WO2024121711A1 - Méthodes de traitement au moyen d'antagonistes d'antigène de maturation des lymphocytes b - Google Patents

Méthodes de traitement au moyen d'antagonistes d'antigène de maturation des lymphocytes b Download PDF

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WO2024121711A1
WO2024121711A1 PCT/IB2023/062182 IB2023062182W WO2024121711A1 WO 2024121711 A1 WO2024121711 A1 WO 2024121711A1 IB 2023062182 W IB2023062182 W IB 2023062182W WO 2024121711 A1 WO2024121711 A1 WO 2024121711A1
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bcma
belantamab
antagonist
patient
antibody
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PCT/IB2023/062182
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English (en)
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Herbert Struemper
Brandon KREMER
Christopher Shelton
Alessandra TOSOLINI
Ira Virendrakumar GUPTA
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Glaxosmithkline Intellectual Property Development Limited
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Publication of WO2024121711A1 publication Critical patent/WO2024121711A1/fr

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    • 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
    • C07K16/2878—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 NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • 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
    • 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
    • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
    • 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
    • A61K47/6851—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 determinant of a tumour cell
    • A61K47/6867—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 determinant of a tumour cell the tumour determinant being from a cell of a blood cancer
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present disclosure generally relates to methods of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) by the administration of one or more BCMA antagonists.
  • BCMA B-cell maturation antigen
  • B-cell maturation antigen is a cell surface receptor expressed in the plasmablast lineage and upregulated on various disease cell types including multiple myeloma (MM) cells.
  • MM is an incurable malignant clonal plasma cell disorder and accounts for 1% of all cancers and for 10% of all hematologic malignancies globally.
  • NDMM multiple myeloma
  • Belantamab mafodotin is a BCMA-directed antibody-drug conjugate (ADC) that is conjugated to a microtubule disrupting agent, monomethyl auristatin-F (MMAF) and has demonstrated antitumor activity in MM cells.
  • ADC BCMA-directed antibody-drug conjugate
  • MMAF monomethyl auristatin-F
  • Belantamab mafodotin is produced in an afucosylated form, which enhances interaction with the FcyRIIIa receptor. This enhanced interaction increases antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) activities, including against MM cells.
  • ADCC antibody-dependent cellular cytotoxicity
  • ADCP antibody-dependent cellular phagocytosis
  • belantamab mafodotin possesses a dual anti-tumor activity via delivery of the MMAF cytotoxin, as well as through ADCC/ADCP.
  • Ocular toxicity has been reported for belantamab mafodotin, as well as in other MMAF containing ADCs, leading to dose delays and dose reductions. Therefore, there is a need for additional therapies for treatment of MM and other diseases associated with abnormal BCMA expression with manageable toxicity.
  • the disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, the method comprising administering to the patient belantamab at a dose of about 300 mg to about 2000 mg.
  • BCMA B-cell maturation antigen
  • the disclosure provides the use of belantamab in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) by administration of belantamab at a dose of about 300 mg to about 2000 mg.
  • BCMA B-cell maturation antigen
  • the disclosure provides use of belantamab in the manufacture of a medicament for use in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) by administration of belantamab at a dose of about 300 mg to about 2000 mg.
  • BCMA B-cell maturation antigen
  • the dose is about 300 mg, about 900 mg, or about 2000 mg.
  • the dose is administered at a regular interval for a period of time.
  • the dose is administered once every week ⁇ 3 days to once every four weeks ⁇ 3 days.
  • the dose is administered once every two weeks ⁇ 3 days.
  • the dose is administered once every three weeks ⁇ 3 days.
  • the dose is administered once every four weeks ⁇ 3 days.
  • the dose is administered on days 1 and 15 of a 28 day cycle.
  • the dose is administered on day 1 of a 21 day cycle.
  • the patient has been treated with at least one prior line of cancer treatment.
  • the patient has been treated with one, two, three, or four prior lines of cancer treatments.
  • the prior lines of cancer treatments include an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.
  • belantamab is administered through an intravenous infusion or a subcutaneous injection.
  • the patient is further receiving at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.
  • the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.
  • the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily for a period of time.
  • the patient is receiving lenalidomide on days 1-21 of a 28 day cycle.
  • the additional cancer treatment is dexamethasone. In an embodiment, the additional cancer treatment is dexamethasone at a dose of 20 mg to 40 mg once weekly. In an embodiment, the patient is receiving dexamethasone on days 1, 8, 15, and 22 of a 28 day cycle. In an embodiment, (i) the patient is less than 75 years old and is receiving dexamethasone at a dose of 40 mg once weekly; or (ii) the patient is at least 75 years old and is receiving dexamethasone at a dose of 20 mg once weekly.
  • the patient has a BMI of at least 18.5 and is receiving dexamethasone at a dose of 40 mg once weekly; or (ii) the patient has a BMI less than 18.5 and is receiving dexamethasone at a dose of 20 mg once weekly.
  • the method or use further comprises discontinuing administration of belantamab and subsequently administering belantamab mafodotin. In an embodiment, the method or use further comprises administering belantamab mafodotin and subsequently discontinuing administration of belantamab. In an embodiment, belantamab mafodotin is administered at a dose of 2.5 mg/kg once every three weeks ⁇ 3 days.
  • the method or use further comprises administering a lead-in dose of belantamab mafodotin prior to beginning administration of belantamab, wherein the lead-in dose of belantamab mafodotin is about 1.4 mg/kg to about 3.4 mg/kg once during a lead-in period.
  • the lead-in dose of belantamab mafodotin is about 1.4 mg/kg to about 1.9 mg/kg once during a lead-in period.
  • the lead-in dose of belantamab mafodotin is about 1.4 mg/kg, about 1.9 mg/kg, about 2.5 mg/kg, or about 3.4 mg/kg once during a lead-in period.
  • the lead-in dose of belantamab mafodotin is about 1.4 mg/kg once during a lead- in period.
  • the lead-in period is four weeks ⁇ 3 days and belantamab mafodotin is administered on day 1 of the lead-in period.
  • the method or use further comprises administering at least one additional cancer treatment to the patient during the lead-in period, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.
  • the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.
  • the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily for a period of time.
  • lenalidomide is administered to the patient on days 1-21 of the lead-in period. In an embodiment, lenalidomide is administered to the patient on days 1-21 of the lead-in period and the lead-in period is four weeks ⁇ 3 days. In an embodiment, lenalidomide is administered to the patient on days 1-21 of the lead-in period and the lead-in period is 28 days.
  • the additional cancer treatment is dexamethasone. In an embodiment, the additional cancer treatment is dexamethasone at a dose of 20 mg to 40 mg once weekly. In an embodiment, dexamethasone is administered to the patient on days 1, 8, 15, and 22 of the lead-in period.
  • dexamethasone is administered to the patient on days 1, 8, 15, and 22 of the lead-in period and the lead-in period is four weeks ⁇ 3 days. In an embodiment, dexamethasone is administered to the patient on days 1, 8, 15, and 22 of the lead-in period and the lead-in period is 28 days. In an embodiment, (i) the patient is less than 75 years old and dexamethasone is administered to the patient at a dose of 40 mg once weekly; or (ii) the patient is at least 75 years old and dexamethasone is administered to the patient at a dose of 20 mg once weekly.
  • the patient has a BMI of at least 18.5 and dexamethasone is administered to the patient at a dose of 40 mg once weekly; or (ii) the patient has a BMI less than 18.5 and dexamethasone is administered to the patient at a dose of 20 mg once weekly.
  • the disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, the method comprising administering to a patient belantamab mafodotin at a dose of about 1.4 mg/kg to about 3.4 mg/kg once every eight weeks ⁇ 3 days, such as about 1.4 mg/kg to about 1.9 mg/kg once every eight weeks ⁇ 3 days.
  • BCMA B-cell maturation antigen
  • the disclosure provides the use of belantamab mafodotin in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) by administration of belantamab mafodotin at a dose of about 1.4 mg/kg to about 3.4 mg/kg once every eight weeks ⁇ 3 days, such as about 1.4 mg/kg to about 1.9 mg/kg once every eight weeks ⁇ 3 days.
  • BCMA B-cell maturation antigen
  • the disclosure provides use of belantamab mafodotin in the manufacture of a medicament for use in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) by administration of belantamab mafodotin at a dose of about 1.4 mg/kg to about 3.4 mg/kg once every eight weeks ⁇ 3 days, such as about 1.4 mg/kg to about 1.9 mg/kg once every eight weeks ⁇ 3 days.
  • BCMA B-cell maturation antigen
  • the dose is about 1.4 mg/kg, about 1.9 mg/kg, about 2.5 mg/kg, or about 3.4 mg/kg once every eight weeks ⁇ 3 days.
  • the disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, the method comprising administering a therapeutically effective amount of a combination comprising a first BCMA antagonist and a second BCMA antagonist to the patient.
  • the disclosure provides the use of a combination comprising a first BCMA antagonist and a second BCMA antagonist to the patient in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA).
  • the disclosure provides use of a combination comprising a first BCMA antagonist and a second BCMA antagonist in the manufacture of a medicament for use in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA).
  • BCMA B-cell maturation antigen
  • the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen binding fragment thereof, an anti- BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • the first and second BCMA antagonists are independently selected from the group consisting of idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.
  • the first BCMA antagonist is belantamab mafodotin.
  • the first BCMA antagonist is belantamab.
  • the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is the corresponding unconjugated anti-BCMA antibody.
  • the anti-BCMA antibody-drug conjugate is selected from the group consisting of belantamab mafodotin, MEDI2228, and CC99712.
  • the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is belantamab.
  • the disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, the method comprising administering a therapeutically effective amount of a combination comprising belantamab mafodotin and belantamab to the patient.
  • BCMA B-cell maturation antigen
  • the disclosure provides the use of a combination comprising belantamab mafodotin and belantamab in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA).
  • BCMA B-cell maturation antigen
  • the disclosure provides use of a combination comprising belantamab mafodotin and belantamab in the manufacture of a medicament for use in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA).
  • BCMA B-cell maturation antigen
  • the method or use further comprises administering at least one additional cancer treatment to the patient, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.
  • the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.
  • the disclosure provides a kit comprising: (i) a first B-cell maturation antigen (BCMA) antagonist; and (ii) instructions for use in treating a disease or disorder responsive to inhibiting or blocking BCMA when combined with a second BCMA antagonist.
  • BCMA B-cell maturation antigen
  • the disclosure provides a kit comprising: (i) belantamab mafodotin; and (ii) instructions for use in treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) when combined with belantamab.
  • BCMA B-cell maturation antigen
  • the disclosure provides a kit comprising: (i) belantamab; and (ii) instructions for use in treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) when combined with belantamab mafodotin.
  • BCMA B-cell maturation antigen
  • the disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient previously treated with a first BCMA antagonist, the method comprising administering a therapeutically effective amount of a second BCMA antagonist to the patient, wherein the patient discontinued administration of the first BCMA antagonist prior to beginning administration of the second BCMA antagonist and the second BCMA antagonist is not the same as the first BCMA antagonist.
  • BCMA B-cell maturation antigen
  • the disclosure provides the use of a second BCMA antagonist in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient previously treated with a first BCMA antagonist wherein administration of the first BCMA antagonist is discontinued prior to beginning administration of the second BCMA antagonist and the second BCMA antagonist is not the same as the first BCMA antagonist.
  • BCMA B-cell maturation antigen
  • the disclosure provides use of a second BCMA antagonist in the manufacture of a medicament for the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient previously treated with a first BCMA antagonist wherein administration of the first BCMA antagonist is discontinued prior to beginning administration of the second BCMA antagonist and the second BCMA antagonist is not the same as the first BCMA antagonist.
  • BCMA B-cell maturation antigen
  • the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen binding fragment thereof, an anti- BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • the first and second BCMA antagonists are independently selected from the group consisting of idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.
  • the first BCMA antagonist is belantamab mafodotin.
  • the first BCMA antagonist is belantamab.
  • the second BCMA antagonist is belantamab mafodotin.
  • the second BCMA antagonist is belantamab.
  • the first BCMA antagonist is an anti- BCMA antibody-drug conjugate and the second BCMA antagonist is the corresponding unconjugated anti-BCMA antibody.
  • the anti-BCMA antibody-drug conjugate is selected from the group consisting of belantamab mafodotin, MEDI2228, and CC99712.
  • the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is belantamab.
  • the second BCMA antagonist is an anti-BCMA antibody-drug conjugate and the first BCMA antagonist is the corresponding unconjugated anti- BCMA antibody.
  • the anti-BCMA antibody-drug conjugate is selected from the group consisting of belantamab mafodotin, MEDI2228, and CC99712.
  • the second BCMA antagonist is belantamab mafodotin and the first BCMA antagonist is belantamab.
  • the disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient previously treated with belantamab mafodotin, the method comprising administering a therapeutically effective amount of belantamab to the patient, wherein the patient discontinued administration of belantamab mafodotin prior to beginning administration of belantamab.
  • BCMA B-cell maturation antigen
  • the disclosure provides the use of belantamab in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient previously treated with belantamab mafodotin, wherein administration of belantamab mafodotin is discontinued prior to beginning administration of belantamab.
  • BCMA B-cell maturation antigen
  • the disclosure provides use of belantamab for use in the manufacture of a medicament for use in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient previously treated with belantamab mafodotin, wherein administration of belantamab mafodotin is discontinued prior to beginning administration of belantamab.
  • BCMA B-cell maturation antigen
  • the disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient previously treated with belantamab, the method comprising administering a therapeutically effective amount of belantamab mafodotin to the patient, wherein the patient discontinued administration of belantamab prior to beginning administration of belantamab mafodotin.
  • BCMA B-cell maturation antigen
  • the disclosure provides the use of belantamab mafodotin in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient previously treated with belantamab wherein administration of belantamab is discontinued prior to beginning administration of belantamab mafodotin.
  • BCMA B-cell maturation antigen
  • the disclosure provides use of belantamab mafodotin in the manufacture of a medicament for use in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient previously treated with belantamab wherein administration of belantamab is discontinued prior to beginning administration of belantamab mafodotin.
  • BCMA B-cell maturation antigen
  • the methods or uses further comprise administering at least one additional cancer treatment to the patient, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.
  • the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.
  • the disclosure provides a method of reducing corneal toxicity in a patient previously treated with a first B-cell maturation antigen (BCMA) antagonist, the method comprising administering a therapeutically effective amount of a second BCMA antagonist to the patient, wherein the patient discontinued administration of the first BCMA antagonist prior to beginning administration of the second BCMA antagonist and the second BCMA antagonist is not the same as the first BCMA antagonist.
  • BCMA B-cell maturation antigen
  • the disclosure provides the use of a second BCMA antagonist for the reduction of corneal toxicity in a patient previously treated with a first B-cell maturation antigen (BCMA) antagonist, wherein administration of the first BCMA antagonist is discontinued prior to beginning administration of the second BCMA antagonist and the second BCMA antagonist is not the same as the first BCMA antagonist.
  • BCMA B-cell maturation antigen
  • the disclosure provides use of a second BCMA antagonist in the manufacture of a medicament for use in the reduction of corneal toxicity in a patient previously treated with a first B-cell maturation antigen (BCMA) antagonist, wherein administration of the first BCMA antagonist is discontinued prior to beginning administration of the second BCMA antagonist and the second BCMA antagonist is not the same as the first BCMA antagonist.
  • BCMA B-cell maturation antigen
  • the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen binding fragment thereof, an anti- BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • the first and second BCMA antagonists are independently selected from the group consisting of idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.
  • the first BCMA antagonist is belantamab mafodotin.
  • the first BCMA antagonist is belantamab.
  • the second BCMA antagonist is belantamab mafodotin.
  • the second BCMA antagonist is belantamab.
  • the first BCMA antagonist is an anti- BCMA antibody-drug conjugate and the second BCMA antagonist is the corresponding unconjugated anti-BCMA antibody.
  • the anti-BCMA antibody-drug conjugate is selected from the group consisting of belantamab mafodotin, MEDI2228, and CC99712.
  • the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is belantamab.
  • the second BCMA antagonist is an anti-BCMA antibody-drug conjugate and the first BCMA antagonist is the corresponding unconjugated anti- BCMA antibody.
  • the anti-BCMA antibody-drug conjugate is selected from the group consisting of belantamab mafodotin, MEDI2228, and CC99712.
  • the second BCMA antagonist is belantamab mafodotin and the first BCMA antagonist is belantamab.
  • the disclosure provides the use of belantamab for the reduction of corneal toxicity in a patient previously treated with belantamab mafodotin, wherein the patient discontinued administration of belantamab mafodotin prior to beginning administration of belantamab.
  • the disclosure provides use of belantamab in the manufacture of a medicament for use in the reduction of corneal toxicity in a patient previously treated with belantamab mafodotin, wherein the patient discontinued administration of belantamab mafodotin prior to beginning administration of belantamab.
  • the disclosure provides a method of reducing corneal toxicity in a patient previously treated with belantamab, the method comprising administering a therapeutically effective amount of belantamab mafodotin to the patient, wherein the patient discontinued administration of belantamab prior to beginning administration of belantamab mafodotin.
  • the disclosure provides the use of belantamab mafodotin for the reduction of corneal toxicity in a patient previously treated with belantamab, wherein the patient discontinued administration of belantamab prior to beginning administration of belantamab mafodotin.
  • the disclosure provides use of belantamab mafodotin in the manufacture of a medicament for use in the reduction of corneal toxicity in a patient previously treated with belantamab, wherein the patient discontinued administration of belantamab prior to beginning administration of belantamab mafodotin.
  • the methods and uses further comprise administering at least one additional cancer treatment to the patient, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.
  • the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.
  • the disclosure provides a method of treating a disease or disorder in a patient, the method comprising administering a therapeutically effective amount of a combination comprising an antibody-drug conjugate and the corresponding unconjugated antibody.
  • the disclosure provides the use of a combination comprising an antibodydrug conjugate and the corresponding unconjugated antibody in the treatment of a disease or disorder.
  • the disclosure provides use of a combination comprising an antibodydrug conjugate and the corresponding unconjugated antibody for use in the manufacture of a medicament for the treatment of a disease or disorder.
  • the disclosure provides a method of treating a disease or disorder in a patient previously treated with an antibody-drug conjugate, the method comprising administering a therapeutically effective amount of the corresponding unconjugated antibody to the patient, wherein the patient discontinued administration of the antibody-drug conjugate prior to beginning administration of the corresponding unconjugated antibody.
