Combination therapy with an anti-BCMA antibody and a gamma-secretase inhibitor

Abstract

The present disclosure relates to a method for treating cancer (particularly such as multiple myeloma), the method involving a combination of an anti-BCMA (B-cell maturation antigen) antibody (belantamab mafodotin - GSK2857916 -) and a γ-secretase inhibitor (such as nilotinib - PF03084014 -). The present disclosure also relates to the dosage, the duration of treatment, and the time interval between the administration of the anti-BCMA antibody and the γ-secretase inhibitor.

Description

Field of the Invention

[0001] The present invention relates to combination therapies of pharmaceutically active antigen-binding proteins for treating cancer, such as monoclonal antibodies and gamma-secretase inhibitors. Specific dosage regimens and methods of administration are also included. BACKGROUND OF THE INVENTION

[0003] Multiple myeloma (MM) is an incurable malignancy and accounts for 1% of all cancers and 10% of all hematologic malignancies. A variety of drugs and combination therapies have been evaluated and found to be effective for treating multiple myeloma (National Comprehensive Cancer Network, 2016; Moreau, San Miguel et al., 2017). However, most of these patients inevitably relapse, if not all (Richardson, Barlogie et al., 2003; Richardson, Barlogie et al., 2006; Jagannath, Barlogie et al., 2008).

[0004] Drug combinations have emerged for patients previously treated for MM, but these regimens may be limited by toxic effects (National Comprehensive Cancer Network, 2016). There is a need for agents with new mechanisms of action that can be combined with existing therapies without adding significant toxicity.

[0005] Low surface expression of B-cell maturation antigen (BCMA) or soluble BCMA on cancer cells can limit or prevent the efficacy of therapeutic agents due to insufficient binding to BCMA present on the cancer cell surface. Low levels of other target molecules (such as CD19, CD20) on tumor cells targeted with antibodies, antibody-drug conjugates or chimeric antigen receptor T cells have been shown to limit the efficacy of these therapies and allow cancer cells expressing low levels of the target molecule to escape elimination. In the case of BCMA, the short extracellular portion of the molecule is cleaved and shed from the cell surface by the action of gamma-secretase (γ-secretase, a membrane-localized cellular enzyme involved in protein cleavage). This cleavage reduces the density of the molecule on cells expressing BCMA, such as myeloma cancer cells, and leads to elevated levels of soluble BCMA (sBCMA) in the serum of patients with certain autoimmune diseases (such as systemic lupus erythematosus) as well as cancer (such as multiple myeloma).

[0006] Currently, there remains a need in the field of immunotherapy for alternative or improved compositions and methods for more effectively treating autoimmune diseases and cancer. SUMMARY OF THE INVENTION

[0008] In one aspect of the present invention, there is provided a combination comprising an anti-BCMA antigen-binding protein and a γ-secretase inhibitor.

[0009] In another aspect of the present invention, the combination comprises belantamab mafodotin and nilotinib.

[0010] In one aspect of the present invention, there is provided herein a combination comprising an anti-BCMA antigen-binding protein and a γ-secretase inhibitor for treating cancer.

[0011] In another aspect of the present invention, there is provided herein a method of treating cancer in a subject in need thereof, which comprises administering a therapeutically effective dose of an anti-BCMA antigen-binding protein and a γ-secretase inhibitor.

[0012] In another aspect of the present invention, there is provided herein a kit for treating cancer, which comprises:

[0013] i) an anti-BCMA antigen-binding protein; and

[0014] ii) instructions for use in combination with a γ-secretase inhibitor. Sequence Listing <110> GlaxoSmithKline Intellectual Property Development Limited <120> Combination Therapy with Anti-BCMA Antibody and Gamma Secretase Inhibitor <130> PB66738P <160> 10 <170> FastSEQ for Windows Version 4.0 <210> 1 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 1 Asn Tyr Trp Met His 1 5 <210> 2 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Artificially synthesized sequence <400> 2 Ala Thr Tyr Arg Gly His Ser Asp Thr Tyr Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <210> 3 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequence <400> 3 Gly Ala Ile Tyr Asp Gly Tyr Asp Val Leu Asp Asn 1 5 10 <210> 4 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequence <400> 4 Ser Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 5 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequence <400> 5 Tyr Thr Ser Asn Leu His Ser 1 5 <210> 6 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequence <400> 6 Gln Gln Tyr Arg Lys Leu Pro Trp Thr 1 5 <210> 7 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Artificially synthesized sequence <400> 7 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asn Tyr 20 25 30 Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Thr Tyr Arg Gly His Ser Asp Thr Tyr Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ala Ile Tyr Asp Gly Tyr Asp Val Leu Asp Asn Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 8 <211> 108 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <400> 8 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Asn Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Arg Lys Leu Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 9 <211> 451 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <400> 9 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asn Tyr 20 25 30 Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ala Thr Tyr Arg Gly His Ser Asp Thr Tyr Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ala Ile Tyr Asp Gly Tyr Asp Val Leu Asp Asn Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 <210> 10 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 10 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Asn Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Arg Lys Leu Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 Description of the Drawings

[0015] Figure 1 Showing the viability of myeloma cell line L363 when treated with different doses of γ-secretase inhibitor (nilotinib) in combination with belantamab mafodotin or control group IgG-MMAF.

[0016] Figure 2 Showing the ADCC activity of belantamab mafodotin in combination with nilotinib evaluated in myeloma cell line L363.

[0017] Figure 3 Showing the ADC activity in cell lines expressing BCMA.

[0018] Figure 4 Showing the ADCC activity in cell lines expressing BCMA.

[0019] Figure 5 Showing the sBCMA level after treatment with nilotinib.

[0020] Figure 6 Showing the cell surface level of BCMA after treatment with nilotinib. DETAILED DESCRIPTION OF THE INVENTION

[0022] In one aspect of the present invention, there is provided a combination comprising an anti-BCMA antigen-binding protein and a γ-secretase inhibitor for treating cancer or other B cell-mediated diseases or disorders.

[0023] B cell disorders can be classified into defects in B cell development / immunoglobulin production (immunodeficiency) and excessive / uncontrolled proliferation (lymphoma, leukemia). As used herein, B cell disorders refer to two types of diseases, and methods for treating B cell disorders with antigen-binding proteins are provided.

[0024] Examples of cancers, and in particular B cell-mediated or plasma cell-mediated diseases or antibody-mediated diseases or disorders, 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 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 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).

[0025] In certain embodiments, the disease or disorder is selected from the group consisting of multiple myeloma (MM), non-Hodgkin lymphoma B cell leukemia (NHL), follicular lymphoma (FL), and diffuse large B cell lymphoma (DLBCL).

[0026] In one embodiment of the invention, the disease is multiple myeloma or non-Hodgkin lymphoma B cell leukemia (NHL).

