Methods of treatment using b-cell maturation antigen antagonists

Abstract

The present disclosure provides methods of treating a disease or disorder responsive to inhibition or blocking of B cell maturation antigen (BCMA) by administering one or more BCMA antagonists.

Description

[0001] Cross - reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 430,249, filed on December 5, 2022, the entire content of which is incorporated herein by reference. Technical field

[0003] The present disclosure generally relates to methods of treating diseases or disorders responsive to inhibition or blockade of B - cell maturation antigen (BCMA) by administering one or more BCMA antagonists. Background art

[0004] B - cell maturation antigen (BCMA) is a cell - surface receptor that is expressed in the plasmablast lineage and is upregulated on multiple 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 10% of all hematological malignancies globally. Patients with newly diagnosed multiple myeloma (NDMM) have multiple available treatment options. Although almost 100% of patients respond to first - line treatment, the disease eventually recurs, and patients will require further treatment. For this malignancy, the duration of response and response rate decline dramatically with each subsequent line of treatment. Most patients with MM eventually become resistant to existing therapies and die from relapse.

[0005] Belantamab mafodotin is an antibody - drug conjugate (ADC) directed against BCMA conjugated to the microtubule - disrupting agent monomethyl auristatin - F (MMAF) and has been shown to have antitumor activity in MM cells. Belantamab mafodotin is produced in an afucosylated form, which enhances its interaction with the FcγRIIIa receptor. This enhanced interaction increases antibody - dependent cellular cytotoxicity (ADCC) and antibody - dependent cellular phagocytosis (ADCP) activities, including against MM cells. Thus, belantamab mafodotin has dual antitumor activity by delivering the MMAF cytotoxin as well as through ADCC / ADCP. Ocular toxicities have been reported for belantamab mafodotin and other MMAF - containing ADCs, leading to treatment delays and dose reductions. Therefore, there is a need for additional therapies with manageable toxicity for treating MM and other diseases associated with abnormal BCMA expression. Summary of the invention

[0006] In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) in a patient, the method comprising administering belantamab to the patient at a dose of from about 300 mg to about 2000 mg.

[0007] In one aspect, the present disclosure provides the use of belantamab in the treatment of a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA), by administering belantamab at a dose of from about 300 mg to about 2000 mg.

[0008] In one aspect, the present disclosure provides the use of belantamab in the manufacture of a medicament for the treatment of a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA), by administering belantamab at a dose of from about 300 mg to about 2000 mg.

[0009] In an embodiment, the dose is about 300 mg, about 900 mg or about 2000 mg. In an embodiment, the dose is administered at regular intervals for a period of time. In an embodiment, the dose is administered once every week ± 3 days to once every four weeks ± 3 days. In an embodiment, the dose is administered once every two weeks ± 3 days. In an embodiment, the dose is administered once every three weeks ± 3 days. In an embodiment, the dose is administered once every four weeks ± 3 days. In an embodiment, the dose is administered on day 1 and day 15 of a 28-day cycle. In an embodiment, the dose is administered on day 1 of a 21-day cycle.

[0010] In an embodiment, the patient has been treated with at least one prior line of cancer treatment. In an embodiment, the patient has been treated with one, two, three or four prior lines of cancer treatment. In an embodiment, the prior line of cancer treatment includes an anti-CD38 monoclonal antibody, a proteasome inhibitor and an immunomodulator.

[0011] In an embodiment, belantamab is administered by intravenous infusion or subcutaneous injection.

[0012] In an embodiment, the patient further receives at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulator, or an anti-PD-1 monoclonal antibody. In an embodiment, the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone. In an embodiment, 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 patient receives lenalidomide on days 1-21 of a 28-day cycle. 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 patient receives dexamethasone on days 1, 8, 15, and 22 of a 28-day cycle. In an embodiment, (i) the patient is less than 75 years of age and is receiving dexamethasone at a dose of 40 mg once weekly; or (ii) the patient is at least 75 years of age and is receiving dexamethasone at a dose of 20 mg once weekly. In an embodiment, (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.

[0013] In an embodiment, the method or use further comprises stopping the administration of belantamab and subsequently administering margetuximab. In an embodiment, the method or use further comprises administering margetuximab and subsequently stopping the administration of belantamab. In an embodiment, margetuximab is administered at a dose of 2.5 mg / kg once every three weeks ± 3 days.

[0014] In an embodiment, the method or use further comprises administering a priming dose of margetuximab prior to initiating the administration of belantamab, wherein the priming dose of margetuximab is from about 1.4 mg / kg to about 3.4 mg / kg once during the priming period. In an embodiment, the priming dose of margetuximab is from about 1.4 mg / kg to about 1.9 mg / kg once during the priming period. In an embodiment, the priming dose of margetuximab is about 1.4 mg / kg, about 1.9 mg / kg, about 2.5 mg / kg, or about 3.4 mg / kg once during the priming period. In an embodiment, the priming dose of margetuximab is about 1.4 mg / kg once during the priming period. In an embodiment, the priming period is four weeks ± 3 days and margetuximab is administered on day 1 of the priming period.

[0015] In an embodiment, the method or use further comprises administering to the patient at least one additional cancer treatment during an induction period, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulator, or an anti-PD-1 monoclonal antibody. In an embodiment, the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone. In an embodiment, 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, lenalidomide is administered to the patient on days 1-21 of the induction period. In an embodiment, lenalidomide is administered to the patient on days 1-21 of the induction period, and the induction period is 4 weeks ± 3 days. In an embodiment, lenalidomide is administered to the patient on days 1-21 of the induction period, and the induction period is 28 days. 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 a week. In an embodiment, dexamethasone is administered to the patient on days 1, 8, 15, and 22 of the induction period. In an embodiment, dexamethasone is administered to the patient on days 1, 8, 15, and 22 of the induction period, and the induction period is 4 weeks ± 3 days. In an embodiment, dexamethasone is administered to the patient on days 1, 8, 15, and 22 of the induction period, and the induction 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 a week; or (ii) the patient is at least 75 years old and dexamethasone is administered to the patient at a dose of 20 mg once a week. In an embodiment, (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 a week; 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 a week.

[0016] In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) in a patient, the method comprising administering to the patient mapatumumab at a dose of about 1.4 mg / kg to about 3.4 mg / kg, such as about 1.4 mg / kg to about 1.9 mg / kg, once every eight weeks ± 3 days.

[0017] In one aspect, the present disclosure provides the use of mapatumumab in the treatment of a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA), by administering mapatumumab at a dose of about 1.4 mg / kg to about 3.4 mg / kg, such as about 1.4 mg / kg to about 1.9 mg / kg, once every eight weeks ± 3 days.

[0018] In one aspect, the present disclosure provides the use of margetuximab in the preparation of a medicament for treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA), by administering margetuximab at a dose of about 1.4 mg / kg to about 3.4 mg / kg, such as about 1.4 mg / kg to about 1.9 mg / kg, once every eight weeks plus or minus 3 days.

[0019] In embodiments, 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 plus or minus 3 days. In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) in a patient, the method comprising administering to the patient a therapeutically effective amount of a combination comprising a first BCMA antagonist and a second BCMA antagonist.

[0020] In one aspect, the present disclosure provides the use of a combination comprising a first BCMA antagonist and a second BCMA antagonist in treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) in a patient.

[0021] In one aspect, the present disclosure provides the use of a combination comprising a first BCMA antagonist and a second BCMA antagonist in the preparation of a medicament for treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA).

[0022] In embodiments, the first and second BCMA antagonists are independently selected from anti-BCMA antibodies or antigen-binding fragments thereof, anti-BCMA antibody-drug conjugates, bispecific anti-BCMA antibodies or antigen-binding fragments thereof, and chimeric antigen receptor T (CAR T) cell therapies targeting BCMA. In embodiments, the first and second BCMA antagonists are independently selected from idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, REGN5458, margetuximab, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712. In embodiments, the first BCMA antagonist is margetuximab. In embodiments, the first BCMA antagonist is belantamab. In embodiments, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is the corresponding unconjugated anti-BCMA antibody. In embodiments, the anti-BCMA antibody-drug conjugates are selected from margetuximab, MEDI2228, and CC99712. In embodiments, the first BCMA antagonist is margetuximab and the second BCMA antagonist is belantamab.

[0023] In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) in a patient, the method comprising administering to the patient a therapeutically effective amount of a combination comprising margetuximab and belantamab.

[0024] In one aspect, the present disclosure provides the use of a combination comprising margetuximab and belantamab in the treatment of a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA).

[0025] In one aspect, the present disclosure provides the use of a combination comprising margetuximab and belantamab in the manufacture of a medicament for treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA).

[0026] In embodiments, the method or use further comprises administering to the patient at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulator, or an anti-PD-1 monoclonal antibody. In embodiments, the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

[0027] In one aspect, the present disclosure provides a kit comprising: (i) a first B cell maturation antigen (BCMA) antagonist; and (ii) instructions for treating a disease or disorder responsive to inhibition or blockade of BCMA when combined with a second BCMA antagonist.

[0028] In one aspect, the present disclosure provides a kit comprising: (i) margetuximab; and (ii) instructions for treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) when combined with belantamab.

[0029] In one aspect, the present disclosure provides a kit comprising: (i) belantamab; and (ii) instructions for treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) when combined with margetuximab.

[0030] In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) in a patient previously treated with a first BCMA antagonist, the method comprising administering to the patient a therapeutically effective amount of a second BCMA antagonist, wherein the patient discontinues administration of the first BCMA antagonist prior to initiation of administration of the second BCMA antagonist, and the second BCMA antagonist is different from the first BCMA antagonist.

[0031] In one aspect, the present disclosure provides the use of a second BCMA antagonist in treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) in a patient previously treated with a first BCMA antagonist, wherein the patient discontinues administration of the first BCMA antagonist prior to initiation of administration of the second BCMA antagonist, and the second BCMA antagonist is different from the first BCMA antagonist.

[0032] In one aspect, the present disclosure provides the use of a second BCMA antagonist in the manufacture of a medicament for treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) in a patient previously treated with a first BCMA antagonist, wherein the patient discontinues administration of the first BCMA antagonist prior to initiation of administration of the second BCMA antagonist, and the second BCMA antagonist is different from the first BCMA antagonist.

[0033] In embodiments, the first and second BCMA antagonists are independently selected from anti-BCMA antibodies or antigen-binding fragments thereof, anti-BCMA antibody-drug conjugates, bispecific anti-BCMA antibodies or antigen-binding fragments thereof, and chimeric antigen receptor T (CAR T) cell therapies targeting BCMA. In embodiments, the first and second BCMA antagonists are independently selected from idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, REGN5458, margetuximab, belantamab mafodotin, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712. In embodiments, the first BCMA antagonist is margetuximab. In embodiments, the first BCMA antagonist is belantamab mafodotin. In embodiments, the second BCMA antagonist is margetuximab. In embodiments, the second BCMA antagonist is belantamab mafodotin. In embodiments, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is the corresponding unconjugated anti-BCMA antibody. In embodiments, the anti-BCMA antibody-drug conjugates are selected from margetuximab, MEDI2228, and CC99712. In embodiments, the first BCMA antagonist is margetuximab and the second BCMA antagonist is belantamab mafodotin. In embodiments, the second BCMA antagonist is an anti-BCMA antibody-drug conjugate and the first BCMA antagonist is the corresponding unconjugated anti-BCMA antibody. In embodiments, the anti-BCMA antibody-drug conjugates are selected from margetuximab, MEDI2228, and CC99712. In embodiments, the second BCMA antagonist is margetuximab and the first BCMA antagonist is belantamab mafodotin.

[0034] In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) in a patient previously treated with margetuximab, the method comprising administering to the patient a therapeutically effective amount of belantamab mafodotin, wherein the patient discontinues administration of margetuximab prior to initiation of administration of belantamab mafodotin.

[0035] In one aspect, the present disclosure provides the use of belantamab mafodotin in treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) in a patient previously treated with margetuximab, wherein administration of margetuximab is discontinued prior to initiation of administration of belantamab mafodotin.

[0036] In one aspect, the present disclosure provides the use of belantamab mafodotin for the manufacture of a medicament for treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) in a patient previously treated with margetuximab, wherein administration of margetuximab is discontinued prior to initiation of administration of belantamab mafodotin.

[0037] In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibition or blockade of B-cell maturation antigen (BCMA) in a patient previously treated with belantamab mafodotin, the method comprising administering to the patient a therapeutically effective amount of margetuximab, wherein the patient discontinues administration of belantamab mafodotin prior to initiating administration of margetuximab.

[0038] In one aspect, the present disclosure provides the use of margetuximab in treating a disease or disorder responsive to inhibition or blockade of B-cell maturation antigen (BCMA) in a patient previously treated with belantamab mafodotin, wherein administration of belantamab mafodotin is discontinued prior to initiating administration of margetuximab.

[0039] In one aspect, the present disclosure provides the use of margetuximab in the manufacture of a medicament for treating a disease or disorder responsive to inhibition or blockade of B-cell maturation antigen (BCMA) in a patient previously treated with belantamab mafodotin, wherein administration of belantamab mafodotin is discontinued prior to initiating administration of margetuximab.

[0040] In embodiments, the method or use further comprises administering to the patient at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulator, or an anti-PD-1 monoclonal antibody. In embodiments, the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

[0041] In one aspect, the present 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 to the patient a therapeutically effective amount of a second BCMA antagonist, wherein the patient discontinues administration of the first BCMA antagonist prior to initiating administration of the second BCMA antagonist, and the second BCMA antagonist is different from the first BCMA antagonist.

[0042] In one aspect, the present disclosure provides the use of a second BCMA antagonist for reducing corneal toxicity in a patient previously treated with a first B-cell maturation antigen (BCMA) antagonist, wherein the patient discontinues administration of the first BCMA antagonist prior to initiating administration of the second BCMA antagonist, and the second BCMA antagonist is different from the first BCMA antagonist.

[0043] In one aspect, the present disclosure provides the use of a second BCMA antagonist in the preparation of a medicament for reducing corneal toxicity in a patient previously treated with a first B cell maturation antigen (BCMA) antagonist, wherein administration of the first BCMA antagonist is stopped before initiating administration of the second BCMA antagonist, and the second BCMA antagonist is different from the first BCMA antagonist.

[0044] In embodiments, the first and second BCMA antagonists are independently selected from anti-BCMA antibodies or antigen-binding fragments thereof, anti-BCMA antibody-drug conjugates, bispecific anti-BCMA antibodies or antigen-binding fragments thereof, and chimeric antigen receptor T (CAR T) cell therapies targeting BCMA. In embodiments, the first and second BCMA antagonists are independently selected from axicabtagene ciloleucel, idecabtagene vicleucel, teclistamab, REGN5458, mabetuzumab, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712. In an embodiment, the first BCMA antagonist is mabetuzumab. In an embodiment, the first BCMA antagonist is belantamab. In an embodiment, the second BCMA antagonist is mabetuzumab. In an embodiment, the second BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is the corresponding unconjugated anti-BCMA antibody. In embodiments, the anti-BCMA antibody-drug conjugate is selected from mabetuzumab, MEDI2228, and CC99712. In an embodiment, the first BCMA antagonist is mabetuzumab and the second BCMA antagonist is belantamab. In an embodiment, the second BCMA antagonist is an anti-BCMA antibody-drug conjugate and the first BCMA antagonist is the corresponding unconjugated anti-BCMA antibody. In embodiments, the anti-BCMA antibody-drug conjugate is selected from mabetuzumab, MEDI2228, and CC99712. In an embodiment, the second BCMA antagonist is mabetuzumab and the first BCMA antagonist is belantamab.

[0045] In one aspect, the present disclosure provides a method for reducing corneal toxicity in a patient previously treated with mabetuzumab, the method comprising administering to the patient a therapeutically effective amount of belantamab, wherein the patient stops administering mabetuzumab before initiating administration of belantamab.

[0046] In one aspect, the present disclosure provides the use of belantamab for reducing corneal toxicity in a patient previously treated with mabetuzumab, wherein the patient stops administering mabetuzumab before initiating administration of belantamab.

[0047] In one aspect, the present disclosure provides the use of belantamab in the preparation of a medicament for reducing corneal toxicity in patients previously treated with margetuximab, wherein the patients discontinue the administration of margetuximab before starting the administration of belantamab.

[0048] In one aspect, the present disclosure provides a method for reducing corneal toxicity in patients previously treated with belantamab, the method comprising administering to the patients a therapeutically effective amount of margetuximab, wherein the patients discontinue the administration of belantamab before starting the administration of margetuximab.

[0049] In one aspect, the present disclosure provides the use of margetuximab for reducing corneal toxicity in patients previously treated with belantamab, wherein the patients discontinue the administration of belantamab before starting the administration of margetuximab.

[0050] In one aspect, the present disclosure provides the use of margetuximab in the preparation of a medicament for reducing corneal toxicity in patients previously treated with belantamab, wherein the patients discontinue the administration of belantamab before starting the administration of margetuximab.

[0051] In embodiments, the methods and uses further comprise administering to the patient at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulator, or an anti-PD-1 monoclonal antibody. In embodiments, the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

[0052] In one aspect, the present disclosure provides a method for 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.

[0053] In one aspect, the present disclosure provides the use of a combination comprising an antibody-drug conjugate and the corresponding unconjugated antibody in the treatment of a disease or disorder.

[0054] In one aspect, the present disclosure provides the use of a combination comprising an antibody-drug conjugate and the corresponding unconjugated antibody in the preparation of a medicament for treating a disease or disorder.

[0055] In one aspect, the present disclosure provides a method for treating a disease or disorder in a patient previously treated with an antibody-drug conjugate, the method comprising administering to the patient a therapeutically effective amount of the corresponding unconjugated antibody, wherein the patient discontinues the administration of the antibody-drug conjugate before starting the administration of the corresponding unconjugated antibody.

[0056] In one aspect, the present disclosure provides the use of an antibody in treating 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 has discontinued administration of the antibody-drug conjugate prior to initiation of administration of the corresponding unconjugated antibody.

[0057] In one aspect, the present disclosure provides the use of an antibody in the manufacture of a medicament for treating 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 has discontinued administration of the antibody-drug conjugate prior to initiation of administration of the corresponding unconjugated antibody.

[0058] In embodiments, 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, margetuximab, loncastuximab tesirine, tisotumab vedotin, moxetumomab pasudotox, MEDI2228 or CC99712.

[0059] In embodiments, the disease or disorder is a plasma cell disorder or a B cell disorder. In embodiments, the disease or disorder is a cancer expressing BCMA. In embodiments, the disease or disorder is multiple myeloma (MM). In embodiments, the MM is relapsed and / or refractory MM, newly diagnosed MM, MM unsuitable for transplantation or newly diagnosed MM unsuitable for transplantation. In embodiments, the MM is relapsed and / or refractory MM, newly diagnosed MM, MM unsuitable for transplantation or newly diagnosed MM unsuitable for transplantation.

[0060] In one aspect, the present disclosure provides a method of treating cancer in a patient who has a grade 1 corneal adverse reaction due to administration of margetuximab, the method comprising temporarily discontinuing administration of margetuximab; administering to the patient a therapeutically effective amount of belantamab during a lead-in period; and resuming administration of margetuximab after the lead-in period.

[0061] In one aspect, the present disclosure provides the use of belantamab in treating cancer in a patient, wherein the patient has a Grade 1 corneal adverse reaction due to administration of margetuximab, and wherein margetuximab is temporarily discontinued during the administration of belantamab for the duration of the induction period and then administration of margetuximab is resumed after the induction period.

[0062] In one aspect, the present disclosure provides the use of belantamab in the preparation of a medicament for treating cancer in a patient, wherein the patient has a Grade 1 corneal adverse reaction due to administration of margetuximab, and wherein margetuximab is temporarily discontinued during the administration of belantamab for the duration of the induction period and then administration of margetuximab is resumed after the induction period.

