Combination treatment for cancer

Abstract

To provide a method of treating cancer, such as multiple myeloma.SOLUTION: The present invention provides a method involving the combination of an anti-BCMA antigen binding protein (e.g. an anti-BCMA antibody) and a proteasome inhibitor (e.g. bortezomib). The combinations can also include an anti-inflammatory compound (e.g. dexamethasone).SELECTED DRAWING: None

Description

[Technical Field]

[0001] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format, the entire contents of which are incorporated herein by reference. The ASCII copy, created on September 10, 2018, is named PU66428_WO_SL.txt and is 10,132 bytes in size.

[0002] FIELD OF THE INVENTION The present invention relates to a method of treating cancer in a subject. In particular, the present invention relates to a combination of an anti-BCMA antigen binding protein and a proteasome inhibitor for treating cancer. The combination may further include an anti-inflammatory compound, such as dexamethasone. [Background technology]

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

[0004] Although triple- and quadruple-drug combinations have emerged for previously treated patients with MM, these treatment regimens may be limited by toxic effects (National Comprehensive Cancer Network, 2016). Drugs with novel mechanisms of action that can be combined with both existing therapies without significant increased toxicity are needed. Thus, there is an urgent need to develop treatment combinations with non-overlapping mechanisms of action that may minimize cross-resistance with prior treatments. Summary of the Invention

[0005] Summary of the Invention The present disclosure relates to a method of treating cancer in a subject, e.g., a human. In particular, the present invention relates to a combination of an anti-BCMA antigen binding protein, such as an antibody, with a proteasome inhibitor to treat cancer. The combination may further include an anti-inflammatory compound, such as dexamethasone. In one embodiment, the cancer is selected from multiple myeloma, chronic lymphocytic leukemia, and non-Hodgkin's lymphoma.

[0006] Provided herein is a method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective dose of a combination comprising an anti-BCMA antigen binding protein and a proteasome inhibitor. In one embodiment, the combination further comprises an anti-inflammatory compound.

[0007] Also provided herein is a method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective dose combination comprising an anti-BCMA antigen binding protein and a proteasome, wherein the antibody comprises: a CDRH1 comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:1; a CDRH2 comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:2; a CDRH3 comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:3; a CDRL1 comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:4; a CDRL2 comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:5; and a CDRL3 comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:6.

[0008] Further provided herein is a method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective dose combination comprising an anti-BCMA antigen binding protein and a proteasome inhibitor, wherein the anti-BCMA antigen binding protein is an antibody comprising a VH comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:7; and a VL comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:8.

[0009] Provided herein are methods of treating cancer in a subject in need thereof, comprising administering therapeutically effective doses of a combination comprising an anti-BCMA antigen binding protein, a proteasome inhibitor, and an anti-inflammatory compound, wherein the anti-inflammatory compound is dexamethasone.

[0010] Also provided herein is a method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective dose of a combination comprising an anti-BCMA antigen binding protein and a proteasome inhibitor, wherein the proteasome inhibitor is bortezomib. In another embodiment, the proteasome inhibitor is carfilzomib. In yet another embodiment, the proteasome inhibitor is ixazomib. In yet another embodiment, the proteasome inhibitor is oprozomib.

[0011] Further provided herein is a method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective dose of a combination comprising an anti-BCMA antigen binding protein and a proteasome inhibitor, wherein the anti-BCMA antigen binding protein is an immunoconjugate comprising an antibody conjugated to a cytotoxin. In one embodiment, the cytotoxin is MMAE or MMAF.

[0012] Provided herein are methods of treating cancer, wherein 1.9 mg / kg, 2.5 mg / kg, or 3.4 mg / kg of an anti-BCMA antigen binding protein is administered on day 1 of a 21 day cycle.

[0013] Further provided herein is a method of treating cancer, wherein the proteasome inhibitor is bortezomib and the dose is 1.3 mg / m 2 of bortezomib is administered on days 1, 4, 8, and 11 of a 21 day cycle.

[0014] Also provided is a method of treating cancer, wherein the anti-inflammatory compound is dexamethasone, and 20 mg of dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21 day cycle.

[0015] Provided herein is a combination for use in the treatment of cancer comprising an anti-BCMA antigen binding protein, a proteasome inhibitor, and optionally an anti-inflammatory compound.

[0016] Also provided is the use of a combination comprising an anti-BCMA antigen binding protein, a proteasome inhibitor, and optionally an anti-inflammatory compound in the manufacture of a medicament for use in the treatment of cancer.

[0017] In this specification, (i) anti-BCMA antigen-binding protein; (ii) instructions for use in the treatment of cancer in combination with a proteasome inhibitor and optionally an anti-inflammatory compound; A kit for use in treating cancer is provided, comprising: DETAILED DESCRIPTION OF THE INVENTION

[0018] Detailed Description of the Invention The present disclosure relates to a method for treating cancer in a subject. In particular, the present invention relates to a combination of an anti-BCMA antigen binding protein and a proteasome inhibitor for treating cancer. The combination may further include an anti-inflammatory compound such as dexamethasone. Without being bound by theory, it is believed that the novel combination described herein results in reduced toxicity due to non-overlapping mechanisms of action.

[0019] Combinations and Pharmaceutical Compositions The term "combination" as used herein refers to at least two therapeutic agents. As used herein, the term "therapeutic agent" is understood to mean a substance that produces a desired effect in a tissue, system, animal, mammal, human, or other subject. In one embodiment, the combination is an anti-BCMA antigen binding protein, preferably an anti-BCMA antibody, and at least one additional therapeutic agent. In one embodiment, the combination is an anti-BCMA antigen binding protein and a proteasome inhibitor. In another embodiment, the combination is an anti-BCMA antigen binding protein, a proteasome inhibitor, and an anti-inflammatory compound. The combinations described herein may be effective in treating cancer.

[0020] In one embodiment, these combinations may include an additional therapeutic agent, such as an additional cancer therapeutic agent, hi one embodiment, the additional cancer therapeutic agent is an immunomodulatory imid drug (IMiD), such as thalidomide, lenalidomide, pomalidomide, apremilast, or other thalidomide analogs.

[0021] Administration of the combinations of the invention may be advantageous over the individual therapeutic agents in that the combination provides one or more of the following improved properties when compared to the individual administration of the single therapeutic agents: i) greater anti-cancer efficacy than the most effective single agent; ii) synergistic or highly synergistic anti-cancer activity; iii) an administration protocol that provides enhanced anti-cancer activity with a reduced side effect profile; iv) a reduced toxic effect profile; v) an increased therapeutic window; or vi) increased bioavailability of one or both therapeutic agents.

[0022] The combination described herein can be in the form of pharmaceutical composition. "Pharmaceutical composition" comprises the combination described herein and one or more pharmaceutically acceptable carriers, diluents or excipients.These carriers, diluents or excipients must be acceptable in the sense that they are compatible with other components of the formulation, can be medicinally prepared, and are not harmful to the recipient.

[0023] In one embodiment, each therapeutic agent in the combination is individually formulated as its own pharmaceutical composition, and each of these pharmaceutical compositions is administered to treat cancer. In this embodiment, each of these pharmaceutical compositions may contain the same or different carriers, diluents, or excipients. For example, in one embodiment, a first pharmaceutical composition contains an anti-BCMA antigen binding protein, a second pharmaceutical composition contains a proteasome inhibitor, and both the first and second pharmaceutical compositions are administered to treat cancer. In another embodiment, a first pharmaceutical composition contains an anti-BCMA antigen binding protein, a second pharmaceutical composition contains a proteasome inhibitor, and a third pharmaceutical composition contains an anti-inflammatory compound, and each of the first, second, and third pharmaceutical compositions is administered to treat cancer.

[0024] In one embodiment, each therapeutic agent in the combination is formulated together in a single pharmaceutical composition and administered to treat cancer. For example, in one embodiment, a single pharmaceutical composition contains both an anti-BCMA antigen binding protein and a proteasome inhibitor and is administered as a single pharmaceutical composition to treat cancer. In another embodiment, a single pharmaceutical composition contains an anti-BCMA antigen binding protein, a proteasome inhibitor, and an anti-inflammatory compound and is administered as a single pharmaceutical composition.

[0025] In this specification, when proteasome inhibitors and anti-inflammatory compounds are mentioned, it should be understood that they refer to the proteasome inhibitors and anti-inflammatory compounds as free base or as salts, for example, pharmaceutically acceptable salts.Pharmaceutically acceptable salts include acid addition salts.For a review of suitable salts, see Berge et al., J. Pharm. Sci., 66:1-19 (1977).

[0026] The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the proteasome inhibitors and anti-inflammatory compounds.