[0027] In one embodiment of the invention, the disease is multiple myeloma.

[0028] In one embodiment of the invention, the cancer can be a hematopoietic (or hematological or hematopathologic or blood-related) cancer, e.g., a cancer derived from blood cells or immune cells, which can be referred to as a "liquid tumor". In one embodiment, the cancer is a B cell-related cancer, and in particular a cancer that expresses BCMA. In a further embodiment, the cancer is a leukemia, such as chronic myelogenous leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and acute lymphocytic leukemia. In another embodiment, the cancer is a lymphoma, such as non-Hodgkin lymphoma, Hodgkin lymphoma; etc. In another embodiment, the cancer is a plasma cell malignancy, such as multiple myeloma, MGUS AL amyloidosis, and Waldenström macroglobulinemia.

[0029] In one embodiment, the cancer is multiple myeloma. In another embodiment, the cancer is relapsed and / or refractory multiple myeloma. In another embodiment, a patient with relapsed and / or refractory multiple myeloma has previously been treated with at least one, at least two, at least three, or at least four therapeutic agents for the treatment of multiple myeloma.

[0030] In another embodiment, the patient may have had 0, 1, 2, 3, or 4 or more prior lines of treatment before being treated with the combination described herein. In another embodiment, the patient may have relapsed and / or refractory multiple myeloma and have had 0, 1, 2, 3, or 4 or more prior lines of treatment before being treated with the combination described herein. In another embodiment, the patient has been previously treated with at least 3 prior lines, which may include the following: immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 therapy (such as daratumumab). Lines of therapy may be defined by a consensus panel of the International Myeloma Working Group (IMWG) [Rajkumar, 2011].

[0031] In one aspect of the invention provided herein, the BCMA antigen-binding protein is administered at a specific dose or dose range. Throughout, mg / kg refers to the milligrams of therapeutic agent (such as the antigen-binding protein) per kilogram of patient body weight. In one aspect of the invention provided herein, the anti-BCMA antigen-binding protein is administered at a dose of about 0.5 - 4.0 mg / kg or about 1.0 to 4.0 mg / kg. In one embodiment, the anti-BCMA antigen-binding protein is administered at a dose of about 0.5 to 2.0 mg / kg, about 0.5 to 1.0 mg / kg, about 1.0 to 3.0 mg / kg, or about 2.0 to 4.0 mg / kg or about 2.0 to 3.0 mg / kg. In a further embodiment, the anti-BCMA antigen-binding protein is administered at a dose of about 0.5 to 2.0 mg / kg or about 2.0 to 3.5 mg / kg. In a further embodiment, the anti-BCMA antigen-binding protein is administered at a dose of about 0.5 mg / kg, about 0.95 mg / kg, about 1 mg / kg, about 1.25 mg / kg, about 1.7 mg / kg, about 1.9 mg / kg, about 2.5 mg / kg, or about 3.4 mg / kg.

[0032] In another embodiment, the therapeutically effective dose of the BCMA antigen-binding protein is a fixed dose rather than in mg / kg. Using a fixed dose may result in a similar exposure range as weight-based dosing. Fixed dosing may offer the advantages of reduced dosing errors, reduced drug waste, shorter preparation times, and improved ease of administration. Thus, in one embodiment, the fixed dose of the BCMA antigen-binding protein is based on a reference body weight of 70 kg or 80 kg (the median participating body weight).

[0033] In one aspect of the invention as provided herein, the γ-secretase inhibitor is administered at a dose of about 25 - 220 mg. In one embodiment, the γ-secretase inhibitor is administered at a dose of about 50 - 150 mg. In one embodiment, the γ-secretase inhibitor is administered at a dose of about 50 mg, about 100 mg, or about 150 mg. In one embodiment, the γ-secretase inhibitor is administered at a dose of 50 mg, 100 mg, or 150 mg. In one embodiment, the γ-secretase inhibitor is administered at a dose of 50 mg. In one embodiment, the γ-secretase inhibitor is administered at a dose of 100 mg. In one embodiment, the γ-secretase inhibitor is administered at a dose of 150 mg.

[0034] In one embodiment, the anti-BCMA antigen-binding protein is administered at a dose of about 3.4 mg / kg, and the γ-secretase inhibitor is administered at a dose of about 150 mg.

[0035] In one embodiment, the anti-BCMA antigen-binding protein is administered at a dose of about 2.5 mg / kg, and the γ-secretase inhibitor is administered at a dose of about 150 mg.

[0036] In a further embodiment, the anti-BCMA antigen-binding protein is administered at a dose of about 1.9 mg / kg, and the γ-secretase inhibitor is administered at a dose of about 150 mg.

[0037] In a further embodiment, the anti-BCMA antigen-binding protein is administered at a dose of about 0.95 mg / kg, and the γ-secretase inhibitor is administered at a dose of about 150 mg.

[0038] In one embodiment, the anti-BCMA antigen-binding protein is administered at a dose of about 3.4 mg / kg, and the γ-secretase inhibitor is administered at a dose of about 100 mg.

[0039] In one embodiment, the anti-BCMA antigen-binding protein is administered at a dose of about 2.5 mg / kg, and the γ-secretase inhibitor is administered at a dose of about 100 mg.

[0040] In a further embodiment, the anti-BCMA antigen-binding protein is administered at a dose of about 1.9 mg / kg, and the γ-secretase inhibitor is administered at a dose of about 100 mg.

[0041] In a further embodiment, the anti-BCMA antigen-binding protein is administered at a dose of about 0.95 mg / kg, and the γ-secretase inhibitor is administered at a dose of about 100 mg.

[0042] In one embodiment, the anti-BCMA antigen-binding protein is administered at a dose of about 3.4 mg / kg, and the γ-secretase inhibitor is administered at a dose of about 50 mg.

[0043] In one embodiment, the anti-BCMA antigen-binding protein is administered at a dose of about 2.5 mg / kg, and the γ-secretase inhibitor is administered at a dose of about 50 mg.

[0044] In a further embodiment, the anti-BCMA antigen-binding protein is administered at a dose of about 1.9 mg / kg, and the γ-secretase inhibitor is administered at a dose of about 50 mg.

[0045] In a further embodiment, the anti-BCMA antigen-binding protein is administered at a dose of about 0.95 mg / kg, and the γ-secretase inhibitor is administered at a dose of about 50 mg.

[0046] In one embodiment, the γ-secretase inhibitor is administered twice daily (BID). In one embodiment, the γ-secretase inhibitor is administered daily. In yet another embodiment, the γ-secretase inhibitor can be administered on a "7 days on / 14 days off" schedule, where the γ-secretase inhibitor is administered twice daily (BID) on days 1 to 7 of a 21-day cycle and not administered on days 8 to 14.

