" refers to a compound or derivative thereof linked to a cell-binding agent (i.e., an anti-CD123 antibody or fragment thereof) and defined by the following general formula: CA (C=cytotoxin (e.g., an indolino-benzodiazepine (IGN) DNA alkylating agent (e.g., DGN549-C)), and A=antibody or antigen-binding fragment thereof, e.g., an anti-CD123 antibody or antibody fragment). The immunoconjugate may optionally contain a linker and may be defined by the general formula CLA (C=cytotoxin, L=linker, and A=antibody or antigen-binding fragment thereof, e.g., an anti-CD123 antibody or antibody fragment). The immunoconjugate may also be defined in the reverse order by the general formula: CA or ALC. The immunoconjugate may also contain multiple cytotoxins (C) per antibody or antigen-binding fragment thereof (A), or multiple cytotoxins (C) and linkers (L) per antibody or antigen-binding fragment thereof (A).

[0079] A "linker" is any chemical moiety that can link a compound, usually a drug (such as an IGN DNA alkylating drug), to a cell-binding agent (such as an anti-CD123 antibody or a fragment thereof) in a stable, covalent manner. The linker can be sensitive or substantially resistant to acid-induced cleavage, photo-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage under conditions in which the compound or antibody remains active. Suitable linkers are well known in the art and include, for example, disulfide groups, thioether groups, acid labile groups, photolabile groups, peptidase labile groups, and esterase labile groups. Linkers also include charged linkers and their hydrophilic forms described herein and known in the art. In some embodiments disclosed herein, the linker is a peptide linker.

[0080] The term "IMGN632" refers to the immunoconjugate composition shown in Figures 6A and 6B. The immunoconjugate composition includes immunoconjugates that contain an average of 1.5 to 2.1 DGN549-C cytotoxic agent per sulfonated version of the huCD123-6Gv4.7 ("G4723A") antibody (Figure 1A). The immunoconjugate composition can also include non-sulfonated immunoconjugates (monoimine structures shown in Figure 1B).

[0081] The term "BCL-2 inhibitor" refers to an agent capable of inhibiting the activity of B-cell leukemia / lymphoma-2 ("BCL-2"). For example, a BCL-2 inhibitor can be used to inhibit the activity of BCL-2. It can bind to and reduce the interaction of BCL-2 with pro-apoptotic proteins (e.g., BH3-only proteins). Venetoclax is an exemplary BCL-2 inhibitor.

[0082] The term "hypomethylating agent" or "HMA" refers to an agent that inhibits DNA methylation. For example, HMAs can act by inhibiting DNA methyltransferase. Azacitidine and decitabine are exemplary HMAs.

[0083] The terms "cancer" and "cancerous" refer to or describe the physiological condition in a mammal in which a population of cells is characterized by uncontrolled cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. "Tumor" and "neoplasm" refer to one or more cells resulting from excessive cell growth or proliferation, either benign (non-cancerous) or malignant (cancerous), including pre-cancerous lesions. The cancers disclosed herein may be hematological malignancies. Examples of hematological malignancies include, for example, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodysplastic syndromes (MDS), acute lymphoblastic leukemia (ALL) such as B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T ALL), mixed lineage leukemia ALL (MLL-ALL), B-cell precursor ALL (BCP-ALL), Ph+ ALL, Ph-like ALL, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia in blast crisis / blast crisis phase (BP-CML), and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Further examples of "cancer" include B-cell lymphomas including NHL, precursor B-cell lymphoblastic leukemia / lymphoma, and mature B-cell neoplasms such as B-cell chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, mantle cell lymphoma (MCL), follicular lymphoma (FL) including low-grade, intermediate-grade, and high-grade FL, cutaneous follicle center lymphoma, marginal zone B-cell lymphoma (MALT, nodal, and splenic), hairy cell leukemia, diffuse large B-cell lymphoma, Burkitt's lymphoma, plasmacytoma, plasma cell myeloma, post-transplant lymphoproliferative disorder, Waldenstrom's macroglobulinemia, and anaplastic large cell lymphoma (ALCL). The cancer may be a cancer that expresses CD123 ("CD123-expressing cancer").

[0084] "Cancer cells", "tumor cells" and grammatically equivalent terms refer to the total population of cells derived from a tumor or precancerous lesion, including both non-tumorigenic cells, which make up the majority of the tumor cell population, and tumorigenic stem cells (cancer stem cells). As used herein, the term "tumor cells" is modified by the term "non-tumorigenic" when referring only to tumor cells that lack the ability to renew and differentiate to distinguish these tumor cells from cancer stem cells.

[0085] A "refractory" cancer is one that progresses despite anti-cancer treatments, such as chemotherapy, being administered to a cancer patient. The cancer may be resistant at the start of treatment or may become resistant during treatment.

[0086] A "primary refractory" cancer is one in which a patient does not achieve complete remission (CR) or complete remission with incomplete recovery (CRi) after receiving two cycles of intensive chemotherapy.

[0087] A "recurrent" cancer is one in which the cancer or signs and symptoms of cancer return after a period of improvement.

[0088] As used herein, the term "matched AML" refers to a subject with AML who is a candidate for intensive therapy. Measures for determining whether a subject has matched AML include, for example, physical performance (e.g., as determined by Eastern Cooperative Oncology Group Performance Status (ECOG PS), Karnofsky Performance Status (KPS), and Short Physical Performance Battery (SPPB)), comorbidity status (CMS), and / or morbidity (MCI) status (e.g., MCSI status), and / or morbidity status (MCI status). The criteria for determining the AML outcome include, but are not limited to, cytogenetic group, age, white blood cell count, LDH, and type of AML, as determined by the CCI or HCT-CI, cognitive function, and prognostic models. In some instances, the matched AML subjects are subjects aged 60 years or younger.

[0089] As used herein, the term "unmatched AML" refers to the subject with AML that is not eligible for intensive therapy.Measures for determining the subject with unmatched AML include, for example, physical performance (e.g., determined by Eastern Cooperative Oncology Group Performance Status (ECOG PS), Karnofsky Performance Status (KPS) and Short Physical Performance Battery (SPPB)), comorbidity status (determined by Charlson Comorbidity Index (CCI) or Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI)), cognitive function, and prognostic model (including but not limited to cytogenetic group, age, white blood cell count, LDH, AML type).In some cases, the unmatched AML subject is a subject over 60 years old.

[0090] The term "increased expression" or "overexpression" of CD123 in a particular tumor, tissue, or cell sample refers to CD123 that is present at levels higher than that present in healthy or non-disease (native, wild-type) tissue or cells of the same type or origin.

[0091] The terms "treat" or "treatment" or "treating" or "palliative" or "alleviating" and the like refer to a therapeutic measure that cures, alleviates, relieves symptoms, and / or halts progression of a diagnosed pathological condition or disorder. Thus, those in need of treatment include those already diagnosed with a disorder or suspected of having a disorder.

[0092] The term "therapeutically effective amount" refers to an amount of an antibody, immunoconjugate, or other drug effective to "treat" a disease or disorder in a subject or mammal. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells, reduce tumor size or burden, inhibit (i.e., to some extent slow, and in certain embodiments, halt) cancer cell invasion into peripheral organs, alleviate to some extent one or more of the symptoms associated with cancer, and / or produce a favorable response, such as complete remission (CR), complete remission with incomplete recovery (CRi), complete remission with partial hematological recovery (CRh), CR without minimal residual disease (CRMRD-), clinical complete remission (CRc), morphological leukemia-free status (MLFS), partial remission (PR), duration of response (DOR), and reduction in progressive disease (PD).

[0093] The term "respond favorably" generally refers to causing a beneficial state in a subject. In the context of cancer treatment, this term refers to providing a therapeutic effect to a subject. Positive therapeutic effect in cancer can be measured in several ways (see WA Weber, J.Nucl.Med.50:1S-10S (2009)). Favorable response can be evaluated, for example, by complete remission (CR), complete remission with incomplete recovery (CRi), CR without minimal residual disease (CRMRD-), clinical complete remission (CRc), morphological leukemia-free state, partial remission (PR), reduction in progressive disease (PD), or any combination thereof.

[0094] "Complete response" or "complete remission" or "CR" indicates the disappearance of all signs of tumor or cancer in response to treatment. It does not necessarily mean that the cancer has been cured. "CRi" refers to a morphologically complete remission with incomplete hematologic (blood count) recovery. "CRMRD-" refers to a complete recovery with no measurable residual disease.

[0095] "Minimal residual disease", "MRD", or "MRD+" refers to the persistence of cancer (e.g., leukemia) cells after treatment at levels below morphological detection. MRD may be assessed, for example, using central flow cytometry. MRD+ status is predictive of relapse and has been associated with decreased survival in AML patients.

[0096] A "partial response" or "PR" refers to a reduction in the size or volume of one or more tumors or lesions, or the extent of cancer in the body, in response to treatment.

[0097] "Progressive disease" refers to the appearance of one or more new lesions or tumors and / or a clear progression of existing non-target lesions. Progressive disease can also refer to tumor growth of more than 20% since treatment has begun, due to either an increase in tumor mass or tumor spread.

[0098] The term "treatment" or "therapy" refers to a therapeutic regimen that may include, but is not limited to, surgery, radiation therapy, chemotherapy, differentiation therapy, biotherapy, immunotherapy, induction therapy, consolidation therapy, transplantation, maintenance therapy, or administration of one or more anti-cancer agents (e.g., cytotoxic agents and / or anti-proliferative compounds).

[0099] The terms "first-line treatment", "first-line therapy", and "frontline therapy" refer to the preferred standard initial treatment for a particular condition, e.g., induction therapy, consolidation therapy, transplant, maintenance therapy. These treatments are distinct from "second-line" therapy, which is attempted if first-line therapy does not work adequately. "Third-line" therapy is attempted if first-line and second-line therapy does not work adequately. "Salvage therapy" or "salvage regimen" is a treatment attempted if the cancer has not responded to other treatments.

[0100] For example, the combination of the CD123 immunoconjugates (e.g., IMGN632) provided herein with a BCL-2 inhibitor and / or HMA may be given as a first line therapy, a second line therapy, or a third line therapy. The combination of the CD123 immunoconjugates (e.g., IMGN632) provided herein with a BCL-2 inhibitor and / or HMA may be given as a therapy in patients who have received at least one, at least two, or at least three therapies (e.g., frontline therapy and one salvage therapy) prior to treatment with the combination of the CD123 immunoconjugates (e.g., IMGN632) provided herein with a BCL-2 inhibitor and / or HMA. In some embodiments, the combination of the CD123 immunoconjugates (e.g., IMGN632) provided herein with a BCL-2 inhibitor and / or HMA may be given as a therapy in patients who have received no more than one, no more than two, no more than three, no more than four, no more than five, or no more than six therapies.

[0101] The term "maintenance therapy" refers to therapy given to prevent cancer from returning after the cancer has gone away following initial therapy.

[0102] The phrase "pharmacologically acceptable" indicates that a substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation, and / or with the mammal being treated with the formulation.

[0103] The term "pharmaceutical formulation" refers to a preparation that is in a form that allows the biological activity of the active ingredient to be effective and does not contain additional ingredients that are unacceptably toxic to the subject to which the formulation is administered. The formulation may be sterile.

[0104] The term "subject" refers to any animal (e.g., mammal) that will be the recipient of a particular treatment, including, but not limited to, humans, non-human primates, rodents, etc. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to human subjects. do.

[0105] Administration "in combination with" one or more further therapeutic agents includes simultaneous (concurrent) or consecutive administration in any order.

[0106] Combination therapy can provide and demonstrate a "synergistic effect", an effect achieved when the active ingredients used together are greater than the sum of the effects resulting from using the compounds separately. Synergistic effects can be obtained when the active ingredients are (1) formulated together and administered or delivered simultaneously in a combined unit dosage formulation, (2) delivered in parallel sequentially, alternatingly, or as separate formulations, or (3) delivered by some other regimen. When delivered in alternating therapy, synergistic effects can be obtained when the compounds are administered or delivered sequentially, for example, by different injections in separate syringes.

[0107] The term "instruct" means providing written instructions for applicable therapies, medications, treatments, therapeutic regimens, etc. by any means, such as, for example, in the form of a package insert or other written promotional material.

[0108] An "effective amount" of an antibody, immunoconjugate, or other drug disclosed herein is an amount sufficient to carry out a specifically described purpose. An "effective amount" can be empirically and routinely determined in relation to the described purpose.

[0109] An "isolated" polypeptide, antibody, polynucleotide, vector, cell, or composition is a polypeptide, antibody, polynucleotide, vector, cell, or composition in a form not found in nature. Isolated polypeptides, antibodies, polynucleotides, vectors, cells, or compositions include those that have been purified to the extent that they are no longer in a form in which they are found in nature. In some embodiments, an isolated antibody, polynucleotide, vector, cell, or composition is substantially pure.

[0110] As used herein, "substantially pure" refers to a material that is at least 50% pure (i.e., free of contaminants), at least 90% pure, at least 95% pure, at least 98% pure, or at least 99% pure.

[0111] As used in this disclosure and claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0112] Where an embodiment is described herein using the language "comprising," it is understood that similar embodiments that are otherwise described using the language "consisting of" and / or "consisting essentially of" are also provided.

[0113] The term "and / or" as used herein in phrases such as "A and / or B" is intended to include both "A and B," "A or B," "A" and "B." Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0114] II. Anti-CD123 immune complex Described herein are methods of administering immunoconjugates that specifically bind to CD123 (e.g., IMGN632) in combination with other agents. The entity is referred to herein as a "CD123-immunoconjugate" or an "anti-CD123 immune conjugate." Such an immune conjugate comprises an anti-CD123 antibody, or antigen-binding fragment thereof, and a drug (e.g., a cytotoxic agent). The drug (e.g., a cytotoxic agent) can be attached to the anti-CD123 antibody, or antigen-binding fragment thereof, by a linker.

[0115] In some embodiments, the anti-CD123 antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof. In some embodiments, the humanized antibody or fragment thereof is a resurfaced antibody or antigen-binding fragment thereof. In other embodiments, the antibody or antigen-binding fragment thereof is a fully human antibody or antigen-binding fragment thereof.

[0116] In one embodiment, the immunoconjugate is represented by the formula: [ka] , wherein CBA is an anti-CD123 antibody or antigen-binding fragment or polypeptide covalently linked to CyC1 via a cysteine ​​residue, and WC is 1 or 2.

[0117] In the above formula, Cy c1 is expressed by the following formula: [ka] [ka] or a pharma- ceutically acceptable salt thereof, wherein the double line between N and C is [ka] represents a single bond or a double bond, with the proviso that when it is a double bond, X is absent and Y is -H or (C1-C4) alkyl, and when it is a single bond, X is -H or an amine protecting moiety, Y is -OH or -SO3M, and M is H or a cation; R 5 is -H or (C 1 ~C 3 ) alkyl, P is an amino acid residue or a peptide containing 2 to 20 amino acid residues; R a and R b represents, independently at each occurrence, -H, (C 1 ~C 3) alkyl, or a charged substituent or ionizable group Q; W' is -NR e’ and R e’ is -(CH 2 -CH 2 -O) n -R k and n is an integer from 2 to 6, R k is -H or -Me, R x3 is (C 1 ~C 6 ) alkyl, L c teeth, [ka] where s1 is the moiety covalently attached to CBA and s2 is the moiety of Cy C1 a moiety covalently bonded to the -C(=O)- group on R 19 and R 20 is, in each occurrence, independently -H or (C 1 ~C 3 ) alkyl, m" is an integer between 1 and 10, R h is -H or (C 1 ~C 3 ) alkyl.

[0118] In certain embodiments, R a and R b are both H and R 5 is H or Me.

[0119] In certain embodiments, P is a peptide containing 2-5 amino acid residues, for example, P can be Gly-Gly-Gly, Ala-Val, Val-Ala, Val-Cit, Val-Lys, Phe-Lys, Lys-Lys, Ala-Lys, Phe-Cit, Leu-Cit, Ile-Cit, Trp, Cit, Phe-Ala, Phe-N 9-Tosyl-Arg, Phe-N 9 -Nitro-Arg, Phe-Phe-Lys, D-Phe-Phe-Lys, Gly-Phe-Lys, Leu-Ala-Leu, Ile-Ala-Leu, Val-Ala-Val , Ala-Leu-Ala-Leu, β-Ala-Leu-Ala-Leu, Gly-Phe-Leu-Gly, Val-Arg, Arg-Val, Arg-Arg, Val-D-Ci t, Val-D-Lys, Val-D-Arg, D-Val-Cit, D-Val-Lys, D-Val-Arg, D-Val-D-Cit, D-Val-D-Lys, D-Val-D-Arg, D-Arg-D-Arg, Ala-Ala, Ala-D-Ala, D-Ala-Ala, D-Ala-D-Ala, Ala-Met, and Met-Ala. In certain embodiments, P is Gly-Gly-Gly, Ala-Val, Ala-Ala, Ala-D-Ala, D-Ala-Ala, or D-Ala-D-Ala. In certain embodiments, Q is -SO 3 It's M.

[0120] In certain embodiments, R 19 and R 20 are both H, and m″ is an integer from 1 to 6.

[0121] In certain embodiments, -L c - is expressed by the following formula. [ka]

[0122] In certain embodiments, the immunoconjugate has the formula: [ka] [ka] or a pharma- ceutically acceptable salt thereof, wherein the double line between N and C is [ka] represents a single bond or a double bond, provided that when it is a double bond, X is absent and Y is -H, and when it is a single bond, X is -H and Y is -OH or -SO3M.

[0123] By way of example, an anti-CD123 antibody or antigen-binding fragment thereof can be present in the immune complex used in the method. Anti-CD123 antibodies or antigen-binding fragments thereof have been described (see, e.g., U.S. Pat. No. 10,077,313 B2, the contents of which are incorporated herein by reference in their entirety). The anti-CD123 antibody or antigen-binding fragment thereof can be the huCD123-6Gv4.7 ("G4723A") antibody (see, e.g., WO2017 / 004025, WO2017 / 004026, and PCT / US2018 / 052212, the contents of each of which are incorporated herein by reference in their entirety), or can contain the sequence of the G4723A antibody, for example, as shown in Tables 1-3 below. For example, an anti-CD123 antibody or antigen-binding fragment thereof for use in the methods provided herein can comprise variable heavy chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 5, 6, and 7, respectively, and / or variable light chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 8, 9, and 10, respectively. An anti-CD123 antibody or antigen-binding fragment thereof for use in the methods provided herein can comprise a variable heavy chain domain comprising the sequence set forth in SEQ ID NO: 1. An anti-CD123 antibody or antigen-binding fragment thereof for use in the methods provided herein can comprise a variable light chain domain comprising the sequence set forth in SEQ ID NO: 2. An anti-CD123 antibody or antigen-binding fragment thereof for use in the methods provided herein can comprise a variable heavy chain domain comprising the sequence set forth in SEQ ID NO: 1 and a variable light chain domain comprising the sequence set forth in SEQ ID NO: 2. An anti-CD123 antibody or antigen-binding fragment thereof for use in the methods provided herein can comprise a heavy chain comprising the sequence set forth in SEQ ID NO: 3. An anti-CD123 antibody, or antigen-binding fragment thereof, for use in the methods provided herein can comprise a light chain comprising the sequence set forth in SEQ ID NO: 4. An anti-CD123 antibody, or antigen-binding fragment thereof, for use in the methods provided herein can comprise a heavy chain comprising the sequence set forth in SEQ ID NO: 3 and a light chain comprising the sequence set forth in SEQ ID NO: 4. [Table 1] [Table 2] [Table 3]

[0124] An anti-CD123 antibody or antigen-binding fragment thereof for use in the methods provided herein can bind to an epitope within amino acids 205-346 of human CD123.

[0125] Anti-CD123 antibodies or antigen-binding fragments thereof for use in the methods provided herein can be recombinantly produced. For example, anti-CD123 antibodies or antigen-binding fragments thereof for use in the methods provided herein can be produced in mammalian cell lines, such as CHO cells.

[0126] The anti-CD123 antibodies or antigen-binding fragments thereof for use in the methods provided herein can be cysteine ​​engineered antibodies or fragments that can be covalently linked to a cytotoxic agent of interest to generate an immunoconjugate.

[0127] As used herein, the phrases "linked to a cell binding agent" or "linked to an anti-CD123 antibody or fragment" refer to a cell-binding agent linked to an anti-CD123 antibody or fragment via a suitable linking group, or precursor thereof. The term "linker" refers to a conjugate molecule comprising at least one cytotoxic agent linked to an agent, e.g., an anti-CD123 antibody or fragment. Linkers include, for example, peptide linkers.

[0128] The immunoconjugate can contain multiple cytotoxic agents linked to the antibody or antigen-binding fragment thereof. As provided herein, in certain cases, about 1 to about 3 drug molecules, e.g., cytotoxic agents, are linked to the anti-CD123 antibody or antigen-binding fragment thereof. In one embodiment, the immunoconjugate comprises 1, 2, or 3 cytotoxic agents per antibody or antigen-binding fragment thereof.

[0129] A composition comprising an immune conjugate can contain immune conjugates with different numbers of conjugated cytotoxic agents per antibody or antigen-binding fragment thereof. Thus, a composition comprising an immune conjugate can contain an average number of conjugated cytotoxic agents per antibody or antigen-binding fragment thereof. In one embodiment, a pharmaceutical composition comprising an anti-CD123 immune conjugate contains about 1 to about 3 cytotoxic agents per anti-CD123 antibody or antigen-binding fragment thereof, about 1.5 to about 2.5 cytotoxic agents per anti-CD123 antibody or antigen-binding fragment thereof, about 1.5 to about 2.1 cytotoxic agents per anti-CD123 antibody or antigen-binding fragment thereof, or about 1.5 to about 2.0 cytotoxic agents per anti-CD123 antibody or antigen-binding fragment thereof.

[0130] In certain instances, pharmaceutical compositions for use in the methods provided herein include, for example, an anti-CD123 immunoconjugate comprising about 1 to about 3 cytotoxic agents per antibody or antigen-binding fragment thereof, where the average number of cytotoxic agents per antibody or antigen-binding fragment thereof is about 1 to about 3 (e.g., 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0).