[0027] It will be recognized that many organic compounds form complexes with the solvents in which they react or from which they precipitate or crystallize. These complexes are known as "solvates." For example, complexes with water are known as "hydrates." Solvents with high boiling points and / or a strong tendency to form hydrogen bonds, such as water, ethanol, isopropyl alcohol, and N-methylpyrrolidinone, can be used to form solvates. Methods for identifying solvates include, but are not limited to, NMR and microanalysis. Solvates of proteasome inhibitors and anti-inflammatory compounds are within the scope of the present invention. As used herein, the term solvate encompasses solvates of both the proteasome inhibitors and anti-inflammatory compounds as free bases and any salts thereof.

[0028] Certain proteasome inhibitors and anti-inflammatory compounds of the present invention may contain chiral atoms, and therefore may exist in one or more stereoisomeric forms.The present invention encompasses all stereoisomers of the proteasome inhibitors and anti-inflammatory compounds of the present invention, including optical isomers, whether as individual stereoisomers or as mixtures thereof, including racemates and racemic mixtures.Any stereoisomer may contain less than 10% by weight, for example, less than 5% by weight, or less than 0.5% by weight of other stereoisomers.For example, any optical isomer may contain less than 10% by weight, for example, less than 5% by weight, or less than 0.5% by weight of its antipode.

[0029] Certain proteasome inhibitors and anti-inflammatory compounds of the present invention may exist in tautomeric forms, and it is understood that the present invention encompasses all tautomeric forms of the proteasome inhibitors and anti-inflammatory compounds of the present invention, whether as individual tautomers or as mixtures thereof.

[0030] The proteasome inhibitors and anti-inflammatory compounds of the present invention may exist in crystalline or amorphous form. Furthermore, some of the crystalline forms of the proteasome inhibitors and anti-inflammatory compounds of the present invention may exist as polymorphs, all of which are included within the scope of the present invention. Of particular interest is the most thermodynamically stable polymorphic form(s) of the proteasome inhibitors and anti-inflammatory compounds of the present invention.

[0031] Polymorphic forms of the proteasome inhibitors and anti-inflammatory compounds of the present invention can be characterized and distinguished using several conventional analytical techniques, including, but not limited to, X-ray powder diffraction (XRPD), infrared spectroscopy (IR), Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solid-state nuclear magnetic resonance (ssNMR).

[0032] The present invention also includes all suitable isotopic variations of the proteasome inhibitors and anti-inflammatory compounds or their pharmaceutically acceptable salts. An isotopic variation of a proteasome inhibitor and anti-inflammatory compound or its pharmaceutically acceptable salt is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass normally found in nature. Examples of isotopes that can be incorporated into the proteasome inhibitor and anti-inflammatory compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 18 F and 36 Specific isotopic variations of the proteasome inhibitors and anti-inflammatory compounds or their salts or solvates, such as 3 H or 14 Incorporation of radioactive isotopes such as C is useful for drug and / or substrate tissue distribution studies. Tritiated, i.e., 3 H isotopes, and carbon-14, i.e., 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium, i.e., 2 Substitution with isotopes such as H may be preferable in some circumstances because it can confer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Isotopic variants of proteasome inhibitors or pharmaceutical salts thereof can generally be prepared by conventional procedures.

[0033] From the foregoing, it will be appreciated that the scope of the present invention includes solvates, hydrates, isomers and polymorphic forms of proteasome inhibitors and anti-inflammatory compounds, and salts and solvates thereof.

[0034] Those skilled in the art will recognize that certain derivatives of proteasome inhibitors and anti-inflammatory compounds do not necessarily have pharmacological activity themselves, but may be administered and then metabolized in the body to form pharmacologically active proteasome inhibitors and anti-inflammatory compounds. Such derivatives are referred to herein as "prodrugs." Thus, the proteasome inhibitors and anti-inflammatory compounds described herein may exist in the form of prodrugs. Examples of suitable derivatives are described in Drugs of Today, Volume 19, Number 9, 1983, pp. 499-538, Topics in Chemistry, Chapter 31, pp. 306-316, and "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1.

[0035] Anti-BCMA antigen-binding protein The anti-BCMA antigen binding proteins in the combinations described herein are useful for treating or preventing cancer. Any of the anti-BCMA antigen binding proteins disclosed herein can be used in combination with a proteasome inhibitor, or in combination with a proteasome inhibitor and an anti-inflammatory compound, to treat cancer. The anti-BCMA antigen binding proteins described herein can bind to human BCMA, including, for example, a human BCMA containing the amino acid sequence of GenBank Accession No. Q02223.2, or a gene encoding a human BCMA having at least 90% homology or at least 90% identity thereto.

[0036] The term "antigen-binding protein" as used herein refers to antibodies, antibody fragments, and other protein constructs capable of binding to human BCMA. Antigen-binding proteins of the present invention may comprise heavy and light chain variable regions of the present invention, which may take the structural form of a natural antibody or a functional fragment or equivalent thereof. Thus, antigen-binding proteins of the present invention may comprise a VH region of the present invention that, when paired with an appropriate light chain, takes the form of a full-length antibody, a (Fab')2 fragment, a Fab fragment, or equivalents thereof (e.g., scFV, bibody, tribody or tetrabody, Tandabs, etc.). The antibody may be IgG1, IgG2, IgG3, or IgG4; or IgM; IgA, IgE, or IgD, or modified variants thereof. The constant domain of the antibody heavy chain may also be selected accordingly. The light chain constant domain may be a kappa or lambda constant domain. Furthermore, antigen-binding proteins may comprise any class of modifications, such as IgG dimers, Fc variants that no longer bind Fc receptors or mediate C1q binding. The antigen binding protein may also be a chimeric antibody of the type described in WO86 / 01533, comprising an antigen binding region and a non-immunoglobulin region.

[0037] In another aspect, the antigen binding protein is selected from the group consisting of a dAb, Fab, Fab', F(ab')2, Fv, diabody, triabody, tetrabody, miniantibody, and minibody. In one aspect of the invention, the antigen binding protein is a humanized or chimeric antibody, and in a further aspect, the antibody is humanized. In one aspect, the antibody is a monoclonal antibody.

[0038] Chimeric antigen receptors (CARs) have been developed as artificial T cell receptors to generate novel specificities in T cells without the need for binding to MHC-antigen peptide complexes. These synthetic receptors contain a target-binding domain linked to one or more signaling domains via a flexible linker as a single fusion molecule. The target-binding domain is used to target T cells to specific targets on the surface of diseased cells, and the signaling domain contains the molecular machinery for T cell activation and expansion. The flexible linker, which penetrates the T cell membrane (i.e., forms a transmembrane domain), allows 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 from various malignancies, including lymphomas and solid tumors (Jena et al. (2010) Blood, 116(7):1035-44).

[0039] The development of CARs has thus far included three generations. First-generation CARs comprised a target-binding domain linked to a signaling domain derived from the cytoplasmic region of the CD3 ζ chain or the Fc receptor γ chain. While first-generation CARs were shown to successfully redirect T cells to selected targets, they failed to provide long-term expansion and antitumor activity in vivo. Second- and third-generation CARs focused on enhancing T cell survival and expansion, which was improved by the inclusion of costimulatory molecules such as CD28, OX-40 (CD134), and 4-1BB (CD137).

[0040] T cells with CARs could be used to eliminate diseased cells in disease states. One clinical purpose would be to transduce patient cells with recombinant DNA containing an expression construct for CARs via a vector (e.g., lentiviral vector) after apheresis and T cell isolation. After T cell expansion, these T cells are reintroduced into the patient to target and kill diseased target cells.

[0041] In one aspect of the invention, the anti-BCMA antigen binding protein is a chimeric antigen receptor. In a further aspect, the CAR comprises a binding domain, a transmembrane domain, and an intracellular effector domain.

[0042] In one aspect, the transmembrane domain may be derived from either natural or synthetic sources. In one aspect, the transmembrane domain may be derived from any membrane-bound or transmembrane protein. Alternatively, the transmembrane domain may be synthetic and comprise primarily hydrophobic residues such as leucine and valine. For example, the transmembrane domain may be the transmembrane domain of a CD protein such as CD4, CD8, CD3, or CD28; a subunit of a T-cell receptor such as α, β, γ, or δ; a subunit of the IL-2 receptor (α chain); a subunit (β chain or γ chain) of the low-affinity nerve growth factor receptor (LNGFR or p75); or a subunit chain of an Fc receptor.

[0043] In one aspect, the transmembrane domain comprises the transmembrane domain of CD4, CD8, or CD28. In a further aspect, the transmembrane domain comprises the transmembrane domain of CD4 or CD8 (e.g., the CD8 α chain as set forth in NCBI Reference Sequence: NP_001139345.1, incorporated herein by reference). In yet a further aspect, the transmembrane domain comprises the transmembrane domain of CD4.