[0047] In one aspect of the invention, the γ-secretase inhibitor can be administered simultaneously or sequentially with the anti-BCMA antigen-binding protein. In one embodiment, the γ-secretase inhibitor is administered before the anti-BCMA antigen-binding protein. For example, in one aspect, the γ-secretase inhibitor is administered at least 1 hour before the anti-BCMA antigen-binding protein.

[0048] In one aspect of the invention, the anti-BCMA antigen-binding protein is administered weekly. In a further aspect, the anti-BCMA antigen-binding protein is administered once every 21 days (i.e., on day 1 of a 21-day cycle).

[0049] In a further embodiment, the dose of the anti-BCMA antigen-binding protein is adjusted to control the maximum plasma concentration, e.g., the dose is divided and administered, for example, one week apart. In one embodiment, the anti-BCMA antigen-binding protein is administered on day 1 (half of the total dose) and day 8 (the other half of the total dose) of a 21-day cycle. For example, if the total dose is 3.4 mg / kg, the "divided dose" regimen can comprise a dose of 1.7 mg / kg on day 1 of a 21-day cycle and another dose of 1.7 mg / kg on day 8. In another embodiment, if the total dose is 2.5 mg / kg, the "divided dose" regimen can comprise a dose of 1.25 mg / kg on day 1 of a 21-day cycle and another dose of 1.25 mg / kg on day 8. In another embodiment, if the total dose is 1.9 mg / kg, the "divided dose" regimen can comprise a dose of 0.95 mg / kg on day 1 of a 21-day cycle and another dose of 0.95 mg / kg on day 8.

[0050] In one embodiment, about 0.95 mg / kg, about 1.9 mg / kg, about 2.5 mg / kg or about 3.4 mg / kg of the anti-BCMA antigen-binding protein is administered on day 1 of a 21-day cycle.

[0051] In one embodiment, 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg or 3.4 mg / kg of the anti-BCMA antigen-binding protein is administered on day 1 of a 21-day cycle. In one embodiment, 0.95 mg / kg of the anti-BCMA antigen-binding protein is administered on day 1 of a 21-day cycle. In one embodiment, 1.9 mg / kg of the anti-BCMA antigen-binding protein is administered on day 1 of a 21-day cycle. In one embodiment, 2.5 mg / kg of the anti-BCMA antigen-binding protein is administered on day 1 of a 21-day cycle.

[0052] In a further embodiment, a loading dose of the anti-BCMA antigen-binding protein is administered on day 1 of a 21-day cycle, followed by a reduced dose in subsequent cycles. As provided herein, any dose contemplated by the present invention is administered in this manner. For example, the first dose can comprise administering about 3.4 mg / kg of the anti-BCMA antigen-binding protein, and subsequent cycles can use a dose of about 2.4 mg / kg of the anti-BCMA antigen-binding protein.

[0053] In one aspect of the invention as described herein, the anti-BCMA antigen-binding protein is an anti-BCMA antibody or a fragment thereof, or a CAR-T or an immunoconjugate. In one embodiment, the anti-BCMA antigen-binding protein is an anti-BCMA antibody. In a further embodiment, the anti-BCMA antigen-binding protein is a monoclonal antibody. In a further embodiment, the anti-BCMA antigen-binding protein is humanized.

[0054] In one aspect of the invention as described herein, the anti-BCMA antigen-binding protein comprises CDR sequences that have at least 90% or 95% or 99% sequence identity with CDRH1 according to SEQ ID NO:1; CDRH2 according to SEQ ID NO:2; CDRH3 according to SEQ ID NO:3; CDRL1 according to SEQ ID NO:4; CDRL2 according to SEQ ID NO:5; and CDRL3 according to SEQ ID NO:6.

[0055] In one embodiment, the anti-BCMA antigen-binding protein comprises CDRH1 according to SEQ ID NO:1; CDRH2 according to SEQ ID NO:2; CDRH3 according to SEQ ID NO:3; CDRL1 according to SEQ ID NO:4; CDRL2 according to SEQ ID NO:5; and CDRL3 according to SEQ ID NO:6. In one embodiment, the anti-BCMA antigen-binding protein comprises a heavy chain variable region (VH) according to SEQ ID NO:7; and a light chain variable region (VL) according to SEQ ID NO:8. In a further embodiment, the anti-BCMA antigen-binding protein comprises a heavy chain (H) according to SEQ ID NO:9 and a light chain (L) according to SEQ ID NO:10.

[0056] In one aspect of the invention as described herein, the anti-BCMA antigen-binding protein is further conjugated.

[0057] In one embodiment, the anti-BCMA antigen-binding protein is an immunoconjugate comprising an antigen-binding protein according to the invention as described herein, including but not limited to an antibody conjugated to one or more cytotoxic agents such as chemotherapeutic agents, drugs, growth inhibitors, toxins (e.g., protein toxins, enzymes, toxins or fragments thereof of bacterial, fungal, plant or animal origin) or radioisotopes (i.e., radio-conjugates). In a further embodiment, the anti-BCMA antigen-binding protein is conjugated to a toxin such as auristatin, e.g., monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF). In one embodiment, the anti-BCMA antigen-binding protein is conjugated to monomethyl auristatin F (MMAF).

[0058] In one embodiment, the anti-BCMA antigen-binding protein is an immunoconjugate having the following general structure:

[0059] ABP-((Linker)n-Ctx)m

[0060] Wherein

[0061] ABP is an antigen-binding protein

[0062] Linker is absent or any cleavable or non-cleavable linker

[0063] Ctx is any cytotoxic agent described herein

[0064] n is 0, 1, 2 or 3 and

[0065] m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0066] Exemplary linkers include 6-maleimidohexanoyl (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).

[0067] In one embodiment, the anti-BCMA antigen-binding protein is an immunoconjugate comprising a monoclonal antibody linked to MMAE or MMAF. In another embodiment, the anti-BCMA antigen-binding protein is an immunoconjugate comprising a monoclonal antibody linked to MMAE or MMAF via an MC linker, as depicted in the following structure:

[0068]

[0069] In one embodiment, the anti-BCMA antigen-binding protein is the antibody belantamab. In another embodiment, the anti-BCMA antigen-binding protein is the immunoconjugate belantamab mafodotin.

[0070] The conjugate antibodies (antibody-drug conjugates or ADCs) of the present invention are powerful anti-cancer agents that are designed to allow highly potent cytotoxic agents to specifically target tumor cells without affecting healthy tissues. Despite the use of tumor-specific antibodies, emerging clinical data for ADCs indicate that adverse events often occur before the ADC reaches its optimal therapeutic dose. Thus, even though these ADCs have high activity in preclinical tumor models, their therapeutic window in the clinic is narrow, and dosing regimens appear to be hampered by dose-limiting toxicities that cannot always be predicted based on data from preclinical models.