  • the disclosure provides the use of an antibody in the treatment of a disease or disorder in a patient previously treated with an antibody-drug conjugate, wherein the antibody is the corresponding unconjugated antibody and the patient discontinued administration of the antibody-drug conjugate prior to beginning administration of the corresponding unconjugated antibody.
  • the disclosure provides use of an antibody in the manufacture of a medicament for use in the treatment of a disease or disorder in a patient previously treated with an antibody-drug conjugate, wherein the antibody is the corresponding unconjugated antibody and the patient discontinued administration of the antibody-drug conjugate prior to beginning administration of the corresponding unconjugated antibody.
  • the antibody-drug conjugate is selected from gemtuzumab ozogamicin, brentuximab vedotin, ado-trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, fam-trastuzumab deruxtecan, sacituzumab govitecan, belantamab mafodotin, loncastuximab tesirine, tisotumab vedotin, moxetumomab pasudotox, MEDI2228, or CC99712.
  • the disease or disorder is a plasma cell disorder or a B-cell disorder. In an embodiment, the disease or disorder is a BCMA-expressing cancer. In an embodiment, the disease or disorder is multiple myeloma (MM). In an embodiment, the MM is relapsed and/or refractory MM, newly-diagnosed MM, transplant-ineligible MM, or transplant-ineligible newly- diagnosed MM. In an embodiment, the MM is relapsed and/or refractory MM, newly-diagnosed MM, transplant-ineligible MM, or transplant-ineligible newly-diagnosed MM.
  • MM is relapsed and/or refractory MM, newly-diagnosed MM, transplant-ineligible MM, or transplant-ineligible newly-diagnosed MM.
  • the disclosure provides a method of treating cancer in a patient, wherein the patient has a Grade 1 corneal adverse reaction resulting from belantamab mafadotin administration, the method comprising temporarily discontinuing administration of belantamab mafadotin; administering to the patient a therapeutically effective amount of belantamab for a lead- in period; and resuming administration of belantamab mafadotin after the lead-in period.
  • the disclosure provides the use of belantamab in the treatment of cancer in a patient, wherein the patient has a Grade 1 corneal adverse reaction resulting from belantamab mafadotin administration, wherein belantamab mafadotin is temporarily discontinued for a lead- in period during which belantamab is administered, followed by resuming administration of belantamab mafadotin after the lead-in period.
  • the disclosure provides use of belantamab in the manufacture of a medicament for use in the treatment of cancer in a patient, wherein the patient has a Grade 1 corneal adverse reaction resulting from belantamab mafadotin administration, wherein belantamab mafadotin is temporarily discontinued for a lead-in period during which belantamab is administered, followed by resuming administration of belantamab mafadotin after the lead-in period.
  • the disclosure provides a method of treating cancer in a patient, wherein the patient has a Grade 2 or above corneal adverse reaction resulting from belantamab mafodotin administration, the method comprising temporarily discontinuing administration of belantamab mafadotin; administering to the patient a therapeutically effective amount of belantamab for a lead- in period; and resuming administration of belantamab mafadotin after the lead-in period.
  • the disclosure provides the use of belantamab in the treatment of cancer in a patient, wherein the patient has a Grade 2 or above corneal adverse reaction resulting from belantamab mafadotin administration, wherein belantamab mafadotin is temporarily discontinued for a lead-in period during which belantamab is administered, followed by resuming administration of belantamab mafadotin after the lead-in period.
  • the disclosure provides use of belantamab in the manufacture of a medicament for use in the treatment of cancer in a patient, wherein the patient has a Grade 2 or above corneal adverse reaction resulting from belantamab mafadotin administration, wherein belantamab mafadotin is temporarily discontinued for a lead-in period during which belantamab is administered, followed by resuming administration of belantamab mafadotin after the lead-in period.
  • FIG. 1 is a graph depicting tumor volume growth curves for all treatment groups as a function of study day, as described in Example 1.
  • FIG. 2 is a graph depicting Kaplan-Meier survival curves for all treatment groups as a function of study day, as described in Example 1.
  • FIG. 3 is a graph depicting tumor volume growth with different drug to antibody ratios (DARs) as a function of study day, as described in Example 3.
  • DARs drug to antibody ratios
  • FIG. 4 are graphs depicting progression free survival of patients grouped according to sBCMA levels for the belantamab mafodotin treatment arm (left) and pom/dex treatment arm (right), as described in Example 4.
  • FIG. 5 is a graph depicting the level of reduction of sBCMA from pre-dosing with belantamab mafodotin to end of infusion (EOI) for cycle 1, day 1 of belantamab mafodotin treatment, as described in Example 4.
  • ETI end of infusion
  • FIG. 6 is a graph depicting level of sBCMA 24 hours post-end of infusion (EOI) of belantamab mafodotin, as described in Example 4.
  • FIGs. 7A and 7B are graphs depicting sBCMA levels in patients grouped according to response to treatment with belantamab mafodotin, as described in Example 4.
  • FIG. 7A shows baseline sBCMA levels prior to administration of belantamab mafodotin; and
  • FIG. 7B shows sBCMA levels 24 hours post-EOI of belantamab mafodotin.
  • CR complete response;
  • MR /SD minimal response/stable disease ;
  • PD/NE progressive disease/non-evaluable.
  • FIG. 8 is a graph depicting the mean tumor volume curves of vehicle control and treatment groups between randomization and study termination of the in vivo efficacy study of belantamab and belantamab mafodotin in human multiple myeloma xenograft NOG mice, as described in Example 5.
  • FIG. 9 is a graph showing the Kaplan-Meier survival curves for all treatment groups as a function of study day of the in vivo efficacy study of belantamab and belantamab mafodotin in human multiple myeloma xenograft NOG mice, as described in Example 5.
  • composition “comprising” encompasses “including” or “consisting,” e.g., a composition “comprising” X may consist exclusively of X or may include something additional, e.g., X + Y.
  • Ranges provided herein include all values within a particular range described and values about an endpoint for a particular range.
  • the figures and tables of the disclosure also describe ranges, and discrete values, which may constitute an element of any of the methods and uses disclosed herein.
  • Concentrations described herein are determined at ambient temperature and pressure. This may be, for example, the temperature and pressure at room temperature or within a particular portion of a process stream. Preferably, concentrations are determined at a standard state of 25 °C and 1 bar of pressure.
  • antigen binding protein refers to antibodies and other protein constructs, such as domains, which are capable of binding to the antigen.
  • antibody is used herein in the broadest sense to refer to molecules with an immunoglobulin-like domain (for example IgG, IgM, IgA, IgD or IgE) and includes monoclonal, recombinant, polyclonal, chimeric, human, humanised, multispecific antibodies, including bispecific antibodies, and heteroconjugate antibodies; a single variable domain (e.g., a domain antibody (DAB)), antigen binding antibody fragments, Fab, F(ab’)2, Fv, disulphide linked Fv, single chain Fv, disulphide-linked scFv, diabodies, TANDABS, etc. and modified versions of any of the foregoing (for a summary of alternative “antibody” formats see Holliger and Hudson, Nature Biotechnology, 2005, Vol 23, No. 9, 1126-1136).
  • DAB domain antibody
  • the term, full, whole or intact antibody refers to a heterotetrameric glycoprotein with an approximate molecular weight of 150,000 daltons.
  • An intact antibody is composed of two identical heavy chains (HCs) and two identical light chains (LCs) linked by covalent disulphide bonds. This H2L2 structure folds to form three functional domains comprising two antigen-binding fragments, known as ‘Fab’ fragments, and a ‘Fc’ crystallisable fragment.
  • the Fab fragment is composed of the variable domain at the amino-terminus, variable heavy (VH) or variable light (VL), and the constant domain at the carboxyl terminus, CHI (heavy) and CL (light).
  • the Fc fragment is composed of two domains formed by dimerization of paired CH2 and CH3 regions.
  • the Fc may elicit effector functions by binding to receptors on immune cells or by binding Clq, the first component of the classical complement pathway.
  • the five classes of antibodies IgM, IgA, IgG, IgE and IgD are defined by distinct heavy chain amino acid sequences, which are called p, a, y, s and 5 respectively, each heavy chain can pair with either a K or X light chain.
  • the majority of antibodies in the serum belong to the IgG class, there are four isotypes of human IgG (IgGl, IgG2, IgG3 and IgG4), the sequences of which differ mainly in their hinge region.
  • Fully human antibodies can be obtained using a variety of methods, for example using yeast-based libraries or transgenic animals (e.g. mice) that are capable of producing repertoires of human antibodies.
  • yeast-based libraries or transgenic animals e.g. mice
  • Yeast presenting human antibodies on their surface that bind to an antigen of interest can be selected using FACS (Fluorescence-Activated Cell Sorting) based methods or by capture on beads using labelled antigens.
  • Transgenic animals that have been modified to express human immunoglobulin genes can be immunized with an antigen of interest and antigen-specific human antibodies isolated using B-cell sorting techniques. Human antibodies produced using these techniques can then be characterized for desired properties such as affinity, developability and selectivity.
  • Alternative antibody formats include alternative scaffolds in which the one or more CDRs of the antigen binding protein can be arranged onto a suitable non-immunoglobulin protein scaffold or skeleton, such as an affibody, a SpA scaffold, an LDL receptor class A domain, an avimer (see, e.g., U.S. Patent Application Publication Nos. 2005/0053973, 2005/0089932, 2005/0164301) or an EGF domain.
  • a suitable non-immunoglobulin protein scaffold or skeleton such as an affibody, a SpA scaffold, an LDL receptor class A domain, an avimer (see, e.g., U.S. Patent Application Publication Nos. 2005/0053973, 2005/0089932, 2005/0164301) or an EGF domain.
  • anti-BCMA antigen binding protein refers to antibodies and other protein constructs, such as domains, which are capable of binding to BCMA.
  • BCMA binding protein and “anti-BCMA antigen binding protein” are used interchangeably herein.
  • the anti-BCMA antigen binding proteins described herein may bind to human BCMA having, including, for example, human BCMA containing the amino acid sequence of GenBank Accession Number Q02223.2, or genes encoding human BCMA having at least 90 percent homology or at least 90 percent identity thereto.
  • Exemplary anti-BCMA antigen binding proteins and methods of making the same are disclosed in International Publication No. WO2012/163805 which is incorporated by reference herein in its entirety. Additional exemplary anti-BCMA antigen binding proteins include those described in WO2016/014789, WO2016/090320, WO2016/090327, W02016/020332, WO2016/079177, WO2014/122143, WO2014/122144, WO2017/021450, WO2016/014565, WO20 14/068079, WO2015/166649, WO2015/158671, WO2015/052536, WO2014/140248, WO2013/072415, WO2013/072406, WO2014/089335, US2017/165373, WO2013/154760, W02018/201051 and W02017/051068, each of which is incorporated by reference herein in its entirety.
  • a BCMA binding protein disclosed herein may be derived from rat, mouse, primate (e.g., cynomolgus, Old World monkey or Great Ape) or human.
  • the BCMA binding protein may be a human, humanized or chimeric antibody.
  • the BCMA binding protein may comprise a constant region, which may be of any isotype or subclass.
  • the constant region may be of the IgG isotype, for example IgGl, IgG2, IgG3, IgG4 or variants thereof.
  • the BCMA binding protein constant region may be IgGl .
  • a BCMA binding protein which can comprise any one or a combination of the following CDRs: CDRH1 of SEQ ID NO: 5, CDRH2 of SEQ ID NO: 6, CDRH3 of SEQ ID NO: 7, CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9, CDRL3 of SEQ ID NO: 10.
  • CDRs may be modified by at least one amino acid substitution, deletion or addition, wherein the variant antigen binding protein substantially retains the biological characteristics of the unmodified protein, such as binding to the antigen.
  • the anti-BCMA antigen binding protein comprises CDRH1 according to SEQ ID NO: 5, CDRH2 according to SEQ ID NO: 6, CDRH3 according to SEQ ID NO: 7, CDRL1 according to SEQ ID NO: 8, CDRL2 according to SEQ ID NO: 9, and CDRL3 according to SEQ ID NO: 10.
  • the anti-BCMA antigen binding protein comprises a heavy chain variable region (VH) according to SEQ ID NO: 3 and a light chain variable region (VL) according to SEQ ID NO: 4.
  • the anti-BCMA antigen binding protein comprises a heavy chain (H) according to SEQ ID NO: 1 and a light chain (L) according to SEQ ID NO: 2.
  • the anti-BCMA antigen binding protein is a T-cell redirecting antibody (BiTE) with dual inhibition of BCMA and CD3 receptors, such as teclistamab (Pillarisetti et al., Blood Advances 4, 4538-49, 2020) and blinatumomab, AMG 424, GBR 1342, BFR4350A, AMG 420, AMG 701, elranatamab (PF-06863135), REGN5458, TNB-383B (Alhallak et al., Cancers 13, 2853, 2021).
  • teclistamab Pillarisetti et al., Blood Advances 4, 4538-49, 2020
  • blinatumomab AMG 424, GBR 1342, BFR4350A, AMG 420, AMG 701, elranatamab (PF-06863135), REGN5458, TNB-383B (Alhallak et al., Cancers 13, 2853, 202
  • the anti-BCMA antigen binding protein is a non- fucosylated BCMA-directed antibody, such as SEA-BCMA (Van Epps et al., Cancer Res 2018;78(13 Suppl) Abstract nr 3833).
  • the anti-BCMA antigen binding protein is a CAR-T cell Therapeutic.
  • the anti-BCMA antigen binding protein is used in an immunoconjugate.
  • An “immunoconjugate” (interchangeably referred to as an “antibody-drug conjugate,” “ADC,” or “antigen binding protein-drug conjugate) comprises an anti-BCMA antigen binding protein conjugated to one or more drugs, such as a cytotoxic agent, such as a chemotherapeutic agent, an immunotherapeutic agent, a growth inhibitory agent, a toxin (e.g., a protein toxin, such as an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), an antiviral agent, a radioactive isotope (i.e., a radioconjugate), an antibiotic, or a small interfering RNA (siRNA).
  • drugs such as a cytotoxic agent, such as a chemotherapeutic agent, an immunotherapeutic agent, a growth inhibitory agent, a toxin (e.g.,
  • the anti-BCMA antigen binding protein can be an immunoconjugate having the following general structure:
  • ABP is an antigen binding protein
  • Linker is either absent or any a cleavable or non-cleavable linker
  • Ctx is any cytotoxic agent described herein n is 0, 1 , 2, or 3 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • Exemplary linkers may include 6- maleimidocaproyl (MC), maleimidopropanoyl (MP), valine-citrulline (val-cit), alanine- phenylalanine (ala-phe), p-aminobenzyloxycarbonyl (PAB), N-Succinimidyl 4-(2- pyridylthio)pentanoate (SPP), N-succinimidyl 4-(N- maleimidomethyl)cyclohexane-l carboxylate (SMCC), and N-succinimidyl (4-iodo-acetyl) aminobenzoate (SIAB).
  • MC 6- maleimidocaproyl
  • MP maleimidopropanoyl
  • val-cit valine-citrulline
  • ala-phe p-aminobenzyloxycarbonyl
  • PAB p-aminobenzyloxycarbonyl
  • SPP N-Succ
  • the anti-BCMA antigen binding protein can be an immunoconjugate containing a monoclonal antibody linked to MMAE or MMAF.
  • the anti- BCMA antigen binding protein can be an immunoconjugate containing a monoclonal antibody linked to MMAE or MMAF by an MC linker as depicted in the following structures:
  • the anti-BCMA antigen binding protein can be the antibody belantamab. In another embodiment, the anti-BCMA antigen binding protein can be the immunoconjugate belantamab mafodotin.
  • a BCMA antagonist is a BCMA-targeted chimeric antigen receptor (CAR)-T cell therapy.
  • CAR chimeric antigen receptor
  • CAR refers to an engineered receptor that consists of an extracellular antigen binding domain (usually derived from a monoclonal antibody, or antigen binding fragment thereof, e.g. a VH domain and a VL domain in the form of a scFv), optionally a spacer region, a transmembrane region, and one or more intracellular effector domains.
  • CARs have also been referred to as chimeric T cell receptors or chimeric immunoreceptors (CIRs).
  • CARs are genetically introduced into hematopoietic cells, such as T cells, to redirect T cell specificity for a desired cell-surface antigen, resulting in a CAR-T therapeutic.
  • spacer region refers to an oligo- or polypeptide that functions to link the transmembrane domain to the target binding domain. This region may also be referred to as a “hinge region” or “stalk region”. The size of the spacer can be varied depending on the position of the target epitope in order to maintain a set distance (e.g. 14 nm) upon CAR: target binding.
  • transmembrane domain refers to the part of the CAR molecule that traverses the cell membrane.
  • intracellular effector domain refers to the domain in the CAR that is responsible for intracellular signalling following the binding of the antigen binding domain to the target.
  • the intracellular effector domain is responsible for the activation of at least one of the normal effector functions of the immune cell in which the CAR is expressed.
  • the effector function of a T cell can be a cytolytic activity or helper activity including the secretion of cytokines.
  • VH and/or VL domains disclosed herein may be incorporated, e.g. in the form of a scFv, into CAR-T therapeutics.
  • CDRs are defined as the complementarity determining region amino acid sequences of an antigen binding protein. These are the hypervariable regions of immunoglobulin heavy and light chains. There are three heavy chain and three light chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. Thus, “CDRs” as used herein refers to all three heavy chain CDRs, all three light chain CDRs, all heavy and light chain CDRs, or at least two CDRs.
  • variable domain sequences and variable domain regions within full-length antigen binding sequences are numbered according to the Kabat numbering convention.
  • CDR Kabat et al., Sequences of Proteins of Immunological Interest, 4 th Ed., U.S. Department of Health and Human Services, National Institutes of Health (1987).
  • Table 1 represents one definition using each numbering convention for each CDR or binding unit. It should be noted that some of the CDR definitions may vary depending on the individual publication used. Table 1
  • An immunoconjugate (interchangeably referred to as an “antibody-drug conjugate,” “ADC” or “antigen binding protein-drug conjugate”) comprises an antigen binding protein (e.g., an antibody or antigen binding fragment thereof) conjugated to one or more drugs, such as a cytotoxic agent, such as a chemotherapeutic agent, an immunotherapeutic agent, a growth inhibitory agent, a toxin (e.g., a protein toxin, such as an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), an antiviral agent, a radioactive isotope (i.e., a radioconjugate), an antibiotic, or a small interfering RNA (siRNA).
