Methods of treating multiple myeloma with bispecific BCMA x CD3 antibodies

Abstract

The present disclosure provides methods for treating multiple myeloma. In certain embodiments, the present methods comprise administering to a subject in need thereof bispecific antibodies or antigen-binding fragments thereof that bind to BCMA and CD3. In certain embodiments, the bispecific BCMAxCD3 antibodies are administered subcutaneously to the subject in need thereof. In certain embodiments, the subject has been previously treated with BCMA-CAR-T cell therapy.

Description

METHODS OF TREATING MULTIPLE MYELOMA WITH BISPECIFIC BCMA x CD3 ANTIBODIES REFERENCE TO A SEQUENCE LISTING

[0001] This application incorporates by reference a computer readable Sequence Listing in ST.26 XML format, titled 11756WO01_Sequence, created on May 9, 2025 and containing 26,876 bytes. FIELD OF THE DISCLOSURE

[0002] The present disclosure relates to methods for treating multiple myeloma, comprising administering to a subject in need thereof a therapeutically effective amount of a bispecific antibody that specifically binds to B-cell maturation antigen (BCMA) and CD3. BACKGROUND

[0003] B-cell maturation antigen (BCMA), also known as TNFRSF17, or CD269, is a type III transmembrane protein lacking a signal peptide and containing a cysteine-rich extracellular domain. BCMA, along with closely related proteins, promotes B-cell survival at distinct stages of development. BCMA is expressed exclusively in B-cell lineage cells, particularly in the interfollicular region of the germinal center as well as on plasmablasts and differentiated plasma cells. BCMA is selectively induced during plasma cell differentiation, and is required for optimal survival of long- lived plasma cells in the bone marrow. In multiple myeloma, BCMA is widely expressed on malignant plasma cells at elevated levels, and BCMA expression is increased with progression from normal cells to active multiple myeloma. BCMA is also expressed in other B-cell malignancies, including Waldenström’s macroglobulinemia, Burkitt lymphoma, and Diffuse Large B-Cell Lymphoma. Tai et al., Immunotherapy, 7(11):1187-1199, 2015.

[0004] CD3 is a homodimeric or heterodimeric antigen expressed on T cells in association with the T cell receptor complex (TCR) and is required for T cell activation. Functional CD3 is formed from the dimeric association of two of four different chains: epsilon, zeta, delta and gamma. The CD3 dimeric arrangements include gamma / epsilon, delta / epsilon and zeta / zeta. Antibodies against CD3 have been shown to cluster CD3 on T cells, thereby causing T cell activation in a manner similar to the engagement of the TCR by peptide-loaded MHC molecules. Thus, anti-CD3 antibodies have been proposed for therapeutic purposes involving the activation of T cells. In addition, bispecific antibodies that are capable of binding CD3 and a target antigen have been proposed for therapeutic uses involving targeting T cell immune responses to tissues and cells expressing the target antigen.

[0005] Multiple myeloma patients who are refractory to multiple classes of therapies have reduced rates of overall survival (triple- and quad-refractory: 9.2 months, and penta-refractory: 5.6months). Gandhi U. et al., Leukemia 33:2266-2275, 2013. Antigen-binding molecules that target BCMA, including bispecific antigen-binding molecules that bind both BCMA and CD3 would be useful in therapeutic settings in which specific targeting and T cell-mediated killing of cells that express BCMA is desired. BRIEF SUMMARY OF THE DISCLOSURE

[0006] In one aspect, the present disclosure provides a method of treating multiple myeloma in a subject in need thereof, comprising administering to the subject a bispecific antibody or antigen- binding fragment thereof comprising a first antigen-binding domain that specifically binds a human B-cell maturation antigen (BCMA), and a second antigen-binding domain that specifically binds human CD3, wherein the bispecific antibody or antigen-binding fragment thereof is administered to the subject in a dosing regimen, wherein the dosing regimen comprises: subcutaneously administering 3-7 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on a first day during week 1 of the dosing regimen; subcutaneously administering 20-30 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on a second day during week 1 of the dosing regimen; subcutaneously administering 50-400 mg of the bispecific antibody or antigen-binding fragment thereof to the subject during week 2 of the dosing regimen; subcutaneously administering 150-400 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 3 to 5 of the dosing regimen; administering 150-400 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 6 to 13 of the dosing regimen; administering 150-400 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) to the subject during weeks 14 to 25 of the dosing regimen; and administering 150-400 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) or once every four weeks (Q4W) to the subject in subsequent weeks of the dosing regimen.

[0007] In some embodiments, the first day is day 1 of week 1, and the second day is day 4 of week 1 of the dosing regimen.

[0008] In some embodiments, the 3-7 mg of the bispecific antibody or antigen-binding fragment thereof is about 5 mg.

[0009] In some embodiments, the 20-30 mg of the bispecific antibody or antigen-binding fragment thereof is about 25 mg.

[0010] In some embodiments, the 50-400 mg of the bispecific antibody or antigen-binding fragment thereof is about 100 mg or about 200 mg.

[0011] In some embodiments, the 150-400 mg of the bispecific antibody or antigen-binding fragment thereof is about 200 mg.

[0012] In some embodiments, the 50-400 mg of the bispecific antibody or antigen-binding fragment thereof is about 300-360 mg, and the 150-400 mg of the bispecific antibody or antigen- binding fragment thereof is 300-360 mg. In some cases, the 300-360 mg is 330-340 mg. In some cases, the 300-360 mg is about 336 mg.

[0013] In some embodiments, the bispecific antibody or antigen-binding fragment thereof is administered Q2W to the subject in the subsequent weeks of the dosing regimen. In some embodiments, the bispecific antibody or antigen-binding fragment thereof is administered Q4W to the subject in the subsequent weeks of the dosing regimen.