[0071] Therapies that can be combined to synergistically enhance therapeutic efficacy without worsening the safety profile would be a major advance in the treatment of cancer patients, particularly with regard to the incidence and severity of adverse events such as ocular toxicity that occur during treatment.

[0072] Fundamentally, combinations with drugs that can enhance the efficacy of the agent such that the overall response rate (ORR) is significantly higher while having an optimal risk-benefit profile would lead to a paradigm shift in the management of patients treated with such antigen-binding proteins.

[0073] The key to achieving an optimal risk-benefit profile depends on the dosing regimen of the therapy.

[0074] In one aspect of the invention as described herein, administering an anti-BCMA antigen-binding protein at a given time, location, and controlled dose (e.g., after a γ-secretase inhibitor) allows the plasma concentration to have the opportunity to reach its peak and thus obtain the maximum effect from the addition of the anti-BCMA antigen-binding protein.

[0075] In one aspect of the invention as described herein, the γ-secretase inhibitor is any of the following: Nilotinib (PF-03084014); LY3039478 (Crenigacestat); CB-103; Tarenflurbil; Semagacestat; RG-4733; EVP-0962; Avagacestat; MK-0752; BMS-906024; or LY450139 (Semagacestat).

[0076] In one embodiment, the γ-secretase inhibitor is Nilotinib ((S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide), (PF-03084014), which has the following chemical structure:

[0077]

[0078] In one aspect of the invention, provided herein is a combination for preventing and / or reducing ocular toxicity in a patient having cancer, such as multiple myeloma, comprising an anti-BCMA antigen-binding protein and a γ-secretase inhibitor. In one embodiment, the ocular toxicity is prevented or reduced when compared to a patient treated with the anti-BCMA antigen-binding protein alone (monotherapy).

[0079] "Prevent" means that a patient does not develop any signs, diagnosis, or symptoms of ocular toxicity. "Reduce" means any reduction in the severity or grade of signs, diagnosis, or symptoms of ocular toxicity.

[0080] "Ocular toxicity" means any unintended exposure of a therapeutic agent to ocular tissue. Ocular toxicity can include: corneal epithelial changes, dry eye, irritation, redness, blurred vision, dry eye, photophobia, and / or changes in visual acuity.

[0081] An eye examination can be performed by an ophthalmologist or an optometrist. The eye examination can include one or more of the following:

[0082] 1. Best corrected visual acuity,

[0083] 2. Record of manifest refraction and method for obtaining best corrected visual acuity,

[0084] 3. Current spectacle prescription (if applicable),

[0085] 4. Intraocular pressure measurement,

[0086] 5. Anterior segment (slit lamp) examination, including fluorescein staining of the cornea and lens examination,

[0087] 6. Dilated fundus examination, and / or

[0088] 7. Ocular Surface Disease Index (OSDI), which is a visual function questionnaire that assesses the impact of potential changes in ocular vision on function and health-related quality of life.

[0089] The above methods are known and practiced by those skilled in the art. The eye examination can be performed before, during, and / or after treatment.

[0090] In one aspect of the invention, provided is a method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective dose of an anti-BCMA antigen-binding protein and a γ-secretase inhibitor according to the invention as described herein.

[0091] In one aspect of the invention, provided is a method of treating cancer in a subject in need thereof, comprising administering:

[0092] i) A therapeutically effective dose of an anti-BCMA antigen-binding protein, which comprises CDRH1 according to SEQ ID NO:1; CDRH2 according to SEQ ID NO:2; CDRH3 according to SEQ ID NO:3; CDRL1 according to SEQ ID NO:4; CDRL2 according to SEQ ID NO:5; and CDRL3 according to SEQ ID NO:6; and

[0093] ii) Nilotinib.

[0094] In one aspect of the present invention, there is provided a method for treating cancer in a subject in need thereof, which comprises administering:

[0095] i) A therapeutically effective dose of an anti-BCMA antigen-binding protein, which comprises a heavy chain variable region (VH) according to SEQ ID NO:7; and a light chain variable region (VL) according to SEQ ID NO:8; and

[0096] ii) Nilotinib.

[0097] In one aspect of the present invention, there is provided a method for treating cancer in a subject in need thereof, which comprises administering:

[0098] i) A therapeutically effective dose of an anti-BCMA antigen-binding protein, which comprises a heavy chain (H) according to SEQ ID NO:9 and a light chain (L) according to SEQ ID NO:10; and

[0099] ii) Nilotinib.

[0100] In one aspect of the present invention, there is provided a method for treating cancer in a subject in need thereof, which comprises administering belantamab mafodotin and nilotinib.

[0101] In one aspect of the present invention, there is provided a method for treating cancer in a subject in need thereof, which comprises administering 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg or 3.4 mg / kg of belantamab mafodotin and 50 mg, 100 mg or 150 mg of nilotinib.

[0102] In one aspect of the present invention, there is provided a method for treating cancer in a subject in need thereof, which comprises administering 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg or 3.4 mg / kg of belantamab mafodotin on day 1 of a 21-day cycle, and administering 50 mg, 100 mg or 150 mg of nilotinib twice a day (BID).

[0103] In one aspect of the present invention, there is provided a method of treating cancer in a subject in need thereof, which comprises administering belantamab mafodotin at 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg or 3.4 mg / kg, wherein half of the dose is administered on day 1 of a 21-day cycle and half of the dose is administered on day 8 of the 21-day cycle; and administering nilotinib at 50 mg, 100 mg or 150 mg twice daily (BID) from day 1 to day 7 of the 21-day cycle.

[0104] In one aspect of the present invention, there is provided a method of treating multiple myeloma in a subject in need thereof, which comprises administering belantamab mafodotin at 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg or 3.4 mg / kg on day 1 of a 21-day cycle, and administering nilotinib at 50 mg, 100 mg or 150 mg twice daily (BID).

[0105] In one aspect of the present invention, there is provided a method of treating multiple myeloma in a subject in need thereof, which comprises administering belantamab mafodotin at 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg or 3.4 mg / kg, wherein half of the dose is administered on day 1 of a 21-day cycle and half of the dose is administered on day 8 of the 21-day cycle; and administering nilotinib at 50 mg, 100 mg or 150 mg twice daily (BID) from day 1 to day 7 of the 21-day cycle.

[0106] In one aspect, there is provided a combination according to the present invention for treating cancer as described herein, which comprises an anti-BCMA antigen-binding protein and a γ-secretase inhibitor.

[0107] In one aspect, there is provided a combination for treating cancer, which comprises a therapeutically effective dose of an anti-BCMA antigen-binding protein; and nilotinib, wherein the antigen-binding protein comprises CDRH1 according to SEQ ID NO:1; CDRH2 according to SEQ ID NO:2; CDRH3 according to SEQ ID NO:3; CDRL1 according to SEQ ID NO:4; CDRL2 according to SEQ ID NO:5; and CDRL3 according to SEQ ID NO:6.