[0131] In certain instances, pharmaceutical compositions for use in the methods provided herein comprise anti-CD123 immunoconjugates having an average of about 1±0.2, about 1.1±0.2, about 1.2±0.2, about 1.3±0.2, about 1.4±0.2, about 1.5±0.2, about 1.6±0.2, about 1.7±0.2, about 1.8±0.2, about 1.9±0.2, about 2.0±0.2, about 2.1±0.2, 2.2±0.2, 2.3±0.2, 2.4±0.2, 2.5±0.2, or 2.6±0.2 drug molecules (e.g., cytotoxic agents) attached per antibody or antigen-binding fragment thereof. In certain embodiments, pharmaceutical compositions provided herein comprise anti-CD123 immunoconjugates having an average of about 1.5 to 2.1 drug molecules (e.g., cytotoxic agents) per antibody.

[0132] The antibody or antigen-binding fragment thereof for use in the present disclosure may be linked to a cytotoxic agent, for example, via a linkage with a Lys side chain amino group, a Cys side chain thiol group, or an oxidized N-terminal Ser / Thr. Cytotoxic agents include DNA alkylating agents, such as indolino-benzodiazepene (IGN) DNA alkylating agents. In certain cases, the cytotoxic agent is an indolino-benzodiazepine pseudodimer. In certain cases, the anti-CD123 immunoconjugate for use in the present disclosure comprises DGN549-C.

[0133] III. BCL-2 Inhibitors Described herein is a method of administering anti-CD123 immunoconjugates such as IMGN632 in combination with BCL-2 inhibitors. Overexpression of BCL-2 has been demonstrated in CLL and AML cells, where BCL-2 mediates tumor cell survival and is associated with resistance to chemotherapeutic agents. BCL-2 inhibitors can reverse this effect, for example, by promoting apoptosis.

[0134] Examples of BCL-2 inhibitors include venetoclax (Venclexta®), GX15-070 (GeminX), AT-101 (Ascenta), and AB Examples include T-263 (Navitoclax, Abbott).

[0135] Venetoclax (also known as 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide) is a selective inhibitor of BCL-2. Venetoclax is believed to help restore the apoptotic process by directly binding to the BCL-2 protein and displacing pro-apoptotic proteins such as BIM, causing permeabilization of the outer mitochondrial membrane and activation of caspases. Venetoclax is the active ingredient in Venclexta®, which is provided as a tablet for oral administration.

[0136] In some embodiments, the BCL-2 inhibitor is a small molecule. In some embodiments, the BCL-2 inhibitor is venetoclax.

[0137] IV. Hypomethylating Agents Described herein are methods of administering an anti-CD123 immunoconjugate, such as IMGN632, in combination with a hypomethylating agent, such as azacytidine or decitabine.

[0138] Azacitidine (also known as "4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one" or "5-azacytidine") is a pyrimidine nucleoside analogue. It is believed to induce antineoplastic activity through two mechanisms: inhibition of DNA methyltransferase at low doses, which causes DNA hypomethylation, and direct cytotoxicity in abnormal hematopoietic cells in the bone marrow by incorporation into DNA and RNA at high doses, which results in cell death. Azacitidine is the active ingredient in Vidaza®, which is provided in a sterile form for reconstitution as a suspension for subcutaneous injection or as a solution with further dilution for intravenous administration.

[0139] Decitabine (also known as 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one) is an analog of the nucleoside 2'-deoxycytidine. It is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, leading to DNA hypomethylation and cell differentiation or apoptosis. Decitabine is the active ingredient in Dacogen®, supplied as a sterile lyophilized powder for reconstitution for intravenous administration.

[0140] Administering an HMA in combination with an anti-CD123 immunoconjugate (e.g., IMGN632) can reduce the amount and / or frequency of HMA needed to achieve the same efficacy, thereby reducing the toxicity of the therapy. Administration of an HMA in combination with an anti-CD123 immunoconjugate (e.g., IMGN632) can also increase the efficacy of the therapy.

[0141] In some embodiments, the HMA is a small molecule. In some embodiments, the HMA is azacitidine. In some embodiments, the HMA is decitabine.

[0142] V. Pharmaceutical Compositions and Kits As provided herein, anti-CD123 immunoconjugates (e.g., IMGN632) can be used in combination with BCL-2 inhibitors (e.g., venetoclax) and / or hypomethylating agents (HMA) (e.g., azacitidine or decitabine) to treat cancer. This can be done.

[0143] In some embodiments, the anti-CD123 immunoconjugate (e.g., IMGN632) and the BCL-2 inhibitor (e.g., venetoclax) are included in the same pharmaceutical composition. In some embodiments, the anti-CD123 immunoconjugate (e.g., IMGN632) and the BCL-2 inhibitor (e.g., venetoclax) are included in two separate pharmaceutical compositions in a single kit. In other embodiments, the kit includes instructions for administering the anti-CD123 immunoconjugate (e.g., IMGN632), and the anti-CD123 immunoconjugate (e.g., IMGN632) and the BCL-2 inhibitor (e.g., venetoclax). In other embodiments, the kit includes instructions for administering the BCL-2 inhibitor (e.g., venetoclax), and the BCL-2 inhibitor (e.g., venetoclax) and the anti-CD123 immunoconjugate (e.g., IMGN632).

[0144] In some embodiments, the anti-CD123 immunoconjugate (e.g., IMGN632) and the HMA (e.g., azacitidine or decitabine) are included in the same pharmaceutical composition. In some embodiments, the anti-CD123 immunoconjugate (e.g., IMGN632) and the HMA (e.g., azacitidine or decitabine) are included in two separate pharmaceutical compositions in a single kit. In other embodiments, the kit includes an anti-CD123 immunoconjugate (e.g., IMGN632) and instructions for administering the anti-CD123 immunoconjugate (e.g., IMGN632) and the HMA (e.g., azacitidine or decitabine). In other embodiments, the kit includes an HMA (e.g., azacitidine or decitabine) and instructions for administering the HMA (e.g., azacitidine or decitabine) and the anti-CD123 immunoconjugate (e.g., IMGN632).

[0145] In some embodiments, the anti-CD123 immunoconjugate (e.g., IMGN632), the BCL-2 inhibitor (e.g., venetoclax), and the HMA (e.g., azacitidine or decitabine) are contained within the same pharmaceutical composition. In some embodiments, the anti-CD123 immunoconjugate (e.g., IMGN632), the BCL-2 inhibitor (e.g., venetoclax), and the HMA (e.g., azacitidine or decitabine) are contained within two or three separate pharmaceutical compositions within a single kit.

[0146] In other embodiments, the kit comprises an anti-CD123 immunoconjugate (e.g., IMGN632) and instructions for administering the anti-CD123 immunoconjugate (e.g., IMGN632) with a BCL-2 inhibitor (e.g., venetoclax) and an HMA (e.g., azacitidine or decitabine). In other embodiments, the kit comprises a BCL-2 inhibitor (e.g., venetoclax) and instructions for administering the BCL-2 inhibitor (e.g., venetoclax) with an anti-CD123 immunoconjugate (e.g., IMGN632) and an HMA (e.g., azacitidine or decitabine). In other embodiments, the kit comprises an HMA (e.g., azacitidine or decitabine) and instructions for administering the HMA (e.g., azacitidine or decitabine) with a BCL-2 inhibitor (e.g., venetoclax) and an anti-CD123 immunoconjugate (e.g., IMGN632).

[0147] In other embodiments, the kit comprises an anti-CD123 immunoconjugate (e.g., IMGN632), a BCL-2 inhibitor (e.g., venetoclax), and instructions for administering the anti-CD123 immunoconjugate (e.g., IMGN632) and a BCL-2 inhibitor (e.g., venetoclax) together with an HMA (e.g., azacitidine or decitabine). In other embodiments, the kit comprises an anti-CD123 immunoconjugate (e.g., IMGN632), an HMA (e.g., azacitidine or decitabine), and instructions for administering the anti-CD123 immunoconjugate (e.g., IMGN632) and a HMA (e.g., azacitidine or decitabine) together with a BCL-2 inhibitor (e.g., venetoclax ... The kit includes a BCL-2 inhibitor (e.g., venetoclax), an HMA (e.g., azacitidine or decitabine), and instructions for administering the anti-BCL-2 inhibitor (e.g., venetoclax), an HMA (e.g., azacitidine or decitabine) together with an anti-CD123 immunoconjugate (e.g., IMGN632).

[0148] In certain embodiments, the pharmaceutical compositions provided herein comprise an anti-CD123 immunoconjugate (e.g., IMGN632), a BCL-2 inhibitor (e.g., venetoclax), and / or an HMA (e.g., azacitidine or decitabine), and a pharma- ceutical acceptable vehicle. These pharmaceutical compositions are used to inhibit tumor growth and treat cancer in a subject (e.g., a human patient).

[0149] Pharmaceutical compositions for use provided herein can have the anti-CD123 immunoconjugate (e.g., IMGN632), BCL-2 inhibitor (e.g., venetoclax), and / or HMA (e.g., azacitidine or decitabine) of the desired purity in a physiologically acceptable carrier, excipient, or stabilizer (Remington's Pharmaceutical Sciences (1990) Mack Publishing Co., Easton, PA). Acceptable carriers, excipients, or stabilizers are non-toxic to recipients at the dosages and concentrations employed. (See, e.g., Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 20th ed. (2003); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems,7th ed.,Lippencott Williams and (See Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd ed., Pharmaceutical Press (2000)). Compositions to be used for in vivo administration can be sterilized. This is readily accomplished, for example, by filtration through sterile filtration membranes.

[0150] In certain embodiments, a pharmaceutical composition comprising an anti-CD123 immunoconjugate (e.g., IMGN632) and / or an HMA (e.g., azacytidine or decitabine) is formulated for parenteral (e.g., intravenous) administration.

[0151] In certain embodiments, a pharmaceutical composition comprising a BCL-2 inhibitor (e.g., venetoclax) is formulated for oral administration, e.g., as a tablet.

[0152] VI.How to use As provided herein, anti-CD123 immunoconjugates (e.g., IMGN632) can be used in combination with BCL-2 inhibitors and / or hypomethylating agents (HMAs) to treat hematological cancers.

[0153] VI(A). Cancer Selection Cancers that may be treated by the methods provided herein include hematological cancers. In certain embodiments, the hematological malignancies are of myeloid origin. In certain embodiments, the hematological malignancies are of lymphatic origin. In certain embodiments, the hematological malignancies are of both myeloid and lymphatic origin. In certain embodiments, the hematological malignancies are B-cell malignancies. In certain embodiments, the hematological malignancies are hematological malignancies that express CD123.

[0154] In certain embodiments, the hematological malignancy is acute myeloid leukemia (AML), myelodysplasia In certain embodiments, the hematological malignancy is selected from the group consisting of myelofibrosis (MF), acute lymphoblastic leukemia (ALL), B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T ALL), chronic myeloid leukemia in blast crisis / blast crisis phase (BP-CML), and blastic plasmacytoid dendritic cell neoplasm (BPDCN). In certain embodiments, the hematological malignancy is chronic myelomonocytic leukemia (CMML). In certain embodiments, the hematological malignancy is myelofibrosis (MF).

[0155] In certain embodiments, the hematological malignancy is a recurrent hematological malignancy. In certain embodiments, the hematological malignancy is a refractory hematological malignancy.

[0156] In certain embodiments, the hematological malignancy is AML. In certain embodiments, the AML is relapsed AML. In certain embodiments, the AML is refractory AML. In certain embodiments, the AML is not secondary AML. In certain embodiments, the AML is matched AML. In certain embodiments, the AML is unmatched AML.

[0157] In certain embodiments, the hematological malignancy is BPDCN. In certain embodiments, the BPDCN is recurrent BPDCN. In certain embodiments, the BPDCN is refractory BPDCN.

[0158] In certain embodiments, the hematological malignancy is ALL. In certain embodiments, the ALL is relapsed ALL. In certain embodiments, the ALL is refractory ALL.

[0159] In certain embodiments, the hematological malignancy is MDS. In certain embodiments, the MDS is high-risk MDS.

[0160] In certain embodiments, the hematological malignancy is chronic myelomonocytic leukemia (CMML).

[0161] In certain embodiments, the hematological malignancy is myelofibrosis (MF).

[0162] In certain embodiments, the hematological malignancy is chemotherapy resistant.

[0163] In certain embodiments, the hematological malignancy is chemotherapy sensitive.

[0164] In certain embodiments, the hematological malignancy expresses multidrug resistance 1 (MDR1). In certain embodiments, the hematological malignancy expresses multidrug resistance (MDR) associated P-glycoprotein (P-gp). In certain embodiments, the hematological malignancy overexpresses MDR1 and P-gp.

[0165] In certain embodiments, the hematological malignancy or subject with hematological malignancy has a FLT3-ITD mutation. In certain embodiments, the hematological malignancy or subject with hematological malignancy does not have a FLT3-ITD mutation.

[0166] In certain embodiments, the hematological malignancy is present in the subject as minimal residual disease (MRD). In certain embodiments, the MRD+ patient has matched AML. In certain embodiments, the MRD+ patient has unmatched AML. The methods provided herein can convert MRD+ patients to MRD- patients. The methods provided herein can also increase recurrence-free survival (e.g., median recurrence-free survival) in MRD+ patients. can.

[0167] In some embodiments, at least about 80% of the cells of the hematological malignancy are CD123+ (eg, as determined by local flow cytometry or immunohistochemistry).

[0168] In some embodiments, at least 80% of the cells of the hematological malignancy are determined to be CD123 positive prior to administration (eg, as determined by local flow cytometry or immunohistochemistry).

[0169] In certain cases, the cancer has not been previously treated.

[0170] In certain cases, the human subject has received at least one prior therapeutic regimen for cancer. In certain cases, the human subject has received one prior therapeutic regimen for cancer. In certain cases, the human subject has received two prior therapeutic regimens for cancer. In certain cases, the human subject has received two prior therapeutic regimens for cancer. In certain cases, the human subject has received six or fewer prior therapeutic regimens for cancer. In certain cases, the human subject has received at least one prior treatment, but not more than six prior therapeutic regimens for cancer.

[0171] In one case, the cancer has been previously treated with a BCL-2 inhibitor. In one case, the cancer has not been previously treated with a BCL-2 inhibitor (i.e., the patient is "BCL-2 inhibitor naive").

[0172] In one case, the cancer has been previously treated with venetoclax. In one case, the cancer has not been previously treated with venetoclax (i.e., the patient is "venetoclax naive").

[0173] In one case, the cancer has been previously treated with a hypomethylating agent. In one case, the cancer has not been previously treated with a hypomethylating agent (i.e., the patient is "hypomethylating agent naive").

[0174] In one case, the cancer has been previously treated with azacitidine. In one case, the cancer has not been previously treated with azacitidine (i.e., the patient is "azacitidine naive").

[0175] In one case, the cancer has been previously treated with decitabine. In one case, the cancer has not been previously treated with decitabine (i.e., the patient is "decitabine naive").

[0176] VI(B). Medication As provided herein, the anti-CD123 immunoconjugate (e.g., IMGN632) may be administered at a specific dose and / or at a specific time interval. Administration of the anti-CD123 immunoconjugate (e.g., IMGN632) may be, for example, intravenous.

[0177] In certain embodiments, the anti-CD123 immunoconjugate (e.g., IMGN632) is administered once in a three-week (21 day) cycle. In certain embodiments, the anti-CD123 immunoconjugate (e.g., IMGN632) is administered three times in a three-week cycle, e.g., a first administration is on the first day (e.g., day 1), a second administration is three days (e.g., day 4) after the first administration, and a third administration is four days (e.g., day 7) after the second administration of the 21 day cycle. By way of example, the first administration of the immunoconjugate (e.g., IMGN632) is administered on the first day (e.g., day 1), a second administration is three days (e.g., day 4) after the first administration, and a third administration is four days (e.g., day 7) after the second administration of the 21 day cycle. When the first dose is day 7 of a 21-day cycle (e.g., when the immunoconjugate is administered in combination with a BCL-2 inhibitor (e.g., venetoclax)), the immunoconjugate (e.g., IMGN632) can be administered on days 7, 10, and 14 of a 21-day cycle.

[0178] In certain embodiments, the anti-CD123 immunoconjugate (e.g., IMGN632) is administered once in a four-week (28-day) cycle. In certain embodiments, the anti-CD123 immunoconjugate (e.g., IMGN632) is administered three times in a four-week cycle, e.g., the first administration is on the first day (e.g., day 1), the second administration is three days after the first administration (e.g., day 4), and the third administration is four days after the second administration (e.g., day 7) of the 28-day cycle. By way of example, when the first administration of the immunoconjugate (e.g., IMGN632) is on day 7 of a 28 day cycle (e.g., when the immunoconjugate is administered in combination with an HMA (e.g., azacitidine), or in combination with a BCL-2 inhibitor (e.g., venetoclax) and an HMA (e.g., azacitidine)), the immunoconjugate (e.g., IMGN632) can be administered on days 7, 10, and 14 of the 28 day cycle.

[0179] In certain embodiments, one cycle of treatment is therapeutically effective. In certain embodiments, two cycles of treatment are therapeutically effective. In certain embodiments, one to four cycles of treatment are therapeutically effective. In certain embodiments, two to twelve cycles of treatment are therapeutically effective.

[0180] In some embodiments, the patient can be treated in one cycle (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle. In some embodiments, the patient can be treated in at least two cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle. In some embodiments, the patient can be treated in at least three cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle. In some embodiments, the patient can be treated in at least four cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle. In some embodiments, the patient can be treated in at least five cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle. In some embodiments, the patient may be treated for at least 6 cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle. In some embodiments, the patient may be treated for at least 7 cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle. In some embodiments, the patient may be treated for at least 8 cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle. In some embodiments, the patient may be treated for at least 9 cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle. In some embodiments, the patient may be treated for at least 10 cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle.In some embodiments, the patient may be treated for at least 11 cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle. In some embodiments, the patient may be treated for at least 12 cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle.

[0181] In some embodiments, the patient can be treated for 1-10 cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate can be administered once or three times per cycle. In some embodiments, the patient can be treated for 2-10 cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle. In some embodiments, the patient can be treated for 3-10 cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle. In some embodiments, the patient can be treated for 4-10 cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle. In some embodiments, the patient can be treated for 5-10 cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle.

[0182] In some embodiments, the patient can be treated for 1-12 cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle. In some embodiments, the patient can be treated for 2-12 cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle. In some embodiments, the patient can be treated for 3-12 cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle. In some embodiments, the patient can be treated for 4-12 cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle. In some embodiments, the patient can be treated for 5-12 cycles (e.g., 21-day or 28-day cycles), e.g., the immunoconjugate is administered once per cycle or three times per cycle.

[0183] In certain embodiments, about 0.015 mg / kg to about 0.09 mg / kg of anti-CD123 immune complex (e.g., IMGN632) is administered once every three weeks (21 days). In certain embodiments, about 0.015 mg / kg to about 0.09 mg / kg of anti-CD123 immune complex (e.g., IMGN632) is administered once every four weeks (28 days). In certain embodiments, about 0.015 mg / kg to about 0.135 mg / kg of anti-CD123 immune complex (e.g., IMGN632) is administered once every three weeks (21 days). In certain embodiments, about 0.015 mg / kg to about 0.135 mg / kg of anti-CD123 immune complex (e.g., IMGN632) is administered once every four weeks (28 days).

[0184] In certain embodiments, 0.015 mg / kg to about 0.045 mg / kg of anti-CD123 immune complex (e.g., IMGN632) is administered once every three weeks (21 days). In certain embodiments, about 0.03 mg / kg of anti-CD123 immune complex (e.g., IMGN632) is administered once every three weeks (21 days). In certain embodiments, 0.015 mg / kg to about 0.045 mg / kg of anti-CD123 immune complex (e.g., IMGN632) is administered once every four weeks (28 days). In certain embodiments, about 0.03 mg / kg of anti-CD123 immune complex (e.g., IMGN632) is administered once every four weeks (28 days).

[0185] In certain embodiments, 0.045 mg / kg to about 0.09 mg / kg of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered once per three week (21 day) cycle. In certain embodiments, 0.045 mg / kg to about 0.09 mg / kg of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered once per four week (28 day) cycle.

[0186] In certain embodiments, 0.045 mg / kg to about 0.135 mg / kg of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every three weeks (21 days). In certain embodiments, 0.045 mg / kg to about 0.135 mg / kg of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every four weeks (28 days).

[0187] In certain embodiments, about 0.015 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every 3 weeks (21 days) or 4 weeks (28 days) cycle. In certain embodiments, about 0.03 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every 3 weeks (21 days) or 4 weeks (28 days) cycle. In certain embodiments, about 0.045 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every 3 weeks (21 days) or 4 weeks (28 days) cycle. In certain embodiments, about 0.09 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every 3 weeks (21 days) or 4 weeks (28 days) cycle. In certain embodiments, about 0.135 mg / kg of the anti-CD123 immunoconjugate (eg, IMGN632) is administered once every three week (21 days) or four week (28 days) cycle.

[0188] In certain embodiments, a total dose of 0.045 mg / kg to about 0.18 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered over the course of a three or four week cycle, with this total dose split into three separate administrations (e.g., on days 1, 4, and 8, or on days 7, 10, and 14 of the cycle). Thus, in certain embodiments, about 0.015 mg / kg to about 0.09 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered three times in a three or four week cycle, e.g., on days 1, 4, and 8, or on days 7, 10, and 14 of the cycle. In certain embodiments, about 0.015 mg / kg to about 0.135 mg / kg of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered three times in a three or four week cycle, e.g., on days 1, 4, and 8, or on days 7, 10, and 14 of the cycle. In certain embodiments, about 0.015 mg / kg to about 0.06 mg / kg of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered three times in a three or four week cycle, e.g., on days 1, 4, and 8, or on days 7, 10, and 14 of the cycle. In certain embodiments, about 0.015 mg / kg to about 0.03 mg / kg of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered three times in a three or four week cycle, e.g., on days 1, 4, and 8, or on days 7, 10, and 14 of the cycle. In certain embodiments, about 0.03 mg / kg to about 0.06 mg / kg of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered three times in a three or four week cycle, e.g., on days 1, 4, and 8, or on days 7, 10, and 14 of the cycle.