[0014] In some embodiments, the bispecific antibody or antigen-binding fragment thereof is administered intravenously during weeks 6 to 13, weeks 14 to 25, and in the subsequent weeks of the dosing regimen. In some embodiments, the bispecific antibody or antigen-binding fragment thereof is administered subcutaneously during weeks 6 to 13, weeks 14 to 25, and in the subsequent weeks of the dosing regimen.

[0015] In some embodiments, the dosing regimen comprises: subcutaneously administering 3-7 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on a first day during week 1 of the dosing regimen; subcutaneously administering 20-30 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on a second day during week 1 of the dosing regimen; subcutaneously administering 325-350 mg of the bispecific antibody or antigen-binding fragment thereof to the subject during week 2 of the dosing regimen; subcutaneously administering 325-350 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 3 to 5 of the dosing regimen; subcutaneously administering 325-350 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 6 to 13 of the dosing regimen; subcutaneously administering 325-350 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) to the subject during weeks 14 to 25 of the dosing regimen; and subcutaneously administering 325-350 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) or once every four weeks (Q4W) to the subject in subsequent weeks of the dosing regimen. In some cases, 3-7 mg is about 5 mg, 20-30 mg is about 25 mg, and 325-350 mg is about 336 mg.

[0016] In any of the various embodiments, the first antigen-binding domain comprises a heavy chain variable region (HCVR) comprising three heavy chain complementarity determining regions, HCDR1, HCDR2 and HCDR3, comprising the amino acid sequences of SEQ ID NOs: 2, 3 and 4, respectively, and a light chain variable region (LCVR) comprising three light chain complementarity determining regions, LCDR1, LCDR2 and LCDR3, comprising the amino acid sequences of SEQ ID NOs: 14, 15 and 16, respectively. In some cases, the HCVR of the first antigen-binding domaincomprises the amino acid sequence of SEQ ID NO: 1, and the LCVR of the first antigen-binding domain comprises the amino acid sequence of SEQ ID NO: 13.

[0017] In any of the various embodiments, the second antigen-binding domain comprises a heavy chain variable region (HCVR) comprising three heavy chain complementarity determining regions, HCDR1, HCDR2 and HCDR3, comprising the amino acid sequences of SEQ ID NOs: 6, 7 and 8, respectively, and a light chain variable region (LCVR) comprising three light chain complementarity determining regions, LCDR1, LCDR2 and LCDR3, comprising the amino acid sequences of SEQ ID NOs: 14, 15 and 16, respectively. In some cases, the HCVR of the second antigen-binding domain comprises the amino acid sequence of SEQ ID NO: 5, and the LCVR of the first antigen-binding domain comprises the amino acid sequence of SEQ ID NO: 13.

[0018] In any of the various embodiments, the second antigen-binding domain comprises a heavy chain variable region (HCVR) comprising three heavy chain complementarity determining regions, HCDR1, HCDR2 and HCDR3, comprising the amino acid sequences of SEQ ID NOs: 10, 11 and 12, respectively, and a light chain variable region (LCVR) comprising three light chain complementarity determining regions, LCDR1, LCDR2 and LCDR3, comprising the amino acid sequences of SEQ ID NOs: 14, 15 and 16, respectively. In some cases, the HCVR of the second antigen-binding domain comprises the amino acid sequence of SEQ ID NO: 9, and the LCVR of the first antigen-binding domain comprises the amino acid sequence of SEQ ID NO: 13.

[0019] In some embodiments, the bispecific antibody comprises a human IgG heavy chain constant region. In some cases, the human IgG heavy chain constant region is isotype IgG1. In some cases, the human IgG heavy chain constant region is isotype IgG4.

[0020] In some embodiments, the bispecific antibody comprises a chimeric hinge that reduces Fcɣ receptor binding relative to a wild-type hinge of the same isotype.

[0021] In some embodiments, the bispecific antibody comprises a first heavy chain and a second heavy chain, and wherein the first heavy chain or the second heavy chain, but not both, comprises a CH3 domain comprising a H435R (EU numbering) modification and a Y436F (EU numbering) modification.

[0022] In some embodiments, the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 17, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 18, and a common light chain paired with each of the first heavy chain and second heavy chain, respectively, comprising the amino acid sequence of SEQ ID NO: 20.

[0023] In some embodiments, the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 17, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 19, and a common light chain paired with each of the first heavy chain and second heavy chain, respectively, comprising the amino acid sequence of SEQ ID NO: 20.

[0024] In some embodiments, the methods further comprise administering a second therapeutic agent or therapeutic regimen. In some cases, the second therapeutic agent or therapeutic regimen comprises a chemotherapeutic drug, DNA alkylators, immunomodulators, proteasome inhibitors, histone deacetylase inhibitors, radiotherapy, a stem cell transplant, a different bispecific antibody that interacts with a different tumor cell surface antigen and a T cell or immune cell antigen, an antibody drug conjugate, a PD-1 antagonist, a PD-L1 antagonist, or CTLA-4 checkpoint inhibitor, or combinations thereof.

[0025] In some embodiments, the subject has been previously treated with an anti-CD38 antibody therapy. In some cases, the anti-CD38 antibody is daratumumab or isatuximab.

[0026] In some embodiments, the subject has been previously treated with a proteasome inhibitor or an immunomodulatory drug. In some cases, the proteasome inhibitor is bortezomib, carfilzomib or ixazomib. In some cases, the immunomodulatory drug is lenalidomide or pomalidomide.

[0027] In some embodiments, the subject has an extramedullary plasmacytoma.

[0028] In some embodiments, the multiple myeloma is relapsed or refractory multiple myeloma.

[0029] In some embodiments, the subject has previously received one to three lines of prior therapy to treat multiple myeloma. In some cases, the subject is at least triple-refractory to prior therapies. In some cases, the subject is quad-refractory or penta-refractory to prior therapies.

[0030] In some embodiments, the subject has been previously treated with a BCMA-directed CAR-T cellular therapy.