[0108] In one aspect, there is provided a combination for treating cancer, which comprises a therapeutically effective dose of an anti-BCMA antigen-binding protein; and nilotinib, wherein the antigen-binding protein comprises a heavy chain variable region (VH) according to SEQ ID NO:7 and a light chain variable region (VL) according to SEQ ID NO:8.

[0109] In one aspect, a combination for treating cancer is provided, which comprises a therapeutically effective dose of an anti-BCMA antigen-binding protein; and nilotinib, wherein the antigen-binding protein comprises a heavy chain (H) according to SEQ ID NO:9 and a light chain (L) according to SEQ ID NO:10.

[0110] In one aspect, a combination for treating cancer is provided, which comprises belantamab mafodotin and nilotinib.

[0111] In one aspect, a combination for treating cancer is provided, which comprises belantamab mafodotin and nilotinib, wherein belantamab mafodotin is administered at 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg or 3.4 mg / kg, and nilotinib is administered at 50 mg, 100 mg or 150 mg.

[0112] In one aspect, a combination for treating cancer is provided, which comprises belantamab mafodotin and nilotinib, wherein belantamab mafodotin is administered at 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg or 3.4 mg / kg on day 1 of a 21-day cycle, and nilotinib is administered at 50 mg, 100 mg or 150 mg twice daily (BID).

[0113] In one aspect, a combination for treating cancer is provided, which comprises belantamab mafodotin and nilotinib, wherein belantamab mafodotin is administered at 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg or 3.4 mg / kg, and half of the dose is administered on day 1 of a 21-day cycle and half of the dose is administered on day 8 of a 21-day cycle; and nilotinib is administered at 50 mg, 100 mg or 150 mg twice daily (BID) from day 1 to day 7 of a 21-day cycle.

[0114] In one aspect, a combination for treating multiple myeloma is provided, which comprises belantamab mafodotin and nilotinib, wherein belantamab mafodotin is administered at 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg or 3.4 mg / kg, and nilotinib is administered at 50 mg, 100 mg or 150 mg.

[0115] In one aspect, a combination for treating multiple myeloma is provided, which comprises belantamab mafodotin and nilotinib, wherein belantamab mafodotin is administered at 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg or 3.4 mg / kg, and half of the dose is administered on day 1 of a 21-day cycle and half of the dose is administered on day 8 of a 21-day cycle; and nilotinib is administered at 50 mg, 100 mg or 150 mg twice daily (BID) from day 1 to day 7 of a 21-day cycle.

[0116] In one aspect, provided according to the present invention as described herein is a combination for preparing a medicament for treating cancer, wherein the combination comprises an anti-BCMA antigen-binding protein and a γ-secretase inhibitor.

[0117] In one aspect, provided is a kit for treating cancer, comprising:

[0118] (i) an anti-BCMA antigen-binding protein according to the present invention as described herein; and,

[0119] (ii) instructions for use when combined with a γ-secretase inhibitor according to the present invention as described herein.

[0120] In one aspect, provided is a kit for treating cancer, comprising:

[0121] (i) a γ-secretase inhibitor according to the present invention as described herein; and,

[0122] (ii) instructions for use when combined with an anti-BCMA antigen-binding protein according to the present invention as described herein.

[0123] In one aspect, provided is a kit for treating cancer, comprising:

[0124] (i) an anti-BCMA antigen-binding protein according to the present invention as described herein;

[0125] (ii) a γ-secretase inhibitor according to the present invention as described herein (as described herein in the present invention); and,

[0126] (iii) instructions for use.

[0127] In one aspect of the present invention, provided is a method for preventing ocular toxicity in a patient suffering from cancer (such as multiple myeloma), which comprises administering a therapeutically effective dose of an anti-BCMA antigen-binding protein and a γ-secretase inhibitor.

[0128] In one aspect of the present invention, provided is a method for reducing ocular toxicity in a patient suffering from cancer (such as multiple myeloma), which comprises administering a therapeutically effective dose of an anti-BCMA antigen-binding protein and a γ-secretase inhibitor.

[0129] DEFINITIONS

[0130] As used herein, the term "combination" refers to at least two therapeutic agents. As used herein, the term "therapeutic agent" can be understood as a substance that produces a desired effect in a tissue, system, animal, mammal, human, or other subject. In one embodiment, the combination can contain additional therapeutic agents, such as, for example, additional cancer therapeutic agents. In one embodiment, the additional cancer therapeutic agent is an immunomodulatory imide drug (IMiD), such as thalidomide, lenalidomide, pomalidomide, apremilast, or other thalidomide analogs.

[0131] Administering the combination of the present invention can be more advantageous than administering a single therapeutic agent alone because the combination can provide one or more of the following improved characteristics: i) greater anti-cancer effect than the most active single agent, ii) synergistic or highly synergistic anti-cancer activity, iii) a dosing regimen that provides enhanced anti-cancer activity and a reduced side effect profile, iv) a reduction in the toxic effect profile, v) an increase in the therapeutic window, or vi) an increase in the bioavailability of one or both therapeutic agents.

[0132] The combinations described herein can be in the form of a pharmaceutical composition. A "pharmaceutical composition" contains the combination described herein, as well as one or more pharmaceutically acceptable carriers, diluents, or excipients. The carrier, diluent, or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation, capable of being formulated into a pharmaceutical formulation, and not harmful to its recipient. In one embodiment, each therapeutic agent in the combination is separately formulated into its own pharmaceutical composition, and each pharmaceutical composition is administered to treat cancer. In this embodiment, each pharmaceutical composition can have the same or different carriers, diluents, or excipients.

[0133] The anti-BCMA antigen-binding protein in the combinations described herein can be used to treat or prevent cancer. The anti-BCMA antigen-binding protein described herein can bind to human BCMA, which includes, for example, human BCMA having an amino acid sequence with at least 90% homology or at least 90% identity to GenBank accession number Q02223.2, or a gene encoding human BCMA.

[0134] As used herein, the term "antigen-binding protein" refers to an antibody, an antibody fragment, or other protein construct capable of binding to human BCMA. The antigen-binding proteins of the invention may comprise the heavy chain variable region and the light chain variable region of the invention, which may form the structure of a natural antibody or a functional fragment or an equivalent thereof. Thus, when paired with a suitable light chain, the antigen-binding proteins of the invention may be full-length antibodies formed by formatting the VH regions of the invention, wherein the VH regions include (Fab')2 fragments, Fab fragments, or equivalents thereof (e.g., scFv, diabodies, triabodies, or tetra-bodies, tandabs, etc.). The antibody may be IgG1, IgG2, IgG3, or IgG; or IgM; IgA, IgE, or IgD; or a modified variant thereof. The constant domain of the antibody heavy chain may be selected accordingly. The constant domain of the light chain may be a κ or λ constant domain. Further, the antigen-binding proteins may comprise modified forms of all of the following classes, e.g., IgG dimers, Fc mutants that do not bind to Fc receptors or mediate C1q binding. The antigen-binding proteins may also be chimeric antibodies, of the type described in WO86 / 01533, which comprise an antigen-binding region and a non-immunoglobulin region.