[0189] In certain embodiments, about 0.015 mg / kg of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered three times in a three or four week cycle, e.g., on days 1, 4, and 8, or on days 7, 10, and 14 of the cycle. In certain embodiments, about 0.03 mg / kg of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered three times in a three or four week cycle, e.g., on days 1, 4, and 8, or on days 7, 10, and 14 of the cycle. In certain embodiments, about 0.06 mg / kg of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered three times in a three or four week cycle, e.g., on days 1 of the cycle. , 4, and 8, or 7, 10, and 14. In certain embodiments, about 0.09 mg / kg of the anti-CD123 immunoconjugate (e.g., IMGN632) is administered three times in a three or four week cycle, for example, on days 1, 4, and 8, or on days 7, 10, and 14 of the cycle. In certain embodiments, about 0.135 mg / kg of the anti-CD123 immunoconjugate (e.g., IMGN632) is administered three times in a three or four week cycle, for example, on days 1, 4, and 8, or on days 7, 10, and 14 of the cycle.

[0190] As provided herein, the BCL-2 inhibitor may be administered at a particular dose and / or at a particular time interval. Administration of the BCL-2 inhibitor (e.g., venetoclax) may be, for example, oral (e.g., in tablet form).

[0191] In certain embodiments, the BCL-2 inhibitor (e.g., venetoclax) is administered at a daily dose of 400 mg. In certain embodiments, the BCL-2 inhibitor (e.g., venetoclax) is administered at a daily dose of 200 mg.

[0192] In certain embodiments, the BCL-2 inhibitor (e.g., venetoclax) is administered in a 21-day cycle. The BCL-2 inhibitor (e.g., venetoclax) can be administered, for example, on days 1-7, 1-8, 1-14, 1-18, or 1-21 of a 21-day cycle. In certain embodiments, the BCL-2 inhibitor (e.g., venetoclax) is administered in a 28-day cycle. The BCL-2 inhibitor (e.g., venetoclax) can be administered, for example, on days 1-7, 1-8, 1-14, 1-18, 1-21, or 1-28 of a 28-day cycle.

[0193] In certain embodiments, for example, in the first cycle, the BCL-2 inhibitor (e.g., venetoclax) is administered orally (PO) at 100 mg on day 1, 200 mg on day 2, and 400 mg on all subsequent days of the cycle, e.g., days 3-21 of a 21 day cycle or days 3-28 of a 28 day cycle.

[0194] In certain embodiments, for example, in the first cycle, the BCL-2 inhibitor (e.g., venetoclax) is administered orally (PO) at 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-18 of a 21-day or 28-day cycle. In certain embodiments, for example, in the first cycle, the BCL-2 inhibitor (e.g., venetoclax) is administered orally (PO) at 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-14 of a 21-day or 28-day cycle. In certain embodiments, for example, in the first cycle, the BCL-2 inhibitor (e.g., venetoclax) is administered orally (PO) at 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-8 of a 21-day or 28-day cycle. In certain embodiments, for example, in the first cycle, the BCL-2 inhibitor (e.g., venetoclax) is administered orally (PO) at 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-7 of a 21-day or 28-day cycle.

[0195] In certain embodiments, e.g., in the first cycle, the BCL-2 inhibitor (e.g., venetoclax) is administered orally (PO) at 100 mg on day 1 and 200 mg on all subsequent days of the cycle, e.g., days 2-21 of a 21-day cycle or days 2-28 of a 28-day cycle. In certain embodiments, e.g., in the first cycle, the BCL-2 inhibitor (e.g., venetoclax) is administered orally (PO) at 100 mg on day 1 and 200 mg on days 2-18 of a 21-day cycle or a 28-day cycle. In certain embodiments, e.g., in the first cycle, the BCL-2 inhibitor (e.g., venetoclax) is administered orally (PO) at 100 mg on day 1 and 200 mg on days 2-18 of a 21-day cycle or a 28-day cycle. In certain embodiments, e.g., in the first cycle, the BCL-2 inhibitor (e.g., venetoclax) is administered orally (PO) at 100 mg on day 1 and 200 mg on days 2-8 of a 21 day or 28 day cycle. In certain embodiments, e.g., in the first cycle, the BCL-2 inhibitor (e.g., venetoclax) is administered orally (PO) at 100 mg on day 1 and 200 mg on days 2-7 of a 21 day or 28 day cycle.

[0196] In certain embodiments, administration of the anti-CD123 immunoconjugate (e.g., IMGN632) begins on day 7 after the seventh BCL-2 inhibitor (e.g., venetoclax) dose.

[0197] The cycle of administration (eg, a 21-day cycle or a 28-day cycle) of the anti-CD123 immunoconjugate and the BCL-2 inhibitor (eg, venetoclax) can be repeated, for example, for 2 to 12 cycles.

[0198] In certain embodiments, the BCL-2 inhibitor (e.g., venetoclax) is administered daily. In certain embodiments, the BCL-2 inhibitor (e.g., venetoclax) is administered orally. In certain embodiments, the BCL-2 inhibitor (e.g., venetoclax) is administered orally daily.

[0199] In certain embodiments, 400 mg of the BCL-2 inhibitor (e.g., venetoclax) is administered daily. In certain embodiments, 400 mg of the BCL-2 inhibitor (e.g., venetoclax) is administered orally. In certain embodiments, 400 mg of the BCL-2 inhibitor (e.g., venetoclax) is administered orally daily.

[0200] Following administration of an anti-CD123 immunoconjugate and a BCL-2 inhibitor (e.g., venetoclax), an anti-CD123 immunoconjugate (e.g., IMGN632) can be administered as maintenance therapy.

[0201] As provided herein, the HMA may be administered at a particular dose and / or at a particular time interval. Administration of the HMA (e.g., azacitidine or decitabine) may be, for example, subcutaneous or intravenous.

[0202] In certain embodiments, azacitidine is administered at 75 mg / m 2 In certain embodiments, azacitidine may be administered subcutaneously (SC) or intravenously (IV) at 75 mg / m daily for seven consecutive days. 2 In certain embodiments, azacitidine is administered at 75 mg / m daily for 7 consecutive days in a 28-day cycle. 2 In certain embodiments, azacitidine may be administered subcutaneously (SC) or intravenously (IV) at 75 mg / m daily for five consecutive days. 2 In certain embodiments, azacitidine is administered at 75 mg / m daily for 5 consecutive days in a 28-day cycle. 2 The drug may be administered subcutaneously (SC) or intravenously (IV).

[0203] In certain embodiments, the HMA (e.g., azacitidine) is administered at 75 mg / m 2 In certain embodiments, the HMA (e.g., azacitidine) is administered at a dose of 100 mg / m 2 is administered at a dose of

[0204] In certain embodiments, the HMA (e.g., azacitidine) is administered daily for 7 days every 4 weeks. In certain embodiments, the HMA (e.g., azacitidine) is administered daily for 5 days every 4 weeks.

[0205] In certain embodiments, 75 mg / m 2 HMAs (e.g., azacitidine) were administered for 4 weeks. In certain embodiments, the dose is 100 mg / m 2 of HMA (e.g., azacitidine) is administered daily for 7 days every 4 weeks. In certain embodiments, 75 mg / m 2 of HMA (e.g., azacitidine) is administered daily for 5 days every 4 weeks. In certain embodiments, 100 mg / m 2 of HMA (e.g., azacitidine) is administered daily for 5 days every 4 weeks.

[0206] In certain embodiments, 75 mg / m 2 of HMA (e.g., azacitidine) is administered subcutaneously or intravenously daily for 7 days every 4 weeks. In certain embodiments, 100 mg / m 2 of HMA (e.g., azacitidine) is administered subcutaneously or intravenously daily for 7 days every 4 weeks. In certain embodiments, 75 mg / m 2 of HMA (e.g., azacitidine) is administered subcutaneously or intravenously daily for 5 days every 4 weeks. In certain embodiments, 100 mg / m 2 of HMA (e.g., azacitidine) is administered subcutaneously or intravenously daily for 5 days every 4 weeks.

[0207] Following administration of the anti-CD123 immunoconjugate and HMA (eg, azacytidine), the anti-CD123 immunoconjugate (eg, IMGN632) can be administered as maintenance therapy.

[0208] In certain embodiments, the HMA (e.g., decitabine) is administered at a dose of 15 mg / m 2In certain embodiments, the HMA (e.g., decitabine) is administered at a dose of 20 mg / m 2 is administered at a dose of

[0209] In certain embodiments, the HMA (e.g., decitabine) is administered by intravenous infusion over 3 hours, repeated every 8 hours for 3 days, and repeated every 6 weeks. In certain embodiments, the HMA (e.g., decitabine) is administered by intravenous infusion over 1 hour for 5 days, and repeated every 4 weeks.

[0210] In certain embodiments, 15 mg / m 2 of HMA (e.g., decitabine) is administered by intravenous infusion over 3 hours, repeated every 8 hours for 3 days, and repeated every 6 weeks. In certain embodiments, 20 mg / m 2 The HMA (eg, decitabine) is administered by intravenous infusion over 1 hour for 5 days, repeated every 4 weeks.

[0211] Following administration of the anti-CD123 immunoconjugate and an HMA (eg, decitabine), the anti-CD123 immunoconjugate (eg, IMGN632) can be administered as maintenance therapy.

[0212] In certain embodiments, 0.015 mg / kg to about 0.09 mg / kg (e.g., 0.015, 0.045, or 0.09 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every 3 or 4 weeks, and 400 mg of a BCL-2 inhibitor (e.g., venetoclax) is administered daily. In certain embodiments, 0.03 mg / kg of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every 3 or 4 weeks, and 400 mg of a BCL-2 inhibitor (e.g., venetoclax) is administered daily. In certain embodiments, 0.015 mg / kg to about 0.09 mg / kg (e.g., 0.015, 0.045, or 0.09 mg / kg) of anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 3 or 4 weeks, and 400 mg of a BCL-2 inhibitor (e.g., venetoclax) is administered orally daily. In certain embodiments, 0.03 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 3 or 4 weeks, and 400 mg of a BCL-2 inhibitor (e.g., venetoclax) is administered orally daily. The BCL-2 inhibitor (e.g., venetoclax) may be administered daily on days 1-7, 1-8, 1-14, 1-18, or 1-21 of a 21-day (3-week) cycle. BCL-2 inhibitors (e.g., venetoclax) are administered on days 1-7, 1-8, 1-14, 1-18, and 1-20 of a 28-day (4-week) cycle. It may be administered daily on day 21, or on days 1-28.

[0213] In certain embodiments, 0.015 mg / kg to about 0.135 mg / kg (e.g., 0.135 mg / kg) of anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every 3 or 4 weeks, and 400 mg of BCL-2 inhibitor (e.g., venetoclax) is administered daily. In certain embodiments, 0.03 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every 3 or 4 weeks, and 400 mg of BCL-2 inhibitor (e.g., venetoclax) is administered daily. In certain embodiments, 0.015 mg / kg to about 0.135 mg / kg (e.g., 0.135 mg / kg) of anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 3 or 4 weeks, and 400 mg of BCL-2 inhibitor (e.g., venetoclax) is administered orally daily. In certain embodiments, 0.03 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 3 or 4 weeks, and 400 mg of BCL-2 inhibitor (e.g., venetoclax) is administered orally daily. In certain embodiments, 0.03 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 3 or 4 weeks, and 400 mg of BCL-2 inhibitor (e.g., venetoclax) is administered orally daily. The BCL-2 inhibitor (e.g., venetoclax) can be administered daily on days 1-7, 1-8, 1-14, 1-18, or 1-21 of a 21-day (3-week) cycle. The BCL-2 inhibitor (e.g., venetoclax) can be administered daily on days 1-7, 1-8, 1-14, 1-18, 1-21, or 1-28 of a 28 day (4 week) cycle.

[0214] In certain embodiments, a total dose of 0.045 mg / kg to about 0.18 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered over the course of a three week cycle, this total dose being split into three separate administrations (e.g., on days 1, 4, and 8, or on days 7, 10, and 14 of the cycle), and the BCL-2 inhibitor (e.g., venetoclax) is administered daily. Thus, in certain embodiments, about 0.015 mg / kg to about 0.06 mg / kg (e.g., 0.015, 0.03, or 0.06 mg / kg) of anti-CD123 immunoconjugate (e.g., IMGN632) is administered three times in a 21 day cycle (e.g., on days 7, 10, and 14 of a 21 day cycle), and the BCL-2 inhibitor (e.g., venetoclax) is administered daily. In certain embodiments, about 0.015 mg / kg to about 0.06 mg / kg (e.g., 0.015, 0.03, or 0.06 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously three times in a 21 day cycle (e.g., days 7, 10, and 14 of a 21 day cycle) and a BCL-2 inhibitor (e.g., venetoclax) is administered orally daily. The BCL-2 inhibitor (e.g., venetoclax) can be administered at doses of 100 mg, 200 mg, and / or 400 mg. The BCL-2 inhibitor (e.g., venetoclax) can be administered at doses of 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3 through 21 of a 21 day cycle (e.g., the first 21 day cycle). The BCL-2 inhibitor (e.g., venetoclax) can be administered at a dose of 100 mg on day 1 of a 21 day cycle (e.g., the first 21 day cycle) and 200 mg on days 2-21. The BCL-2 inhibitor (e.g., venetoclax) can be administered as an oral daily dose of 400 mg on all days (e.g., days 1-21) of a 21 day cycle. The BCL-2 inhibitor (e.g., venetoclax) can be administered as an oral daily dose of 200 mg on all days (e.g., days 1-21) of a 21 day cycle.

[0215] In certain embodiments, 0.015 mg / kg to about 0.09 mg / kg (e.g., 0.015, 0.045, or 0.09 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every 4 weeks, with 75 mg / m 2 or 100 mg / m 2 A HMA (e.g., azacitidine) is administered daily for 7 days every 4 weeks. In one embodiment, 0.03 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every 4 weeks, and 75 mg / m 2 or 100 mg / m 2 of HMA (e.g., azacytidine) is administered daily for 7 days every 4 weeks. In certain embodiments, 0.015 mg / kg to about 0.09 mg / kg (e.g., 0.015, 0.045, or 0.09 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 4 weeks, and 75 mg / m 2 or 100 mg / m 2 of HMA (e.g., azacytidine) is administered subcutaneously or intravenously daily for 7 days every 4 weeks. In certain embodiments, 0.03 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 4 weeks and 75 mg / m 2 or 100 mg / m 2 of HMA (e.g., azacitidine) administered subcutaneously or intravenously daily for 7 days every 4 weeks.

[0216] In certain embodiments, 0.015 mg / kg to about 0.09 mg / kg (e.g., 0.015, 0.045, or 0.09 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every 4 weeks, with 75 mg / m 2 or 100 mg / m 2 of HMA (e.g., azacytidine) is administered daily for 5 days every 4 weeks. In certain embodiments, 0.03 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every 4 weeks and 75 mg / m 2 or 100 mg / m 2of HMA (e.g., azacytidine) is administered daily for 5 days every 4 weeks. In certain embodiments, 0.015 mg / kg to about 0.09 mg / kg (e.g., 0.015, 0.045, or 0.09 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 4 weeks, and 75 mg / m 2 or 100 mg / m 2 of HMA (e.g., azacytidine) is administered subcutaneously or intravenously daily for 5 days every 4 weeks. In certain embodiments, 0.03 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 4 weeks and 75 mg / m 2 or 100 mg / m 2 of HMA (e.g., azacitidine) administered subcutaneously or intravenously daily for 5 days every 4 weeks.

[0217] In certain embodiments, 0.015 mg / kg to about 0.135 mg / kg (e.g., 0.135 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every 4 weeks, and 75 mg / m 2 or 100 mg / m 2 of HMA (e.g., azacytidine) is administered daily for 7 days every 4 weeks. In certain embodiments, 0.015 mg / kg to about 0.135 mg / kg (e.g., 0.135 mg / kg) of anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 4 weeks, and 75 mg / m 2 or 100 mg / m 2 of HMA (e.g., azacitidine) administered subcutaneously or intravenously daily for 7 days every 4 weeks.

[0218] In certain embodiments, 0.015 mg / kg to about 0.135 mg / kg (e.g., 0.135 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every 4 weeks, and 75 mg / m 2 or 100 mg / m 2of HMA (e.g., azacytidine) is administered daily for 5 days every 4 weeks. In certain embodiments, 0.015 mg / kg to about 0.135 mg / kg (e.g., 0.135 mg / kg) of anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 4 weeks, and 75 mg / m 2 or 100 mg / m 2 of HMA (e.g., azacitidine) administered subcutaneously or intravenously daily for 5 days every 4 weeks.

[0219] In certain embodiments, a total dose of 0.045 mg / kg to about 0.18 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered over the course of a four week cycle, with this total dose divided into three separate administrations (e.g., on days 1, 4, and 8, or days 7, 10, and 14 of the cycle), totaling 75 mg / m 2 or 100 mg / m 2 of HMA (e.g., azacitidine) is administered daily for 7 days every 4 weeks. In certain embodiments, about 0.015 mg / kg to about 0.06 mg / kg (e.g., 0.015, 0.03, or 0.06 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) administered three times in a 21-day cycle (e.g., on days 7, 10, and 14 of a 28-day cycle) and 75 mg / m 2 or 100 mg / m 2 of HMA (e.g., azacytidine) is administered daily for 7 days every 4 weeks. In certain embodiments, about 0.015 mg / kg to about 0.06 mg / kg (e.g., 0.015, 0.03, or 0.06 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously three times in a 28 day cycle (e.g., on days 7, 10, and 14 of a 28 day cycle) and 75 mg / m 2 or 100 mg / m 2 of HMA (e.g., azacitidine) administered subcutaneously or intravenously daily for 7 days every 4 weeks.

[0220] In certain embodiments, about 0.015 mg / kg to about 0.09 mg / kg (e.g., 0.015, 0.045, or 0.09 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every three weeks, and 15 mg / m 2 of HMA (e.g., decitabine) is administered over 3 hours and repeated every 8 hours for 3 days, repeated every 6 weeks. In certain embodiments, about 0.03 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every 3 weeks and 15 mg / m 2 of HMA (e.g., decitabine) is administered over 3 hours and repeated every 8 hours for 3 days, repeated every 6 weeks. In certain embodiments, about 0.015 mg / kg to about 0.09 mg / kg (e.g., 0.015, 0.045, or 0.09 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 3 weeks and 15 mg / m 2 of HMA (e.g., decitabine) is administered by intravenous infusion over 3 hours, repeated every 8 hours for 3 days, and repeated every 6 weeks. In certain embodiments, about 0.03 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 3 weeks, and 15 mg / m 2 of HMA (e.g., decitabine) is administered by intravenous infusion over 3 hours, repeated every 8 hours for 3 days, and repeated every 6 weeks.

[0221] In certain embodiments, about 0.015 mg / kg to about 0.135 mg / kg (e.g., 0.135 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every three weeks, and 15 mg / m 2 of HMA (e.g., decitabine) is administered over 3 hours and repeated every 8 hours for 3 days, repeated every 6 weeks. In certain embodiments, 0.015 mg / kg to about 0.135 mg / kg (e.g., 0.135 mg / kg) of anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 3 weeks and 15 mg / m 2of HMA (e.g., decitabine) is administered by intravenous infusion over 3 hours, repeated every 8 hours for 3 days, and repeated every 6 weeks.

[0222] In certain embodiments, a total dose of 0.045 mg / kg to about 0.18 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered over the course of a four week cycle, with this total dose divided into three separate administrations (e.g., on days 1, 4, and 8, or days 7, 10, and 14 of the cycle), totaling 15 mg / m 2 of HMA (e.g., decitabine) is administered over 3 hours and repeated every 8 hours for 3 days, and repeated every 6 weeks. In certain embodiments, about 0.015 mg / kg to about 0.09 mg / kg (e.g., 0.015, 0.03, or 0.06 mg / kg) of anti-CD123 immunoconjugate (e.g., IMGN632) is administered three times in a 21 day cycle (e.g., on days 7, 10, and 14 of a 21 day cycle) and 15 mg / m 2 of HMA (e.g., decitabine) is administered over 3 hours and repeated every 8 hours for 3 days, and repeated every 6 weeks. In certain embodiments, about 0.015 mg / kg to about 0.135 mg / kg (e.g., 0.135 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered three times in a 21 day cycle (e.g., on days 7, 10, and 14 of a 21 day cycle) and 15 mg / m 2 of HMA (e.g., decitabine) is administered over a 3 hour period, repeated every 8 hours for 3 days, and repeated every 6 weeks. In certain embodiments, 0.015 mg / kg to about 0.06 mg / kg (e.g., 0.015, 0.045, or 0.09 mg / kg) of anti-CD123 immunoconjugate (e.g., IMGN632) administered three times in a 21-day cycle (e.g., on days 7, 10, and 14 of a 21-day cycle) at 15 mg / m 2 of HMA (e.g., decitabine) is administered by intravenous infusion over 3 hours, repeated every 8 hours for 3 days, and repeated every 6 weeks.

[0223] In certain embodiments, about 0.015 mg / kg to about 0.09 mg / kg (e.g., 0.015, 0.045, or 0.09 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every four weeks, and 20 mg / m 2 of HMA (e.g., decitabine) is administered over 1 hour for 5 days and repeated every 4 weeks. In certain embodiments, about 0.03 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every 4 weeks and 20 mg / m 2 of HMA (e.g., decitabine) is administered over 1 hour for 5 days, repeated every 4 weeks. In certain embodiments, about 0.015 mg / kg to about 0.09 mg / kg (e.g., 0.015, 0.045, or 0.09 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 4 weeks, and 20 mg / m 2 of HMA (e.g., decitabine) is administered by intravenous infusion over 1 hour for 5 days, repeated every 4 weeks. In certain embodiments, about 0.03 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 4 weeks, and 20 mg / m 2 of HMA (eg, decitabine) is administered by intravenous infusion over 1 hour for 5 days, repeated every 4 weeks.

[0224] In certain embodiments, about 0.015 mg / kg to about 0.135 mg / kg (e.g., 0.135 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every four weeks, and 20 mg / m 2 of HMA (e.g., decitabine) is administered over 1 hour for 5 days, repeated every 4 weeks. In certain embodiments, about 0.015 mg / kg to about 0.135 mg / kg (e.g., 0.135 mg / kg) of anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 4 weeks, and 20 mg / m 2 of HMA (eg, decitabine) is administered by intravenous infusion over 1 hour for 5 days, repeated every 4 weeks.