[0063] In one aspect, the present disclosure provides a method for treating cancer in a patient, wherein the patient has a Grade 2 or higher corneal adverse reaction due to administration of margetuximab, the method comprising temporarily discontinuing the administration of margetuximab; administering a therapeutically effective amount of belantamab to the patient for the duration of the induction period; and resuming the administration of margetuximab after the induction period.

[0064] In one aspect, the present disclosure provides the use of belantamab in treating cancer in a patient, wherein the patient has a Grade 2 or higher corneal adverse reaction due to administration of margetuximab, and wherein margetuximab is temporarily discontinued during the administration of belantamab for the duration of the induction period and then administration of margetuximab is resumed after the induction period.

[0065] In one aspect, the present disclosure provides the use of belantamab in the preparation of a medicament for treating cancer in a patient, wherein the patient has a Grade 2 or higher corneal adverse reaction due to administration of margetuximab, and wherein margetuximab is temporarily discontinued during the administration of belantamab for the duration of the induction period and then administration of margetuximab is resumed after the induction period.

[0066] It should be understood that any and all embodiments of the present disclosure may be combined with any other one or more embodiments to describe further and more preferred embodiments. It should also be understood that each individual element of a preferred embodiment is a preferred embodiment in its own right. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe further embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] Figure 1 is a graph depicting the tumor volume growth curves of all treatment groups as a function of the study day, as described in Example 1.

[0068] Figure 2 is a graph depicting the Kaplan-Meier survival curves of all treatment groups as a function of the study day, as described in Example 1.

[0069] Figure 3 It is a graph depicting tumor volume growth as a function of the study day at different drug-to-antibody ratios (DARs), as described in Example 3.

[0070] Figure 4 It is a chart depicting the progression-free survival of patients grouped according to their sBCMA levels in the margetuximab treatment arm (left) and the pom / dex treatment arm (right), as described in Example 4.

[0071] Figure 5 It is a graph depicting the reduction level of sBCMA from pre-treatment with margetuximab to the end of infusion (EOI) on Day 1 of Cycle 1 of margetuximab treatment, as described in Example 4.

[0072] Figure 6 It is a graph depicting the level of sBCMA 24 hours after the end of margetuximab infusion (EOI), as described in Example 4.

[0073] Figure 7A and 7B It is a graph depicting the sBCMA levels of patients grouped according to their response to treatment with margetuximab, as described in Example 4. Figure 7A shows the baseline sBCMA level before margetuximab administration; and Figure 7B shows the sBCMA level 24 hours after margetuximab EOI. CR = complete response; VGPR = very good partial response; PR = partial response; MR / SD = minimal response / disease stable; PD / NE = progressive disease / not evaluable.

[0074] Figure 8 It is a graph depicting the mean tumor volume curves of the vehicle control group and the treatment groups between randomization and study termination in an in vivo efficacy study of belantamab and margetuximab in human multiple myeloma xenograft NOG mice, as described in Example 5.

[0075] Figure 9 It is a graph showing the Kaplan-Meier survival curves of all treatment groups in human multiple myeloma xenograft NOG mice as a function of the study day in an in vivo efficacy study of belantamab and margetuximab, as described in Example 5. Detailed Description

[0076] Definitions

[0077] As used herein and in the claims, the term "comprising" encompasses "including" or "consisting of", e.g., a composition "comprising" X can consist solely of X or can include something additional, e.g., X + Y.

[0078] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Although any compositions and methods similar or equivalent to those described herein can be used in the practice or testing of the methods of this disclosure, exemplary compositions and methods are described herein. Any aspect and embodiment of the disclosure described herein can be combined. For example, the subject matter of any dependent or independent claim disclosed herein can be combined multiplicatively (e.g., one or more recitations from each dependent claim can be combined into a single claim based on the independent claim on which it depends).

[0079] The ranges provided herein include all values within the specified ranges as well as values near the endpoints of the specified ranges. The figures and tables of this disclosure also describe ranges and discrete values, which can constitute elements of any method and use disclosed herein.

[0080] The concentrations described herein are determined at ambient temperature and pressure. This can be, for example, at room temperature or the temperature and pressure within a specific portion of a process stream. Concentrations are preferably determined at standard conditions of 25 ºC and 1 bar pressure.

[0081] As used herein, the term "antigen-binding protein" refers to antibodies and other protein constructs, such as domains, that are capable of binding to an antigen.

[0082] As used herein, the term "antibody" refers to a molecule having immunoglobulin-like domains (e.g., IgG, IgM, IgA, IgD, or IgE), and includes monoclonal, recombinant, polyclonal, chimeric, human, humanized, multispecific antibodies (including bispecific antibodies) and heteroconjugate antibodies; single variable domains (e.g., domain antibodies (DAB)), antigen-binding antibody fragments, Fab, F(ab’)2, Fv, disulfide-linked Fv, single-chain Fv, disulfide-linked scFv, diabodies, tandabs, etc. and any modified versions of any of the foregoing (see Holliger and Hudson, Nature Biotechnology, 2005, Vol 23, No. 9, 1126-1136 for a summary of alternative "antibody" forms).

[0083] The terms full antibody, whole antibody, or intact antibody, which are used interchangeably herein, refer to a heterotetrameric glycoprotein having a molecular weight of approximately 150,000 daltons. An intact antibody consists of two identical heavy chains (HC) and two identical light chains (LC) linked by covalent disulfide bonds. This H2L2 structure folds to form three functional domains, which include two antigen-binding fragments (referred to as "Fab" fragments) and one "Fc" crystallizable fragment. The Fab fragment consists of the variable domains at the amino terminus (heavy chain variable (VH) or light chain variable (VL)) and the constant domains at the carboxyl terminus (CH1 (heavy chain) and CL (light chain)). The Fc fragment consists of two domains formed by dimerization of paired CH2 and CH3 regions. The Fc can initiate 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 different heavy chain amino acid sequences, which are designated μ, α, γ, ε, and δ, respectively, and each heavy chain can pair with a K or λ light chain. Most antibodies in serum belong to the IgG class, and there are four subtypes of human IgG (IgG1, IgG2, IgG3, and IgG4), which differ mainly in their hinge regions in terms of sequence.

[0084] Fully human antibodies can be obtained using a variety of methods, such as yeast-based libraries or transgenic animals (e.g., mice) capable of generating a human antibody repertoire. Yeast presenting human antibodies that bind to an antigen of interest can be selected using FACS (fluorescence-activated cell sorting)-based methods or by capture on beads using a labeled antigen. Transgenic animals that have been modified to express human immunoglobulin genes can be immunized with an antigen of interest, and antigen-specific human antibodies can be isolated using B cell sorting techniques. The desired properties of the human antibodies generated using these techniques, such as affinity, developability, and selectivity, can then be characterized.

[0085] Alternative antibody forms include alternative scaffolds, where one or more CDRs of an antigen-binding protein can be arranged onto a suitable non-immunoglobulin scaffold or framework, such as an affibody, SpA scaffold, LDL receptor class A domain, avimer (see, e.g., U.S. Patent Application Publication Nos. 2005 / 0053973, 2005 / 0089932, 2005 / 0164301), or EGF domain.

[0086] As used herein, the term "anti-BCMA antigen-binding protein" refers to antibodies and other protein constructs, such as domains, that are capable of binding BCMA. The terms "BCMA-binding protein" and "anti-BCMA antigen-binding protein" are used interchangeably herein.

[0087] The anti-BCMA antigen-binding proteins described herein can bind to human BCMA, which includes, for example, human BCMA having the amino acid sequence of GenBank accession number Q02223.2, or a gene encoding human BCMA having at least 90% homology or at least 90% identity thereto.

[0088] Exemplary anti-BCMA antigen-binding proteins and methods for their preparation are disclosed in International Publication No. WO2012 / 163805, the entire content of which is incorporated herein by reference. Other exemplary anti-BCMA antigen-binding proteins include those described in WO2016 / 014789, WO2016 / 090320, WO2016 / 090327, WO2016 / 020332, WO2016 / 079177, WO2014 / 122143, WO2014 / 122144, WO2017 / 021450, WO2016 / 014565, WO2014 / 068079, WO2015 / 166649, WO2015 / 158671, WO2015 / 052536, WO2014 / 140248, WO2013 / 072415, WO2013 / 072406, WO2014 / 089335, US2017 / 165373, WO2013 / 154760, WO2018 / 201051, and WO2017 / 051068, each of which is incorporated herein by reference in its entirety.

[0089] In some embodiments, the BCMA-binding proteins disclosed herein can be derived from rats, mice, primates (e.g., cynomolgus monkeys, Old World monkeys, or great apes), or humans. The BCMA-binding protein can be a human, humanized, or chimeric antibody. The BCMA-binding protein can comprise a constant region, which can be any isotype or subclass. The constant region can be an IgG isotype, such as IgG1, IgG2, IgG3, IgG4, or variants thereof. The BCMA-binding protein constant region can be IgG1.

[0090] Accordingly, BCMA-binding proteins are provided that 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. The CDRs can be modified by at least one amino acid substitution, deletion, or addition, wherein the variant antigen-binding protein substantially retains the biological properties of the unmodified protein, such as binding to the antigen.

[0091] In some embodiments, 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.

[0092] In some embodiments, 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.

[0093] In some embodiments, 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.

[0094] In some embodiments, 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). In some embodiments, 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 nr3833).

[0095] In some embodiments, the anti-BCMA antigen-binding protein is a CAR-T cell therapeutic agent.

[0096] In some embodiments, the anti-BCMA antigen-binding protein is used in an immunoconjugate. An "immunoconjugate" (which may be 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 cytotoxic agents, including chemotherapeutic agents, immunotherapeutic agents, growth inhibitors, toxins (e.g., protein toxins, such as enzymatically active toxins or fragments thereof from bacteria, fungi, plants, or animals), antiviral agents, radioisotopes (i.e., radiolabeled conjugates), antibiotics, or small interfering RNAs (siRNAs).

[0097] In some cases, the anti-BCMA antigen-binding protein can be an immunoconjugate having the following general formula structure:

[0098] ABP-((linker)n-Ctx)m

[0099] wherein

[0100] ABP is an antigen-binding protein

[0101] the linker is absent or is any cleavable or non-cleavable linker

[0102] Ctx is any cytotoxic agent described herein

[0103] n is 0, 1, 2, or 3, and

[0104] m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0105] Exemplary linkers can include 6-maleimidocaproyl (MC), maleimidopropionyl (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-1-carboxylate (SMCC), and N-succinimidyl (4-iodo-acetyl)aminobenzoate (SIAB).

[0106] In some cases, the anti-BCMA antigen-binding protein can be an immunoconjugate comprising a monoclonal antibody conjugated to MMAE or MMAF. In another embodiment, the anti-BCMA antigen-binding protein can be an immunoconjugate comprising a monoclonal antibody conjugated to MMAE or MMAF via an MC linker, as shown in the following structure:

[0107]

[0108]

[0109] Wherein "p" is the drug - antibody ratio (DAR) and is an integer from 1 to 8, such as 2, 4, 6, or 8.

[0110] In some cases, the anti - BCMA antigen - binding protein can be the antibody belantamab. In another embodiment, the anti - BCMA antigen - binding protein can be the immunoconjugate melflufen.

[0111] In some embodiments, the BCMA antagonist is a chimeric antigen receptor (CAR) - T cell therapy targeting BCMA. As used herein, the term "chimeric antigen receptor" ("CAR") refers to an engineered receptor composed of an extracellular antigen - binding domain (usually derived from a monoclonal antibody or its antigen - binding fragment, such as the VH domain and VL domain in scFv form), an optional spacer region, a transmembrane domain, and one or more intracellular effector domains. CAR is also referred to as a chimeric T - cell receptor or chimeric immunoreceptor (CIR). The CAR is genetically introduced into hematopoietic cells, such as T cells, to redirect the specificity of T cells to a desired cell - surface antigen, thereby generating a CAR - T therapeutic agent.

[0112] As used herein, the term "spacer region" refers to an oligopeptide or polypeptide having the function of connecting the transmembrane domain to the target - binding domain. This region can also be referred to as the "hinge region" or "stalk region". The size of the spacer region can vary according to the position of the target epitope to maintain a set distance (e.g., 14 nm) upon CAR:target binding.

[0113] As used herein, the term "transmembrane domain" refers to the part of the CAR molecule that crosses the cell membrane.

[0114] As used herein, the term "intracellular effector domain" (also referred to as the "signaling domain") refers to the domain in the CAR responsible for intracellular signaling after antigen - binding domain binding to the target. The intracellular effector domain is responsible for activating at least one normal effector function of the immune cell in which the CAR is expressed. For example, the effector function of a T cell can be cytolytic activity or helper activity including cytokine secretion.

[0115] Those skilled in the art should understand that the VH and / or VL domains disclosed herein can be incorporated into the CAR - T therapeutic agent in the form of scFv, for example.

[0116] "CDR" is defined as the amino acid sequences of the complementarity determining regions of an antigen-binding protein. These are the hypervariable regions of the immunoglobulin heavy and light chains. There are three heavy-chain CDRs and three light-chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. Thus, as used herein, "CDR" refers to all three heavy-chain CDRs, all three light-chain CDRs, all heavy and light-chain CDRs, or at least two CDRs.

[0117] In this specification, amino acid residues in the variable domain sequences and variable domain regions within a full-length antigen-binding sequence (such as within an antibody heavy-chain sequence or an antibody light-chain sequence) are numbered according to the Kabat numbering convention. Similarly, the terms "CDR", "CDRL1", "CDRL2", "CDRL3", "CDRH1", "CDRH2", "CDRH3" follow the Kabat numbering convention. For further information, see 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).

[0118] It will be apparent to those skilled in the art that there are alternative numbering conventions for amino acid residues in variable domain sequences and full-length antibody sequences. There are also alternative numbering conventions for CDR sequences, such as those presented by Chothia et al. (1989) Nature 342: 877-883. The structure and protein folding of an antigen-binding protein can mean that other residues are considered part of the CDR sequence, and those skilled in the art will understand this to be the case.

[0119] Other numbering conventions for CDR sequences available to those skilled in the art include the "AbM" (University of Bath) and "contact" (University College London) methods.

[0120] Table 1 below shows a definition for each CDR or binding unit using each numbering convention. It should be noted that some CDR definitions may vary depending on the individual publications used.

[0121] Table 1

[0122]

[0123] 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 an antigen-binding fragment thereof) conjugated to one or more drugs, such as cytotoxic agents, e.g., chemotherapeutic agents, immunotherapeutic agents, growth inhibitors, toxins (e.g., protein toxins, e.g., enzymatically active toxins or fragments thereof from bacteria, fungi, plants, or animals), antiviral agents, radioisotopes (i.e., radiolabeled conjugates), antibiotics, or small interfering RNAs (siRNAs).

[0124] Immunoconjugates have been used for the local delivery of cytotoxic agents, i.e., drugs that kill or inhibit cell growth or proliferation (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 and Epenetos (1999) Anticancer Research 19:605-614; Niculescu-Duvazand Springer (1997) Adv. Drug Deliv. Rev. 26:151-172; U.S. Pat. No. 4,975,278). Immunoconjugates in particular allow for the targeted delivery of the drug moiety to tumors and its intracellular accumulation therein, where systemic administration of the unconjugated drug may result in unacceptable levels of toxicity to normal cells (Tsuchikama and An, Proteinand Cell, (2018) 9: 33–46). Compared to traditional chemotherapy, immunoconjugates are able to selectively deliver a potent cytotoxic payload to target cancer cells, thereby improving efficacy, reducing systemic toxicity, and achieving better pharmacokinetic (PK) / pharmacodynamic (PD) and biodistribution (Tsuchikama and An 2018); Beck A. et al. (2017) NatureRev. Drug Disc. 16: 315-337).

[0125] Polyclonal and monoclonal antibodies have been reported to be useful in these strategies (Rowland et al., (1986) Cancer Immunol. Immunother. 21:183-87). Drugs used in these methods include daunomycin, doxorubicin, methotrexate, and vindesine (Rowland et al., (1986) supra). Toxins used in antibody-toxin conjugates include bacterial toxins such as diphtheria toxin, plant toxins such as ricin, small molecule toxins such as geldanamycin (Mandler et al (2000) J. Nat. Cancer Inst. 92(19):1573-1581; Mandler et al (2000) Bioorganic& Med. Chem. Letters 10:1025-1028; Mandler et al (2002) Bioconjugate Chem. 13:786-791), maytansinoid (EP 1391213; Liu et al., (1996) Proc. Natl.Acad. Sci. USA 93:8618-8623), and calicheamicin (Lode et al (1998)Cancer Res. 58:2928; Hinman et al (1993) Cancer Res. 53:3336-3342).

[0126] In certain embodiments, the immunoconjugate comprises an antigen-binding protein (such as an antibody) and a drug (such as a toxin, such as a chemotherapeutic agent). The drug can be modified (e.g., via standard synthetic chemistry) to permit its chemical attachment (e.g., containing a reactive handle to permit its chemical attachment) to the reactive end of a linker that attaches the drug to the antigen-binding protein.

[0127] Drugs for generating immunoconjugates, such as chemotherapeutic agents, are described herein. Enzymatically active toxins and fragments thereof that can be used include diphtheria toxin A chain, non-binding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, viscumin, saporin, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica inhibitor, bryodin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and tricothecene. See, e.g., WO 93 / 21232, published Oct. 28, 1993.

[0128] In addition to toxins, radioactive substances (such as radioactive nucleotides) can also be used as drugs in ADCs. A variety of radioactive nucleotides can be used to produce radioactively conjugated antibodies. Examples include 212Bi, 131I, 131In, 90Y, and 186Re.

[0129] An antigen-binding protein (such as an antibody) can also be conjugated with one or more toxins, including but not limited to calicheamicin, maytansinoids, dolastatin, auristatin, trichothecene, and CC1065, as well as derivatives of these toxins having toxin activity. Suitable cytotoxic agents include but are not limited to auristatin, including valine-valine-dolaisoleucine-dolaproine-phenylalanine (MMAF) and monomethyl auristatin E (MMAE) and the ester form of MMAE, DNA minor groove binders, DNA minor groove alkylating agents, enediynes, lexitropsin, duocarmycin, taxanes (such as paclitaxel and docetaxel), puromycin, dolastatin, maytansinoids, vinca alkaloids. Specific cytotoxic agents include topotecan, morpholino-doxorubicin, rhizoxin, cyanomorpholino-doxorubicin, dolastatin-10, echinosporin, combretatstatin, calicheamicin, maytansine, DM-1, DM-4, and netropsin. Other suitable cytotoxic agents include antimicrotubule agents, such as auristatin, vinca alkaloids, podophyllotoxin, taxanes, baccatin derivatives, cryptophysin, maytansinoids, combretastatin, or dolastatin. Antimicrotubule agents include dimethylvaline-valine-dolaisoleucine-dolaproine-phenylalanine-p-phenylenediamine (AFP), MMAF, MMAE, auristatin E, vincristine, vinblastine, vindesine, vinorelbine, VP-16, camptothecin, paclitaxel, docetaxel, epothilone A, epothilone B, nocodazole, colchicine, colcimid, estramustine, simadotin, discodermolide, maytansine, DM-1, DM-4, and acanthifolicin.

[0130] Antibody-drug conjugates can be prepared by conjugating an anti-tubulin agent, monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF), to an antigen-binding protein such as an antibody. In the case of MMAE, the linker can consist of a thiol-reactive maleimide, a hexanoyl spacer, a dipeptide valine-citrulline, or a carbobenzoxy (self-immolative) fragmentation group. In the case of MMAF, a protease-resistant maleimidocaproyl linker can be used. The conjugation process results in heterogeneity in the drug-antibody linkage, differing both in the number of drugs bound to each antibody molecule (drug-antibody ratio [DAR]) and the site of linkage. The most prevalent species is the material with DAR = 4; materials with DARs of 0, 2, 6, and 8 are less common. The overall average drug-to-antibody ratio (DAR) is approximately 4.