[0135] In another aspect, the antigen-binding proteins are selected from the group consisting of dAbs, Fabs, Fab', F(ab')2, Fvs, diabodies, triabodies, tetra-bodies, minibodies, and microbodies. In one aspect of the invention, the antigen-binding proteins are humanized or chimeric antibodies. In another aspect, the antibodies are humanized. In one aspect, the antibodies are monoclonal antibodies. Chimeric antigen receptors (CARs) have been developed as artificial T cell receptors that enable T cells to acquire new specificities without the need to bind to MHC antigen peptide complexes. These synthetic receptors comprise a target-binding domain that is linked, in a single fusion molecule, to one or more signaling domains by a flexible linker. The target-binding domain is used to target a specific target on the surface of a pathological cell, and the signaling domains comprise the molecular machinery that enables T cell activation and proliferation. The flexible linker is capable of passing through the T cell membrane (or forming a transmembrane domain), allowing the target-binding domain of the CAR to be displayed on the cell membrane. CARs have successfully redirected T cells to antigens expressed on the surface of tumor cells of a variety of malignancies, including lymphomas and solid tumors (Jena et al. (2010) Blood, 116(7):1035-44).

[0136] In one embodiment, the anti-BCMA antigen-binding protein is an antibody that has enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) effector function. As used herein, the term "effector function" means one or more of the following, which includes antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC)-mediated responses, Fc-mediated phagocytosis, and antibody recycling via the FcRn receptor.

[0137] "γ-secretase" is a multi-subunit membrane-integrated protease that cleaves within the transmembrane domain of a single transmembrane protein. The γ-secretase complex plays a role in the processing of various substrates, including Notch, CD44, cadherin, and ephrin B2, and γ-secretase cleaves amyloid precursor protein into amyloid-β peptides associated with Alzheimer's disease. The γ-secretase complex is also known to cleave B cell maturation antigen (BCMA). Exemplary γ-secretase inhibitors (GSIs) include small molecules, peptidomimetic compounds, or γ-secretase-specific binding proteins. A GSI can target any one or more of the γ-secretase complex proteins, and the cleavage activity of γ-secretase is reduced compared to the γ-secretase activity without inhibition. In certain embodiments, the activity of γ-secretase is reduced by at least about 80%. Assays for measuring γ-secretase activity are known in the art (see, e.g., Laurent et al., 2015). For example, the level of soluble BCMA can be used as a surrogate marker for measuring γ-secretase activity. The γ-secretase inhibitor nilotinib is rapidly absorbed, and the median time to the Cmax (Tmax) value is 1 to 2.5 hours. Nilotinib is slowly eliminated in cancer patients, with a terminal half-life of 22.5 to 38.6 hours. The exposure of nilotinib is typically 20 to 330 mg BID (administered twice a day), and it increases in a dose-proportional manner. After repeated BID administration, steady state is reached by day 8, and the median accumulation ratio ranges from 1.18 to 2.84.

[0138] "CDR" is defined as the amino acid sequence of the complementarity-determining regions of an antigen-binding protein. It is the highly variable region of the immunoglobulin heavy and light chains. There are three heavy-chain and three light-chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. Thus, as used herein, "CDR" refers to all three heavy-chain CDRs, all three light-chain CDRs, all heavy-chain and light-chain CDRs, or at least two CDRs. The terms "VH" and "VL" as used herein refer to the heavy-chain variable region and the light-chain variable region of an antigen-binding protein, respectively.

[0139] In this specification, the amino acid residues of variable domain sequences and full-length antibody sequences are numbered according to the Kabat numbering convention. Similarly, the terms "CDR", "CDRL1", "CDRL2", "CDRL3", "CDRH1", "CDRH2", "CDRH3" used in the examples follow the Kabat numbering convention (see Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed., U.S. Department of Health and Human Services, National Institutes of Health (1991)). Alternative CDR sequence numbering conventions, such as those proposed by Chothia et al., refer to Chothia et al. (1989) Nature 342:877-883. Those skilled in the art can also obtain other CDR sequence numbering conventions, including the "AbM" (University of Bath) and "Contact" (University College London) methods.

[0140] SEQUENCE LISTING

[0141] SEQ.ID.NO.1–CDRH1

[0142] NYWMH

[0143] SEQ.ID.NO.2:CDRH2

[0144] ATYRGHSDTYYNQKFKG

[0145] SEQ.ID.NO.3:CDRH3

[0146] GAIYDGYDVLDN

[0147] SEQ.ID.NO.4:CDRL1

[0148] SASQDISNYLN

[0149] SEQ.ID.NO.5:CDRL2

[0150] YTSNLHS

[0151] SEQ.ID.NO.6:CDRL3

[0152] QQYRKLPWT

[0153] SEQ.ID.NO.7:Heavy chain variable region

[0154] QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGATYRGHSDTYYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYDGYDVLDNWGQGTLVTVSS

[0155] SED.ID.NO.8:Light chain variable region

[0156] DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSNLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYRKLPWTFGQGTKLEIKR

[0157] SEQ.ID.NO.9:Heavy chain region

[0158] QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGATYRGHSDTYYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYDGYDVLDNWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0159] SEQ.ID.NO.10:Light chain region

[0160] DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSNLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYRKLPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0161] Rationale for the combination of examples

[0162] γ-secretase inhibitor is an integral membrane protein complex that has protease activity towards single transmembrane proteins within the transmembrane domain (Wolfe, 2010). One of the substrates of γ-secretase is BCMA, which is the target of belantamab mafodotin and belantamab. Among the substrates of γ-secretase, BCMA is different in that it does not require an additional proteolytic step to release the extracellular domain of BCMA either before or after γ-secretase cleavage. This cleavage produces a soluble form of BCMA (“sBCMA”). γ-secretase is the only enzyme responsible for producing sBCMA, and in vitro and in vivo, inhibition of γ-secretase reduces sBCMA and increases the cell surface level of BCMA on plasma cells. In the case of multiple myeloma, the level of sBCMA is elevated in multiple myeloma patients and is correlated with the percentage of plasma cells in the bone marrow (Sanchez, 2018). Additionally, sBCMA is associated with immunodeficiency in patients with multiple myeloma.