[0225] In certain embodiments, a total dose of 0.045 mg / kg to about 0.18 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered over the course of a four week cycle, this total dose being divided into three separate administrations (e.g., on days 1, 4, and 8, or days 7, 10, and 14 of the cycle) totaling 20 mg / m 2 of HMA (e.g., decitabine) is administered over 1 hour for 5 days, repeated every 4 weeks. In certain embodiments, about 0.015 mg / kg to about 0.06 mg / kg (e.g., 0.015, 0.03, or 0.06 mg / kg) of anti-CD123 immunoconjugate (e.g., IMGN632) is administered three times in a 28 day cycle (e.g., on days 7, 10, and 14 of a 21 day cycle) and 20 mg / m 2 of HMA (e.g., decitabine) is administered over 1 hour for 5 days, repeated every 4 weeks. In certain embodiments, about 0.015 mg / kg to about 0.06 mg / kg (e.g., 0.015, 0.03, or 0.06 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously three times in a 28 day cycle (e.g., on days 7, 10, and 14 of a 21 day cycle) and 20 mg / m 2 of HMA (eg, decitabine) is administered by intravenous infusion over 1 hour for 5 days, repeated every 4 weeks.

[0226] In certain embodiments, 0.015 mg / kg to about 0.09 mg / kg (e.g., 0.015, 0.045, or 0.09 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every four weeks, and 100, 200, and / or 400 mg of a BCL-2 inhibitor (e.g., venetoclax) is administered daily (e.g., in Cycle 1). 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-28, then 400 mg daily on days 1-28 of each cycle), 75 mg / m 2 or 100 mg / m 2of an HMA (e.g., azacitidine) administered daily (e.g., days 1-7). In certain embodiments, 0.03 mg / kg of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every 4 weeks, 100, 200, and / or 400 mg of a BCL-2 inhibitor (e.g., venetoclax) is administered daily (e.g., 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-28 of cycle 1, then 400 mg daily on days 1-28 of subsequent cycles), and 75 mg / m 2 or 100 mg / m 2 of an HMA (e.g., azacitidine) is administered daily (e.g., on days 1-7). In certain embodiments, 0.015 mg / kg to about 0.09 mg / kg (e.g., 0.015, 0.045, or 0.09 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 4 weeks, 100, 200, and / or 400 mg of a BCL-2 inhibitor (e.g., venetoclax) is administered orally daily (e.g., 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-28 of cycle 1, then 400 mg daily on days 1-28 of subsequent cycles), and 75 mg / m 2 or 100 mg / m 2 of HMA (e.g., azacitidine) administered subcutaneously or intravenously daily for 7 days (e.g., days 1-7). In certain embodiments, 0.03 mg / kg of anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 4 weeks, 100, 200, and / or 400 mg of a BCL-2 inhibitor (e.g., venetoclax) is administered orally daily (e.g., 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-28 of cycle 1, then 400 mg daily on days 1-28 of subsequent cycles), and 75 mg / m 2 or 100 mg / m 2 Administer one HMA (e.g., azacytidine) subcutaneously or intravenously daily (e.g., on days 1-7) for 7 days.

[0227] In certain embodiments, 0.015 mg / kg to about 0.09 mg / kg (e.g., 0.015, 0.03, 0.045, or 0.09 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every 4 weeks; 100, 200, and / or 400 mg of a BCL-2 inhibitor (e.g., venetoclax) is administered daily (e.g., 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-7, 3-8, 3-14, 3-18, or 3-21, or 3-28 of cycle 1, and 400 mg daily on days 1-7, 1-8, 1-14, 1-18, 1-21, or 1-28 of subsequent cycles); and 75 mg / m 2 or 100 mg / m 2 Administer one or more of an HMA (e.g., azacitidine) daily (e.g., on days 1-5 or 1-7). In certain embodiments, 0.015 mg / kg to about 0.09 mg / kg (e.g., 0.015, 0.03, 0.045, or 0.09 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 4 weeks; 100, 200, and / or 400 mg of a BCL-2 inhibitor (e.g., venetoclax) is administered orally daily (e.g., 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-7, 3-8, 3-14, 3-18, or 3-21, or 3-28 of cycle 1, and 400 mg daily on days 1-7, 1-8, 1-14, 1-18, 1-21, or 1-28 of subsequent cycles); and 75 mg / m 2 or 100 mg / m 2 of HMA (e.g., azacitidine) is administered subcutaneously or intravenously daily (e.g., on days 1-5 or 1-7) for 7 days.

[0228] In certain embodiments, 0.015 mg / kg to about 0.135 mg / kg (e.g., 0.135 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered once every 4 weeks, 100, 200, and / or 400 mg of a BCL-2 inhibitor (e.g., venetoclax) is administered daily (e.g., 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-28 of cycle 1, then 400 mg daily on days 1-28 of each cycle), and 75 mg / m 2 or 100 mg / m 2 HMAs (e.g., azacitidine In certain embodiments, 0.015 mg / kg to about 0.135 mg / kg (e.g., 0.135 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously once every 4 weeks, 100, 200, and / or 400 mg of a BCL-2 inhibitor (e.g., venetoclax) is administered orally daily (e.g., 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-28 of cycle 1, then 400 mg daily on days 1-28 of each cycle thereafter), and 75 mg / m 2 or 100 mg / m 2 Administer one HMA (e.g., azacytidine) subcutaneously or intravenously daily (e.g., on days 1-7) for 7 days.

[0229] In certain embodiments, a total dose of 0.045 mg / kg to about 0.18 mg / kg of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered over the course of a four week cycle, this total dose being split into three separate administrations (e.g., on days 1, 4, and 8, or on days 7, 10, and 14 of the cycle), 100, 200, and / or 400 mg of a BCL-2 inhibitor (e.g., venetoclax) is administered daily (e.g., 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-28 of cycle 1, followed by 400 mg on days 1-28 of subsequent cycles), and 75 mg / m 2 or 100 mg / m 2of an HMA (e.g., azacitidine) is administered daily for 7 days (e.g., on days 1-7). In certain embodiments, about 0.015 mg / kg to about 0.06 mg / kg (e.g., 0.015, 0.03, or 0.06 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered three times in a 28 day cycle (e.g., on days 7, 10, and 14 of a 28 day cycle), 100, 200, and / or 400 mg of a BCL-2 inhibitor (e.g., venetoclax) is administered daily (e.g., 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-28 of cycle 1, and 400 mg daily on days 1-28 of subsequent cycles), and 75 mg / m 2 or 100 mg / m 2 of an HMA (e.g., azacitidine) is administered daily for 7 days (e.g., on days 1-7). In certain embodiments, about 0.015 mg / kg to about 0.06 mg / kg (e.g., 0.015, 0.03, or 0.06 mg / kg) of an anti-CD123 immunoconjugate (e.g., IMGN632) is administered intravenously three times in a 28 day cycle (e.g., on days 7, 10, and 14 of a 28 day cycle), 100, 200, and / or 400 mg of a BCL-2 inhibitor (e.g., venetoclax) is administered orally daily (e.g., 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-28 of cycle 1, and 400 mg daily on days 1-28 of subsequent cycles), and 75 mg / m 2 or 100 mg / m 2 Administer one HMA (e.g., azacytidine) subcutaneously or intravenously daily (e.g., on days 1-7) for 7 days.

[0230] Following administration of the anti-CD123 immunoconjugate, a BCL-2 inhibitor, and an HMA (eg, azacitidine or decitabine), the anti-CD123 immunoconjugate (eg, IMGN632) can be administered as maintenance therapy.

[0231] In one case, the immunoconjugate that binds CD123 (e.g., IMGN632) and the BCL-2 inhibitor are administered simultaneously. In one case, the anti-CD123 immunoconjugate (e.g., IMGN632) and the BCL-2 inhibitor are administered in separate pharmaceutical compositions. In one case, the anti-CD123 immunoconjugate (e.g., IMGN632) and the BCL-2 inhibitor are administered sequentially. In one case, the BCL-2 inhibitor is administered over a period of time, after which both the BCL-2 inhibitor and the anti-CD123 immunoconjugate (e.g., IMGN632) are administered (either simultaneously or sequentially). In such cases, the HMA can optionally be administered simultaneously (in the same pharmaceutical composition or separate pharmaceutical compositions) or sequentially with the anti-CD123 immunoconjugate (e.g., IMGN632) or the BCL-2 inhibitor.

[0232] In one example, the immunoconjugate that binds CD123 (e.g., IMGN632) and the HMA are administered simultaneously. ) and the HMA are administered in the same pharmaceutical composition. In one case, the anti-CD123 immunoconjugate (e.g., IMGN632) and the HMA are administered in separate pharmaceutical compositions. In one case, the anti-CD123 immunoconjugate (e.g., IMGN632) and the HMA are administered sequentially. In one case, the HMA is administered over a period of time, after which both the HMA and the anti-CD123 immunoconjugate (e.g., IMGN632) are administered (either simultaneously or sequentially). In such cases, the BCL-2 inhibitor can optionally be administered simultaneously or sequentially with the anti-CD123 immunoconjugate (e.g., IMGN632) or the HMA.

[0233] VI(C) Evaluation and Monitoring In certain embodiments, the combination of anti-CD123 immunoconjugates (e.g., IMGN632) and BCL-2 inhibitors and / or HMAs is useful for inhibiting tumor growth. In certain embodiments, the combination of anti-CD123 immunoconjugates (e.g., IMGN632) and BCL-2 inhibitors and / or HMAs is useful for reducing tumor volume. In certain embodiments, the combination of anti-CD123 immunoconjugates (e.g., IMGN632) and BCL-2 inhibitors and / or HMAs is useful for increasing survival rates.

[0234] For example, in some embodiments, treatment with a combination of an anti-CD123 immunoconjugate (e.g., IMGN632) and a BCL-2 inhibitor and / or HMA results in a %T / C value that is less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5%.

[0235] In certain embodiments, the combination of an anti-CD123 immunoconjugate (e.g., IMGN632) and a BCL-2 inhibitor and / or an HMA can inhibit tumor growth in an EOL-1 subcutaneous xenograft model. In certain embodiments, the combination of an anti-CD123 immunoconjugate (e.g., IMGN632) and a BCL-2 inhibitor and / or an HMA can inhibit tumor growth in a KG-1 subcutaneous xenograft model.

[0236] In certain embodiments, the combination of an anti-CD123 immunoconjugate (e.g., IMGN632) and a BCL-2 inhibitor and / or HMA can increase survival in a MOLM-1 disseminated xenograft model. In certain embodiments, the combination of an anti-CD123 immunoconjugate (e.g., IMGN632) and a BCL-2 inhibitor and / or HMA can increase survival in a MV4-11 disseminated xenograft model.

[0237] In certain embodiments, the combination of an anti-CD123 immunoconjugate (eg, IMGN632) and a BCL-2 inhibitor and / or HMA produces a synergistic effect.

[0238] In certain embodiments, administration of a combination of an anti-CD123 immunoconjugate (e.g., IMGN632) and a BCL-2 inhibitor and / or HMA does not result in more toxicity than administration of a BCL-2 inhibitor and / or HMA. In some embodiments, administration of a combination of an anti-CD123 immunoconjugate (e.g., IMGN632) and a BCL-2 inhibitor and / or HMA does not result in more toxicity than administration of an anti-CD123 immunoconjugate. In some embodiments, administration of a combination of an anti-CD123 immunoconjugate (e.g., IMGN632) and a BCL-2 inhibitor and / or HMA does not result in more toxicity than administration of either an anti-CD123 immunoconjugate or a BCL-2 inhibitor and / or HMA.

[0239] VI(D).Additional therapy In some embodiments, a BCL-2 inhibitor disclosed herein (e.g., venetoclax) and / or a hypomethylating agent (HMA) (e.g., azacitidine or decitabine) are used. The patient receiving the anti-CD123 immunoconjugate in combination with the anti-CD123 immunoconjugate was pretreated with a corticosteroid. Thus, in some embodiments, the methods provided herein include administering a corticosteroid to the patient prior to administering the anti-CD123 immunoconjugate to the patient. In certain cases, the corticosteroid may be selected from the group consisting of prednisone, prednisolone, methylprednisolone, beclamethasone, betamethasone, dexamethasone, fludrocortisone, hydrocortisone, and triamcinolone. In certain cases, the corticosteroid is administered intravenously. In certain cases, the steroid is administered orally.

[0240] For example, in some embodiments, a patient receiving an anti-CD123 immunoconjugate in combination with a BCL-2 inhibitor (e.g., venetoclax) and / or a hypomethylating agent (HMA) (e.g., azacitidine or decitabine) disclosed herein was pretreated with diphenhydramine. In some embodiments, a patient receiving an anti-CD123 immunoconjugate in combination with a BCL-2 inhibitor (e.g., venetoclax) and / or a hypomethylating agent (HMA) (e.g., azacitidine or decitabine) disclosed herein was pretreated with 25-50 mg of diphenhydramine. In some embodiments, the diphenhydramine is administered intravenously. In some embodiments, the diphenhydramine is administered orally. Thus, in some embodiments, the methods provided herein include administering diphenhydramine to the patient prior to administering the anti-CD123 immunoconjugate to the patient.

[0241] In some embodiments, a patient receiving an anti-CD123 immunoconjugate in combination with a BCL-2 inhibitor (e.g., venetoclax) and / or a hypomethylating agent (HMA) (e.g., azacitidine or decitabine) disclosed herein has been pretreated with acetaminophen. In some embodiments, a patient receiving an anti-CD123 immunoconjugate in combination with a BCL-2 inhibitor (e.g., venetoclax) and / or a hypomethylating agent (HMA) (e.g., azacitidine or decitabine) disclosed herein has been pretreated with 325-650 mg of acetaminophen. In some embodiments, the acetaminophen is administered intravenously. In some embodiments, the acetaminophen is administered orally. Thus, in some embodiments, the methods provided herein include administering acetaminophen to the patient prior to administering the anti-CD123 immunoconjugate to the patient.

[0242] In some embodiments, a patient receiving an anti-CD123 immunoconjugate in combination with a BCL-2 inhibitor (e.g., venetoclax) and / or a hypomethylating agent (HMA) (e.g., azacitidine or decitabine) disclosed herein has been pretreated with paracetamol. In some embodiments, a patient receiving an anti-CD123 immunoconjugate in combination with a BCL-2 inhibitor (e.g., venetoclax) and / or a hypomethylating agent (HMA) (e.g., azacitidine or decitabine) disclosed herein has been pretreated with 325-650 mg of paracetamol. In some embodiments, paracetamol is administered intravenously. In some embodiments, paracetamol is administered orally. Thus, in some embodiments, the methods provided herein include administering paracetamol to the patient prior to administering the anti-CD123 immunoconjugate to the patient.

[0243] In some embodiments, patients receiving an anti-CD123 immunoconjugate in combination with a BCL-2 inhibitor disclosed herein (e.g., venetoclax) and / or a hypomethylating agent (HMA) (e.g., azacitidine or decitabine) have been pretreated with dexamethasone. In some embodiments, patients receiving an anti-CD123 immunoconjugate in combination with a BCL-2 inhibitor disclosed herein (e.g., venetoclax) and / or a hypomethylating agent (HMA) (e.g., azacitidine or decitabine) have been pretreated with 8 mg of dexamethasone. In some embodiments, the patient has been pretreated with dexamethasone. In some embodiments, the dexamethasone is administered intravenously. In some embodiments, the dexamethasone is administered orally. Thus, in some embodiments, the methods provided herein include administering dexamethasone to the patient prior to administering the anti-CD123 immunoconjugate to the patient.

[0244] Embodiments of the present disclosure can be further defined by reference to the following non-limiting examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of the disclosure. EXAMPLES

[0245] It is understood that the examples and embodiments described herein are set forth for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to those skilled in the art and are to be included within the spirit and scope of the present application.

[0246] Example 1 In vitro testing of IMGN632 in combination with venetoclax in AML cell lines The activity of IMGN632 alone, venetoclax alone, and the combination of IMGN632 and venetoclax was investigated in in vitro cytotoxicity assays in four different acute myeloid leukemia (AML) cell lines: EOL-1, KG-1, Molm-13, and MV4-11.

[0247] EOL-1, KG-1, Molm-13, and MV4-11 cell lines were obtained at low passages (less than 10 passages) and cell cultures were maintained according to their supplier's recommendations. Cells were collected from logarithmic growth phase cell cultures, counted by an automated hemocytometer, and evenly distributed into wells in a 96-well plate such that each well contained 5,000 viable cells per well. Each well contained an Fc receptor blocking, non-mammalian targeting chKTI monoclonal antibody such that the final well volume (200 μL) contained chKTI at 100 nM. Dose ranges of IMGN632 alone, venetoclax alone, and IMGN632 + venetoclax (with respective DMSO controls in the case of venetoclax) were then prepared in the appropriate medium for the cell line being assayed.

[0248] Dilutions were prepared and then added to the cells in the 96-well plates on the same day the cells were seeded. Cell and drug additions were made such that the final well volume was always 200 μL. Each treatment condition was prepared in triplicate for each assay run. Treated 96-well plates were kept in 90% humidity and 10% CO 2They were left in a dark 37°C incubator for 4 days (EOL-1, Molm-13; MV4-11) or 5 days (KG-1). On the 4th or 5th day, 20 μL of WST-8 was added to each well, and the 96-well plate was incubated in the incubator for 2 hours (EOL-1; Molm-13) to 7 hours (MV4-11; KG-1) for development. At the time of development, the plate was read with a spectrophotometer, and the reading was performed at an absorbance of 650 nm. Each dose-setting assay was performed once. Each combination assay was repeated 3 times (EOL-1, Molm-13, MV4-11) or 4 times (KG-1).

[0249] Two-step calculations were performed on the collected data. The average absorbance of the control with only medium was subtracted from each condition containing cells, and the background-corrected absorbance was indexed to the average background-corrected absorbance of their untreated control counterparts. These calculated values were plotted in GraphPad Prism as the mean and standard deviation of technical replicates across the execution of the bioreplicate assays. The same final calculated values entered into GraphPad were further processed for the evaluation of synergistic effects via CalcuSyn. The average "survival rate" from each condition was subtracted from 1 to obtain the average "inhibition rate" (Fa) from each condition. These F a values were entered into CalcuSyn along with the drug doses (NB: only values of 0 < x < 1 for the usable value "x"). Using the input values, both the combination index (CI) that measures the observed drug and the expected effect, and the normalized inhibition rate values used in the combination treatment isobologram were calculated.

[0250] The results of in vitro cytotoxicity assays of IMGN632 and venetoclax alone are shown in Figures 2A-2D. A broad dose range of IMGN632 (Figure 2A) and venetoclax (Figure 2B) doses were tested for efficacy against three AML cell lines (EOL-1, MV4-11, KG-1). Doses near the inflection points of these sensitivity curves were selected for use in the IMGN632 and venetoclax combination assays. A narrower range of IMGN632 (Figure 2C) and venetoclax (Figure 2D) doses were run as single agent controls for the combination studies, and these doses represent the dynamic range of drug efficacy. Figures 3A-3D show the results of the combination of IMGN632 and venetoclax evaluated in four AML cell lines: EOL-1 (Figure 3A), MV4-11 (Figure 3B), KG-1 (Figure 3C), and Molm-13 (Figure 3D). In each of the four AML cell lines evaluated, IMGN632 and venetoclax kill more cells in combination than IMGN632 alone in a dose-dependent manner. Figures 4A-4L show combination efficacy readouts for the combination of IMGN632 and venetoclax, comparing the observed combination results of Figures 3A-3D with the expected combination results based on the single agent treatment results of Figures 2C and 2D. Combination index values ​​and normalized relative efficacy values ​​were generated for each IMGN632 and venetoclax dose pairing. Results were plotted to show combination efficacy as a function of drug dose (Figures 4A, 4D, 4G, and 4J), combination efficacy as a function of treatment effect (Figures 4B, 4E, 4H, and 4K), and combination efficacy against expected dose effect on a normalized scale (Figures 4C, 4F, 4I, and 4L). Each row represents results from a single cell line: EOL-1 (Figures 4A-4C), MV4-11 (Figures 4D-4F), KG-1 (Figures 4G-4I), or Molm-13 (Figures 4J-4L).

[0251] Results from in vitro cytotoxicity assays of AML cell lines treated with IMGN632 and venetoclax demonstrate additive versus synergistic combined cytotoxic effects of the combination.

[0252] Example 2 Materials and methods used in subcutaneous and disseminated xenograft models For all subcutaneous xenograft models, mice were weighed twice weekly and monitored for clinical signs throughout the study. Animals were euthanized when hind leg paralysis was present, body weight loss was greater than 20% of pre-treatment weight, tumor ulceration occurred, or any signs of distress were observed.

[0253] Tumor volumes in subcutaneous xenograft models were measured in three dimensions using calipers once or twice a week. Tumor volumes were calculated in mm using the formula V = length × width × height × ½. 3 (Tomayko and Reynolds, Cancer Chemother. Pharmacol. 24:148-54 (1989)). Activity was assessed as described by Bissery et al. Cancer Res. 51:4845-52 (1991).

[0254] Tumor growth inhibition (T / C value) was evaluated in a subcutaneous xenograft model using the following formula: T / C (%) = (median treated tumor volume / median control tumor volume) × 100%. Tumor volumes were determined simultaneously for the treatment (T) and vehicle control (C) groups when the tumor volume of the vehicle control reached a predetermined size (Bissery et al. Cancer, Res. 51:4845-52 (1991)). Tumor-free mice (0 mm 3 The median daily tumor volume for each treatment group was determined, including the mean daily tumor volume for each treatment group. According to this standard, T / C≦42% is the minimum level of antitumor activity. T / C<10% is considered a high level of antitumor activity.

[0255] For all seeded xenograft models, mice were weighed twice weekly and monitored for clinical signs throughout the study. The endpoint measured was survival rate. Animals were euthanized when hind leg paralysis was present, when body weight was reduced by more than 20% of pre-treatment weight, when visible tumors appeared, or when any signs of distress were observed. Natural deaths were recorded when they were observed.

[0256] Tumor growth delay in the seeded xenograft model was calculated as TC, where T is the median survival time (days) of the treatment group and C is the median survival time (days) of the vehicle control group. Percentage increased life span (%ILS) in the seeded model was calculated using the following formula: %ILS=(TC) / C×100%. Antitumor activity was evaluated according to the NCI criteria in the seeded model: ILS<25% is inactive, ILS≧25% is minimally active, ILS>40% is active, and ILS≧50% is highly active.