[0131] As used herein, the terms "progression" or "progressive disease" ("PD") of tumor growth with respect to a cancer status indicate an increase in the sum of the diameters of the target lesions (tumors). In some embodiments, progressive disease is measured and defined according to the 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.). In some embodiments, tumor growth progression refers to an increase in the sum of the diameters of the target lesions of at least 20%, with reference to the smallest sum in the study (which includes the baseline sum if that sum is the smallest in the study). In some embodiments, in addition to the 20% relative increase, the sum of the diameters of the target lesions must also exhibit an absolute increase of at least 5 mm. The appearance of one or more new lesions can also be considered as a factor in determining tumor growth progression.

[0132] As used herein, "about" means ±10% of a specified value.

[0133] As used herein, "treatment" refers to alleviating one or more symptoms associated with a disorder and / or slowing the progression of the disorder. For example, in some embodiments, the disclosed therapies reduce ocular toxicity. "Ocular toxicity" refers to any unplanned exposure of a therapeutic agent to ocular tissue and includes changes in the corneal epithelium, dry eye, irritation, redness, blurred vision, dry eye, photophobia, and / or changes in vision. Detection of ocular toxicity can be determined by an ophthalmologist or optometrist through an eye examination before, during, and / or after treatment.

[0134] The eye examination may include one or more of the following:

[0135] 1. Best corrected visual acuity,

[0136] 2. Record of manifest refraction and the method used to obtain best corrected visual acuity,

[0137] 3. Current glasses prescription (if applicable),

[0138] 4. Tonometry,

[0139] 5. Anterior segment (slit lamp) examination, including corneal fluorescein staining and lens examination,

[0140] 6. Dilated fundus examination, and / or

[0141] 7. Ocular Surface Disease Index (OSDI), which is a visual function questionnaire that assesses the impact of potential ocular changes in vision on function and health-related quality of life.

[0142] Treatment methods using belantamab mafodotin

[0143] Described herein are methods of treating a disease or disorder in a patient who would benefit from inhibition or blockade of B-cell maturation antigen (BCMA). Also described is the use of BCMA inhibition or blockade therapy in treating a disease or disorder in a patient. In one aspect, the present disclosure provides a method of treating a disease or disorder in a patient responsive to inhibition or blockade of B-cell maturation antigen (BCMA), the method comprising administering belantamab to the patient. Belantamab is the non-conjugated monoclonal antibody component of margetuximab that targets BCMA and thus lacks the cytotoxic payload of margetuximab.

[0144] In an embodiment, belantamab is administered at a dose of from about 300 mg to about 2000 mg. In an embodiment, belantamab is administered at a dose of from about 300 mg to about 900 mg. In an embodiment, belantamab is administered at a dose of from 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.

[0145] In an embodiment, the dose of belantamab is administered at regular intervals 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 a week ± 3 days, once a week ± 3 days to once every 8 weeks ± 3 days, once a week ± 3 days to once every 6 weeks ± 3 days, once a week ± 3 days to once every 4 weeks ± 3 days, once a week ± 3 days to once every 3 weeks ± 3 days, once a 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 days, and / or once every 7 weeks ± 3 days to once every 8 weeks ± 3 days. In an embodiment, the period of time is until progressive disease occurs.

[0146] In an embodiment, 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 a week ± 3 days, once a week ± 3 days to once every 8 weeks ± 3 days, once a week ± 3 days to once every 6 weeks ± 3 days, once a week ± 3 days to once every 4 weeks ± 3 days, once a week ± 3 days to once every 3 weeks ± 3 days, once a 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 days, and / or once every 7 weeks ± 3 days to once every 8 weeks ± 3 days. In an embodiment, the dose of belantamab is administered once a 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.

[0147] In an embodiment, the dose of belantamab is administered parenterally, i.e., subcutaneously (s.c. or SC), intrathecally, intraperitoneally, intramuscularly (i.m. or IM), or intravenously (i.v. or IV), including administration by intravenous infusion. In an embodiment, the dose of belantamab is administered intravenously. In an embodiment, the dose of belantamab is administered by intravenous infusion. In an embodiment, the dose of belantamab is administered subcutaneously.

[0148] In an embodiment, belantamab is administered as a first-line treatment for a disease or disorder. In an embodiment, belantamab is administered after one or more prior lines of treatment for a disease or disorder. In an embodiment, belantamab is administered after 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 a disease or disorder. In an embodiment, belantamab is administered as a first-line 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, at least 2 prior lines of cancer treatment, at least 3 prior lines of cancer treatment, at least 4 prior lines of cancer treatment, 1 to 4 prior lines of cancer treatment, 2 to 4 prior lines of cancer treatment, 1 to 2 prior lines of cancer treatment, 2 to 3 prior lines of cancer treatment, 3 to 4 prior lines of cancer treatment, 1 prior line of cancer treatment, 2 prior lines of cancer treatment, 3 prior lines of cancer treatment, or 4 prior lines of cancer treatment. In an embodiment, 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.

[0149] In an embodiment, the patient has relapsed or refractory multiple myeloma and has previously received at least four prior therapies to treat the multiple myeloma.

[0150] In an embodiment, prior lines of cancer treatment are selected from anti-CD38 monoclonal antibodies, proteasome inhibitors, immunomodulators, or combinations thereof. For example, a patient who has had 0, 1, 2, 3, or 4 or more prior lines of treatment prior to treatment as described herein may have previously been treated with an immunomodulator (e.g., immunomodulatory imide drug (ImiD)), a proteasome inhibitor (PI), anti-CD38 treatment, or a combination thereof. In an embodiment, prior lines of cancer treatment include anti-CD38 monoclonal antibodies, proteasome inhibitors, and immunomodulators.

[0151] Examples of anti-CD38 antibodies that can be used 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®). In an embodiment, the anti-CD38 monoclonal antibody is selected from daratumumab or isatuximab.

[0152] Examples of proteasome inhibitors that can be used 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. In an embodiment, the proteasome inhibitor is selected from bortezomib, carfilzomib, or ixazomib. In an embodiment, the proteasome inhibitor is bortezomib.

[0153] Examples of immunomodulatory imide drugs (ImiDs) that can be used in the methods described herein include, but are not limited to, thalidomide (e.g., THALOMID®), lenalidomide (e.g., REVLIMID®), and pomalidomide (e.g., POMALYST®). In an embodiment, the immunomodulator is selected from thalidomide, lenalidomide, or pomalidomide. In an embodiment, the immunomodulator is lenalidomide or pomalidomide. In an embodiment, the immunomodulator is lenalidomide.

[0154] In an embodiment, belantamab is administered as a single therapy. In an embodiment, belantamab is administered in combination with at least one additional therapy. In an embodiment, belantamab is administered in combination with at least one additional cancer therapy. 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 days 1 and 15 of a 28-day treatment cycle. In an embodiment, belantamab is administered on day 1 of a 21-day treatment cycle.

[0155] In an embodiment, the additional cancer therapy is selected from an anti-CD38 monoclonal antibody, a gamma-secretase inhibitor, a proteasome inhibitor, an immunomodulator, or an anti-PD-1 monoclonal antibody.

[0156] Examples of anti-CD38 antibodies that can be used 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®). In an embodiment, the anti-CD38 monoclonal antibody is selected from daratumumab or isatuximab.

[0157] Examples of γ-secretase inhibitors that can be used 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.

[0158] Examples of proteasome inhibitors that can be used 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. In an embodiment, the proteasome inhibitor is selected from bortezomib, carfilzomib, or ixazomib. In an embodiment, the proteasome inhibitor is bortezomib.

[0159] Examples of immunomodulatory imide drugs (ImiD) that can be used in the methods described herein include, but are not limited to, thalidomide (e.g., THALOMID®), lenalidomide (e.g., REVLIMID®), and pomalidomide (e.g., POMALYST®). In an embodiment, the immunomodulator is selected from thalidomide, lenalidomide, or pomalidomide. In an embodiment, the immunomodulator is lenalidomide or pomalidomide. In an embodiment, the immunomodulator is lenalidomide. In an embodiment, the immunomodulator is pomalidomide.

[0160] Examples of anti-PD-1 monoclonal antibodies that can be used in the methods described herein include, but are not limited to, pembroluzimab and dostarlimab. In an embodiment, the anti-PD-1 monoclonal antibody is selected from pembroluzimab or dostarlimab.

[0161] Other additional cancer treatments include corticosteroids. Examples of corticosteroids include, but are not limited to, dexamethasone (e.g., DECADRON®, DEXASONE®, DIODEX®, HEXADROL®, MAXIDEX®), prednisone (e.g., DELTASONE®), and methylprednisolone (e.g., MEDROL®).

[0162] In embodiments, the additional cancer treatment is selected from lenalidomide, pomalidomide, dexamethasone, or combinations thereof. In embodiments, the additional cancer treatment is lenalidomide and dexamethasone. In embodiments, the additional cancer treatment is pomalidomide and dexamethasone. In embodiments, the additional cancer treatment is bortezomib and dexamethasone. In embodiments, the additional cancer treatment is pomalidomide, bortezomib, and dexamethasone. In embodiments, the additional cancer treatment is lenalidomide, bortezomib, and dexamethasone.

[0163] In embodiments, the additional cancer treatment is standard of care treatment.

[0164] In embodiments, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily for a period of time. In embodiments, the additional cancer treatment is lenalidomide administered at a dose of 10 mg to 25 mg once daily on days 1-21 of a 28-day cycle.

[0165] In embodiments, the additional cancer treatment is dexamethasone. In embodiments, the additional cancer treatment is dexamethasone at a dose of 20 mg to 40 mg once weekly. In embodiments, if the patient is less than 75 years of age, the additional cancer treatment is dexamethasone at a dose of 40 mg once weekly. In embodiments, if the patient is at least 75 years of age, the additional cancer treatment is dexamethasone at a dose of 20 mg once weekly. In embodiments, if the patient's BMI is at least 18.5, the additional cancer treatment is dexamethasone at a dose of 40 mg once weekly. In embodiments, if the patient's BMI is less than 18.5, the additional cancer treatment is dexamethasone at a dose of 20 mg once weekly. In embodiments, dexamethasone is administered on days 1, 8, 15, and 22 of a 28-day cycle.

[0166] In an embodiment, the additional cancer treatment is the administration of a dose of lenalidomide from 10 mg to 25 mg once daily for days 1 - 21 of a 28 - day cycle and a dose of dexamethasone from 20 mg to 40 mg on days 1, 8, 15, and 22 of a 28 - day cycle. In an embodiment, if the patient is less than 75 years of age or has a BMI of at least 18.5, the additional cancer treatment is the administration of a dose of lenalidomide from 10 mg to 25 mg once daily for days 1 - 21 of a 28 - day cycle and a dose of dexamethasone of 40 mg on days 1, 8, 15, and 22 of a 28 - day cycle. In an embodiment, if the patient is at least 75 years of age or has a BMI less than 18.5, the additional cancer treatment is the administration of a dose of lenalidomide from 10 mg to 25 mg once daily for days 1 - 21 of a 28 - day cycle and a dose of dexamethasone of 20 mg on days 1, 8, 15, and 22 of a 28 - day cycle.

[0167] Induction dose period

[0168] In some cases, the patient is receiving an initial therapy or combination of therapies (referred to as a lead - in dose) prior to the administration of a subsequent therapy or combination of therapies. The "lead - in period" is a period of time during which a specified initial therapy or combination of therapies is administered prior to the administration of a subsequent therapy or combination of therapies.

[0169] In an embodiment, the method further comprises administering a lead - in dose of mapatumumab prior to the initiation of the administration of belantamab. In an embodiment, the lead - in dose of mapatumumab is from about 1.4 mg / kg to about 3.4 mg / kg, once during the lead - in period. In an embodiment, the lead - in dose of mapatumumab is from about 1.4 mg / kg to about 1.9 mg / kg, once during the lead - in period. In an embodiment, the lead - in dose of mapatumumab 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 the lead - in period. In an embodiment, the lead - in dose of mapatumumab is about 1.4 mg / kg, once during the lead - in period. In an embodiment, the lead - in dose of mapatumumab is about 1.9 mg / kg, once during the lead - in period.

[0170] In an embodiment, the lead - in period is four weeks ± 3 days, and mapatumumab is administered on day 1 of the lead - in period.

[0171] In an embodiment, the dose of margetuximab is administered parenterally, i.e., subcutaneously ((s.c. or SC), intrathecally, intraperitoneally, intramuscularly (i.m. or IM), or intravenously (i.v. or IV), including administration by intravenous infusion. In an embodiment, the dose of margetuximab is administered intravenously. In an embodiment, the dose of margetuximab is administered by intravenous infusion.

[0172] In an embodiment, margetuximab is administered as a single agent during the lead-in period. In an embodiment, margetuximab is administered in combination with at least one additional therapy during the lead-in period. In an embodiment, margetuximab is administered in combination with at least one additional cancer therapy during the lead-in period.

[0173] In an embodiment, the additional cancer therapy for administration during the lead-in period is selected from anti-CD38 monoclonal antibodies, gamma-secretase inhibitors, proteasome inhibitors, immunomodulators, or anti-PD-1 monoclonal antibodies.

[0174] Examples of anti-CD38 antibodies that can be used 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®). In an embodiment, the anti-CD38 monoclonal antibody for administration during the lead-in period is selected from daratumumab or isatuximab.

[0175] Examples of gamma-secretase inhibitors that can be used in the methods described herein include, but are not limited to, LY-450139, PF-0308014, crenigacestat (LY3039478), CB-103, tarenflurbil, semagacestat (LY450139), RG-4733, EVP-0962, celecoxib, MK-0752, and BMS-906024, and derivatives and polymorphs thereof.

[0176] Examples of proteasome inhibitors that can be used 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. In an embodiment, the proteasome inhibitor for administration during the lead-in period is selected from bortezomib, carfilzomib, or ixazomib. In an embodiment, the proteasome inhibitor for administration during the lead-in period is bortezomib.

[0177] Examples of immunomodulatory imide drugs (ImiD) that can be used in the methods described herein include, but are not limited to, thalidomide (e.g., THALOMID®), lenalidomide (e.g., REVLIMID®), and pomalidomide (e.g., POMALYST®). In an embodiment, the immunomodulator used during the lead-in period is selected from thalidomide, lenalidomide, or pomalidomide. In an embodiment, the immunomodulator used during the lead-in period is lenalidomide or pomalidomide. In an embodiment, the immunomodulator used during the lead-in period is lenalidomide. In an embodiment, the immunomodulator used during the lead-in period is pomalidomide.

[0178] Examples of anti-PD-1 monoclonal antibodies that can be used in the methods described herein include, but are not limited to, pembrolizumab and dostarlimab. In an embodiment, the anti-PD-1 monoclonal antibody is selected from pembrolizumab or dostarlimab.

[0179] Other additional cancer treatments include corticosteroids. Examples of corticosteroids include, but are not limited to, dexamethasone (e.g., DECADRON®, DEXASONE®, DIODEX®, HEXADROL®, MAXIDEX®), prednisone (e.g., DELTASONE®), and methylprednisolone (e.g., MEDROL®).

[0180] In an embodiment, the additional cancer treatment used during the lead-in period is selected from lenalidomide, pomalidomide, dexamethasone, or a combination thereof. In an embodiment, the additional cancer treatment used during the lead-in period is lenalidomide and dexamethasone. In an embodiment, the additional cancer treatment used during the lead-in period is pomalidomide and dexamethasone. In an embodiment, the additional cancer treatment used during the lead-in period is lenalidomide and dexamethasone. In an embodiment, the additional cancer treatment used during the lead-in period is bortezomib and dexamethasone. In an embodiment, the additional cancer treatment used during the lead-in period is pomalidomide, bortezomib, and dexamethasone. In an embodiment, the additional cancer treatment used during the lead-in period is lenalidomide, bortezomib, and dexamethasone.

[0181] In an embodiment, the additional cancer treatment used during the lead-in period is standard of care treatment.

[0182] In an embodiment, the additional cancer treatment used 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 used during the lead-in period is lenalidomide administered at a dose of 10 mg to 25 mg once daily on days 1 - 21 of a 28-day lead-in period.

[0183] In an embodiment, an additional cancer treatment for administration during the induction period is dexamethasone. In an embodiment, an additional cancer treatment for administration during the induction period is dexamethasone at a dose of 20 mg to 40 mg once a week. In an embodiment, if the patient is less than 75 years old, an additional cancer treatment for administration during the induction period is dexamethasone at a dose of 40 mg once a week. In an embodiment, if the patient is at least 75 years old, an additional cancer treatment for administration during the induction period is dexamethasone at a dose of 20 mg once a week. In an embodiment, if the patient's BMI is at least 18.5, an additional cancer treatment for administration during the induction period is dexamethasone at a dose of 40 mg once a week. In an embodiment, if the patient's BMI is less than 18.5, an additional cancer treatment for administration during the induction period is dexamethasone at a dose of 20 mg once a week. In an embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of the 28-day induction period.

[0184] In an embodiment, an additional cancer treatment for administration during the induction period is lenalidomide at a dose of 10 mg to 25 mg once daily for days 1 - 21 of the 28-day induction period and dexamethasone at a dose of 20 mg to 40 mg on days 1, 8, 15, and 22 of the 28-day induction period. In an embodiment, if the patient is less than 75 years old or has a BMI of at least 18.5, an additional cancer treatment for administration during the induction period is lenalidomide at a dose of 10 mg to 25 mg once daily for days 1 - 21 of the 28-day induction period and dexamethasone at a dose of 40 mg on days 1, 8, 15, and 22 of the 28-day induction period. In an embodiment, if the patient is at least 75 years old or has a BMI less than 18.5, an additional cancer treatment for administration during the induction period is lenalidomide at a dose of 10 mg to 25 mg once daily for days 1 - 21 of the 28-day induction period and dexamethasone at a dose of 20 mg on days 1, 8, 15, and 22 of the 28-day induction period.

[0185] In an embodiment, the method includes administering an induction dose of margetuximab during an induction period and then administering belantamab during a subsequent treatment period. In an embodiment, the method includes administering the induction dose of margetuximab at a dose of about 1.4 mg / kg to about 3.4 mg / kg (once during the induction period) and then administering belantamab at a dose of about 300 mg to about 2000 mg during the subsequent treatment period. In an embodiment, the method includes administering the induction dose of margetuximab 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 the induction period) and then administering belantamab at a dose of about 300 mg, 900 mg, or about 2000 mg during the subsequent treatment period.

[0186] In some embodiments, the method further includes applying a bandage contact lens during the induction period and / or the subsequent treatment period. A bandage contact lens is a therapeutic contact lens made of a soft flexible plastic that allows oxygen to reach the cornea and is worn in one or both eyes for a period of time to protect the cornea and / or treat ocular toxicity, such as ocular toxicity resulting from treatment with a therapeutic agent such as margetuximab. In some embodiments, the bandage contact lens is composed of N-carboxyvinyl ester (NCVE), N-vinylpyrrolidone (NVE), poly[dimethylsiloxyl]bis[vinylcarbamate] (PBVC), and / or tris-(trimethylsilyloxy)silylpropyl vinylcarbamate (TPVC). In some embodiments, the bandage contact lens is composed of NCVE, NVE, PBVC, and TPVC. In some embodiments, the bandage contact lens is composed of NCVE, NVE, PBVC, and TPVC and has a water content of 30% to 40%, such as 30%, 32%, 34%, 36%, 38%, or 40%. In some embodiments, the bandage contact lens is composed of NCVE, NVE, PBVC, and TPVC and has a water content of about 36%. In some embodiments, the bandage contact lens is made of silicone hydrogel A. Silicone hydrogel A is a copolymer of silicone vinylcarbamate, N-vinyl-pyrrolidone, a silicone crosslinker, and a vinylalanine wetting monomer and is 36% water by weight when immersed in a solution (such as a saline solution).

[0187] Discontinuation of belantamab mafodotin

[0188] In an embodiment, the method further includes stopping the administration of belantamab and subsequently administering margetuximab. In an embodiment, margetuximab is administered at a dose of 2.5 mg / kg once every three weeks ± 3 days. In an embodiment, the administration of belantamab is stopped after the patient exhibits progressive disease.