  • drugs such as a cytotoxic agent, such as a chemotherapeutic agent, an immunotherapeutic agent, a growth inhibitory agent, a toxin (e.g., a protein toxin, such as an enzymatic
  • Immunoconjugates have been used for the local delivery of cytotoxic agents, i.e., drugs that kill or inhibit the growth or proliferation of cells, in the treatment of cancer (Lambert, J. (2005) Curr. Opinion in Pharmacology 5:543-549; Wu et al. (2005) Nature Biotechnology 23(9): 1137- 1146; Payne, G. (2003) Cancer Cell 3:207-212; Syrigos andEpenetos (1999) Anticancer Research 19:605-614; Niculescu-Duvaz and Springer (1997) Adv. Drug Deliv. Rev. 26:151-172; U.S. Pat. No. 4,975,278).
  • cytotoxic agents i.e., drugs that kill or inhibit the growth or proliferation of cells
  • Immunoconjugates allow for, inter alia, the targeted delivery of a drug moiety to a tumor, and intracellular accumulation therein, where systemic administration of unconjugated drugs may result in unacceptable levels of toxicity to normal cells (Tsuchikama and An, Protein and Cell, (2016) 9: 33-46).
  • Immunoconjugates can enable selective delivery of a potent cytotoxic payload to target cancer cells, resulting in improved efficacy, reduced systemic toxicity, and preferable pharmacokinetics (PK)/pharmacodynamics (PD) and biodistribution compared to traditional chemotherapy (Tsuchikama and An 2018); Beck A. et al (2017) Nature Rev. Drug Disc. 16: 315-337).
  • an immunoconjugate comprises an antigen binding protein, such as an antibody, and a drug, such as toxin, such as a chemotherapeutic agent.
  • the drug can be modified (e.g., via standard synthetic chemistry) to allow its chemical attachment (e.g., to contain a reaction handle to allow its chemical attachment) to a reactive end of a linker that joins the drug to the antigen binding protein.
  • Drugs such as chemotherapeutic agents, useful in the generation of immunoconjugates are described herein.
  • Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. See, e.g., WO 93/21232 published Oct. 28, 1993.
  • a radioactive material such as a radionucleotide
  • a radionucleotide may be used as the drug in an ADC.
  • a variety of radionucleotides are available for the production of radioconjugated antibodies. Examples include 212Bi, 1311, 131In, 90Y, and 186Re.
  • Antigen binding proteins may also be conjugated to one or more toxins, including, but not limited to, a calicheamicin, a maytansinoid, a dolastatin, an aurostatin, a trichothecene, and CC1065, and a derivative of these toxins that have toxin activity.
  • toxins including, but not limited to, a calicheamicin, a maytansinoid, a dolastatin, an aurostatin, a trichothecene, and CC1065, and a derivative of these toxins that have toxin activity.
  • Suitable cytotoxic agents include, but are not limited to, an auristatin including dovaline-valine- dolaisoleunine-dolaproine-phenylalanine (MMAF) and monomethyl auristatin E (MMAE) as well as an ester form of MMAE, a DNA minor groove binding agent, a DNA minor groove alkylating agent, an enediyne, a lexitropsin, a duocarmycin, a taxane (such as paclitaxel and docetaxel), a puromycin, a dolastatin, a maytansinoid, and a vinca alkaloid.
  • an auristatin including dovaline-valine- dolaisoleunine-dolaproine-phenylalanine (MMAF) and monomethyl auristatin E (MMAE) as well as an ester form of MMAE
  • a DNA minor groove binding agent e.g., a DNA minor groove alkylating
  • cytotoxic agents include topotecan, morpholino-doxorubicin, rhizoxin, cyanomorpholino-doxorubicin, dolastatin- 10, 1 echinomycin, combretatstatin, chalicheamicin, maytansine, DM-1, DM-4, and netropsin.
  • Other suitable cytotoxic agents include anti-tubulin agents, such as an auristatin, a vinca alkaloid, a podophyllotoxin, a taxane, a baccatin derivative, a cryptophysin, a maytansinoid, a combretastatin, or a dolastatin.
  • Antitubulin agents include dimethylvaline-valine-dolaisoleuine-dolaproine- phenylalanine-p-phenylenediamine (AFP), MMAF, MMAE, auristatin E, vincristine, vinblastine, vindesine, vinorelbine, VP- 16, camptothecin, paclitaxel, docetaxel, epothilone A, epothilone B, nocodazole, colchicines, colcimid, estramustine, cemadotin, discodermolide, maytansine, DM-1, DM-4, and eleutherobin.
  • AFP dimethylvaline-valine-dolaisoleuine-dolaproine- phenylalanine-p-phenylenediamine
  • MMAF methylvaline-valine-dolaisoleuine-dolaproine- phenylalanine-p-phenylenediamine
  • Antibody drug conjugates can be produced by conjugating the anti-tubulin agent monomethylauristatin E (MMAE) or monomethylauristatin F (MMAF) to an antigen binding protein (such as an antibody).
  • the linker can consist of a thiol-reactive maleimide, a caproyl spacer, the dipeptide valine-citrulline, or p-aminobenzyloxy carbonyl, a self- immolative fragmenting group.
  • MMAF a protease-resistant maleimidocaproyl linker can be used.
  • the conjugation process leads to heterogeneity in drug-antibody attachment, varying in both the number of drugs bound to each antibody molecule (drug-antibody ratio [DAR]) and the site of attachment.
  • DAR drug-antibody ratio
  • the overall average drug-to-antibody ratio (DAR) is approximately 4.
  • progression of tumor growth or a “progressive disease” (“PD”) as used herein in reference to cancer status indicates an increase in the sum of the diameters of the target lesions (tumors).
  • progressive disease is measured and defined as per International Myeloma Working Group (IMWG) criteria (see, e.g., Kumar S, Paiva B, Anderson KC., et al. International myeloma working group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-46.).
  • IMWG International Myeloma Working Group
  • progression of tumor growth refers to at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
  • the sum of diameters of target lesions in addition to a relative increase of 20%, must also demonstrate an absolute increase of at least 5 mm. An appearance of one or more new lesions may also be factored into the determination of progression of tumor growth.
  • “Treating” as used herein refers to alleviating one or more symptoms or effects associated with a disorder and/or slowing the progression of the disorder.
  • the disclosed therapies reduce ocular toxicity.
  • “Ocular toxicity” refers to any unintended exposure of a therapeutic agent to ocular tissue, and includes changes in corneal epithelium, dry eyes, irritation, redness, blurred vision, dry eyes, photophobia, and/or changes in visual acuity. Detection of ocular toxicity may be determined by ophthalmic examination by an ophthalmologist or optometrist, before, during, and/or after treatment.
  • An ophthalmic examination may include one or more of the following:
  • Anterior segment (slit lamp) examination including fluorescein staining of the cornea and lens examination,
  • OSDI ocular surface disease index
  • the disclosure provides methods of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, the method comprising administering belantamab to the patient.
  • BCMA B-cell maturation antigen
  • belantamab is administered at a dose of about 300 mg to about 2000 mg. In an embodiment, belantamab is administered at a dose of about 300 mg to about 900 mg. In an embodiment, belantamab is administered at a dose of about 900 mg to about 2000 mg. In an embodiment, belantamab is administered at a dose of about 300 mg. In an embodiment, belantamab is administered at a dose of about 900 mg. In an embodiment, belantamab is administered at a dose of about 2000 mg.
  • the dose of belantamab is administered at a regular interval for a period of time. In an embodiment, the dose of belantamab is administered on day 1 of the regular interval. In an embodiment, the regular interval is at least once every 8 weeks ⁇ 3 days, at least once every 6 weeks ⁇ 3 days, at least once every 4 weeks ⁇ 3 days, at least once every 3 weeks ⁇ 3 days, at least once every 2 weeks ⁇ 3 days, at least once every week ⁇ 3 days, once every week ⁇ 3 days to once every 8 weeks ⁇ 3 days, once every week ⁇ 3 days to once every 6 weeks ⁇ 3 days, once every week ⁇ 3 days to once every 4 weeks ⁇ 3 days, once every week ⁇ 3 days to once every 3 weeks ⁇ 3 days, once every week ⁇ 3 days to once every 2 weeks ⁇ 3 days, once every 2 weeks ⁇ 3 days to once every 3 weeks ⁇ 3 days, once every 3 weeks ⁇ 3 days to once every 4 weeks ⁇ 3 days, once every 4 weeks ⁇ 3 days to once every 3 days to once every every 3
  • the dose of belantamab is administered at least once every 8 weeks ⁇ 3 days, at least once every 6 weeks ⁇ 3 days, at least once every 4 weeks ⁇ 3 days, at least once every 3 weeks ⁇ 3 days, at least once every 2 weeks ⁇ 3 days, at least once every week ⁇ 3 days, once every week ⁇ 3 days to once every 8 weeks ⁇ 3 days, once every week ⁇ 3 days to once every 6 weeks ⁇ 3 days, once every week ⁇ 3 days to once every 4 weeks ⁇ 3 days, once every week ⁇ 3 days to once every 3 weeks ⁇ 3 days, once every week ⁇ 3 days to once every 2 weeks ⁇ 3 days, once every 2 weeks ⁇ 3 days to once every 3 weeks ⁇ 3 days, once every 3 weeks ⁇ 3 days to once every 4 weeks ⁇ 3 days, once every 4 weeks ⁇ 3 days to once every 5 weeks ⁇ 3 days, once every 5 weeks ⁇ 3 days to once every 6 weeks ⁇ 3 days, once every 6 weeks ⁇ 3 days to once every 7 weeks ⁇ 3
  • the dose of belantamab is administered once every week ⁇ 3 days to once every 4 weeks ⁇ 3 days. In an embodiment, the dose of belantamab is administered once every 2 weeks ⁇ 3 days to once every 4 weeks ⁇ 3 days. In an embodiment, the dose of belantamab is administered once every 2 weeks ⁇ 3 days. In an embodiment, the dose of belantamab is administered once every 3 weeks ⁇ 3 days. In an embodiment, the dose of belantamab is administered once every 4 weeks ⁇ 3 days.
  • the dose of belantamab is administered by parenteral administration, i.e., subcutaneously (s.c. or SC), intrathecally, intraperitoneally, intramuscularly (i.m. or IM) or intravenously (i.v. or IV), including by intravenous infusion.
  • parenteral administration i.e., subcutaneously (s.c. or SC), intrathecally, intraperitoneally, intramuscularly (i.m. or IM) or intravenously (i.v. or IV), including by intravenous infusion.
  • the dose of belantamab is administered intravenously.
  • the dose of belantamab is administered through an intravenous infusion.
  • the dose of belantamab is administered subcutaneously.
  • belantamab is administered as a first line of treatment for the disease or disorder. In an embodiment, belantamab is administered after one or more prior lines of treatment for the disease or disorder. In an embodiment, belantamab is administered after at least 1 prior line of treatment, after at least 2 prior lines of treatment, after at least 3 prior lines of treatment, after at least 4 prior lines of treatment, after 1 to 4 prior lines of treatment, after 2 to 4 prior lines of treatment, after 1 to 2 prior lines of treatment, after 2 to 3 prior lines of treatment, after 3 to 4 prior lines of treatment, after 1 prior line of treatment, after 2 prior lines of treatment, after 3 prior lines of treatment, or after 4 prior lines of treatment for the disease or disorder.
  • belantamab is administered as a first line of cancer treatment. In an embodiment, belantamab is administered after one or more prior lines of cancer treatment. In an embodiment, belantamab is administered after at least 1 prior line of cancer treatment, after at least 2 prior lines of cancer treatment, after at least 3 prior lines of cancer treatment, after at least 4 prior lines of cancer treatment, after 1 to 4 prior lines of cancer treatment, after 2 to 4 prior lines of cancer treatment, after 1 to 2 prior lines of cancer treatment, after 2 to 3 prior lines of cancer treatment, after 3 to 4 prior lines of cancer treatment, after 1 prior line of cancer treatment, after 2 prior lines of cancer treatment, after 3 prior lines of cancer treatment, or after 4 prior lines of cancer treatment.
  • the patient has not been treated with a prior treatment for the disease or disorder. In an embodiment, the patient has been treated with at least one prior treatment for the disease or disorder. In an embodiment, the patient has been treated with at least 1 prior line of treatment, at least 2 prior lines of treatment, at least 3 prior lines of treatment, at least 4 prior lines of treatment, 1 to 4 prior lines of treatment, 2 to 4 prior lines of treatment, 1 to 2 prior lines of treatment, 2 to 3 prior lines of treatment, 3 to 4 prior lines of treatment, 1 prior line of treatment, 2 prior lines of treatment, 3 prior lines of treatment, or 4 prior lines of treatment for the disease or disorder. [00134] In an embodiment, the patient has relapsed or refractory multiple myeloma and had previously received at least four prior therapies to treat the multiple myeloma.
  • the prior lines of cancer treatments are selected from an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or a combination thereof.
  • a patient that has had 0, 1, 2, 3, or 4 or more prior lines of treatment before being treated as described herein can have previously been treated with an immunomodulatory agent (e.g., an immunomodulatory imide drug (ImiD)), a proteasome inhibitor (PI), an anti-CD38 treatment or combinations thereof.
  • an immunomodulatory agent e.g., an immunomodulatory imide drug (ImiD)
  • PI proteasome inhibitor
  • the prior lines of cancer treatments include an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.
  • anti-CD38 antibodies useful in the methods described herein include, but are not limited to, isatuximab or isatuximab-irfc (e.g., SARCLISA®) and daratumumab (e.g, DARZALEX®, DARZALEX FASPRO®).
  • the anti-CD38 monoclonal antibody is selected from daratumumab or isatuximab.
  • proteasome inhibitors useful in the methods described herein include, but are not limited to, bortezomib (e.g., VELCADE®), ixazomib (e.g., NINLARO®), carfilzomib (e.g., KYPROLIS®), oprozomib, and delanzomib.
  • the proteasome inhibitor is selected from bortezomib, carfilzomib, or ixazomib.
  • the proteasome inhibitor is bortezomib.
  • immunomodulatory imide drugs useful in the methods described herein include, but are not limited to, thalidomide (e.g., THALOMID®), lenalidomide (e.g., REVLIMID®), and pomalidomide (e.g., POMALYST®).
  • the immunomodulatory agent is selected from thalidomide, lenalidomide, or pomalidomide.
  • the immunomodulatory agent is lenalidomide or pomalidomide.
  • the immunomodulatory agent is lenalidomide.
  • belantamab is administered as a monotherapy. In an embodiment, belantamab is administered in combination with at least one additional treatment. In an embodiment, belantamab is administered in combination with at least one additional cancer treatment. In an embodiment, belantamab is administered on day 1 of a treatment cycle. In an embodiment, belantamab is administered on day 1 of a 28-day treatment cycle. In an embodiment, belantamab is administered on day 1 and day 15 of a 28-day treatment cycle. In an embodiment, belantamab is administered on day 1 of a 21 -day treatment cycle.
  • the additional cancer treatment is selected from an anti-CD38 monoclonal antibody, a gamma-secretase inhibitor, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.
  • anti-CD38 antibodies useful in the methods described herein include, but are not limited to, isatuximab or isatuximab-irfc (e.g., SARCLISA®) and daratumumab (e.g, DARZALEX®, DARZALEX FASPRO®).
  • the anti-CD38 monoclonal antibody is selected from daratumumab or isatuximab.
  • Examples of gamma-secretase inhibitors useful in the methods described herein include, but are not limited to, nirogacestat (PF-0308014), crenigacestat (LY3039478), CB-103, tarenflurbil, semagacestat (LY450139), RG-4733, EVP-0962, avagacestat, MK-0752, and BMS- 906024, as well as derivatives and polymorphs thereof.
  • proteasome inhibitors useful in the methods described herein include, but are not limited to, bortezomib (e.g., VELCADE®), ixazomib (e.g., NINLARO®), carfilzomib (e.g., KYPROLIS®), oprozomib, and delanzomib.
  • the proteasome inhibitor is selected from bortezomib, carfilzomib, or ixazomib.
  • the proteasome inhibitor is bortezomib.
  • immunomodulatory imide drugs useful in the methods described herein include, but are not limited to, thalidomide (e.g., THALOMID®), lenalidomide (e.g., REVLIMID®), and pomalidomide (e.g., POMALYST®).
  • the immunomodulatory agent is selected from thalidomide, lenalidomide, or pomalidomide.
  • the immunomodulatory agent is lenalidomide or pomalidomide.
  • the immunomodulatory agent is lenalidomide.
  • the immunomodulatory agent is pomalidomide.
  • anti-PD-1 monoclonal antibodies useful in the methods described herein include, but are not limited to, pembroluzimab and dostarlimab.
  • the anti-PD-1 monoclonal antibody is selected from pembroluzimab or dostarlimab.
  • corticosteroids examples include, but are not limited to, dexamethasone (e.g., DECADRON®, DEXASONE®, DIODEX®, HEXADROL®, MAXIDEX®), prednisone (e.g., DELTASONE®), and methylprednisolone (e.g., MEDROL®).
  • the additional cancer treatment is selected from lenalidomide, pomalidomide, dexamethasone, or a combination thereof.
  • the additional cancer treatments are lenalidomide and dexamethasone.
  • the additional cancer treatments are pomalidomide and dexamethasone. In an embodiment, the additional cancer treatments are bortezomib and dexamethasone. In an embodiment, the additional cancer treatments are pomalidomide, bortezomib, and dexamethasone. In an embodiment, the additional cancer treatments are lenalidomide, bortezomib, and dexamethasone.
  • the additional cancer treatment is standard of care treatment.
  • the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily for a period of time. In an embodiment, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily administered on days 1-21 of a 28 day cycle. [00150] In an embodiment, the additional cancer treatment is dexamethasone. In an embodiment, the additional cancer treatment is dexamethasone at a dose of 20 mg to 40 mg once weekly. In an embodiment, the additional cancer treatment is dexamethasone at a dose of 40 mg once weekly if the patient is less than 75 years old.