[0031] In some embodiments, the subject is eligible for a stem cell transplant or has undergone a stem cell transplant. In some embodiments, the subject is not eligible for a stem cell transplant.

[0032] In one aspect, the present disclosure provides a method of treating multiple myeloma in a subject that has failed prior CAR-T therapy or is not responsive to prior CAR-T therapy to treat the multiple myeloma, comprising administering to the subject a bispecific antibody or antigen-binding fragment thereof comprising a first antigen-binding domain that specifically binds a human B-cell maturation antigen (BCMA), and a second antigen-binding domain that specifically binds human CD3. In various embodiments of this method, the bispecific antibody or antigen-binding fragment may be administered to the subject in a dosing regimen as discussed herein (in some cases, all doses are administered intravenously in this context, even if the referenced regimen herein refers to subcutaneous dosing). In various embodiments, the bispecific antibody or antigen-binding fragment may be administered intravenously, or the bispecific antibody or antigen-binding fragment may be administered subcutaneously. In some cases, the bispecific antibody or antigen-binding fragment is administered to the subject in a dosing regimen, wherein the dosing regimen comprises: intravenously administering 3-7 mg (e.g., about 5 mg) of the bispecific antibody or antigen-binding fragment thereof to the subject during week 1 of the dosing regimen; intravenously administering20-30 mg (e.g., about 25 mg) of the bispecific antibody or antigen-binding fragment thereof to the subject during week 2 of the dosing regimen; intravenously administering 150-250 mg (e.g., about 200 mg) of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 3 to 13 of the dosing regimen; intravenously administering 150-250 mg (e.g., about 200 mg) of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) to the subject during weeks 14 to 25 of the dosing regimen; and intravenously administering 150-250 mg (e.g., about 200 mg) of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) or once every four weeks (Q4W) to the subject in subsequent weeks of the dosing regimen.

[0033] In any of the various embodiments, the subject may be administered a dose of an anti-IL- 6R antibody (e.g., tocilizumab or sarilumab) prior to receiving a first dose of the bispecific antibody or antigen-binding fragment thereof (e.g., an IV dose of the bispecific antibody or antigen-binding fragment).

[0034] The present disclosure also encompasses the use of the bispecific antibodies (and antigen-binding fragments) in the manufacture of a medicament for treating a BCMA-expressing cancer (e.g., relapsed or refractory multiple myeloma) as set forth in any of the embodiments of the methods discussed above or herein. The present disclosure also encompasses bispecific antibodies (and antigen-binding fragments) for use in any of the embodiments of the methods discussed above or herein. The present disclosure also encompasses pharmaceutical compositions comprising the bispecific antibodies (and antigen-binding fragments) for use in any of the embodiments of the methods discussed above or herein.

[0035] In various embodiments, any of the features or components of embodiments discussed above or herein may be combined, and such combinations are encompassed within the scope of the present disclosure. Any specific value discussed above or herein may be combined with another related value discussed above or herein to recite a range with the values representing the upper and lower ends of the range, and such ranges are encompassed within the scope of the present disclosure.

[0036] Other embodiments will become apparent from a review of the ensuing detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 illustrates an exemplary dosing regimen in accordance with embodiments of the present disclosure, including stepped-up subcutaneous dosing during weeks 1-5 followed by intravenous administration of REGN5458 QW, Q2W or Q4W.

[0038] Figure 2 illustrates an exemplary dosing regimen in accordance with embodiments of the present disclosure, including stepped-up subcutaneous dosing during weeks 1-5 followed by intravenous administration of REGN5458 QW, Q2W or Q4W.

[0039] Figure 3 illustrates an exemplary dosing regimen in accordance with embodiments of the present disclosure, including stepped-up subcutaneous dosing followed by subcutaneous administration of REGN5458 QW, Q2W or Q4W.

[0040] Figure 4A illustrates a predicted REGN5458 concentration in serum over time comparing subcutaeous to intravenous administration using estimated parameters from prior study data, in accordance with the part A dosing regimen discussed in Example 2.

[0041] Figure 4B illustrates a predicted REGN5458 concentration in serum over time comparing subcutaeous to intravenous administration using estimated parameters from prior study data, in accordance with the part B dosing regimen discussed in Example 2.

[0042] Figure 5 illustrates a predicted serum concentration-time profile of REGN5458 with subcutaneous does simulation in accordance with the part C dosing regimen discussed in Example 2. The simulation is discussed in Example 3, and consists of the same 1000 patients undergoing SC treatment as planned for part C, along with the approved IV treatment. The dashed line represents the median SC profile, while the solid line depicts the median IV profile. The shaded area indicates the 90% PI. Although the SC simulations were conducted using a 330 mg full dose, the actual administered dose in part C is adjusted to 336 mg as noted in Example 3. DETAILED DESCRIPTION

[0043] It is to be understood that this disclosure is not limited to particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0044] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the term "about," when used in reference to a particular recited numerical value, means that the value may vary from the recited value by no more than 1%. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.). About 5 mg means 5 mg ± 0.05 mg. About 25 mg means 25 mg ± 0.25 mg. About 100 mg means 100 mg ± 1 mg. About 200 mg means 200 mg ± 2 mg. About 336 mg means 336 mg ± 3.36 mg.

[0045] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the subject matter of the present disclosure, the preferred methods and materials are now described. All patents, applications and non-patent publications mentioned in this specification are incorporated herein by reference in their entireties. Definitions

[0046] The expression "CD3," as used herein, refers to an antigen which is expressed on T cells as part of the multimolecular T cell receptor (TCR) and which consists of a homodimer or heterodimer formed from the association of two of four receptor chains: CD3-epsilon, CD3-delta, CD3-zeta, and CD3-gamma. All references to proteins, polypeptides and protein fragments herein are intended to refer to the human version of the respective protein, polypeptide or protein fragment unless explicitly specified as being from a non-human species. Thus, the expression "CD3" means human CD3 unless specified as being from a non-human species, e.g., "mouse CD3," "monkey CD3," etc.