[0189] In an embodiment, the method further comprises administering margetuximab and then discontinuing the administration of belantamab. In an embodiment, margetuximab is administered at a dose of 2.5 mg / kg once every three weeks ± 3 days. In an embodiment, the administration of belantamab is discontinued after the patient exhibits progressive disease.

[0190] Treatment methods using margetuximab

[0191] In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) in a patient, the method comprising administering margetuximab to the patient.

[0192] In an embodiment, margetuximab is administered at a dose of about 1.4 mg / kg to about 3.4 mg / kg. In an embodiment, margetuximab is administered at a dose of about 1.4 mg / kg to about 1.9 mg / kg. In an embodiment, margetuximab 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. In an embodiment, margetuximab is administered at a dose of about 1.4 mg / kg. In an embodiment, margetuximab is administered at a dose of about 1.9 mg / kg. In an embodiment, belantamab is administered once every eight weeks ± 3 days.

[0193] In an embodiment, margetuximab 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, margetuximab is administered at a dose of about 1.4 mg / kg to about 1.9 mg / kg once every eight weeks ± 3 days. In an embodiment, margetuximab is administered at a dose of about 1.4 mg / kg to about 1.9 mg / kg once every eight weeks ± 3 days. In an embodiment, margetuximab 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. In an embodiment, margetuximab is administered at a dose of about 1.4 mg / kg once every eight weeks ± 3 days. In an embodiment, margetuximab is administered at a dose of about 1.9 mg / kg once every eight weeks ± 3 days.

[0194] In some embodiments, the method further comprises applying a corneal bandage contact lens.

[0195] Co - administration of BCMA antagonists

[0196] The present disclosure describes methods of treating a disease or disorder in a patient who would benefit from inhibiting or blocking B cell maturation antigen (BCMA). Also described is the use of a BCMA inhibition or blocking therapy in treating a disease or disorder in a patient. In addition, the present disclosure describes a kit comprising a BCMA inhibition or blocking therapy and instructions for use.

[0197] In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibition or blocking of B cell maturation antigen (BCMA) in a patient, the method comprising administering to the patient a therapeutically effective amount of a combination comprising a first BCMA antagonist and a second BCMA antagonist. The term "BCMA antagonist" refers to a molecule that specifically binds to B cell maturation antigen (BCMA) and inhibits the binding of BAFF and / or APRIL to the BCMA receptor. Examples of BCMA antagonists include, but are not limited to, an anti-BCMA antibody or an antigen-binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or an antigen-binding fragment thereof, and a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA.

[0198] In embodiments, the first and second BCMA antagonists are independently selected from an anti-BCMA antibody or an antigen-binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or an antigen-binding fragment thereof, and a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA. The first BCMA antagonist is different from the second BCMA antagonist. In embodiments, both the first and second BCMA antagonists are an anti-BCMA antibody or a fragment thereof, both are an anti-BCMA antibody-drug conjugate, both are a bispecific anti-BCMA antibody or a fragment thereof, or both are a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA. In embodiments, the first BCMA antagonist is an anti-BCMA antibody or an antigen-binding fragment thereof, and the second BCMA antagonist is a different anti-BCMA antibody or an antigen-binding fragment thereof. In embodiments, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate, and the second BCMA antagonist is a different anti-BCMA antibody-drug conjugate. In embodiments, the first BCMA antagonist is a bispecific anti-BCMA antibody or an antigen-binding fragment thereof, and the second BCMA antagonist is a different bispecific anti-BCMA antibody or an antigen-binding fragment thereof. In embodiments, the first BCMA antagonist is a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA, and the second BCMA antagonist is a different chimeric antigen receptor T (CAR T) cell therapy targeting BCMA.

[0199] In an embodiment, the bispecific anti-BCMA antibody or its antigen-binding fragment comprises an anti-BCMA antibody or its antigen-binding fragment and an anti-CD38 antibody or its antigen-binding fragment. In an embodiment, the bispecific anti-BCMA antibody or its antigen-binding fragment specifically binds to BCMA and CD3.

[0200] In an embodiment, the first and second BCMA antagonists are independently selected from idecabtagene vicleucel, cilta-cel, teclistamab, REGN5458, mabetuzumab, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.

[0201] In an embodiment, the first BCMA antagonist is mabetuzumab. In an embodiment, the first BCMA antagonist is belantamab.

[0202] In an embodiment, the first BCMA antagonist is mabetuzumab and the second BCMA antagonist is an anti-BCMA antibody or its antigen-binding fragment. In an embodiment, the first BCMA antagonist is mabetuzumab and the second BCMA antagonist is an anti-BCMA antibody-drug conjugate. In an embodiment, the first BCMA antagonist is mabetuzumab and the second BCMA antagonist is a bispecific anti-BCMA antibody or its antigen-binding fragment. In an embodiment, the first BCMA antagonist is mabetuzumab and the second BCMA antagonist is a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA.

[0203] In an embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is an anti-BCMA antibody or its antigen-binding fragment. In an embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is an anti-BCMA antibody-drug conjugate. In an embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is a bispecific anti-BCMA antibody or its antigen-binding fragment. In an embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA.

[0204] In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is idecabtagene vicleucel. In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is ciltacabtagene autoleucel. In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is talquetamab. In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is REGN5458. In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is SEA-BCMA. In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is ABBV-383. In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is elrantamab. In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is pavurutumab. In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is alnuctamab. In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is MEDI2228. In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is CC99712.

[0205] In an embodiment, 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 talquetamab. 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. In an embodiment, 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.

[0206] In embodiments, the combination further comprises a third BCMA antagonist. In embodiments, the third BCMA antagonist is selected from an anti-BCMA antibody or an antigen-binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or an antigen-binding fragment thereof, and a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA. The third BCMA antagonist is different from the first and second BCMA antagonists. In embodiments, the third BCMA antagonist is selected from idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, REGN5458, margetuximab, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.

[0207] In embodiments, the combination comprises margetuximab, belantamab, and an anti-BCMA antibody or an antigen-binding fragment thereof. In embodiments, the combination comprises margetuximab, belantamab, and an anti-BCMA antibody-drug conjugate. In embodiments, the combination comprises margetuximab, belantamab, and a bispecific anti-BCMA antibody or an antigen-binding fragment thereof. In embodiments, the combination comprises margetuximab, belantamab, and a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA.

[0208] In embodiments, the combination comprises margetuximab, belantamab, and idecabtagene vicleucel. In embodiments, the combination comprises margetuximab, belantamab, and ciltacabtagene autoleucel. In embodiments, the combination comprises margetuximab, belantamab, and teclistamab. In embodiments, the combination comprises margetuximab, belantamab, and REGN5458. In embodiments, the combination comprises margetuximab, belantamab, and SEA-BCMA. In embodiments, the combination comprises margetuximab, belantamab, and ABBV-383. In embodiments, the combination comprises margetuximab, belantamab, and elrantamab. In embodiments, the combination comprises margetuximab, belantamab, and pavurutumab. In embodiments, the combination comprises margetuximab, belantamab, and alnuctamab. In embodiments, the combination comprises margetuximab, belantamab, and MEDI2228. In embodiments, the combination comprises margetuximab, belantamab, and CC99712.

[0209] In an embodiment, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate, and the second BCMA antagonist is the corresponding unconjugated anti-BCMA antibody. In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is belantamab. In an embodiment, 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. In an embodiment, the first and second BCMA antagonists and the third BCMA antagonist (if present) are administered on the same day of a treatment cycle. In an embodiment, the first and second BCMA antagonists and the third BCMA antagonist (if present) are administered on different days of a treatment cycle during the same treatment cycle.

[0210] In an embodiment, the first and second BCMA antagonists and the third BCMA antagonist (if present) are each 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 a week ± 3 days, once a week ± 3 days to once every 8 weeks ± 3 days, once a week ± 3 days to once every 6 weeks ± 3 days, once a week ± 3 days to once every 4 weeks ± 3 days, once a week ± 3 days to once every 3 weeks ± 3 days, once a 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 days, and / or once every 7 weeks ± 3 days to once every 8 weeks ± 3 days.

[0211] In some embodiments, the first and second BCMA antagonists and the third BCMA antagonist (if present) are administered in combination with the application of a corneal bandage lens.

[0212] In an embodiment, the first and second BCMA antagonists and the third BCMA antagonist (if present) are administered in combination with at least one additional therapy. In an embodiment, the additional cancer therapy is selected from an anti-CD38 monoclonal antibody, a gamma-secretase inhibitor, a proteasome inhibitor, an immunomodulator, or an anti-PD-1 monoclonal antibody.

[0213] Examples of anti-CD38 antibodies that can be used in the methods described herein include, but are not limited to, isatuximab or isatuximab-irfc (such as SARCLISA®) and daratumumab (such as DARZALEX®, DARZALEX FASPRO®). In an embodiment, the anti-CD38 monoclonal antibody is selected from daratumumab or isatuximab.

[0214] Examples of γ-secretase inhibitors useful in the methods described herein include, but are not limited to, ogsevacor (PF-0308014), crenigacestat (LY3039478), CB-103, tarenflurbil, semagacestat (LY450139), RG-4733, EVP-0962, celecoxib, MK-0752, and BMS-906024, as well as derivatives and polymorphs thereof.

[0215] Examples of 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. In an embodiment, the proteasome inhibitor is selected from bortezomib, carfilzomib, or ixazomib. In an embodiment, the proteasome inhibitor is bortezomib.

[0216] Examples of immunomodulatory imide drugs (ImiD) 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®). In an embodiment, the immunomodulator is selected from thalidomide, lenalidomide, or pomalidomide. In an embodiment, the immunomodulator is lenalidomide or pomalidomide. In an embodiment, the immunomodulator is lenalidomide.

[0217] Examples of anti-PD-1 monoclonal antibodies useful in the methods described herein include, but are not limited to, pembrolizumab and dostarlimab. In an embodiment, the anti-PD-1 monoclonal antibody is selected from pembrolizumab or dostarlimab.

[0218] Other additional cancer treatments include corticosteroids. Examples of corticosteroids include, but are not limited to, dexamethasone (e.g., DECADRON®, DEXASONE®, DIODEX®, HEXADROL®, MAXIDEX®), prednisone (e.g., DELTASONE®), and methylprednisolone (e.g., MEDROL®).

[0219] In an embodiment, the additional cancer treatment is selected from lenalidomide, pomalidomide, dexamethasone, or a combination thereof. In an embodiment, the additional cancer treatment is lenalidomide and dexamethasone. In an embodiment, the additional cancer treatment is pomalidomide and dexamethasone. In an embodiment, the additional cancer treatment is bortezomib and dexamethasone. In an embodiment, the additional cancer treatment is pomalidomide, bortezomib, and dexamethasone. In an embodiment, the additional cancer treatment is lenalidomide, bortezomib, and dexamethasone.

[0220] In an embodiment, the additional cancer treatment is standard of care treatment.

[0221] In an embodiment, 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. In an embodiment, 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 administered at a dose of 10 mg to 25 mg once daily from Day 1 to Day 21 of a 28-day cycle. 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, if the patient is less than 75 years of age, the additional cancer treatment is dexamethasone at a dose of 40 mg once weekly. In an embodiment, if the patient is at least 75 years of age, the additional cancer treatment is dexamethasone at a dose of 20 mg once weekly. In an embodiment, if the patient's BMI is at least 18.5, the additional cancer treatment is dexamethasone at a dose of 40 mg once weekly. In an embodiment, if the patient's BMI is less than 18.5, the additional cancer treatment is dexamethasone at a dose of 20 mg once weekly. In an embodiment, dexamethasone is administered on Days 1, 8, 15, and 22 of a 28-day cycle. In an embodiment, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily from Day 1 to Day 21 of a 28-day cycle and dexamethasone at a dose of 20 mg to 40 mg on Days 1, 8, 15, and 22 of a 28-day cycle. In an embodiment, if the patient is less than 75 years of age or has a BMI of at least 18.5, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily from Day 1 to Day 21 of a 28-day cycle and dexamethasone at a dose of 40 mg on Days 1, 8, 15, and 22 of a 28-day cycle. In an embodiment, if the patient is at least 75 years of age or has a BMI less than 18.5, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily from Day 1 to Day 21 of a 28-day cycle and dexamethasone at a dose of 20 mg on Days 1, 8, 15, and 22 of a 28-day cycle.

[0222] In one aspect, the present disclosure provides a kit comprising: (i) a first B cell maturation antigen (BCMA) antagonist; and (ii) instructions for treating a disease or disorder responsive to inhibition or blockade of BCMA when combined with a second BCMA antagonist. In an embodiment, the kit further comprises a third BCMA antagonist. In an embodiment, the instructions further describe treating a disease or disorder responsive to inhibition or blockade of BCMA when combined with the second and third BCMA antagonists.

[0223] In an embodiment, the first, second, and third BCMA antagonists are independently selected from anti-BCMA antibodies or antigen-binding fragments thereof, anti-BCMA antibody-drug conjugates, bispecific anti-BCMA antibodies or antigen-binding fragments thereof, and chimeric antigen receptor T (CAR T) cell therapies targeting BCMA. In an embodiment, the first, second, and third BCMA antagonists are independently selected from axicabtagene ciloleucel, ciltacabtagene autoleucel, teclistamab, REGN5458, mavrilimumab, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.

[0224] In one aspect, the present disclosure provides a kit comprising: (i) mavrilimumab; and (ii) instructions for treating a disease or disorder responsive to inhibition or blockade of BCMA when combined with belantamab.

[0225] In one aspect, the present disclosure provides a kit comprising: (i) belantamab; and (ii) instructions for treating a disease or disorder responsive to inhibition or blockade of BCMA when combined with mavrilimumab.

[0226] Sequential use of BCMA antagonists

[0227] Methods of treating a disease or disorder in a patient who would benefit from inhibition or blockade of B cell maturation antigen (BCMA) are described herein. The use of BCMA inhibition or blockade therapies in treating a disease or disorder in a patient is also described. In addition, kits comprising BCMA inhibition or blockade therapies and instructions for use are described herein.

[0228] In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) in a patient previously treated with a first BCMA antagonist, the method comprising administering to the patient a therapeutically effective amount of a second BCMA antagonist, wherein the patient discontinues administration of the first BCMA antagonist prior to initiation of administration of the second BCMA antagonist, and the second BCMA antagonist is different from the first BCMA antagonist.

[0229] In one aspect, the present disclosure provides a method for reducing corneal toxicity in a patient previously treated with a first B-cell maturation antigen (BCMA) antagonist, the method comprising administering to the patient a therapeutically effective amount of a second BCMA antagonist, wherein the patient discontinues administration of the first BCMA antagonist prior to initiation of administration of the second BCMA antagonist, and the second BCMA antagonist is different from the first BCMA antagonist. "Corneal toxicity" or "corneal adverse reaction" refers to changes in the cornea, including corneal lesions (e.g., mild superficial corneal lesions, moderate superficial corneal lesions, severe superficial corneal lesions) and corneal epithelial defects, such as corneal ulcers. In some embodiments, corneal toxicity or corneal adverse reaction refers to corneal lesions, and the severity or grade of such corneal adverse reactions can be determined using the keratopathy visual acuity (KVA) scale for treatment-related corneal toxicity in Table 2. In some embodiments, the patient has a grade 1 corneal adverse reaction. In some embodiments, the patient has a grade 2 corneal adverse reaction. In some embodiments, the patient has a grade 3 corneal adverse reaction. In some embodiments, the patient has a grade 4 corneal adverse reaction. In some embodiments, reducing ocular toxicity refers to reducing the severity of corneal adverse reactions or the grade of treatment-related corneal toxicity, as determined using the KVA scale.

[0230] Table 2

[0231]

[0232] Abbreviations: BCVA = best corrected visual acuity; KVA = keratopathy visual acuity; logMAR = logarithm of the minimum angle of resolution; SPK = superficial punctate keratitis.

[0233] In embodiments, the first and second BCMA antagonists are independently selected from anti-BCMA antibodies or antigen-binding fragments thereof, anti-BCMA antibody-drug conjugates, bispecific anti-BCMA antibodies or antigen-binding fragments thereof, and chimeric antigen receptor T (CAR T) cell therapies targeting BCMA. The first BCMA antagonist is different from the second BCMA antagonist. In embodiments, both the first and second BCMA antagonists are anti-BCMA antibodies or fragments thereof, both are anti-BCMA antibody-drug conjugates, both are bispecific anti-BCMA antibodies or fragments thereof, or both are chimeric antigen receptor T (CAR T) cell therapies targeting BCMA. In embodiments, 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. In embodiments, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate, and the second BCMA antagonist is a different anti-BCMA antibody-drug conjugate. In embodiments, 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. In embodiments, the first BCMA antagonist is a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA, and the second BCMA antagonist is a different chimeric antigen receptor T (CAR T) cell therapy targeting BCMA.

[0234] In embodiments, 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 embodiments, 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.

[0235] In embodiments, the first and second BCMA antagonists are independently selected from axicabtagene ciloleucel, idecabtagene vicleucel, teclistamab, REGN5458, margetuximab, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.

[0236] In embodiments, the first BCMA antagonist is margetuximab. In embodiments, the first BCMA antagonist is belantamab. In embodiments, the second BCMA antagonist is margetuximab. In embodiments, the second BCMA antagonist is belantamab.

[0237] In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is an anti-BCMA antibody or an antigen-binding fragment thereof. In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is an anti-BCMA antibody-drug conjugate. In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is a bispecific anti-BCMA antibody or an antigen-binding fragment thereof. In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA. In an embodiment, the first BCMA antagonist is an anti-BCMA antibody or an antigen-binding fragment thereof, and the second BCMA antagonist is margetuximab. In an embodiment, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate, and the second BCMA antagonist is margetuximab. In an embodiment, the first BCMA antagonist is a bispecific anti-BCMA antibody or an antigen-binding fragment thereof, and the second BCMA antagonist is margetuximab. In an embodiment, the first BCMA antagonist is a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA, and the second BCMA antagonist is margetuximab.

[0238] In an embodiment, the first BCMA antagonist is belantamab, and the second BCMA antagonist is an anti-BCMA antibody or an antigen-binding fragment thereof. In an embodiment, the first BCMA antagonist is belantamab, and the second BCMA antagonist is an anti-BCMA antibody-drug conjugate. In an embodiment, the first BCMA antagonist is belantamab, and the second BCMA antagonist is a bispecific anti-BCMA antibody or an antigen-binding fragment thereof. In an embodiment, the first BCMA antagonist is belantamab, and the second BCMA antagonist is a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA. In an embodiment, the first BCMA antagonist is an anti-BCMA antibody or an antigen-binding fragment thereof, and the second BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate, and the second BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is a bispecific anti-BCMA antibody or an antigen-binding fragment thereof, and the second BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA, and the second BCMA antagonist is belantamab.

[0239] In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is idecabtagene vicleucel. In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is ciltacabtagene autoleucel. In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is talquetamab. In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is REGN5458. In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is SEA-BCMA. In an embodiment, the first BCMA antagonist is idecabtagene vicleucel, and the second BCMA antagonist is margetuximab. In an embodiment, the first BCMA antagonist is ciltacabtagene autoleucel, and the second BCMA antagonist is margetuximab. In an embodiment, the first BCMA antagonist is talquetamab, and the second BCMA antagonist is margetuximab. In an embodiment, the first BCMA antagonist is REGN5458, and the second BCMA antagonist is margetuximab. In an embodiment, the first BCMA antagonist is SEA-BCMA, and the second BCMA antagonist is margetuximab. In an embodiment, the first BCMA antagonist is ABBV-383, and the second BCMA antagonist is margetuximab. In an embodiment, the first BCMA antagonist is elrantamab, and the second BCMA antagonist is margetuximab. In an embodiment, the first BCMA antagonist is pavurutumab, and the second BCMA antagonist is margetuximab. In an embodiment, the first BCMA antagonist is alnuctamab, and the second BCMA antagonist is margetuximab. In an embodiment, the first BCMA antagonist is MEDI2228, and the second BCMA antagonist is margetuximab. In an embodiment, the first BCMA antagonist is CC99712, and the second BCMA antagonist is margetuximab.