  • the additional cancer treatment is dexamethasone at a dose of 20 mg once weekly if the patient is at least 75 years old. In an embodiment, the additional cancer treatment is dexamethasone at a dose of 40 mg once weekly if the patient has a BMI of at least 18.5. In an embodiment, the additional cancer treatment is dexamethasone at a dose of 20 mg once weekly if the patient has a BMI less than 18.5. In an embodiment, the dexamethasone is administered on days 1, 8, 15, and 22 of a 28 day cycle.
  • the additional cancer treatments are lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28 day cycle and dexamethasone at a dose of 20 mg to 40 mg administered on days 1, 8, 15, and 22 of a 28 day cycle.
  • the additional cancer treatments are lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28 day cycle and dexamethasone at a dose of 40 mg administered on days 1, 8, 15, and 22 of a 28 day cycle if the patient is less than 75 years old or has a BMI of at least 18.5.
  • the additional cancer treatments are lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28 day cycle and dexamethasone at a dose of 20 mg administered on days 1, 8, 15, and 22 of a 28 day cycle if the patient is at least 75 years old or has a BMI of less than 18.5.
  • a patient is receiving an initial therapy or combination of initial therapies, referred to as a lead-in doses, prior to administration of a subsequent therapy or combination of therapies.
  • the “lead-in period” refers to a period of time in which a specified initial therapy or combination of initial therapies is administered prior to administration of a subsequent therapy or combination of therapies.
  • the method further comprises administering a lead-in dose of belantamab mafodotin prior to beginning administration of belantamab.
  • the lead-in dose of belantamab mafodotin is about 1.4 mg/kg to about 3.4 mg/kg once during a lead- in period.
  • the lead-in dose of belantamab mafodotin is about 1.4 mg/kg to about 1.9 mg/kg once during a lead-in period.
  • the lead-in dose of belantamab mafodotin is about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2.0 mg/kg, about 2.5 mg/kg, about 3.0 mg/kg, or about 3.4 mg/kg once during a lead-in period.
  • the lead-in dose of belantamab mafodotin is about 1.4 mg/kg once during a lead-in period.
  • the lead-in dose of belantamab mafodotin is about 1.9 mg/kg once during a lead-in period.
  • the lead-in period is four weeks ⁇ 3 days and belantamab mafodotin is administered on day 1 of the lead-in period.
  • the dose of belantamab mafodotin is administered by parenteral administration, i.e., subcutaneously (s.c. or SC), intrathecally, intraperitoneally, intramuscularly (i.m. or IM) or intravenously (i.v. or IV), including by intravenous infusion.
  • parenteral administration i.e., subcutaneously (s.c. or SC), intrathecally, intraperitoneally, intramuscularly (i.m. or IM) or intravenously (i.v. or IV), including by intravenous infusion.
  • the dose of belantamab mafodotin is administered intravenously.
  • the dose of belantamab mafodotin is administered through an intravenous infusion.
  • belantamab mafodotin is administered as a monotherapy during the lead-in period. In an embodiment, belantamab mafodotin is administered in combination with at least one additional treatment during the lead-in period. In an embodiment, belantamab mafodotin is administered in combination with at least one additional cancer treatment during the lead-in period.
  • the additional cancer treatment for administration during the lead- in period is selected from an anti-CD38 monoclonal antibody, a gamma-secretase inhibitor, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.
  • anti-CD38 antibodies useful in the methods described herein include, but are not limited to, isatuximab or isatuximab-irfc (e.g., SARCLISA®) and daratumumab (e.g, DARZALEX®, DARZALEX FASPRO®).
  • the anti-CD38 monoclonal antibody for administration during the lead-in period is selected from daratumumab or isatuximab.
  • gamma-secretase inhibitors useful in the methods described herein include, but are not limited to, nirogacestat (PF-0308014), crenigacestat (LY3039478), CB-103, tarenflurbil, semagacestat (LY450139), RG-4733, EVP-0962, avagacestat, MK-0752, and BMS- 906024, as well as derivatives and polymorphs thereof.
  • proteasome inhibitors useful in the methods described herein include, but are not limited to, bortezomib (e.g., VELCADE®), ixazomib (e.g., NINLARO®), carfilzomib (e.g., KYPROLIS®), oprozomib, and delanzomib.
  • the proteasome inhibitor for administration during the lead-in period is selected from bortezomib, carfilzomib, or ixazomib.
  • the proteasome inhibitor for administration during the lead-in period is bortezomib.
  • immunomodulatory imide drugs useful in the methods described herein include, but are not limited to, thalidomide (e.g., THALOMID®), lenalidomide (e.g., REVLIMID®), and pomalidomide (e.g., POMALYST®).
  • the immunomodulatory agent for administration during the lead-in period is selected from thalidomide, lenalidomide, or pomalidomide.
  • the immunomodulatory agent for administration during the lead-in period is lenalidomide or pomalidomide.
  • the immunomodulatory agent for administration during the lead-in period is lenalidomide.
  • the immunomodulatory agent for administration during the lead-in period is pomalidomide.
  • anti-PD-1 monoclonal antibodies useful in the methods described herein include, but are not limited to, pembroluzimab and dostarlimab.
  • the anti-PD-1 monoclonal antibody is selected from pembroluzimab or dostarlimab.
  • corticosteroids include corticosteroids.
  • corticosteroids include, but are not limited to, dexamethasone (e.g., DECADRON®, DEXASONE®, DIODEX®, HEXADROL®, MAXIDEX®), prednisone (e.g., DELTASONE®), and methylprednisolone (e.g., MEDROL®).
  • the additional cancer treatment for administration during the lead- in period is selected from lenalidomide, pomalidomide, dexamethasone, or a combination thereof.
  • the additional cancer treatments for administration during the lead-in period are lenalidomide and dexamethasone.
  • the additional cancer treatments for administration during the lead-in period are pomalidomide and dexamethasone. In an embodiment, the additional cancer treatments for administration during the lead-in period are lenalidomide and dexamethasone. In an embodiment, the additional cancer treatments for administration during the lead-in period are bortezomib and dexamethasone. In an embodiment, the additional cancer treatments for administration during the lead-in period are pomalidomide, bortezomib, and dexamethasone. In an embodiment, the additional cancer treatments for administration during the lead-in period are lenalidomide, bortezomib, and dexamethasone.
  • the additional cancer treatment for administration during the lead- in period is standard of care treatment.
  • the additional cancer treatment for administration during the lead- in period is lenalidomide at a dose of 10 mg to 25 mg once daily for a period of time. In an embodiment, the additional cancer treatment for administration during the lead-in period is lenalidomide at a dose of 10 mg to 25 mg once daily administered on days 1-21 of a 28 day lead- in period.
  • the additional cancer treatment for administration during the lead- in period is dexamethasone.
  • the additional cancer treatment for administration during the lead-in period is dexamethasone at a dose of 20 mg to 40 mg once weekly.
  • the additional cancer treatment for administration during the lead-in period is dexamethasone at a dose of 40 mg once weekly if the patient is less than 75 years old.
  • the additional cancer treatment for administration during the lead-in period is dexamethasone at a dose of 20 mg once weekly if the patient is at least 75 years old.
  • the additional cancer treatment for administration during the lead-in period is dexamethasone at a dose of 40 mg once weekly if the patient has a BMI of at least 18.5. In an embodiment, the additional cancer treatment for administration during the lead-in period is dexamethasone at a dose of 20 mg once weekly if the patient has a BMI less than 18.5. In an embodiment, the dexamethasone is administered on days 1, 8, 15, and 22 of a 28 day lead-in period.
  • the additional cancer treatments for administration during the lead- in period are lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28 day lead-in period and dexamethasone at a dose of 20 mg to 40 mg administered on days 1, 8, 15, and 22 of a 28 day lead-in period.
  • the additional cancer treatments for administration during the lead-in period are lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28 day lead-in period and dexamethasone at a dose of 40 mg administered on days 1, 8, 15, and 22 of a 28 day lead-in period if the patient is less than 75 years old or has a BMI of at least 18.5.
  • the additional cancer treatments for administration during the lead-in period are lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28 day lead-in period and dexamethasone at a dose of 20 mg administered on days 1, 8, 15, and 22 of a 28 day lead-in period if the patient is at least 75 years old or has a BMI of less than 18.5.
  • the method comprises administering a lead-in dose of belantamab mafodotin during a lead-in period, followed by administering belantamab during a subsequent treatment period.
  • the method comprises administering a lead-in dose of belantamab mafodotin at a dose of about 1.4 mg/kg to about 3.4 mg/kg once during a lead-in period, followed by administering belantamab at a dose of about 300 mg to about 2000 mg during a subsequent treatment period.
  • the method comprises administering a lead-in dose of belantamab mafodotin at a dose of about 1.4 mg/kg, about 1.9 mg/kg, about 2.5 mg/kg, or about 3.4 mg/kg once during a lead-in period, followed by administering belantamab at a dose of about 300 mg, 900 mg, or about 2000 mg during a subsequent treatment period.
  • the method further comprises application of a bandage contact lens during the lead-in period and/or subsequent treatment period.
  • a bandage contact lens is a therapeutic contact lens made of soft, flexible plastics that allow oxygen to pass through to the cornea which is worn in one or both eyes for a period of time to protect the cornea and/or treat ocular toxicities, e.g., ocular toxicities resulting from treatment with a therapeutic agent such as belantamab mafodotin.
  • a bandage contact lens is comprised of N-carboxy vinyl ester (NCVE), N-vinyl pyrrolidone (NVE), poly[dimethylsiloxyl] di [silylbutanol] bis[vinyl carbamate] (PBVC) and/or tris-(trimethylsiloxysilyl) propylvinyl carbamate (TPVC).
  • NVE N-carboxy vinyl ester
  • NVE N-vinyl pyrrolidone
  • PBVC poly[dimethylsiloxyl] di [silylbutanol] bis[vinyl carbamate]
  • TPVC tris-(trimethylsiloxysilyl) propylvinyl carbamate
  • a bandage contact lens of comprises of NCVE, NVE, PBVC, and TPVC.
  • a bandage contact lens of comprises of NCVE, NVE, PBVC, and TPVC and has a water content of 30% to 40%, such as 30%, 3
  • a bandage contact lens of comprises of NCVE, NVE, PBVC, and TPVC and has a water content of about 36%.
  • a bandage contact lens is made of balafilcon A.
  • Balafilcon A is a copolymer of silicone vinyl carbamate, N-vinyl-pyrrolidone, a siloxane crosslinker and a vinyl alanine wetting monomer, and is 36% water by weight when immersed in solution, e.g., saline solution.
  • the method further comprises discontinuing administration of belantamab and subsequently administering belantamab mafodotin.
  • belantamab mafodotin is administered at a dose of 2.5 mg/kg once every three weeks ⁇ 3 days.
  • administration of belantamab is discontinued after the patient demonstrates progressive disease.
  • the method further comprises administering belantamab mafodotin and subsequently discontinuing administration of belantamab.
  • belantamab mafodotin is administered at a dose of 2.5 mg/kg once every three weeks ⁇ 3 days.
  • administration of belantamab is discontinued after the patient demonstrates progressive disease.
  • the disclosure provides methods of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, the method comprising administering belantamab mafodotin to the patient.
  • BCMA B-cell maturation antigen
  • belantamab mafodotin is administered at a dose of about 1.4 mg/kg to about 3.4 mg/kg. In an embodiment, belantamab mafodotin is administered at a dose of about 1.4 mg/kg to about 1.9 mg/kg. In an embodiment, belantamab mafodotin is administered at a dose of about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2.0 mg/kg, about 2.5 mg/kg, about 3.0 mg/kg, or about 3.4 mg/kg.
  • belantamab mafodotin is administered at a dose of about 1.4 mg/kg. In an embodiment, belantamab mafodotin is administered at a dose of about 1.9 mg/kg. In an embodiment, belantamab is administered once every eight weeks ⁇ 3 days. [00175] In an embodiment, belantamab mafodotin is administered at a dose of about 1.4 mg/kg to about 3.4 mg/kg once every eight weeks ⁇ 3 days. In an embodiment, belantamab mafodotin is administered at a dose of about 1.4 mg/kg to about 1.9 mg/kg once every eight weeks ⁇ 3 days.
  • belantamab mafodotin is administered at a dose of about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2.0 mg/kg, about 2.5 mg/kg, about 3.0 mg/kg, or about 3.4 mg/kg once every eight weeks ⁇ 3 days.
  • belantamab mafodotin is administered at a dose of about 1.4 mg/kg once every eight weeks ⁇ 3 days.
  • belantamab mafodotin is administered at a dose of about 1.9 mg/kg once every eight weeks ⁇ 3 days.
  • the method further comprises application of a bandage contact lens.
  • BCMA-inhibiting or blocking therapies are also described.
  • kits comprising BCMA-inhibiting or blocking therapies and instructions for use.
  • the disclosure provides methods of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, the method comprising administering a therapeutically effective amount of a combination comprising a first BCMA antagonist and a second BCMA antagonist to the patient.
  • BCMA antagonist refers to a molecule that specifically binds B-cell maturation antigen (BCMA) and inhibits the binding of BAFF and/or APRIL to the BCMA receptor.
  • BCMA antagonists include, but are not limited to, anti-BCMA antibodies or antigen binding fragments thereof, anti-BCMA antibody-drug conjugates, bispecific anti-BCMA antibodies or antigen binding fragments thereof, and BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • CAR T BCMA-targeted chimeric antigen receptor T
  • the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen binding fragment thereof, an anti- BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • the first BCMA-antagonist differs from the second BCMA-antagonist.
  • the first and second BCMA-antagonists are both anti-BCMA antibodies or fragments thereof, both anti-BCMA antibody-drug conjugates, both bispecific anti-BCMA antibodies or fragments thereof, or both BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapies.
  • the first BCMA-antagonist is an anti-BCMA antibody or antigen binding fragment thereof and the second BCMA-antagonist is a different anti-BCMA antibody or antigen binding fragment thereof.
  • the first BCMA-antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA-antagonist is a different anti-BCMA antibody-drug conjugate.
  • the first BCMA-antagonist is a bispecific anti-BCMA antibody or antigen binding fragment thereof and the second BCMA-antagonist is a different bispecific anti-BCMA antibody or antigen binding fragment thereof.
  • the first BCMA-antagonist is a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy and the second BCMA-antagonist is a different BCMA- targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • CAR T BCMA-targeted chimeric antigen receptor T
  • CAR T BCMA-targeted chimeric antigen receptor T
  • the bispecific anti-BCMA antibody or antigen binding fragment thereof comprises an anti-BCMA antibody or antigen binding fragment thereof and an anti-CD38 antibody or antigen binding fragment thereof. In an embodiment, the bispecific anti-BCMA antibody or antigen binding fragment thereof specifically binds both BCMA and CD3.
  • the first and second BCMA antagonists are independently selected from the group consisting of idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.
  • the first BCMA antagonist is belantamab mafodotin. In an embodiment, the first BCMA antagonist is belantamab.
  • the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is an anti-BCMA antibody or antigen binding fragment thereof.
  • the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is an anti-BCMA antibody-drug conjugate.
  • the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is a bispecific anti-BCMA antibody or antigen binding fragment thereof.
  • the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • CAR T BCMA-targeted chimeric antigen receptor T
  • the first BCMA antagonist is belantamab and the second BCMA antagonist is an anti-BCMA antibody or antigen binding fragment thereof.
  • the first BCMA antagonist is belantamab and the second BCMA antagonist is an anti-BCMA antibody-drug conjugate.
  • the first BCMA antagonist is belantamab and the second BCMA antagonist is a bispecific anti-BCMA antibody or antigen binding fragment thereof.
  • the first BCMA antagonist is belantamab and the second BCMA antagonist is a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • CAR T BCMA-targeted chimeric antigen receptor T
  • the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is idecabtagene vicleucel. In an embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is ciltacabtagene autoleucel. In an embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is teclistamab. In an embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is REGN5458. In an embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is SEA-BCMA.
  • the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is ABBV-383. In an embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is elrantamab. In an embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is pavurutumab. In an embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is alnuctamab. In an embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is MEDI2228. In an embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is CC99712.
  • the first BCMA antagonist is belantamab and the second BCMA antagonist is idecabtagene vicleucel. In an embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is ciltacabtagene autoleucel. In an embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is teclistamab. In an embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is REGN5458. In an embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is SEA- BCMA. In an embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is ABBV-383.
  • the first BCMA antagonist is belantamab and the second BCMA antagonist is elrantamab. In an embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is pavurutumab. In an embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is alnuctamab. In an embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is MEDI2228. In an embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is and CC99712.
  • the combination further comprises a third BCMA antagonist.
  • the third BCMA antagonist is selected from the group consisting of an anti-BCMA antibody or antigen binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • the third BCMA-antagonist differs from the first and second BCMA-antagonists.
  • the third BCMA antagonist is selected from the group consisting of idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.
  • the combination comprises belantamab mafodotin, belantamab, and an anti-BCMA antibody or antigen binding fragment thereof.
  • the combination comprises belantamab mafodotin, belantamab, and an anti-BCMA antibody-drug conjugate.
  • the combination comprises belantamab mafodotin, belantamab, and a bispecific anti- BCMA antibody or antigen binding fragment thereof.
  • the combination comprises belantamab mafodotin, belantamab, and a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • CAR T BCMA-targeted chimeric antigen receptor T
  • the combination comprises belantamab mafodotin, belantamab, and idecabtagene vicleucel. In an embodiment, the combination comprises belantamab mafodotin, belantamab, and ciltacabtagene autoleucel. In an embodiment, the combination comprises belantamab mafodotin, belantamab, and teclistamab. In an embodiment, the combination comprises belantamab mafodotin, belantamab, and REGN5458. In an embodiment, the combination comprises belantamab mafodotin, belantamab, and SEA-BCMA.
  • the combination comprises belantamab mafodotin, belantamab, and ABBV-383. In an embodiment, the combination comprises belantamab mafodotin, belantamab, and elrantamab. In an embodiment, the combination comprises belantamab mafodotin, belantamab, and pavurutumab. In an embodiment, the combination comprises belantamab mafodotin, belantamab, and alnuctamab. In an embodiment, the combination comprises belantamab mafodotin, belantamab, and MEDI2228. In an embodiment, the combination comprises belantamab mafodotin, belantamab, and CC99712.
  • the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is the corresponding unconjugated anti-BCMA antibody.
  • the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is belantamab.
  • the first and second BCMA antagonists, and the third BCMA antagonist, if present are administered simultaneously, such as on the same day of a treatment cycle.