[0044] The intracellular effector domain or "signaling domain" is responsible for intracellular signal transduction after the target binding domain binds to the target.The intracellular effector domain is responsible for activating at least one of the normal effector functions of the immune cell in which the CAR is expressed.For example, the effector function of T cells can be cytolytic activity or helper activity, including secretion of cytokines.Preferred examples of effector domains for use in CAR scaffolds can be the cytoplasmic sequences of natural T cell receptors and co-receptors, which act together to initiate signal transduction after antigen binding, as well as any derivatives or variants of these sequences and any synthetic sequences with the same functional capabilities.

[0045] Effector domains can be divided into two classes: those that initiate antigen-dependent primary activation and those that act in an antigen-independent manner to provide secondary or costimulatory signals. Primary activation effector domains comprise signaling motifs known as immunoreceptor tyrosine-based activation motifs (ITAMs). ITAMs are well-defined signaling motifs commonly found in the cytoplasmic tails of various receptors and serve as binding sites for syk / zap70 class tyrosine kinases. Examples of ITAMs used in the present invention may include, but are not limited to, those derived from CD3ζ, FcRγ, FcRβ, FcRε, CD3γ, CD3δ, CD3ε, CD5, CD22, CD79a, CD79b, and CD66d. In one aspect, the intracellular effector domain comprises the CD3ζ signaling domain (also known as CD247). Because native TCRs contain the CD3ζ signaling molecule, the use of this effector domain most closely resembles naturally occurring TCR constructs.

[0046] In one aspect of the present invention, the intracellular signaling domain is a CD3ζ effector domain. The effector domain can also provide a secondary or costimulatory signal. The T cell further comprises a costimulatory molecule that binds to a cognate costimulatory ligand on an antigen-presenting cell to enhance the T cell response, e.g., by enhancing activation of proliferation and differentiation. Thus, in one aspect, the intracellular effector domain further comprises a costimulatory domain. In a further aspect, the costimulatory domain comprises the intracellular domain of a costimulatory molecule selected from CD28, CD27, 4-1BB (CD137), OX40 (CD134), ICOS (CD278), CD30, CD40, PD-1 (CD279), CD2, CD7, NKG2C (CD94), B7-H3 (CD276), or any combination thereof. In still a further aspect, the costimulatory domain comprises the intracellular domain of a costimulatory molecule selected from CD28, CD27, 4-1BB, OX40, ICOS, or any combination thereof.

[0047] Exemplary anti-BCMA antigen binding proteins and methods of making the same are disclosed in International Publication No. WO2012 / 163805, the entire contents of which are incorporated herein by reference. Further exemplary anti-BCMA antigen binding proteins include WO2016 / 014789, WO2016 / 090320, WO2016 / 090327, WO2016 / 020332, WO2016 / 079177, WO2014 / 122143, WO2014 / 122144, WO2017 / 021450, WO2016 / 01 4565, WO2014 / 068079, WO2015 / 166649, WO2015 / 158671, WO2015 / 052536, WO2014 / 140248, WO2013 / 072415, WO2013 / 072406, WO2014 / 089335, US2017 / 165373, WO2013 / 154760, and WO2017 / 051068.

[0048] In one embodiment, the anti-BCMA antigen binding protein has enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) effector function. The term "effector function," as used herein, refers to one or more of antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC)-mediated responses, Fc-mediated phagocytosis, and antibody recycling via the FcRn receptor. In IgG antibodies, effector functions, including ADCC and ADCP, are mediated by interactions between the heavy chain constant region and a family of Fcγ receptors present on the surface of immune cells. In humans, these include FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16). The interaction between the antigen-bound antigen binding protein and the formation of Fc / Fcγ complexes induces cytotoxicity, immune cell activation, phagocytosis, and the release of inflammatory cytokines.

[0049] In another embodiment, the anti-BCMA antigen binding proteins described herein inhibit the binding of BAFF and / or APRIL to the BCMA receptor. In another embodiment, the anti-BCMA antigen binding proteins described herein are capable of binding to FcγRIIIA or are capable of effector function mediated by FcγRIIIA.

[0050] In one embodiment, the anti-BCMA antigen binding protein is an antibody comprising a heavy chain variable region CDR1 ("CDRH1") comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1. In one embodiment, the heavy chain variable region CDR1 ("CDRH1") comprises an amino acid sequence having a single amino acid mutation (variant) in the amino acid sequence set forth in SEQ ID NO: 1.

[0051] In one embodiment, the anti-BCMA antigen binding protein is an antibody comprising a heavy chain variable region CDR2 ("CDRH2") comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 2. In one embodiment, the heavy chain variable region CDR2 ("CDRH2") comprises an amino acid sequence having a single amino acid mutation (variant) in the amino acid sequence set forth in SEQ ID NO: 2.

[0052] In one embodiment, the anti-BCMA antigen binding protein is an antibody comprising a heavy chain variable region CDR3 ("CDRH3") comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 3. In one embodiment, the heavy chain variable region CDR3 ("CDRH3") comprises an amino acid sequence having a single amino acid mutation (variant) in the amino acid sequence set forth in SEQ ID NO: 3.

[0053] In one embodiment, the anti-BCMA antigen binding protein is an antibody comprising a light chain variable region CDR1 ("CDRL1") comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 4. In one embodiment, the light chain variable region CDL1 ("CDR1") comprises an amino acid sequence having a single amino acid mutation (variant) in the amino acid sequence set forth in SEQ ID NO: 4.

[0054] In one embodiment, the anti-BCMA antigen binding protein is an antibody comprising a light chain variable region CDR2 ("CDRL2") comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 5. In one embodiment, the light chain variable region CDL2 ("CDR2") comprises an amino acid sequence having a single amino acid mutation (variant) in the amino acid sequence set forth in SEQ ID NO: 5.

[0055] In one embodiment, the anti-BCMA antigen binding protein is an antibody comprising a light chain variable region CDR3 ("CDRL3") comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 6. In one embodiment, the light chain variable region CDL3 ("CDR3") comprises an amino acid sequence having a single amino acid mutation (variant) in the amino acid sequence set forth in SEQ ID NO: 6.

[0056] In one embodiment, the anti-BCMA antigen binding protein is a CDRH1 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1; a CDRH2 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 2; a CDRH3 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 3; RH3; an antibody comprising a CDRL1 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:4; a CDRL2 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:5; and / or a CDRL3 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:6.

[0057] In one embodiment, the anti-BCMA antigen binding protein is an antibody comprising a heavy chain variable region ("VH") comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:7.

[0058] In one embodiment, the anti-BCMA antigen binding protein is an antibody comprising a light chain variable region ("VL") comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:8.

[0059] In one embodiment, the anti-BCMA antigen binding protein is an antibody comprising a VH comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:7; and a VL comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:8.

[0060] In one embodiment, the anti-BCMA antigen binding protein is an antibody comprising a heavy chain region ("HC") comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:9.

[0061] In one embodiment, the anti-BCMA antigen binding protein is an antibody comprising a light chain region ("LC") comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 10.

[0062] In one embodiment, the anti-BCMA antigen binding protein is an antibody comprising an HC comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 9; and an LC comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 10.

[0063] 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 an antibody conjugated to one or more cytotoxic agents such as, but not limited to, a chemotherapeutic agent, a drug, a growth inhibitory agent, a toxin (e.g., a protein toxin, an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate). In a further embodiment, the anti-BCMA antigen binding protein is conjugated to a toxin such as an auristatin, for example, monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF).

[0064] In one embodiment, the anti-BCMA antigen binding protein has the following general structure: ABP-((linker) n -Ctx) m wherein: ABP is an antigen-binding protein, The linker is absent or is any cleavable or non-cleavable linker; Ctx is any cytotoxic agent described herein, n is 0, 1, 2, or 3, and m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0065] Exemplary linkers include 6-maleimidocaproyl (MC), maleimidopropanoyl (MP), valine-citrulline (val-cit), alanine-phenylalanine (ala-phe), p-aminobenzyloxycarbonyl (PAB), N-succinimidyl 4-(2-pyridylthio)pentanoate (SPP), N-succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and N-succinimidyl (4-iodo-acetyl)aminobenzoate (SIAB).

[0066] In one embodiment, the anti-BCMA antigen binding protein is an immunoconjugate containing a monoclonal antibody linked to MMAE or MMAF. In another embodiment, the anti-BCMA antigen binding protein is an immunoconjugate containing a monoclonal antibody linked to MMAE or MMAF by an MC linker as shown in the structure below.