[0163] γ-secretase inhibition will potentially enhance the mechanism of action of belantamab mafodotin and belantamab by increasing the cell surface expression of BCMA in multiple myeloma and enhancing internalization. The increased cell surface expression of BCMA will increase the amount of belantamab mafodotin and belantamab bound to the cell surface, thus potentially enhancing the ADCC mechanism of belantamab mafodotin and belantamab by increasing FcγR interaction and immune cell recruitment. Additionally, blocking the shedding of BCMA will potentially increase the internalization of bound belantamab mafodotin and belantamab, thus allowing enhanced delivery of the cys-mcMMAF toxin to multiple myeloma cells.

[0164] In preclinical experiments, using a panel of multiple myeloma and lymphoma cell lines with different BCMA expression levels, broad synergy was observed in assays designed to measure ADC and ADCC activity with the combination therapy of niraparib and belantamab mafodotin and belantamab.

[0165] Example 1

[0166] In Figure 1 the example shown, multiple myeloma cell line L363 was pretreated with four different concentrations of niraparib (PF-03084014) for 24 hours, then treated with a range of doses of belantamab mafodotin or control for an additional 72 hours and cell viability was measured. Belantamab, niraparib alone, conjugated isotype antibody (IgG-MMAF), or a combination of IgG-MMAF and niraparib had no effect on cell viability. However, a shift in EC50 of up to 1000-fold was observed with the combination of niraparib and belantamab mafodotin compared to belantamab alone.

[0167] Example 2

[0168] In Figure 2 the example shown, the ADCC activity of belantamab mafodotin in combination with niraparib was evaluated. L363 cells were pretreated with different concentrations of niraparib for 24 hours, exposed to belantamab, and FcγR engagement was evaluated using an engineered Jurkat cell line. The EC50 for FcγR engagement was increased 10-fold with the combination of niraparib and belantamab compared to belantamab alone. Similar log-fold shifts were observed with the combination of niraparib and belantamab mafodotin in an additional 19 multiple myeloma and lymphoma cell lines with evidence of belantamab mafodotin activity. Thus, preclinical data support a mechanistic rationale for enhancing belantamab mafodotin activity through γ-secretase inhibition.

[0169] Although similar results have been observed with other γ-secretase inhibitors, niraparstat appears to have a better safety profile than other γ-secretase inhibitors that have been evaluated. Compared to many other GSIs, the improved safety profile may enable niraparstat to be administered daily. Additionally, due to more consistent drug exposure, daily administration of niraparstat may improve target coverage by continuously blocking BCMA cleavage. Specifically, when compared to other γ-secretase inhibitors such as RO4929097 or MK-0752, the incidence of dose-limiting diarrhea and elevated liver enzymes does not appear to be as high (Messersmith, 2015). Furthermore, unlike other γ-secretase inhibitors (e.g., semagacestat), the incidence of secondary primary malignancies (SPMs) or infections that occur during treatment does not appear to increase with niraparstat treatment (Messersmith, 2015)(Henley, 2014). Since γ-secretase inhibitors are pharmacologically and functionally diverse (Ran, 2017), these comparative findings between different γ-secretase inhibitors may be related to differences in target binding affinity and drug penetration into specific organ stem cell compartments.

[0170] Example 3

[0171] In this contemplated embodiment, the synergistic activity of belantamab mafodotin and niraparstat will be investigated clinically:

[0172] Group 1: Two doses of belantamab mafodotin (i.e., 1.9 mg / kg and 2.5 mg / kg) will be evaluated in up to five separate dosing cohorts in combination with up to three different doses of niraparstat administered on a continuous BID schedule.

[0173] The primary objective of Group 1 is to obtain confirmatory evidence that the 1.9 mg / kg dose of belantamab mafodotin has an overall response rate (“ORR”) that is at least similar to the dose of belantamab mafodotin monotherapy used in the common control arm when combined with 50 mg, 100 mg, or 150 mg BID niraparstat.

[0174] The administration of the dosing cohorts for Groups 2 and 3 in Group 1 may be initiated in parallel only if the safety profiles of the starting doses of belantamab mafodotin (1.9 mg / kg) and niraparstat (100 mg BID) are acceptable.

[0175] In the event that the overall safety profile of the starting dose (cohort 1) is unfavorable, nilotinib is reduced to 50 mg BID, and the dose of belantamab mafodotin will remain unchanged at 1.9 mg / kg (i.e., dosing cohort -1). The dose intensity of nilotinib is not permitted to be further reduced to <50 mg BID, as the pharmacodynamic activity of the drug at such dose levels (i.e., γ-secretase inhibition) is considered to be low.

[0176] If it is determined that a 2.5 mg / kg dose of belantamab mafodotin administered as a single infusion has an unacceptable safety profile, a "mezzanine" dose level of 2.5 mg / kg administered as two equal doses of 1.25 mg / kg on days 1 and 8 of a Q3W schedule of this dosing schedule is selected. Compared to Q3W dosing, this will provide a reduction in maximum concentration of approximately 25% while maintaining the same exposure (AUC) within one cycle, thus potentially positively affecting the benefit / risk of belantamab mafodotin.

[0177] The maximum evaluable dose in cohort 1 is 2.5 mg / kg belantamab mafodotin and 150 mg BID nilotinib (cohort 4). Cohort 4 will only be initiated if the overall safety profile of cohort 3 (i.e., 2.5 mg / kg belantamab mafodotin and 100 mg BID nilotinib) is determined to be acceptable. For the avoidance of doubt, the abbreviation BID refers to twice-daily dosing.

[0178] Dosing levels for cohort 1

[0179] The second and third dosing levels can be initiated simultaneously

[0180]

[0181] Cohort 2: This is an optional cohort that will only be initiated if the primary objective of cohort 1 (as described above) is met and if the overall benefit-risk profile of 1.9 mg / kg belantamab mafodotin in combination with 50 mg, 100 mg, or 150 mg BID nilotinib is determined to be acceptable.

[0182] The primary objective of cohort 2 is to identify a single dose of belantamab mafodotin <1.9 mg / kg that has a higher ORR when combined with 50 mg, 100 mg, or 150 mg BID nilotinib than the single-agent belantamab mafodotin dose in the common control arm.

[0183] A specific dose of nilotinib can be combined to evaluate one or more individual dosing cohorts in Group 2 at belantamab mafodotin dose levels < 1.9 mg / kg. These lower belantamab mafodotin dose levels will be selected for evaluation based on pharmacokinetics (“PK”), treatment-emergent adverse events (“TEAE”), and ORR findings.

[0184] Group 3: This is an optional group that will only be initiated if the safety / tolerability of 3.4 mg / kg belantamab mafodotin as monotherapy in the common control arm and 2.5 mg / kg belantamab mafodotin administered as a single infusion on Day 1 or as two equal divided doses on Day 1 and Day 8 is favorable.

