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WO2024123765A1 - Combinaisons thérapeutiques comprenant des conjugués anticorps-médicament anti-cd123 et des anticorps anti-cd47 - Google Patents

Combinaisons thérapeutiques comprenant des conjugués anticorps-médicament anti-cd123 et des anticorps anti-cd47 Download PDF

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Publication number
WO2024123765A1
WO2024123765A1 PCT/US2023/082499 US2023082499W WO2024123765A1 WO 2024123765 A1 WO2024123765 A1 WO 2024123765A1 US 2023082499 W US2023082499 W US 2023082499W WO 2024123765 A1 WO2024123765 A1 WO 2024123765A1
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antibody
antigen
binding fragment
adc
administered
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Patrick Zweidler-Mckay
Giridharan RAMSINGH
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Gilead Sciences Inc
Immunogen Inc
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Gilead Sciences Inc
Immunogen Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68035—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a pyrrolobenzodiazepine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Definitions

  • the field of the invention generally relates to combinations of an anti-CD123 antibody- drug conjugates (ADCs) and anti-CD47 antibodies or antigen-binding fragments thereof use in the treatment of hematologic malignancies.
  • ADCs anti-CD123 antibody- drug conjugates
  • Antigen-binding fragments thereof use in the treatment of hematologic malignancies.
  • Cross-refrence to Related Applications [0002] This application claims the benefit of U.S. Application No.63/386,627, filed December 8, 2022, which is incorporated herein by reference in its entirety.
  • Background [0003] Cancer is one of the leading causes of death in the developed world, with over one million people diagnosed with cancer and 500,000 deaths per year in the United States alone.
  • AML Acute myeloid leukemia
  • CRC complete response
  • “Fit” patients are judged to be able to tolerate intensive treatment, are often younger ( ⁇ 60 years), and typically receive one to two cycles of induction with "7 + 3," a combination of cytarabine and anthracycline, typically daunorubicin. Following this, these fit patients may receive high-dose cytarabine for one or more cycles and may receive a stem cell transplant. Standard induction and post-induction therapies result in a median duration of remission of approximately one year and potential cures in 25%-35% of the patients. "Unfit" patients, often older, typically receive venetoclax, azacitidine, a hypomethylating agent. The majority of AML patients will eventually relapse, and AML salvage regimens offer poor outcomes with significant toxicity.
  • Blastic plasmacytoid dendritic cell neoplasm is a rare, aggressive hematologic malignancy derived from myeloid dendritic cell precursors, which often manifests with skin lesions in addition to lymph node, blood, and bone marrow involvement. Characterized by CD4, CD56, and CD123 expression among other markers, BPDCN blasts express high levels of CD123.
  • ALL acute lymphoblastic leukemia
  • AML AML
  • Acute lymphoblastic leukemia is a rare, aggressive hematologic malignancy derived from lymphoid precursors, which often manifests 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.
  • initial remission rates are high, long-term survival rates are 35%-40% in patients less than 60 years of age, and less than 10% for older patients (Goldstone 2008).
  • Patients with relapsed ALL have several chemotherapeutic options, as well as immunotherapy with United States Food and Drug Administration-approved anti-CD19 bispecific blinatumomab. However, long-term survival remains poor for these patients.
  • CD123 has been proposed as a potential target for the treatment of some hematological malignancies.
  • CD123 is the alpha-subunit of the interleukin-3 receptor (IL-3R ⁇ ).
  • IL-3R ⁇ interleukin-3 receptor
  • CD123 expression is low on normal hematopoietic stem cells (Testa et al., Biomark Res., 10;2(1):4.(2014), Jordan et al., Leukemia, 14(10):1777-84 (2000)).
  • CD123 is overexpressed in multiple hematological malignancies of both myeloid and lymphoid origins, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), B-cell acute lymphoblastic leukemia (B-ALL), chronic myeloid leukemia in blast crisis/phase (BP-CML), and blastic plasmacytoid dendritic cell neoplasm (BPDCN) (Testa 2014).
  • IMGN632 also known as pivekimab sunirine or PVEK
  • ADC antibody-drug conjugate
  • CD47 Cluster of differentiation 47
  • Magrolimab is a monoclonal antibody against CD47 and thus a macrophage checkpoint inhibitor that is designed to interfere with recognition of CD47 by the SIRP ⁇ receptor on macrophages, thereby allowing the activation of macrophages, resulting in specific tumor cell phagocytosis.
  • ADC antibody drug conjugate
  • said ADC comprises a DNA-alklyating agent conjugated to an anti-CD123 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 (b) an anti-CD47 antibody or antigen-binding fragment thereof comprising a heavy chain variable region CDR1 comprising the amino acid sequence
  • the anti-CD123 antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 1 or a VL comprising the amino acid sequence set forth in SEQ ID NO: 2. In some aspects, the anti-CD123 antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 1 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 2. In some aspects, the anti-CD123 antibody or antigen-binding fragment thereof is an antibody.
  • the anti-CD123 antibody or antigen-binding fragment thereof is a human IgG antibody or antigen-binding fragment thereof, optionally wherein the antibody or antigen-binding fragment thereof is a human IgG1 antibody or antigen-binding fragment thereof.
  • the anti- CD123 antibody or antigen-binding fragment comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 3 or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 4.
  • the anti-CD123 antibody or antigen-binding fragment 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.
  • the DNA- agent is indolino-benzodiazepine (IGN) DNA- alkylator.
  • the ADC is IMGN632/PVEK.
  • the ADC is administered in a pharmaceutical composition comprising ADCs with the following structure: ,wherein in SEQ ID NO: 3 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 4.
  • the ADC is administered intravenously.
  • the ADC is administered once every 28 days.
  • the ADC is administered at a dose of 0.045 mg/kg.
  • the ADC is administered at a dose of 0.045 mg/kg for two doses. In some aspects, the ADC is administered at a dose of 0.03 mg/kg. In some aspects, the ADC is administered at a dose of 0.03 mg/kg for two doses.
  • the anti-CD123 ADC and the anti-CD47 antibody or antigen-binding fragment thereof are administered in separate pharmaceutical compositions. [0019] In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 13 or a VL comprising the amino acid sequence set forth in SEQ ID NO: 14.
  • the anti-CD47 antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 13 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 14.
  • the anti-CD47 antibody or antigen-binding fragment thereof is an antibody.
  • the anti-CD47 antibody or antigen-binding fragment thereof is a human IgG antibody or antigen-binding fragment thereof, optionally wherein the antibody or antigen-binding fragment thereof is a human IgG4 antibody or antigen-binding fragment thereof.
  • the anti-CD47 antibody or antigen-binding fragment comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 21 or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 22. In some aspects, the anti-CD47 antibody or antigen-binding fragment comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 21 and a light chain comprising the sequence set forth in SEQ ID NO: 22. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof is magrolimab. [0020] In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof is administered intravenously.
  • the anti-CD47 antibody or antigen-binding fragment thereof is administered once every week. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof is administered once every two weeks. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof is administered once every week and once every two weeks (e.g., once every week and then once every two weeks). [0022] In some aspects, administering the anti-CD47 antibody or antigen-binding fragment thereof comprises administering a priming regimen and administering a maintenance regimen. [0023] In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof is administered once every two weeks in the maintenance regimen.
  • the anti-CD47 antibody or antigen-binding fragment thereof is administered at a dose of 30 mg/kg in the maintenance regimen. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof is administered at a dose of 25 mg/kg in the maintenance regimen. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof is administered at a dose of 20 mg/kg in the maintenance regimen. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof is administered at a dose of 15 mg/kg in the maintenance regimen. [0024] In some aspects,the anti-CD47 antibody or antigen-binding fragment thereof is administered once every 3 or 4 days.
  • the anti-CD47 antibody or antigen-binding fragment thereof is administered once every week in the priming regimen. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof is administered once every 3 or 4 days and/or once every week in the priming regimen. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof is administered in at least two increasing doses in the priming regimen. In some aspects, the at least two increasing doses in the priming regimen are from 1 mg/kg to 30 mg/kg. In some aspects, the at least two increasing doses in the priming regimen are selected from the group consisting of 1 mg/kg, 15 mg/kg, and 30 mg/kg doses.
  • the anti-CD47 antibody or antigen-binding fragment thereof is administered in three increasing doses in the priming regimen.
  • the three increasing doses in the priming regimen are from 1 mg/kg to 30 mg/kg.
  • the at least three increasing doses in the priming regimen are 1 mg/kg, 15 mg/kg, and 30 mg/kg doses.
  • the three increasing doses comprise a first dose administered on Days 1 and 4, a second dose administered on Day 8, and a third dose administered on Days 11, 15 and then once every week for 5 doses.
  • the anti-CD47 antibody or antigen-binding fragment thereof is administered at 1 mg/kg on Days 1 and 4, at 15 mg/kg 8, and at 30 mg/kg on Days 11, 15, and then once every week for 5 doses.
  • the ADC is administered intravenously once every 28 days at a dose of 0.045 mg/kg and the anti-CD47 antibody or antigen-binding fragment thereof is administered in a priming regimen comprising 1 mg/kg on Days 1 and 4, at 15 mg/kg on Day 8, and at 30 mg/kg on Days 11, 15, and then once every week for 5 doses and then a maintenance regimen comprising 30 mg/kg once every two weeks.
  • the ADC is administered intravenously once every 28 days at a dose of 0.03 mg/kg and the anti-CD47 antibody or antigen-binding fragment thereof is administered in a priming regimen comprising 1 mg/kg on Days 1 and 4, at 15 mg/kg on Day 8, and at 30 mg/kg on Days 11, 15, and then once every week for 5 doses and then a maintenance regimen comprising 30 mg/kg once every two weeks.
  • the ADC is administered intravenously once every 28 days at a dose of 0.045 mg/kg and the anti-CD47 antibody or antigen-binding fragment thereof is administered in a priming regimen comprising 1 mg/kg on Days 1 and 4, at 15 mg/kg on Day 8, and at 25 mg/kg on Days 11, 15, and then once every week for 5 doses and then a maintenance regimen comprising 25 mg/kg once every two weeks.
  • the ADC is administered intravenously once every 28 days at a dose of 0.03 mg/kg and the anti-CD47 antibody or antigen-binding fragment thereof is administered in a priming regimen comprising 1 mg/kg on Days 1 and 4, at 15 mg/kg on Day 8, and at 25 mg/kg on Days 11, 15, and then once every week for 5 doses and then a maintenance regimen comprising 25 mg/kg once every two weeks.
  • the ADC is administered intravenously once every 28 days at a dose of 0.045 mg/kg and the anti-CD47 antibody or antigen-binding fragment thereof is administered in a priming regimen comprising 1 mg/kg on Days 1 and 4, at 15 mg/kg on Day 8, and at 20 mg/kg on Days 11, 15, and then once every week for 5 doses and then a maintenance regimen comprising 20 mg/kg once every two weeks.
  • the ADC is administered intravenously once every 28 days at a dose of 0.03 mg/kg and the anti-CD47 antibody or antigen-binding fragment thereof is administered in a priming regimen comprising 1 mg/kg on Days 1 and 4, at 15 mg/kg on Day 8, and at 20 mg/kg on Days 11, 15, and then once every week for 5 doses and then a maintenance regimen comprising 20 mg/kg once every two weeks.
  • the ADC is administered intravenously once every 28 days at a dose of 0.045 mg/kg and the anti-CD47 antibody or antigen-binding fragment thereof is administered in a priming regimen comprising 1 mg/kg on Days 1 and 4, at 15 mg/kg on Days 8, 11, 15, and then once every week for 5 doses and then a maintenance regimen comprising 15 mg/kg once every two weeks.
  • the ADC is administered intravenously once every 28 days at a dose of 0.03 mg/kg and the anti-CD47 antibody or antigen-binding fragment thereof is administered in a priming regimen comprising 1 mg/kg 1 and 4, at 15 mg/kg on Days 8, 11, 15, and then once every week for 5 doses and then a maintenance regimen comprising 15 mg/kg once every two weeks.
  • the ADC is further administered as a maintenance therapy.
  • the ADC is administered once every two weeks during the maintenance therapy.
  • the ADC is administered once every four weeks during the maintenance therapy.
  • the ADC is administered at 0.045 mg/kg during the maintenance therapy.
  • the ADC is administered at 0.03 mg/kg during the maintenance therapy.
  • the hematological malignancy is a relapsed or refractory hematological malignancy. In some aspects, the hematological malignancy is a relapsed hematological malignancy. In some aspects, the hematological malignancy is a refractory hematological malignancy. In some aspects, the hematological malignancy is acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), B-cell acute lymphoblastic leukemia (B-ALL), chronic myeloid leukemia in blast crisis/phase (BP-CML), and blastic plasmacytoid dendritic cell neoplasm (BPDCN).
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • B-ALL B-cell acute lymphoblastic leukemia
  • BP-CML chronic myeloid leukemia in blast crisis/phase
  • BPDCN blastic plasmacytoid dendritic cell neoplasm
  • the hematological malignancy is a CD123+ hematological malignancy. In some aspects, the hematological malignancy has an FLT3-ITD mutation. In some aspects, the hematological malignancy expresses multidrug resistance 1 (MDR1). In some aspects, the hematological malignancy expresses P-glycoprotein (P-gp).