[0067] [ka]

[0068] An appropriate therapeutically effective dose of an anti-BCMA antigen binding protein can be readily determined by one of skill in the art. As used herein, the term "effective dose" refers to a dose of a drug or pharmaceutical that elicits the biological or medical response in a tissue, system, animal, or human that is desired by, for example, a researcher or clinician. Furthermore, the term "therapeutically effective dose" refers to any dose that results in improved treatment, cure, prevention, or amelioration of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding subject not receiving such a dose. The term also includes within its scope a dose effective to enhance normal physiological function.

[0069] Suitable doses of the anti-BCMA antigen binding proteins described herein may be calculated for a patient according to the patient's body weight, for example, suitable doses may range from about 0.1 to about 20 mg / kg, such as from about 1 to about 20 mg / kg, for example, from about 10 to about 20 mg / kg or for example, from about 1 to about 15 mg / kg, for example, from about 10 to about 15 mg / kg.

[0070] In one embodiment, the therapeutically effective dose of the anti-BCMA antigen binding protein ranges from about 0.03 mg / kg to about 4.6 mg / kg. In yet another embodiment, the therapeutically effective dose of the anti-BCMA antigen binding protein is 0.03 mg / kg, 0.06 mg / kg, 0.12 mg / kg, 0.24 mg / kg, 0.48 mg / kg, 0.96 mg / kg, 1.92 mg / kg, 3.4 mg / kg, or 4.6 mg / kg. In yet another embodiment, the therapeutically effective dose of the anti-BCMA antigen binding protein is 1.9 mg / kg, 2.5 mg / kg, or 3.4 mg / kg.

[0071] Proteasome inhibitors The term " proteasome inhibitor " as used herein refers to a class of drugs that block the action of proteasome, a complex of enzymes found in cells that normally regulates the removal of defective proteins.Without being bound by theory, it is believed that proteasome inhibition prevents the degradation of apoptosis-inducing factors such as p53 protein, allowing the activation of programmed cell death in neoplastic cells that depend on the suppression of apoptosis-inducing pathways, causing the proliferation and death of defective proteins.Since cancer cells are thought to be more sensitive to the effects of proteasome inhibitors than normal cells, proteasome inhibitors are useful for treating cancer.

[0072] For example, various proteasome inhibitors are known to those skilled in the art, including bortezomib, carfilzomib, ixazomib, oprozomib, and their analogs.The term "analog" as used herein refers to compounds that have similar structures to each other but differ in specific components, for example, analogs differ in one or more atoms, functional groups, or substructures, and these are replaced by other atoms, groups, or substructures.This structural difference can be at least theoretically imagined by those skilled in the art from other compounds.

[0073] In one embodiment, the proteasome inhibitor includes bortezomib or an analog thereof. Bortezomib is registered under the trademark Velcade® (Millennium Pharmaceuticals) and has the following chemical structure:

[0074] [ka]

[0075] Bortezomib and its analogs, as well as methods for producing same, are known to those skilled in the art, for example, as described in U.S. Pat. Nos. 5,780,454; 6,713,446; and 6,958,319, the disclosures of which are incorporated herein by reference in their entireties.

[0076] In one embodiment, the proteasome inhibitor includes carfilzomib or an analog thereof, which is registered under the trademark Kyprolis® (Onyx Pharmaceuticals) and has the following chemical structure:

[0077] [ka]

[0078] Carfilzomib and its analogs, as well as methods for their preparation, are known to those of skill in the art, for example, as described in U.S. Pat. Nos. 7,232,818; 7,417,042; 7,737,112; 8,207,125; 8,207,126; 8,207,297; and 9,493,582, the disclosures of which are incorporated herein by reference in their entireties.

[0079] In one embodiment, the proteasome inhibitor includes ixazomib, or an analog thereof, which is registered under the trademark NINLARO® (Millennium Pharmaceuticals) and has the following chemical structure:

[0080] [ka]

[0081] Ixazomib and its analogs, as well as methods for their preparation, are known to those of skill in the art, for example, as described in U.S. Pat. Nos. 7,442,830; 7,687,662; 8,003,819; 8,530,694; 8,546,608; and 8,859,504, the disclosures of which are incorporated herein by reference in their entireties.

[0082] In one embodiment, the proteasome inhibitor includes oprozomib, or an analog thereof. Oprozomib (Onyx Pharmaceuticals - ONX 0912 and PR-047) has the following chemical structure:

[0083] [ka]

[0084] Oprozomib and its analogs, as well as methods for their preparation, are known to those skilled in the art, for example, as described in WO2007 / 056464; WO2011 / 060179; WO2010 / 108172; and WO2014 / 066681, the disclosures of which are incorporated herein by reference in their entireties.

[0085] The appropriate therapeutically effective dose of a proteasome inhibitor can be easily determined by one skilled in the art. Suitable doses of the proteasome inhibitors described herein may be calculated for a patient based on the patient's weight. Therapeutically effective doses are generally about 1-2000 mg, 5-2000 mg, 10-2000 mg, and preferably about 30-1500 mg. Other ranges, including, for example, 50-500 mg, 50-300 mg, 50-100 mg, 100-200 mg, 5-100 mg, and 5-50 mg, can also be used. The therapeutically effective dose, when used for acute or chronic human treatment, is in the range of 0.01 to 250 mg / kg body weight, preferably 0.1 to 5 mg / kg body weight, preferably 0.1 to 10 mg / kg body weight, preferably 2 to 100 mg / kg body weight, or preferably 5 to 60 mg / kg body weight, which may be administered, for example, in 1 to 4 daily doses depending on the route of administration and the condition of the subject.

[0086] In one embodiment, the proteasome inhibitor is bortezomib and the therapeutically effective dose is about 0.5 mg / m 2 ~about 5mg / m 2 In another embodiment, the proteasome inhibitor is bortezomib and the therapeutically effective dose is about 0.75 mg / m 2 ~about 2.5mg / m 2 In a further embodiment, the proteasome inhibitor is bortezomib and the therapeutically effective dose is in the range of 1.3 mg / m 2 is.

[0087] In one embodiment, the proteasome inhibitor is carfilzomib and the therapeutically effective dose is about 5 mg / m 2 ~about 100mg / m 2 In another embodiment, the proteasome inhibitor is carfilzomib and the therapeutically effective dose is about 10 mg / m 2 ~about 60mg / m 2 In a further embodiment, the proteasome inhibitor is carfilzomib and the therapeutically effective dose is in the range of 15 mg / m 2 , 20 mg / m 2 , 27 mg / m 2, 36 mg / m 2 , 45 mg / m 2 , or 56 mg / m 2 is.

[0088] In one embodiment, the proteasome inhibitor is ixazomib and the therapeutically effective dose ranges from about 0.5 mg to about 10 mg. In another embodiment, the proteasome inhibitor is ixazomib and the therapeutically effective dose ranges from about 1 mg to about 5 mg. In a further embodiment, the proteasome inhibitor is ixazomib and the therapeutically effective dose is 2.3 mg, 3 mg, or 4 mg.

[0089] anti-inflammatory compounds Anti-inflammatory compounds such as dexamethasone are compounds that reduce inflammation or swelling in various parts of the body.Anti-inflammatory compounds have been used to reduce the swelling (edema) associated with tumors in the spine and brain, and to treat eye inflammation, and to treat various cancers such as leukemia, lymphoma and multiple myeloma.Various anti-inflammatory compounds and methods of preparation are known to those skilled in the art.

[0090] Anti-inflammatory compounds can include both steroidal and non-steroidal (NSAID) compounds.

[0091] In one embodiment, the anti-inflammatory compound is a steroid.Examples of steroid include but are not limited to cortisone, cortisol, corticosterone, hydrocortisone, hydrocortisol, prednisone, prednisolone, dexamethasone, beclomethasone, betamethasone, mometasone, mometasone furoate, budesonide, triamcinolone acetonide and fluticasone.In one embodiment, the anti-inflammatory compound is a corticosteroid selected from dexamethasone, prednisone, prednisolone, methylprednisone and methylprednisolone.