[0185] The primary objective of Group 3 is to demonstrate that 3.4 mg / kg belantamab mafodotin, when combined with a specific dose of nilotinib and administered as two equal divided doses of 1.7 mg / kg on Day 1 and Day 8 (to mitigate the risk of potential Cmax-driven toxicity), has a higher ORR than the common control arm but does not have a significantly worse overall safety profile than 3.4 mg / kg belantamab mafodotin monotherapy within the platform trial.

[0186] If potentially overlapping nilotinib-related grade 3 toxicities occur more than 7 days after treatment initiation, nilotinib may be administered on a twice-daily dosing schedule of “7 days on / 14 days off” because, in particular, the pharmacodynamic active plasma levels of nilotinib are rapidly achieved, typically within < 48 hours after treatment initiation, and steady-state plasma levels of nilotinib are reached by Day 8 of the twice-daily dosing schedule.

[0187] Example 4

[0188] A lower starting dose of 0.95 mg / kg belantamab mafodotin has been selected for this prospective substudy. Bayesian logistic regression modeling (BLRM) based on FTIH trial data predicted low clinical activity for belantamab mafodotin monotherapy doses < 1.9 mg / kg, although a small number of participants were treated at doses < 1.9 mg / kg (e.g., n = 3 at 0.48 mg / kg and n = 4 at 0.96 mg / kg). Although the starting dose of 0.95 mg / kg is expected to have only limited efficacy on its own, nilotinib is expected to potentiate the effect of belantamab mafodotin. This lower starting dose is expected to have an improved safety profile compared to the higher doses used in belantamab mafodotin monotherapy trials. For example, compared to the higher doses of 2.5 mg / kg and 3.4 mg / kg (which are associated with higher predicted levels of hematologic response), corneal toxicity events may be associated with a lower incidence of grade 2 events.

[0189] Three cohorts will be given belantamab mafodotin at 0.95 mg / kg, but with different doses of nilotinib:

[0190] · 0.95 mg / kg belantamab mafodotin in combination with nilotinib 50 mg BID

[0191] · 0.95 mg / kg belantamab mafodotin in combination with nilotinib 100 mg BID

[0192] · 0.95 mg / kg belantamab mafodotin in combination with nilotinib 150 mg BID.

[0193] Nilotinib will be administered intermittently, e.g., in a 7 days on / 14 days off schedule or continuously. The results of the clinical trial will provide data to support the optimal dosing regimen required for maximum risk-benefit.

[0194] Example 5: ADC activity

[0195] To determine whether belantamab mafodotin shows combinatorial synergy with GSI in an antibody-dependent cytotoxicity assay, multiple myeloma and lymphoma cancer cell lines expressing BCMA were tested in a 3-day cell proliferation assay. After plating the cells in a 384-well plate, nilotinib was dosed at fixed concentrations of 2.5 μM, 0.25 μM, 0.025 μM, and 0.0025 μM. The plates were incubated overnight and then, for each fixed concentration of nilotinib, belantamab mafodotin was dosed in a 10-point dose titration from 9.9 μg / mL to 0.00025 μg / mL. After 3 days of incubation, cell viability was analyzed using Promega's Cell-titer Glo and analyzed using Graphpad software. Representative data are shown in Figure 3 as shown. The results showed a shift in potency of up to 3 log-fold with belantamab mafodotin in combination with nilotinib.

[0196] Example 6: ADCC activity

[0197] Assess the ADCC activity of belantamab mafodotin, the unconjugated form of MMAF, using Promega's Jurkat ADCC assay in combination with nilotinib. Plate multiple myeloma and lymphoma cancer cell lines expressing BCMA at a ratio of 10:1 (Jurkat effector cells: cancer cells) in 1536-well format. Then immediately administer the cells with nilotinib at fixed concentrations of 2.5 μM, 0.25 μM, 0.025 μM, and 0.0025 μM. Then titrate belantamab from 9.9 μg / mL to 0.00025 μg / mL at each fixed concentration. Incubate the plates for 24 hours and assess ADCC activity by adding Promega Bio-glo. Analyze the data using Graphpad software. Representative data of ADCC activity are shown as Figure 4 shown in

[0198] Example 7: sBCMA levels

[0199] Detect soluble BCMA in the 3-day-old cell culture supernatant of BCMA-expressing cell lines treated with nilotinib at fixed concentrations of 2.5 μM, 0.25 μM, 0.025 μM, and 0.0025 μM using the R&D human sBCMA ELISA kit. We detected a dose-dependent loss of sBCMA after treatment with nilotinib ( Figure 5 ).

[0200] Example 8: Cell surface detection of BCMA levels

[0201] In BCMA-expressing cell lines, after 3-day treatment with nilotinib at fixed concentrations of 2.5 μM, 0.25 μM, 0.025 μM, and 0.0025 μM, examine the BCMA cell surface levels by flow cytometry. Compare the levels of BCMA with the isotype control group. An increase in cell surface BCMA was detected in a dose-dependent manner. Representative data of cell surface BCMA levels are shown as Figure 6 shown in

Claims

1. Use of a combination in the preparation of a medicament for treating multiple myeloma in a subject, wherein the combination comprises: i) a therapeutically effective dose of belantamab mafodotin; and ii) nirogacestat.

2. The use according to claim 1, wherein the multiple myeloma is relapsed and / or refractory multiple myeloma.

3. The use according to claim 2, wherein the subject has received at least one prior line of cancer treatment.

4. The use according to claim 2, wherein the subject has received at least 3 prior lines of cancer treatment, including immunomodulatory drugs, proteasome inhibitors, and anti-CD38 therapy.

5. The use according to any one of the preceding claims, wherein administration of the combination reduces ocular toxicity in the subject compared to administration of a therapeutically effective dose of belantamab mafodotin alone for treating cancer.

6. The use according to claim 5, wherein the ocular toxicity is at least one of the following: corneal epithelial changes, dry eye, irritation, redness, blurred vision, photophobia, or change in visual acuity.

7. The use according to claim 5, wherein the ocular toxicity is measured by at least one of the following methods: best corrected visual acuity, recording of manifest refraction and methods for obtaining best corrected visual acuity, current spectacle prescription, intraocular pressure measurement, anterior segment slit lamp examination, fluorescein staining including examination of the cornea and lens, dilated fundus examination, or ocular surface disease index.

8. The use according to claim 6, wherein the ocular toxicity is measured by at least one of the following methods: best corrected visual acuity, recording of manifest refraction and methods for obtaining best corrected visual acuity, current spectacle prescription, intraocular pressure measurement, anterior segment slit lamp examination, fluorescein staining including examination of the cornea and lens, dilated fundus examination, or ocular surface disease index.

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