  • the administration is a first-line therapy. In some aspects, the subject received one prior line of therapy. In some aspects, the subject received two prior lines of therapy. [0032] In some aspects, the cancer has not previously been treated with IMGN632/PVEK. In some aspects, the cancer has not previously been treated with magrolimab.
  • the cancer has not previously been treated with an SIRP ⁇ -targeting agent.
  • administration of the ADC and the anti-CD47 antibody or antigen- binding fragment thereof produces a synergistic effect.
  • administration of the ADC and the anti-CD47 antibody or antigen-binding fragment thereof does not produce more toxicity than administration of the ADC alone.
  • administration of the ADC and the anti-CD47 antibody or antigen-binding fragment thereof does not produce more toxicity than administration of the anti-CD47 antibody or antigen-binding fragment thereof alone.
  • the subject received dexamethasone on the day prior to the administration of the ADC.
  • the subject received 8 mg dexamethasone twice on the day prior to the administration of the ADC. In some aspects, the method further comprises administering dexamethasone to the subject on the day prior to the administration of the ADC. In some aspects, the method further comprises administering 8 mg dexamethasone to the subject twice on the day prior to the administration of the ADC. [0035] In some aspects, the subject diphenhydramine prior to the administration of the ADC. In some aspects, the subject received 25 mg to 50 mg diphenhydramine prior to the administration of the ADC. In some aspects, the method further comprises administering diphenhydramine to the subject prior the administration of the ADC.
  • the method further comprises method further comprises administering 25 mg to 50 mg diphenhydramine, to the subject prior the administration of the ADC.
  • the subject received acetaminophen or paracetamol prior to the administration of the ADC.
  • the subject received 325 mg to 650 mg acetaminophen or paracetamol prior to the administration of the ADC.
  • the method further comprises administering acetaminophen or paracetamol, optionally 325 mg to 650 mg acetaminophen or paracetamol, to the subject prior to the administration of the ADC.
  • the subject received dexamethasone prior to the administration of the ADC.
  • the subject received 8 mg dexamethasone prior to the administration of the ADC. In some aspects, the method further comprises administering dexamethasone to the subject prior to the administration of the ADC. In some aspects, the method further comprises administering 8 mg dexamethasone to the subject prior to the administration of the ADC. [0038] In some aspects, the the subject received acetaminophen (optionally 650 mg to 1000 mg acetaminophen), diphenhydramine (optionally 35 mg to 50 mg diphenhydramine), or comparable regimen prior to the administration of the anti-CD47 antibody or antigen-binding fragment thereof.
  • acetaminophen optionally 650 mg to 1000 mg acetaminophen
  • diphenhydramine optionally 35 mg to 50 mg diphenhydramine
  • the method further comprises administering acetaminophen (optionally 650 mg to 1000 mg acetaminophen), diphenhydramine (optionally 35 mg to 50 mg diphenhydramine), or comparable regimen to the subject prior to the administration of the anti- CD47 antibody or antigen-binding fragment thereof.
  • acetaminophen optionally 650 mg to 1000 mg acetaminophen
  • diphenhydramine optionally 35 mg to 50 mg diphenhydramine
  • the ADC is IMGN632/PVEK
  • the ADC is administered intravenously at a dose of 0.045 mg/kg once every 28 days
  • the anti-CD47 antibody or antigen-binding fragment thereof is magrolimab
  • the magrolimab is administered intravenously in a priming regimen comprising 1 mg/kg on Days 1 and 4, at 15 mg/kg on Day 8, and at 30 mg/kg on Days 11, 15, and then once every week for 5 doses and then a maintenance regimen comprising 30 mg/kg once every two weeks.
  • the ADC is IMGN632/PVEK
  • the ADC is administered intravenously at a dose of 0.03 mg/kg once every 28 days
  • the anti-CD47 antibody or antigen-binding fragment thereof is magrolimab
  • the magrolimab is administered intravenously in a priming regimen comprising 1 mg/kg on Days 1 and 4, at 15 mg/kg on Day 8, and at 30 mg/kg on Days 11, 15, and then once every week for 5 doses and then a maintenance regimen comprising 30 mg/kg once every two weeks.
  • the ADC is twice.
  • the subject is human.
  • compositions comprising an ADC that binds to CD123 for use in combination with an anti-CD47 antibody or antigen-binding fragment thereof for treating a hematologic malignancy in any method provided herein.
  • compositions comprising an ADC that binds to CD123, wherein the composition is to be administered with an anti-CD47 antibody or antigen-binding fragment thereof for treating a hematologic malignancy in any method provided herein.
  • composition comprising an anti-CD47 antibody or antigen-binding fragment thereof for use in combination with an ADC that binds to CD123 for treating a hematologic malignancy in any method provided herein.
  • FIG.1A shows the chemical structure for IMGN632 (PVEK).
  • IMGN632 is composition comprising ADCs containing the anti-CD123 G4723A antibody linked to the cytotoxic payload DGN549-C in sodium bisulfite. The majority of the ADC in the composition is in the sulfonated version shown in FIG.1A.
  • FIG.1B shows an unsulfonated form of the ADC containing the anti-CD123 G4723A antibody linked to the cytotoxic payload DGN549-C (the mono-imine structure), which can also be present in an IMGN632 composition.
  • FIG.2 shows the study schema for a trial demonstrating the efficacy of the combination of IMGN632 and magrolimab. After acceptable safety and sufficient efficacy are observed in the Safety Phase, and futility is passed (Stage 1), up to an additional 14 efficacy-evaluable patients are enrolled in the Full Expansion Phase to allow further demonstration of repeated dosing safety and efficacy (Stage 2).
  • the present invention provides combinations of an anti-CD123 antibody drug conjugate (ADC) with an anti-CD47 antibody or antigen-binding fragment thereof and the use of the combinations in the treatment of hematologic malignancies.
  • ADC anti-CD123 antibody drug conjugate
  • CD123 polypeptides encompass “full-length,” unprocessed CD123 polypeptides as well as any form of CD123 polypeptide that results from processing within the cell.
  • the term also encompasses naturally occurring variants of CD123, e.g., those encoded by splice variants and allelic variants.
  • the CD123 polypeptides described herein can be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods. Where specifically indicated, "CD123” can be used to refer to a nucleic acid that encodes a CD123 polypeptide.
  • Human CD123 sequences are known and include, for example, those sequences associated with NCBI reference numbers NP_002174 & NM_002183 (protein and nucleic acid sequences for human CD123 variant 1), and NP_001254642 & NM_001267713 (protein and nucleic acid sequences for human CD123 variant 2).
  • the term "human CD123” refers to CD123 comprising the sequence of SEQ ID NO: 25 or SEQ ID NO: 26.
  • CD47 polypeptides encompass “full-length,” polypeptides as well as any form of CD47 polypeptide that results from processing within the cell.
  • the term also encompasses naturally occurring variants of CD47, e.g., those encoded by splice variants and allelic variants.
  • the CD47 polypeptides described herein can be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods. Where specifically indicated, “CD47” can be used to refer to a nucleic acid that encodes a CD47 polypeptide. Human CD47 sequences are known and include, for example, those sequences associated with UniProt reference number Q08722.
  • human CD47 refers to CD47 comprising the sequence of SEQ ID NO: 27.
  • "human CD47” can comprise the leader sequence MWPLVAALLLGSACCGSA (SEQ ID NO: 28) at the N-terminus of SEQ ID NO:
  • antibody means an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or combinations of the foregoing through at
  • an antibody encompasses intact polyclonal antibodies, intact monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising an antibody, and any other modified immunoglobulin molecule so long as the antibodies exhibit the desired biological activity.
  • An antibody can be of any the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g. IgG3, IgG4, IgA1 and IgA2), based on the identity of their heavy-chain constant domains referred to as alpha, delta, epsilon, gamma, and mu, respectively.
  • anti-CD123 antibody or "an antibody that binds to CD123” refers to an antibody that is capable of binding 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/PVEK).
  • the extent of binding of an anti-CD123 antibody to an unrelated, non-CD123 protein can be less than about 10% of the binding of the antibody to CD123 measured, e.g., by a radioimmunoassay (RIA).
  • anti-CD47 antibody or “an antibody that binds to CD47” refers to an antibody that is capable of binding CD47 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting CD47 (e.g., the antibody magrolimab).
  • the extent of binding of an anti-CD47 antibody to an unrelated, non-CD47 protein can be less than about 10% of the binding of the antibody to CD47 measured, e.g., by a radioimmunoassay (RIA).
  • RIA radioimmunoassay
  • antibody fragment refers to a portion of an intact antibody with a 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 a sufficient positive charge to bind to a cation exchange resin.
  • An antigen-binding fragment can contain the antigenic determining variable regions 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.
  • the term "cysteine engineered” antibody or antigen-binding fragment thereof includes an antibody or antigen-binding fragment thereof with at least one cysteine (“Cys”) that is not normally present at a given residue of the antibody or antigen-binding fragment thereof light chain or heavy chain.
  • Such Cys which may also be referred to as "engineered Cys,” can be engineered using any conventional molecular biology or recombinant technology (e.g. , by replacing the coding sequence for a non-Cys residue at the target residue with a coding sequence for 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 encodes Cys.
  • the Cys engineered antibody or antigen-binding fragment thereof has an engineered Cys in the heavy chain.
  • the engineered Cys is in or near the CH3 domain of the heavy chain.
  • 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).
  • 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 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.
  • any one or more of the following residues may be substituted with 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.
  • the variable light chain domain e.g., of an scFv
  • the variable heavy chain domain e.g. of an scFv
  • Cysteine engineered antibodies may be generated as described, e.g., in U.S. Pat. No.7,521,541, U.S. Pat. No.7,855,275, U.S. Published Application No.
  • a "monoclonal" antibody or antigen-binding fragment thereof refers to a homogeneous antibody or antigen-binding fragment population involved in the highly specific recognition and binding of a single antigenic determinant, or epitope. This is in contrast to polyclonal antibodies that typically include 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 (such as Fab, Fab', F(ab')2, Fv), single chain (scFv) mutants, fusion proteins comprising an antibody portion, and any other modified immunoglobulin molecule comprising an antigen recognition site.
  • “monoclonal” antibody or antigen-binding fragment thereof refers to such antibodies and antigen- binding fragments thereof made in any number of manners including but not limited to by hybridoma, phage selection, recombinant expression, and transgenic animals.
  • 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.
  • humanized antibodies or antigen-binding fragments thereof are human immunoglobulins in which residues from the complementary determining region (CDR) are replaced by residues from the CDR of a non-human species (e.g.
  • CDR grafted mouse, rat, rabbit, hamster
  • Fv framework region (FR) residues of a human immunoglobulin are replaced with the corresponding residues in an antibody or fragment from a non-human species that has the desired specificity, affinity, and capability.
  • the humanized antibody or antigen-binding fragment thereof can be further modified by the substitution of additional residues either in the Fv framework region and/or within the replaced non-human residues to refine and optimize antibody or antigen-binding fragment thereof specificity, affinity, and/or capability.
  • the humanized antibody or antigen-binding fragment thereof will comprise substantially all of at least one, and typically two or three, variable domains containing all or substantially all of the CDR regions that correspond to the non-human immunoglobulin whereas all or substantially all of the FR regions are those 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.
  • 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 variable regions of the heavy and light chain each consist of four framework regions (FR) 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, with the CDRs from the other chain, contribute to the formation of the antigen-binding site of antibodies.
  • the Kabat numbering system is generally used when referring to a residue in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. (5th Ed., 1991, National Institutes of Health, Bethesda, Md.) ("Kabat").
  • the amino acid position numbering as in Kabat refers to the numbering system used for heavy chain variable domains or light chain variable domains of the compilation of antibodies in Kabat et al. (Sequences of Immunological Interest.
  • a heavy chain variable domain can include a single amino acid insert (residue 52a according to Kabat) after residue 52 of H2 and inserted residues (e.g. residues 82a, 82b, and 82c, etc. according to Kabat) after heavy chain FR residue 82.
  • the Kabat numbering of residues can be determined for a given antibody by alignment at regions of homology of the sequence of with a "standard" Kabat numbered sequence. Chothia refers instead 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 insertions 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 Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software. Loop Kabat AbM Chothia L1 L24-L34 L24-L34 L24-L34 L2 L50-L56 L50-L56 L50-L56 L3 L89-L97 L89-L97 L89-L97 H1 H31-H35B H26-H35B H26-H32..34 (Kabat Numbering) H1 H31-H35 H26-H35 H26-H32 (Chothia Numbering) H2 H50-H65 H50-H58 H52-H56 H3 H95-H102 H95-H102 H95-H102 [0065]
  • 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 corresponding to an antibody or antigen-binding fragment thereof produced
  • a human antibody or antigen-binding fragment thereof includes intact or full-length antibodies and fragments thereof.
  • the term "chimeric" antibodies or antigen-binding fragments thereof refers to antibodies or antigen-binding fragments thereof wherein the amino acid sequence is derived from two or more species.
  • the variable region of both light and heavy chains corresponds to the variable region of antibodies or antigen-binding fragments thereof derived from one species of mammals (e.g. mouse, rat, rabbit, etc.) with the desired specificity, affinity, and capability while the constant regions are homologous to the sequences in antibodies or antigen-binding fragments thereof derived from another (usually human) to avoid eliciting an immune response in that species.