[0092] In another embodiment, the anti-inflammatory compound is dexamethasone, which has the following chemical structure and is registered under the trademark Decadron® (Merck & Co., Inc.):

[0093] [ka]

[0094] In another embodiment, the anti-inflammatory compound is an NSAID. Examples of NSAIDs that can be used in the present invention include, but are not limited to, aspirin, acetaminophen, ibuprofen, esculetin, phenidone, quercetin, ketoprofen, nordihydroguaiaretic acid (NDGA), sulindac, sulindac sulfone, sulindac sulfonate, indomethacin, NS-398 (a cyclooxygenase-2 inhibitor), cyclooxygenase-1 inhibitor, methylheptylimidazole, sodium furegrelate, S NSAIDs include KF525AHCL, thromboxane inhibitors, toradol, ecasa, salsalate, diflunisal, mefenamic acid, naproxen, naproxen sodium, floctafenine, meclofenamic acid, phenylbutazone, oxyphenbutazone, diclofenac, etodolac, fenoprofen, flufenamic acid, flurbiprofen, pirprofen, tolmetin, apazone, fenbufen, nabumetone, oxaprozin, piroxicam, salicylate, and tenoxicam.Preferred NSAIDs are sulindac, sulindac sulfone, sulindac sulfonate, indomethacin, NS-398, methylheptylimidazole, flegrelate sodium, and SKF525AHCL.Particularly preferred NSAIDs are indomethacin and sulindac.

[0095] An appropriate therapeutically effective dose of an anti-inflammatory compound can be readily determined by one of ordinary skill in the art. Suitable doses of the anti-inflammatory compounds described herein may be calculated for a patient according to the patient's body weight. Therapeutically effective doses are generally about 1-2000 mg, 5-2000 mg, 10-2000 mg, and preferably about 30-1500 mg. Other ranges, including, for example, 50-500 mg, 50-300 mg, 50-100 mg, 100-200 mg, 5-100 mg, and 5-50 mg, may also be used. The daily dose, when used for acute or chronic human disease, is 0.01-250 mg / kg body weight, preferably 0.1-5 mg / kg body weight, preferably 0.1-10 mg / kg body weight, preferably 2-100 mg / kg body weight, or preferably 5-60 mg / kg body weight, which may be administered, for example, in 1-4 daily doses depending on the route of administration and the condition of the subject.

[0096] In one embodiment, the anti-inflammatory compound is dexamethasone and the therapeutically effective dose is from about 5 mg to about 100 mg, hi another embodiment, the anti-inflammatory compound is dexamethasone and the therapeutically effective dose is 20 mg or 40 mg.

[0097] Treatment method Described herein are methods for treating cancer in a subject with the combinations described herein. As used herein, the terms "cancer" and "tumor" are used interchangeably in either the singular or plural and refer to cells that have undergone malignant transformation that renders them pathological to the host organism. Primary cancer cells can be easily distinguished from non-cancerous cells by well-established techniques, particularly histological examination. The definition of cancer cells as used herein includes not only primary cancer cells but also any cells derived from cancer cell prototypes. This includes metastatic cancer cells, as well as in vitro cultures and cell lines derived from cancer cells. When referring to a type of cancer that typically manifests as a solid tumor, a "clinically detectable" tumor is one that can be detected based on the tumor mass, for example, by techniques such as computed tomography (CT) scan, magnetic resonance imaging (MRI), X-ray, ultrasound, or palpation during a physical examination, and / or can be detected due to the expression of one or more cancer-specific antigens in a sample obtainable from a patient. The tumor may be a hematopoietic (or blood system or hematological or blood-related) cancer, such as a cancer derived from blood cells or immune cells, which can be referred to as a "liquid tumor." Specific examples of hematopoietic tumor-based conditions include leukemias such as chronic myeloid leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and acute lymphocytic leukemia; plasma cell malignancies such as multiple myeloma, MGUS, and Waldenstrom's macroglobulinemia; lymphomas such as non-Hodgkin's lymphoma and Hodgkin's lymphoma.

[0098] The cancer may be any of those diagnosed as having an abnormal number of blast cells or unwanted cell proliferation, or as a hematological cancer, including both lymphoid and myeloid malignancies. Myeloid malignancies include, but are not limited to, acute myeloid (or myelocytic or myelogenous or myeloblastic) leukemia (undifferentiated or differentiated), acute promyeloid (or promyelocytic or promyelogenous or promyeloblastic) leukemia, acute myelomonocytic (or myelomonoblastic) leukemia, acute monocytic (or monoblastic) leukemia, erythroleukemia, and megakaryocytic (or megakaryoblastic) leukemia. These leukemias may be collectively referred to as acute myeloid (or myelocytic or myelogenous) leukemia (AML). Myeloid malignancies also include myeloproliferative disorders (MPDs), including, but not limited to, chronic myelogenous (or myeloid) leukemia (CML), chronic myelomonocytic leukemia (CMML), essential thrombocythemia (or thrombocytosis), and polycythemia vera (PCV). Myeloid malignancies also include myelodysplasia (or myelodysplastic syndrome or MDS), which are sometimes called refractory anemia (RA), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transition (RAEBT); and myelofibrosis with or without idiopathic myeloid metaplasia (MFS).

[0099] Hematopoietic cancers also include lymphoid malignancies that can affect lymph nodes, spleen, bone marrow, peripheral blood, and / or extranodal sites. Lymphoid cancers include B-cell malignancies, including, but not limited to, B-cell non-Hodgkin's lymphoma (B-NHL). B-NHL can be indolent (or low-grade), intermediate (or aggressive), or high-grade (ultra-aggressive). Indolent B-cell lymphomas include follicular lymphoma (FL); small lymphocytic lymphoma (SLL); marginal zone lymphoma (MZL), including nodal MZL, extranodal MZL, splenic MZL, and splenic MZL with villous lymphocytes; lymphoplasmacytic lymphoma (LPL); and mucosa-associated lymphoid tissue (MALT or extranodal marginal zone) lymphoma. Intermediate-grade B-NHL includes mantle cell lymphoma (MCL) with or without leukemic cell infiltration, diffuse large cell lymphoma (DLBCL), follicular large cell (or grade 3 or grade 3B) lymphoma, and primary mediastinal lymphoma (PML). High-grade B-NHL includes Burkitt lymphoma (BL), Burkitt-like lymphoma, small noncleaved cell lymphoma (SNCCL), and lymphoblastic lymphoma. Other B-NHLs include immunoblastic lymphoma (or immunocytoma), primary effusion lymphoma, HIV-associated (or AIDS-associated) lymphoma, and post-transplant lymphoproliferative disorder (PTLD) or lymphoma. B-cell malignancies also include, but are not limited to, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), Waldenstrom's macroglobulinemia (WM), hairy cell leukemia (HCL), large granular lymphocyte (LGL) leukemia, acute lymphocytic (or lymphocytic or lymphoblastic) leukemia, and Castleman's disease. NHL can also include T-cell non-Hodgkin's lymphoma (T-NHL), including, but not limited to, T-cell non-Hodgkin's lymphoma, non-specific type (NOS), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphoid disorder (AILD), nasal natural killer (NK) cell / T-cell lymphoma, gamma / delta lymphoma, cutaneous T-cell lymphoma, mycosis fungoides, and Sézary syndrome.

[0100] Hematopoietic cancers also include Hodgkin lymphoma (or Hodgkin's disease), including classical Hodgkin lymphoma, nodular sclerosing Hodgkin lymphoma, mixed cytology Hodgkin lymphoma, lymphocyte-predominant (LP) Hodgkin lymphoma, nodular LP Hodgkin lymphoma, and lymphocyte-depleted Hodgkin lymphoma. Hematopoietic cancers also include plasma cell disorders or cancers such as multiple myeloma (MM), including smoldering MM, monoclonal gammopathy of undetermined (or unknown or unclear) significance (MGUS), plasmacytoma (bone, extramedullary), lymphoplasmacytic lymphoma (LPL), Waldenstrom's macroglobulinemia, plasma cell leukemia, and primary amyloidosis (AL). Hematopoietic cancers can also include other cancers of additional hematopoietic cells, including polymorphonuclear leukocytes (or neutrophils), basophils, eosinophils, dendritic cells, platelets, erythrocytes, and natural killer cells. Tissues containing hematopoietic cells, referred to herein as "hematopoietic cell tissues," include bone marrow; peripheral blood; thymus; and peripheral lymphoid tissues, such as the spleen, lymph nodes, mucosa-associated lymphoid tissue (e.g., gut-associated lymphoid tissue), tonsils, Peyer's patches, and appendix, and lymphoid tissue associated with other mucous membranes, e.g., the bronchial lining.

[0101] The term "treat" and its derivatives, as used herein, is intended to include therapeutic therapy. With respect to a particular condition, treatment means (1) ameliorating the condition or one or more of its biological manifestations; (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition, or (b) one or more of its biological manifestations; (3) alleviating one or more of the symptoms, effects, or side effects associated with the condition or one or more of its treatment; (4) delaying the condition or one or more of its biological manifestations, and / or (5) eliminating or reducing to undetectable levels one or more of its biological manifestations, thereby curing the condition or one or more of its biological manifestations for a period of time considered to be in remission for that manifestation without further treatment. Those skilled in the art will understand the period of time considered to be in remission for a particular disease or condition.