[0047] As used herein, "an antibody that binds CD3" or an "anti-CD3 antibody" includes antibodies and antigen-binding fragments thereof that specifically recognize a single CD3 subunit (e.g., epsilon, delta, gamma or zeta), as well as antibodies and antigen-binding fragments thereof that specifically recognize a dimeric complex of two CD3 subunits (e.g., gamma / epsilon, delta / epsilon, and zeta / zeta CD3 dimers). The antibodies and antigen-binding fragments of the present disclosure may bind soluble CD3 and / or cell surface expressed CD3. Soluble CD3 includes natural CD3 proteins as well as recombinant CD3 protein variants such as, e.g., monomeric and dimeric CD3 constructs, that lack a transmembrane domain or are otherwise unassociated with a cell membrane.

[0048] As used herein, the expression "cell surface-expressed CD3" means one or more CD3 protein(s) that is / are expressed on the surface of a cell in vitro or in vivo, such that at least a portion of a CD3 protein is exposed to the extracellular side of the cell membrane and is accessible to an antigen-binding portion of an antibody. "Cell surface-expressed CD3" includes CD3 proteins contained within the context of a functional T cell receptor in the membrane of a cell. The expression "cell surface-expressed CD3" includes CD3 protein expressed as part of a homodimer or heterodimer on the surface of a cell (e.g., gamma / epsilon, delta / epsilon, and zeta / zeta CD3 dimers). The expression, "cell surface-expressed CD3" also includes a CD3 chain (e.g., CD3- epsilon, CD3-delta or CD3-gamma) that is expressed by itself, without other CD3 chain types, on the surface of a cell. A "cell surface-expressed CD3" can comprise or consist of a CD3 protein expressed on the surface of a cell which normally expresses CD3 protein. Alternatively, "cell surface-expressed CD3" can comprise or consist of CD3 protein expressed on the surface of a cellthat normally does not express human CD3 on its surface but has been artificially engineered to express CD3 on its surface.

[0049] The expression “BCMA,” as used herein, refers to B-cell maturation antigen. BCMA (also known as TNFRSF17 and CD269) is a cell surface protein expressed on malignant plasma cells, and plays a central role in regulating B cell maturation and differentiation into immunoglobulin- producing plasma cells. The amino acid sequence of human BCMA can be found in GenBank accession number NP_001183.2.

[0050] As used herein, "an antibody that binds BCMA" or an "anti-BCMA antibody" includes antibodies and antigen-binding fragments thereof that specifically recognize BCMA.

[0051] The term "antigen-binding molecule" includes antibodies and antigen-binding fragments of antibodies, including, e.g., bispecific antibodies.

[0052] The term "antibody", as used herein, means any antigen-binding molecule or molecular complex comprising at least one complementarity determining region (CDR) that specifically binds to or interacts with a particular antigen (e.g., BCMA or CD3). The term "antibody" includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as multimers thereof (e.g., IgM). The term “antibody” also includes immunoglobulin molecules consisting of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2 and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (CL1). The VHand VLregions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VHand VLis composed of three CDRs and four FRs, arranged from amino- terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the disclosure, the FRs of the anti-BCMA antibody or anti-CD3 antibody (or antigen-binding portion thereof) may be identical to the human germline sequences, or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.

[0053] The term "antibody", as used herein, also includes antigen-binding fragments of full antibody molecules. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody may be derived, e.g., fromfull antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and / or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and / or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.

[0054] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigen- binding fragment," as used herein.

[0055] In certain embodiments of the disclosure, the anti-BCMA monospecific antibodies or anti- BCMA x anti-CD3 bispecific antibodies of the disclosure are human antibodies. The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3. However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0056] The antibodies of the disclosure may, in some embodiments, be recombinant human antibodies. The term "recombinant human antibody", as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res.20:6287-6295) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.

[0057] Human antibodies can exist in two forms that are associated with hinge heterogeneity. In one form, an immunoglobulin molecule comprises a stable four chain construct of approximately 150-160 kDa in which the dimers are held together by an interchain heavy chain disulfide bond. In a second form, the dimers are not linked via inter-chain disulfide bonds and a molecule of about 75- 80 kDa is formed composed of a covalently coupled light and heavy chain (half-antibody). These forms have been extremely difficult to separate, even after affinity purification. The frequency of appearance of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the appearance of the second form (Angal et al. (1993) Molecular Immunology 30:105) to levels typically observed using a human IgG1 hinge. The instant disclosure encompasses antibodies having one or more mutations in the hinge, CH2 or CH3 region which may be desirable, for example, in production, to improve the yield of the desired antibody form.

[0058] The antibodies of the disclosure may be isolated antibodies. An "isolated antibody," as used herein, means an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally exists or is naturally produced, is an "isolated antibody" for purposes of the present disclosure. An isolated antibody also includes an antibody in situ within a recombinant cell. Isolated antibodies are antibodies that have been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0059] The anti-BCMA x anti-CD3 antibodies disclosed herein may comprise one or more amino acid substitutions, insertions and / or deletions in the framework and / or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences from which the antibodies were derived. Such mutations can be readily ascertained by comparing the aminoacid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. The present disclosure also includes anti-BCMA x anti-CD3 antibodies comprising variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the present disclosure includes anti-BCMA x anti-CD3 antibodies having HCVR, LCVR, and / or CDR amino acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. conservative amino acid substitutions relative to any of the HCVR, LCVR, and / or CDR amino acid sequences set forth herein. In some cases, the antibodies share 95%, 96%, 97%, 98% or 99% amino acid sequence identity with the HCVR(s) and / or LCVR or heavy chain(s) and / or light chain discussed herein.