[0240] In an embodiment, 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 idecabtagene vicleucel, and the second BCMA antagonist is belantamab. In an embodiment, 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. In an embodiment, 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.

[0241] In an embodiment, the method further comprises administering to the patient a combination of a therapeutically effective amount of a third BCMA antagonist and the second BCMA antagonist, wherein the patient discontinues administration of the first BCMA antagonist prior to initiation of administration of the second and third BCMA antagonists, and the third BCMA antagonist is different from the first and second BCMA antagonists.

[0242] In an embodiment, the first BCMA antagonist is an anti-BCMA antibody or an antigen-binding fragment thereof, the second BCMA antagonist is margetuximab, and the third BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate, the second BCMA antagonist is margetuximab, and the third BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is a bispecific anti-BCMA antibody or an antigen-binding fragment thereof, the second BCMA antagonist is margetuximab, and the third BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA, the second BCMA antagonist is margetuximab, and the third BCMA antagonist is belantamab.

[0243] In an embodiment, the first BCMA antagonist is idecabtagene vicleucel, the second BCMA antagonist is margetuximab, and the third BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is cilta-cel, the second BCMA antagonist is margetuximab, and the third BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is talquetamab, the second BCMA antagonist is margetuximab, and the third BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is REGN5458, the second BCMA antagonist is margetuximab, and the third BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is SEA-BCMA, the second BCMA antagonist is margetuximab, and the third BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is ABBV-383, the second BCMA antagonist is margetuximab, and the third BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is elrantamab, the second BCMA antagonist is margetuximab, and the third BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is pavurutumab, the second BCMA antagonist is margetuximab, and the third BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is alnuctamab, the second BCMA antagonist is margetuximab, and the third BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is MEDI2228, the second BCMA antagonist is margetuximab, and the third BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is CC99712, the second BCMA antagonist is margetuximab, and the third BCMA antagonist is belantamab.

[0244] In an embodiment, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate, and the second BCMA antagonist is the corresponding unconjugated anti-BCMA antibody. In an embodiment, the second BCMA antagonist is an anti-BCMA antibody-drug conjugate, and the first BCMA antagonist is the corresponding unconjugated anti-BCMA antibody. In an embodiment, the first BCMA antagonist is margetuximab, and the second BCMA antagonist is belantamab. In an embodiment, the first BCMA antagonist is belantamab, and the second BCMA antagonist is margetuximab.

[0245] In an embodiment, the second BCMA antagonist and the third BCMA antagonist (if present) are administered independently 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 a week ± 3 days, once a week ± 3 days to once every 8 weeks ± 3 days, once a week ± 3 days to once every 6 weeks ± 3 days, once a week ± 3 days to once every 4 weeks ± 3 days, once a week ± 3 days to once every 3 weeks ± 3 days, once a 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 days, and / or once every 7 weeks ± 3 days to once every 8 weeks ± 3 days.

[0246] In an embodiment, the second BCMA antagonist and the third BCMA antagonist (if present) are administered in combination with the application of a corneal bandage contact lens.

[0247] In an embodiment, the second BCMA antagonist and the third BCMA antagonist (if present) are administered in combination with at least one additional therapy. In an embodiment, the additional cancer therapy is selected from an anti-CD38 monoclonal antibody, a gamma-secretase inhibitor, a proteasome inhibitor, an immunomodulator, or an anti-PD-1 monoclonal antibody.

[0248] Examples of anti-CD38 antibodies that can be used 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®). In an embodiment, the anti-CD38 monoclonal antibody is selected from daratumumab or isatuximab.

[0249] Examples of γ-secretase inhibitors useful in the methods described herein include, but are not limited to, Ogeprevir (PF-0308014), Crenigacestat (LY3039478), CB-103, Tarenflurbil, Semagacestat (LY450139), RG-4733, EVP-0962, Celecoxib, MK-0752, and BMS-906024, and derivatives and polymorphs thereof.

[0250] Examples of 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. In an embodiment, the proteasome inhibitor is selected from Bortezomib, Carfilzomib, or Ixazomib. In an embodiment, the proteasome inhibitor is Bortezomib.

[0251] Examples of immunomodulatory imide drugs (ImiD) 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®). In an embodiment, the immunomodulator is selected from Thalidomide, Lenalidomide, or Pomalidomide. In an embodiment, the immunomodulator is Lenalidomide or Pomalidomide. In an embodiment, the immunomodulator is Lenalidomide.

[0252] Examples of anti-PD-1 monoclonal antibodies useful in the methods described herein include, but are not limited to, Pembrolizumab and Dostarlimab. In an embodiment, the anti-PD-1 monoclonal antibody is selected from Pembrolizumab or Dostarlimab.

[0253] Other additional cancer treatments include corticosteroids. Examples of corticosteroids include, but are not limited to, Dexamethasone (e.g., DECADRON®, DEXASONE®, DIODEX®, HEXADROL®, MAXIDEX®), Prednisone (e.g., DELTASONE®), and Methylprednisolone (e.g., MEDROL®).

[0254] In an embodiment, the additional cancer treatment is selected from Lenalidomide, Pomalidomide, Dexamethasone, or a combination thereof. In an embodiment, the additional cancer treatment is Lenalidomide and Dexamethasone. In an embodiment, the additional cancer treatment is Pomalidomide and Dexamethasone. In an embodiment, the additional cancer treatment is Bortezomib and Dexamethasone. In an embodiment, the additional cancer treatment is Pomalidomide, Bortezomib, and Dexamethasone. In an embodiment, the additional cancer treatment is Lenalidomide, Bortezomib, and Dexamethasone.

[0255] In an embodiment, the additional cancer treatment is standard of care treatment.

[0256] In an embodiment, the second BCMA antagonist and the third BCMA antagonist (if present) are administered on Day 1 of the 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. In an embodiment, 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, which is administered once daily at a dose of 10 mg to 25 mg on Days 1-21 of a 28-day cycle. 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 a week. In an embodiment, if the patient is less than 75 years of age, the additional cancer treatment is dexamethasone at a dose of 40 mg once a week. In an embodiment, if the patient is at least 75 years of age, the additional cancer treatment is dexamethasone at a dose of 20 mg once a week. In an embodiment, if the patient's BMI is at least 18.5, the additional cancer treatment is dexamethasone at a dose of 40 mg once a week. In an embodiment, if the patient's BMI is less than 18.5, the additional cancer treatment is dexamethasone at a dose of 20 mg once a week. In an embodiment, dexamethasone is administered on Days 1, 8, 15, and 22 of a 28-day cycle. In an embodiment, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily on Days 1-21 of a 28-day cycle and dexamethasone at a dose of 20 mg to 40 mg on Days 1, 8, 15, and 22 of a 28-day cycle. In an embodiment, if the patient is less than 75 years of age or has a BMI of at least 18.5, the additional cancer treatment regimen is lenalidomide at a dose of 10 mg to 25 mg once daily on Days 1-21 of a 28-day cycle and dexamethasone at a dose of 40 mg on Days 1, 8, 15, and 22 of a 28-day cycle. In an embodiment, if the patient is at least 75 years of age or has a BMI less than 18.5, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily on Days 1-21 of a 28-day cycle and dexamethasone at a dose of 20 mg on Days 1, 8, 15, and 22 of a 28-day cycle.

[0257] In an embodiment, the first BCMA antagonist is discontinued after the patient exhibits progressive disease.

[0258] Combination of antibody - drug conjugate and the corresponding unconjugated antibody

[0259] In some cases, an immunoconjugate or antibody-drug conjugate is used in combination with its corresponding unconjugated antibody. When used in combination with the immunoconjugate or antibody-drug conjugate (ADC) mentioned, the corresponding unconjugated antibody refers to the antibody portion of the immunoconjugate or ADC that lacks the cytotoxic payload of the immunoconjugate or ADC and optionally any linker moiety. In one aspect, the present disclosure provides a method of treating a disease or disorder in a patient, the method comprising administering to the patient a therapeutically effective amount of a combination comprising an antibody-drug conjugate and its corresponding unconjugated antibody.

[0260] In one aspect, the present disclosure provides a method of reducing the 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 for the patient and its corresponding unconjugated antibody.

[0261] In one aspect, the present disclosure provides a method of treating a disease or disorder in a patient previously treated with an antibody-drug conjugate, the method comprising administering to the patient a therapeutically effective amount of the corresponding unconjugated antibody, wherein the patient has discontinued administration of the antibody-drug conjugate prior to initiation of administration of the corresponding unconjugated antibody.

[0262] In one aspect, the present disclosure provides a method of treating the toxicity in a patient previously treated with an antibody-drug conjugate, the method comprising administering to the patient a therapeutically effective amount of the corresponding unconjugated antibody, wherein the patient has discontinued administration of the antibody-drug conjugate prior to initiation of administration of the corresponding unconjugated antibody.

[0263] In embodiments, the antibody-drug conjugate is selected from gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, venetoclax, deruxtecan, sacituzumab govitecan, margetuximab, loncastuximab tesirine, tisotumab vedotin, moxetumomab pasudotox, MEDI2228 or CC99712.

[0264] Diseases and disorders

[0265] Methods of treating a disease or disorder in a patient who would benefit from inhibition or blockade of B cell maturation antigen (BCMA) are described herein. The use of BCMA inhibition or blockade therapy in treating a disease or disorder in a patient is also described.

[0266] In embodiments, the disease or disorder is a plasma cell disorder or a B-cell disorder. B-cell disorders can be classified into B-cell development / immunoglobulin production defects (immunodeficiencies) and excessive / uncontrolled proliferation (lymphomas, leukemias). As used herein, B-cell disorder refers to both types of diseases and provides methods for treating B-cell disorders. In some embodiments, the cancer can be a B-cell cancer (e.g., leukemia and lymphoma).

[0267] Examples of diseases or disorders that can be treated according to the methods described herein include multiple myeloma (MM), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), non-secretory multiple myeloma, smoldering multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), solitary plasmacytoma (bone, extramedullary), lymphoplasmacytic lymphoma (LPL), Waldenström’s Macroglobulinemia, plasma cell leukemia, primary amyloidosis (AL), heavy chain disease, systemic lupus erythematosus (SLE), POEMS syndrome / osteosclerotic myeloma, type I and type II cryoglobulinemia, light chain deposition disease, Goodpasture’s syndrome, idiopathic thrombocytopenic purpura (ITP), acute glomerulonephritis, pemphigus and pemphigoid disorders, and epidermolysis bullosa acquisita; or any non-Hodgkin lymphoma B-cell leukemia (NHL) and Hodgkin lymphoma (HL). In some cases, the disease or disorder can be selected from multiple myeloma (MM), non-Hodgkin lymphoma B-cell leukemia (NHL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). In embodiments, the disease can be multiple myeloma or non-Hodgkin lymphoma B-cell leukemia (NHL). In embodiments, the disease can be multiple myeloma.

[0268] In embodiments, the disease or disorder is a cancer expressing BCMA. In embodiments, the disease or disorder is multiple myeloma (MM). In embodiments, the MM is relapsed and / or refractory MM, newly diagnosed MM, MM unsuitable for transplantation, or newly diagnosed MM unsuitable for transplantation. In embodiments, the disease or disorder is multiple myeloma that has been previously treated for multiple myeloma with at least one, at least two, at least three, or at least four therapeutic agents. In embodiments, the disease or disorder is relapsed and / or refractory multiple myeloma that has been previously treated for multiple myeloma with at least one, at least two, at least three, or at least four therapeutic agents. In another embodiment, the disease or disorder is relapsed and / or refractory multiple myeloma previously treated with at least 3 prior lines of therapy, which may include the following: immunomodulatory drugs (ImiD), proteasome inhibitors (PI), and anti-CD38 therapy (e.g., daratumumab) or combinations thereof. The lines of therapy may be defined by a consensus panel of the International Myeloma Working Group (IMWG). In some embodiments, patients receiving prior lines of therapy may have recurrent, relapsed, and / or refractory cancer. In some cases, the cancer may be primary cancer. In some cases, the cancer may be metastatic cancer. In some cases, the cancer may be chemoresistant cancer.

[0269] In embodiments, the disease or disorder is an autoimmune disease or disorder. In embodiments, the disease or disorder is systemic lupus erythematosus (SLE), idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, type 1 diabetes, multiple sclerosis, or psoriasis.

[0270] Antibody sequences

[0271] The term "belantamab" refers to a B-cell maturation antigen (BCMA)-blocking antibody ("anti-BCMA antibody") or a functional fragment or functional variant thereof that specifically binds to BCMA and inhibits the binding of BAFF and / or APRIL to the BCMA receptor, and that comprises an immunoglobulin heavy-chain variable domain (VH), the VH comprising a complementarity-determining region (CDR) H1 that contains the amino acid sequence of SEQ ID NO: 5; a CDRH2 that contains the amino acid sequence of SEQ ID NO: 6; a CDRH3 that contains the amino acid sequence of SEQ ID NO: 7; and an immunoglobulin light-chain variable domain (VL) that comprises a CDRL1 that contains the amino acid sequence of SEQ ID NO: 8; a CDRL2 that contains the amino acid sequence of SEQ ID NO: 9; and a CDRL3 that contains the amino acid sequence of SEQ ID NO: 10. Exemplary heavy-chain variable region and light-chain variable region sequences of the antibody are provided in Table 3 below. In certain embodiments, the VH contains the amino acid sequence of SEQ ID NO: 3. In certain embodiments, the VL contains the amino acid sequence of SEQ ID NO: 4. In certain embodiments, the heavy chain contains the amino acid sequence of SEQ ID NO: 1. In certain embodiments, the light chain contains the amino acid sequence of SEQ ID NO: 2. In certain other embodiments, belantamab comprises a VH that contains the amino acid sequence of SEQ ID NO: 3 and a VL that contains the amino acid sequence of SEQ ID NO: 4. In other embodiments, belantamab comprises heavy-chain and light-chain sequences that are SEQ ID NO: 1 and SEQ ID NO: 2, respectively.

[0272] The terms "margetuximab" and "belamaf" are used interchangeably and refer to an immunoconjugate that comprises belantamab conjugated to monomethyl auristatin F (MMAF) via a 6-maleimidocaproyl (MC) linker.

[0273] The term "biosimilar" refers to a biopharmaceutical or biological product that is highly similar to a reference biological product (e.g., belantamab or margetuximab), notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biological product and the reference product in terms of the product's safety, purity, and potency (Section 351(i) of the Public Health Service Act (42 U.S.C. 262(i)).

[0274] Thus, the term "biosimilar" refers to a biological product that is highly similar to a reference product (e.g., belantamab or margetuximab) and is approved by a regulatory agency (e.g., the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA)) based on data from: (a) analytical studies showing that the biological product is highly similar to the reference product despite minor differences in clinically inactive components; (b) animal studies (including toxicity assessments); and / or (c) one or more clinical studies (including immunogenicity and pharmacokinetic or pharmacodynamic assessments) that are sufficient to demonstrate safety, purity, and potency under one or more appropriate conditions of use for which the reference product is approved and intended and for which approval is being sought (e.g., there are no clinically meaningful differences between the biological product and the reference product with respect to the safety, purity, and potency of the product). In certain embodiments, the biosimilar product is an interchangeable product as determined by a regulatory agency (e.g., the FDA).

[0275] It will generally be understood that biosimilars of margetuximab will include post - translational modifications that are critical to the function and efficacy of margetuximab (as disclosed in International Patent Application Publication No. WO 2021 / 024133). However, in certain embodiments, a biosimilar (e.g., a biosimilar of belantamab or margetuximab) may include one or more molecular differences, such as post - translational modifications, such as (but not limited to) glycosylation, oxidation, deamidation, and / or truncation, that differ from the post - translational modifications of the reference drug product (e.g., belantamab or margetuximab), provided that these differences do not result in a significant change in the safety and / or efficacy of the drug product. In certain embodiments, a biosimilar (e.g., a biosimilar of belantamab or margetuximab) may have the same or different glycosylation patterns as the reference drug product (e.g., belantamab or margetuximab). Specifically, but not exclusively, a biosimilar (e.g., a biosimilar of belantamab or margetuximab) may have a different glycosylation pattern, for example, if the difference is to address or is intended to address a safety issue associated with the reference drug product (e.g., belantamab or margetuximab). In addition, a biosimilar (e.g., a biosimilar of belantamab or margetuximab) may deviate from the reference drug product (e.g., belantamab or margetuximab) in, for example, its strength, drug form, formulation, excipients, and / or presentation, provided that the safety and efficacy of the drug product are not compromised. In other embodiments, a biosimilar (e.g., a biosimilar of belantamab or margetuximab) may include differences in, for example, pharmacokinetic (PK) and / or pharmacodynamic (PD) profiles compared to the reference drug product (e.g., belantamab or margetuximab), but is still considered to be sufficiently similar to the reference drug product to be authorized or to be considered suitable for authorization. In certain embodiments, a biosimilar (e.g., a biosimilar of belantamab or margetuximab) may exhibit different binding characteristics compared to the reference drug product (e.g., belantamab or margetuximab), where the different binding characteristics are not considered by regulatory agencies (such as the FDA and / or EMA) to be an obstacle to authorization as a biosimilar product. The term "biosimilar" is also used synonymously by regulatory agencies in other countries and regions.

[0276] It should be understood that the International Non - Proprietary Name (INN) of a drug (e.g., belantamab or margetuximab) shall be interpreted to include generic, bioequivalent, and / or biosimilar versions of that drug, including but not limited to any drug that obtains simplified regulatory approval by reference to an earlier regulatory approval of that drug. In addition, the INN of a drug optionally includes but is not limited to glycosylation variants of belantamab or margetuximab and their biosimilars.

[0277] Table 3

[0278]

[0279] Embodiment

[0280] Embodiment 1 is a method of treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) in a patient, the method comprising administering belantamab to the patient at a dose of from about 300 mg to about 2000 mg.

[0281] Embodiment 2 is the method of Embodiment 1, wherein the dose is about 300 mg, about 900 mg, or about 2000 mg.

[0282] Embodiment 3 is the method of Embodiment 1 or 2, wherein the dose is administered at regular intervals for a period of time.

[0283] 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.

[0284] Embodiment 5 is the method of Embodiment 1 or 2, wherein the dose is administered once every two weeks ± 3 days.

[0285] Embodiment 6 is the method of Embodiment 1 or 2, wherein the dose is administered once every three weeks ± 3 days.

[0286] Embodiment 7 is the method of Embodiment 1 or 2, wherein the dose is administered once every four weeks ± 3 days.

[0287] Embodiment 8 is the method of Embodiment 1 or 2, wherein the dose is administered on Day 1 and Day 15 of a 28-day cycle.

[0288] Embodiment 9 is the method of Embodiment 1 or 2, wherein the dose is administered on Day 1 of a 21-day cycle.

[0289] Embodiment 10 is the method of any of the foregoing embodiments, wherein the patient has been treated with at least one prior line of cancer treatment.

[0290] Embodiment 11 is the method of any of the foregoing embodiments, wherein the patient has been treated with one, two, three, or four prior lines of cancer treatment.

[0291] Embodiment 12 is the method of Embodiment 11, wherein the prior line of cancer treatment comprises an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulator.

[0292] Embodiment 13 is the method of any of the foregoing embodiments, wherein belantamab is administered by intravenous infusion or subcutaneous injection.

[0293] Embodiment 14 is the method according to any one of the foregoing embodiments, wherein the patient further receives at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulator, or an anti-PD-1 monoclonal antibody.

[0294] Embodiment 15 is the method according to 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.

[0295] Embodiment 16 is the method according to 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.

[0296] Embodiment 17 is the method according to Embodiment 16, wherein the patient receives lenalidomide on days 1 - 21 of a 28-day cycle.

[0297] Embodiment 18 is the method according to any one of Embodiments 14 to 17, wherein the additional cancer treatment is dexamethasone.

[0298] Embodiment 19 is the method according to Embodiment 18, wherein the additional cancer treatment is dexamethasone at a dose of 20 mg to 40 mg once a week.