  • epitopes or "antigenic determinant” are used interchangeably herein and refer to that portion of an antigen capable of being recognized and specifically bound by a particular antibody.
  • the antigen is a polypeptide
  • epitopes can be formed both from contiguous amino acids and noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are upon protein denaturing, whereas epitopes formed by tertiary folding are typically lost upon protein denaturing.
  • An epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acids in a unique spatial conformation.
  • Binding affinity generally refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen).
  • the affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein.
  • binding affinity refers to a stronger binding between a molecule and its binding partner.
  • Or better when used herein refers to a stronger binding, represented by a smaller numerical Kd value. For example, an antibody which has an affinity for an antigen of "0.6 nM or better", the antibody's affinity for the antigen is ⁇ 0.6 nM, i.e.
  • telomere binding domain an antibody binds to an epitope via its antigen binding domain, and that the binding entails some 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 that epitope, via its antigen binding domain more readily than it would bind to a random, unrelated epitope.
  • the term "specificity" is used herein to qualify the relative affinity by which a certain antibody binds to a certain epitope.
  • antibody “A” may be deemed to have a higher specificity for a given epitope than antibody "B,” or antibody “A” may be said to bind to epitope “C” with a higher specificity than it has for related epitope “D.”
  • preferentially binds it is meant that the antibody specifically binds to an epitope more readily than it would bind to a related, similar, homologous, or analogous epitope.
  • an antibody which "preferentially binds" to a given epitope would more likely bind to that epitope than to a related epitope, even though such an antibody may cross-react with the related epitope.
  • polypeptide polypeptide
  • peptide protein
  • polymers of amino acids of any length can be linear or branched, it can comprise modified amino acids, and it can be by non-amino acids.
  • the terms also encompass an amino acid polymer that has been 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.
  • polypeptides containing one or more analogs of an amino acid including, for example, unnatural amino acids, etc.
  • cytotoxin e.g., such as an indolino-benzodiazepine (IGN) DNA-alkylator (e.g., DGN549-C)
  • A antibody or antigen-binding fragment thereof, e.g., an anti-CD123 antibody or antibody fragment.
  • ADCs can also be defined by the generic formula in reverse order: C-A or A-L-C.
  • ADCs can 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).
  • a "linker” is any chemical moiety that is capable of linking a compound, usually a drug (such as IGN DNA-alkylators), to a cell-binding agent (such as an anti-CD123 antibody or a fragment thereof) in a stable, covalent manner.
  • Linkers can be susceptible to or be substantially resistant to acid-induced cleavage, light-induced cleavage, peptidase-induced cleavage, esterase- induced cleavage, and disulfide bond cleavage, at conditions under which the compound or the 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 hydrophilic forms thereof as described herein and know in the art. In some aspects disclosed herein, the linker is a peptide linker.
  • IMGN632 also known as pivekimab sunirine or PVEK refers to the ADC composition shown in FIGs.1A and 1B.
  • composition comprises ADCs with an average of 1.5 to 2.1 DGN549-C cytotoxic agents per huCD123-6Gv4.7 ("G4723A") antibody in a sulfonated version (Figure 1A).
  • the composition can also comprise the unsulfonated ADC (the mono-imine structure shown in Figure 1B).
  • magrolimab also as Hu5F9-G4 refers to an anti-CD47 antibody comprising a heavy chain comprising SEQ ID NO: 21 and a light chain comprising SEQ ID NO: 22.
  • cancer and “cancerous” refer to or describe the physiological condition in mammals in which a population of cells are characterized by unregulated cell growth.
  • cancer examples include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia.
  • Tumor and “neoplasm” refer to one or more cells that result from excessive cell growth or proliferation, either benign (noncancerous) or malignant (cancerous) including pre-cancerous lesions.
  • a cancer as disclosed herein can be a hematological malignancy.
  • hematological malignancies include, for example, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodysplastic syndrome (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/phase (BP-CML), and blastic plasmacytoid dendritic cell neoplasm (BPDCN).
  • AML acute myeloid leukemia
  • CML chronic myeloid leukemia
  • MDS myelodysplastic syndrome
  • ALL acute lymphoblastic leukemia
  • B-ALL B-cell acute lymphoblastic leukemia
  • T ALL T-cell acute lymphoblastic leukemia
  • 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 type, nodal and splenic type), 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).
  • NHL B-cell chronic lympho
  • a "CD123-positive” cancer is a caner that has CD123-positive blasts as determined by flow cytometry or immunohistochemistry (IHC).
  • the terms "cancer cell,” “tumor cell,” and grammatical equivalents refer to the total population of cells derived from a tumor or a pre-cancerous lesion, including both non- tumorigenic cells, which comprise the bulk of the tumor cell population, and tumorigenic stem cells (cancer stem cells).
  • tumorigenic stem cells cancer stem cells.
  • tumorigenic stem cells tumorigenic stem cells
  • a "refractory” cancer is one that progresses even though an anti-cancer treatment, such as a chemotherapy, is administered to the cancer patient.
  • the cancer may be resistant at the beginning of treatment or it may become resistant during treatment.
  • a “primary refractory” cancer that does not achieve complete remission (CR) or complete remission with incomplete recovery (CRi) after a patient has received 2 cycles of intense chemotherapy.
  • a “relapsed” cancer is one in which the cancer or the signs and symptoms of a cancer returns after a period of improvement.
  • the term "fit AML” as used herein refers to a subject having AML who is eligible for intensive therapy.
  • the measures for determining a subject with fit AML include, e.g., physical performance (as determined by e.g., the Eastern Cooperative Oncology Group performance status (ECOG PS), the Karnofsky performance status (KPS), and the short physical performance battery (SPPB)), comorbid conditions (as determined by the Charlson comorbidity index (CCI) or the hematopoietic cell transplantation-specific comorbidity index (HCT-CI)), cognitive function, and prognostic models (including but not limited to, cytogenetic group, age, white blood cell count, LDH, type of AML).
  • a fit AML subject is a subject at the age of 60 or under the age of 60.
  • unfit AML refers to a subject having AML who is ineligible for intensive therapy.
  • the measures for determining a subject with unfit AML include, e.g., physical performance (as determined by e.g., the Eastern Cooperative Oncology Group performance status (ECOG PS), the Karnofsky performance status (KPS), and the short physical performance battery (SPPB)), comorbid conditions (as determined by the Charlson comorbidity index (CCI) or the hematopoietic cell transplantation-specific comorbidity index (HCT-CI)), cognitive function, and prognostic models (including but not limited to, cytogenetic group, age, white blood cell count, LDH, type of AML).
  • ECOG PS Eastern Cooperative Oncology Group performance status
  • KPS Karnofsky performance status
  • SPPB short physical performance battery
  • comorbid conditions as determined by the Charlson comorbidity index (CCI) or the hematopoietic cell transplantation-
  • an unfit AML subject is a subject over the age of 60.
  • Terms such as “treating” or “treatment” or “to treat” or “alleviating” or “to alleviate” refer to therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder. Thus, those in need of treatment include those already diagnosed with or suspected of having the disorder.
  • the term "therapeutically effective amount” refers to an amount of an antibody, antigen- binding fragment thereof, ADC, or other drug effective to "treat" a disease or disorder in a subject or mammal.
  • the therapeutically effective amount of the drug can reduce the number of cancer cells; reduce the tumor size or burden; inhibit (i.e., slow to some extent and in a certain aspect, stop) cancer cell infiltration into peripheral organs; relieve to some extent one or more of the symptoms associated with the cancer; and/or result in a favorable response such as complete remission (CR), complete remission with incomplete recovery (CRi); complete remission with incomplete platelet recovery (CRp), complete remission with partial hematologic recovery (CRh); CR without minimal residual disease (CRMRD-); complete remission clinical (CRc); morphologic leukemia-free state ; partial remission (PR); increased duration of response (DOR); and decrease in progressive disease (PD).
  • CR complete remission
  • CRi complete remission with incomplete recovery
  • CRp complete remission with incomplete platelet recovery
  • CRh complete remission with partial hematologic recovery
  • CRMRD- complete remission clinical
  • CRc morphologic leukemia-free
  • the term "respond favorably” generally refers to causing a beneficial state in a subject. With respect to cancer treatment, the term refers to providing a therapeutic effect on the subject. Positive therapeutic effects in cancer can be measured in a number of ways (See, W.A. Weber, J. Nucl. Med.50:1S-10S (2009)). A favorable response can be assessed, for example, by complete remission (CR), complete remission with incomplete recovery (CRi); CR without minimal residual disease (CRMRD-); complete remission clinical (CRc); morphologic leukemia-free state; partial remission (PR); a decrease in progressive disease (PD), or any combination thereof.
  • CR complete remission
  • CRi complete remission with incomplete recovery
  • CMRD- complete CR without minimal residual disease
  • CRc complete remission clinical
  • PR partial remission
  • PD progressive disease
  • a "complete response” or “complete remission” or “CR” indicates the disappearance of all signs of tumor or cancer in response to treatment. This does not always mean the cancer has been cured.
  • a “CRi” refers to a morphologically complete remissions with an incomplete hematological (blood count) recovery.
  • a “CRMRD-” refers to a complete recovery without measurable residual disease.
  • Minimal residual disease refers to post-therapy persistence of cancerous (e.g., leukemic) cells at levels below morphological detection. MRD can be assessed using, for example, central flow cytometry.
  • MRD+ status is a predictor of relapse, and it is associated with decrease survival in AML patients.
  • a "partial response” or “PR” refers to a decrease in the size or volume of one or more tumors or lesions, or in the extent of cancer in the body, in response to treatment.
  • Progressive disease refers to the appearance of one more new lesions or tumors and/or the unequivocal progression of existing non-target lesions. Progressive disease can also refer to a tumor growth of more than 20% since treatment began, either due to an increases in mass or in spread of the tumor.
  • line of treatment or “line of therapy” refer to a therapeutic regimen that can include but is not limited to surgery, radiation therapy, chemotherapy, differentiating therapy, biotherapy, immune therapy, induction therapy, consolidation therapy, transplant, maintenance therapy, or the administration of one or more anti-cancer agents (e.g., a cytotoxic agent and/or an anti-proliferative compound).
  • anti-cancer agents e.g., a cytotoxic agent and/or an anti-proliferative compound.
  • first-line treatment “first-line therapy,” “front-line treatment,” and “front-line therapy” refer to the preferred and standard initial treatment for a particular condition, e.g., induction therapy, consolidation therapy, transplant, maintenance therapy. These treatments differ from “second-line” therapies, which are tried when a first-line therapy does not work adequately.
  • “Third-line” therapies are tried when a first-line therapy and a second-line therapy do not work adequately.
  • “Salvage regimen” is a treatment that is tried when the cancer has not responded to other treatments.
  • the combination of an anti-CD123 ADC (e.g. IMGN632/PVEK) with anti- CD47 antibody or antigen-binding fragment thereof provided herein can be given as first-line therapy.
  • the combination of an anti-CD123 ADC (e.g. IMGN632/PVEK) with anti-CD47 antibody or antigen-binding fragment thereof provided herein can be given as a second-line therapy, or a third-line therapy.
  • the combination of an anti-CD123 ADC e.g.
  • IMGN632/PVEK with anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) provided herein can be given as a line of therapy in patients who have received at least 1, at least 2, (e.g., front- line therapy and one salvage therapy), or at least 3 lines of therapy prior to treatment with the combination of an anti-CD123 ADC (e.g. IMGN632/PVEK) with anti-CD47 antibody or antigen- binding fragment thereof (e.g., magrolimab) provided herein.
  • an anti-CD123 ADC e.g.
  • IMGN632/PVEK with anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) provided herein can be given as a line of therapy in patients having received no more than 1, no more than 2, no more than 3, no more than 4, no more than 5, or no more than 6 lines of therapy.
  • the term "maintenance therapy” refers to therapy that is given to help keep cancer from coming back after it has disappeared following the initial therapy.
  • pharmaceutically acceptable indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • the term "pharmaceutical formulation” refers to a preparation which is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.
  • the formulation can be sterile.
  • the term “subject” refers to any animal (e.g., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms “subject” and “patient” are used interchangeably herein in reference to a human subject.
  • Administration "in combination with" one or more further therapeutic agents includes simultaneous (concurrent) or consecutive administration in any order.
  • the combination therapy can provide "synergy” and prove “synergistic", i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
  • a synergistic effect can be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit dosage formulation; (2) delivered by alternation, or in parallel as separate formulations; or (3) by some other regimen.
  • alternation therapy a synergistic effect can be attained when the compounds are administered or delivered sequentially, e.g., by different injections in separate syringes.
  • the term "instructing” means providing directions for applicable therapy, medication, treatment, treatment regimens, and the like, by any means, for example, in writing, such as in the form of package inserts or other written promotional material.
  • An "effective amount" of an antibody, ADC, or other drug as disclosed herein is an amount sufficient to carry out a specifically stated purpose. An “effective amount” can be determined empirically and in a routine manner, in relation to the stated purpose.
  • a polypeptide, antibody, polynucleotide, vector, cell, or composition which is “isolated” is a polypeptide, antibody, polynucleotide, vector, cell, or composition which is in a form not found in nature.