  • the first and second BCMA antagonists, and the third BCMA antagonist, if present are administered on the same day of a treatment cycle.
  • the first and second BCMA antagonists, and the third BCMA antagonist, if present are administered during the same treatment cycle on different days of the treatment cycle.
  • the first and second BCMA antagonists, and the third BCMA antagonist, if present, are independently administered at least once every 8 weeks ⁇ 3 days, at least once every 6 weeks ⁇ 3 days, at least once every 4 weeks ⁇ 3 days, at least once every 3 weeks ⁇ 3 days, at least once every 2 weeks ⁇ 3 days, at least once every week ⁇ 3 days, once every week ⁇ 3 days to once every 8 weeks ⁇ 3 days, once every week ⁇ 3 days to once every 6 weeks ⁇ 3 days, once every week ⁇ 3 days to once every 4 weeks ⁇ 3 days, once every week ⁇ 3 days to once every 3 weeks ⁇ 3 days, once every week ⁇ 3 days to once every 2 weeks ⁇ 3 days, once every 2 weeks ⁇ 3 days to once every 3 weeks ⁇ 3 days, once every 3 weeks ⁇ 3 days to once every 4 weeks ⁇ 3 days, once every 4 weeks ⁇ 3 days to once every 5 weeks ⁇ 3 days, once every 5 weeks ⁇ 3 days to once every 6 weeks ⁇ 3 days, once every 4 weeks ⁇ 3 days,
  • the first and second BCMA antagonists, and the third BCMA antagonist, if present are administered in combination with application of a bandage contact lens.
  • the first and second BCMA antagonists, and the third BCMA antagonist, if present are administered in combination with at least one additional treatment.
  • the additional cancer treatment is selected from an anti-CD38 monoclonal antibody, a gamma-secretase inhibitor, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD- 1 monoclonal antibody.
  • anti-CD38 antibodies useful in the methods described herein include, but are not limited to, isatuximab or isatuximab-irfc (e.g., SARCLISA®) and daratumumab (e.g, DARZALEX®, DARZALEX FASPRO®).
  • the anti-CD38 monoclonal antibody is selected from daratumumab or isatuximab.
  • Examples of gamma-secretase inhibitors useful in the methods described herein include, but are not limited to, nirogacestat (PF-0308014), crenigacestat (LY3039478), CB-103, tarenflurbil, semagacestat (LY450139), RG-4733, EVP-0962, avagacestat, MK-0752, and BMS- 906024, as well as derivatives and polymorphs thereof.
  • proteasome inhibitors useful in the methods described herein include, but are not limited to, bortezomib (e.g., VELCADE®), ixazomib (e.g., NINLARO®), carfilzomib (e.g., KYPROLIS®), oprozomib, and delanzomib.
  • the proteasome inhibitor is selected from bortezomib, carfilzomib, or ixazomib.
  • the proteasome inhibitor is bortezomib.
  • immunomodulatory imide drugs useful in the methods described herein include, but are not limited to, thalidomide (e.g., THALOMID®), lenalidomide (e.g., REVLIMID®), and pomalidomide (e.g., POMALYST®).
  • the immunomodulatory agent is selected from thalidomide, lenalidomide, or pomalidomide.
  • the immunomodulatory agent is lenalidomide or pomalidomide.
  • the immunomodulatory agent is lenalidomide.
  • anti-PD-1 monoclonal antibodies useful in the methods described herein include, but are not limited to, pembroluzimab and dostarlimab.
  • the anti-PD-1 monoclonal antibody is selected from pembroluzimab or dostarlimab.
  • corticosteroids include, but are not limited to, dexamethasone (e.g., DECADRON®, DEXASONE®, DIODEX®, HEXADROL®, MAXIDEX®), prednisone (e.g., DELTASONE®), and methylprednisolone (e.g., MEDROL®).
  • dexamethasone e.g., DECADRON®, DEXASONE®, DIODEX®, HEXADROL®, MAXIDEX®
  • prednisone e.g., DELTASONE®
  • methylprednisolone e.g., MEDROL®
  • the additional cancer treatment is selected from lenalidomide, pomalidomide, dexamethasone, or a combination thereof.
  • the additional cancer treatments are lenalidomide and dexamethasone.
  • the additional cancer treatments are pomalidomide and dexamethasone.
  • the additional cancer treatments are bortezomib and dexamethasone.
  • the additional cancer treatments are pomalidomide, bortezomib, and dexamethasone.
  • the additional cancer treatments are lenalidomide, bortezomib, and dexamethasone.
  • the additional cancer treatment is standard of care treatment.
  • the first and second BCMA antagonists, and the third BCMA antagonist, if present, are administered on day 1 of a treatment cycle. In an embodiment, the first and second BCMA antagonists, and the third BCMA antagonist, if present, are administered on day 1 of a 28-day treatment cycle.
  • the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily for a period of time. In an embodiment, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily administered on days 1-21 of a 28 day cycle.
  • the additional cancer treatment is dexamethasone. In an embodiment, the additional cancer treatment is dexamethasone at a dose of 20 mg to 40 mg once weekly.
  • the additional cancer treatment is dexamethasone at a dose of 40 mg once weekly if the patient is less than 75 years old. In an embodiment, the additional cancer treatment is dexamethasone at a dose of 20 mg once weekly if the patient is at least 75 years old. In an embodiment, the additional cancer treatment is dexamethasone at a dose of 40 mg once weekly if the patient has a BMI of at least 18.5. In an embodiment, the additional cancer treatment is dexamethasone at a dose of 20 mg once weekly if the patient has a BMI less than 18.5. In an embodiment, the dexamethasone is administered on days 1, 8, 15, and 22 of a 28 day cycle.
  • the additional cancer treatments are lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28 day cycle and dexamethasone at a dose of 20 mg to 40 mg administered on days 1, 8, 15, and 22 of a 28 day cycle.
  • the additional cancer treatments are lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28 day cycle and dexamethasone at a dose of 40 mg administered on days 1, 8, 15, and 22 of a 28 day cycle if the patient is less than 75 years old or has a BMI of at least 18.5.
  • the additional cancer treatments are lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28 day cycle and dexamethasone at a dose of 20 mg administered on days 1, 8, 15, and 22 of a 28 day cycle if the patient is at least 75 years old or has a BMI of less than 18.5.
  • the disclosure provides a kit comprising: (i) a first B-cell maturation antigen (BCMA) antagonist; and (ii) instructions for use in treating a disease or disorder responsive to inhibiting or blocking BCMA when combined with a second BCMA antagonist.
  • the kit further comprises a third BCMA antagonist.
  • the instructions further describe use in treating a disease or disorder responsive to inhibiting or blocking BCMA when combined with second and third BCMA antagonist.
  • the first, second, and third BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • an anti-BCMA antibody or antigen binding fragment thereof an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • CAR T BCMA-targeted chimeric antigen receptor T
  • the first, second, and third BCMA antagonists are independently selected from the group consisting of idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.
  • the disclosure provides a kit comprising: (i) belantamab mafodotin; and (ii) instructions for use in treating a disease or disorder responsive to inhibiting or blocking BCMA when combined with belantamab.
  • the disclosure provides a kit comprising: (i) belantamab; and (ii) instructions for use in treating a disease or disorder responsive to inhibiting or blocking BCMA when combined with belantamab mafodotin.
  • BCMA-inhibiting or blocking therapies are also described.
  • kits comprising BCMA-inhibiting or blocking therapies and instructions for use.
  • the disclosure provides methods of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient previously treated with a first BCMA antagonist, the method comprising administering a therapeutically effective amount of a second BCMA antagonist to the patient, wherein the patient discontinued administration of the first BCMA antagonist prior to beginning administration of the second BCMA antagonist and the second BCMA antagonist is not the same as the first BCMA antagonist.
  • BCMA B-cell maturation antigen
  • the disclosure provides methods of reducing corneal toxicity in a patient previously treated with a first B-cell maturation antigen (BCMA) antagonist, the method comprising administering a therapeutically effective amount of a second BCMA antagonist to the patient, wherein the patient discontinued administration of the first BCMA antagonist prior to beginning administration of the second BCMA antagonist and the second BCMA antagonist is not the same as the first BCMA antagonist.
  • BCMA B-cell maturation antigen
  • Corneal toxicity” or “corneal adverse reaction” refers to changes in the cornea, including keratopathy (e.g., mild superficial keratopathy, moderate superficial keratopathy, severe superficial keratopathy) and corneal epithelial defect, such as corneal ulcers.
  • corneal toxicity or corneal adverse reaction refers to keratopathy, and the severity or grade of such corneal adverse reaction can be determined using the keratopathy visual acuity (KVA) scale for treatment-related corneal toxicities according to Table 2.
  • KVA keratopathy visual acuity
  • a patient has a Grade 1 corneal adverse reaction.
  • a patient has a Grade 2 corneal adverse reaction.
  • a patient has a Grade 3 corneal adverse reaction.
  • a patient has a Grade 4 corneal adverse reaction.
  • reducing ocular toxicity refers to reducing the severity of a corneal adverse reaction or the grade of a treatment related corneal toxicity as determined according to the KVA scale.
  • the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen binding fragment thereof, an anti- BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • the first BCMA-antagonist differs from the second BCMA-antagonist.
  • the first and second BCMA-antagonists are both anti-BCMA antibodies or fragments thereof, both anti-BCMA antibody-drug conjugates, both bispecific anti-BCMA antibodies or fragments thereof, or both BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapies.
  • the first BCMA-antagonist is an anti-BCMA antibody or antigen binding fragment thereof and the second BCMA-antagonist is a different anti-BCMA antibody or antigen binding fragment thereof.
  • the first BCMA-antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA-antagonist is a different anti-BCMA antibody-drug conjugate.
  • the first BCMA-antagonist is a bispecific anti-BCMA antibody or antigen binding fragment thereof and the second BCMA-antagonist is a different bispecific anti-BCMA antibody or antigen binding fragment thereof.
  • the first BCMA-antagonist is a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy and the second BCMA-antagonist is a different BCMA- targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • CAR T BCMA-targeted chimeric antigen receptor T
  • CAR T BCMA-targeted chimeric antigen receptor T
  • the bispecific anti-BCMA antibody or antigen binding fragment thereof comprises an anti-BCMA antibody or antigen binding fragment thereof and an anti-CD38 antibody or antigen binding fragment thereof. In an embodiment, the bispecific anti-BCMA antibody or antigen binding fragment thereof comprises an anti-BCMA antibody or antigen binding fragment thereof and an anti-CD3 antibody or antigen binding fragment thereof.
  • the first and second BCMA antagonists are independently selected from the group consisting of idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.
  • the first BCMA antagonist is belantamab mafodotin. In an embodiment, the first BCMA antagonist is belantamab. In an embodiment, the second BCMA antagonist is belantamab mafodotin. In an embodiment, the second BCMA antagonist is belantamab.
  • the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is an anti-BCMA antibody or antigen binding fragment thereof.
  • the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is an anti-BCMA antibody-drug conjugate.
  • the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is a bispecific anti-BCMA antibody or antigen binding fragment thereof.
  • the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • CAR T BCMA-targeted chimeric antigen receptor T
  • the first BCMA antagonist is an anti-BCMA antibody or antigen binding fragment thereof and the second BCMA antagonist is belantamab mafodotin.
  • the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is belantamab mafodotin.
  • the first BCMA antagonist is a bispecific anti-BCMA antibody or antigen binding fragment thereof and the second BCMA antagonist is belantamab mafodotin.
  • the first BCMA antagonist is a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy and the second BCMA antagonist is belantamab mafodotin.
  • CAR T BCMA-targeted chimeric antigen receptor T
  • the first BCMA antagonist is belantamab and the second BCMA antagonist is an anti-BCMA antibody or antigen binding fragment thereof.
  • the first BCMA antagonist is belantamab and the second BCMA antagonist is an anti-BCMA antibody-drug conjugate.
  • the first BCMA antagonist is belantamab and the second BCMA antagonist is a bispecific anti-BCMA antibody or antigen binding fragment thereof.
  • the first BCMA antagonist is belantamab and the second BCMA antagonist is a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • the first BCMA antagonist is an anti-BCMA antibody or antigen binding fragment thereof and the second BCMA antagonist is belantamab.
  • the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is belantamab.
  • the first BCMA antagonist is a bispecific anti-BCMA antibody or antigen binding fragment thereof and the second BCMA antagonist is belantamab.
  • the first BCMA antagonist is a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy and the second BCMA antagonist is belantamab.
  • the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is idecabtagene vicleucel. In an embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is ciltacabtagene autoleucel. In an embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is teclistamab. In an embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is REGN5458. In an embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is SEA-BCMA.
  • the first BCMA antagonist is idecabtagene vicleucel and the second BCMA antagonist is belantamab mafodotin.
  • the first BCMA antagonist is ciltacabtagene autoleucel and the second BCMA antagonist is belantamab mafodotin.
  • the first BCMA antagonist is teclistamab and the second BCMA antagonist is belantamab mafodotin.
  • the first BCMA antagonist is REGN5458 and the second BCMA antagonist is belantamab mafodotin.
  • the first BCMA antagonist is SEA-BCMA and the second BCMA antagonist is belantamab mafodotin.
  • the first BCMA antagonist is ABBV-383 and the second BCMA antagonist is belantamab mafodotin.
  • the first BCMA antagonist is elrantamab and the second BCMA antagonist is belantamab mafodotin.
  • the first BCMA antagonist is pavurutumab and the second BCMA antagonist is belantamab mafodotin.
  • the first BCMA antagonist is alnuctamab and the second BCMA antagonist is belantamab mafodotin.
  • the first BCMA antagonist is MEDI2228 and the second BCMA antagonist is belantamab mafodotin.
  • the first BCMA antagonist is CC99712 and the second BCMA antagonist is belantamab mafodotin.
  • the first BCMA antagonist is belantamab and the second BCMA antagonist is idecabtagene vicleucel.
  • the first BCMA antagonist is belantamab and the second BCMA antagonist is ciltacabtagene autoleucel.
  • the first BCMA antagonist is belantamab and the second BCMA antagonist is teclistamab.
  • the first BCMA antagonist is belantamab and the second BCMA antagonist is REGN5458.
  • the first BCMA antagonist is belantamab and the second BCMA antagonist is SEA- BCMA.
  • the first BCMA antagonist is idecabtagene vicleucel and the second BCMA antagonist is belantamab.
  • the first BCMA antagonist is ciltacabtagene autoleucel and the second BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is teclistamab and the second BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is REGN5458 and the second BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is SEA-BCMA and the second BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is ABBV-383 and the second BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is elrantamab and the second BCMA antagonist is belantamab.
  • the first BCMA antagonist is pavurutumab and the second BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is alnuctamab and the second BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is MEDI2228 and the second BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is CC99712 and the second BCMA antagonist is belantamab.
  • the method further comprises administering a therapeutically effective amount of a third BCMA antagonist to the patient in combination with the second BCMA antagonist, wherein the patient discontinued administration of the first BCMA antagonist prior to beginning administration of the second and third BCMA antagonists and the third BCMA antagonist is not the same as the first and second BCMA antagonists.
  • the first BCMA antagonist is an anti-BCMA antibody or antigen binding fragment thereof
  • the second BCMA antagonist is belantamab mafodotin
  • the third BCMA antagonist is belantamab.
  • the first BCMA antagonist is an anti-BCMA antibody-drug conjugate
  • the second BCMA antagonist is belantamab mafodotin
  • the third BCMA antagonist is belantamab.
  • the first BCMA antagonist is a bispecific anti-BCMA antibody or antigen binding fragment thereof
  • the second BCMA antagonist is belantamab mafodotin
  • the third BCMA antagonist is belantamab.
  • the first BCMA antagonist is a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy
  • the second BCMA antagonist is belantamab mafodotin
  • the third BCMA antagonist is belantamab.
  • the first BCMA antagonist is idecabtagene vicleucel
  • the second BCMA antagonist is belantamab mafodotin
  • the third BCMA antagonist is belantamab.
  • the first BCMA antagonist is ciltacabtagene autoleucel
  • the second BCMA antagonist is belantamab mafodotin
  • the third BCMA antagonist is belantamab.
  • the first BCMA antagonist is teclistamab
  • the second BCMA antagonist is belantamab mafodotin
  • the third BCMA antagonist is belantamab.
  • the first BCMA antagonist is REGN5458
  • the second BCMA antagonist is belantamab mafodotin
  • the third BCMA antagonist is belantamab.
  • the first BCMA antagonist is SEA-BCMA
  • the second BCMA antagonist is belantamab mafodotin
  • the third BCMA antagonist is belantamab.
  • the first BCMA antagonist is ABBV-383
  • the second BCMA antagonist is belantamab mafodotin
  • the third BCMA antagonist is belantamab.
  • the first BCMA antagonist is elrantamab
  • the second BCMA antagonist is belantamab mafodotin
  • the third BCMA antagonist is belantamab.
  • the first BCMA antagonist is pavurutumab
  • the second BCMA antagonist is belantamab mafodotin
  • the third BCMA antagonist is belantamab.
  • the first BCMA antagonist is alnuctamab
  • the second BCMA antagonist is belantamab mafodotin
  • the third BCMA antagonist is belantamab.
  • the first BCMA antagonist is MEDI2228
  • the second BCMA antagonist is belantamab mafodotin
  • the third BCMA antagonist is belantamab.
  • the first BCMA antagonist is CC99712
  • the second BCMA antagonist is belantamab mafodotin
  • the third BCMA antagonist is belantamab.
  • the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is the corresponding unconjugated anti-BCMA antibody.
  • the second BCMA antagonist is an anti-BCMA antibody-drug conjugate and the first BCMA antagonist is the corresponding unconjugated anti-BCMA antibody.
  • the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is belantamab.
  • the first BCMA antagonist is belantamab and the second BCMA antagonist is belantamab mafodotin.