[0299] Embodiment 20 is the method according to Embodiment 19, wherein the patient receives dexamethasone on days 1, 8, 15, and 22 of a 28-day cycle.

[0300] Embodiment 21 is the method according to Embodiment 19, wherein (i) the patient is less than 75 years old and is receiving dexamethasone at a dose of 40 mg once a week; or (ii) the patient is at least 75 years old and is receiving dexamethasone at a dose of 20 mg once a week.

[0301] Embodiment 22 is the method according to 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 a week; or (ii) the patient has a BMI less than 18.5 and is receiving dexamethasone at a dose of 20 mg once a week.

[0302] Embodiment 23 is the method according to any one of the foregoing embodiments, which further comprises stopping the administration of belantamab and subsequently administering margetuximab.

[0303] Embodiment 24 is the method according to any one of Embodiments 1 to 22, which further comprises administering margetuximab and then discontinuing the administration of belantamab.

[0304] Embodiment 25 is the method according to Embodiment 23 or 24, wherein margetuximab is administered at a dose of 2.5 mg / kg once every three weeks ± 3 days.

[0305] Embodiment 26 is the method according to any one of the foregoing embodiments, which further comprises administering a loading dose of margetuximab before starting the administration of belantamab, wherein the loading dose of margetuximab is about 1.4 mg / kg to about 3.4 mg / kg, once during the loading period.

[0306] Embodiment 27 is the method according to Embodiment 26, wherein the loading dose of margetuximab is about 1.4 mg / kg to about 1.9 mg / kg, once during the loading period.

[0307] Embodiment 28 is the method according to Embodiment 26, wherein the loading dose of margetuximab is about 1.4 mg / kg, about 1.9 mg / kg, about 2.5 mg / kg or about 3.4 mg / kg, once during the loading period.

[0308] Embodiment 29 is the method according to Embodiment 26, wherein the loading dose of margetuximab is about 1.4 mg / kg, once during the loading period.

[0309] Embodiment 30 is the method according to any one of Embodiments 26 to 29, wherein the loading period is four weeks ± 3 days, and margetuximab is administered on Day 1 of the loading period.

[0310] Embodiment 31 is the method according to any one of Embodiments 26 to 30, which further comprises administering to the patient at least one additional cancer treatment during the loading period, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulator or an anti-PD-1 monoclonal antibody.

[0311] Embodiment 32 is the method according to 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.

[0312] Embodiment 33 is the method according to 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.

[0313] Embodiment 34 is the method according to embodiment 33, wherein lenalidomide is administered to the patient on days 1 - 21 of the induction period.

[0314] Embodiment 35 is the method according to any one of embodiments 32 to 34, wherein the additional cancer treatment is dexamethasone.

[0315] Embodiment 36 is the method according to embodiment 35, wherein the additional cancer treatment is dexamethasone at a dose of 20 mg to 40 mg once a week.

[0316] Embodiment 37 is the method according to embodiment 36, wherein dexamethasone is administered to the patient on days 1, 8, 15, and 22 of the induction period.

[0317] Embodiment 38 is the method according to 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 a week; or (ii) the patient is at least 75 years old and dexamethasone is administered to the patient at a dose of 20 mg once a week.

[0318] Embodiment 39 is the method according to 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 a week; 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 a week.

[0319] Embodiment 40 is a method of treating a disease or disorder responsive to inhibition or blockade of B - cell maturation antigen (BCMA) in a patient, the method comprising administering margetuximab to the patient at a dose of about 1.4 mg / kg to about 3.4 mg / kg, such as about 1.4 mg / kg to about 1.9 mg / kg, once every eight weeks ± 3 days.

[0320] Embodiment 41 is the method according to 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.

[0321] Embodiment 42 is a method of treating a disease or disorder responsive to inhibition or blockade of B - cell maturation antigen (BCMA) in a patient, the method comprising administering to the patient a therapeutically effective amount of a combination comprising a first BCMA antagonist and a second BCMA antagonist.

[0322] Embodiment 43 is the method according to Embodiment 42, wherein the first and second BCMA antagonists are independently selected from anti-BCMA antibodies or antigen-binding fragments thereof, anti-BCMA antibody-drug conjugates, bispecific anti-BCMA antibodies or antigen-binding fragments thereof, and chimeric antigen receptor T (CAR T) cell therapies targeting BCMA.

[0323] Embodiment 44 is the method according to Embodiment 42 or 43, wherein the first and second BCMA antagonists are independently selected from idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, REGN5458, mabetuzumab, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.

[0324] Embodiment 45 is the method according to any one of Embodiments 42 to 44, wherein the first BCMA antagonist is mabetuzumab.

[0325] Embodiment 46 is the method according to any one of Embodiments 42 to 44, wherein the first BCMA antagonist is belantamab.

[0326] Embodiment 47 is the method according to 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.

[0327] Embodiment 48 is the method according to Embodiment 47, wherein the anti-BCMA antibody-drug conjugate is selected from mabetuzumab, MEDI2228, and CC99712.

[0328] Embodiment 49 is the method according to Embodiment 48, wherein the first BCMA antagonist is mabetuzumab and the second BCMA antagonist is belantamab.

[0329] Embodiment 50 is a method of treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) in a patient, the method comprising administering to the patient a therapeutically effective amount of a combination comprising mabetuzumab and belantamab.

[0330] Embodiment 51 is the method according to any one of Embodiments 42 to 50, further comprising administering to the patient at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulator, or an anti-PD-1 monoclonal antibody.

[0331] Embodiment 52 is the method according to 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.

[0332] Embodiment 53 is a kit comprising: (i) a first B-cell maturation antigen (BCMA) antagonist; and (ii) instructions for treating a disease or disorder responsive to inhibiting or blocking BCMA when combined with a second BCMA antagonist.

[0333] Embodiment 54 is a kit comprising: (i) mapatumumab; and (ii) instructions for treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) when combined with belantamab.

[0334] Embodiment 55 is a kit comprising: (i) belantamab; and (ii) instructions for treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) when combined with mapatumumab.

[0335] 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 to the patient a therapeutically effective amount of a second BCMA antagonist, wherein the patient discontinues administration of the first BCMA antagonist prior to initiation of administration of the second BCMA antagonist, and the second BCMA antagonist is different from the first BCMA antagonist.

[0336] Embodiment 57 is the method according to Embodiment 56, wherein the first and second BCMA antagonists are independently selected from anti-BCMA antibodies or antigen-binding fragments thereof, anti-BCMA antibody-drug conjugates, bispecific anti-BCMA antibodies or antigen-binding fragments thereof, and chimeric antigen receptor T (CAR T) cell therapies targeting BCMA.

[0337] Embodiment 58 is the method according to Embodiment 56 or 57, wherein the first and second BCMA antagonists are independently selected from axicabtagene ciloleucel, ciltacabtagene autoleucel, teclistamab, REGN5458, mapatumumab, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.

[0338] Embodiment 59 is the method according to any one of Embodiments 56 to 58, wherein the first BCMA antagonist is mapatumumab.

[0339] Embodiment 60 is the method according to any one of embodiments 56 to 58, wherein the first BCMA antagonist is belantamab mafodotin.

[0340] Embodiment 61 is the method according to any one of embodiments 56 to 58, wherein the second BCMA antagonist is melflufen.

[0341] Embodiment 62 is the method according to any one of embodiments 56 to 58, wherein the second BCMA antagonist is belantamab mafodotin.

[0342] Embodiment 63 is the method according to 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.

[0343] Embodiment 64 is the method according to embodiment 63, wherein the anti-BCMA antibody-drug conjugate is selected from melflufen, MEDI2228, and CC99712.

[0344] Embodiment 65 is the method according to embodiment 63, wherein the first BCMA antagonist is melflufen, and the second BCMA antagonist is belantamab mafodotin.

[0345] Embodiment 66 is the method according to 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.

[0346] Embodiment 67 is the method according to embodiment 66, wherein the anti-BCMA antibody-drug conjugate is selected from melflufen, MEDI2228, and CC99712.

[0347] Embodiment 68 is the method according to embodiment 66, wherein the second BCMA antagonist is melflufen and the first BCMA antagonist is belantamab mafodotin.

[0348] Embodiment 69 is a method of treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) in a patient previously treated with melflufen, the method comprising administering to the patient a therapeutically effective amount of belantamab mafodotin, wherein the patient discontinues administration of melflufen prior to initiation of administration of belantamab mafodotin.

[0349] Embodiment 70 is a method of treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) in a patient previously treated with belantamab, the method comprising administering to the patient a therapeutically effective amount of margetuximab, wherein the patient discontinues administration of belantamab prior to initiation of administration of margetuximab.

[0350] Embodiment 71 is the method according to any one of Embodiments 56 to 70, further comprising administering to the patient at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulator, or an anti-PD-1 monoclonal antibody.

[0351] Embodiment 72 is the method according to 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.

[0352] 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 to the patient a therapeutically effective amount of a second BCMA antagonist, wherein the patient discontinues administration of the first BCMA antagonist prior to initiation of administration of the second BCMA antagonist, and the second BCMA antagonist is different from the first BCMA antagonist.

[0353] Embodiment 74 is the method according to Embodiment 73, wherein the first and second BCMA antagonists are independently selected from anti-BCMA antibodies or antigen-binding fragments thereof, anti-BCMA antibody-drug conjugates, bispecific anti-BCMA antibodies or antigen-binding fragments thereof, and chimeric antigen receptor T (CAR T) cell therapies targeting BCMA.

[0354] Embodiment 75 is the method according to Embodiment 73 or 74, wherein the first and second BCMA antagonists are independently selected from axicabtagene ciloleucel, ciltacabtagene autoleucel, teclistamab, REGN5458, margetuximab, belantamab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.

[0355] Embodiment 76 is the method according to any one of Embodiments 73 to 75, wherein the first BCMA antagonist is margetuximab.

[0356] Embodiment 77 is the method according to any one of Embodiments 73 to 75, wherein the first BCMA antagonist is belantamab.

[0357] Embodiment 78 is the method according to any one of embodiments 73 to 75, wherein the second BCMA antagonist is margetuximab.

[0358] Embodiment 79 is the method according to any one of embodiments 73 to 75, wherein the second BCMA antagonist is belantamab.

[0359] Embodiment 80 is the method according to 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.

[0360] Embodiment 81 is the method according to embodiment 80, wherein the anti-BCMA antibody-drug conjugate is selected from margetuximab, MEDI2228, and CC99712.

[0361] Embodiment 82 is the method according to embodiment 80, wherein the first BCMA antagonist is margetuximab and the second BCMA antagonist is belantamab.

[0362] Embodiment 83 is the method according to 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.

[0363] Embodiment 84 is the method according to embodiment 83, wherein the anti-BCMA antibody-drug conjugate is selected from margetuximab, MEDI2228, and CC99712.

[0364] Embodiment 85 is the method according to embodiment 83, wherein the second BCMA antagonist is margetuximab and the first BCMA antagonist is belantamab.

[0365] Embodiment 86 is a method of reducing corneal toxicity in a patient previously treated with margetuximab, the method comprising administering to the patient a therapeutically effective amount of belantamab, wherein the patient discontinues administration of margetuximab prior to initiation of administration of belantamab.

[0366] Embodiment 87 is a method of reducing corneal toxicity in a patient previously treated with belantamab, the method comprising administering to the patient a therapeutically effective amount of margetuximab, wherein the patient discontinues administration of belantamab prior to initiation of administration of margetuximab.

[0367] Embodiment 88 is the method according to any one of embodiments 73 to 87, further comprising administering to the patient at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulator, or an anti-PD-1 monoclonal antibody.

[0368] Embodiment 89 is the method according to 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.

[0369] 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.

[0370] 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 to the patient a therapeutically effective amount of the corresponding unconjugated antibody, wherein the patient stops administering the antibody-drug conjugate before starting to administer the corresponding unconjugated antibody.

[0371] Embodiment 92 is the method according to embodiment 90 or 91, wherein the antibody-drug conjugate is selected from gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, deruxtecan, 66andomized66 govitecan, margetuximab, loncastuximab tesirine, tisotumab vedotin, motixafortide, MEDI2228, or CC99712.

[0372] Embodiment 93 is the method according to any one of embodiments 1 to 52 or 56 to 92, or the kit according to any one of embodiments 53 to 55, wherein the disease or disorder is a plasma cell disorder or a B cell disorder.

[0373] Embodiment 94 is the method according to any one of embodiments 1 to 52 or 56 to 92, or the kit according to any one of embodiments 53 to 55, wherein the disease or disorder is a cancer expressing BCMA.

[0374] Embodiment 95 is the method according to any one of embodiments 1 to 52 or 56 to 92, or the kit according to any one of embodiments 53 to 55, wherein the disease or disorder is multiple myeloma (MM).

[0375] Embodiment 96 is the method according to embodiment 95, wherein the MM is relapsed and / or refractory MM, newly diagnosed MM, MM not suitable for transplantation, or newly diagnosed MM not suitable for transplantation.

[0376] Embodiment 97 is the kit according to embodiment 95, wherein the MM is relapsed and / or refractory MM, newly diagnosed MM, MM not suitable for transplantation, or newly diagnosed MM not suitable for transplantation.

[0377] Embodiment 98 is a method for treating cancer in a patient who has a Grade 1 corneal adverse reaction due to administration of margetuximab, the method comprising temporarily discontinuing administration of margetuximab; administering a therapeutically effective amount of belantamab to the patient for a lead-in period; and resuming administration of margetuximab after the lead-in period.

[0378] Embodiment 99 is a method for treating cancer in a patient who has a Grade 2 or higher corneal adverse reaction due to administration of margetuximab, the method comprising temporarily discontinuing administration of margetuximab; administering a therapeutically effective amount of belantamab II to the patient for a lead-in period; and resuming administration of margetuximab after the lead-in period.

[0379] Examples

[0380] The following examples are provided to illustrate but not limit the claimed disclosure.

[0381] Example 1: In vivo efficacy of belantamab mafodotin in a subcutaneous NCI - H929 human multiple myeloma model in NOD / SCID mice Model.

[0382] Studies were conducted to evaluate the in vivo therapeutic efficacy of belantamab (GSK2857914) and margetuximab (GSK2857916) in a subcutaneous NCI-H929 human multiple myeloma model in NOD / SCID mice. Groups of 10 mice were dosed by intraperitoneal administration at the amounts, frequencies, and durations shown in Table 4.

[0383] Table 4

[0384]

[0385] Methods NCI-H929 tumor cells were cultured in vitro in RPMI 1640 medium supplemented with 10% fetal bovine serum and 0.05 mM β-ME at 37 °C in an atmosphere of 5% CO2 / air. Cells in exponential growth phase were harvested and counted for tumor inoculation. Each mouse was subcutaneously inoculated in the right anterior flank area with NCI-H929 tumor cells (5x10 6 ) in PBS (1:1) mixed with Matrigel in 0.1 ml for tumor development. Randomization was started when the mean tumor size reached 121 mm 3 . Eighty mice were enrolled in the study. All animals were randomly assigned to 8 study groups. Randomization was performed based on a "matched distribution" method (StudyDirector TM software, version 3.1.399.19) randomized block design. The randomization date was designated as Day 0. Treatment started on the same day as randomization (Day 0) according to the study design.

[0386] After inoculation of tumor cells, the morbidity and mortality of the animals were examined daily. During the regular monitoring period, any effects of the tumor growth and treatment on the behavior of the animals (such as activity, food and water consumption, weight gain / loss (weight was measured twice a week after randomization), eye / hair tangling, and any other abnormalities) were examined. The mortality of individual animals and the observed clinical signs were recorded in detail. After randomization, the tumor volume was measured twice a week in two dimensions using calipers, and the volume was expressed in mm using the formula "V = (L x W x W) x 0.52" 3 , where V is the tumor volume, L is the tumor length (the longest tumor dimension), and W is the tumor width (the longest tumor dimension perpendicular to L). Administration of the drug and measurement of the tumor and body weight were performed in a laminar flow cabinet. Both body weight and tumor volume were measured using StudyDirectorTM software (version 3.1.399.19).

[0387] Statistical analysis : To compare the tumor volumes of different groups on pre-specified days, first, the Bartlett test was used to examine the assumption of homogeneity of variances across all groups. When the p-value of the Bartlett test >= 0.05, a one-way ANOVA was run to test the overall equality of means across all groups. If the p-value of the one-way ANOVA < 0.05, post hoc tests were further performed by running Tukey’s HSD (honest significant difference) test for all pairwise comparisons and running Dunnett test for comparing each treatment group with the vehicle group. When the p-value of the Bartlett test < 0.05, the Kruskal-Wallis test was run to test the overall equality of medians across all groups. If the p-value of the Kruskal-Wallis test < 0.05, post hoc tests were further performed by running Conover non-parametric test for all pairwise comparisons or for comparing each treatment group with the vehicle group, both with a one-step p-value adjustment.

[0388] In addition, pairwise comparisons were made without multiple comparison correction, and the nominal / uncorrected p-values were reported directly from the Welch t-test or Mann-Whitney U-test. Specifically, first, the Bartlett test was used to examine the assumption of homogeneity of variances for a pair of groups. When the p-value of the Bartlett test ≥ 0.05, the Welch t-test was run, otherwise the Mann-Whitney U-test was run to obtain the nominal p-value.

[0389] All statistical analyses were performed using the R-a language and environment (version 3.3.1) for statistical calculations and graphics. Unless otherwise stated, all tests were two-sided, and a p-value < 0.05 was considered statistically significant.

[0390] Survival time was analyzed by the Kaplan-Meier method. The event of interest was animal death. Survival time was defined as the time from the date of randomization to the date when the tumor volume reached 2500 mm 3 . For each group, the median survival time (MST), the corresponding 95% confidence interval, and the increase in life span (ILS) were calculated. Kaplan-Meier curves for each group were constructed, and the survival curves between groups were compared using the log-rank test. All data were analyzed using SPSS 18.0. P < 0.05 was considered statistically significant.

[0391] Results : Tumor volume analysis showed that compared with the vehicle (G1), 4 mg / kg of GSK2857916 and 8 mg / kg of GSK2857914 as single agents or in combination with different dosing regimens (G2 - G8) showed significant anti-tumor efficacy in the NCI-H929 xenograft model. In addition, compared with the single agent of GSK2857916 (G2), the combination of GSK2857916 and GSK2857914 (G4 and G6) showed significantly improved anti-tumor efficacy. The tumor volume growth curves between randomization and study termination are shown as Figure 1 . The tumor growth inhibition (TGI) from the data collected on day 24 is provided in Table 5.

[0392] Table 5

[0393]

[0394] Survival analysis showed that compared with the vehicle (G1), 4 mg / kg of GSK2857916 and 8 mg / kg of GSK2857914 as single agents or in combination with different dosing regimens (G2 - G8) significantly increased the lifespan of mice in the NCI-H929 xenograft model. In addition, compared with the single agent of GSK2857916 (G2), the combination of GSK2857916 and GSK2857914 (G4 and G6) further increased the lifespan of mice. Figure 2 The Kaplan-Meier survival curves for all treatment groups are shown as a function of the study day. The median survival days of mice in each group are provided in Table 6.

[0395] Table 6

[0396]

[0397] Note: 1. A vs. G1;

[0398] Note 2. Compared with G4, p < 0.001 for G2; compared with G6, p = 0.003 for G2; compared with G7, p = 0.122 for G2.

[0399] Example 2: A phase 1 / 2 study to evaluate the safety and efficacy of belantamab mafodotin in multiple myeloma (MM).

[0400] A study was conducted to evaluate the safety and efficacy of belantamab in participants with relapsed or refractory multiple myeloma (RRMM).

[0401] Study design

[0402] Part 1: Dose - escalation phase in RRMM.