  • Isolated polypeptides, antibodies, polynucleotides, vectors, cell or compositions include those which have been purified to a degree that they are no longer in a form in which they are found in nature.
  • an antibody, polynucleotide, vector, cell, or composition which is isolated is substantially pure.
  • substantially pure refers to material which is at least 50% pure (i.e., free from contaminants), at least 90% pure, at least 95% pure, at least 98% pure, or at least 99% pure.
  • ADCs Anti-CD123 Antibody-Drug Conjugates
  • CD123 ADCs e.g., IMGN632/PVEK
  • anti-CD123 ADCs Such ADCs comprise an anti- CD123 antibody or antigen-binding thereof and a cytotoxin.
  • the cytotoxin can be attached to the anti-CD123 antibody or antigen-binding fragment thereof by a linker.
  • the anti-CD123 antibodies or antigen-binding fragments thereof are humanized antibodies or antigen-binding fragments thereof.
  • the humanized antibody or fragment is a resurfaced antibody or antigen-binding fragment thereof.
  • the antibodies or antigen-binding fragments thereof is a fully human antibody or antigen- binding fragment thereof.
  • an ADC is represented by the following formula: , wherein CBA is an anti-CD123 antibody or antigen-binding fragment or polypeptide, covalently linked to CyC1 through a cysteine residue; and WC is 1 or 2.
  • Cy C1 is represented by the following formulae: ; ; or , or a pharmaceutically acceptable salt wherein the double line between N and C represents a single bond or a double bond, provided that when it is a double bond, X is absent and Y is -H or a (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; [0113] R 5 is -H or a (C 1 -C 3 )alkyl; [0114] P is an amino acid residue or a peptide containing 2 to 20 amino acid residues; [0115] R a and R b , for each occurrence, are independently -H, (C 1 -C 3 )alkyl, or a charged substituent or an ionizable group Q; [0116] W’ is -NR e’
  • Ra and Rb are both H; and R5 is H or Me.
  • P is a peptide containing 2 to 5 amino acid residues.
  • P may be selected from 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, ⁇ - Ala-Leu-Ala-Leu, Gly-Phe-Leu-Gly
  • P is Gly-Gly-Gly, Ala-Val, Ala-Ala, Ala-D-Ala, D-Ala-Ala, or D-Ala-D-Ala.
  • Q is -SO3M.
  • R19 and R20 are both H; and m" is an integer from 1 to 6.
  • -LC- is represented by the following formula: .
  • the ADC is by one of the following formulae: ; ; or a N and C 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.
  • An anti-CD123 ADC for use in the present methods can comprise an anti-CD123 antibody or antigen-binding fragment thereof. Anti-CD123 antibodies or antigen-binding fragments thereof have been described US Patent No.10,077,313 B2, the contents of which are herein incorporated by reference in their entirety).
  • the anti-CD123 antibody or antigen- binding fragment thereof can be the huCD123-6Gv4.7 ("G4723A") antibody (see WO 2017/004025, WO 2017/004026, and PCT/US2018/052212, each of which is herein incorporated by reference in its entirety) or can comprise sequences of the G4723A antibody, e.g., as shown below in Tables 1-3.
  • G4723A huCD123-6Gv4.7
  • 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. huCD123-6Gv4.7 Heavy and Light Chain Variable Regions Name Sequence R T K Q Table 2.
  • huCD123-6Gv4.7-C442 Full Heavy and Light Chain Name Sequence h 12 442 ll A A A IMH R T V T D V : K Q F S E Table 3.
  • prov e eren, an ant- ant oy or antgen- n ng ragment 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; variable light chain CDR-1, CDR-2, and CDR-3 the sequences of SEQ ID NOs: 8, 9, and 10, respectively; and an IgG constant region.
  • An anti-CD123 antibody or antigen-binding fragment thereof for use in the methods provided herein can comprise a variable heavy chain CDR-1, CDR- 2, and CDR-3 comprising the sequences of SEQ ID NOs: 5, 6, and 7, respectively; a variable light chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 8, 9, and 10, respectively; and a human IgG constant region.
  • An anti-CD123 antibody or antigen-binding fragment thereof for use in the methods provided herein can comprise a variable heavy chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 5, 6, and 7, respectively; a variable light chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 8, 9, and 10, respectively; and an IgG1 constant region.
  • An anti-CD123 antibody or antigen-binding fragment thereof for use in the methods provided herein can comprise a variable heavy chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 5, 6, and 7, respectively; a variable light chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 8, 9, and 10, respectively; and a human IgG1 constant region.
  • An anti-CD123 antibody or antigen-binding fragment thereof for use in the methods provided herein can comprise a variable heavy chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 5, 6, and 7, respectively; a variable light chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 8, 9, and 10, respectively; and a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 11.
  • An anti-CD123 antibody or antigen-binding fragment thereof for use in the methods provided herein can comprise a variable heavy chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 5, 6, and 7, respectively; a variable light chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 8, 9, and 10, respectively; and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 12.
  • An anti-CD123 antibody or antigen-binding fragment thereof for use in the methods provided herein can comprise a variable heavy chain CDR-1, CDR- 2, and CDR-3 comprising the sequences of SEQ ID NOs: 5, 6, and 7, respectively; a variable light chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 8, 9, and 10, respectively; a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 11; and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 12.
  • 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; a variable light chain domain comprising the sequence set forth in SEQ ID NO: 2; and a human IgG constant region.
  • 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; a variable light chain domain comprising the sequence set forth in SEQ ID NO: 2; and an IgG1 constant region.
  • 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; a variable light chain domain comprising the sequence set forth in SEQ ID NO: 2; and a human IgG1 constant region.
  • 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; a variable light chain domain comprising the sequence set forth in SEQ ID NO: 2; and a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 11.
  • 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; a variable light chain domain comprising the sequence set forth in SEQ ID NO: 2; and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 12.
  • 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; a variable light chain domain comprising the sequence set forth in SEQ ID NO: 2; a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 11; and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 12.
  • 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 to 346 of human CD123.
  • An anti-CD123 antibody or antigen-binding fragment thereof for use in methods provided herein can be recombinantly produced.
  • an anti-CD123 antibody or antigen-binding fragment thereof for use in the methods herein can be produced in a mammalian cell line, e.g., a CHO cell.
  • An anti-CD123 antibody or antigen-binding fragment thereof for use in the methods provided herein can be a cysteine-engineered antibody or fragment.
  • Cysteine-engineered antibodies can be covalently conjugated to cytotoxic agents of interest to generate ADCs.
  • the expression "linked to a cell-binding agent" or “linked to an anti-CD123 antibody or fragment” refers to a conjugate molecule comprising at least one cytotoxic agent bound to a cell-binding agent, e.g., anti-CD123 antibody or fragment, via a suitable linking group, or a precursor thereof.
  • Linkers include, for example, peptide linkers.
  • An ADC can contain multiple cytotoxic agents bound to an antibody or antigen-binding fragment thereof.
  • an ADC comprises 1, 2, or 3, cytotoxic agents per antibody or antigen-binding fragment thereof.
  • a composition comprising ADCs can contain ADCs with varying numbers of cytotoxic agents bound per antibody or antigen-binding fragment thereof.
  • compositions comprising ADCs can contain an average number of cytotoxic agents bound per antibody or antigen-binding fragment thereof.
  • a pharmaceutical composition comprising anti-CD123 ADCs comprises 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 cytotoxic agents per anti-CD123 antibody or antigen-binding fragment thereof.
  • a pharmaceutical composition for use in the methods provided herein comprises anti-CD123 ADCs comprising about 1 to about 3 cytotoxic agents per antibody or antigen-binding fragment thereof, for example, wherein the average number of cytotoxic agents per antibody or antigen-binding fragment thereof is from 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).
  • a pharmaceutical composition for use in the methods provided herein comprises anti-CD123 ADCs with 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.
  • drug molecules e.g., cytotoxic agents
  • a pharmaceutical composition provided herein comprises anti-CD123 ADCs with an average of about 1.5 to 2.1 drug molecules (e.g., cytotoxic agents) per antibody.
  • the antibodies or antigen- thereof for use in the present disclosure may be linked to cytotoxic agents, for example, through linkage with the Lys side chain amino group, the Cys side chain thiol group, or an oxidized N-terminal Ser/Thr.
  • Cytotoxic agents include, for example, DNA alkylating agents such as indolino-benzodiazepene (IGN) DNA alkylators.
  • a cytotoxic agent is a indolino-benzodiazepine pseudodimer.
  • an anti-CD123 ADC for use in the present disclosure comprises DGN549-C.
  • Anti-CD47 Antibodies and Antigen-Binding Fragments Thereof Described herein are methods of administering anti-CD123 ADCs such as IMGN632/PVEK in combination with anti-CD47 antibodies or antigen-binding fragments thereof.
  • the anti-CD47 antibody can be magrolimab (see WO 2011/143624, which is herein incorporated by reference in its entirety; see in particular discussion of humanized “5F9”; see also Liu J.. et al., (2015) Pre-Clinical Development of a Humanized Anti-CD47 Antibody with Anti- Cancer Therapeutic Potential.
  • magrolimab is a recombinant humanized monoclonal antibody of the immunoglobulin G4 kappa (IgG4) isotype that binds to CD47.
  • the primary mechanism of action of magrolimab is to block the inhibitory CD47-signal regulatory protein alpha (SIRP ⁇ ) interaction, enhancing the ability of macrophages and other phagocytes to identify and destroy foreign and malignant cells.
  • Magrolimab is a novel immunotherapy based on its ability to enhance immune response to cancer by blocking inhibitory signals on phagocytic cells. Magrolimab was specifically engineered with a human IgG4 isotype that is relatively inefficient at recruiting Fc-dependent effector functions to minimize any deleterious effects on CD47-expressing normal cells. Consequently, magrolimab has been shown to lack antibody-dependent cellular cytotoxicity (ADCC) activity in vitro.
  • ADCC antibody-dependent cellular cytotoxicity
  • magrolimab Heavy and Light Chain Variable Regions Name Sequence V S L Magrolimab Light Chain Variable Region YLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKI D Name Sequence V S L E S E V Y E V I PS V Tab e 6.
  • an anti-CD47 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: 15, 16, and 17, respectively and/or variable light chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 18, 19, and 20, respectively.
  • An anti- CD47 antibody or antigen-binding fragment thereof for use in the methods provided herein can comprise a variable chain domain comprising the sequence set forth in SEQ ID NO: 13.
  • An anti- CD47 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: 14.
  • An anti- CD47 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: 13 and a variable light chain domain comprising the sequence set forth in SEQ ID NO: 14.
  • an anti-CD47 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: 15, 16, and 17, respectively; variable light chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 18, 19, and 20, respectively; and an IgG constant region.
  • An anti- CD47 antibody or antigen-binding fragment thereof for use in the methods provided herein can comprise a variable heavy chain CDR-1, CDR- 2, and CDR-3 comprising the sequences of SEQ ID NOs: 15, 16, and 17, respectively; a variable light chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 18, 19, and 20, respectively; and a human IgG constant region.
  • An anti-CD123 antibody or antigen-binding fragment thereof for use in the methods provided herein can comprise a variable heavy chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 15, 16, and 17, respectively; a variable light chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 18, 19, and 20, respectively; and an IgG4 constant region, optionally wherein the IgG4 constant region comprises a Ser228Pro substitution.
  • An anti-CD123 antibody or antigen-binding fragment thereof for use in the methods provided herein can comprise a variable heavy chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 15, 16, and 17, respectively; a variable light chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 18, 19, and 20, respectively; and a human IgG4 constant region, optionally wherein the human IgG4 constant region comprises a Ser228Pro substitution.
  • An anti-CD47 antibody or antigen-binding fragment thereof for use in the methods provided herein can comprise a variable heavy chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 15, 16, and 17, respectively; a variable light chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 18, 19, and 20, respectively; and a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 23.
  • An anti-CD123 antibody or antigen-binding fragment thereof for use in the methods provided herein can comprise a variable heavy chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 15, 16, and 17, respectively; a variable light chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 18, 19, and 20, respectively; and a light chain constant region comprising the amino acid sequence of NO: 24.
  • An anti-CD123 antibody or antigen- binding fragment thereof for use in the methods provided herein can comprise a variable heavy chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 15, 16, and 17, respectively; a variable light chain CDR-1, CDR-2, and CDR-3 comprising the sequences of SEQ ID NOs: 18, 19, and 20, respectively; a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 23; and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 24.
  • An anti-CD47 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: 13; a variable light chain domain comprising the sequence set forth in SEQ ID NO: 14; and a human IgG constant region.
  • An anti-CD47 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: 13; a variable light chain domain comprising the sequence set forth in SEQ ID NO: 14; and an IgG4 constant region, optionally wherein the IgG4 constant region comprises a Ser228Pro substitution.
  • An anti- CD47 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: 13; a variable light chain domain comprising the sequence set forth in SEQ ID NO: 14; and a human IgG4 constant region, optionally wherein the human IgG4 constant region comprises a Ser228Pro substitution.
  • An anti-CD47 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: 13; a variable light chain domain comprising the sequence set forth in SEQ ID NO: 14; and a heavy chain constant region the amino acid sequence of SEQ ID NO: 23.