  • the second BCMA antagonist, and the third BCMA antagonist are independently administered at least once every 8 weeks ⁇ 3 days, at least once every 6 weeks ⁇ 3 days, at least once every 4 weeks ⁇ 3 days, at least once every 3 weeks ⁇ 3 days, at least once every 2 weeks ⁇ 3 days, at least once every week ⁇ 3 days, once every week ⁇ 3 days to once every 8 weeks ⁇ 3 days, once every week ⁇ 3 days to once every 6 weeks ⁇ 3 days, once every week ⁇ 3 days to once every 4 weeks ⁇ 3 days, once every week ⁇ 3 days to once every 3 weeks ⁇ 3 days, once every week ⁇ 3 days to once every 2 weeks ⁇ 3 days, once every 2 weeks ⁇ 3 days to once every 3 weeks ⁇ 3 days, once every 3 weeks ⁇ 3 days to once every 4 weeks ⁇ 3 days, once every 4 weeks ⁇ 3 days to once every 5 weeks ⁇ 3 days, once every 5 weeks ⁇ 3 days to once every 3 days to once every
  • the second BCMA antagonist and the third BCMA antagonist are administered in combination with application of bandage contact lens.
  • the second BCMA antagonist, and the third BCMA antagonist, if present, are administered in combination with at least one additional treatment.
  • the additional cancer treatment is selected from an anti-CD38 monoclonal antibody, a gamma- secretase inhibitor, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.
  • anti-CD38 antibodies useful in the methods described herein include, but are not limited to, isatuximab or isatuximab-irfc (e.g., SARCLISA®) and daratumumab (e.g, DARZALEX®, DARZALEX FASPRO®).
  • the anti-CD38 monoclonal antibody is selected from daratumumab or isatuximab.
  • Examples of gamma-secretase inhibitors useful in the methods described herein include, but are not limited to, nirogacestat (PF-0308014), crenigacestat (LY3039478), CB-103, tarenflurbil, semagacestat (LY450139), RG-4733, EVP-0962, avagacestat, MK-0752, and BMS- 906024, as well as derivatives and polymorphs thereof.
  • proteasome inhibitors useful in the methods described herein include, but are not limited to, bortezomib (e.g., VELCADE®), ixazomib (e.g., NINLARO®), carfilzomib (e.g., KYPROLIS®), oprozomib, and delanzomib.
  • the proteasome inhibitor is selected from bortezomib, carfilzomib, or ixazomib.
  • the proteasome inhibitor is bortezomib.
  • immunomodulatory imide drugs useful in the methods described herein include, but are not limited to, thalidomide (e.g., THALOMID®), lenalidomide (e.g., REVLIMID®), and pomalidomide (e.g., POMALYST®).
  • the immunomodulatory agent is selected from thalidomide, lenalidomide, or pomalidomide.
  • the immunomodulatory agent is lenalidomide or pomalidomide.
  • the immunomodulatory agent is lenalidomide.
  • anti-PD-1 monoclonal antibodies useful in the methods described herein include, but are not limited to, pembroluzimab and dostarlimab.
  • the anti-PD-1 monoclonal antibody is selected from pembroluzimab or dostarlimab.
  • corticosteroids include, but are not limited to, dexamethasone (e.g., DECADRON®, DEXASONE®, DIODEX®, HEXADROL®, MAXIDEX®), prednisone (e.g., DELTASONE®), and methylprednisolone (e.g., MEDROL®).
  • dexamethasone e.g., DECADRON®, DEXASONE®, DIODEX®, HEXADROL®, MAXIDEX®
  • prednisone e.g., DELTASONE®
  • methylprednisolone e.g., MEDROL®
  • the additional cancer treatment is selected from lenalidomide, pomalidomide, dexamethasone, or a combination thereof.
  • the additional cancer treatments are lenalidomide and dexamethasone.
  • the additional cancer treatments are pomalidomide and dexamethasone.
  • the additional cancer treatments are bortezomib and dexamethasone.
  • the additional cancer treatments are pomalidomide, bortezomib, and dexamethasone.
  • the additional cancer treatments are lenalidomide, bortezomib, and dexamethasone.
  • the additional cancer treatment is standard of care treatment.
  • the second BCMA antagonist, and the third BCMA antagonist, if present, are administered on day 1 of a treatment cycle. In an embodiment, the second BCMA antagonist, and the third BCMA antagonist, if present, are administered on day 1 of a 28-day treatment cycle.
  • the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily for a period of time. In an embodiment, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily administered on days 1-21 of a 28 day cycle.
  • the additional cancer treatment is dexamethasone. In an embodiment, the additional cancer treatment is dexamethasone at a dose of 20 mg to 40 mg once weekly.
  • the additional cancer treatment is dexamethasone at a dose of 40 mg once weekly if the patient is less than 75 years old. In an embodiment, the additional cancer treatment is dexamethasone at a dose of 20 mg once weekly if the patient is at least 75 years old. In an embodiment, the additional cancer treatment is dexamethasone at a dose of 40 mg once weekly if the patient has a BMI of at least 18.5. In an embodiment, the additional cancer treatment is dexamethasone at a dose of 20 mg once weekly if the patient has a BMI less than 18.5. In an embodiment, the dexamethasone is administered on days 1, 8, 15, and 22 of a 28 day cycle.
  • the additional cancer treatments are lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28 day cycle and dexamethasone at a dose of 20 mg to 40 mg administered on days 1, 8, 15, and 22 of a 28 day cycle.
  • the additional cancer treatments are lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28 day cycle and dexamethasone at a dose of 40 mg administered on days 1, 8, 15, and 22 of a 28 day cycle if the patient is less than 75 years old or has a BMI of at least 18.5.
  • the additional cancer treatments are lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28 day cycle and dexamethasone at a dose of 20 mg administered on days 1, 8, 15, and 22 of a 28 day cycle if the patient is at least 75 years old or has a BMI of less than 18.5.
  • the first BCMA antagonist is discontinued after the patient demonstrates progressive disease.
  • an immunoconjugate or antibody-drug conjugate is used in combination with its corresponding unconjugated antibody.
  • a corresponding unconjugated antibody refers to the antibody portion of the immunoconjugate or ADC that lacks the cytotoxic payload and optionally any linker portion of the immunoconjugate or ADC.
  • the disclosure provides methods of treating a disease or disorder in a patient, the method comprising administering a therapeutically effective amount of a combination comprising an antibody-drug conjugate and the corresponding unconjugated antibody to the patient.
  • the disclosure provides methods of reducing toxicity of an antibody-drug conjugate, the method comprising administering to a patient in need thereof a therapeutically effective amount of a combination comprising the antibody-drug conjugate and the corresponding unconjugated antibody to the patient.
  • the disclosure provides methods of treating a disease or disorder in a patient previously treated with an antibody-drug conjugate, the method comprising administering a therapeutically effective amount of the corresponding unconjugated antibody to the patient, wherein the patient discontinued administration of the antibody-drug conjugate prior to beginning administration of the corresponding unconjugated antibody.
  • the disclosure provides methods of reducing toxicity in a patient previously treated with an antibody-drug conjugate, the method comprising administering a therapeutically effective amount of the corresponding unconjugated antibody to the patient, wherein the patient discontinued administration of the antibody-drug conjugate prior to beginning administration of the corresponding unconjugated antibody.
  • the antibody-drug conjugate is selected from gemtuzumab ozogamicin, brentuximab vedotin, ado-trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, fam-trastuzumab deruxtecan, sacituzumab govitecan, belantamab mafodotin, loncastuximab tesirine, tisotumab vedotin, moxetumomab pasudotox, MEDI2228, or CC99712. Diseases and Disorders
  • BCMA-inhibiting or blocking therapies in the treatment of a disease or disorder in a patient.
  • the disease or disorder is a plasma cell disorder or a B-cell disorder.
  • B-cell disorders can be divided into defects of B-cell development/immunoglobulin production (immunodeficiencies) and excessive/uncontrolled proliferation (lymphomas, leukemias).
  • B-cell disorder refers to both types of diseases, and methods are provided for treating B- cell disorders.
  • the cancer can be a B cell cancer (e.g., leukemias and lymphomas).
  • MM Multiple Myeloma
  • CLL chronic lymphocytic leukemia
  • FL Follicular Lymphoma
  • Non-secretory multiple myeloma Smoldering multiple myeloma
  • Monoclonal gammopathy of undetermined significance MGUS
  • Solitary plasmacytoma Bone, Extramedullary
  • Lymphoplasmacytic lymphoma LPL
  • Waldenstrom’s Macroglobulinemia Plasma cell leukemia, Primary Amyloidosis (AL), Heavy chain disease, Systemic lupus erythematosus (SLE), POEMS syndrome / osteosclerotic myeloma, Type I and II cryoglobulinemia, Light chain deposition disease, Goodpasture’s syndrome, Idiopathic thrombocytopenic purpura (ITP), Acute glomerulonep
  • the disease or disorder can be selected from the group consisting of Multiple Myeloma (MM), Non-Hodgkin’s Lymphoma B- cell leukemia (NHL), Follicular Lymphoma (FL), and Diffuse Large B-Cell Lymphoma (DLBCL).
  • MM Multiple Myeloma
  • NHL Non-Hodgkin’s Lymphoma B- cell leukemia
  • FL Follicular Lymphoma
  • the disease can be Multiple Myeloma or Non-Hodgkin’s Lymphoma B-cell leukemia (NHL).
  • the disease can be Multiple Myeloma.
  • the disease or disorder is a BCMA-expressing cancer.
  • the disease or disorder is multiple myeloma (MM).
  • the MM is relapsed and/or refractory MM, newly-diagnosed MM, transplant-ineligible MM, or transplant- ineligible newly-diagnosed MM.
  • the disease or disorder is multiple myeloma previously treated with at least one, at least two, at least three, or at least four therapeutics to treat the multiple myeloma.
  • the disease or disorder is relapsed and/or refractory multiple myeloma previously treated with at least one, at least two, at least three or at least four therapeutics to treat the multiple myeloma.
  • the disease or disorder is relapsed and/or refractory multiple myeloma previously treated with at least 3 prior lines of therapy that may include the following: an immunomodulatory drug (ImiD), a proteasome inhibitor (PI) and anti-CD38 treatment (e.g., daratumumab) or combinations thereof. Lines of therapy may be defined by consensus panel of the International Myeloma Workshop (IMWG).
  • a patient that had prior lines of treatment may have a cancer that is recurrent, relapsed and/or refractory.
  • a cancer can be a primary cancer.
  • a cancer can be metastatic cancer.
  • a cancer can be chemo-resistant cancer.
  • the disease or disorder is an autoimmune disease or disorder.
  • the disease or disorder is systemic lupus erythematosus (SLE), idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, Type 1 diabetes mellitus, multiple sclerosis, or psoriasis.
  • belantamab refers to a B-cell maturation antigen (BCMA)-blocking antibody (“anti-BCMA antibody”) or a functional fragment or functional variant thereof which specifically binds to BCMA and which inhibits the binding of BAFF and/or APRIL to the BCMA receptor, comprising an immunoglobulin heavy chain variable domain (VH) comprising a complementary determining region (CDR) Hl comprising the amino acid sequence of SEQ ID NO 5; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 6; a CDRH3 comprising the amino acid sequence of SEQ ID NO: 7; and an immunoglobulin light chain variable domain (VL) comprising a CDRL1 comprising the amino acid sequence of SEQ ID NO: 8; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 9; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 10.
  • VH immunoglobulin heavy chain variable domain
  • CDR complementary determining region
  • VL immunoglobulin light chain
  • the VH comprises an amino acid sequence of SEQ ID NO: 3.
  • the VL comprises an amino acid sequence of SEQ ID NO 4.
  • the heavy chain comprises the amino acid sequence of SEQ ID NO 1.
  • the light chain comprises the amino acid sequence of SEQ ID NO 2.
  • belantamab comprises a VH comprising an amino acid sequence of SEQ ID NO: 3 and a VL comprising an amino acid sequence of SEQ ID NO: 4.
  • belantamab comprises the heavy and light chain sequences of SEQ ID NO: 1 and SEQ ID NO: 2, respectively.
  • belantamab mafodotin and “belamaf ’ are used interchangeably and refer to an immunoconjugate comprising belantamab conjugated to monomethyl auristatin F (MMAF) via a 6- maleimidocaproyl (MC) linker.
  • MMAF monomethyl auristatin F
  • MC 6- maleimidocaproyl
  • biosimilar refers to a biopharmaceutical or a biologic product that is highly similar to a reference biologic product (e.g., belantamab or belantamab mafodotin) notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biologic product and the reference product in terms of the safety, purity, and potency of the product (Section 351 (i) of the Public Health Service Act (42 U.S.C. 262(i)).
  • a reference biologic product e.g., belantamab or belantamab mafodotin
  • biosimilar refers to a biologic product that is highly similar to the reference product (e.g., belantamab or belantamab mafodotin) approved by a regulatory agency (e.g., the Federal Drug Administration (FDA) or the European Medicines Agency (EMA)) based on data from (a) analytical studies demonstrating that the biologic product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; (b) animal studies (including the assessment of toxicity); and/or (c) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is approved and intended to be used and for which approval is sought (e.g., that there are no clinically meaningful differences between the biologic product and the reference product in terms of the safety, purity and potency of the product).
  • the biosimilar product is an interchangeable product as determined by a regulatory agency (e.g., the Federal Drug Administration (
  • the biosimilar may comprise one or more molecular differences, such as post-translational modifications, for example, although not limited to, glycosylation, oxidation, deamidation, and/or truncation which is/are different to the post-translational modifications of the reference medicinal product (e.g., belantamab or belantamab mafodotin) provided that the differences do not result in a significant change in safety and/or efficacy of the medicinal product.
  • the reference medicinal product e.g., belantamab or belantamab mafodotin
  • the biosimilar may have an identical or different glycosylation pattern to the reference medicinal product (e.g., belantamab or belantamab mafodotin).
  • the biosimilar e.g., a biosimilar of belantamab or belantamab mafodotin
  • the biosimilar may have a different glycosylation pattern, such as, if the differences address or are intended to address safety concerns associated with the reference medicinal product (e.g., belantamab or belantamab mafodotin).
  • biosimilar e.g., a biosimilar of belantamab or belantamab mafodotin
  • the reference medicinal product e.g., belantamab or belantamab mafodotin
  • the biosimilar e.g., a biosimilar of belantamab or belantamab mafodotin
  • the biosimilar may comprise differences in, for example, pharmacokinetic (PK) and/or pharmacodynamic (PD) profiles as compared to the reference medicinal product (e.g., belantamab or belantamab mafodotin) but is still deemed sufficiently similar to the reference medicinal product as to be authorized or considered suitable for authorization.
  • PK pharmacokinetic
  • PD pharmacodynamic
  • the biosimilar e.g., a biosimilar of belantamab or belantamab mafodotin
  • the reference medicinal product e.g., belantamab or belantamab mafodotin
  • biosimilar is also used synonymously by other national and regional regulatory agencies.
  • a drug’s international nonproprietary name (e.g., belantamab or belantamab mafodotin)
  • INN international nonproprietary name
  • a drug’s INN optionally includes, but is not limited to, glycosylation variants of belantamab or belantamab mafodotin, and biosimilars thereof.
  • Embodiment 1 is a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, the method comprising administering to the patient belantamab at a dose of about 300 mg to about 2000 mg.
  • Embodiment 2 is the method of embodiment 1, wherein the dose is about 300 mg, about 900 mg, or about 2000 mg.
  • Embodiment 3 is the method of embodiment 1 or 2, wherein the dose is administered at a regular interval for a period of time.
  • Embodiment 4 is the method of embodiment 1 or 2, wherein the dose is administered once every week ⁇ 3 days to once every four weeks ⁇ 3 days.
  • Embodiment 5 is the method of embodiment 1 or 2, wherein the dose is administered once every two weeks ⁇ 3 days.
  • Embodiment 6 is the method of embodiment 1 or 2, wherein the dose is administered once every three weeks ⁇ 3 days.
  • Embodiment 7 is the method of embodiment 1 or 2, wherein the dose is administered once every four weeks ⁇ 3 days.
  • Embodiment 8 is the method of embodiment 1 or 2, wherein the dose is administered on days 1 and 15 of a 28 day cycle.
  • Embodiment 9 is the method of embodiment 1 or 2, wherein the dose is administered on day 1 of a 21 day cycle.
  • Embodiment 10 is the method of any one of the preceding embodiments, wherein the patient has been treated with at least one prior line of cancer treatment.
  • Embodiment 11 is the method of any one of the preceding embodiments, wherein the patient has been treated with one, two, three, or four prior lines of cancer treatments.
  • Embodiment 12 is the method of embodiment 11, wherein the prior lines of cancer treatments include an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.
  • Embodiment 13 is the method of any one of the preceding embodiments, wherein belantamab is administered through an intravenous infusion or a subcutaneous injection.
  • Embodiment 14 is the method of any one of the preceding embodiments, wherein the patient is further receiving at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.
  • additional cancer treatment such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.
  • Embodiment 15 is the method of embodiment 14, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.
  • Embodiment 16 is the method of embodiment 15, wherein the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily for a period of time.
  • Embodiment 17 is the method of embodiment 16, wherein the patient is receiving lenalidomide on days 1-21 of a 28 day cycle.
  • Embodiment 18 is the method of any one of embodiments 14 to 17, wherein the additional cancer treatment is dexamethasone.
  • Embodiment 19 is the method of embodiment 18, wherein the additional cancer treatment is dexamethasone at a dose of 20 mg to 40 mg once weekly.
  • Embodiment 20 is the method of embodiment 19, wherein the patient is receiving dexamethasone on days 1, 8, 15, and 22 of a 28 day cycle.
  • Embodiment 21 is the method of embodiment 19, wherein (i) the patient is less than 75 years old and is receiving dexamethasone at a dose of 40 mg once weekly; or (ii) the patient is at least 75 years old and is receiving dexamethasone at a dose of 20 mg once weekly.
  • Embodiment 22 is the method of embodiment 19, wherein (i) the patient has a BMI of at least 18.5 and is receiving dexamethasone at a dose of 40 mg once weekly; or (ii) the patient has a BMI less than 18.5 and is receiving dexamethasone at a dose of 20 mg once weekly.
  • Embodiment 23 is the method of any one of the preceding embodiments, further comprising discontinuing administration of belantamab and subsequently administering belantamab mafodotin.
  • Embodiment 24 is the method of any one of embodiments 1 to 22, further comprising administering belantamab mafodotin and subsequently discontinuing administration of belantamab.
  • Embodiment 25 is the method of embodiment 23 or 24, wherein belantamab mafodotin is administered at a dose of 2.5 mg/kg once every three weeks ⁇ 3 days.
  • Embodiment 26 is the method of any one of the preceding embodiments, further comprising administering a lead-in dose of belantamab mafodotin prior to beginning administration of belantamab, wherein the lead-in dose of belantamab mafodotin is about 1.4 mg/kg to about 3.4 mg/kg once during a lead-in period.