[0060] As used herein, the term "binding" in the context of the binding of an antibody, immunoglobulin, antibody-binding fragment, or Fc-containing protein to either, e.g., a predetermined antigen, such as a cell surface protein or fragment thereof, typically refers to an interaction or association between a minimum of two entities or molecular structures, such as an antibody-antigen interaction. For instance, binding affinity typically corresponds to a KD value of about 10-7M or less, such as about 10-8M or less, such as about 10-9M or less when determined by, for instance, surface plasmon resonance (SPR) technology in a BIAcore 3000 instrument using the antigen as the ligand and the antibody, Ig, antibody-binding fragment, or Fc-containing protein as the analyte (or antiligand). Cell-based binding strategies, such as fluorescent-activated cell sorting (FACS) binding assays, are also routinely used, and FACS data correlates well with other methods such as radioligand competition binding and SPR (Benedict, CA, J Immunol Methods.1997, 201(2):223-31; Geuijen, CA, et al. J Immunol Methods.2005, 302(1-2):68-77). Accordingly, the antibody or antigen-binding protein of the disclosure binds to the predetermined antigen or cell surface molecule (receptor) having an affinity corresponding to a KDvalue that is at least ten-fold lower than its affinity for binding to a non-specific antigen (e.g., BSA, casein). According to the present disclosure, the affinity of an antibody corresponding to a KDvalue that is equal to or less than ten- fold lower than a non-specific antigen may be considered non-detectable binding, however such an antibody may be paired with a second antigen binding arm for the production of a bispecific antibody of the disclosure. Methods for Treating or Inhibiting the Growth of Cancers

[0061] The present disclosure includes methods for treating, ameliorating or reducing the severity of at least one symptom or indication, or inhibiting the growth of a BCMA+ cancer (e.g., multiple myeloma) in a subject, including relapsed or refractory multiple myeloma (RRMM). The methods according to this aspect of the disclosure comprise administering a therapeutically effective amount of a bispecific antibody against BCMA and CD3 to a subject in need thereof. As used herein, theterms "treat", "treating", or the like, mean to alleviate symptoms, eliminate the causation of symptoms either on a temporary or permanent basis, to delay or inhibit tumor growth, to reduce tumor cell load or tumor burden, to promote tumor regression, to cause tumor shrinkage, necrosis and / or disappearance, to prevent tumor recurrence, and / or to increase duration of survival of the subject.

[0062] As used herein, the expressions “a subject” or "a subject in need thereof" means a human or non-human mammal that exhibits one or more symptoms or indications of cancer, and / or who has been diagnosed with cancer, including multiple myeloma and who needs treatment for the same. In many embodiments, the term "subject" may be interchangeably used with the term "patient". For example, a human subject may be diagnosed with a primary or a metastatic tumor and / or with one or more symptoms or indications including, but not limited to, enlarged lymph node(s), swollen abdomen, unexplained pain, unexplained weight loss, fever, night sweats, persistent fatigue, loss of appetite, and / or enlargement of spleen. The expression includes subjects with multiple myeloma, including relapsed or refractory multiple myeloma. In specific embodiments, the expression includes human subjects that have and need treatment for a BCMA-expressing multiple myeloma. In other specific embodiments, the expression includes subjects with BCMA+ tumors (e.g., a tumor with BCMA expression as determined by flow cytometry). In certain embodiments, the expression "a subject in need thereof" includes patients with multiple myeloma that is resistant to or refractory to or is inadequately controlled by prior therapy (e.g., treatment with an anti-CD38 antibody therapy, treatment with a proteasome inhibitory, or treatment with an immunomodulatory drug). The expression also includes subjects with multiple myeloma who have relapsed following BCMA-directed CAR-T cellular therapy.

[0063] In certain embodiments, the methods of the present disclosure may be used to treat patients diagnosed with multiple myeloma, including relapsed or refractory multiple myeloma. The terms "tumor", "cancer" and "malignancy" are interchangeably used herein.

[0064] According to certain embodiments, the present disclosure includes methods for treating, or delaying or inhibiting the growth of a tumor. In certain embodiments, the present disclosure includes methods to promote tumor regression. In certain embodiments, the present disclosure includes methods to reduce tumor cell load or to reduce tumor burden. In certain embodiments, the present disclosure includes methods to prevent tumor recurrence. The methods, according to this aspect of the disclosure, comprise administering a therapeutically effective amount of a bispecific anti- BCMA / anti-CD3 antibody or antigen-binding fragment thereof to a subject in need thereof, wherein each antibody or fragment is administered to the subject in multiple doses, e.g., as part of a specific therapeutic dosing regimen. For example, the therapeutic dosing regimen may comprise administering one or more doses of an anti-BCMA x CD3 antibody or antigen-binding fragmentthereof to the subject at a frequency of about once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every two months, once every three months, once every four months, or less frequently. In certain embodiments, the anti-BCMA x anti-CD3 antibody or antigen-binding fragment thereof is administered in a dosing regimen comprising: subcutaneously administering 3-7 mg (e.g., 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, or 7 mg) of the bispecific antibody or antigen-binding fragment thereof to the subject on a first day during week 1 of the dosing regimen; subcutaneously administering 20-30 mg (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg) of the bispecific antibody or antigen-binding fragment thereof to the subject on a second day during week 1 of the dosing regimen; subcutaneously administering 50- 400 mg (e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 300, 305, 310, 315, 320, 325, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 394, or 400 mg) of the bispecific antibody or antigen-binding fragment thereof to the subject during week 2 of the dosing regimen; subcutaneously administering 150-400 mg (e.g., 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 300, 305, 310, 315, 320, 325, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 394, or 400 mg) of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 3 to 5 of the dosing regimen; administering 150-400 mg (e.g., 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 300, 305, 310, 315, 320, 325, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 394, or 400 mg) of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 6 to 13 of the dosing regimen; administering 150- 400 mg (e.g., 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 300, 305, 310, 315, 320, 325, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 394, or 400 mg) of the bispecific antibody or antigen- binding fragment thereof once every two weeks (Q2W) to the subject during weeks 14 to 25 of the dosing regimen; and administering 150-400 mg (e.g., 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 300, 305, 310, 315, 320, 325, 330, 331, 332, 333,334, 335, 336, 337, 338, 339, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 394, or 400 mg) of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) or once every four weeks (Q4W) to the subject in subsequent weeks of the dosing regimen. In any of these embodiments, the bispecific antibody or antigen-binding fragment thereof may be administered Q2W to the subject in the subsequent weeks of the dosing regimen, or the bispecific antibody or antigen-binding fragment thereof may be administered Q4W to the subject in the subsequent weeks of the dosing regimen. In any of these embodiments, the bispecific antibody or antigen-binding fragment thereof may be administered intravenously during weeks 6 to 13, weeks 14 to 25, and in the subsequent weeks of the dosing regimen, or the bispecific antibody or antigen- binding fragment thereof may be administered subcutaneously during weeks 6 to 13, weeks 14 to 25, and in the subsequent weeks of the dosing regimen.