  • An anti-CD47 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: 13; a variable light chain domain comprising the sequence set forth in SEQ ID NO: 14; and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 24.
  • An anti- CD47 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: 13; a variable light chain domain comprising the sequence set forth in SEQ ID NO: 14; a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 23; and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 24.
  • An anti-CD47 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: 21.
  • An anti-CD47 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: 22.
  • An anti- CD47 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: 21 and a light chain comprising the sequence set forth in SEQ ID NO: 22.
  • an anti-CD47 antibody or antigen-binding fragment thereof provided herein is an IgG4 antibody.
  • an IgG4 anti-CD47 antibody or antigen-binding fragment thereof comprises a Ser228Pro substitution, wherein the numbering of the residues in the heavy chain is that of the EU index (see Kabat et al., “Sequences of Proteins of Immunological Interest,” 5.sup.th Ed., National Institutes of Health, Bethesda, Md. (1991)). Position 228 is naturally occupied by P in human IgG1 and IgG2 but is occupied by S in human IgG4 and R in human IgG3.
  • an anti-CD47 antibody or antigen-binding fragment thereof binds to monomeric human CD47 with a KD of about 8x10 -9 M as measured using surface plasmon resonance.
  • an anti-CD47 antibody or antigen-binding fragment thereof provided herein blocks the interaction between CD47 and SIRP ⁇ .
  • an anti-CD47 antibody or antigen-binding fragment thereof enables human peripheral blood-derived macrophages to phagocytose HL-60 AML cells and primary human AML cells.
  • Methods of determining (i) whether an anti-CD47 antibody or antigen-binding fragment thereof provided herein blocks the interaction between CD47 and SIRP ⁇ and (ii) whether an anti-CD47 antibody or antigen-binding fragment thereof are provided in also Liu J.. et al., (2015) Pre-Clinical Development of a Humanized Anti-CD47 Antibody with Anti-Cancer Therapeutic Potential.
  • PLoS ONE 10(9): e0137345. doi:10.1371/journal.pone.0137345 which is herein incorporated by reference in its entirety. IV.
  • Antibodies and Antigen-Binding Fragments Thereof are combinations of anti-CD123 ADCs, which contain anti-CD123 antibodies or antigen-binding fragments thereof and anti-CD47 antibodies and antigen-binding fragments thereof.
  • An antibody or antigen-binding fragment thereof provided herein e.g., an anti-CD123 antibody or antigen-binding fragment thereof and/or an anti-CD47 antibody or antigen-binding fragment thereof
  • Monoclonal antibodies or antigen-binding fragments thereof can be prepared using a wide variety of techniques known in the art including the use of hybridoma, recombinant, and phage display technologies, yeast-based presentation technologies, or a combination thereof.
  • monoclonal antibodies or antigen-binding fragments thereof can be produced using hybridoma techniques including those known in the art and taught, for example, in Harlow E & Lane D, Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed.1988); Hammerling GJ et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563681 (Elsevier, N.Y., 1981), or as described in Kohler G & Milstein C (1975) Nature 256: 495.
  • a monoclonal antibody or antigen-binding fragment is an antibody or antigen-binding fragment produced by a clonal cell (e.g., hybridoma or host cell producing a recombinant antibody or antigen-binding fragment).
  • a monoclonal antibody or antigen-binding fragment thereof can be a human antibody or antigen-binding fragment thereof.
  • a monoclonal antibody or antigen-binding fragment thereof can be a Fab fragment or a F(ab’)2 fragment.
  • Monoclonal antibodies or antigen-binding fragments thereof described herein can, for example, be made by the hybridoma method as described in Kohler G & Milstein C (1975) Nature 256: 495 or can, e.g., be isolated from phage libraries using the techniques as described herein, for example.
  • Other methods for the preparation of clonal cell lines and of monoclonal antibodies and antigen-binding fragments thereof expressed thereby are well known in the art (see, for example, Chapter 11 in: Short Protocols in Molecular Biology, (2002) 5th Ed., Ausubel FM et al., supra).
  • An antibody or antigen-binding thereof provided herein can be a recombinant antibody.
  • An antibody or antigen-binding fragment thereof provided herein e.g., an anti-CD123 antibody or antigen-binding fragment thereof and/or an anti-CD47 antibody or antigen-binding fragment thereof
  • An antibody or antigen-binding fragment thereof provided herein can be described by its VL domain alone, or its VH domain alone, or by its 3 VL CDRs alone, or its 3 VH CDRs alone.
  • the screen produced 14 new partners for a specific VH domain and 13 new partners for a specific VL domain, which were strong binders, as determined by ELISA. See also Kim SJ & Hong HJ, (2007) J Microbiol 45: 572-577, which is incorporated herein by reference in its entirety, describing methods of producing antibodies that bind a specific antigen by using a specific VH domain and screening a library (e.g., human VL library) for complementary VL domains; the selected VL domains in turn could be used to guide selection of additional complementary (e.g., human) VH domains.
  • a library e.g., human VL library
  • the CDRs of an antibody or antigen-binding fragment thereof provided herein can be determined according to the Chothia numbering scheme, which refers to the location of immunoglobulin structural loops (see, e.g., Chothia C & Lesk AM, (1987), J Mol Biol 196: 901-917; Al-Lazikani B et al., (1997) J Mol Biol 273: 927-948; Chothia C et al., (1992) J Mol Biol 227: 799-817; Tramontano A et al., (1990) J Mol Biol 215(1): 175-82; and U.S.
  • Chothia numbering scheme refers to the location of immunoglobulin structural loops
  • the Chothia CDR-H1 loop is present at heavy chain amino acids 26 to 32, 33, or 34
  • the Chothia CDR-H2 loop is present at heavy chain amino acids 52 to 56
  • the Chothia CDR-H3 loop is present at heavy chain amino acids 95 to 102
  • the Chothia CDR- L1 loop is present at light chain amino acids 24 to 34
  • the Chothia CDR-L2 loop is present at light chain amino acids 50 to 56
  • the L3 loop is present at light chain amino acids 89 to 97.
  • 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 insertions 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).
  • an antibody or antigen-binding fragment thereof provided herein comprises the Chothia VH and VL CDRs of an antibody listed in Table 1, 2, 4, or 5.
  • the antibodies or antigen-binding fragments comprise one or more CDRs, in which the Chothia and Kabat CDRs have the same amino acid sequence.
  • provided herein are antibodies and antigen-binding fragments thereof that comprise combinations of Kabat CDRs and Chothia CDRs.
  • the CDRs of an antibody or antigen-binding fragment thereof provided herein can be determined according to the IMGT numbering system as described in Lefranc M-P, (1999) The Immunologist 7: 132-136 and Lefranc M-P et al., (1999) Nucleic Acids Res 27: 209-212.
  • VH-CDR1 is at positions 26 to 35
  • VH-CDR2 is at positions 51 to 57
  • VH-CDR3 is at positions 93 to 102
  • VL-CDR1 is at positions 27 to 32
  • VL-CDR2 is at positions 50 to 52
  • VL-CDR3 is at positions 89 to 97.
  • antibodies and antigen- binding fragments thereof that comprise the IMGT VH and VL CDRs of an antibody listed in Table 1, 2, 4, or 5, for example, as described in Lefranc M-P (1999) supra and Lefranc M-P et al., (1999) supra).
  • the CDRs of an antibody or antigen-binding fragment thereof provided herein can be determined according to MacCallum RM et al., (1996) J Mol Biol 262: 732-745. See also, e.g., Martin A. “Protein Sequence and Structure Analysis of Antibody Variable Domains,” in Antibody Engineering, Kontermann and Dübel, eds., Chapter 31, pp.422-439, Springer-Verlag, Berlin (2001).
  • antibodies or antigen-binding fragments thereof that comprise VH and VL CDRs of an antibody listed in Table 1, 2, 4, or 5 as determined by the method in MacCallum RM et al.
  • the CDRs of an antibody or antigen-binding fragment thereof provided herein can be determined according to the AbM numbering scheme, which refers AbM regions which represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software (Oxford Molecular Group, Inc.).
  • antibodies or antigen-binding fragments thereof that comprise VH and VL CDRs of an antibody listed in Table 1, 2, 4, or 5 as determined by the AbM numbering scheme.
  • antibodies or antigen-binding fragments thereof e.g., anti-CD123 antibodies or antigen-binding fragments thereof and/or anti-CD47 antibodies or antigen-binding fragments thereof
  • Non-limiting examples of human constant region sequences have been described in the art, e.g., see U.S. Patent No.5,693,780 and Kabat EA et al., (1991) supra.
  • the heavy chain of an antibody or antigen-binding fragment thereof provided herein can be an alpha ( ⁇ ), delta ( ⁇ ), epsilon ( ⁇ ), gamma ( ⁇ ) or mu ( ⁇ ) heavy chain.
  • the heavy chain of an antibody or antigen-binding fragment thereof provided can comprise a human alpha ( ⁇ ), delta ( ⁇ ), epsilon ( ⁇ ), gamma ( ⁇ ) or mu ( ⁇ ) heavy chain.
  • an antibody or antigen-binding fragment thereof provided herein comprises a heavy chain wherein the amino acid sequence of the VH domain comprises an amino acid sequence set forth in Table 1 or 4 and wherein the constant region of the heavy chain comprises the amino acid sequence of a human gamma ( ⁇ ) heavy chain constant region (e.g., a human IgG1 heavy chain constant region).
  • an antibody or antigen-binding fragment thereof provided herein comprises a heavy chain wherein the amino acid sequence of the VH domain comprises a sequence set forth in Table 1 or 4, and wherein the constant region of the heavy chain comprises the amino acid of a human heavy chain described herein or known in the art.
  • the light chain of an antibody or antigen-binding fragment thereof provided herein is a human kappa light chain or a human lambda light chain.
  • an antibody described herein comprises a light chain wherein the amino acid sequence of the VL domain comprises a sequence set forth in Table 1 or 4 and wherein the constant region of the light chain comprises the amino acid sequence of a human kappa or lambda light chain constant region.
  • an antibody or antigen-binding fragment thereof provided herein comprises a light chain wherein the amino acid sequence of the VL domain comprises a sequence set Table 1 or 4, and wherein the constant region of the light chain comprises the amino acid sequence of a human kappa light chain constant region.
  • the light chain of an antibody or antigen-binding fragment thereof provided herein is a lambda light chain.
  • an antibody described herein comprises a light chain wherein the amino acid sequence of the VL domain comprises a sequence set forth in Table 1 or 4 and wherein the constant region of the light chain comprises the amino acid sequence of a human lambda light chain constant region.
  • an antibody or antigen-binding fragment thereof provided herein e.g., an anti-CD123 antibody or antigen-binding fragment thereof and/or an anti-CD47 antibody or antigen-binding fragment thereof
  • an antibody or antigen-binding fragment provided herein comprises a VH domain and a VL domain comprising any amino acid sequence described herein, and wherein the constant regions comprise the amino acid sequences of the constant regions of an IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule, any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or any subclass (e.g., IgG2a and IgG2b) of immunoglobulin molecule.
  • the constant regions comprise the amino acid sequences of the constant regions of a human IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule, any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or any subclass (e.g., IgG2a and IgG2b) of immunoglobulin molecule.
  • Fc region engineering is used in the art, e.g., to extend the half-life of therapeutic antibodies and antigen-binding fragments thereof and protect from degradation in vivo.
  • one, two, or more mutations are introduced into the Fc region of an antibody or antigen-binding fragment thereof provided herein (e.g., into the CH2 domain (residues 231-340 of human IgG1) and/or CH3 domain (residues 341- 447 of human IgG1) and/or the hinge region, with numbering according to the Kabat numbering system (e.g., the EU index in Kabat)) to alter one or more functional properties of the antibody or antigen-binding fragment thereof, such as serum half-life, complement fixation, Fc receptor binding, and/or antigen-dependent cellular cytotoxicity.
  • the Kabat numbering system e.g., the EU index in Kabat
  • one, two, or more mutations are introduced into the hinge region of the Fc region (CH1 domain) such that the number of cysteine residues in the hinge region are altered (e.g., increased or decreased) as described in, e.g., U.S. Patent No.5,677,425.
  • the number of cysteine residues in the hinge region of the CH1 domain may be altered to, e.g., facilitate light and heavy chains, or to alter (e.g., increase or decrease) the stability of the antibody or antigen-binding fragment thereof.
  • one, two, or more mutations are introduced into the Fc region of an antibody or antigen-binding fragment thereof provided herein (e.g., CH2 domain (residues 231-340 of human IgG1) and/or CH3 domain (residues 341-447 of human IgG1) and/or the hinge region, with numbering according to the Kabat numbering system (e.g., the EU index in Kabat)) to increase or decrease the affinity of the antibody or antigen- binding fragment thereof for an Fc receptor (e.g., an activated Fc receptor) on the surface of an effector cell.
  • an Fc receptor e.g., an activated Fc receptor
  • Mutations in the Fc region that decrease or increase affinity for an Fc receptor and techniques for introducing such mutations into the Fc receptor or fragment thereof are known to one of skill in the art. Examples of mutations in the Fc receptor that can be made to alter the affinity of the antibody or antigen-binding fragment thereof for an Fc receptor are described in, e.g., Smith P et al., (2012) PNAS 109: 6181-6186, U.S. Patent No.6,737,056, and International Publication Nos. WO 02/060919; WO 98/23289; and WO 97/34631, which are incorporated herein by reference.