[0257] Example 3 In vivo efficacy of the combination of IMGN632 (single dose) and venetoclax (QD×28) in the EOL-1 subcutaneous model To test the efficacy of IMGN632, venetoclax, or the combination of these two agents for their ability to reduce tumor burden in vivo, a subcutaneous tumor model was used, as described in the protocol below.

[0258] Female athymic nude mice were each administered 1 × 10 7 EOL-1 cells (human AML cell line) were inoculated subcutaneously into the right flank. On day 9, 24 hours prior to administration of the conjugate in the groups receiving the conjugate treatment (either alone or in combination with venetoclax), all mice in these treatment groups were injected intraperitoneally with 150 mg / kg of non-targeting chKTI antibody to block Fc receptors on EOL-1 AML cells and prevent non-specific uptake of the conjugate. On day 9 after EOL-1 inoculation, mice were randomized into study groups based on tumor volume.

[0259] On day 10 post-EOL-1 inoculation, mice received a single intravenous injection in the lateral tail vein of either vehicle, or IMGN632 at 1 μg / kg (with DGN549; 0.080 mg / kg with huCD123Ab), or IMGN632 at 0.5 μg / kg (with DGN549; 0.040 mg / kg with huCD123Ab). Venetoclax administration also began on day 10, and mice receiving venetoclax were given a single oral dose of 100 mg / kg venetoclax on each of days 10-37 for a total of 28 consecutive days, including after cell implantation. In the combination group, mice received both IMGN632 and venetoclax as outlined above.

[0260] The results are reported in Table 4 (below) and FIG.

[0261] A single dose of 1 μg / kg or 0.5 μg / kg of IMGN632 resulted in T / C values ​​of 10.7% (active) or 45.0% (inactive), respectively, and 2 / 6 or 0 / 6 long-term complete regressions (tumor-free survivors, TFS), respectively, at the end of the study (day 85).

[0262] A regimen of venetoclax 100 mg / kg once daily (QD) for 28 days (×28) was inactive, with a T / C of 69.1% and a TFS of 1 / 6 at day 85.

[0263] The combination of a single dose of IMGN632 at 1ug / kg with a QDx28 regimen of venetoclax was highly active, with a T / C of 0% and a TFS of 4 / 6 at day 85, which is 2 TFS more than that obtained with IMGN632 monotherapy, demonstrating the additional benefit of the combination treatment. The combination of a single dose of IMGN632 at 0.5ug / kg with a QDx28 regimen of venetoclax was active, with a T / C of 21.1% and a TFS of 1 / 6 at day 85, which is a lower %T / C value than that produced by either 0.5ug / kg IMGN632 alone (45%) or venetoclax alone (69.1%), indicating that the combination was able to slow tumor growth more than either of the corresponding monotherapies. [Table 4]

[0264] Example 4 In vivo efficacy of the combination of IMGN632 (QW×3) and venetoclax (QD×28) in the KG-1 subcutaneous model To test the efficacy of IMGN632, venetoclax, or the combination of these two agents for their ability to reduce tumor burden in vivo, a subcutaneous tumor model was used, as described in the protocol below.

[0265] Female C.B17 SCID mice were each administered 1 × 10 7 KG-1 cells (a relatively IMGN632-resistant human AML cell line) were inoculated subcutaneously into the right flank. On days 17, 24, and 31, 24 hours prior to each conjugate administration day for groups receiving conjugate treatment (either alone or in combination with venetoclax), all mice in these treatment groups were injected intraperitoneally with 150 mg / kg of non-targeting chKTI antibody to block Fc receptors on KG-1 AML cells and prevent non-specific uptake of the conjugate. On day 17 after KG-1 inoculation, mice were randomized into study groups based on tumor volume.

[0266] On days 18, 25, and 32 post-KG-1 inoculation, mice received a single intravenous injection in the lateral tail vein of either vehicle, 3 μg / kg (by DGN549; 0.24 mg / kg by huCD123Ab) IMGN632, or 10 μg / kg (by DGN549; 0.80 mg / kg by huCD123Ab) IMGN632. Venetoclax administration also began on day 18, and mice receiving venetoclax received a single oral dose of 100 mg / kg venetoclax each day for 28 consecutive days (days 18-45). In the combination group, mice received both IMGN632 and venetoclax as outlined above.

[0267] The results are reported in Table 5 (below) and FIG.

[0268] In this study, IMGN632 3 μg / kg QW×3 was inactive with a T / C of 78% and long-term complete regressions (tumor-free survivors, TFS) of 0 / 6 at the end of the study (day 56). Similarly, IMGN632 10 μg / kg QW×3 was inactive in this study with a T / C of 73% and a TFS of 0 / 6. Venetoclax 100 mg / kg once daily (QD) for 28 days (×28) was also inactive with a T / C of 82% and a TFS of 0 / 6.

[0269] The combination of IMGN632 at 3 μg / kg, QW×3, and venetoclax QD×28 regimen was also inactive, with a T / C of 76% and a TFS of 0 / 6. However, the combination of IMGN632 at 10 μg / kg, QW×3, and venetoclax QD×28 regimen was also active, with a T / C of 40% and a TFS of 0 / 6. These results demonstrate that combination treatment is effective even when either agent alone is inactive. [Table 5]

[0270] In conclusion, the combination of IMGN632 and venetoclax demonstrated synergistic cytotoxicity in vitro, greater tumor growth inhibition, and extended survival in vivo.

[0271] Example 5 In vivo efficacy of the combination of IMGN632 (QW×3) and Azacitidine (QD×5) in the Molm-13 disseminated model To test the efficacy of IMGN632, azacytidine, or the combination of these two agents for their ability to reduce tumor burden in vivo, a disseminated tumor model was used, as described in the protocol below.

[0272] Female NOD SCID mice were pretreated with 150 mg / kg cyclophosphamide to partially ablate the bone marrow and improve Molm-13 cell engraftment. Cyclophosphamide (Sigma, C0768, lot no. MKBX1822V) was dissolved in 0.9% NaCl and administered intraperitoneally to mice 2 days prior to Molm-13 cell inoculation on day 0.

[0273] After cyclophosphamide treatment as described above, 2 × 10 5 Molm-13 cells (human AML cell line) were intravenously injected into the lateral tail vein of each mouse. Six days after Molm inoculation, mice were randomized into study groups based on body weight. 24 hours prior to each conjugate administration, for all groups receiving conjugate treatment (either alone or in combination with azacytidine), mice were injected intraperitoneally with 150 mg / kg of non-targeting chKTI antibody to block Fc receptors on Molm-13 AML cells and prevent non-specific uptake of the conjugate.

[0274] Mice received IMGN632 at a dose of 0.3 μg / kg with DGN549 (0.024 mg / kg with huCD123Ab) once a week (QW) for three doses (×3) alone or in combination with azacitidine according to three different IMGN632 dosing schedules: i) days 7, 14, and 21 (referred to as "day 7" for IMGN632), ii) days 11, 18, and 25 (referred to as "day 11" for IMGN632), and iii) days 14, 21, and 28 (referred to as "day 14" for IMGN632), where the start date of IMGN632 treatment as described was progressively moved away from day 0 (the day of Molm-13 inoculation) of the study timeline.

[0275] Azacitidine was administered at a dose of 3.5 mg / kg once daily (QD) for 5 consecutive days (×5; days 7, 8, 9, 10, and 11; "day 7" schedule), alone or in combination with IMGN632.

[0276] Mice were treated with a combination regimen of IMGN632 (QW×3) and 3.5 mg / kg azacitidine (QD×5) according to one of three different dosing schedules for combining the two drugs: i) a 7-day schedule of IMGN632 and a 7-day schedule of azacitidine (Group F), ii) an 11-day schedule of IMGN632 and a 7-day schedule of azacitidine (Group G), and iii) a 14-day schedule of IMGN632 and a 7-day schedule of azacitidine (Group H).

[0277] The results are shown in Table 6 (below) and FIG.

[0278] Single-agent azacitidine administered at 3.5 mg / kg QD×5 according to a 7-day schedule (Group B) was the least active in this study, resulting in a 6-day tumor growth delay (TC value) and an ILS of 30% (increased life span) compared to vehicle treatment. Three different treatment schedules of single-agent IMGN632 were either highly active ("Day 7" or "Day 11") or minimally active ("Day 14") in this study, resulting in the following TC values ​​and %ILS: i) IMGN632 7-day schedule (Group C) had a TC of >101 days and an ILS of >505% (high activity); ii) IMGN632 11-day schedule (Group D) had a TC of 9.5 days and an ILS of 47.5% (high activity); iii) IMGN632 14-day schedule (Group E) had a TC of 6.5 days and an ILS of 32.5% (minimum activity).

[0279] The three different azacitidine + IMGN632 combination therapy regimens outlined above resulted in the following antitumor activity: i) 7-day schedule of IMGN632 + azacitidine combination (group F), TC value of 23.5 days and ILS of 117.5% (high activity); ii) 11-day schedule of IMGN632 + azacitidine combination (group G), TC value of 60.5 days and ILS of 302.5% (high activity); iii) 14-day schedule of IMGN632 + azacitidine combination (group H), TC value of 37 days and ILS of 185% (high activity). Comparing all three combination schedules, the combination schedule that resulted in the highest %ILS was group G (ILS 302.5%), where IMGN632 treatment was started on the last azacitidine administration day (day 11).

[0280] Of note, all three of the tested IMGN632 + azacitidine combination drug administration schedules resulted in highly active combinations, whereas the corresponding IMGN632 monotherapy regimens (group D, “day 11”: ILS 47.5% and group E, “day 14”: ILS 47.5%, respectively) were significantly more effective than the corresponding IMGN632 monotherapy (group D, “day 11”: ILS 47.5%, respectively). Only the Group G (ILS 302.5%) and Group H (ILS 185%) schedules (where the initiation of IMGN632 treatment was delayed relative to the initiation of azacitidine treatment) yielded a %ILS greater than 32.5%). In contrast, the Group F drug combination schedule (using the same start date for both IMGN632 and azacitidine, day 7) yielded an ILS of 117.5%, which was highly active but significantly lower than the corresponding IMGN632 monotherapy group (Group C, "Day 7"), which yielded an ILS of over 505%. [Table 6]

[0281] Example 6 In vivo efficacy of the combination of IMGN632 (QW×3) and Azacitidine (QD×5) in the Molm-13 disseminated model To test the efficacy of IMGN632, decitabine, or the combination of these two agents for their ability to reduce tumor burden in vivo, a disseminated tumor model was used, as described in the protocol below.

[0282] Female NOD SCID mice were pretreated with 150 mg / kg cyclophosphamide to partially ablate the bone marrow and improve Molm-13 cell engraftment. Cyclophosphamide (Sigma, C0768, lot no. MKBX1822V) was dissolved in 0.9% NaCl and administered intraperitoneally to mice 2 days prior to Molm-13 cell inoculation on day 0.

[0283] After cyclophosphamide treatment as described above, 2 × 10 5 Molm-13 cells (human AML cell line) were injected intravenously into the lateral tail vein of each mouse. Five days after Molm inoculation, mice were randomized into study groups based on body weight. 24 hours prior to each conjugate administration, for all groups receiving conjugate treatment (either alone or in combination with decitabine), mice were injected intraperitoneally with 150 mg / kg of non-targeting chKTI antibody to block Fc receptors on Molm-13 AML cells and prevent non-specific uptake of the conjugate.

[0284] Mice received IMGN632 at a dose of 0.3 μg with DGN549 (0.024 mg / kg with huCD123Ab) once a week (QW) for three doses (×3) alone or in combination with decitabine according to three different IMGN632 dosing schedules: i) days 7, 14, and 21 (referred to as "day 7" for IMGN632), ii) days 11, 18, and 25 (referred to as "day 11" for IMGN632), and iii) days 14, 21, and 28 (referred to as "day 14" for IMGN632), where the start date of IMGN632 treatment as described was progressively moved away from day 0 (the day of Molm-13 inoculation) of the study timeline.

[0285] Decitabine was administered at a dose of 0.75 mg / kg once daily (QD) for 5 consecutive days (×5; days 7, 8, 9, 10, and 11; "day 7" schedule), alone or in combination with IMGN632.

[0286] Mice were treated with a combination regimen of IMGN632 (QW x 3) and 0.75 mg / kg decitabine (QD x 5) according to one of three different dosing schedules for combining the two drugs: i) a 7-day schedule of IMGN632 and a 7-day schedule of decitabine (group F), ii) an 11-day schedule of IMGN632 and a 7-day schedule of decitabine (group G), and iii) a 14-day schedule of IMGN632 and a 7-day schedule of decitabine (group H).

[0287] The results are shown in Table 7 (below) and FIG.

[0288] Single-agent decitabine administered at 0.75 mg / kg QD×5 according to a 7-day schedule (Group B) was the least active in this study, resulting in a 6-day tumor growth delay (TC value) and 28.6% ILS (increased life span) compared to vehicle treatment. Three different treatment schedules of single-agent IMGN632 were either highly active ("Day 7" or "Day 11") or inactive ("Day 14") in this study, resulting in the following TC values ​​and %ILS: i) IMGN632 7-day schedule (Group C) had a TC of 49.5 days and an ILS of 235.7% (highly active); ii) IMGN632 11-day schedule (Group D) had a TC of 20 days and an ILS of 95.2% (highly active); iii) IMGN632 14-day schedule (Group E) had a TC of 0 days and an ILS of 0% (inactive).

[0289] The three different decitabine + IMGN632 combination therapy regimens outlined above resulted in the following antitumor activity: i) for the combination of IMGN632 on a 7-day schedule + decitabine (group F), the TC value was 34 days and the ILS was 161.9% (high activity); ii) for the combination of IMGN632 on an 11-day schedule + decitabine (group G), the TC value was 38.5 days and the ILS was 183.3% (high activity); iii) for the combination of IMGN632 on a 14-day schedule + decitabine (group H), the TC value was 22 days and the ILS was 104.8% (high activity). Comparing all three combination schedules, the combination schedule resulting in the highest %ILS was group G (ILS 183.3%), where IMGN632 treatment was initiated on the day of the last decitabine administration (day 11).

[0290] Of note, all three of the tested IMGN632+decitabine combination drug administration schedules resulted in highly active combinations, but only the Group G (ILS 183.3%) and Group H (ILS 104.8%) schedules resulted in a better %ILS than the corresponding IMGN632 monotherapy regimens (Group D, "Day 11": 95.2% ILS, and Group E, "Day 14": 0% ILS, respectively), where the initiation of IMGN632 treatment was delayed relative to the initiation of decitabine treatment. In contrast, the Group F combination drug administration schedule (using the same initiation date for both IMGN632 and decitabine, Day 7) resulted in an ILS of 161.9%, which was highly active but notably lower than the corresponding IMGN632 monotherapy group (Group C, "Day 7"), resulting in an ILS of over 235.7%. [Table 7]

[0291] Example 7 In vivo efficacy of IMGN632 (single dose) in combination with azacitidine (QD×5) and venetoclax (QD×28) in the EOL-1 subcutaneous model To test the efficacy of the combination of IMGN632, azacitidine and venetoclax, or the combination of these three agents, for their ability to reduce tumor burden in vivo, a subcutaneous tumor model was used, as described in the protocol below.

[0292] Female athymic nude mice were each administered 1 × 10 7 EOL-1 cells (human AML cell line) were inoculated subcutaneously in the right flank. Conjugate treatment was administered (either alone or in combination with azacitidine + venetoclax). On day 12, 24 hours prior to administration of the conjugates in the groups receiving EOL-1 AML (with or without immunization), all mice in these treatment groups were injected intraperitoneally with 150 mg / kg of non-targeting chKTI antibody to block Fc receptors on EOL-1 AML cells and prevent non-specific uptake of the conjugates. On day 12 after EOL-1 inoculation, mice were randomized into test groups based on tumor volume.

[0293] On day 13 post-EOL-1 inoculation, mice received a single intravenous injection of either vehicle or IMGN632 at 1 μg / kg (with DGN549; 0.080 mg / kg with huCD123Ab) in the lateral tail vein. Venetoclax administration also began on day 13, with mice receiving venetoclax receiving a single oral dose of 100 mg / kg venetoclax administered daily (QD) on each of days 13–40 for a total of 28 consecutive days (×28), including after cell transplantation. Azacitidine administration also began on day 13, with mice receiving azacitidine receiving a single intraperitoneal dose of 3 mg / kg azacitidine administered daily (QD) on each of 5 consecutive days (×5). In the combination group, mice received IMGN632 and either venetoclax plus azacitidine, or just azacitidine, as outlined above.

[0294] The results are shown in Table 8 and FIG.

[0295] A single dose of 1 μg / kg of single-agent IMGN632 resulted in a T / C value of 64% (inactive) and 2 / 6 long-term complete regressions (tumor-free survivors, TFS) at the end of the study (day 77). A single-agent regimen of azacitidine 3 mg / kg once daily (QD) for 5 days (×5) was inactive with a T / C of 96% and a TFS of 0 / 6 at day 77. The dual combination of azacitidine (QD ×5) and venetoclax (QD ×28) was inactive with a T / C of 46% and a TFS of 1 / 6 at day 77.

[0296] The triple combination of IMGN632, azacitidine, and venetoclax was highly active with a T / C of 0% and a TFS of 5 / 6 at the end of the study. The triple combination produced a smaller %T / C (0%) than that produced by either IMGN632 alone (64%) or the doublet combination of azacitidine + venetoclax (46%), indicating that the triple combination was more effective at slowing tumor growth than either IMGN632 alone or the doublet combination of azacitidine + venetoclax.

[0297] The two-drug combination of IMGN632 and azacitidine was also highly active, with a T / C of 0% and a TFS of 4 / 6 at the end of the study. The two-drug combination of IMGN632 and azacitidine resulted in a smaller %T / C (0%) than that afforded by either IMGN632 (64%) or azacitidine (96%) alone, indicating that the two-drug combination was more effective at slowing tumor growth than the corresponding single-agent treatments. [Table 8]

[0298] Example 8 In vivo efficacy of the combination of IMGN632 (QW×3), azacitidine (QD×5), and venetoclax (QD×28) in the Molm-13 disseminated model To test the efficacy of IMGN632, venetoclax, the combination of azacitidine + venetoclax, the combination of IMGN632 + venetoclax, or the triple combination of IMGN632, azacitidine, and venetoclax in reducing tumor burden in vivo, a disseminated tumor model was used as described in the protocol below.

[0299] Female NOD SCID mice were pretreated with 150 mg / kg cyclophosphamide to partially ablate the bone marrow and improve Molm-13 cell engraftment. Cyclophosphamide (Sigma, C0768, lot no. MKBX1822V) was dissolved in 0.9% NaCl and administered intraperitoneally to mice 2 days prior to Molm-13 cell inoculation on day 0.

[0300] After cyclophosphamide treatment as described above, 2 × 10 5 Molm-13 cells (human AML cell line) were injected intravenously into the lateral tail vein of each mouse. 24 hours prior to each conjugate administration, for all groups receiving conjugate treatment (either alone, or in combination with venetoclax, or in combination with azacitidine + venetoclax), mice were injected intraperitoneally with 150 mg / kg of non-targeting chKTI antibody to block Fc receptors on Molm-13 AML cells and prevent non-specific uptake of the conjugate.

[0301] On days 11, 18, and 25 after Molm-13 inoculation, mice received a single intravenous injection of either vehicle or 0.3 μg / kg (with DGN549; 0.024 mg / kg with huCD123Ab) IMGN632 in the lateral tail vein. Venetoclax administration began on day 7 after cell inoculation, and mice receiving venetoclax received a single oral dose of 100 mg / kg venetoclax administered daily (QD) on each of days 7 through 34 (inclusive) for a total of 28 consecutive days (×28). Azacitidine administration also began on day 7, and mice receiving azacitidine received a single intraperitoneal dose of 3.5 mg / kg azacitidine administered daily (QD) on each of 5 consecutive days (×5). In the azacitidine and venetoclax combination group or the triple combination group of all three drugs, mice received IMGN632, venetoclax, and azacitidine as outlined above.

[0302] Results up to 80 days after tumor cell inoculation are shown in Table 9A (below) and FIG. 10A.

[0303] IMGN632 monotherapy (group B) resulted in a tumor growth delay (TC value) of more than 59.5 days and an increase in life span (%ILS) of more than 277% compared to vehicle treatment. Venetoclax monotherapy (group E) resulted in a TC of 11.5 days and an ILS of 53.5% (high activity). Azacitidine and venetoclax dual combination (group C) resulted in a TC of 14.5 days and an ILS of 67.4% (high activity). IMGN632 and venetoclax dual combination (group F) resulted in a TC of more than 59.5 and an ILS of more than 277% (high activity) (TC and %ILS values ​​greater than those provided by venetoclax alone), indicating that the addition of IMGN632 to venetoclax provides additional benefit compared to venetoclax monotherapy. The triple combination of IMGN632 and azacitidine and venetoclax (Arm D) achieved a TC of greater than 59.5 days and an ILS of greater than 277% (high activity) (TC and %ILS values ​​greater than those achieved by the dual combination of azacitidine and venetoclax), indicating that the addition of IMGN632 to the dual combination of azacitidine and venetoclax provides additional benefit compared to treatment with azacitidine and venetoclax alone. [Table 9A]

[0304] Results up to 109 days after tumor cell inoculation are shown in Table 9B (below) and FIG. 10B. IMGN632 monotherapy (group B) resulted in a tumor growth delay (TC value) of more than 87.5 days and an increase in life span (%ILS) of more than 407% compared to vehicle treatment. Venetoclax monotherapy (group E) resulted in a TC of 11.5 days and an ILS of 53.5% (high activity). Azacitidine and venetoclax dual combination (group C) resulted in a TC of 14.5 days and an ILS of 67.4% (high activity). The dual combination of IMGN632 and venetoclax (arm F) achieved a TC of >87.5 and an ILS of >407% (high activity) (TC and %ILS greater than those achieved by venetoclax alone), indicating that the addition of IMGN632 to venetoclax provides additional benefit compared to venetoclax monotherapy. The triple combination of IMGN632 and azacitidine and venetoclax (arm D) achieved a TC of >87.5 days and an ILS of >407% (high activity) (TC and %ILS greater than those achieved by the dual combination of azacitidine and venetoclax), indicating that the addition of IMGN632 to the dual combination of azacitidine and venetoclax provides additional benefit compared to the dual combination of azacitidine and venetoclax alone. Shown to provide additional benefit compared to treatment with toclax. [Table 9B]

[0305] Example 9 In vivo efficacy of the combination of IMGN632 (QW×3), azacitidine (QD×5), and venetoclax (QD×28) in the MV4-11 disseminated model To test the efficacy of the combination of IMGN632, azacitidine and venetoclax, or the combination of these three agents, for their ability to reduce tumor burden in vivo, a disseminated tumor model was used, as described in the protocol below.