[0102] Preventive therapy is also contemplated.Those skilled in the art will recognize that "prevention" is not an absolute term.In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially reduce the likelihood or severity of a pathological condition or its biological manifestation, or to delay the onset of such a pathological condition or its biological manifestation.Preventive therapy is appropriate, for example, when a subject is considered to be at high risk of developing cancer, for example, when the subject has a strong family history of cancer or when the subject has been exposed to a carcinogen.

[0103] A "subject" is broadly defined to include any patient in need of treatment, such as a patient in need of cancer treatment. A subject may include a mammal. In one embodiment, the subject is a human patient. A subject in need of cancer treatment may include patients in various stages of the disease, including newly diagnosed, relapsed, refractory, progressive disease, in remission, and others. A subject in need of cancer treatment may also include patients who have undergone stem cell transplantation or who are deemed transplant ineligible.

[0104] Subjects may be pre-screened to select for treatment with the combinations described herein, hi one embodiment, a sample from a subject is tested for BCMA expression prior to treatment with the combinations described herein.

[0105] The subject may have undergone at least one prior cancer therapy before being treated with the combination of the invention, hi one embodiment, the subject has been treated with at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 prior cancer therapies before being treated with the combination of the invention.

[0106] In another embodiment, the subject has newly diagnosed cancer and has not received prior treatment prior to being treated with the combination of the present invention.

[0107] The individual therapeutic agents of the combinations of the invention, and pharmaceutical compositions comprising such therapeutic agents, may be administered together or separately. When administered separately, this may be simultaneously or sequentially in any order (by the same route of administration or by different routes of administration). Such sequential administration may be close in time or remote in time. The dosages and relative timings of administration of the therapeutic agents of the invention, or pharmaceutically acceptable salts thereof, and the additional therapeutically active agent(s) are selected to achieve the desired combined therapeutic effect.

[0108] The therapeutic agents of the present invention may be administered by any suitable route of administration. For some therapeutic agents, suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be recognized that the preferred route may vary depending, for example, on the condition of the recipient of the combination and the cancer being treated. It will also be recognized that each of the administered agents may be administered by the same or different routes, and that the therapeutic agents may be formulated together or in separate pharmaceutical compositions.

[0109] In one embodiment, one or more of the therapeutic agents of the combination of the invention are administered intravenously. In another embodiment, one or more of the therapeutic agents of the combination of the invention are administered intratumorally. In another embodiment, one or more of the therapeutic agents of the combination of the invention are administered orally. In another embodiment, one or more of the therapeutic agents of the combination of the invention are administered systemically, e.g., intravenously, and one or more other therapeutic agents of the combination of the invention are administered intratumorally. In another embodiment, all of the therapeutic agents of the combination of the invention are administered systemically, e.g., intravenously. In another embodiment, all of the therapeutic agents of the combination of the invention are administered intratumorally. In any embodiment, e.g., in this paragraph, the therapeutic agents of the invention are administered as one or more pharmaceutical compositions.

[0110] In one embodiment, the present invention provides a method of treating cancer in a subject in need thereof by administering a therapeutically effective dose combination described herein.

[0111] In one embodiment, the invention provides a method of treating cancer in a subject in need thereof by administering a therapeutically effective dose combination comprising an anti-BCMA antigen binding protein and a proteasome inhibitor.

[0112] In one embodiment, the invention provides a method of treating cancer in a subject in need thereof by administering a therapeutically effective dose combination comprising an anti-BCMA antigen binding protein, a proteasome inhibitor, and an anti-inflammatory compound.

[0113] In one embodiment, the invention comprises an anti-BCMA antibody and a proteasome inhibitor, wherein the anti-BCMA antibody is a CDRH1 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1; a CDRH2 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 2; a CDRH3 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 3; a CDRH4 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 4; and / or CDRL3 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:6.

[0114] In one embodiment, the invention provides a method of treating cancer in a subject in need thereof by administering a therapeutically effective dose of a combination comprising an anti-BCMA antibody and a proteasome inhibitor, wherein the anti-BCMA antibody comprises a VH comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:7; and / or a VL comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:8.

[0115] In one embodiment, the invention provides a method of treating cancer in a subject in need thereof by administering a therapeutically effective dose of a combination comprising an anti-BCMA antibody and a proteasome inhibitor, wherein the anti-BCMA antibody comprises an HC comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 9; and / or an LC comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 10.

[0116] In one embodiment, the invention provides a method for treating BCMA comprising administering to a subject an anti-BCMA antibody, a proteasome inhibitor, and an anti-inflammatory compound, wherein the anti-BCMA antibody is a CDRH1 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1; a CDRH2 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 2; a CDRH3 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 3; a CDRH4 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 3; and / or CDRL3 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:6.

[0117] In one embodiment, the invention provides a method of treating cancer in a subject in need thereof by administering therapeutically effective doses of a combination comprising an anti-BCMA antibody, a proteasome inhibitor, and an anti-inflammatory compound, wherein the anti-BCMA antibody comprises an anti-BCMA antibody and a proteasome inhibitor, and the anti-BCMA antibody comprises a VH comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:7; and / or a VL comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:8.

[0118] In one embodiment, the invention provides a method of treating cancer in a subject in need thereof by administering therapeutically effective doses of a combination comprising an anti-BCMA antibody, a proteasome inhibitor, and an anti-inflammatory compound, wherein the anti-BCMA antibody comprises an HC comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 9; and / or an LC comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 10.

[0119] In one embodiment, the invention provides a method of treating cancer in a subject in need thereof by administering a therapeutically effective dose combination comprising an anti-BCMA antigen binding protein and bortezomib.

[0120] In one embodiment, the invention provides a method of treating cancer in a subject in need thereof by administering a therapeutically effective dose combination comprising an anti-BCMA antigen binding protein, bortezomib, and an anti-inflammatory compound.

[0121] In one embodiment, the invention provides a method of treating multiple myeloma in a subject in need thereof by administering a therapeutically effective dose combination comprising an anti-BCMA antibody, bortezomib, and dexamethasone. In another embodiment, the invention provides a method of treating multiple myeloma in a subject in need thereof by administering a therapeutically effective dose combination comprising an anti-BCMA antibody at 1.9 mg / kg, 2.5 mg / kg, or 3.4 mg / kg, an anti-BCMA antibody at 1.3 mg / kg, or a combination of bortezomib and dexamethasone. 2 The present invention provides a method of treating multiple myeloma in a subject in need thereof by administering 10 mg of bortezomib and 20 mg or 40 mg of dexamethasone.

[0122] In one embodiment, the invention provides a method of treating cancer in a subject in need thereof by administering a therapeutically effective dose combination comprising an anti-BCMA antigen binding protein and carfilzomib.

[0123] In one embodiment, the invention provides a method of treating cancer in a subject in need thereof by administering a therapeutically effective dose combination comprising an anti-BCMA antigen binding protein, carfilzomib, and an anti-inflammatory compound.

[0124] In one embodiment, the invention provides a method of treating multiple myeloma in a subject in need thereof by administering a therapeutically effective dose combination comprising an anti-BCMA antibody, carfilzomib, and dexamethasone. In another embodiment, the invention provides a method of treating multiple myeloma in a subject in need thereof by administering a therapeutically effective dose combination comprising an anti-BCMA antibody, carfilzomib, and dexamethasone. In another embodiment, the invention provides a method of treating multiple myeloma in a subject in need thereof by administering a therapeutically effective dose combination comprising an anti-BCMA antibody at 1.9 mg / kg, 2.5 mg / kg, or 3.4 mg / kg; 2 , 20 mg / m 2 , 27 mg / m 2 , 36 mg / m 2 , 45 mg / m 2 , or 56 mg / m 2 and 20 mg or 40 mg of dexamethasone.

[0125] In one embodiment, the invention provides a method of treating cancer in a subject in need thereof by administering a therapeutically effective dose combination comprising an anti-BCMA antigen binding protein and ixazomib.

[0126] In one embodiment, the invention provides a method of treating cancer in a subject in need thereof by administering a therapeutically effective dose combination comprising an anti-BCMA antigen binding protein, ixazomib, and an anti-inflammatory compound.

[0127] In one embodiment, the invention provides a method of treating multiple myeloma in a subject in need thereof by administering a therapeutically effective dose combination comprising an anti-BCMA antibody, ixazomib, and dexamethasone. In another embodiment, the invention provides a method of treating multiple myeloma in a subject in need thereof by administering 1.9 mg / kg, 2.5 mg / kg, or 3.4 mg / kg of an anti-BCMA antibody; 2.3 mg, 3 mg, or 4 mg of ixazomib; and 20 mg or 40 mg of dexamethasone.

[0128] In one embodiment, the invention provides a method of treating cancer in a subject in need thereof by administering a therapeutically effective dose combination comprising an anti-BCMA antigen binding protein and oprozomib.