[0403] Part 1 was a Phase I open-label study to evaluate the safety, tolerability, and clinical activity of escalating doses of single-agent belantamab in participants with RRMM who had received at least 3 prior lines of therapy to determine the recommended dose for Part 2. Belantamab was administered twice per cycle on Days 1 and 15 of a 28-day cycle, starting at a dose of 300 mg IV. Dose escalation was guided by modifying the toxicity probability interval to 900 mg and then to the maximum dose of 2000 mg according to the dose escalation plan and as directed by the Dose Escalation Committee. Exploration of additional intermediate doses was permitted if recommended by the Dose Escalation Committee and agreed upon by the Medical Monitor and the treating investigators. Progression from one dose level to another and the recommended dose for Part 2 were based on all available data from Part 1 of the belantamab treatment; the Dose Escalation Committee specifically considered the safety and tolerability at each dose level, the available PK and PD data, and the preliminary efficacy to recommend two dose levels for further characterization in Part 2.

[0404] Participants were dosed until progressive disease (PD), after which they had the option to receive treatment with single-agent margetuximab at 2.5 mg / kg Q3W (Part 1B). Participants who elected to receive margetuximab treatment after the first PD had an end-of-treatment (EOT) visit before starting margetuximab treatment and then continued to be monitored for safety, tolerability, and disease response during margetuximab treatment until the next PD. After the second PD, participants underwent a second EOT margetuximab visit (if feasible) and were monitored for safety until at least 70 days after the last margetuximab dose. Participants who elected to discontinue margetuximab treatment after the first PD terminated treatment and had an EOT visit and subsequent safety monitoring.

[0405] The duration of belantamab treatment was until the first PD (subsequently followed by optional margetuximab treatment until the second PD), unacceptable toxicity, or any other treatment termination criterion. For example, the treatment duration could be up to approximately 8 months.

[0406] The visit frequency is once every 2 weeks forward from Cycle 3. More visits are scheduled in Cycle 1 and Cycle 2.

[0407] Part 2: Combination evaluation in RRMM.

[0408] Part 2 is a 2-arm safety lead-in randomized open-label study evaluating the safety, tolerability, and clinical activity of receiving 1 cycle of Margetuximab-xRd (Margetuximab, Therapy x, Lenalidomide, and Dexamethasone), followed by continuous treatment with Belantamab-xRd (Belantamab, Therapy x, Lenalidomide, and Dexamethasone) in participants with relapsed MM who have received at least 1 prior line of therapy (2L+). In some cases, Therapy 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 Ogegovor). In some cases, Therapy x includes, but is not limited to, a proteasome inhibitor (such as Bortezomib).

[0409] The combination therapy xRd includes Lenalidomide (R) and Dexamethasone (d). The choice of Therapy x is based on data from ongoing Margetuximab clinical studies and is a standard or emerging treatment for MM.

[0410] The Belantamab dose is based on the totality of available Part 1 data. Two different dose levels of Belantamab (Arm A and Arm B) are administered every 4 weeks. More frequent dosing is used if justified by Part 1 data based on safety, tolerability, PK / PD models, or other data. Up to approximately 20 participants evaluable for safety and tolerability are randomly assigned equally to Arm A and Arm B after receiving 1 cycle (28 days) of Margetuximab-xRd. The single-dose Margetuximab 1.4 mg / kg is administered in combination with Therapy x, 25 or 10 mg of Lenalidomide once daily (days 1-21 of the cycle), and 40 mg of Dexamethasone once daily (days 1, 8, 15, and 22 of the cycle) (or 20 mg if age ≥75 years or BMI <18.5).

[0411] Continue to administer Belantamab-xRd until progressive disease (PD).

[0412] Part 2 of the study evaluated overall safety events, tolerability, and corneal adverse events in 10 participants / arm after 3 treatment cycles. Safety and tolerability were considered evaluable if participants completed at least 3 cycles of treatment (including 1 cycle of margetuximab-xRd followed by 2 cycles of belantamab-xRd). Participants who did not meet the definition of evaluable could be replaced if they withdrew due to treatment-related adverse events, death, or reasons other than PD. All data from Parts 1 and 2 were used to determine the recommended Phase 2 dose of belantamab to be used in Part 3.

[0413] Participants who terminated treatment for reasons other than PD in Part 2 of the study will continue to be followed for progression-free survival and overall survival.

[0414] Treatment duration was until PD, unacceptable toxicity, or any other treatment discontinuation criteria. For example, treatment duration could be up to approximately 15 months.

[0415] The visit frequency was once every 4 weeks starting from Cycle 3, unless data from Part 1 and ongoing margetuximab clinical trials suggested more frequent administration of belantamab-xRd. More visits were planned during Cycles 1 and 2.

[0416] Part 3: Combination evaluation in newly diagnosed multiple myeloma not eligible for transplantation (TI - NDMM).

[0417] Part 3 was a 4-arm Phase 2 randomized open-label study that evaluated the safety and efficacy of continuing belantamab-xRd after 1 cycle of margetuximab-xRd treatment in participants with TI-NDMM. Cycle length was 4 weeks. Two different doses of belantamab were administered every 4 weeks (Arms A and B). The belantamab dose levels were selected based on all available data from Parts 1 and 2 and may be different from the dose levels administered in Part 2; the selection process by the dose escalation committee considered the overall safety and tolerability of the combination, available PK / PD data, and efficacy evidence at different dose levels. Belantamab-xRd administration continued until PD. The margetuximab and xRd doses were the same in Arms A and B: a single dose of margetuximab 1.4 mg / kg was administered in combination with treatment x, lenalidomide 25 or 10 mg once daily (on Days 1-21 of the cycle) and dexamethasone 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).

[0418] Part 3 also tested the results of the following: 1) treatment with continuous dosing of margetuximab-xRd (Arm C), and 2) treatment with continuous dosing of belantamab-xRd without an initial dose of margetuximab-xRd (Arm D).

[0419] In Arm C, margetuximab was dosed at 1.4 mg / kg once every two 28-day cycles (Q8W) in combination with Treatment x, lenalidomide 25 or 10 mg once daily (days 1-21 of the cycle), and dexamethasone 40 mg once daily (days 1, 8, 15, and 22 of the cycle) (or 20 mg if age ≥75 years or BMI < 18.5).

[0420] In Arm D, belantamab was administered once every 28-day cycle in combination with Treatment x, lenalidomide 25 or 10 mg once daily (days 1-21 of the cycle), and dexamethasone 40 mg once daily (days 1, 8, 15, and 22 of the cycle) (or 20 mg if age ≥75 years or BMI < 18.5).

[0421] Approximately 80 participants were randomly assigned 1:1:1:1 to Arm A, Arm B, Arm C, or Arm D with the aim of obtaining data on 20 evaluable participants per arm. Participants were considered evaluable if they had completed at least 4 cycles of treatment (including 1 cycle of margetuximab-xRd followed by 3 cycles of belantamab-xRd). If participants who did not meet the definition of evaluable withdrew for reasons other than treatment-related adverse events, death, or disease progression, they could be replaced.

[0422] The xRd dose was the same in all four arms of the study, while the margetuximab and belantamab doses and dosing frequencies in Arms C and D may have differed compared to those in Arms A and B.

[0423] The study terminated 18 months after the first dose was administered to the last subject. At that time, data collection stopped for all enrolled participants who were no longer receiving study treatment, and the clinical trial database was closed. If the disease had not progressed at the time of study termination, participants who were continuing to benefit from treatment as recommended by the investigator were transferred to a post-analysis - continued treatment study to continue treatment. In this case, the treatment duration for Part 3 participants up to the data cut-off date of this study was up to approximately 24 months.

[0424] The visit frequency was once every 4 weeks starting from Cycle 3, unless data from Parts 1 and 2 and from ongoing margetuximab clinical trials recommended more frequent dosing of belantamab-xRd. More visits were planned during Cycles 1 and 2.

[0425] An overview of the investigational treatments is provided in Table 7.

[0426] Table 7

[0427]

[0428] 1 Dose-limiting toxicity (DLT)

[0429] 2 Belapectin (bela)

[0430] 3 Belantamab mafodotin (belamaf)

[0431] 4 Belapectin recommended Part 2 dose level 1 (bela RPart2 DL1)

[0432] 5 Belapectin recommended Part 2 dose level 2 (bela RPart2 DL2)

[0433] 6 Belapectin recommended Phase 2 dose level 1 (bela RP2 DL1)

[0434] 7 Belapectin recommended Phase 2 dose level 2 (bela RP2 DL2)

[0435] A summary of the treatment doses and administration frequencies is provided in Table 8. As provided in Table 8, standard of care (SoC) treatments or emerging MM treatments were also administered.

[0436] Table 8

[0437]

[0438]

[0439]

[0440] Dosing adjustments: Margetuximab

[0441] In Part 3 Arm C, continuous belantamab mafodotin 1.4 mg / kg Q8W was administered, and based on emerging data from ongoing belantamab mafodotin trials, the dose level could be increased to 1.9 mg / kg Q8W, unless the data supported more frequent administration. The initial dose was matched to Parts A and B, and the ongoing doses were selected based on consideration of data from other studies and belantamab mafodotin clinical experience.

[0442] Dosing adjustments: Lenalidomide and dexamethasone

[0443] Lenalidomide is administered orally at a dose of 25 mg daily on Days 1 - 21 of each 28 - day cycle in participants with a CLcr ≥ 60 mL / min (according to Cockcroft - Gault). In participants with a CLcr of 30 - 60 mL / min, the dose of lenalidomide will be reduced to 10 mg daily on Days 1 to 21. Lenalidomide is administered at a fixed dose level and does not require adjustment for body weight or BSA. On days when lenalidomide and belantamab mafodotin are co - administered, lenalidomide should be administered as close as possible to the end of the 1 - 2 - hour rest period after belantamab mafodotin administration, and on PK days, lenalidomide should be administered no later than 6 hours after the end of the rest period following belantamab mafodotin administration. Dexamethasone will be given orally at 40 mg weekly (or 20 mg if age ≥ 7.5 years or BMI < 18.5 kg / m 2 , then 20 mg) on Days 1, 8, 15, and 22 of each cycle.

[0444] Eligibility criteria

[0445] Inclusion criteria:

[0446] Participants are eligible to be included in the study only if all of the following criteria are met:

[0447] 1. The participant is at least 18 years of age or has the legal age of consent in the jurisdiction where the study is conducted.

[0448] 2. The participant has a histologically or cytologically confirmed diagnosis of MM, as defined by the International Myeloma Working Group (IMWG).

[0449] Part 1: Participants who have received at least 3 prior lines of anti - myeloma therapy and have received an immunomodulatory agent, a proteasome inhibitor, and an anti - CD38 mAb (unless contraindicated or unavailable). The number of lines of therapy is defined by the International Myeloma Workshop Consensus Panel.

[0450] Part 2: Participants who meet all of the following: (1) have undergone autologous stem cell transplantation (ASCT) or are considered ineligible for transplantation; (2) have previously been treated with at least one prior line of MM therapy; (3) have documented disease progression during or after their most recent therapy.

[0451] Part 3: Participants who meet both of the following: (1) NDMM with a treatment need, as documented according to IMWG criteria; and (2) are not considered candidates for high-dose chemotherapy with ASCT due to: (a) age ≥ 65 years; or (b) age 18 - 65 years with comorbid conditions that may negatively impact tolerance to high-dose chemotherapy with ASCT, or who decline high-dose chemotherapy with ASCT as initial treatment.

[0452] 3. Participants with a history of ASCT are eligible to participate in the study if they meet the following eligibility criteria: (a) transplantation was > 100 days prior to screening; and (b) no active infection.

[0453] 4. Eastern Cooperative Oncology Group - Performance Status (ECOG-PS) of 0 - 2.

[0454] 5. Measurable disease is 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: involving FLC level ≥ 10 mg / dL (≥ 100 mg / L) and abnormal serum FLC ratio (< 0.26 or > 1.65).

[0455] 6. Have adequate organ system function as specified in Table 9:

[0456] Table 9

[0457]

[0458]

[0459] 7. All prior treatment-related toxicities (defined by NCI-CTCAE, v5.0, 2017) must be ≤ Grade 1 at screening, except for alopecia (any grade), neuropathy (≤ Grade 2), or endocrine lesions treated with alternative therapy (any grade).

[0460] 8. Participants currently receiving physiological doses of oral steroids (< 10 mg / day), inhaled steroids, or ophthalmic steroids are permitted to participate in the study.

[0461] Exclusion criteria:

[0462] Participants are excluded from the study if any of the following criteria apply:

[0463] Medical Conditions:

[0464] 1. Diagnosed with primary AL amyloidosis, active POEMS syndrome, primary plasma cell leukemia.

[0465] 2. Any pre-existing medical, psychiatric disorder or other condition (including laboratory abnormalities) that is severe and / or unstable and may affect the safety of the participant, the obtaining of informed consent, or compliance with the study procedures.

[0466] 3. The participant shows signs of meningeal or central nervous system involvement of MM.

[0467] 4. Current corneal epithelial disease, except for non-confluent SPK.

[0468] 5. Currently unstable liver or biliary tract disease as defined by the investigator: the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. Note: Stable chronic liver disease (including Gilbert syndrome or asymptomatic gallstones) is acceptable if the participant otherwise meets the inclusion criteria.

[0469] 6. The presence of malignancies other than the disease under study, except for any other malignancies in which the participant has been disease-free for more than 2 years and, in the opinion of the PI and the GSK Medical Director, will not affect the assessment of the effect of the current trial treatment on the current target malignancy (MM). Note: Participants with curatively treated non-melanoma skin cancer are not excluded.

[0470] 7. 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 second degree (Mobiz type II) or third degree AV block; (b) QTcF interval > 450 milliseconds (QT interval corrected for heart rate according to the Fridericia formula), and / or hypokalemia, and / or family history of long QT syndrome (for Part 1); (c) History of MI, acute coronary syndrome (including unstable angina), coronary angioplasty, stent implantation, 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.

[0471] 8. Known immediate or delayed hypersensitivity or idiosyncrasy to any drug chemically related to belantamab / maxorvalan or any component of the study treatment. History of severe hypersensitivity to other mAbs.

[0472] 9. Active infection requiring antibiotic, antiviral, or antifungal treatment.

[0473] 10. Known HIV infection, unless the participant meets all of the following criteria: (a) ART has been established for at least 4 weeks and the HIV viral load is < 400 copies / mL; (b) CD4+ T cell (CD4+) count ≥ 350 cells / μL; (c) no history of AIDS-defining opportunistic infections in the past 12 months.

[0474] 11. History of recent (within the past 6 months) acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or gastrointestinal obstruction.

[0475] 12. Presence of HBsAg or HBcAb at screening. Note: The presence of HBsAb indicates that previous vaccination does not exclude the participant.

[0476] 13. Positive hepatitis C antibody test result or positive hepatitis C RNA test result at screening or within 3 months before the first dose of study treatment, unless the participant can meet the following criteria: (a) negative RNA test; (b) requires successful antiviral treatment (usually 8-week duration), and negative HCV RNA test result after at least a 4-week washout period after completion of antiviral treatment.

[0477] 14. Presence of active kidney disease (infection, requiring dialysis, or any other condition that may affect the safety of the participant). Participants with isolated proteinuria caused by MM are eligible provided that the criteria for adequate organ system function given in the table (Table 9) are met.

[0478] Prior / concomitant therapy:

[0479] 15. Parts 1 and 2: Refractory to melflufen (PD as confirmed according to IMWG criteria during or within 60 days of completion of melflufen therapy). If melflufen was discontinued due to toxicity and the subsequent toxicity resolved, the previous melflufen is permitted. Note: Previous treatment with other anti-BCMA agents is permitted.

[0480] 16. Parts 2 and 3: Discontinuation of previous lenalidomide treatment due to intolerable AE.

[0481] 17. Parts 1 and 2: Refractoriness to previous standard anti-myeloma therapy including lenalidomide permits other mAbs within 30 days of the first dose of study drug, or systemic anti-myeloma therapy within 14 days of the first dose of study drug.

[0482] 18. Prior radiotherapy within 2 weeks of the start of the study therapy. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. For palliative radiotherapy for non-CNS diseases (≤2 weeks of radiotherapy), a 1-week washout period is permitted.

[0483] 19. Only Part 3: Prior systemic therapy for MM.

[0484] Note: An emergency course of steroids (defined as no more than 40 mg of dexamethasone or equivalent per day for a maximum of 4 days (i.e., a total of 160 mg) is permitted.

[0485] Note: Focal palliative radiotherapy is permitted prior to enrollment provided it occurred at least 2 weeks before the first dose of the study intervention, the participant has recovered from radiation-related toxicities, and the participant does not require corticosteroids for radiation-induced AEs.

[0486] 20. Plasmapheresis within 7 days before the first dose of the study drug.

[0487] 21. Prior allogeneic transplantation is prohibited.

[0488] 22. Participants who received prior CAR-T therapy within 3 months of screening and had lymphocyte depletion with chemotherapy.

[0489] 23. Any major surgery (except bone stabilization surgery) within 2 weeks of the first dose, or not fully recovered from surgery.

[0490] 24. Prior treatment with mAb within 30 days of receiving the first dose of the study drug, or treatment with the study drug or an approved systemic anti-myeloma therapy (including systemic steroids) within 14 days or 5 half-lives (whichever is longer) of receiving the first dose of the study drug.

[0491] Other exclusions:

[0492] 25. Receipt of a blood product (including platelets or red blood cells) transfusion or colony-stimulating factor (including G-CSF, GM-CSF, recombinant erythropoietin) or administration of any thrombopoietin receptor agonist within 2 weeks before the first dose of the study drug.

[0493] 26. Participants must not receive live / attenuated live vaccines within 30 days prior to the first dose of study treatment or at least 70 days after the last study treatment while receiving belantamab. Examples of live vaccines include, but are not limited to, the following: measles vaccine, mumps vaccine, rubella vaccine, varicella / zoster (chickenpox) vaccine, yellow fever vaccine, rabies vaccine, BCG, and typhoid vaccine. Injectable seasonal influenza vaccines and COVID-19 vaccines are not live or attenuated vaccines and are permitted; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not permitted.

[0494] 27. Known current drug or alcohol abuse.

[0495] Dietary and food restrictions (only for Part 2 and Part 3)

[0496] Beginning on the day before each bela / belamaf administration and 1 day prior to study visits independent of belantamab / mabilamab administration, and continuing until the day of belantamab / mabilamab administration or the end of the study visit, avoid consumption of red wine, Seville oranges, grapefruit or grapefruit juice, pomelos, exotic citrus fruits, grapefruit hybrids, or juices.

[0497] Water is not permitted until 2 hours after oral drug administration; water is permitted ad libitum at all other times.

[0498] Lenalidomide capsules should be swallowed whole with water; the capsules should not be opened, crushed, or chewed.

[0499] Lenalidomide should be taken orally at approximately the same time each day.

[0500] Lenalidomide capsules contain lactose. The risk-benefit should be evaluated in participants with lactose intolerance.

[0501] Caffeine, alcohol, and tobacco (for Parts 1, 2, and 3)

[0502] Throughout the study, participants will avoid ingestion of caffeine- or xanthine-containing products (e.g., coffee, tea, cola beverages, and chocolate) for 24 hours prior to clinic visits on days of scheduled regular PK and pharmacodynamic sample collections.

[0503] Throughout the study, participants will abstain from alcohol for 24 hours prior to clinic visits on days of scheduled regular PK and pharmacodynamic sample collections.

[0504] Participants who use tobacco products will be instructed not to use nicotine-containing products (including nicotine patches and other delivery devices such as vaporizers) while they are in the clinical unit.

[0505] Dose adjustments (dose reduction and dose delay)

[0506] Dose adjustments may be made for individual participants based on the safety findings for that participant. After Cycle 1, the dose of belantamab mafodotin or margetuximab for a participant may be reduced or delayed due to toxicity (including corneal events / toxicity).