[0306] Female NOD SCID mice were pretreated with 150 mg / kg cyclophosphamide to partially ablate the bone marrow and improve engraftment of MV4-11 cells. Cyclophosphamide (Sigma, C0768, lot no. MKBX1822V) was dissolved in 0.9% NaCl and administered intraperitoneally to mice on day 0, 3 days and 2 days prior to inoculation with MV4-11 cells.

[0307] After cyclophosphamide treatment as described above, 3 × 10 6 MV4-11 cells (a human AML cell line) were injected intravenously into the lateral tail vein of each mouse. On day 3 after MV4-11 inoculation, mice were randomized into study groups based on body weight. 24 hours prior to each conjugate administration, for all groups receiving conjugate treatment (either alone or in combination with azacytidine and venetoclax), mice were injected intraperitoneally with 150 mg / kg of non-targeting chKTI antibody to target Fc receptors on MV4-11 AML cells. Blocking was performed to prevent non-specific uptake of the complex.

[0308] On days 25, 32, and 39 after MV4-11 inoculation, mice received a single intravenous injection of vehicle or 1 μg / kg (with DGN549; 0.080 mg / kg with huCD123Ab) IMGN632 in the lateral tail vein. Venetoclax administration began on day 21 after cell inoculation, and mice receiving venetoclax received a single oral dose of 100 mg / kg venetoclax administered daily (QD) on each of days 21 through 48 (inclusive) for a total of 28 consecutive days (×28). Azacitidine administration also began on day 21, and mice receiving azacitidine received a single intraperitoneal dose of 4.5 mg / kg or 3 mg / kg azacitidine administered daily (QD) on each of five consecutive days (×5). In the azacitidine + venetoclax combination group or triple combination group, mice received IMGN632, venetoclax, and azacitidine as outlined above.

[0309] The results are shown in Table 10 and FIG.

[0310] IMGN632 monotherapy (group B) resulted in a tumor growth delay (TC value) of more than 81 days and an increase in life span (%ILS) of more than 180% compared to vehicle treatment. The doublet combination of azacitidine (4.5 mg / kg) and venetoclax (group C) resulted in a TC of 28 days and an ILS of 62.2% (high activity). The triplet combination of IMGN632, azacitidine (4.5 mg / kg) and venetoclax (group D) resulted in a TC of 64 days and an ILS of more than 142.2% (high activity) (TC and %ILS values ​​greater than those provided by the doublet combination of azacitidine (4.5 mg / kg) and venetoclax), indicating that the addition of IMGN632 to the doublet combination of azacitidine and venetoclax provides additional benefits compared to treatment with azacitidine and venetoclax alone.

[0311] The dual combination of azacitidine (3 mg / kg) and venetoclax (group E) resulted in a TC of 20 days and an ILS of 44.4% (active). The triple combination of IMGN632, azacitidine (3 mg / kg) and venetoclax (group D) resulted in a TC of 76 days and an ILS of 168.9% (highly active) (TC and %ILS greater than those provided by the dual combination of azacitidine (3 mg / kg) and venetoclax), indicating that the addition of IMGN632 to the dual combination of azacitidine and venetoclax provides additional benefit compared to treatment with azacitidine and venetoclax alone. [Table 10]

[0312] Example 10: Administration of IMGN632 combinations to humans Unmatched frontline and relapsed / refractory BPDCN and relapsed / refractory ALL patients will be treated with the recommended phase 2 dose (RP2D) of IMGN632 monotherapy as 0.045 mg / kg once every 21-day cycle (Q3W). Based on the above experiments, the following three dosing schedules were selected for administration to human subjects:

[0313] Schedule A: IMGN632 + Azacitidine: The cycle of IMGN632 and azacitidine is 28 days. In this 28-day cycle, azacitidine is administered at 75 mg / m daily on days 1 to 7. 2 Subcutaneous (SC) or intravenous Alternatively, azacitidine is administered at 75 mg / m daily on days 1-5. 2 IMGN632 may be administered subcutaneously (SC) or intravenously (IV) at 100 mg / kg. Administration of IMGN632 begins on the 7th day of the last azacitidine dose. IMGN632 is administered at a total dose of 0.015 mg / kg, 0.045 mg / kg, 0.09 mg / kg, or 0.18 mg / kg per 28-day cycle. For example, IMGN632 is administered at a dose of 0.015 mg / kg, 0.045 mg / kg, or 0.09 mg / kg once (i.e., on the 7th day) per 28-day cycle. IMGN632 may also be administered at a dose of 0.03 mg / kg once (e.g., on the 7th day) per 28-day cycle. Alternatively, IMGN632 is administered at doses of 0.015 mg / kg, 0.03 mg / kg, or 0.06 mg / kg three times (i.e., on days 7, 10, and 14) every 28 day cycle.

[0314] After cycle 1, if a patient experiences toxicity associated with azacitidine (e.g., cytopenias), azacitidine dosing may be reduced to 5 days by omitting treatment on days 1 and 2 and administering azacitidine on days 3-7 in subsequent cycles.

[0315] A total of 2 to 12 cycles can be administered. IMGN632 can then be administered as maintenance therapy once every 3 weeks (e.g., at a dose of 0.015 mg / kg, 0.045 mg / kg, or 0.09 mg / kg on day 1 of a 21-day cycle) or three times every 3 weeks (e.g., at a dose of 0.015 mg / kg, 0.03 mg / kg, or 0.06 mg / kg on days 1, 4, and 8 of a 21-day cycle). [Table 11-1] [Table 11-2]

[0316] Schedule B: IMGN632 + venetoclax The cycle of IMGN632 and venetoclax is 21 days. In the first cycle, venetoclax is administered orally (PO) at 100 mg on day 1, 200 mg on day 2, and 400 mg on all subsequent days (days 3-21), and in subsequent cycles, venetoclax is administered at the maximum dose (e.g., 400 mg) on ​​all subsequent days). Administration of IMGN632 begins on day 7 after the seventh venetoclax administration. IMGN632 is administered at a total dose of 0.015 mg / kg, 0.045 mg / kg, 0.09 mg / kg, or 0.18 mg / kg per 21-day cycle. For example, IMGN632 is administered once per 21-day cycle (e.g., on day 7) at a dose of 0.015 mg / kg, 0.045 mg / kg, or 0.09 mg / kg. IMGN632 may also be administered at a dose of 0.03 mg / kg once every 28 day cycle (e.g., on day 7). Alternatively, IMGN632 is administered at a dose of 0.015 mg / kg, 0.03 mg / kg, or 0.06 mg / kg three times every 21 day cycle (i.e., on days 7, 10, and 14).

[0317] According to the venetoclax FDA label, strong cytochrome P450 (CYP) 3A inhibitors, such as voriconazole and posaconazole, are to be avoided. If a patient is taking a moderate CYP3A inhibitor (e.g., Cresemba), the venetoclax dose is capped at 200 mg.

[0318] After cycle 1, if a patient experiences toxicity associated with venetoclax (e.g., cytopenias), venetoclax dosing may be reduced to days 1-14 (or days 1-7). Venetoclax dosing can also be reduced to days 1-8.

[0319] A total of 2 to 12 cycles can be administered. IMGN632 is then administered once every 3 weeks (e.g., at doses of 0.015 mg / kg, 0.045 mg / kg, or 0.09 mg / kg on day 1 of a 21-day cycle) or three times every 3 weeks (e.g., at doses of 0.025 mg / kg, 0.045 mg / kg, or 0.09 mg / kg on day 1 of a 21-day cycle). It may be administered as a maintenance therapy (at doses of 0.015 mg / kg, 0.03 mg / kg, or 0.06 mg / kg on days 1, 4, and 8 of the treatment). [Table 12-1] [Table 12-2]

[0320] Schedule C: IMGN632 + azacitidine + venetoclax The cycle of IMGN632, azacitidine, and venetoclax is 28 days. In this 28-day cycle, azacitidine is administered at 75 mg / m daily on days 1 to 7. 2 Alternatively, azacitidine is administered at 75 mg / m daily on days 1-5. 2 It can be administered subcutaneously (SC) or intravenously (IV).

[0321] In the first cycle, venetoclax is administered orally (PO) at 100 mg on day 1, 200 mg on day 2, and 400 mg all days thereafter (days 3-28), and in subsequent cycles, venetoclax is administered orally (PO) at the maximum dose (e.g., 400 mg all days) in the first cycle. Alternatively, venetoclax can be administered orally (PO) at 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-8, 3-14, or 3-21 of a 28 day cycle, and in subsequent cycles, venetoclax can be administered orally (PO) at the maximum dose (e.g., 400 mg) on ​​days 1-8, 1-14, 1-18, or 1-21 of a 28 day cycle.

[0322] Administration of IMGN632 begins on day 7, for example, after the seventh administration of venetoclax and azacitidine. IMGN632 is administered at a total dose of 0.015 mg / kg, 0.045 mg / kg, 0.09 mg / kg, or 0.18 mg / kg per 28-day cycle. For example, IMGN632 is administered at a dose of 0.015 mg / kg, 0.045 mg / kg, or 0.09 mg / kg once (e.g., on day 7) per 28-day cycle. IMGN632 can also be administered at a dose of 0.03 mg / kg once (e.g., on day 7) per 28-day cycle. Alternatively, IMGN632 is administered at a dose of 0.015 mg / kg, 0.03 mg / kg, or 0.06 mg / kg three times (i.e., on days 7, 10, and 14) per 28-day cycle.

[0323] A total of 2 to 12 cycles can be administered. IMGN632 can then be administered as a maintenance therapy once every 3 weeks (e.g., at a dose of 0.015 mg / kg, 0.045 mg / kg, or 0.09 mg / kg on day 1 of a 21-day cycle) or three times every 3 weeks (e.g., at a dose of 0.015 mg / kg, 0.03 mg / kg, or 0.06 mg / kg on days 1, 4, and 8 of a 21-day cycle). IMGN632 can also be administered as a maintenance therapy once every 3 weeks (e.g., at a dose of 0.03 mg / kg on day 1 of a 21-day cycle). [Table 13-1] [Table 13-2]

[0324] Example 11: Dosing of IMGN632 Human Patients with Minimal Residual Disease The IMGN632 study was designed to evaluate the effect of intravenous administration of IMGN632 in adult leukemia patients with minimal residual disease (MRD). Patients included both matched and unmatched patients. Patients with MRD may have a lower leukemia burden and therefore less CD123 than other patients. Therefore, it is important to consider the efficacy of IMGN632 in these patients, as a lower dose (e.g., 15-45 mcg / kg) may be effective. There may be a ratio of IMGN632 to CD123.

[0325] Patients enrolled in this study must be in complete remission (CR / CRi), MRD+ after intensive induction / consolidation therapy, and have no suitable standard of care available. A central flow cytometry-based test will be used to assess MRD status.

[0326] Patients may receive a premedication regimen prior to each IMGN632 infusion. Premedication may include: (i) 25-50 mg diphenhydramine (IV or oral [PO]), (ii) 325-650 mg acetaminophen or paracetamol (IV or PO), and / or (iii) 8 mg dexamethasone (PO or IV). If an individual patient requires more intensive or alternative treatments to prevent infusion reactions (e.g., different corticosteroids, different doses of any agent), the regimen may be modified according to standard institutional practice.

[0327] IMGN632 will be administered at doses of 0.015 mg / kg, 0.045 mg / kg, 0.09 mg / kg, 0.135 mg / kg, or 0.18 mg / kg once every 3 weeks (21 days).

[0328] The treatment consists of two cycles (i.e., a total of six weeks), with the patient's second dose being administered at least 21 days after the first dose. For example, a total of up to 10 or more additional cycles can be administered to patients who benefit from this regimen.

[0329] Anti-leukemic activity is demonstrated by measuring the rate of conversion from MRD+ to MRD-. Recurrence-free survival (RFS) and event-free survival (EFS) are also assessed to indicate anti-tumor activity.

[0330] Illustrative examples provided herein In one example (I1) provided herein, a method for treating a hematological malignancy in a subject includes administering to the subject in need thereof an immune complex that binds to CD123 (the immune complex comprises an antibody or antigen-binding fragment thereof comprising 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), and a BCL-2 inhibitor, a hypomethylating agent, or a combination thereof.

[0331] In one instance of I1 (I2), the immunoconjugate is administered in combination with a BCL-2 inhibitor. In one instance of I1 (I3), the immunoconjugate is administered in combination with a hypomethylating agent. In one instance of I1 (I4), the immunoconjugate is administered in combination with a BCL-2 inhibitor and a hypomethylating agent.

[0332] In one example (I5) of any one of I1-I4, 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. In one example (I6) of I5, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region and / or a light chain constant region.

[0333] In one example (I7) of any one of I1 to I4, the antibody or antigen-binding fragment comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:3 and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO:4.

[0334] In one instance (I8) of any one of I1-I7, the immunoconjugate comprises a cytotoxin, and optionally the cytotoxin is a DNA alkylating agent. In one instance (I9) of any one of I8, the DNA alkylating agent is an indolino-benzodiazepine (IGN) DNA alkylating agent.

[0335] In one instance (I10) of any one of I1-I9, the immunoconjugate comprises a peptide linker.

[0336] In one case (I11) of any one of I1 to I10, the immune complex is IMGN632.

[0337] In one embodiment (I12) of any one of I1-I0, the immunoconjugate is administered in a pharmaceutical composition comprising an immunoconjugate having the structure: [ka] , in the formula, 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.

[0338] In one instance (I13) of any one of I1-I12, the administration is frontline therapy.

[0339] In one embodiment (I14) of any one of I1-I13, the immunoconjugate is administered intravenously.

[0340] In one case (15) of any one of I1-I14, administration of the immunoconjugate with a BCL-2 inhibitor, a hypomethylating agent, or a combination thereof produces a synergistic effect.

[0341] In one case (I16) of any one of I1, I2, and I4-I15, administration of the immunoconjugate and the BCL-2 inhibitor does not result in more toxicity than administration of the immunoconjugate alone or the BCL-2 inhibitor alone. In one case (I17) of any one of I1 and I3-I15, administration of the immunoconjugate and the hypomethylating agent does not result in more toxicity than administration of the immunoconjugate alone or the hypomethylating agent alone. In one case (I18) of any one of I1 and I4-I15, administration of the immunoconjugate, the BCL-2 inhibitor, and the hypomethylating agent does not result in more toxicity than administration of the immunoconjugate, the BCL-2 inhibitor, and / or the hypomethylating agent.

[0342] In one instance (I19) of any one of I1, I2, and I5-I18, the immunoconjugate is administered once every 21 day cycle. In one instance (I20) of I19, the immunoconjugate is administered once every 21 day cycle at a dose of about 0.015 mg / kg to about 0.09 mg / kg, optionally at a dose of about 0.015 mg / kg, about 0.045 mg / kg, or about 0.05 mg / kg. is approximately 0.09 mg / kg.

[0343] In one instance (I21) of any one of I1-I18, the immunoconjugate is administered three times in a 21 day cycle. In one instance (I22) of I21, the total amount of immunoconjugate administered in the 21 day cycle is about 0.045 mg / kg, about 0.09 mg / kg, or about 0.18 mg / kg. In one instance (I23) of I22, about 0.015 mg / kg to about 0.06 mg / kg of the immunoconjugate is administered each of three times in the 21 day cycle, optionally about 0.015 mg / kg, about 0.03 mg / kg, or about 0.06 mg / kg of the immunoconjugate is administered each of three times in the 21 day cycle. In one instance (I24) of any one of I21-I23, the first administration of the immunoconjugate is on day 7 of the 21 day cycle. In one case (I25) of any one of I21-I24, the second administration of the immunoconjugate is on day 10 of a 21-day cycle. In one case (I26) of any one of I21-I25, the third administration of the immunoconjugate is on day 14 of a 21-day cycle. In one case (I27) of any one of I21-I26, the first, second, and third administrations are on days 7, 10, and 14, respectively, of a 21-day cycle.

[0344] In one example (I28) of any one of I1, I2, and I4-I27, the BCL-2 inhibitor is venetoclax.

[0345] In one instance (I29) of any one of I1, I2, and I4-I28, the BCL-2 inhibitor is administered at a dose of 400 mg. In one instance (I30) of any one of I1, I2, and I4-I28, the BCL-2 inhibitor is administered at a dose of 200 mg.

[0346] In one instance (I31) of any one of I1, I2, and I4-I30, the BCL-2 inhibitor is administered daily in a 21 day cycle. In one instance (I32) of any one of I1, I2, and I4-I28, the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of a 21 day cycle, at a dose of 200 mg on day 2 of a 21 day cycle, and at a dose of 400 mg on days 3-21 of a 21 day cycle. In one instance (I33) of any one of I1, I2, and I4-I28, the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of a 21 day cycle, at a dose of 200 mg on day 2 of a 21 day cycle, and at a dose of 400 mg on days 3-7 or 3-14 of a 21 day cycle. In one instance (I34) of any one of I1, I2, and I4-I28, the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of a 21 day cycle and at a dose of 200 mg on days 2-21, 2-14, or 2-7 of a 21 day cycle.

[0347] In one instance (I35) of any one of I1, I2, and I4-I34, the BCL-2 inhibitor is administered orally.

[0348] In one instance (I36) of any one of I1, I2, and I4-I35, administration of the immunoconjugate begins 6 days after the start of administration of the BCL-2 inhibitor.

[0349] In one instance (I37) of any one of I1 and I3-I18, the immunoconjugate is administered once every 28 day cycle. In one instance (I38) of I37, the immunoconjugate is administered once every 28 day cycle at a dose of about 0.015 mg / kg to about 0.09 mg / kg, optionally at a dose of about 0.015 mg / kg, about 0.045 mg / kg, or about 0.09 mg / kg.

[0350] In one instance (I39) of any one of I1-I18, the immunoconjugate is administered three times in a 28-day cycle. In one instance (I40) of I39, the immunoconjugate is administered in a 28-day cycle. The total amount of immunoconjugate is about 0.045 mg / kg, about 0.09 mg / kg, or about 0.18 mg / kg. In one instance of I40 (I41), about 0.015 mg / kg to about 0.06 mg / kg of the immunoconjugate is administered each of three times during the 28 day cycle, and optionally about 0.015 mg / kg, about 0.03 mg / kg, or about 0.06 mg / kg of the immunoconjugate is administered each of three times during the 28 day cycle. In one instance of any one of I39-I41 (I42), the first administration of the immunoconjugate is on day 7 of the 28 day cycle. In one instance of any one of I39-I42 (I43), the second administration of the immunoconjugate is on day 10 of the 28 day cycle. In one instance of any one of I39-I43 (I44), the third administration of the immunoconjugate is on day 14 of the 28 day cycle. In one instance (I45) of any one of I39-I44, the first, second, and third administrations are on days 7, 10, and 14, respectively, of a 28-day cycle.

[0351] In one instance (I46) of any one of I37-I45, the BCL-2 inhibitor is venetoclax. In one instance (I47) of any one of I37-I46, the BCL-2 inhibitor is administered at a dose of 400 mg. In one instance (I48) of any one of I37-I46, the BCL-2 inhibitor is administered at a dose of 200 mg. In one instance (I49) of any one of I37-I48, the BCL-2 inhibitor is administered daily in a 28 day cycle. In one instance (I50) of any one of I37-I46, the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of a 28 day cycle, at a dose of 200 mg on day 2 of a 28 day cycle, and at a dose of 400 mg on days 3-28 of a 28 day cycle. In one instance (I51) of any one of I37-I46, the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of a 28 day cycle, at a dose of 200 mg on day 2 of a 28 day cycle, and at a dose of 400 mg on days 3-7 or 3-14 of a 28 day cycle. In one instance (I52) of any one of I37-I46, the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of a 28 day cycle, and at a dose of 200 mg on days 2-28, 2-14, or 2-7 of a 28 day cycle. In one instance (I53) of any one of I37-I52, the BCL-2 inhibitor is administered orally. In one instance (I54) of any one of I37-I53, administration of the immunoconjugate is initiated 6 days after initiation of administration of the BCL-2 inhibitor.

[0352] In one instance (I55) of any one of I1, I3-I18, and I37-I54, the hypomethylating agent is azacitidine. In one instance (I56) of I55, the azacitidine is administered in a 28-day cycle. In one instance (I57) of I55 or I56, the azacitidine is administered once daily on days 1-7 of a 28-day cycle. In one instance (I58) of I55 or I56, the azacitidine is administered once daily on days 3-7 of a 28-day cycle. In one instance (I59) of any one of I56-I58, the azacitidine is administered at a dose of about 75 mg / m 2In one embodiment (I60) of any one of I56 to I59, azacitidine is administered subcutaneously or intravenously.

[0353] In one instance (I61) of any one of I1 and I3-I54, the hypomethylating agent is decitabine. In one instance (I62) of I61, decitabine is administered intravenously.

[0354] In one instance (I63) of any one of I1-I62, the hematological malignancy is present in the subject as minimal residual disease (MRD).

[0355] In one instance (I64), a method for treating a hematological malignancy presenting as minimal residual disease in a human subject comprises administering to the subject an anti-CD123 immunoconjugate comprising an anti-CD123 antibody or antigen-binding fragment thereof linked to a cytotoxic agent. In one instance (I65) of I64, the immunoconjugate is administered at a dose of about 0.045 mg / kg to about 0.18 mg / kg. I64 Or in one instance of I65 (I66), about 0.045 mg / kg, about 0.09 mg / kg, about 0.135 mg / kg, or about 0.18 mg / kg is administered to the subject. In one instance of any one of I64-I66 (I67), the immunoconjugate is administered intravenously. In one instance of any one of I64-I67 (I68), the hematological malignancy is leukemia. In one instance of any one of I64-I68 (I69), the immunoconjugate is administered to the subject once in a 21 day cycle.