[0065] In some embodiments, the anti-BCMA x anti-CD3 antibody or antigen-binding fragment thereof is administered in a dosing regimen comprising: subcutaneously administering about 5 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on day 1 during week 1 of the dosing regimen; subcutaneously administering about 25 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on day 4 during week 1 of the dosing regimen; subcutaneously administering about 100 mg of the bispecific antibody or antigen-binding fragment thereof to the subject during week 2 of the dosing regimen; subcutaneously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 3 to 5 of the dosing regimen; administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 6 to 13 of the dosing regimen; administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) to the subject during weeks 14 to 25 of the dosing regimen; and administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) or once every four weeks (Q4W) to the subject in subsequent weeks of the dosing regimen.

[0066] In some embodiments, the anti-BCMA x anti-CD3 antibody or antigen-binding fragment thereof is administered in a dosing regimen comprising: subcutaneously administering about 5 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on day 1 during week 1 of the dosing regimen; subcutaneously administering about 25 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on day 4 during week 1 of the dosing regimen; subcutaneously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof to the subject during week 2 of the dosing regimen; subcutaneously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 3 to 5 of the dosing regimen; administering about 200 mg of the bispecificantibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 6 to 13 of the dosing regimen; administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) to the subject during weeks 14 to 25 of the dosing regimen; and administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) or once every four weeks (Q4W) to the subject in subsequent weeks of the dosing regimen.

[0067] In some embodiments, the anti-BCMA x anti-CD3 antibody or antigen-binding fragment thereof is administered in a dosing regimen comprising: subcutaneously administering about 5 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on day 1 during week 1 of the dosing regimen; subcutaneously administering about 25 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on day 4 during week 1 of the dosing regimen; subcutaneously administering about 100 mg of the bispecific antibody or antigen-binding fragment thereof to the subject during week 2 of the dosing regimen; subcutaneously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 3 to 5 of the dosing regimen; intravenously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 6 to 13 of the dosing regimen; intravenously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) to the subject during weeks 14 to 25 of the dosing regimen; and inravenously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) or once every four weeks (Q4W) to the subject in subsequent weeks of the dosing regimen.

[0068] In some embodiments, the anti-BCMA x anti-CD3 antibody or antigen-binding fragment thereof is administered in a dosing regimen comprising: subcutaneously administering about 5 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on day 1 during week 1 of the dosing regimen; subcutaneously administering about 25 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on day 4 during week 1 of the dosing regimen; subcutaneously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof to the subject during week 2 of the dosing regimen; subcutaneously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 3 to 5 of the dosing regimen; intravenously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 6 to 13 of the dosing regimen; intravenously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) to the subject during weeks 14 to 25 of the dosing regimen; and intravenously administering about 200 mg of thebispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) or once every four weeks (Q4W) to the subject in subsequent weeks of the dosing regimen.

[0069] In some embodiments, the anti-BCMA x anti-CD3 antibody or antigen-binding fragment thereof is administered in a dosing regimen comprising: subcutaneously administering about 5 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on day 1 during week 1 of the dosing regimen; subcutaneously administering about 25 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on day 4 during week 1 of the dosing regimen; subcutaneously administering about 100 mg of the bispecific antibody or antigen-binding fragment thereof to the subject during week 2 of the dosing regimen; subcutaneously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 3 to 5 of the dosing regimen; subcutaneously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 6 to 13 of the dosing regimen; subcutaneously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) to the subject during weeks 14 to 25 of the dosing regimen; and subcutaneously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) or once every four weeks (Q4W) to the subject in subsequent weeks of the dosing regimen.

[0070] In some embodiments, the anti-BCMA x anti-CD3 antibody or antigen-binding fragment thereof is administered in a dosing regimen comprising: subcutaneously administering about 5 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on day 1 during week 1 of the dosing regimen; subcutaneously administering about 25 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on day 4 during week 1 of the dosing regimen; subcutaneously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof to the subject during week 2 of the dosing regimen; subcutaneously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 3 to 5 of the dosing regimen; subcutaneously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 6 to 13 of the dosing regimen; subcutaneously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) to the subject during weeks 14 to 25 of the dosing regimen; and subcutaneously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) or once every four weeks (Q4W) to the subject in subsequent weeks of the dosing regimen.

[0071] In some embodiments, the anti-BCMA x anti-CD3 antibody or antigen-binding fragment thereof is administered in a dosing regimen comprising: intravenously administering about 5 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on day 1 during week 1 ofthe dosing regimen; intravenously administering about 25 mg of the bispecific antibody or antigen- binding fragment thereof to the subject on day 8 during week 2 of the dosing regimen; intravenously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof to the subject during week 3 of the dosing regimen; intravenously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 4 to 5 of the dosing regimen; intravenously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 6 to 13 of the dosing regimen; intravenously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) to the subject during weeks 14 to 25 of the dosing regimen; and intravenously administering about 200 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) or once every four weeks (Q4W) to the subject in subsequent weeks of the dosing regimen. In some cases, a dose of an anti-IL-6R antibody (e.g., tocilizumab or sarilumab) is administed prior to the first intravenous dose of the anti- BCMA x anti-CD3 antibody or antigen-binding fragment thereof.