  • one, two, or more amino acid mutations are introduced into an IgG constant domain, or FcRn-binding fragment thereof (e.g., an Fc or hinge-Fc domain fragment) to alter (e.g., decrease or increase) half-life of the antibody or antigen-binding fragment thereof in vivo.
  • FcRn-binding fragment thereof e.g., an Fc or hinge-Fc domain fragment
  • Patent Nos.5,869,046, 6,121,022, 6,277,375 and 6,165,745 for examples of mutations that will alter (e.g., decrease or increase) the half-life of an antibody or antigen-binding fragment thereof in vivo.
  • one, two or more amino acid mutations i.e., substitutions, insertions, or deletions
  • an IgG constant domain, or FcRn-binding fragment thereof preferably an Fc or hinge-Fc domain fragment
  • one, two or more amino acid mutations are introduced into an IgG constant domain, or FcRn-binding fragment thereof (preferably an Fc or hinge-Fc domain fragment) to increase the half-life of the antibody or antigen-binding fragment thereof in vivo.
  • the antibodies or antigen-binding fragments thereof may have one or more amino acid mutations (e.g., substitutions) in the second constant (CH2) domain (residues 231-340 of human IgG1) and/or the third constant (CH3) domain (residues 341-447 of human IgG1), with numbering according to the EU index in Kabat (Kabat EA et al., (1991) supra).
  • one, two, or more amino acid substitutions are introduced into an IgG constant domain Fc region to alter the effector function(s) of the antibody or antigen-binding fragment thereof.
  • one or acids can be replaced with a different amino acid residue such that the antibody or antigen-binding fragment thereof has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody.
  • Engineered glycoforms may be useful for a variety of purposes, including but not limited to enhancing or reducing effector function.
  • Methods for generating engineered glycoforms in an antibody or antigen-binding fragment thereof described herein include but are not limited to those disclosed, e.g., in Uma ⁇ a P et al., (1999) Nat Biotechnol 17: 176-180; Davies J et al., (2001) Biotechnol Bioeng 74: 288-294; Shields RL et al., (2002) J Biol Chem 277: 26733-26740; Shinkawa T et al., (2003) J Biol Chem 278: 3466-3473; Niwa R et al., (2004) Clin Cancer Res 1: 6248-6255; Presta LG et al., (2002) Biochem Soc Trans 30: 487-490; Kanda Y et al., (2007) Glycobiology 17: 104-118; U.S.
  • any of the constant region mutations or modifications described herein can be introduced into one or both heavy chain constant regions of an antibody or antigen-binding fragment thereof described herein having two heavy chain constant regions.
  • Antigen-binding fragments of antibodies described herein can be generated by any technique known to those of skill in the art.
  • Fab and F(ab’)2 fragments described herein can be produced by proteolytic cleavage of immunoglobulin molecules, using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab’)2 fragments).
  • a Fab fragment corresponds to one of the two identical arms of a tetrameric antibody molecule and contains the complete light chain paired with the VH and CH1 domains of the heavy chain.
  • a F(ab’) 2 fragment contains the two antigen-binding arms of a tetrameric antibody molecule linked by disulfide bonds in the hinge region.
  • an antigen-binding fragment as described herein is selected from the group consisting of a Fab, Fab', F(ab')2, and scFv, wherein the Fab, Fab', F(ab')2, or scFv comprises a heavy chain variable region sequence and a light chain variable region sequence of an antibody or antigen-binding fragment thereof provided herein.
  • a Fab, Fab', F(ab')2, or scFv can be produced by any technique known to those of skill in the art.
  • the Fab, Fab', F(ab')2, or scFv further comprises a moiety that extends the half-life of the antibody in vivo.
  • the moiety is also termed a "half-life extending moiety.” Any moiety known to those of skill in the art for extending the half-life of a Fab, (ab')2, or scFv in vivo can be used.
  • the half-life extending moiety can include a Fc region, a polymer, an albumin, or an albumin binding protein or compound.
  • the polymer can include a natural or synthetic, optionally substituted straight or branched chain polyalkylene, polyalkenylene, polyoxylalkylene, polysaccharide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, methoxypolyethylene glycol, lactose, amylose, dextran, glycogen, or derivative thereof.
  • Substituents can include one or more hydroxy, methyl, or methoxy groups.
  • the Fab, Fab', F(ab') 2 , or scFv can be modified by the addition of one or more C-terminal amino acids for attachment of the half-life extending moiety.
  • the half-life extending moiety is polyethylene glycol or human serum albumin.
  • the Fab, Fab', F(ab')2, or scFv is fused to a Fc region. V.
  • anti-CD123 ADCs e.g., IMGN632/PVEK
  • an anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab
  • an anti-CD123 ADC and an anti-CD47 antibody or antigen-binding fragment thereof are contained within the same pharmaceutical composition.
  • an anti-CD123 ADC e.g., IMGN632/PVEK
  • an anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab
  • a kit comprises an anti-CD123 ADC (e.g., IMGN632/PVEK) and instructions to administer the anti- CD123 ADC (e.g., IMGN63/PVEK 2) and an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab).
  • kits comprises an anti-CD47 antibody or antigen- binding fragment thereof (e.g., magrolimab) and instructions to administer the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) and an anti-CD123 ADC (e.g., IMGN632/PVEK).
  • an anti-CD47 antibody or antigen- binding fragment thereof e.g., magrolimab
  • instructions to administer the anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab
  • an anti-CD123 ADC e.g., IMGN632/PVEK
  • compositions for use as provided herein can have an anti-CD123 ADC (e.g., IMGN632/PVEK) and/or an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) having the desired degree of 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 nontoxic 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.
  • compositions to be in vivo administration can be sterile. This is readily accomplished by filtration through, e.g., sterile filtration membranes.
  • a pharmaceutical composition comprising an anti-CD123 ADC (e.g., IMGN632/PVEK) and/or an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is formulated for parenteral (e.g., intravenous) administration.
  • anti-CD123 ADCs e.g., IMGN632/PVEK
  • IMGN632/PVEK can be used in combination anti-CD47 antibody or antigen-binding fragments thereof to treat hematological cancers.
  • the DNA-damaging effects of an anti-CD123 ADCs e.g., IMGN632/PVEK
  • can trigger enhanced anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab
  • the combination of an anti-CD123 ADC (e.g., IMGN632/PVEK) and an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is synergistic.
  • Cancers that can be treated by the methods provided herein include hematological cancers.
  • the hematological malignancy is of myeloid origin.
  • the hematological malignancy is of lymphoid origin.
  • the hematological malignancy is of both myeloid and lymphoid origins.
  • the hematological malignancy is a B-cell malignancy.
  • the hematological malignancy is a CD123- positive hematological malignancy.
  • the hematological malignancy is selected from the group consisting of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL), B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T ALL), chronic myeloid leukemia in blast crisis/phase (BP-CML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), (CMML), and malignancy is myelofibrosis (MF).
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • ALL acute lymphoblastic leukemia
  • B-ALL B-cell acute lymphoblastic leukemia
  • T ALL T-cell acute lymphoblastic leukemia
  • BP-CML blastic plasmacytoid dendritic cell neoplasm
  • the hematological malignancy is a relapsed or refractory hematological malignancy. In some aspects, the hematological malignancy is a relapsed hematological malignancy. In some aspects, the hematological malignancy is a refractory hematological malignancy. [0188] In some aspects, the hematological malignancy is AML. In some aspects, the AML is relapsed or refractory AML. In some aspects, the AML is relapsed AML. In some aspects, the AML is refractory AML. In some aspects, the AML is not secondary AML. In certain some, the AML is fit AML.
  • the AML is unfit AML.
  • the is BPDCN.
  • the BPDCN is relapsed or refractory BPDCN.
  • the BPDCN is relapsed BPDCN.
  • the BPDCN is refractory BPDCN.
  • the hematological malignancy is ALL.
  • the ALL is relapsed or refractory ALL.
  • the ALL is relapsed ALL.
  • the ALL is refractory ALL.
  • the hematological malignancy is MDS.
  • the MDS is high risk MDS.
  • the hematological malignancy is chronic myelomonocytic leukemia (CMML). [0193] In some aspects, the hematological malignancy is myelofibrosis (MF). [0194] In some aspects, the hematological malignancy is chemotherapy resistant. [0195] In some aspects, the hematological malignancy is chemotherapy sensitive. [0196] In some aspects, the hematological malignancy expresses multidrug resistance 1 (MDR1). In some aspects, the hematological malignancy expresses the multidrug resistance (MDR)-related P-glycoprotein (P-gp).
  • MDR1 multidrug resistance 1
  • P-gp P-glycoprotein
  • the hematological malignancy overexpresses MDR1 and P-gp.
  • the hematological malignancy is a CD123-positive hematological malignancy.
  • the hematological malignancy or the subject with the hematological malignancy has an FLT3-ITD mutation.
  • the hematological malignancy or the subject with the hematological malignancy does not have an FLT3-ITD mutation.
  • the hematological malignancy is present in the subject as minimal residual disease (MRD).
  • MRD+ patient has fit AML.
  • an MRD+ patient has unfit AML.
  • the methods provided herein can covert MRD+ patients to MRD- patients.
  • the methods provided herein can also increase the relapse-free survival time (e.g., the median relapse-free survival time) in MRD+ patients.
  • the human subject has received at least one prior treatment regimen for the cancer.
  • the human subject has received one prior treatment regimen for the cancer.
  • the human subject has received two prior treatment regimens for the cancer.
  • the human subject has received two prior treatment regimens for the cancer.
  • the human subject has received no more than six prior treatment regimens for the cancer.
  • the human subject has received at least one prior treatment, but no more than six prior treatment regimens for the cancer.
  • the cancer has not previously been treated with IMGN632/PVEK.
  • the cancer has been treated with magrolimab.
  • the cancer has not previously been treated with an SIRP ⁇ -targeting agent.
  • the cancer has not previously been treated with IMGN632/PVEK and has not previously been treated with magrolimab.
  • the cancer has not previously been treated with IMGN632/PVEK and has not previously been treated with an SIRP ⁇ -targeting agent.
  • an anti-CD123 ADC e.g., IMGN632/PVEK
  • an anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab
  • an anti-CD123 ADC e.g., IMGN632/PVEK
  • an anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab
  • an anti-CD123 ADC e.g., IMGN632/PVEK
  • an anti-CD123 ADC e.g., IMGN632/PVEK
  • Administration of anti-CD123 ADCs e.g., IMGN632
  • an anti-CD123 ADC (e.g., IMGN632/PVEK) is administered once in a four-week (28-day) cycle.
  • the anti-CD123 ADC (e.g., IMGN632) is administered on Day 1 of a 28-day cycle.
  • ADC e.g., IMGN632/PVEK
  • one cycle of treatment with an anti-CD123 ADC (e.g., IMGN632/PVEK) is therapeutically effective.
  • two cycles of treatment with an anti-CD123 ADC (e.g., IMGN632/PVEK) are therapeutically effective.
  • one to four cycles of treatment with an anti-CD123 ADC are therapeutically effective.
  • two to twelve cycles of treatment with an anti-CD123 ADC are therapeutically effective.
  • about 0.03 mg/kg to about 0.45 mg/kg of an anti-CD123 ADC is administered.
  • about 0.03 mg/kg of an anti-CD123 ADC is administered.
  • an anti-CD123 ADC e.g., IMGN632/PVEK
  • about 0.03 mg/kg to about 0.45 mg/kg of an anti-CD123 ADC is administered once in a four-week (28-day) cycle.
  • about 0.03 mg/kg of an anti-CD123 ADC is administered once in a four-week (28-day) cycle.
  • an anti-CD123 ADC e.g., IMGN632/PVEK
  • an anti-CD47 antibody or antigen-binding fragment thereof can be administered at a particular dose and/or at particular timing intervals.
  • Administration of a an anti-CD47 antibody or antigen-binding fragment thereof can be, for example, intravenous.
  • an anti-CD47 or antigen-binding fragment thereof is administered every 2 days to every 14 days.
  • an anti-CD47 antibody or antigen-binding fragment thereof is administered every 3 or 4 days. In some aspects, an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered once every week. In some aspects, an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered once every two weeks. [0211] In some aspects, an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered once every three or four days for a first interval and then once every week for a second interval.
  • the anti-CD47 antibody or antigen-binding fragment thereof is administered about two to about twenty times in the first interval. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered about four times in the first interval. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered about five times in the first interval. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered about six times in the first interval.
  • the anti-CD47 antibody or antigen-binding fragment thereof is administered about two to about twenty times in the second interval. In some aspects, the anti-CD47 antibody or antigen- binding fragment thereof (e.g., magrolimab) is administered about four times in the second interval. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered about five times in the second interval. In some aspects, the anti- CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered about six times in the second interval.
  • the anti-CD47 antibody or antigen-binding fragment thereof is administered about five times in the first interval and about five times in the second interval.
  • an anti-CD47 antibody or antigen-binding fragment thereof is administered once every week for a first interval and then once every two weeks for a second interval.