[0129] In one embodiment, the invention provides a method of treating cancer in a subject in need thereof by administering a therapeutically effective dose combination comprising an anti-BCMA antigen binding protein, oprozomib, and an anti-inflammatory compound.

[0130] In one embodiment, the invention provides a method of treating multiple myeloma in a subject in need thereof by administering a therapeutically effective dose combination comprising an anti-BCMA antibody, oprozomib, and dexamethasone.

[0131] In one embodiment, the invention provides a combination as described herein for use in therapy.

[0132] In one embodiment, the invention provides a combination as described herein for use in the treatment of cancer.

[0133] In one embodiment, the invention provides a combination as described herein comprising an anti-BCMA antigen binding protein and a proteasome inhibitor for use in the treatment of cancer.

[0134] In one embodiment, the invention provides a combination as described herein comprising an anti-BCMA antigen binding protein, a proteasome inhibitor, and an anti-inflammatory compound for use in the treatment of cancer.

[0135] In one embodiment, the invention provides an anti-BCMA antibody and a proteasome inhibitor for use in treating cancer, wherein the anti-BCMA antibody is a CDRH1 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1; a CDRH2 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 2; or a CDRH3 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 3. a CDRH1 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:4; a CDRL2 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:5; and / or a CDRL3 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:6.

[0136] In one embodiment, the invention provides a combination as described herein, comprising an anti-BCMA antibody and a proteasome inhibitor, wherein the anti-BCMA antibody comprises a VH comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 7; and / or a VL comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 8, for use in the treatment of cancer.

[0137] In one embodiment, the invention provides a combination as described herein, comprising an anti-BCMA antibody and a proteasome inhibitor, wherein the anti-BCMA antibody comprises an HC comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 9; and / or an LC comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 10, for use in the treatment of cancer.

[0138] In one embodiment, the invention comprises an anti-BCMA antibody, a proteasome inhibitor, and an anti-inflammatory compound for use in the treatment of cancer, wherein the anti-BCMA antibody is a CDRH1 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1; a CDRH2 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 2; a CDRH3 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 3; a CDRH3 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:4; a CDRL2 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:5; and / or a CDRL3 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:6.

[0139] In one embodiment, the invention provides a combination as described herein comprising an anti-BCMA antibody, a proteasome inhibitor, and an anti-inflammatory compound for use in the treatment of cancer, wherein the anti-BCMA antibody comprises a VH comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:7; and / or a VL comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:8.

[0140] In one embodiment, the invention provides a combination as described herein comprising an anti-BCMA antibody, a proteasome inhibitor, and an anti-inflammatory compound for use in the treatment of cancer, wherein the anti-BCMA antibody comprises an HC comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 9; and / or an LC comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 10.

[0141] In one embodiment, the invention provides a combination as described herein comprising an anti-BCMA antigen binding protein and bortezomib for use in the treatment of cancer.

[0142] In one embodiment, the invention provides a combination as described herein comprising an anti-BCMA antigen binding protein, bortezomib, and an anti-inflammatory compound for use in the treatment of cancer.

[0143] In one embodiment, the invention provides a combination as described herein comprising an anti-BCMA antibody, bortezomib, and dexamethasone for use in the treatment of multiple myeloma. In another embodiment, the invention provides 1.9 mg / kg, 2.5 mg / kg, or 3.4 mg / kg of an anti-BCMA antibody; 1.3 mg / kg 2 of bortezomib; and 20 mg or 40 mg of dexamethasone.

[0144] In one embodiment, the invention provides a combination as described herein comprising an anti-BCMA antigen binding protein and carfilzomib for use in the treatment of cancer.

[0145] In one embodiment, the invention provides a combination as described herein comprising an anti-BCMA antigen binding protein, carfilzomib, and an anti-inflammatory compound for use in the treatment of cancer.

[0146] In one embodiment, the invention provides a combination as described herein comprising an anti-BCMA antibody, carfilzomib, and dexamethasone for use in the treatment of multiple myeloma. In another embodiment, the invention provides 1.9 mg / kg, 2.5 mg / kg, or 3.4 mg / kg of an anti-BCMA antibody; 15 mg / kg 2 , 20 mg / m 2 , 27 mg / m 2 , 36 mg / m 2 , 45 mg / m 2 , or 56 mg / m 2 carfilzomib; and 20 mg or 40 mg of dexamethasone.

[0147] In one embodiment, the invention provides a combination as described herein comprising an anti-BCMA antigen binding protein and ixazomib for use in the treatment of cancer.

[0148] In one embodiment, the invention provides a combination as described herein comprising an anti-BCMA antigen binding protein, ixazomib, and an anti-inflammatory compound for use in the treatment of cancer.

[0149] In one embodiment, the invention provides a combination as described herein comprising an anti-BCMA antibody, carfilzomib, and dexamethasone for use in the treatment of multiple myeloma. In another embodiment, the invention provides a combination as described herein comprising 1.9 mg / kg, 2.5 mg / kg, or 3.4 mg / kg of an anti-BCMA antibody; 2.3 mg, 3 mg, or 4 mg of ixazomib; and 20 mg or 40 mg of dexamethasone for use in the treatment of multiple myeloma.

[0150] In one embodiment, the invention provides a combination as described herein comprising an anti-BCMA antigen binding protein and oprozomib for use in the treatment of cancer.

[0151] In one embodiment, the invention provides a combination as described herein comprising an anti-BCMA antigen binding protein, oprozomib, and an anti-inflammatory compound for use in the treatment of cancer.

[0152] In one embodiment, there is provided the use of a combination in the manufacture of a medicament for use in the treatment of cancer. In another embodiment, there is provided the use of a combination comprising an anti-BCMA antigen binding protein and a proteasome inhibitor in the manufacture of a medicament for use in the treatment of cancer. In yet another embodiment, there is provided the use of a combination comprising an anti-BCMA antigen binding protein, a proteasome inhibitor, and an anti-inflammatory compound in the manufacture of a medicament for use in the treatment of cancer.

[0153] Treatment planning An appropriate treatment regimen of anti-BCMA antigen binding protein, proteasome inhibitor, and anti-inflammatory compound can be readily determined by one of skill in the art.

[0154] In one exemplary treatment regimen, one dose of the anti-BCMA antigen binding protein is administered every three weeks (a 21-day cycle) for up to 16 cycles. In another exemplary treatment regimen, one dose of the anti-BCMA antigen binding protein is administered once a week for three consecutive weeks, followed by one week off (a 28-day cycle) for up to 16 cycles. In yet another exemplary treatment regimen, one dose of the anti-BCMA antigen binding protein is administered on day 1 of a 28-day cycle. In a further exemplary treatment regimen, one dose of the anti-BCMA antigen binding protein is administered on day 1 of a 21-day cycle for up to one year.

[0155] In one exemplary embodiment, the proteasome inhibitor is bortezomib and the treatment regimen includes nine 6-week cycles, with bortezomib administered on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycles 1 through 4 and on days 1, 8, 22, and 29 of cycles 5 through 9. In another exemplary embodiment, the proteasome inhibitor is bortezomib and the treatment regimen includes administration of a single dose of bortezomib on days 1, 4, 8, and 11 of a 21-day cycle for up to eight cycles.

[0156] In one exemplary embodiment, the proteasome inhibitor is carfilzomib, the treatment regimen includes 28-day cycles, and carfilzomib is administered on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. In another exemplary embodiment, the proteasome inhibitor is carfilzomib, the treatment regimen includes 28-day cycles, and carfilzomib is administered on days 1, 2, 8, 9, 15, and 16 of cycles 1 through 12 and days 1, 2, 15, and 16 of cycles 13 and beyond.

[0157] In one exemplary embodiment, the proteasome inhibitor is ixazomib, and the treatment regimen comprises 28-day cycles, with ixazomib administered on days 1, 8, and 15 of each 28-day cycle.

[0158] In one exemplary embodiment, the anti-inflammatory compound is dexamethasone and the treatment regimen comprises administering a dose of dexamethasone on days 1-4, 9-12, and 17-20 of a 28-day cycle. In another exemplary embodiment, the anti-inflammatory compound is dexamethasone and the treatment regimen comprises administering a dose of dexamethasone on days 1, 8, 15, and 22 of a 28-day cycle. In yet another embodiment, the anti-inflammatory compound is dexamethasone and the treatment regimen comprises administering dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle. In yet another embodiment, the anti-inflammatory compound is dexamethasone and the treatment regimen comprises administering dexamethasone on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle.