[0356] In one instance (I70) of any one of I20 to I63 or I69, the administration is one cycle. In one instance (I71) of any one of I20 to I63 or I69, the administration is two or more cycles. In one instance (I72) of any one of I20 to I63 or I69, the administration is at least two cycles, at least three cycles, at least four cycles, at least five cycles, at least six cycles, at least seven cycles, at least eight cycles, at least nine cycles, or at least ten cycles. In one instance (I73) of any one of I20 to I63 or I69, the administration is about two to four cycles, about two to six cycles, about two to eight cycles, about two to ten cycles, or about two to twelve cycles.

[0357] In one instance (I74) of any one of I1-I73, the method further comprises administering a reduced dose of the immunoconjugate after dose-limiting toxicity occurs in the subject and is reduced to baseline or below Grade 2.

[0358] In one instance (I75) of any one of I1-I73, the immunoconjugate is further administered as a maintenance therapy. In one instance (I76) of I75, the maintenance therapy comprises administering the immunoconjugate once every 21 day cycle. In one instance (I77) of I76, the maintenance therapy comprises administering the immunoconjugate at a dose of about 0.015 mg / kg to about 0.09 mg / kg once every 21 day cycle, optionally with the dose being about 0.015 mg / kg, about 0.045 mg / kg, or about 0.09 mg / kg. In one instance (I78) of I75, the maintenance therapy comprises administering the immunoconjugate three times in a 21 day cycle. In one instance (I79) of I78, the total amount of immunoconjugate administered in a 21 day cycle during the maintenance therapy is about 0.045 mg / kg, about 0.09 mg / kg, or about 0.18 mg / kg. In one instance (I80) of I79, during maintenance therapy, about 0.015 mg / kg to about 0.06 mg / kg of the immunoconjugate is administered each of three times during a 21 day cycle, optionally about 0.015 mg / kg, about 0.03 mg / kg, or about 0.06 mg / kg of the immunoconjugate is administered each of three times during a 21 day cycle. In one instance (I81) of any one of I78-I80, during maintenance therapy, the first, second, and third administrations are on days 1, 4, and 8, respectively, of a 21 day cycle.

[0359] In one case (I82) of any one of I1-I12, I14-I62, and I69-I81, the hematological malignancy is a recurrent hematological malignancy.

[0360] In one case (I83) of any one of I1 to I82, the hematological malignancy is acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), B-cell acute lymphoblastic leukemia (B-ALL), chronic myeloid leukemia in blast crisis / blast crisis phase (BP-CML), and blastic plasmacytoid dendritic cell neoplasm (BPDCN).

[0361] In one case (I84) of any one of I1-I82, the hematological malignancy is AML. In one case (I85) of I84, the AML is relapsed AML. In one case (I86) of I84 or I85, the AML is refractory AML.

[0362] In one case (I87) of any one of I1 to I82, the hematological malignancy was BPD. In one case of I88 (I88), the BPDCN is recurrent BPDCN. In one case of I87 or I88 (I89), the BPDCN is refractory BPDCN.

[0363] In one instance (I90) of any one of I1-I82, the hematological malignancy is ALL. In one instance (I91) of I90, the ALL is relapsed ALL. In one instance (I92) of I90 or I91, the ALL is refractory ALL.

[0364] In one case (I93) of any one of I1-I82, the hematological malignancy is chronic myelomonocytic leukemia (CMML). In one case (I94) of I93, the CMML is relapsed CMML. In one case (I95) of I93 or I94, the CMML is refractory CMML.

[0365] In one case (I96) of any one of I1-I82, the hematological malignancy is myelofibrosis (MF). In one case (I97) of I96, the MF is relapsed MF. In one case (I98) of I96 or I97, the MF is refractory MF.

[0366] In one example (I99) of any one of I1 to I82, the hematological malignancy is myelodysplastic syndrome (MDS). In one example (I100) of I99, the MDS is recurrent MDS. In one example (I101) of I99 or I100, the MDS is refractory MDS.

[0367] In one example (I102) of any one of I1 to I101, the hematological malignancy is a hematological malignancy that expresses CD123.

[0368] In one case (I103) of any one of I1-I102, CD123 was detected in a sample obtained from a hematological malignancy prior to administration. In one case (I104) of I103, CD123 was detected using flow cytometry.

[0369] In one instance (I105) of any one of I1-I105, the method further comprises detecting CD123 in a sample obtained from the hematological malignancy prior to the administration.

[0370] In one case (I106) of any one of I1-I105, at least 80% of the cells in the hematological malignancy express CD 123. In one case (I107) of any one of I1-I106, CD123 is detected in at least 80% of the cells in a sample obtained from the hematological malignancy prior to administration.

[0371] In one instance (I108) of any one of I1-I107, the method further comprises detecting CD123 in at least 80% of cells in a sample obtained from the hematological malignancy prior to the administration.

[0372] In one case (I109) of any one of I1-I63 and I69-I108, the hematological malignancy is resistant to IMGN632.

[0373] In one instance (I110) of any one of I1-I109, the hematological malignancy expresses multidrug resistance 1 (MDR1). In one instance (I111) of any one of I1-I110, the hematological malignancy expresses P-glycoprotein (P-gp). In one instance (I112) of any one of I1-I111, the subject has an absolute neutrophil count greater than 500 / μL.

[0374] In one case (I113) of any one of I1 to I12 and I14 to I112, The subject had received at least one prior therapy. In one case (I114) of any one of I1-I12 and I14-I112, the subject had received at least two prior therapies. In one case (I115) of any one of I1-I12 and I14-I112, the subject had received at least three prior therapies.

[0375] In one case (I116) of any one of I1-I12 and I14-I115, the cancer has been previously treated with venetoclax. In one case (I117) of any one of I1-I115, the cancer has not been previously treated with venetoclax.

[0376] In one case (I118) of any one of I1-I12 and I14-I117, the cancer has been previously treated with a hypomethylating agent. In one case (I119) of any one of I1-I117, the cancer has not been previously treated with a hypomethylating agent.

[0377] In one instance (I120) of any one of I1-I119, the subject is pretreated with a corticosteroid prior to administration of the immunoconjugate. In one instance (I121) of any one of I1-I119, the method further comprises pretreating the subject with a corticosteroid prior to administration of the immunoconjugate. In one instance (I122) of I120 or I121, the corticosteroid is diphenhydramine, acetaminophen, paracetamol, dexamethasone, or a combination thereof.

[0378] In one instance (I123) of any one of I1-I63 and I69-I122, the immunoconjugate and the BCL-2 inhibitor, hypomethylating agent, or combination thereof are administered in separate pharmaceutical compositions.

[0379] In one embodiment (I124) of any one of I1-I123, the subject is a human.

[0380] In one case (I125), a method for treating a hematological malignancy in a human subject includes administering to the subject in need thereof IMGN632 and venetoclax in a 21 day cycle, where IMGN632 is administered intravenously at a dose of about 0.015 mg / kg to about 0.09 mg / kg on day 7 of the cycle (optionally, the dose is about 0.015 mg / kg, about 0.045 mg / kg, or about 0.09 mg / kg), and venetoclax is administered orally at a dose of 100 mg on day 1 of the cycle, at a dose of 200 mg on day 2 of the cycle, and at a dose of 400 mg on days 3-21 of the cycle.

[0381] In one case (I126), a method for treating a hematological malignancy in a human subject includes administering to said subject in need thereof IMGN632 and venetoclax in a 21 day cycle, where IMGN632 is administered intravenously on day 7 of the cycle at a dose of about 0.015 mg / kg to about 0.09 mg / kg (optionally, the dose is about 0.015 mg / kg, about 0.045 mg / kg, or about 0.09 mg / kg), and venetoclax is administered at an oral daily dose of 400 mg.

[0382] In one instance (I127), a method for treating a hematological malignancy in a human subject includes administering to said subject in need thereof IMGN632 and venetoclax in a 21 day cycle, where IMGN632 at a dose of about 0.015 mg / kg to about 0.06 mg / kg is administered intravenously on each of days 7, 10, and 14 of the cycle, optionally about 0.015 mg / kg, about 0.03 mg / kg, or about 0.06 mg / kg is administered each day, and venetoclax is administered orally at a dose of 100 mg on day 1 of the cycle, at a dose of 200 mg on day 2 of the cycle, and at a dose of 400 mg on days 3-21 of the cycle.

[0383] In one case (I128), a method for treating a hematological malignancy in a human subject includes administering to said subject in need thereof IMGN632 and venetoclax in a 21 day cycle, where a dose of about 0.015 mg / kg to about 0.06 mg / kg of IMGN632 is administered intravenously on each of days 7, 10, and 14 of the cycle, optionally, about 0.015 mg / kg, about 0.03 mg / kg, or about 0.06 mg / kg is administered each day, and venetoclax is administered at an oral daily dose of 400 mg.

[0384] In one case (I129), a method for treating a hematological malignancy in a human subject includes administering to said subject in need thereof IMGN632 and azacitidine in a 28 day cycle, where IMGN632 is administered intravenously at a dose of about 0.015 mg / kg to about 0.09 mg / kg on day 7 of the cycle (optionally, the dose is about 0.015 mg / kg, about 0.045 mg / kg, or about 0.09 mg / kg), and azacitidine is administered intravenously at a dose of 75 mg / m on days 1-7 of the cycle. 2 It is administered subcutaneously or intravenously at a dose of

[0385] In one instance (I130), a method for treating a hematological malignancy in a human subject includes administering to said subject in need thereof IMGN632 and azacitidine in a 28 day cycle, wherein about 0.015 mg / kg to about 0.06 mg / kg of IMGN632 is administered intravenously on each of days 7, 10, and 14 of the cycle (optionally, a dose of about 0.015 mg / kg, about 0.03 mg / kg, or about 0.06 mg / kg is administered each day), and azacitidine is administered at a dose of 75 mg / m on days 1-7 of the cycle. 2 It is administered subcutaneously or intravenously at a dose of

[0386] In one instance of I129 or I130 (I131), the method further includes orally administering venetoclax at a dose of 100 mg on day 1 of the cycle, at a dose of 200 mg on day 2 of the cycle, and at a dose of 400 mg on days 3-28 of the cycle.

[0387] In one instance of I129 or I130 (I132), the method further includes administering venetoclax at an oral daily dose of 400 mg.

[0388] In one instance (I133) of any one of I125-I132, the hematological malignancy is AML. In one instance (I134) of any one of I125-I132, the hematological malignancy is BPDCN. In one instance (I135) of any one of I125-I132, the hematological malignancy is chronic myelomonocytic leukemia (CMML). In one instance (I136) of any one of I125-I132, the hematological malignancy is myelofibrosis (MF). In one instance (I137) of any one of I125-I132, the hematological malignancy is myelodysplastic syndrome (MDS). * * *

[0389] It is understood that the Detailed Description section, and not the Summary and Abstract sections, are intended to be used to interpret the claims. The Summary and Abstract sections present one or more, but not all, exemplary embodiments of the invention as contemplated by the inventors, and thus are not intended to limit the scope of the invention and the appended claims in any manner.

[0390] The present invention has been described above using functional components that illustrate the implementation of specified functions and their relationships. The boundaries of these functional components have been arbitrarily defined herein for the convenience of description. Alternative boundaries may be defined so long as the specified functions and their relationships are appropriately performed.

[0391] The foregoing description of specific embodiments is intended to fully clarify the general nature of the present invention. Thus, others can easily modify and / or adapt such specific embodiments for various uses without undue experimentation by applying knowledge within the art without departing from the general concept of the invention. Such adaptations and modifications are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the terms or phrases herein are for the purpose of description and not for the purpose of limitation, as they would be interpreted by one of ordinary skill in the art in light of the teaching and guidance.

[0392] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents. In certain embodiments, for example, the following items are provided: (Item 1) 1. A method for treating a hematological malignancy in a subject, comprising administering to a subject in need thereof an immune complex that binds to CD123 (the immune complex comprises an antibody or antigen-binding fragment thereof, the antibody comprising 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), and a BCL-2 inhibitor, a hypomethylating agent, or a combination thereof. (Item 2) 2. The method of claim 1, wherein the immunoconjugate is administered in combination with the BCL-2 inhibitor. (Item 3) 2. The method of claim 1, wherein the immunoconjugate is administered in combination with the hypomethylating agent. (Item 4) 2. The method of claim 1, wherein the immunoconjugate is administered in combination with the BCL-2 inhibitor and the hypomethylating agent. (Item 5) 5. The method according to any one of items 1 to 4, wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence shown in SEQ ID NO: 1 and / or a VL comprising the amino acid sequence shown in SEQ ID NO: 2. (Item 6) 5. The method according to any one of items 1 to 4, wherein the antibody or antigen-binding fragment comprises a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 3 and / or a light chain comprising the amino acid sequence shown in SEQ ID NO: 4. (Item 7) 7. The method of any one of items 1 to 6, wherein the immunoconjugate comprises a cytotoxin, optionally wherein the cytotoxin is a DNA alkylating agent, optionally wherein the DNA alkylating agent is an indolino-benzodiazepine (IGN) DNA alkylating agent. (Item 8) 8. The method according to any one of items 1 to 7, wherein the immune complex is IMGN632. (Item 9) The immunoconjugate is administered in a pharmaceutical composition comprising an immunoconjugate having the structure: [ka] , in the formula, 8. The method according to any one of items 1 to 7, wherein G4723A comprises a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 3 and a light chain comprising the amino acid sequence shown in SEQ ID NO: 4. (Item 10) 10. The method of any one of items 1 to 9, wherein the administration is frontline therapy. (Item 11) 11. The method according to any one of items 1 to 10, wherein the immunoconjugate is administered intravenously. (Item 12) 12. The method of any one of items 1 to 11, wherein administration of the immunoconjugate with the BCL-2 inhibitor, the hypomethylating agent, or a combination thereof produces a synergistic effect. (Item 13) 13. The method of any one of items 1, 2, and 4-12, wherein administration of the immunoconjugate and the BCL-2 inhibitor does not result in more toxicity than administration of the immunoconjugate alone or the BCL-2 inhibitor alone. (Item 14) 13. The method according to any one of items 1 and 3 to 12, wherein administration of the immunoconjugate and the hypomethylating agent does not result in more toxicity than administration of the immunoconjugate alone or the hypomethylating agent alone. (Item 15) 13. The method of any one of items 1 and 4-12, wherein administration of the immunoconjugate, the BCL-2 inhibitor, and the hypomethylating agent does not result in more toxicity than the administration of the immunoconjugate, the BCL-2 inhibitor, and / or the hypomethylating agent. (Item 16) 16. The method of any one of items 1, 2, and 5-15, wherein the immunoconjugate is administered once every 21 day cycle. (Item 17) 17. The method of claim 16, wherein the immunoconjugate is administered once in the 21 day cycle at a dose of about 0.015 mg / kg to about 0.09 mg / kg, optionally wherein the dose is about 0.015 mg / kg, about 0.045 mg / kg, or about 0.09 mg / kg. (Item 18) 18. The method of claim 17, wherein the immunoconjugate is administered at a dose of about 0.045 mg / kg once in the 21 day cycle. (Item 19) 18. The method of claim 17, wherein the immunoconjugate is administered once in the 21 day cycle at a dose of about 0.03 mg / kg. (Item 20) 18. The method of claim 17, wherein the immunoconjugate is administered once in the 21 day cycle at a dose of about 0.015 mg / kg. (Item 21) 21. The method of any one of items 1, 2, and 4-20, wherein the BCL-2 inhibitor is administered daily in a 21 day cycle. (Item 22) 21. The method of any one of items 1, 2, and 4-20, wherein the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of a 21 day cycle, at a dose of 200 mg on day 2 of said 21 day cycle, and at a dose of 400 mg on days 3 to 21 of said 21 day cycle. (Item 23) 21. The method of any one of items 1, 2, and 4-20, wherein the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of a 21 day cycle, at a dose of 200 mg on day 2 of said 21 day cycle, and at a dose of 400 mg on days 3-7 or days 3-14 of said 21 day cycle. (Item 24) 16. The method according to any one of items 1 and 3 to 15, wherein the immunoconjugate is administered once in a 28 day cycle. (Item 25) 25. The method of claim 24, wherein the immunoconjugate is administered once in the 28 day cycle at a dose of about 0.015 mg / kg to about 0.09 mg / kg, optionally wherein the dose is about 0.015 mg / kg, about 0.045 mg / kg, or about 0.09 mg / kg. (Item 26) 25. The method of claim 24, wherein the immunoconjugate is administered once in the 28 day cycle at a dose of about 0.03 mg / kg. (Item 27) 25. The method of claim 24, wherein the immunoconjugate is administered once in the 28 day cycle at a dose of about 0.045 mg / kg. (Item 28) 28. The method of any one of items 1, 2, and 4-27, wherein the BCL-2 inhibitor is venetoclax. (Item 29) 29. The method of any one of items 1, 2, 4-21, and 23-28, wherein the BCL-2 inhibitor is administered at a dose of 400 mg. (Item 30) 29. The method of any one of items 1, 2, 4-21, and 23-28, wherein the BCL-2 inhibitor is administered at a dose of 200 mg. (Item 31) 31. The method of any one of items 23 to 30, wherein the BCL-2 inhibitor is administered daily in a 28 day cycle. (Item 32) 32. The method of any one of items 21 and 28-31, wherein the BCL-2 inhibitor is administered daily on days 1 to 7 of the cycle. (Item 33) 32. The method of any one of items 21 and 28-31, wherein the BCL-2 inhibitor is administered daily on days 1 to 8 of the cycle. (Item 34) 32. The method of any one of items 21 and 28-31, wherein the BCL-2 inhibitor is administered daily on days 1 to 14 of the cycle. (Item 35) 32. The method of any one of items 21 and 28-31, wherein the BCL-2 inhibitor is administered daily on days 1 to 18 of the cycle. (Item 36) 32. The method of any one of items 21 and 28-31, wherein the BCL-2 inhibitor is administered daily on days 1 to 21 of the cycle. (Item 37) 32. The method of claim 31, wherein the BCL-2 inhibitor is administered daily on days 1 to 28 of the cycle. (Item 38) 29. The method of any one of items 24-28, wherein the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of a 28 day cycle, at a dose of 200 mg on day 2 of said 28 day cycle, and at a dose of 400 mg on days 3 to 28 of said 28 day cycle. (Item 39) 29. The method of any one of items 24-28, wherein the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of a 28 day cycle, at a dose of 200 mg on day 2 of said 28 day cycle, and at a dose of 400 mg on days 3-7 or days 3-14 of said 28 day cycle. (Item 40) 29. The method of any one of items 24-28, wherein the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of the 28 day cycle and at a dose of 200 mg on days 2-28, 2-14, or 2-7 of the 28 day cycle. (Item 41) 41. The method of any one of items 1, 2, and 4-40, wherein the BCL-2 inhibitor is administered orally. (Item 42) 42. The method of any one of items 1, 2, and 4-41, wherein administration of the immunoconjugate is initiated 6 days after initiation of the administration of the BCL-2 inhibitor. (Item 43) 43. The method according to any one of items 1, 3 to 15, and 23 to 42, wherein the hypomethylating agent is azacytidine. (Item 44) 44. The method of claim 43, wherein the azacitidine is administered in a 28 day cycle. (Item 45) 45. The method of claim 43 or 44, wherein the azacitidine is administered once daily on days 1 to 7 of a 28 day cycle. (Item 46) 45. The method of claim 43 or 44, wherein the azacitidine is administered once daily on days 1 to 5 of a 28 day cycle. (Item 47) 45. The method of claim 43 or 44, wherein the azacitidine is administered once daily on days 3 to 7 of a 28 day cycle. (Item 48) The azacitidine is about 75 mg / m 2 48. The method according to any one of items 43 to 47, wherein the dose is (Item 49) 49. The method of any one of items 43 to 48, wherein the azacitidine is administered subcutaneously or intravenously. (Item 50) 43. The method according to any one of items 1 and 3 to 42, wherein the hypomethylating agent is decitabine. (Item 51) 51. The method of item 50, wherein the decitabine is administered intravenously. (Item 52) 52. The method of any one of items 1 to 51, wherein the hematological malignancy is present in the subject as minimal residual disease (MRD). (Item 53) 1. A method for treating a hematological malignancy present as minimal residual disease in a human subject, comprising administering to the subject an anti-CD123 immunoconjugate comprising an anti-CD123 antibody or antigen-binding fragment thereof linked to a cytotoxic agent. (Item 54) 54. The method of claim 53, wherein the immunoconjugate is administered at a dose of about 0.045 mg / kg to about 0.18 mg / kg. (Item 55) 54. The method of claim 53, wherein the immunoconjugate is administered at a dose of about 0.045 mg / kg. (Item 56) 55. The method of claim 53 or 54, wherein about 0.045 mg / kg, about 0.09 mg / kg, about 0.135 mg / kg, or about 0.18 mg / kg is administered to the subject. (Item 57) The method according to any one of items 53 to 56, wherein the immunoconjugate is administered intravenously. 58. The method according to any one of items 53 to 57, wherein the hematological malignancy is leukemia. (Item 59) 59. The method of any one of items 53 to 58, wherein the immunoconjugate is administered to the subject once every 21 day cycle. (Item 60) 60. The method of any one of items 16 to 52 or 59, wherein the administration is one cycle. (Item 61) 60. The method of any one of items 16-52 or 59, wherein the administration is for two or more cycles, optionally wherein the administration is for at least two cycles, at least three cycles, at least four cycles, at least five cycles, at least six cycles, at least seven cycles, at least eight cycles, at least nine cycles, or at least ten cycles, or wherein the administration is for about two to four cycles, about two to six cycles, about two to eight cycles, about two to ten cycles, or about two to twelve cycles. (Item 62) 62. The method of any one of items 1-61, wherein the method further comprises administering a reduced dose of the immunoconjugate after dose-limiting toxicity occurs in the subject and is reduced to baseline or below Grade 2. (Item 63) 63. The method according to any one of items 1 to 62, wherein the immunoconjugate is further administered as a maintenance therapy. (Item 64) 64. The method of item 63, wherein the maintenance therapy comprises administering the immunoconjugate once every 21 day cycle. (Item 65) 65. The method of item 64, wherein the maintenance therapy comprises administering the immunoconjugate once in the 21 day cycle at a dose of about 0.015 mg / kg to about 0.09 mg / kg, optionally wherein the dose is about 0.015 mg / kg, about 0.045 mg / kg, or about 0.09 mg / kg. (Item 66) 65. The method of item 64, wherein the maintenance therapy comprises administering the immunoconjugate at a dose of about 0.045 mg / kg once in the 21 day cycle. (Item 67) 67. The method according to any one of items 1 to 9, 11 to 50, and 60 to 66, wherein the hematological malignancy is a recurrent hematological malignancy. (Item 68) 68. The method according to any one of items 1 to 9, 11 to 50, and 60 to 67, wherein the hematological malignancy is a refractory hematological malignancy. (Item 69) 69. The method according to any one of items 1 to 68, wherein the hematological malignancy is acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), B-cell acute lymphoblastic leukemia (B-ALL), blast crisis / chronic myeloid leukemia in blast crisis phase (BP-CML), and blastic plasmacytoid dendritic cell neoplasm (BPDCN). (Item 70) 69. The method according to items 1 to 68, wherein the hematological malignancy is AML. (Item 71) The method according to any one of items 1 to 68, wherein the hematological malignancy is BPDCN. 69. The method according to any one of items 1 to 68, wherein the hematological malignancy is ALL. (Item 73) 73. The method according to any one of items 1 to 72, wherein the hematological malignancy is a hematological malignancy that expresses CD123. (Item 74) 74. The method of any one of items 1 to 73, wherein CD123 is detected in a sample obtained from said hematological malignancy prior to said administering, and optionally, said CD123 is detected using flow cytometry. (Item 75) 75. The method of any one of items 1 to 74, further comprising detecting CD123 in a sample obtained from said hematological malignancy prior to said administering. (Item 76) 76. The method of any one of items 1 to 75, wherein at least 80% of cells in the hematological malignancy express CD123. (Item 77) 77. The method of any one of items 1 to 76, wherein CD123 is detected in at least 80% of cells in a sample obtained from said hematological malignancy prior to said administering. (Item 78) 78. The method of any one of items 1 to 77, further comprising detecting CD123 in at least 80% of cells in a sample obtained from said hematological malignancy prior to said administering. (Item 79) 79. The method of any one of items 1 to 52 and 60 to 78, wherein the hematological malignancy is resistant to IMGN632. (Item 80) 80. The method of any one of items 1 to 79, wherein the hematological malignancy expresses multidrug resistance 1 (MDR1). (Item 81) 81. The method of any one of items 1 to 80, wherein the hematological malignancy expresses P-glycoprotein (P-gp). (Item 82) 82. The method of any one of items 1 to 81, wherein the subject has an absolute neutrophil count of more than 500 / μL. (Item 83) The subject has had at least one prior therapy, at least two prior therapies, or at least The method according to any one of items 1-9 and 11-82, wherein the patient has received at least three prior therapies. (Item 84) The method of any one of items 1-9 and 11-83, wherein the cancer has been previously treated with venetoclax. (Item 85) 84. The method of any one of items 1-83, wherein the cancer has not been previously treated with venetoclax. (Item 86) 86. The method of any one of items 1-9 and 11-85, wherein the cancer has previously been treated with a hypomethylating agent. (Item 87) 86. The method of any one of items 1 to 85, wherein the cancer has not been previously treated with a hypomethylating agent. (Item 88) 88. The method of any one of items 1-87, wherein the subject is pre-treated with a corticosteroid prior to administration of the immunoconjugate, and optionally the corticosteroid is diphenhydramine, acetaminophen, paracetamol, dexamethasone, or a combination thereof. (Item 89) 88. The method of any one of items 1-87, further comprising pretreating the subject with a corticosteroid prior to administration of the immunoconjugate, optionally wherein the corticosteroid is diphenhydramine, acetaminophen, paracetamol, dexamethasone, or a combination thereof. (Item 90) 90. The method of any one of items 1-52 and 60-89, wherein the immunoconjugate and the BCL-2 inhibitor, the hypomethylating agent, or a combination thereof, are administered in separate pharmaceutical compositions. (Item 91) 91. The method according to any one of items 1 to 90, wherein the subject is a human. (Item 92) 1. A method of treating a hematological malignancy in a human subject, comprising administering to the subject in need thereof IMGN632 and venetoclax in a 21 day cycle, wherein the IMGN632 is administered intravenously at a dose of about 0.015 mg / kg to about 0.09 mg / kg on day 7 of the cycle, and the venetoclax is administered at an oral daily dose of 400 mg. (Item 93) 93. The method of claim 92, wherein IMGN632 is administered at a dose of about 0.045 mg / kg. (Item 94) 93. The method of item 92, wherein IMGN632 is administered at a dose of about 0.03 mg / kg. (Item 95) A method for treating a hematological malignancy in a human subject, comprising administering to the subject in need thereof IMGN632 and azacitidine in a 28 day cycle, wherein the IMGN632 is administered intravenously at a dose of about 0.015 mg / kg to about 0.09 mg / kg on day 7 of the cycle, and the azacitidine is administered intravenously at a dose of about 0.015 mg / kg to about 0.09 mg / kg on day 7 of the cycle, and the azacitidine is administered intravenously at a dose of about 75 mg / m 2 The therapeutic method is administered subcutaneously or intravenously at a dose of (Item 96) 96. The method of claim 95, wherein the azacitidine is administered on days 1 to 7 of the cycle. . (Item 97) 96. The method of item 95, wherein the azacitidine is administered on days 1 to 5 of the cycle. (Item 98) 98. The method of any one of items 95-97, wherein IMGN632 is administered at a dose of about 0.045 mg / kg. (Item 99) 98. The method of any one of items 95-97, wherein IMGN632 is administered at a dose of about 0.03 mg / kg. (Item 100) 98. The method of any one of items 95-97, wherein IMGN632 is administered at a dose of about 0.015 mg / kg. (Item 101) 101. The method of any one of items 95 to 100, further comprising administering venetoclax at an oral daily dose of 400 mg. (Item 102) The method of any one of items 92-94 and 101, wherein venetoclax is administered on days 1 to 7 of the cycle. (Item 103) The method of any one of items 92-94 and 101, wherein venetoclax is administered on days 1 to 8 of the cycle. (Item 104) The method of any one of items 92-94 and 101, wherein venetoclax is administered on days 1 to 14 of the cycle. (Item 105) The method of any one of items 92-94 and 101, wherein venetoclax is administered on days 1 to 18 of the cycle. (Item 106) 102. The method of any one of items 92-94 and 101, wherein venetoclax is administered on days 1 to 21 of the cycle. (Item 107) 102. The method of claim 101, wherein venetoclax is administered on days 1 to 28 of the cycle. (Item 108) 108. The method of any one of items 92 to 107, wherein the hematological malignancy is AML, BPDCN, or ALL.