  • the anti-CD47 antibody or antigen-binding fragment thereof is administered about two to about twenty times in the first interval.
  • the anti-CD47 antibody or antigen-binding fragment thereof is administered about four times in the first interval.
  • the anti-CD47 antibody or antigen-binding fragment thereof is administered about five times in the first interval. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered about six times in the first interval. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered at least twice in the second interval. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered at times in the second interval.
  • the anti-CD47 antibody or antigen-binding fragment thereof is administered at least four times in the second interval. In some aspects, the anti-CD47 antibody or antigen- binding fragment thereof (e.g., magrolimab) is administered at least five times in the second interval. [0213] In some aspects, an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered once every three or four days for a first interval; then once every week for a second interval; then once every two weeks for a third interval.
  • the anti-CD47 antibody or antigen-binding fragment thereof is administered about two to about twenty times in the first interval. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered about four times in the first interval. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered about five times in the first interval. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered about six times in the first interval.
  • the anti-CD47 antibody or antigen-binding fragment thereof is administered about two to about twenty times in the second interval. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered about four times in the second interval. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered about five times in the second interval. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered about six times in the second interval.
  • the anti-CD47 antibody or antigen-binding fragment thereof is administered at least twice in the third interval. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered at least three times in the third interval. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered at least four times in the third interval. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered at least five times in the third interval.
  • the anti-CD47 antibody or antigen-binding fragment thereof is administered about five times in the first interval, about five times in the second interval, and at least twice in the third interval.
  • about 1 mg/kg to about 30 mg/kg of an anti-CD47 antibody or antigen- binding fragment thereof is administered.
  • about 1 mg/kg to about 10 mg/kg of an anti-CD47 antibody or antigen- binding fragment thereof is administered.
  • an anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab
  • about to about 60 mg/kg of an anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab is administered.
  • about 1 mg/kg to about 10 mg/kg of an anti-CD47 antibody or antigen-binding fragment thereof is administered; then about 10 mg/kg to about 20 mg/kg of an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered; and then about 20 mg/kg to about 60 mg/kg of an anti-CD47 antibody or antigen-binding fragment thereof is administered.
  • about 1 mg/kg of an anti-CD47 antibody or antigen-binding fragment thereof is administered.
  • about 15 mg/kg of an anti-CD47 antibody or antigen-binding fragment thereof is administered. In some aspects, about 30 mg/kg of an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered. In some aspects, about 1 mg/kg of an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered; then about 15 mg/kg of an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered; and then about 30 mg/kg of an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered.
  • an anti-CD47 antibody or antigen-binding fragment thereof is administered in a priming regimen and then a maintenance regimen.
  • a maintenance regimen can comprise administering an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) about once every two weeks.
  • the anti-CD47 antibody or antigen-binding fragment thereof can be administered at a dose of about 15 mg/kg to about 30 mg/kg during the maintenance regimen.
  • the anti-CD47 antibody or antigen-binding fragment thereof is administered at a dose of about 15 mg/kg during the maintenance regimen. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered at a dose of about 15 mg/kg during about once every two weeks during the maintenance regimen. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered at a dose of about 20 mg/kg during the maintenance regimen.
  • the anti-CD47 antibody or antigen-binding fragment thereof is administered at a dose of about 20 mg/kg during about once every two weeks during the maintenance regimen. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered at a dose of about 25 mg/kg during the maintenance regimen. In some aspects, the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) is administered at a dose of about 25 mg/kg during about once every two weeks during the maintenance regimen.
  • the anti-CD47 antibody or antigen-binding fragment thereof is administered at a dose of about 30 mg/kg during the maintenance regimen. In some aspects, the anti-CD47 antibody or antigen-binding thereof (e.g., magrolimab) is administered at a dose of about 30 mg/kg during about once every two weeks during the maintenance regimen.
  • a priming regimen can comprise administering an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) at a dose that is lower than the dose administered during a maintenance regimen and/or a dose that is administered more frequently than during a maintenance regimen.
  • a priming regimen comprises administering an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) at a multiple doses (e.g., increasing doses) that are less than the dose administered during a maintenance regimen.
  • an anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab
  • a multiple doses e.g., increasing doses
  • a priming regimen comprises administering an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) at a first dose of about 1 mg/kg to about 10 mg/kg and then a second, higher dose of about 10 mg/kg to about 20 mg/kg (e.g., wherein the maintenance regimen comprises administering the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) at about 30 mg/kg to about 60 mg/kg).
  • an anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab
  • a priming regimen comprises administering an anti-CD47 antibody or antigen- binding fragment thereof (e.g., magrolimab) at a first dose of about 1 mg/kg and then a second dose of about 15 mg/kg (e.g., wherein the maintenance regimen comprises administering the anti- CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) at about 30 mg/kg.
  • an anti-CD47 antibody or antigen- binding fragment thereof e.g., magrolimab
  • the maintenance regimen comprises administering the anti- CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) at about 30 mg/kg.
  • a priming regimen comprises administering an anti-CD47 antibody or antigen- binding fragment thereof (e.g., magrolimab) at a first interval of about once every week (e.g., wherein the maintenance regiment comprises administering the anti-CD47 antibody or antigen- binding fragment thereof (e.g., magrolimab) about once every two weeks.
  • an anti-CD47 antibody or antigen- binding fragment thereof e.g., magrolimab
  • a priming regimen comprises administering an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) at a first dose of about 1 mg/kg, then a second dose of about 15 mg/kg, and then a third dose of 30 mg/kg about once every week (e.g., wherein the maintenance regimen comprises administering the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) at about 30 mg/kg about once every two weeks).
  • a priming regimen comprises administering an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) once every three or four days.
  • a priming regimen comprises administering an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) about once every week. In some aspects, a priming regimen comprises administering an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) once every three or four days and then about once every week. [0221] In some aspects, a priming regimen comprises administering three increasing doses. In some aspects, the three increasing doses comprise a first dose administered on Days 1 and 4, a second dose administered on Day 8, and dose administered on Days 11, 15 and then once every week for 5 doses.
  • an anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab
  • an anti-CD47 antibody or antigen-binding fragment thereof is administered at 1 mg/kg on Days 1 and 4, at 15 mg/kg on Day 8, and at 30 mg/kg on Days 11, 15, and then once every week for 5 doses.
  • an anti-CD123 ADC is administered (e.g., intravenously) once every 28 days at a dose of 0.045 mg/kg and an anti-CD47 antibody or antigen-binding fragment thereof is administered (e.g., intravenously) in a priming regimen comprising about 1 mg/kg on Days 1 and 4, about 15 mg/kg on Day 8, and about 30 mg/kg on Days 11, 15, and then once every week for five doses and then a maintenance regimen comprising about 30 mg/kg once every two weeks.
  • an anti-CD123 ADC is administered (e.g., intravenously) once every 28 days at a dose of 0.03 mg/kg and an anti-CD47 antibody or antigen- binding fragment thereof is administered (e.g., intravenously) in a priming regimen comprising about 1 mg/kg on Days 1 and 4, about 15 mg/kg on Day 8, and about 30 mg/kg on Days 11, 15, and then once every week for five doses and then a maintenance regimen comprising about 30 mg/kg once every two weeks.
  • an anti-CD123 ADC is administered (e.g., intravenously) once every 28 days at a dose of 0.045 mg/kg and an anti-CD47 antibody or antigen-binding fragment thereof is administered (e.g., intravenously) in a priming regimen comprising about 1 mg/kg on Days 1 and 4, about 15 mg/kg on Day 8, and about 25 mg/kg on Days 11, 15, and then once every week for five doses and then a maintenance regimen comprising about 25 mg/kg once every two weeks.
  • an anti-CD123 ADC is administered (e.g., intravenously) once every 28 days at a dose of 0.03 mg/kg and an anti-CD47 antibody or antigen- binding fragment thereof is administered (e.g., intravenously) in a priming regimen comprising about 1 mg/kg on Days 1 and 4, about 15 mg/kg on Day 8, and about 25 mg/kg on Days 11, 15, and then once every week for five doses and then a maintenance regimen comprising about 25 mg/kg once every two weeks.
  • an anti-CD123 ADC is administered (e.g., intravenously) once every 28 days at a dose of 0.045 mg/kg and an anti-CD47 antibody or antigen-binding fragment thereof is administered (e.g., intravenously) in a priming regimen comprising about 1 mg/kg on Days 1 and 4, about 15 mg/kg on Day 8, and about 20 mg/kg on Days 11, 15, and then once every week for five doses and then a maintenance regimen comprising about 20 mg/kg once every two weeks.
  • CD123 ADC is administered (e.g., intravenously) once every 28 days at a dose of 0.03 mg/kg and an anti-CD47 antibody or antigen- binding fragment thereof is administered (e.g., intravenously) in a priming regimen comprising about 1 mg/kg on Days 1 and 4, about 15 mg/kg on Day 8, and about 20 mg/kg on Days 11, 15, and then once every week for five doses and then a maintenance regimen comprising about 20 mg/kg once every two weeks.
  • a priming regimen comprising about 1 mg/kg on Days 1 and 4, about 15 mg/kg on Day 8, and about 20 mg/kg on Days 11, 15, and then once every week for five doses and then a maintenance regimen comprising about 20 mg/kg once every two weeks.
  • an anti-CD123 ADC is administered (e.g., intravenously) once every 28 days at a dose of 0.045 mg/kg and an anti-CD47 antibody or antigen-binding fragment thereof is administered (e.g., intravenously) in a priming regimen comprising about 1 mg/kg on Days 1 and 4, about 15 mg/kg on Days 8, Days 11, 15, and then once every week for five doses and then a maintenance regimen comprising about 15 mg/kg once every two weeks.
  • an anti-CD123 ADC is administered (e.g., intravenously) once every 28 days at a dose of 0.03 mg/kg and an anti-CD47 antibody or antigen- binding fragment thereof is administered (e.g., intravenously) in a priming regimen comprising about 1 mg/kg on Days 1 and 4, about 15 mg/kg on Days 8, 11, 15, and then once every week for five doses and then a maintenance regimen comprising about 15 mg/kg once every two weeks.
  • a method of treating a hematological malignancy in a patient comprises administering an anti-CD123 ADC (e.g., IMGN632/PVEK) and an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) and further comprises administering a corticosteroid, e.g., dexamethasone, to the patient on the day prior to the administration of the anti-CD123 ADC.
  • a corticosteroid e.g., dexamethasone
  • 8 mg dexamethasone is administered to the patient twice on the day prior to the administration of the anti-CD123 ADC.
  • a method of treating a hematological malignancy in a patient comprises administering an anti-CD123 ADC (e.g., IMGN632/PVEK) and an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) and further comprises administering (i) diphenhydramine, (ii) acetaminophen or paracetamol, and/or (iii) dexamethasone to the patient prior to the administration of the anti-CD123 ADC on the day the anti-CD123 ADC is administered.
  • an anti-CD123 ADC e.g., IMGN632/PVEK
  • an anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab
  • (i) 25 to 50 mg diphenhydramine (IV), (ii) 325 to 650 mg acetaminophen or paracetamol (IV or PO), and (iii) 8 mg dexamethasone (IV) is administered to the patient prior to the administration of the anti-CD123 ADC on the day the anti-CD123 ADC is administered.
  • a method of treating a hematological malignancy in a patient comprises administering an anti-CD123 ADC (e.g., IMGN632/PVEK) and an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) and further comprises administering acetaminophen and/or to the patient prior to the administration of the anti-CD47 antibody or antigen-binding fragment thereof.
  • an anti-CD123 ADC e.g., IMGN632/PVEK
  • an anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab
  • oral acetaminophen 650 to 1000 mg and oral or IV diphenhydramine 25 to 50 mg is administered to the patient prior to the administration of the anti-CD47 antibody or antigen-binding fragment thereof.
  • the combination of an anti-CD123 ADC e.g., IMGN632/PVEK
  • an anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab
  • an anti-CD123 ADC e.g., IMGN632/PVEK
  • an anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab
  • the combination of an anti-CD123 ADC (e.g., IMGN632/PVEK) and an anti-CD47 antibody or antigen-binding fragment thereof increases a full complete response (CR) rate, e.g., as compared to monotherapy with the anti-CD123 ADC and/or monotherapy with the anti-CD47 antibody or antigen-binding fragment thereof.
  • Full CR rate includes complete remission without minimal residual disease (CR MRD- ), complete remission (CR).
  • the combination of an anti-CD123 ADC (e.g., IMGN632/PVEK) and an anti-CD47 antibody or antigen-binding fragment thereof increases a f composite CR rate (CCR), e.g., as compared to monotherapy with the anti-CD123 ADC and/or monotherapy with the anti-CD47 antibody or antigen-binding fragment thereof.
  • Composite CR rate (CCR) includes complete remission without minimal residual disease (CRMRD-), complete remission (CR), complete remission with partial hematologic recovery (CRh), complete remission with incomplete platelet recovery (CRp), complete remission with incomplete recovery (CRi).
  • the combination of an anti-CD123 ADC (e.g., IMGN632/PVEK) and an anti-CD47 antibody or antigen-binding fragment thereof increases an overall response rate (ORR), e.g., as compared to monotherapy with the anti-CD123 ADC and/or monotherapy with the anti-CD47 antibody or antigen-binding fragment thereof.