[0507] If the dose is delayed, the participant should wait for the next scheduled dose to resume treatment. In individual cases, if the investigator determines that waiting for the entire cycle to resume treatment after a delay (skipped dose) related to resolved toxicity would be harmful to the participant's health, the investigator should contact the medical monitor to discuss an earlier restart. Only participants who have recovered to a maximum of Grade 1 from toxicity may be considered for an earlier restart. Administration of margetuximab in Parts 2 and 3 cannot be more frequent than every 28 days (+3-day window period). In such cases, efficacy and safety assessments must be maintained every 4 weeks, consistent with the initial efficacy and safety assessments in the study, which may require 2 separate visits (1 for dosing and 1 for disease assessment). Only Part 1B participants who elected to receive margetuximab after PD during treatment with belantamab mafodotin therapy will receive margetuximab once every 3 weeks (+3-day window period) and have efficacy and safety evaluated once every 3 weeks, subject to approval by EMA and FDA. Dose-related assessments will be entered into the electronic case report form (eCRF) in the next scheduled cycle.

[0508] In the case of a medical / surgical event or for logistical reasons unrelated to the study therapy (e.g., elective surgery, unrelated medical event, participant vacation and / or holidays, but not due to a decision by the participant to delay treatment), delayed dosing is permitted. The reason for any dosing delay must be recorded in the participant's eCRF and clinical record and discussed with the medical monitor.

[0509] In the absence of evidence of PD or significant toxicity related to the study product, the maximum permitted dose delay for belantamab mafodotin or margetuximab is 16 weeks, unless the medical monitor gives written consent.

[0510] In Part 1, based on safety, tolerability, and the preliminary PK data obtained in participants at the previous dose level, the decision to proceed to the next dose level (increase or decrease) of belantamab mafodotin will be made by the DEC.

[0511] Example 3: Analyze the effect of differences in the drug - to - antibody ratio (DAR) of GSK2857916 on in vivo antitumor activity.

[0512] The effect of the drug-to-antibody ratio (DAR) on the in vitro and in vivo activity of GSK2857916 was evaluated. The results showed that DAR differences had no significant effect on in vivo anti-tumor activity, and the activity depended on the dose rather than the DAR.

[0513] Experimental procedures

[0514] Female severe combined immunodeficient (SCID) mice were nine weeks old on day 1 of the study and weighed between 15.6 and 23.8 grams. The H929 human plasmacytoma cell line was obtained from the American Type Culture Collection (ATCC). Cells were maintained as an exponentially growing suspension culture in RPMI 1640 medium supplemented with 20% fetal bovine serum, 2 mM glutamine, 50 μM mercaptoethanol, 100 units / mL penicillin G sodium, 100 μg / mL streptomycin sulfate, and 25 μg / mL gentamicin. Tumor cells were cultured in tissue culture flasks in a humidified incubator at 37 °C in an atmosphere of 5% CO2 and 95% air.

[0515] H929 cells for implantation were harvested during the logarithmic growth phase and resuspended in 50% Matrigel (BD Biosciences) in cold PBS. Each mouse was injected subcutaneously in the right flank with 1x10 7 tumor cells (0.1 mL of cell suspension). Twenty days after tumor implantation (which was designated as day 1 of the study), mice bearing established H929 tumors were divided into four groups (n = 10 / group). For all groups, individual tumor volumes ranged from 126 to 288 mm 3 and group mean tumor volumes ranged from 195 to 198 mm 3 . Administration of the drug was initiated according to the treatment schedule summarized in Table 10, and the volume of administration was scaled to the body weight of the individual animal.

[0516] Results and discussion

[0517] The study results are shown in Figure 3 . The results showed that GSK2857916 DAR4.1 at 2 mg / kg caused a significant delay in tumor growth but no initial tumor regression. GSK2857916 DAR2.1 at 4 mg / kg was significantly more effective than GSK2857916 DAR4.1 at 2 mg / kg, even though the same dose of toxin was expected to be delivered under each condition. In addition, GSK2857916 DAR2.1 at 4 mg / kg was more effective than GSK2857916 DAR2.1 at 2 mg / kg, even though more toxin was expected to be delivered in the latter condition. These results suggest that the dose of the antibody is a more important determinant of antitumor activity than the DAR of the molecule.

[0518] In summary, the change in DAR from 2.1 to 5.7 had no effect on the antitumor activity of 2 mg / kg of GSK2857916. Instead, the administered ADC dose was the major determinant of antitumor activity because the activity of 4 mg / kg of GSK2857916 DAR2.1 was significantly higher than that of 2 mg / kg of GSK2857916 DAR4.1, even though the same amount of toxin was administered in both cases. Thus, this analysis indicates that at a given drug concentration, DAR variation has no significant effect on antitumor activity in vivo.

[0519] Table 10. Study treatment groups

[0520]

[0521] Example 4: Evaluate soluble BCMA (sBCMA) levels in patients with relapsed / refractory multiple myeloma (RRMM) treated with margetuximab Experimental procedures

[0522] Soluble BCMA (sBCMA) levels were analyzed as an exploratory endpoint in patients in a phase 3 open-label randomized clinical trial evaluating the safety and efficacy of single-agent margetuximab compared to the combination of pomalidomide and dexamethasone in participants with RRMM (DREAMM-3 study; NCT04162210). Overall, the results showed that administration of unconjugated belantamab in combination with margetuximab could affect sBCMA levels, thereby improving the efficacy of margetuximab treatment.

[0523] Results and discussion

[0524] Study participants with RRMM were randomized in a 2:1 ratio to receive single-agent margetuximab or the combination of pomalidomide and dexamethasone (pom / dex). Margetuximab was administered at a dose of 2.5 mg / kg by intravenous (IV) infusion on day 1 of a 21-day cycle, i.e., every three weeks (Q3W). Pomalidomide was administered daily on each of days 1 to 21 of a 28-day cycle, and dexamethasone was administered once a week (i.e., on days 1, 8, 15, and 22 of each 28-day cycle). Participants in both study arms were treated until disease progression, death, unacceptable toxicity, withdrawal of consent, and loss to follow-up or study completion (whichever occurred first).

[0525] Serum samples were obtained from patients in both study arms at the following time points relative to margetuximab infusion: pre-dose, end of infusion, 2 hours post-infusion, 24 hours post-infusion, 4 days post-infusion, and days 8 - 15 post-infusion. Soluble BCMA levels in cell supernatants were measured using a validated electrochemiluminescence immunoassay.

[0526] Effect of sBCMA levels on treatment with margetuximab

[0527] Figure 4 Analysis of sBCMA levels in patients treated with margetuximab relative to pom / dex showed a difference in sBCMA levels between the two treatment arms, with sBCMA levels being specifically affected by margetuximab treatment compared to pom / dex treatment. As Margetuximab binds to sBCMA in patient samples shown, progression-free survival (PFS) was lowest in both treatment arms in patients in the highest quartile (Q4) of baseline sBCMA levels (i.e., before administration of margetuximab), indicating a poorer response to treatment. The response in patients in the highest quartiles (Q3 and Q4) of baseline sBCMA levels in the pom / dex arm was essentially similar between the two quartiles (PFS of approximately 4 - 5 months). However, in the margetuximab arm, the response in patients in the highest quartiles (Q3 and Q4) of baseline sBCMA levels was differentiated between the two quartiles, with observed PFS of approximately 7 months and 15 months for Q4 and Q3 patients, respectively. These data suggest that the response to margetuximab treatment is directly influenced by the sBCMA level at baseline, while this effect was not observed with pom / dex treatment.

[0528] Figure 5 。At the end of margetuximab infusion (EOI), sBCMA levels were measured in participants in the margetuximab treatment arm. Patient samples were obtained within 30 minutes after the end of margetuximab infusion, and sBCMA levels in the samples were measured. Based on the sBCMA levels detected at EOI, margetuximab was determined to bind essentially all peripheral sBCMA at a dose level of 2.5 mg / kg. See sBCMA binds immediately after margetuximab infusion, but sBCMA levels rebound after 24 hours , which shows that for cycle 1, day 1 of margetuximab treatment, sBCMA levels decreased from before administration of margetuximab to the EOI level, where the x-axis represents the pre-dose sBCMA level and the y-axis represents the difference in sBCMA levels from pre-infusion to EOI. The level of decrease in sBCMA at EOI was consistent across each cycle (data not shown). In the data shown, approximately 89% sBCMA binding was detected by ELISA, which may be the limit of detection of the assay as there was no evidence that the amount of sBCMA exceeded the amount of the study drug.

[0529] Figure 6 。In participants treated with margetuximab, an increase in sBCMA levels was detected 24 hours after the end of margetuximab infusion (EOI). Although a linear decline in sBCMA levels was observed, an exponential increase in sBCMA levels was observed 24 hours later, indicating that sBCMA rebound has a non-linear relationship with the sBCMA baseline level and follows a different pattern from the decline in sBCMA levels ( Figure 7A)。However, the sBCMA levels observed 24 hours after EOI were not solely due to dissociation of sBCMA from margetuximab, as the half-life of sBCMA is approximately 24 hours, suggesting that the increase in sBCMA levels was mostly due to fresh shedding of tumor cells. Additionally, when evaluating sBCMA levels in patients grouped by response to margetuximab treatment, patients with progressive disease (PD) had the highest baseline sBCMA levels, but there was a large overlap in baseline sBCMA levels between responders and non-responders( Figure 7B )。Although the sBCMA level rebound was also the greatest in the progressive disease group after infusion of margetuximab, the differences( Example 5: In vivo efficacy of belantamab mafodotin and margetuximab in a human multiple myeloma xenograft model in NOG mice ) observed between responders (including groups of patients with complete response (CR), very good partial response (VGPR), and partial response (PR)) and non-responders (including groups of patients with stable disease (SD) or progressive disease (PD)) increased compared to the baseline levels. This suggests that the presence of peripheral sBCMA and the rate / level of sBCMA rebound after margetuximab infusion may have a direct impact on margetuximab treatment.

[0530] In summary, these data suggest that eliminating or binding free sBCMA may be a favorable strategy to increase the efficacy of margetuximab.

[0531] Cell culture Tumor inoculation

[0532] Studies were conducted to evaluate the in vivo therapeutic efficacy of belantamab (GSK2857914), margetuximab (GSK2857916), and ozogamicin as single agents and combination drugs in the NOG mouse model of MM.1S-Luc human multiple myeloma xenograft.

[0533] Experimental procedures

[0534] Treatment administration 。MM.1S-Luc cancer cells were maintained in vitro in RPMI 1640 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. Cells in exponential growth phase were collected and quantified by a cell counter prior to tumor inoculation.

[0535] Tumor monitoring 。Each mouse was inoculated intravenously via the tail vein with MM.1S-Luc tumor cells (1x10 7 ) in 0.1 mL PBS for tumor development. Seven days after tumor cell inoculation, the mice were imaged and randomly assigned to 7 study groups.

[0536] Figure 8 Administer to a group of ten (10) mice by intraperitoneal (ip) administration in the amounts, frequencies, and durations shown in Table 11.

[0537] Table 11

[0538]

[0539] Figure 9 Image tumor growth twice a week by bioluminescence imaging. Fifteen minutes before imaging, inject the mice subcutaneously with 150 mg / kg of D-luciferin (PerkinElmer, catalog number 122799). Image the mice on a PerkinElmer IVIS Lumina Series III in vivo imaging system.

[0540] Results

[0541] ​ Show the mean tumor volume curves for the vehicle group and the treatment groups between randomization and study termination, and Table 12 shows the tumor growth inhibition (TGI) from the data collected on Day 11. ​ Show the Kaplan-Meier survival curves for all treatment groups as a function of the study, and Table 13 presents the median survival days and the Kaplan-Meier statistical analysis. The results indicate that single-agent treatment with GSK2857916 (Group 2), the combination of GSK2857916 and GSK2857914 (Groups 3 and 4), and the combination of GSK2857916 and ogeprevir (Group 5) produced significant anti-tumor efficacy against the MM1s-Luc model, with TGI values of 98.87%, 99.19%, 97.88%, and 99.19% on Day 11, respectively, showing significant statistical differences compared to the vehicle control group (p < 0.01). The combination of GSK2857916 and GSK2857914 (Groups 3 and 4) showed the strongest anti-tumor efficacy across all treatment groups during the study. In addition, compared to the vehicle control group (median survival days 25.00 days), the combination of GSK2857916 and GSK2857914 (Groups 3 and 4) and the combination of GSK2857916 and ogeprevir (Group 5) significantly prolonged the survival of the animals (median survival days were 54.5, 58.00, and 53.50, respectively).

[0542] Table 12

[0543]

[0544] Table 13

[0545]

[0546]

[0547] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties (such as molecular weight), reaction conditions, etc. recited in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0548] While numerical ranges and parameters setting forth the broad scope of the present disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0549] The terms "a", "an", "the", and similar referents used in the context of describing the present disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural unless otherwise indicated herein or clearly contradicted by context. The recitation of a range of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is merely intended to better illuminate the present disclosure and does not pose a limitation on the scope of the present disclosure that is otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present disclosure.

[0550] The grouping of alternative elements or embodiments of the present disclosure disclosed herein should not be construed as a limitation. Each member of the group can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is contemplated that, for reasons of convenience and / or patentability, one or more members of the group may be included in or deleted from the group. When any such inclusion or deletion occurs, the specification is deemed to contain the modified group and thus to satisfy the written description of all Markush groups used in the appended claims.

[0551] This document describes certain embodiments of the present disclosure, including the best mode known to the inventors for carrying out the present disclosure. Of course, variations of these described embodiments will become apparent to those skilled in the art after reading the foregoing description. The inventors expect those skilled in the art to appropriately adopt such variations, and the inventors intend for the present disclosure to be practiced in a manner different from that specifically described herein. Accordingly, the present disclosure includes all modifications and equivalents of the subject matter recited in the appended claims as permitted by applicable law. In addition, unless otherwise stated herein or clearly contradicted by context, the present disclosure covers any combination of the above elements in all possible variations thereof.

[0552] The specific embodiments disclosed herein may be further limited in the claims by the language “consisting of” or “consisting essentially of”. When used in the claims, whether submitted or added by amendment, the transitional term “consisting of” excludes any element, step, or ingredient not specified in the claims. The transitional term “consisting essentially of” limits the scope of the claim to the specified materials or steps and those that do not materially affect the basic and novel characteristics. Embodiments of the present disclosure so claimed are inherently or explicitly described and enabled herein.

[0553] It should be understood that the embodiments of the present disclosure disclosed herein are illustrative of the principles of the present disclosure. Other modifications that may be employed are within the scope of the present disclosure. Thus, by way of example and not limitation, alternative configurations of the present disclosure may be utilized in accordance with the teachings herein. Accordingly, the present disclosure is not limited to exactly as shown and described.

[0554] Although the present disclosure has been described and illustrated herein by reference to various specific materials, procedures, and examples, it should be understood that the present disclosure is not limited to the particular combinations of materials and procedures selected for that purpose. As will be understood by those skilled in the art, many variations of these details may be implied. The specification and examples are intended to be considered only exemplary, and the true scope and spirit of the present disclosure are indicated by the following claims. All references, patents, and patent applications mentioned in this application are incorporated herein by reference in their entirety.

Claims

1. A method of treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) in a patient, the method comprising administering belantamab to the patient at a dose of about 300 mg to about 2000 mg.

2. The method of claim 1, wherein the dose is about 300 mg, about 900 mg, or about 2000 mg.

3. The method according to any one of the preceding claims, wherein the patient has been treated with one, two, three, or four prior lines of cancer therapy, wherein the prior lines of cancer therapy include anti-CD38 monoclonal antibodies, proteasome inhibitors, and immunomodulators.

4. The method according to any one of the preceding claims, wherein the patient further receives at least one additional cancer therapy, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulator, or an anti-PD-1 monoclonal antibody.

5. The method of claim 4, wherein the additional cancer therapy is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

6. The method according to any one of the preceding claims, further comprising administering a priming dose of mapatumumab to the patient prior to initiation of belantamab administration, wherein the priming dose of mapatumumab is about 1.4 mg / kg to about 3.4 mg / kg, once during the priming period.

7. The method of claim 6, wherein the priming dose of mapatumumab is about 1.4 mg / kg, about 1.9 mg / kg, about 2.5 mg / kg, or about 3.4 mg / kg, once during the priming period.

8. The method of claim 6 or claim 7, wherein the priming period is four weeks ± 3 days, and mapatumumab is administered on day 1 of the priming period.

9. The method according to any one of claims 6 to 8, further comprising administering to the patient at least one additional cancer therapy during the priming period, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulator, or an anti-PD-1 monoclonal antibody.

10. The method of claim 9, wherein the additional cancer therapy is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

11. A method of treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) in a patient, the method comprising administering to the patient a therapeutically effective amount of a combination comprising a first BCMA antagonist and a second BCMA antagonist.

12. The method of claim 11, wherein the first and second BCMA antagonists are independently selected from anti-BCMA antibodies or antigen-binding fragments thereof, anti-BCMA antibody-drug conjugates, bispecific anti-BCMA antibodies or antigen-binding fragments thereof, and chimeric antigen receptor T (CAR T) cell therapies targeting BCMA.

13. The method according to claim 11, wherein the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is the corresponding unconjugated anti-BCMA antibody.

14. A method of treating a disease or disorder responsive to inhibition or blockade of B-cell maturation antigen (BCMA) in a patient, the method comprising administering to the patient a therapeutically effective amount of a combination comprising margetuximab and belantamab.

15. The method according to any one of claims 11 to 14, further comprising administering to the patient at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulator, or an anti-PD-1 monoclonal antibody.

16. The method according to claim 15, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

17. A method of treating a disease or disorder responsive to inhibition or blockade of B-cell maturation antigen (BCMA) in a patient previously treated with a first BCMA antagonist, the method comprising administering to the patient a therapeutically effective amount of a second BCMA antagonist, wherein the patient discontinues administration of the first BCMA antagonist prior to initiation of administration of the second BCMA antagonist, and the second BCMA antagonist is different from the first BCMA antagonist.

18. The method according to claim 17, wherein the first and second BCMA antagonists are independently selected from anti-BCMA antibodies or antigen-binding fragments thereof, anti-BCMA antibody-drug conjugates, bispecific anti-BCMA antibodies or antigen-binding fragments thereof, and chimeric antigen receptor T (CAR T) cell therapies targeting BCMA.

19. The method according to claim 17, wherein the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is the corresponding unconjugated anti-BCMA antibody; or wherein the second BCMA antagonist is an anti-BCMA antibody-drug conjugate and the first BCMA antagonist is the corresponding unconjugated anti-BCMA antibody.

20. The method according to claim 19, wherein the first BCMA antagonist is margetuximab and the second BCMA antagonist is belantamab; or wherein the second BCMA antagonist is margetuximab and the first BCMA antagonist is belantamab.

21. A method of reducing corneal toxicity in a patient previously treated with margetuximab, the method comprising administering to the patient a therapeutically effective amount of belantamab, wherein the patient discontinues administration of margetuximab prior to initiation of administration of belantamab.

22. The method according to any one of claims 17 to 21, further comprising administering to the patient at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulator, or an anti-PD-1 monoclonal antibody.

23. The method according to claim 22, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

24. 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.

25. A method of treating a disease or disorder in a patient previously treated with an antibody-drug conjugate, the method comprising administering to the patient a therapeutically effective amount of the corresponding unconjugated antibody, wherein the patient discontinues administration of the antibody-drug conjugate prior to initiation of administration of the corresponding unconjugated antibody.

26. The method according to any one of claims 1 to 25, wherein the disease or disorder is a plasma cell disorder or a B cell disorder.

27. The method according to any one of claims 1 to 25, wherein the disease or disorder is a cancer expressing BCMA.

28. The method according to any one of claims 1 to 25, wherein the disease or disorder is multiple myeloma (MM).

29. The method according to claim 28, wherein the MM is relapsed and / or refractory MM, newly diagnosed MM, MM unsuitable for transplantation, or newly diagnosed MM unsuitable for transplantation.

30. A method of treating cancer in a patient, wherein the patient has a corneal adverse reaction of grade 2 or higher due to administration of margetuximab, the method comprising temporarily discontinuing administration of margetuximab; administering to the patient a therapeutically effective amount of belantamab during a lead-in period; and resuming administration of margetuximab after the lead-in period.

Images