  • Embodiment 27 is the method of embodiment 26, wherein the lead-in dose of belantamab mafodotin is about 1.4 mg/kg to about 1.9 mg/kg once during a lead-in period.
  • Embodiment 28 is the method of embodiment 26, wherein the lead-in dose of belantamab mafodotin is about 1.4 mg/kg, about 1.9 mg/kg, about 2.5 mg/kg, or about 3.4 mg/kg once during a lead-in period.
  • Embodiment 29 is the method of embodiment 26, wherein the lead-in dose of belantamab mafodotin is about 1.4 mg/kg once during a lead-in period.
  • Embodiment 30 is the method of any one of embodiments 26 to 29, wherein the lead- in period is four weeks ⁇ 3 days and belantamab mafodotin is administered on day 1 of the lead- in period.
  • Embodiment 31 is the method of any one of embodiments 26 to 30, further comprising administering at least one additional cancer treatment to the patient during the lead-in period, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.
  • at least one additional cancer treatment such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.
  • Embodiment 32 is the method of embodiment 31, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.
  • Embodiment 33 is the method of embodiment 32, wherein the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily for a period of time.
  • Embodiment 34 is the method of embodiment 33, wherein lenalidomide is administered to the patient on days 1-21 of the lead-in period.
  • Embodiment 35 is the method of any one of embodiments 32 to 34, wherein the additional cancer treatment is dexamethasone.
  • Embodiment 36 is the method of embodiment 35, wherein the additional cancer treatment is dexamethasone at a dose of 20 mg to 40 mg once weekly.
  • Embodiment 37 is the method of embodiment 36, wherein dexamethasone is administered to the patient on days 1, 8, 15, and 22 of the lead-in period.
  • Embodiment 38 is the method of embodiment 36, wherein (i) the patient is less than 75 years old and dexamethasone is administered to the patient at a dose of 40 mg once weekly; or (ii) the patient is at least 75 years old and dexamethasone is administered to the patient at a dose of 20 mg once weekly.
  • Embodiment 39 is the method of embodiment 36, wherein (i) the patient has a BMI of at least 18.5 and dexamethasone is administered to the patient at a dose of 40 mg once weekly; or (ii) the patient has a BMI less than 18.5 and dexamethasone is administered to the patient at a dose of 20 mg once weekly.
  • Embodiment 40 is a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, the method comprising administering to a patient belantamab mafodotin at a dose of about 1.4 mg/kg to about 3.4 mg/kg once every eight weeks ⁇ 3 days, such as about 1.4 mg/kg to about 1.9 mg/kg once every eight weeks ⁇ 3 days.
  • BCMA B-cell maturation antigen
  • Embodiment 41 is the method of embodiment 40, wherein the dose is about 1.4 mg/kg, about 1.9 mg/kg, about 2.5 mg/kg, or about 3.4 mg/kg once every eight weeks ⁇ 3 days.
  • Embodiment 42 is a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, the method comprising administering a therapeutically effective amount of a combination comprising a first BCMA antagonist and a second BCMA antagonist to the patient.
  • BCMA B-cell maturation antigen
  • Embodiment 43 is the method of embodiment 42, wherein the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • Embodiment 44 is the method of embodiment 42 or 43, wherein the first and second BCMA antagonists are independently selected from the group consisting of idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.
  • the first and second BCMA antagonists are independently selected from the group consisting of idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.
  • Embodiment 45 is the method of any one of embodiments 42 to 44, wherein the first BCMA antagonist is belantamab mafodotin.
  • Embodiment 46 is the method of any one of embodiments 42 to 44, wherein the first BCMA antagonist is belantamab.
  • Embodiment 47 is the method of embodiment 42, wherein the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is the corresponding unconjugated anti-BCMA antibody.
  • Embodiment 48 is the method of embodiment 47, wherein the anti-BCMA antibodydrug conjugate is selected from the group consisting of belantamab mafodotin, MEDI2228, and CC99712.
  • Embodiment 49 is the method of embodiment 48, wherein the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is belantamab.
  • Embodiment 50 is a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, the method comprising administering a therapeutically effective amount of a combination comprising belantamab mafodotin and belantamab to the patient.
  • BCMA B-cell maturation antigen
  • Embodiment 51 is the method of any one of embodiments 42 to 50, further comprising administering at least one additional cancer treatment to the patient, such as an anti- CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD- 1 monoclonal antibody.
  • at least one additional cancer treatment such as an anti- CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD- 1 monoclonal antibody.
  • Embodiment 52 is the method of embodiment 51 , wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.
  • Embodiment 53 is a kit comprising: (i) a first B-cell maturation antigen (BCMA) antagonist; and (ii) instructions for use in treating a disease or disorder responsive to inhibiting or blocking BCMA when combined with a second BCMA antagonist.
  • BCMA B-cell maturation antigen
  • Embodiment 54 is a kit comprising: (i) belantamab mafodotin; and (ii) instructions for use in treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) when combined with belantamab.
  • BCMA B-cell maturation antigen
  • Embodiment 55 is a kit comprising: (i) belantamab; and (ii) instructions for use in treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) when combined with belantamab mafodotin.
  • BCMA B-cell maturation antigen
  • Embodiment 56 is a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient previously treated with a first BCMA antagonist, the method comprising administering a therapeutically effective amount of a second BCMA antagonist to the patient, wherein the patient discontinued administration of the first BCMA antagonist prior to beginning administration of the second BCMA antagonist and the second BCMA antagonist is not the same as the first BCMA antagonist.
  • BCMA B-cell maturation antigen
  • Embodiment 57 is the method of embodiment 56, wherein the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • Embodiment 58 is the method of embodiment 56 or 57, wherein the first and second BCMA antagonists are independently selected from the group consisting of idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.
  • the first and second BCMA antagonists are independently selected from the group consisting of idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.
  • Embodiment 59 is the method of any one of embodiments 56 to 58, wherein the first BCMA antagonist is belantamab mafodotin.
  • Embodiment 60 is the method of any one of embodiments 56 to 58, wherein the first BCMA antagonist is belantamab.
  • Embodiment 61 is the method of any one of embodiments 56 to 58, wherein the second BCMA antagonist is belantamab mafodotin.
  • Embodiment 62 is the method of any one of embodiments 56 to 58, wherein the second BCMA antagonist is belantamab.
  • Embodiment 63 is the method of embodiment 56, wherein the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is the corresponding unconjugated anti-BCMA antibody.
  • Embodiment 64 is the method of embodiment 63, wherein the anti-BCMA antibodydrug conjugate is selected from the group consisting of belantamab mafodotin, MEDI2228, and CC99712.
  • Embodiment 65 is the method of embodiment 63, wherein the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is belantamab.
  • Embodiment 66 is the method of embodiment 56, wherein the second BCMA antagonist is an anti-BCMA antibody-drug conjugate and the first BCMA antagonist is the corresponding unconjugated anti-BCMA antibody.
  • Embodiment 67 is the method of embodiment 66, wherein the anti-BCMA antibodydrug conjugate is selected from the group consisting of belantamab mafodotin, MEDI2228, and CC99712.
  • Embodiment 68 is the method of embodiment 66, wherein the second BCMA antagonist is belantamab mafodotin and the first BCMA antagonist is belantamab.
  • Embodiment 69 is a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient previously treated with belantamab mafodotin, the method comprising administering a therapeutically effective amount of belantamab to the patient, wherein the patient discontinued administration of belantamab mafodotin prior to beginning administration of belantamab.
  • BCMA B-cell maturation antigen
  • Embodiment 70 is a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient previously treated with belantamab, the method comprising administering a therapeutically effective amount of belantamab mafodotin to the patient, wherein the patient discontinued administration of belantamab prior to beginning administration of belantamab mafodotin.
  • BCMA B-cell maturation antigen
  • Embodiment 71 is the method of any one of embodiments 56 to 70, further comprising administering at least one additional cancer treatment to the patient, such as an anti- CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD- 1 monoclonal antibody.
  • at least one additional cancer treatment such as an anti- CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD- 1 monoclonal antibody.
  • Embodiment 72 is the method of embodiment 71, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.
  • the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.
  • Embodiment 73 is a method of reducing corneal toxicity in a patient previously treated with a first B-cell maturation antigen (BCMA) antagonist, the method comprising administering a therapeutically effective amount of a second BCMA antagonist to the patient, wherein the patient discontinued administration of the first BCMA antagonist prior to beginning administration of the second BCMA antagonist and the second BCMA antagonist is not the same as the first BCMA antagonist.
  • BCMA B-cell maturation antigen
  • Embodiment 74 is the method of embodiment 73, wherein the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T)-cell therapy.
  • Embodiment 75 is the method of embodiment 73 or 74, wherein the first and second BCMA antagonists are independently selected from the group consisting of idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.
  • the first and second BCMA antagonists are independently selected from the group consisting of idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.
  • Embodiment 76 is the method of any one of embodiments 73 to 75, wherein the first BCMA antagonist is belantamab mafodotin.
  • Embodiment 77 is the method of any one of embodiments 73 to 75, wherein the first BCMA antagonist is belantamab.
  • Embodiment 78 is the method of any one of embodiments 73 to 75, wherein the second BCMA antagonist is belantamab mafodotin.
  • Embodiment 79 is the method of any one of embodiments 73 to 75, wherein the second BCMA antagonist is belantamab.
  • Embodiment 80 is the method of embodiment 73, wherein the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is the corresponding unconjugated anti-BCMA antibody.
  • Embodiment 81 is the method of embodiment 80, wherein the anti-BCMA antibodydrug conjugate is selected from the group consisting of belantamab mafodotin, MEDI2228, and CC99712.
  • Embodiment 82 is the method of embodiment 80, wherein the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is belantamab.
  • Embodiment 83 is the method of embodiment 73, wherein the second BCMA antagonist is an anti-BCMA antibody-drug conjugate and the first BCMA antagonist is the corresponding unconjugated anti-BCMA antibody.
  • Embodiment 84 is the method of embodiment 83, wherein the anti-BCMA antibodydrug conjugate is selected from the group consisting of belantamab mafodotin, MEDI2228, and CC99712.
  • Embodiment 85 is the method of embodiment 83, wherein the second BCMA antagonist is belantamab mafodotin and the first BCMA antagonist is belantamab.
  • Embodiment 86 is a method of reducing corneal toxicity in a patient previously treated with belantamab mafodotin, the method comprising administering a therapeutically effective amount of belantamab to the patient, wherein the patient discontinued administration of belantamab mafodotin prior to beginning administration of belantamab.
  • Embodiment 87 is a method of reducing corneal toxicity in a patient previously treated with belantamab, the method comprising administering a therapeutically effective amount of belantamab mafodotin to the patient, wherein the patient discontinued administration of belantamab prior to beginning administration of belantamab mafodotin.
  • Embodiment 88 is the method of any one of embodiments 73 to 87, further comprising administering at least one additional cancer treatment to the patient, such as an anti- CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD- 1 monoclonal antibody.
  • at least one additional cancer treatment such as an anti- CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD- 1 monoclonal antibody.
  • Embodiment 89 is the method of embodiment 88, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.
  • Embodiment 90 is a method of treating a disease or disorder in a patient, the method comprising administering a therapeutically effective amount of a combination comprising an antibody-drug conjugate and the corresponding unconjugated antibody.
  • Embodiment 91 is a method of treating a disease or disorder in a patient previously treated with an antibody-drug conjugate, the method comprising administering a therapeutically effective amount of the corresponding unconjugated antibody to the patient, wherein the patient discontinued administration of the antibody-drug conjugate prior to beginning administration of the corresponding unconjugated antibody.
  • Embodiment 92 is the method of embodiment 90 or 91, wherein the antibody-drug conjugate is selected from gemtuzumab ozogamicin, brentuximab vedotin, ado-trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, fam-trastuzumab deruxtecan, 66andomized66 govitecan, belantamab mafodotin, loncastuximab tesirine, tisotumab vedotin, moxetumomab pasudotox, MEDI2228, or CC99712.
  • the antibody-drug conjugate is selected from gemtuzumab ozogamicin, brentuximab vedotin, ado-trastuzumab
  • Embodiment 93 is the method of any one of embodiments 1 to 52 or 56 to 92, or the kit of any one of embodiments 53 to 55, wherein the disease or disorder is a plasma cell disorder or a B-cell disorder.
  • Embodiment 94 is the method any one of embodiments 1 to 52 or 56 to 92, or the kit of any one of embodiments 53 to 55, wherein the disease or disorder is a BCMA-expressing cancer.
  • Embodiment 95 is the method any one of embodiments 1 to 52 or 56 to 92, or the kit of any one of embodiments 53 to 55, wherein the disease or disorder is multiple myeloma (MM).
  • Embodiment 96 is the method of embodiment 95, wherein the MM is relapsed and/or refractory MM, newly-diagnosed MM, transplant-ineligible MM, or transplant-ineligible newly- diagnosed MM.
  • Embodiment 97 is the kit of embodiment 95, wherein the MM is relapsed and/or refractory MM, newly-diagnosed MM, transplant-ineligible MM, or transplant-ineligible newly- diagnosed MM.
  • Embodiment 98 is a method of treating cancer in a patient, wherein the patient has a Grade 1 corneal adverse reaction resulting from belantamab mafadotin administration, the method comprising temporarily discontinuing administration of belantamab mafadotin; administering to the patient a therapeutically effective amount of belantamab for a lead-in period; and resuming administration of belantamab mafadotin after the lead-in period.
  • Embodiment 99 is a method of treating cancer in a patient, wherein the patient has a Grade 2 or above corneal adverse reaction resulting from belantamab mafodotin administration, the method comprising temporarily discontinuing administration of belantamab mafadotin; administering to the patient a therapeutically effective amount of belantamab I Ifor a lead-in period; and resuming administration of belantamab mafadotin after the lead-in period.
  • Example 1 In Vivo Efficacy of Belantamab in the Treatment of Subcutaneous NCI-H929 Human Multiple Myeloma Model in NOD/SCID Mice.
  • NCI-H929 tumor cells were maintained in vitro with RPMI1640 medium supplemented with 10% fetal bovine serum and 0.05mM 0-ME at 37°C in an atmosphere of 5% C0 2 in air. Cells in an exponential growth phase were harvested and counted for tumor inoculation. Each mouse was inoculated subcutaneously in the right front flank region with NCI-H929 tumor cells (5x 10 6 ) in 0.1 ml of PBS mixed with matrigel (1: 1) for tumor development. The randomization started when the mean tumor size reached 121 mm 3 . 80 mice were enrolled in the study. All animals were randomly allocated to 8 study groups.
  • Randomization was performed based on “Matched distribution” method (Study DirectorTM software, version 3.1.399.19) randomized block design. The date of randomization was denoted as day 0. The treatment was initiated on the same day of randomization (day 0) per study design.
  • the survival time was analyzed by Kaplan-Meier method.
  • the event of interest was the animal death.
  • the survival time was defined as the time from the day of randomization to the day when the tumor volume reached to 2500 mm 3 .
  • MST median survival time
  • ILS increased in life-span
  • the Kaplan-Meier curves was constructed for each group and the log-rank test was used to compare survival curves between groups. All data were analyzed using SPSS 18.0. P ⁇ 0.05 was considered to be statistically significant.
  • Results The tumor volume analysis showed that GSK2857916 at 4 mg/kg and GSK2857914 at 8 mg/kg as the single agent or in combination with different dosing schedules (G2-G8) demonstrated significant anti-tumor efficacy in NCLH929 Xenograft model compared with vehicle (Gl).
  • GSK2857916 in combination with GSK2857914 (G4 and G6) showed significant improved anti-tumor efficacy compared with the single agent of GSK2857916 (G2).
  • the tumor volume growth curves between randomization grouping and study termination are shown in FIG. 1.
  • Tumor growth inhibition (TGI) from data collected on day 24 is provided in Table 5.
  • GSK2857916 at 4 mg/kg and GSK2857914 at 8 mg/kg as the single agent or in combination with different dosing schedules significantly increased the life-span of mice in NCI-H929 Xenograft model compared with vehicle (Gl).
  • GSK2857916 in combination with GSK2857914 (G4 and G6) could further increase the life-span of mice compared with the single agent of GSK2857916 (G2).
  • Kaplan-Meier survival curves for all treatment groups as a function of study day are shown in FIG. 2. Median survival day for mice in each group is provided in Table 6.
  • Example 2 Phase 1/2 Study to Evaluate the Safety and Efficacy of Belantamab in Multiple Myeloma .
  • Part 1 is a Phase 1 open-label study evaluating the safety, tolerability, and clinical activity of escalating doses of single agent belantamab in participants with RRMM who have received at least 3 prior lines of treatment to determine the recommended part 2 dose.
  • Belantamab is dosed twice a cycle on Days 1 and 15 of a 28-day cycle, starting at a dose of 300 mg IV.
  • Dose escalation is guided by modified toxicity probability interval to 900 mg and then to the maximum dose of 2000 mg according to a dose escalation plan and as directed by a dose escalation committee.
  • the exploration of an additional intermediate dose is allowed if suggested by the dose escalation committee and agreed upon by the Medical Monitor and treating investigators.
  • the progression from one dose level to another and the recommended Part 2 doses are based on the totality of available data from Part 1 of belantamab treatment; the dose escalation committee takes into consideration, in particular, the safety and tolerability of each dose level, available PK and PD data and preliminary efficacy to recommend two dose levels to further characterize in Part 2.
  • Participants are dosed until progressive disease (PD) after which they have the option to receive treatment with single agent belantamab mafodotin (Part IB) at 2.5 mg/kg Q3W.
  • Participants who opt to be treated with belantamab mafodotin following the first PD proceed with an end of treatment (EOT) visit before starting belantamab mafodotin treatment, and then continue to be monitored for safety, tolerability and disease response during belantamab mafodotin treatment until the next PD.
  • EOT end of treatment
  • Participants who opt out of belantamab mafodotin treatment after the first PD terminate the treatment and proceed with the EOT visit and follow-up safety monitoring.
  • the belantamab treatment duration is until first PD (followed by optional belantamab mafodotin treatment until second PD), unacceptable toxicity, or any other treatment termination criteria.
  • the treatment duration could be up to approximately 8 months.
  • the visit frequency is every 2 weeks from Cycle 3 forward. More visits are scheduled in Cycles 1 and 2.