  • ORR overall response rate
  • ORR is defined as the proportion of patients with a best overall response of of complete remission without minimal residual disease (CRMRD-), complete remission (CR), complete remission with partial hematologic recovery (CRh), complete remission with incomplete platelet recovery (CRp), complete remission with incomplete recovery (CRi), morphologic leukemia-free state (MLFS), or partial remission (PR).
  • CMRD- complete remission without minimal residual disease
  • CR complete remission
  • CRh complete remission with partial hematologic recovery
  • CRp complete remission with incomplete platelet recovery
  • CRi complete remission with incomplete recovery
  • MLFS morphologic leukemia-free state
  • PR partial remission
  • the anti-CD123 ADC e.g., IMGN632/PVEK
  • an anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab
  • a duration of complete remission e.g., as compared to monotherapy with the anti-CD123 ADC and/or monotherapy with the anti-CD47 antibody or antigen-binding fragment thereof.
  • DOCR is the date of achieving CR MRD- /CR until the date of relapse or death from any cause, whichever occurs first.
  • the combination of an anti-CD123 ADC (e.g., IMGN632/PVEK) and an anti-CD47 antibody or antigen-binding fragment thereof increases a duration of response (DOR), e.g., as compared to monotherapy with the anti-CD123 ADC and/or monotherapy with the anti-CD47 antibody or antigen-binding fragment thereof.
  • DOR is defined for patients who have achieved a complete or partial remission (CRMRD-, CR, CRh, CRp, and CRi) and is measured from the date of the first specific response until the date of relapse or death from any cause, whichever comes first.
  • the combination of combination of an anti-CD123 ADC (e.g., IMGN632/PVEK) and an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) produces a synergistic effect.
  • administration of the combination of an anti-CD123 ADC (e.g., IMGN632/PVEK) and an anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) does not produce more toxicity than administration of the anti-CD123 ADC (e.g., IMGN632/PVEK) as a monotherapy.
  • administering does not produce more toxicity than administration of the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) as a monotherapy.
  • an anti-CD123 ADC e.g., IMGN632/PVEK
  • an anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab
  • administering combination of an anti-CD123 ADC e.g., IMGN632/PVEK
  • an anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab
  • administration of combination of an anti-CD123 ADC does not produce more toxicity than administration of the anti-CD123 ADC (e.g., IMGN632/PVEK) as a monotherapy and does not produce more toxicity than the anti-CD47 antibody or antigen-binding fragment thereof (e.g., magrolimab) as a monotherapy.
  • patients receiving therapy with anti-CD123 ADC e.g., IMGN632/PVEK
  • an anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab
  • the corticosteroid can be selected from the group consisting of prednisone, prednisolone, methylprednisolone, beclamethasone, betamethasone, dexamethasone, fludrocortisone, hydrocortisone, and triamcinolone.
  • the corticosteroid is dexamethasone.
  • the corticosteroid (e.g., dexamethasone) was administered orally (PO) or intravenously (IV). In some aspects, dexamethasone is given orally. In some aspects, dexamethasone is given intravenously. In some aspects, the corticosteroid (e.g., dexamethasone) was administered on the day prior to the administration of the anti-CD123 ADC. In some aspects, the patient received 8 mg dexamethasone (PO or IV) BID on the day prior to the administration of the anti-CD123 ADC.
  • patients receiving therapy with anti-CD123 ADC e.g., IMGN632/PVEK
  • an anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab
  • patients receiving therapy with anti-CD123 ADC have received pretreatment prior to the administration of the anti- CD123 ADC on the day of administration of the anti-CD123 ADC.
  • the patient was pretreated with (i) diphenhydramine, (ii) acetaminophen or paracetamol, and/or (iii) dexamethasone.
  • the patient was pretreated with (i) diphenhydramine, (ii) acetaminophen or paracetamol, and (iii) dexamethasone.
  • acetaminophen is given intravenously. In some aspects, acetaminophen is given orally. In some aspects, paracetamol is given intravenously. In some aspects, paracetamol is given orally. In some aspects, diphenhydramine is given intravenously. In some aspects, diphenhydramine is given orally. In some aspects, the patient was pretreated with (i) 25 to 50 mg diphenhydramine (IV), (ii) 325 to 650 mg acetaminophen or paracetamol (IV or PO), and (iii) 8 mg dexamethasone (IV) prior to the administration of the anti-CD123 ADC on the day of administration of the anti-CD123 ADC.
  • patients receiving therapy with anti-CD123 ADC e.g., IMGN632/PVEK
  • an anti-CD47 antibody or antigen-binding fragment thereof e.g., magrolimab
  • the patient was pretreated with acetaminophen and/or diphenhydramine prior to the administration of the anti-CD47 antibody or antigen-binding fragment thereof.
  • diphenhydramine is given intravenously. In some aspects, diphenhydramine is given orally.
  • the patient received oral acetaminophen 650 to 1000 mg and oral or IV diphenhydramine 25 to 50 mg (or a comparable regimen prior) to the administration of the anti-CD47 antibody or antigen-binding fragment thereof.
  • Example 1 The combination of IMGN632/PVEK and magrolimab for the treatment of relapsed or refractor CD123-positive acute myeloid leukemia (AML) [0247] An open-label, multicenter, Phase 1b/2 study of the combination of IMGN632/PVEK and magrolimab is performed to demonstrate the safety of the combination and its efficacy in treating relapsed or refractory CD123-positive acute myeloid leukemia (AML).
  • the study comprises a Phase 1b Safety Phase and by Phase 2 Expansion Phase.
  • the Safety and Expansion Phases include an antileukemia activity futility assessment using a Simon’s 2-stage design.
  • the Expansion Phase occurs after acceptable safety and sufficient efficacy are demonstrated in the Safety Phase.
  • the schema for the study is provided in Figure 2.
  • Patients are enrolled in a 3 + 3 design with 3, then 3 additional, then up to 16 additional patients, for a total of up to 22 efficacy-evaluable patients treated at the same dose to assess safety and signal findings for anti-leukemia activity.
  • Patient Inclusion Criteria Patients are adults (( ⁇ 18 years of age) and are evaluated for any available standard of care therapies (including induction, consolidation chemotherapy and/or transplant) and are deemed appropriate for this experimental therapy. Patients meet all of the following inclusion criteria: ⁇ confirmed diagnosis of AML (excluding acute promyelocytic leukemia) based on World Health Organization classification (Arber DA, et al., The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405 (2016)).
  • ⁇ have qualitative CD123-positive AML blasts as confirmed by local flow cytometry (or immunohistochemistry (IHC)); ⁇ may have received prior CD123-targeted therapies, except IMGN632/PVEK, as long as CD123 remains detectable during screening; ⁇ relapsed or refractory CD123-positive AML with up to 2 prior lines of therapy (Prior lines of therapy may include multiple regimens, e.g., frontline treatment may include induction, consolidation [including transplant], and maintenance as one line of therapy); ⁇ Eastern Cooperative Oncology performance status ⁇ 1.
  • Leukapheresis and/or hydroxyurea may be used to control blood counts before Cycle 1 Day 1; ⁇ Hemoglobin must be ⁇ 9 g/dL prior to initial dose of magrolimab (transfusions are allowed to meet hemoglobin eligibility); ⁇ Liver enzymes (AST and ALT) ⁇ 3 ⁇ the upper limit of normal (ULN); ⁇ Total bilirubin ⁇ 1.5 ⁇ the ULN; ⁇ An estimated glomerular filtration rate (eGFR) of > 30 mL/min/1.73 m 2 or creatinine clearance of > 30 mL/min; and ⁇ Left ventricular ejection fraction (LVEF) ⁇ 50% based on locally available assessment, e.g., echocardiogram or other modality.
  • eGFR estimated glomerular filtration rate
  • LVEF Left ventricular ejection fraction
  • IMGN632/PVEK is administered intravenously on Day 1 of a 28-day cycle at doses of 0.045 mg/kg or 0.03 mg/kg.
  • 15 mg/kg IV over 3 hours ( ⁇ 30 minutes) on Day 8; and at 30 mg/kg IV over 2 hours ( ⁇ 30 minutes) on Days 11, 15, and then weekly for 5 doses is referred to as “magrolimab priming.”
  • Magrolimab given at 30 mg/kg IV over 2 hours ( ⁇ 30 minutes) every 2 weeks beginning 1 week after the fifth weekly 30 mg/kg dose is referred to as “magrolimab maintenance dose.”
  • Premedication is required prior to the administration of the first 4 doses of magrolimab.
  • magrolimab oral acetaminophen 650 to 1000 mg and oral or IV diphenhydramine 25 to 50 mg or comparable regimen. If less than 4 hours has elapsed since a prior dose of acetaminophen has been given, the dose of acetaminophen premedication may be omitted. [0256] Given the large CD47 antigen sink on normal cells, patients who have a long dose delay of magrolimab are required to be reprimed with magrolimab dosing to resaturate the CD47 antigen sink. The repriming guidelines presented in Table 8 are followed for patients with dose delays.
  • magrolimab Repriming Dose of Magrolimab Minimum Duration of Treatment Gap That Will Lead to R i i [0257] If both IMGN632/PVEK and magrolimab are given on the same day, IMGN632/PVEK is administered first. The magrolimab infusion starts at least 1 hour after the end of IMGN632/PVEK infusion.
  • IMGN632/PVEK Up to 22 patients are evaluated (Phase 1b), and then IMGN632/PVEK in combination with magrolimab will be evaluated with up to 14 efficacy-evaluable patients (Phase 2).
  • the initial treatment consists of of IMGN632/PVEK in combination with magrolimab. Additional treatments may be administered until progression for patients deriving benefit from the treatment regimen.
  • Results Blood samples are taken to assess the pharmacokinetic (PK) properties of IMGN632/PVEK concentrations when administered in combination with magrolimab.
  • AE adverse events
  • LVEF left ventricular ejection fraction assessment
  • response assessments comprising primarily bone marrow aspirates (BMAs) and/or biopsies assessed by morphology and minimal residual disease (MRD) testing at the end of IMGN632/PVEK Cycle 1 and Cycle 2 and every other subsequent cycle to demonstrate that the combination of IMGN632/PVEK and magrolimab is effective.
  • BMAs bone marrow aspirates
  • MRD minimal residual disease
  • ORR overall response rate
  • DOR duration of complete remission
  • ORR is defined as the proportion of patients with a best overall response of complete remission without minimal residual disease (CR MRD- ), complete remission (CR), complete remission with partial hematologic recovery (CRh), complete remission with incomplete platelet recovery (CRp), complete remission with incomplete recovery (CRi), morphologic leukemia-free state (MLFS), or partial remission (PR).
  • Full CR rate (CR) includes CRMRD- and CR
  • composite CR rate (CCR) includes CRMRD-, CR, CRh, CRp, and CR.
  • DOCR is defined from the date of achieving CRMRD-/CR until the date of relapse or death from any cause, whichever occurs first. For a patient who is not known to have relapsed or died by the end of study follow-up, observation of DOCR is censored on the date of his or her last bone marrow disease assessment. [0263] DOR is defined for patients who have achieved a complete or partial remission (CR MRD- , CR, CRh, CRp, and CRi) and is be measured from the date of the first specific response until the date of relapse or death from any cause, whichever comes first.

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Abstract

L'invention concerne des combinaisons thérapeutiques de ADC qui se lient à CD123 (par exemple, IMGN632/PVEK) avec un anticorps anti-CD47 ou un fragment de liaison à l'antigène de celui-ci (par exemple, magrolimab). L'invention concerne également des méthodes d'administration des combinaisons pour traiter des malignités hématologiques telles que la leucémie myéloïde aiguë (LMA), avec une efficacité clinique améliorée et/ou une absence de toxicité accrue.
PCT/US2023/082499 2022-12-08 2023-12-05 Combinaisons thérapeutiques comprenant des conjugués anticorps-médicament anti-cd123 et des anticorps anti-cd47 Ceased WO2024123765A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200147117A1 (en) * 2017-07-09 2020-05-14 Biosight Ltd. Combination cancer therapy
US20200283536A1 (en) * 2017-10-27 2020-09-10 Pfizer Inc. Antibodies and antibody-drug conjugates specific for cd123 and uses thereof
US20210023237A1 (en) * 2019-04-29 2021-01-28 Immunogen, Inc. Therapeutic combinations comprising anti-cd123 immunoconjugates
WO2021206965A1 (fr) * 2020-04-06 2021-10-14 The Board Of Trustees Of The Leland Stanford Junior University Formulation d'anticorps

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200147117A1 (en) * 2017-07-09 2020-05-14 Biosight Ltd. Combination cancer therapy
US20200283536A1 (en) * 2017-10-27 2020-09-10 Pfizer Inc. Antibodies and antibody-drug conjugates specific for cd123 and uses thereof
US20210023237A1 (en) * 2019-04-29 2021-01-28 Immunogen, Inc. Therapeutic combinations comprising anti-cd123 immunoconjugates
WO2021206965A1 (fr) * 2020-04-06 2021-10-14 The Board Of Trustees Of The Leland Stanford Junior University Formulation d'anticorps

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