[0072] In some embodiments, the anti-BCMA x anti-CD3 antibody or antigen-binding fragment thereof is administered in a dosing regimen comprising: subcutaneously administering 3-7 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on day 1 during week 1 of the dosing regimen; subcutaneously administering about 20-30 mg of the bispecific antibody or antigen- binding fragment thereof to the subject on day 4 during week 1 of the dosing regimen; subcutaneously administering 325-350 mg of the bispecific antibody or antigen-binding fragment thereof to the subject during week 2 of the dosing regimen; subcutaneously administering 325-350 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 3 to 5 of the dosing regimen; subcutaneously administering 325-350 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 6 to 13 of the dosing regimen; subcutaneously administering 325-350 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) to the subject during weeks 14 to 25 of the dosing regimen; and subcutaneously administering 325-350 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) or once every four weeks (Q4W) to the subject in subsequent weeks of the dosing regimen.

[0073] In some embodiments, the anti-BCMA x anti-CD3 antibody or antigen-binding fragment thereof is administered in a dosing regimen comprising: subcutaneously administering about 5 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on day 1 during week 1 of the dosing regimen; subcutaneously administering about 25 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on day 4 during week 1 of the dosing regimen; subcutaneously administering about 336 mg of the bispecific antibody or antigen-binding fragmentthereof to the subject during week 2 of the dosing regimen; subcutaneously administering about 336 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 3 to 5 of the dosing regimen; subcutaneously administering about 336 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 6 to 13 of the dosing regimen; subcutaneously administering about 336 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) to the subject during weeks 14 to 25 of the dosing regimen; and subcutaneously administering about 336 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) or once every four weeks (Q4W) to the subject in subsequent weeks of the dosing regimen.

[0074] In any of these various embodiments, the choice between Q2W and Q4W dosing during the subsequent weeks (e.g., weeks 26 and later) in the dosing regimen may be determined based on an objective response rate of very good partial response (VGPR) or greater. If the patient has obtained a VGPR or greater following dosing through week 25 of the dosing regimen, further administration of the bispecific antibody or antigen-binding fragment thereof may proceed on a Q4W schedule, whereas if the patient has obtained less than a VGPF through week 25 of the dosing regimen, further administration of the bispecific antibody or antigen-binding fragment thereof may proceed on a Q2W schedule.

[0075] In certain embodiments, the methods of the present disclosure are used to treat a patient with a MRD-positive disease. Minimum residual disease (MRD) refers to small numbers of cancer cells that remain in the patient during or after treatment, wherein the patient may or may not show symptoms or signs of the disease. Such residual cancer cells, if not eliminated, frequently lead to relapse of the disease. The present disclosure includes methods to inhibit and / or eliminate residual cancer cells in a patient upon MRD testing. MRD may be assayed according to methods known in the art (e.g., MRD flow cytometry). The methods, according to this aspect of the disclosure, comprise administering a bispecific anti-BCMA / anti-CD3 antibody or antigen-binding fragment thereof to a subject in need thereof.

[0076] In various embodiments, treatment of multiple myeloma includes treatment of multiple myeloma that is resistant to or refractory to or is inadequately controlled by prior therapy (e.g., treatment with an anti-CD38 antibody therapy, treatment with a proteasome inhibitor, or treatment with an immunomodulatory drug). In some embodiments, treatment of multiple myeloma includes treatment of subjects who have relapsed following BCMA-directed CAR-T cellular therapy.

[0077] In certain embodiments, the methods of the present disclosure also include prophylactic use of anti-IL-6R therapy to decrease the incidence and severity of cytokine release syndrome. A single dose of tocilizumab or sarilumab, an anti-IL-6R therapy, may be administered prior to the first dose (e.g., IV) of REGN5458.

[0078] In certain embodiments, the methods of the present disclosure also include administration of a bispecific anti-BCMA x CD3 antibody or antigen-binding fragment thereof to subjects who have relapsed after a BCMA CAR-T cellular therapy.

[0079] The methods of the present disclosure, according to certain embodiments, comprise administering to a subject a therapeutically effective amount of a bispecific anti-BCMA / anti-CD3 antibody or antigen-binding fragment thereof, optionally in combination with a second therapeutic agent or therapy. In certain embodiments, the antibodies may be administered in combination with therapy including a chemotherapeutic agent, radiation and surgery. As used herein, the phrase “in combination with" means that the antibody or antibodies are administered to the subject at the same time as, just before, or just after administration of the second therapeutic agent or therapy. In certain embodiments, the antibody or antibodies and the second therapeutic agent are administered in separate formulations.

[0080] In certain embodiments, the methods of the present disclosure comprise administering to a subject in need thereof a therapeutically effective amount of a bispecific anti-BCMA / anti-CD3 antibody or antigen-binding fragment thereof, which results in tumor growth inhibition by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70% or about 80% as compared to an untreated subject. In certain embodiments, the administration of the bispecific antibody leads to increased tumor regression, tumor shrinkage and / or disappearance. In certain embodiments, the administration of the bispecific antibody leads to delay in tumor growth and development, e.g., tumor growth may be delayed by about 3 days, more than 3 days, about 7 days, more than 7 days, more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 1 year, more than 2 years, or more than 3 years as compared to an untreated subject. In certain embodiments, administration of the bispecific antibody prevents tumor recurrence and / or increases duration of survival of the subject, e.g., increases duration of survival by more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 12 months, more than 18 months, more than 24 months, more than 36 months, or more than 48 months relative to an untreated subject. In certain embodiments, administration of the bispecific antibody increases progression-free survival or overall survival. In certain embodiments, administration of the bispecific antibody increases response and duration of response in a subject, e.g., by more than 2%, more than 3%, more than 4%, more than 5%, more than 6%, more than 7%, more than 8%, more than 9%, more than 10%, more than 20%, more than 30%, more than 40% or more than 50% over an untreated subject. In certain embodiments, administration of the bispecific antibody to a subject with relapsed or refractory multiple myeloma leads to a stringent complete response (sCR), a complete response (CR), a very good partial response (VGPR), a partial response (PR), or stable disease (SD), as defined by IMWG criteria. Responses can be measured by any of the methods known inthe art, e.g., X-rays, positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), cytology, histology, or molecular genetic analyses.