[0159] In one exemplary treatment regimen, the treatment regimen comprises administration of 1.9 mg / kg, 2.5 mg / kg, or 3.4 mg / kg of anti-BCMA antigen binding protein on day 1 of a 21 day cycle; 1.3 mg / m on days 1, 4, 8, and 11 of a 21 day cycle. 2 of bortezomib; and optionally, administration of 20 mg or 40 mg of dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle.

[0160] In one exemplary treatment regimen, the treatment regimen comprises administration of 1.9 mg / kg, 2.5 mg / kg, or 3.4 mg / kg of anti-BCMA antigen binding protein on day 1 of a 28 day cycle; 15 mg / m on days 1, 2, 8, 9, 15, and 16 of a 28 day cycle. 2 , 20 mg / m 2 , 27 mg / m 2 , 36 mg / m 2 , 45 mg / m 2 , or 56 mg / m 2 carfilzomib; and optionally 20 mg or 40 mg dexamethasone on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle.

[0161] In one exemplary treatment regimen, the treatment regimen comprises administration of 1.9 mg / kg, 2.5 mg / kg, or 3.4 mg / kg of anti-BCMA antigen binding protein on day 1 of a 28 day cycle; 15 mg / m on days 1, 2, 15, and 16 of a 28 day cycle. 2 , 20 mg / m 2 , 27 mg / m 2 , 36 mg / m 2 , 45 mg / m 2 , or 56 mg / m 2 carfilzomib; and optionally 20 mg or 40 mg dexamethasone on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle.

[0162] In one exemplary treatment regimen, the treatment regimen comprises administration of 1.9 mg / kg, 2.5 mg / kg, or 3.4 mg / kg of an anti-BCMA antigen binding protein on day 1 of a 28 day cycle; administration of 2.3 mg, 3 mg, or 4 mg of ixazomib on days 1, 8, and 15 of a 28 day cycle; and optionally administration of 20 mg or 40 mg of dexamethasone on days 1, 8, 15, and 22 of a 28 day cycle.

[0163] kit In some aspects, the present disclosure provides: (i) anti-BCMA antigen-binding protein; (ii) a proteasome inhibitor; and (iii) instructions for use in treating cancer The present invention provides a kit for use in treating cancer, comprising:

[0164] In some embodiments, the anti-BCMA antigen binding protein and the proteasome inhibitor are each formulated individually with one or more pharmaceutically acceptable carriers as their own pharmaceutical compositions.

[0165] In some aspects, the present disclosure provides: (i) anti-BCMA antigen-binding protein; (ii) proteasome inhibitors; (iii) anti-inflammatory compounds; and (iii) instructions for use in treating cancer The present invention provides a kit for use in treating cancer, comprising:

[0166] In some embodiments, the anti-BCMA antigen binding protein, the proteasome inhibitor, and the anti-inflammatory compound are each individually formulated with one or more pharmaceutically acceptable carriers as their own pharmaceutical compositions.

[0167] In some aspects, the present disclosure provides: (i) anti-BCMA antigen-binding protein; (ii) instructions for use in the treatment of cancer when combined with a proteasome inhibitor; The present invention provides a kit for use in treating cancer, comprising:

[0168] In some aspects, the present disclosure provides: (i) anti-BCMA antigen-binding protein; (ii) instructions for use in the treatment of cancer when combined with a proteasome inhibitor and an anti-inflammatory compound; The present invention provides a kit for use in treating cancer, comprising: [Example]

[0169] Example 1 Treatment of multiple myeloma with anti-BCMA antibody-drug conjugate, bortezomib, and dexamethasone A Phase I / II study will be conducted in human subjects to determine the safety and tolerability of anti-BCMA antigen binding proteins administered in combination with bortezomib and dexamethasone in subjects with relapsed / refractory multiple myeloma (RRMM), to determine the Phase II recommended dose (RP2D), and to evaluate the safety and clinical activity of the RP2D combination treatment in participants with RRMM.

[0170] The anti-BCMA antigen binding protein is an anti-BCMA antibody comprising a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO: 1; a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO: 2; a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO: 3; a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO: 4; a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO: 5; and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO: 6; conjugated to monomethyl auristatin F (MMAF) as described in Tai et al Blood. 2014 May 15; 123(20): 3128-3138.

[0171] A single treatment cycle consists of 21 days. Subjects who do not experience dose-limiting or intolerable adverse events may continue treatment for up to one year.

[0172] The study consists of two parts: Part 1 is a dose escalation study and Part 2 is a dose expansion study.

[0173] The first part of the study is a dose-escalation phase to evaluate the safety and tolerability of combination dose levels. This is designed to identify the recommended phase 2 dose (RP2D) level of anti-BCMA antigen binding protein when combined with bortezomib and dexamethasone. Subjects will initially be tested with 2.5 mg / kg anti-BCMA antigen binding protein on day 1 of a 21-day cycle; 1.3 mg / m² bortezomib on days 1, 4, 8, and 11 of a 21-day cycle; and 20 mg dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle.

[0174] After the first cycle, the dose of the anti-BCMA antigen binding protein can be adjusted to 1.9 mg / kg or 3.4 mg / kg.

[0175] The treatment plan is outlined in Table 1.

[0176] [Table 1]

[0177] In Part 2 (dose expansion), additional subjects will be enrolled and studied at the RP2D of each of the anti-BCMA antigen binding protein, bortezomib, and dexamethasone. Safety (AEs, ECG, MM symptoms, and laboratory assessments), clinical response, and change in symptoms / quality of life will be assessed at the end of Cycle 1 and all subsequent cycles.

[0178] Sequence Listing SEQ ID NO:1-CDRH1 [ka]

[0179] SEQ ID NO: 2: CDRH2 [ka]

[0180] SEQ ID NO: 3: CDRH3 [ka]

[0181] SEQ ID NO: 4: CDRL1 [ka]

[0182] SEQ ID NO: 5: CDRL2 [ka]

[0183] SEQ ID NO: 6: CDRL3 [ka]

[0184] SEQ ID NO: 7: Heavy chain variable region [ka]

[0185] SEQ ID NO: 8: Light chain variable region [ka]

[0186] SEQ ID NO: 9: Heavy chain region [ka]

[0187] SEQ ID NO: 10: Light chain region [ka]

Claims

1. A method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective dose combination comprising an anti-BCMA antigen binding protein and a proteasome inhibitor.

2. 10. The method of claim 1, wherein the combination further comprises an anti-inflammatory compound.

3. The method of claim 1 or claim 2, wherein the anti-BCMA antigen binding protein comprises: a CDRH1 comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1; a CDRH2 comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 2; a CDRH3 comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 3; a CDRL1 comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 4; a CDRL2 comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 5; and a CDRL3 comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:

6.

4. 4. The method of any one of claims 1 to 3, wherein the anti-BCMA antigen binding protein is an antibody comprising a heavy chain variable region (VH) comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:7; and a light chain variable region (VL) comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:

8.

5. The method of any one of claims 2 to 4, wherein the anti-inflammatory compound is dexamethasone.

6. The method of any one of claims 1 to 5, wherein the proteasome inhibitor is bortezomib.

7. The method of any one of claims 1 to 5, wherein the proteasome inhibitor is carfilzomib.

8. The method of any one of claims 1 to 5, wherein the proteasome inhibitor is ixazomib.

9. The method of any one of claims 1 to 5, wherein the proteasome inhibitor is oprozomib.

10. 10. The method of any one of claims 1 to 9, wherein the anti-BCMA antigen binding protein is an immunoconjugate comprising an antibody conjugated to a cytotoxin.

11. 11. The method of claim 10, wherein the cytotoxin is selected from MMAE or MMAF.

12. The method of any one of claims 1 to 11, wherein the cancer is selected from multiple myeloma, chronic lymphocytic leukemia and non-Hodgkin's lymphoma.

13. 13. The method of any one of claims 1-12, wherein 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.

14. The proteasome inhibitor is bortezomib, and the dose is 1.3 mg / m ２ 7. The method of any one of claims 1 to 6, wherein bortezomib is administered on days 1, 4, 8 and 11 of a 21 day cycle.

15. 15. The method of any one of claims 2 to 14, wherein the anti-inflammatory compound is dexamethasone and 20 mg of dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21 day cycle.

16. A combination for use in the treatment of cancer comprising an anti-BCMA antigen binding protein, a proteasome inhibitor, and optionally an anti-inflammatory compound.

17. 1. Use of a combination comprising an anti-BCMA antigen binding protein, a proteasome inhibitor, and optionally an anti-inflammatory compound in the manufacture of a medicament for use in the treatment of cancer.

18. (i) an anti-BCMA antigen-binding protein; (ii) instructions for use in the treatment of cancer when combined with a proteasome inhibitor and an anti-inflammatory compound.

10. A kit for use in treating cancer comprising:

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