  • Part 2 is a 2-arm safety run-in randomized, open-label study evaluating the safety, tolerability, and clinical activity of 1 cycle of belantamab mafodotin-xRd (belantamab mafodotin, treatment x, lenalidomide, and dexamethasone) followed by continuous treatment with belantamab-xRd (belantamab, treatment x, lenalidomide, and dexamethasone) in participants with recurrent MM who have received at least 1 prior line of treatment (2L+).
  • belantamab mafodotin-xRd belantamab mafodotin, treatment x, lenalidomide, and dexamethasone
  • treatment x includes, but is not limited to, a combination of an anti-CD38 antibody such as daratumumab or isatuximab) and a gamma secretase inhibitor such as nirogacestat. In some cases, treatment x includes, but is not limited to, a proteasome inhibitor such as bortezomib.
  • the combination treatment xRd includes lenalidomide (R) and dexamethasone (d).
  • the selection of treatment x is based on data from on-going belantamab mafodotin clinical studies and is either a standard of care or an emerging treatment for MM.
  • the belantamab doses are based on the totality of available Part 1 data. Two different dose levels of belantamab (Arms A and B) are dosed every 4 weeks. More frequent dosing is used if justified by Part 1 data based on safety, tolerability, PK/PD modelling or other data.
  • Part 2 of the study assesses overall safety events and tolerability and corneal adverse events for 10 parti cipants/ Arm after 3 cycles of treatment. Participants are considered evaluable for safety and tolerability if they have completed at least 3 cycles of treatment including one cycle of belantamab mafodotin-xRd followed by 2 cycles of belantamab-xRd. Participants not meeting the definition of evaluable may be replaced if they withdraw for reason other than treatment related adverse event, death or PD. The totality of data from Part 1 and Part 2 are used to determine the belantamab recommended Phase 2 dose(s) to be used in Part 3.
  • the treatment duration is until PD, unacceptable toxicity, or any other treatment termination criteria.
  • the treatment duration could be up to approximately 15 months.
  • the visit frequency is every 4 weeks from Cycle 3 unless data from Part 1 and from on-going belantamab mafodotin clinical trials suggest more frequent dosing with administration of belantamab-xRd. More visits are planned during Cycles 1 and 2.
  • Part 3 is a 4-arm Phase 2 randomized, open-label study evaluating the safety and efficacy of continuous belantamab-xRd following treatment with 1 cycle of belantamab mafodotin-xRd in participants with TI-NDMM. Cycle length is 4 weeks. Two different doses of belantamab (Arms A and B) are dosed every 4 weeks. The belantamab dose levels are selected based on the totality of available data from Parts 1 and 2 and may be different to the ones administered in Part 2; the selection process by the dose escalation committee takes into consideration the overall safety and tolerability of the combination, available PK/PD data and evidence of efficacy of the different dose levels.
  • belantamab mafodotin and xRd doses are the same in Arms A and B: a single dose of belantamab mafodotin at 1.4 mg/kg administered in combination with treatment x, lenalidomide at 25 or 10 mg once daily (on days 1-21 of the cycle), and dexamethasone at 40 mg once daily (on days 1, 8, 15, and 22 of the cycle) (or 20 mg if age ⁇ 75 years or BMI ⁇ 18.5).
  • Part 3 also tests the outcome of: 1) treatment with continuous dosing of belantamab mafodotin-xRd (Arm C), and 2) treatment with a continuous dosing of belantamab-xRd in absence of the belantamab mafodotin-xRd initial dose (Arm D).
  • belantamab mafodotin is dosed once every two 28-days cycles (Q8W) at a dose of 1.4 mg/kg in combination with treatment x, lenalidomide at 25 or 10 mg once daily (on days 1-21 of the cycle), and dexamethasone at 40 mg once daily (on days 1, 8, 15, and 22 of the cycle) (or 20 mg if age ⁇ 75 years or BMI ⁇ 18.5).
  • belantamab is administered once per 28-day cycle in combination with treatment x, lenalidomide at 25 or 10 mg once daily (on days 1-21 of the cycle), and dexamethasone at 40 mg once daily (on days 1, 8, 15, and 22 of the cycle) (or 20 mg if age ⁇ 75 years or BMI ⁇ 18.5).
  • participant A or B or C or D are randomised 1 : 1 : 1 : 1 to either Arm A or B or C or D with the aim to obtain data on 20 evaluable participants per arm. Participants are considered evaluable if they have completed at least 4 cycles of treatment, including one cycle of belantamab mafodotin-xRd followed by 3 cycles of belantamab-xRd. Participants not meeting the definition of evaluable may be replaced if they withdraw for reason other than treatment related adverse event, death or disease progression.
  • the xRd doses are the same in all four arms of the study, while the belantamab mafodotin and belantamab doses and dosing frequencies may differ in Arm C and Arm D, respectively, compared to the ones in Arms A and B.
  • the study terminates 18 months after last subject first dose. At that time, data collection for all recruited participants who no longer receive study treatment stops and the clinical trial database is closed. If the disease has not progressed at time of study termination, participants who continue benefitting by the treatment as suggested by the investigator are transferred in a post- analysis-continual-treatment study to continue receiving treatment. Under these circumstances, the
  • the visit frequency is every 4 weeks starting from Cycle 3, unless data from Parts 1 and 2 and from on-going belantamab mafodotin clinical trials suggest more frequent dosing with belantamab-xRd. More visits are planned during Cycles 1 and 2.
  • a standard of care (SoC) treatment or emerging MM treatment is also administered as provided in Table 8.
  • the infusion duration may be adjusted to 30-60 mins.
  • Premedication e.g., systemic corticosteroids
  • Premedication is not required unless deemed medically necessary by the investigator, in which case it should be administered according to institutional recommendations.
  • Infusions may be prolonged in the event of an infusion reaction. If multiple participants experience clinically significant infusion reactions, the infusion rate may be slowed for all future administrations of study treatment for all participants. Should this global change in infusion rate be required, it will be communicated to the sites in writing.
  • Part 3 Arm C continuous belantamab mafodotin is administered 1.4 mg/kg Q8W, and based on emerging data from ongoing belantamab mafodotin trials, the dose level may be increased to 1.9 mg/kg Q8W unless data supports more frequent administration.
  • the initial dose(s) match Parts A and B with the ongoing dose selected based on considerations of data from other studies and clinical experience with belantamab mafodotin.
  • Lenalidomide is administered as 25 mg PO daily on days 1-21 of each 28-day cycle, in participants with CLcr of >60 mL/min (by Cockcroft-Gault). The dose of lenalidomide will be reduced to 10 mg daily on Days 1 to 21 in participants with CLcr of 30-60 mL/min. Lenalidomide is administered at a fixed dose level, with no adjustments needed for body weight or BSA.
  • lenalidomide On lenalidomide and belantamab/belantamab mafodotin co-administration days, lenalidomide should be administered as close as possible to the end of the 1-2 hours rest period after administration of belantamab/belantamab mafodotin, and on PK days no later than 6 hours after the end of the rest period after administration of belantamab/belantamab mafodotin.
  • Dexamethasone will be given at 40 mg (or 20 mg if age ⁇ 75 years or BMI ⁇ 18.5 kg/m 2 ) weekly PO on Days 1, 8, 15 and 22 of each cycle.
  • Part 1 Participants who have received at least 3 prior lines of anti-myeloma treatments, and have already received an immunomodulating agent, a proteasome inhibitor, and an anti-CD38 mAb (unless contraindicated or unavailable). Lines of therapy are defined by consensus panel of the International Myeloma Workshop.
  • Part 2 Participants who meet all of the following: (1) have undergone autologous stem cell transplant (ASCT) or are considered transplant ineligible; (2) have been previously treated with at least one prior line of MM therapy; (3) have documented disease progression during or after their most recent therapy.
  • ASCT autologous stem cell transplant
  • Part 3 Participants who meet both of the following: (1) NDMM with a requirement for treatment as documented per IMWG criteria; and (2) not considered a candidate for high dose chemotherapy with ASCT due to: (a) Age 65 years; or (b) age 18-65 years with presence of comorbid condition(s) likely to have a negative impact on tolerability of high-dose chemotherapy with ASCT or who refuse high-dose chemotherapy with ASCT as an initial treatment.
  • [00392] 4. Eastern cooperative oncology group-performance status (ECOG-PS) of 0-2. [00393] 5. Measurable disease defined as at least ONE of the following: (a) serum M-protein concentration 0.5 g/dL ( ⁇ 5 g/L); (b) urine M-protein excretion -'200 mg/24 hours ( '0.2 g/24 hours); or (c) serum free light chain (FLC) assay: involved FLC level ⁇ 10 mg/dL ( ' 100 mg/L) and an abnormal serum FLC ratio ( ⁇ 0.26 or >1.65).
  • FLC serum free light chain
  • Laboratory results obtained during screening should be used to determine eligibility criteria. In situations where laboratory results are outside the permitted range, the investigator may re-test the participant and the subsequent within range screening result may be used to confirm eligibility.
  • Grade ⁇ 1 at the time of screening except for alopecia any grade
  • neuropathy Grade ⁇ 2
  • endocrinopathy managed with replacement therapy any grade
  • Participant is exhibiting signs of meningeal or central nervous system involvement with MM.
  • Evidence of cardiovascular risk including any of the following: (a) Evidence of current clinically significant untreated arrhythmias, including, but not limited to, clinically significant ECG abnormalities such as 2nd degree (Mobiz Type II) or 3rd degree AV block; (b) QTcF interval >450 msec (QT interval corrected for heart rate according to Fridericia’s formula), and/or hypokalemia, and/or family history of long QT syndrome (for Part 1); (c) History of MI, acute coronary syndromes (including unstable angina), coronary angioplasty, stenting or bypass grafting, all within three months of screening; (d) Class III or IV heart failure as defined by the NYHA functional classification system; (e) Uncontrolled hypertension.
  • ECG abnormalities such as 2nd degree (Mobiz Type II) or 3rd degree AV block
  • Part 1 and 2 Refractory to belantamab mafodotin (confirmed PD as per IMWG criteria while on belantamab mafodotin therapy or within 60 days of completing that treatment). Prior belantamab mafodotin is allowed if it was discontinued due to toxicity which subsequently resolved. Note: Prior treatment with other Anti-BCMA directed agents is allowed.
  • Part 1 and 2 Refractoriness to prior standard anti-myeloma therapies including lenalidomide is allowed for other mAbs within 30 days or systemic anti-myeloma therapy within 14 days of first dose of study drug.
  • Focal palliative radiation is permitted prior to enrolment, provided it occurred at least 2 weeks prior to the first dose of study intervention, that the participant has recovered from radiation-related toxicities, and that the participant did not require corticosteroids for radiation- induced AEs.
  • [00427] 25 Has received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including G-CSF, GMCSF, recombinant erythropoietin) or any thrombopoietin receptor agonists within 2 weeks before the first dose of study drug.
  • blood products including platelets or red blood cells
  • colony stimulating factors including G-CSF, GMCSF, recombinant erythropoietin
  • any thrombopoietin receptor agonists within 2 weeks before the first dose of study drug.
  • live vaccines include, but are not limited to the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid vaccine.
  • Seasonal influenza and COVID-19 vaccines for injection are not live or attenuated virus vaccines and are allowed; however, intranasal influenza vaccines (for example, FluMist) are live attenuated vaccines and are not allowed.
  • Lenalidomide capsules should be swallowed whole with water; the capsules should not be opened, broken, or chewed.
  • Lenalidomide should be taken orally at approximately the same time each day.
  • Lenalidomide capsules contain lactose. The risk-benefit of should be evaluated in participants with lactose intolerance.
  • Participants will abstain from ingesting caffeine- or xanthine- containing products (e.g., coffee, tea, cola drinks, and chocolate) for 24 hours before clinic visits on days scheduled for periodic PK and pharmacodynamic sample collection throughout the study.
  • caffeine- or xanthine- containing products e.g., coffee, tea, cola drinks, and chocolate
  • Dose modifications may be made for individual participants, based on safety findings for that participant. After Cycle 1, participants may have their belantamab or belantamab mafodotin dose reduced or delayed due to toxicities, including corneal events/toxicity. [00439] If a dose is delayed, the participant should wait for the next scheduled dose to resume treatment. In individual cases, where in the judgment of the investigator waiting a full cycle to resume treatment after delay (skipping dose) related to toxicity which has resolved would be detrimental to the participant’s health, the investigator should contact the Medical Monitor to discuss an earlier re-start. An earlier re-start may be considered only for participants who have recovered from toxicity to at most Grade 1.
  • Dosing delays are permitted in the case of medical/surgical events or for logistical reasons not related to study therapy (e.g., elective surgery, unrelated medical events, participant vacation, and/or holidays, but not for participants’ decision to delay treatment).
  • the reason for any dose delay must be documented in the participant’s eCRF and clinic record and discussed with the Medical Monitor.
  • Part 1 the decision to proceed to the next dose level of belantamab (either an increase or a decrease) will be made by the DEC based on safety, tolerability, and preliminary PK data obtained in participants at the prior dose level.
  • mice Female severe combined immunodeficient (SCID) mice were nine weeks old with a body weight range of 15.6 to 23.8 grams on Day 1 of the study.
  • H929 human plasmacytoma cell line was obtained from the American Type Culture Collection (ATCC). The cells were maintained as exponentially growing suspension cultures in RPMI 1640 medium supplemented with 20% fetal bovine serum, 2 mM glutamine, 50 pM mercaptoethanol, 100 units/mL sodium penicillin G, 100 pg/mL streptomycin sulfate, and 25 pg/mL gentamicin.
  • the tumor cells were cultured in tissue culture flasks in a humidified incubator at 37 °C, in an atmosphere of 5% CO2 and 95% air.
  • Example 4 Evaluation of soluble BCMA (sBCMA) levels in relapsed/refractory multiple myeloma (RRMM) patients treated with belantamab mafodotin
  • Soluble BCMA (sBCMA) levels were analyzed as an exploratory endpoint in patients enrolled in a phase III open-label randomized clinical trial evaluating the safety and efficacy of single agent belantamab mafodotin compared to a combination of pomalidomide dexamethasone in participants with RRMM (DREAMM-3 study; NCT04162210).
  • sBCMA Soluble BCMA
  • Serum samples were obtained from patients in both study arms at the following timepoints relative to belantamab mafodotin infusion: pre-dose, at end of infusion, 2 hours postinfusion, 24 hours post-infusion, 4 days post- infusion, and 8-15 days post- infusion.
  • sBCMA levels in cell supernatants were measured using a validated electrochemiluminescent immunoassay.
  • sBCMA levels are impacted by treatment with belantamab mafodotin.
  • Analysis of sBCMA levels in patients treated with belantamab mafodotin versus pom/dex demonstrated a difference in sBCMA levels between the two treatment arms with sBCMA levels being impacted specifically by belantamab mafodotin treatment compared to pom/dex treatment.
  • progression free survival (PFS) of patients in the highest quartile (Q4) of baseline sBCMA levels was the lowest in both treatment arms, indicating a worse response to treatment.
  • Belantamab mafodotin binds sBCMA in patient samples.
  • sBCMA levels were measured at the end of infusion (EOI) of belantamab mafodotin in participants in the belantamab mafodotin treatment arm.
  • EOI end of infusion
  • Patient samples were obtained within 30 minutes following the end of infusion of belantamab mafodotin and sBCMA levels in the samples were measured. Based on sBCMA levels detected at EOI, it was determined that belantamab mafodotin substantially bound all sBCMA in the periphery at a dose level of 2.5 mg/kg. See FIG.
  • sBCMA is immediately bound following belantamab mafodotin infusion, but sBCMA levels rebound 24 hours later.
  • sBCMA levels were detected to be increasing in participants treated with belantamab mafodotin at 24 hours post-end of infusion (EOI) of belantamab mafodotin. While a linear decrease in sBCMA levels was observed, an exponential increase in sBCMA levels was observed 24 hours later suggesting that sBCMA rebound is non-linear with baseline level of sBCMA and follows a different pattern than the decrease of sBCMA levels (FIG. 6).
  • sBCMA levels observed at 24 hours post-EOI is not due solely to dissociation of sBCMA from belantamab mafodotin because the half-life of sBCMA is approximately 24 hours suggesting that the majority of the increase in sBCMA levels is due to fresh shedding from tumor cells.
  • patients with progressive disease (PD) had the highest baseline sBCMA levels, but there was a large overlap observed in baseline sBCMA levels between responders and nonresponders (FIG. 7A).
  • Example 5 In Vivo Efficacy of Belantamab and Belantamab Mafodotin in the Treatment of Human Multiple Myeloma Xenograft Model in NOG Mice
  • MM.1 S-Luc cancer cells were maintained in vitro with RMPI1640 medium supplemented with 10% fetal bovine serum and 1% sodium pyruvate + 1% L-glutamine + 1% penicillin-streptomycin at 37°C in an atmosphere of 5% CO2. The cells in exponential growth phase were harvested and quantitated by cell counter before tumor inoculation.
  • Tumor inoculation Each mouse was inoculated intravenously via tail vein with MM.1S-Luc tumor cells (1 x 10 7 ) in 0.1 mL PBS for tumor development. Mice were imaged 7 days after tumor cell inoculation and randomly allocated to seven study groups.
  • mice were dosed by intraperitoneal (ip) administration in the amount and at the frequency and duration shown in Table 11.
  • Tumor monitoring Tumor growth was imaged twice per week by bioluminescent imaging. At 15 minutes prior to imaging, mice were injected subcutaneously with D-Luciferin (PerkinElmer, Catalog Number 122799) at 150 mg/kg. Mice were imaged on a PerkinElmer IVIS Lumina Series III in vivo imaging system.
  • GSK2857916 in combination with GSK2857914 (Groups 3 and 4) and GSK2857916 in combination with nirogacestat (Group 5) significantly prolonged animals’ survival (Median Survival Day 54.5, 58.00, and 53.50, respectively), compared with vehicle control group (Median Survival Day 25.00).

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Abstract

La divulgation concerne des méthodes de traitement d'une maladie ou d'un trouble sensible à l'inhibition ou au blocage de l'antigène de maturation des lymphocytes B (BCMA) par l'administration d'un ou de plusieurs antagonistes BCMA.
PCT/IB2023/062182 2022-12-05 2023-12-04 Méthodes de traitement au moyen d'antagonistes d'antigène de maturation des lymphocytes b WO2024121711A1 (fr)

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