Claims

1. 1. A method for treating a hematological malignancy in a subject, the method comprising administering to a subject in need thereof an immune complex that binds to CD123 (the immune complex comprises an antibody or antigen-binding fragment thereof, the antibody comprising 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), and a BCL-2 inhibitor, a hypomethylating agent, or a combination thereof.

2. The method of claim 1, wherein the immunoconjugate is administered in combination with the BCL-2 inhibitor.

3. The method of claim 1 , wherein the immunoconjugate is administered in combination with the hypomethylating agent.

4. The method of claim 1, wherein the immunoconjugate is administered in combination with the BCL-2 inhibitor and the hypomethylating agent.

5. The method according to any one of claims 1 to 4, wherein the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence shown in SEQ ID NO: 1 and / or a VL comprising the amino acid sequence shown in SEQ ID NO:

2.

6. The method of any one of claims 1 to 4, wherein the antibody or antigen-binding fragment comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:3 and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO:

4.

7. 7. The method of any one of claims 1 to 6, wherein the immunoconjugate comprises a cytotoxin, optionally the cytotoxin is a DNA alkylating agent, optionally the DNA alkylating agent is an indolino-benzodiazepine (IGN) DNA alkylating drug.

8. The method of any one of claims 1 to 7, wherein the immune complex is IMGN632.

9. The immunoconjugate is administered in a pharmaceutical composition comprising an immunoconjugate having the structure: 【Chemistry 1】 , in the formula, The method of any one of claims 1 to 7, 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. The method of any one of claims 1 to 9, wherein the administration is frontline therapy.

11. The method of any one of claims 1 to 10, wherein the immunoconjugate is administered intravenously.

12. The method of any one of claims 1 to 11, wherein administration of the immunoconjugate with the BCL-2 inhibitor, the hypomethylating agent, or a combination thereof produces a synergistic effect.

13. 13. The method of any one of claims 1, 2, and 4-12, wherein administration of the immunoconjugate and the BCL-2 inhibitor does not result in more toxicity than administration of the immunoconjugate alone or the BCL-2 inhibitor alone.

14. 13. The method of any one of claims 1 and 3-12, wherein administration of the immunoconjugate and the hypomethylating agent does not result in more toxicity than administration of the immunoconjugate alone or the hypomethylating agent alone.

15. 13. The method of any one of claims 1 and 4-12, wherein administration of the immunoconjugate, the BCL-2 inhibitor, and the hypomethylating agent does not result in more toxicity than the administration of the immunoconjugate, the BCL-2 inhibitor, and / or the hypomethylating agent.

16. 16. The method of any one of claims 1, 2, and 5-15, wherein the immunoconjugate is administered once every 21 day cycle.

17. 17. The method of claim 16, wherein the immunoconjugate is administered once in the 21 day cycle at a dose of about 0.015 mg / kg to about 0.09 mg / kg, optionally wherein the dose is about 0.015 mg / kg, about 0.045 mg / kg, or about 0.09 mg / kg.

18. 18. The method of claim 17, wherein said immunoconjugate is administered once in said 21 day cycle at a dose of about 0.045 mg / kg.

19. 18. The method of claim 17, wherein said immunoconjugate is administered once in said 21 day cycle at a dose of about 0.03 mg / kg.

20. 18. The method of claim 17, wherein said immunoconjugate is administered once in said 21 day cycle at a dose of about 0.015 mg / kg.

21. 21. The method of any one of claims 1, 2, and 4-20, wherein the BCL-2 inhibitor is administered daily in a 21 day cycle.

22. 21. The method of any one of claims 1, 2, and 4-20, wherein the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of a 21 day cycle, at a dose of 200 mg on day 2 of said 21 day cycle, and at a dose of 400 mg on days 3-21 of said 21 day cycle.

23. 21. The method of any one of claims 1, 2, and 4-20, wherein the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of a 21 day cycle, at a dose of 200 mg on day 2 of said 21 day cycle, and at a dose of 400 mg on days 3-7 or 3-14 of said 21 day cycle.

24. The method of any one of claims 1 and 3-15, wherein the immunoconjugate is administered once every 28 day cycle.

25. 25. The method of claim 24, wherein the immunoconjugate is administered once in said 28 day cycle at a dose of about 0.015 mg / kg to about 0.09 mg / kg, optionally wherein the dose is about 0.015 mg / kg, about 0.045 mg / kg, or about 0.09 mg / kg.

26. 25. The method of claim 24, wherein said immunoconjugate is administered once in said 28 day cycle at a dose of about 0.03 mg / kg.

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

28. The method of any one of claims 1, 2, and 4-27, wherein the BCL-2 inhibitor is venetoclax.

29. 30. The method of any one of claims 1, 2, 4-21, and 23-28, wherein the BCL-2 inhibitor is administered at a dose of 400 mg.

30. 30. The method of any one of claims 1, 2, 4-21, and 23-28, wherein the BCL-2 inhibitor is administered at a dose of 200 mg.

31. 31. The method of any one of claims 23 to 30, wherein the BCL-2 inhibitor is administered daily in a 28 day cycle.

32. 32. The method of any one of claims 21 and 28-31, wherein the BCL-2 inhibitor is administered daily on days 1-7 of the cycle.

33. 32. The method of any one of claims 21 and 28-31, wherein the BCL-2 inhibitor is administered daily on days 1-8 of the cycle.

34. 32. The method of any one of claims 21 and 28-31, wherein the BCL-2 inhibitor is administered daily on days 1-14 of the cycle.

35. 32. The method of any one of claims 21 and 28-31, wherein the BCL-2 inhibitor is administered daily on days 1-18 of the cycle.

36. 32. The method of any one of claims 21 and 28-31, wherein the BCL-2 inhibitor is administered daily on days 1-21 of the cycle.

37. 32. The method of claim 31 , wherein the BCL-2 inhibitor is administered daily on days 1 to 28 of the cycle.

38. 29. The method of any one of claims 24-28, wherein the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of a 28 day cycle, at a dose of 200 mg on day 2 of said 28 day cycle, and at a dose of 400 mg on days 3-28 of said 28 day cycle.

39. 29. The method of any one of claims 24-28, wherein the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of a 28 day cycle, at a dose of 200 mg on day 2 of said 28 day cycle, and at a dose of 400 mg on days 3-7 or 3-14 of said 28 day cycle.

40. 29. The method of any one of claims 24-28, wherein the BCL-2 inhibitor is administered at a dose of 100 mg on day 1 of the 28 day cycle and at a dose of 200 mg on days 2-28, 2-14, or 2-7 of the 28 day cycle.

41. 41. The method of any one of claims 1, 2, and 4-40, wherein the BCL-2 inhibitor is administered orally.

42. 42. The method of any one of claims 1, 2, and 4-41, wherein administration of the immunoconjugate is initiated 6 days after the initiation of administration of the BCL-2 inhibitor.

43. The method of any one of claims 1, 3-15, and 23-42, wherein the hypomethylating agent is azacytidine.

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

45. 45. The method of claim 43 or 44, wherein the azacitidine is administered once daily on days 1 to 7 of a 28 day cycle.

46. 45. The method of claim 43 or 44, wherein the azacitidine is administered once daily on days 1-5 of a 28 day cycle.

47. 45. The method of claim 43 or 44, wherein the azacitidine is administered once daily on days 3 to 7 of a 28 day cycle.

48. The azacitidine is at about 75 mg / m ２ The method according to any one of claims 43 to 47, wherein the dose is

49. 49. The method of any one of claims 43-48, wherein the azacitidine is administered subcutaneously or intravenously.

50. 43. The method of any one of claims 1 and 3-42, wherein the hypomethylating agent is decitabine.

51. 51. The method of claim 50, wherein the decitabine is administered intravenously.

52. 52. The method of any one of claims 1-51, wherein the hematological malignancy is present in the subject as minimal residual disease (MRD).

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

54. 54. The method of claim 53, wherein the immunoconjugate is administered at a dose of about 0.045 mg / kg to about 0.18 mg / kg.

55. 54. The method of claim 53, wherein the immunoconjugate is administered at a dose of about 0.045 mg / kg.

56. 55. The method of claim 53 or 54, wherein about 0.045 mg / kg, about 0.09 mg / kg, about 0.135 mg / kg, or about 0.18 mg / kg is administered to the subject.

57. 57. The method of any one of claims 53 to 56, wherein the immunoconjugate is administered intravenously.

58. 58. The method of any one of claims 53 to 57, wherein the hematological malignancy is leukemia.

59. 59. The method of any one of claims 53-58, wherein the immunoconjugate is administered to the subject once every 21 day cycle.

60. 60. The method of any one of claims 16-52 or 59, wherein the administration is one cycle.

61. 60. The method of any one of claims 16-52 or 59, wherein the administration is for more than one cycle, optionally the administration is for at least 2 cycles, at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, at least 7 cycles, at least 8 cycles, at least 9 cycles, or at least 10 cycles, or the administration is for about 2-4 cycles, about 2-6 cycles, about 2-8 cycles, about 2-10 cycles, or about 2-12 cycles.

62. 62. The method of any one of claims 1-61, wherein the method further comprises administering a reduced dose of the immunoconjugate after dose-limiting toxicity occurs in the subject and is reduced to baseline or grade 2 or less.

63. The method of any one of claims 1 to 62, wherein the immunoconjugate is further administered as a maintenance therapy.

64. 64. The method of claim 63, wherein the maintenance therapy comprises administering the immunoconjugate once every 21 day cycle.

65. 65. The method of claim 64, wherein the maintenance therapy comprises administering the immunoconjugate once in said 21 day cycle at a dose of about 0.015 mg / kg to about 0.09 mg / kg, optionally wherein the dose is about 0.015 mg / kg, about 0.045 mg / kg, or about 0.09 mg / kg.

66. 65. The method of claim 64, wherein said maintenance therapy comprises administering said immunoconjugate at a dose of about 0.045 mg / kg once in said 21 day cycle.

67. 67. The method of any one of claims 1-9, 11-50, and 60-66, wherein the hematological malignancy is a recurrent hematological malignancy.

68. 70. The method of any one of claims 1 to 9, 11 to 50, and 60 to 67, wherein the hematological malignancy is a refractory hematological malignancy.

69. 69. The method of any one of claims 1 to 68, 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 / blast crisis phase (BP-CML), and blastic plasmacytoid dendritic cell neoplasm (BPDCN).

70. The method of claims 1-68, wherein the hematological malignancy is AML.

71. 69. The method of any one of claims 1 to 68, wherein the hematological malignancy is BPDCN.

72. 69. The method of any one of claims 1 to 68, wherein the hematological malignancy is ALL.

73. 73. The method of any one of claims 1 to 72, wherein the hematological malignancy is a CD123 expressing hematological malignancy.

74. 74. The method of any one of claims 1 to 73, wherein CD123 is detected in a sample obtained from said hematological malignancy prior to said administering, and optionally said CD123 is detected using flow cytometry.

75. 75. The method of any one of claims 1 to 74, further comprising detecting CD123 in a sample obtained from said hematological malignancy prior to said administering.

76. The method of any one of claims 1 to 75, wherein at least 80% of cells in the hematological malignancy express CD123.

77. 77. The method of any one of claims 1 to 76, wherein CD123 is detected in at least 80% of cells in a sample obtained from said hematological malignancy prior to said administering.

78. 78. The method of any one of claims 1 to 77, further comprising detecting CD123 in at least 80% of cells in a sample obtained from said hematological malignancy prior to said administering.

79. 80. The method of any one of claims 1-52 and 60-78, wherein the hematological malignancy is resistant to IMGN632.

80. 80. The method of any one of claims 1-79, wherein the hematological malignancy expresses multidrug resistance 1 (MDR1).

81. 81. The method of any one of claims 1 to 80, wherein the hematological malignancy expresses P-glycoprotein (P-gp).

82. The method of any one of claims 1 to 81, wherein the subject has an absolute neutrophil count of greater than 500 / μL.

83. 83. The method of any one of claims 1-9 and 11-82, wherein the subject has received at least one prior therapy, at least two prior therapies, or at least three prior therapies.

84. The method of any one of claims 1-9 and 11-83, wherein the cancer has been previously treated with venetoclax.

85. The method of any one of claims 1-83, wherein the cancer has not been previously treated with venetoclax.

86. 86. The method of any one of claims 1-9 and 11-85, wherein the cancer has previously been treated with a hypomethylating agent.

87. Any one of claims 1 to 85, wherein the cancer has not been previously treated with a hypomethylating agent. The method described above.

88. 88. The method of any one of claims 1-87, wherein the subject is pre-treated with a corticosteroid prior to administration of the immunoconjugate, and optionally the corticosteroid is diphenhydramine, acetaminophen, paracetamol, dexamethasone, or a combination thereof.

89. 88. The method of any one of claims 1-87, further comprising pretreating the subject with a corticosteroid prior to administration of the immunoconjugate, optionally wherein the corticosteroid is diphenhydramine, acetaminophen, paracetamol, dexamethasone, or a combination thereof.

90. 90. The method of any one of claims 1-52 and 60-89, wherein the immunoconjugate and the BCL-2 inhibitor, the hypomethylating agent, or a combination thereof, are administered in separate pharmaceutical compositions.

91. The method of any one of claims 1 to 90, wherein the subject is a human.

92. 1. A method of treating a hematological malignancy in a human subject, comprising administering to the subject in need thereof IMGN632 and venetoclax in a 21 day cycle, wherein the IMGN632 is administered intravenously at a dose of about 0.015 mg / kg to about 0.09 mg / kg on day 7 of the cycle, and the venetoclax is administered at an oral daily dose of 400 mg.

93. 93. The method of claim 92, wherein IMGN632 is administered at a dose of about 0.045 mg / kg.

94. 93. The method of claim 92, wherein IMGN632 is administered at a dose of about 0.03 mg / kg.

95. 1. A method for treating a hematological malignancy in a human subject, comprising administering to said subject in need thereof IMGN632 and azacitidine in a 28 day cycle, wherein said IMGN632 is administered intravenously at a dose of about 0.015 mg / kg to about 0.09 mg / kg on day 7 of said cycle, and said azacitidine is administered intravenously at a dose of about 0.015 mg / kg to about 0.09 mg / kg on day 7 of said cycle, and ２ The therapeutic method is administered subcutaneously or intravenously at a dose of

96. 96. The method of claim 95, wherein the azacitidine is administered on days 1 to 7 of the cycle.

97. 96. The method of claim 95, wherein the azacitidine is administered on days 1 to 5 of the cycle.

98. 98. The method of any one of claims 95-97, wherein IMGN632 is administered at a dose of about 0.045 mg / kg.

99. 98. The method of any one of claims 95-97, wherein IMGN632 is administered at a dose of about 0.03 mg / kg.

100. 98. The method of any one of claims 95-97, wherein IMGN632 is administered at a dose of about 0.015 mg / kg.

101. The method of any one of claims 95-100, further comprising administering venetoclax at an oral daily dose of 400 mg.

102. The method of any one of claims 92-94 and 101, wherein venetoclax is administered on days 1 to 7 of the cycle.

103. The method of any one of claims 92-94 and 101, wherein venetoclax is administered on days 1 to 8 of the cycle.

104. The method of any one of claims 92-94 and 101, wherein venetoclax is administered on days 1 to 14 of the cycle.

105. The method of any one of claims 92-94 and 101, wherein venetoclax is administered on days 1 to 18 of the cycle.

106. The method of any one of claims 92-94 and 101, wherein venetoclax is administered on days 1 to 21 of the cycle.

107. The method of claim 101, wherein venetoclax is administered on days 1 to 28 of the cycle.

108. The method of any one of claims 92-107, wherein the hematological malignancy is AML, BPDCN, or ALL.

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