[0081] In certain cases, the response of a subject to therapy is categorized (per IMWG crieria) as sCR - negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow, plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. In certain cases, the response of a subject to therapy is categorized as a CR - negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow. In certain cases, the response of a subject to therapy is categorized as VGPR - serum and urine M-protein detectable by immunofixation but not on electrophoresis or > 90% reduction in serum M-protein plus urine M-protein level < 100 mg / 24 h. In certain cases, the response of a subject to therapy is categorized as PR - > 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by >90% or to < 200 mg / 24 h (if the serum and urine M-protein are unmeasurable, a > 50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria; if serum and urine M-protein are not measurable, and serum free light assay is also not measureable, > 50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was > 30%; in addition, if present at baseline, a > 50% reduction in the size of soft tissue plasmacytomas is also required. In certain cases, the response of a subject to therapy is categorized as SD – not meeting any of the criteria for CR, VGPR, or PR, but not an increase of >25% from lowest response value in any of (a) serum M-component and / or (the absolute increase must be > 0.5 g / dL); (b) urine M-component and / or (the absolute increase must be > 200 mg / 24 h); (c) in patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels; the absolute increase must be > 10 mg / dL; (d) bone marrow plasma cell percentage; the absolute percentage must be > 10%;(e) definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; or (f) development of hypercalcaemia (corrected serum calcium > 11.5 mg / dL or 2.65 mmol / L) that can be attributed solely to the plasma cell proliferative disorder. Bispecific Anti-BCMA x Anti-CD3 Antibodies

[0082] According to certain exemplary embodiments of the present disclosure, the methods comprise administering a therapeutically effective amount of a bispecific antibody that specifically binds BCMA and CD3 or antigen-binding fragment thereof. Such antibodies and fragments may be referred to herein as, e.g., "anti-BCMA / anti-CD3," or "anti-BCMA x CD3" or "BCMA x CD3" bispecific antibodies or antigen-binding fragments thereof, or other similar terminology.

[0083] As used herein, the expression "bispecific antibody" refers to an immunoglobulin protein comprising at least a first antigen-binding domain and a second antigen-binding domain. In the context of the present disclosure, the first antigen-binding domain specifically binds a first antigen (e.g., BCMA), and the second antigen-binding domain specifically binds a second, distinct antigen (e.g., CD3). Each antigen-binding domain of a bispecific antibody comprises a heavy chain variable domain (HCVR) and a light chain variable domain (LCVR), each comprising three complementarity determining regions (CDRs). In the context of a bispecific antibody, the CDRs of the first antigen- binding domain may be designated with the prefix "A" and the CDRs of the second antigen-binding domain may be designated with the prefix "B". Thus, the CDRs of the first antigen-binding domain may be referred to herein as A-HCDR1, A-HCDR2, and A-HCDR3; and the CDRs of the second antigen-binding domain may be referred to herein as B-HCDR1, B-HCDR2, and B-HCDR3.

[0084] The first antigen-binding domain and the second antigen-binding domain are each connected to a separate multimerizing domain. As used herein, a "multimerizing domain" is any macromolecule, protein, polypeptide, peptide, or amino acid that has the ability to associate with a second multimerizing domain of the same or similar structure or constitution. In the context of the present disclosure, the multimerizing component is an Fc portion of an immunoglobulin (comprising a CH2-CH3domain), e.g., an Fc domain of an IgG selected from the isotypes IgG1, IgG2, IgG3, and IgG4, as well as any allotype within each isotype group.

[0085] Bispecific antibodies of the present disclosure typically comprise two multimerizing domains, e.g., two Fc domains that are each individually part of a separate antibody heavy chain. The first and second multimerizing domains may be of the same IgG isotype such as, e.g., IgG1 / IgG1, IgG2 / IgG2, IgG4 / IgG4. Alternatively, the first and second multimerizing domains may be of different IgG isotypes such as, e.g., IgG1 / IgG2, IgG1 / IgG4, IgG2 / IgG4, etc.

[0086] Any bispecific antibody format or technology may be used to make the bispecific antibodies of the present disclosure. For example, an antibody or fragment thereof having a first antigen binding specificity can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment having a second antigen-binding specificity to produce a bispecific antibody. Specific exemplary bispecific formats that can be used in the context of the present disclosure include, without limitation, e.g., scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, Quadroma, knobs-into-holes, common light chain (e.g., common light chain with knobs-into-holes, etc.), CrossMab, CrossFab, (SEED)body, leucine zipper, Duobody, IgG1 / IgG2, dual acting Fab (DAF)-IgG, and Mab2bispecific formats (see, e.g., Klein et al. 2012, mAbs 4:6, 1-11, and references cited therein, for a review of the foregoing formats).

[0087] In the context of bispecific antibodies of the present disclosure, Fc domains may compriseone or more amino acid changes (e.g., insertions, deletions or substitutions) as compared to the wild-type, naturally occurring version of the Fc domain. For example, the disclosure includes bispecific antibodies comprising one or more modifications in the Fc domain that results in a modified Fc domain having a modified binding interaction (e.g., enhanced or diminished) between Fc and FcRn. In one embodiment, the bispecific antibody comprises a modification in a CH2 or a CH3 region, wherein the modification increases the affinity of the Fc domain to FcRn in an acidic environment (e.g., in an endosome where pH ranges from about 5.5 to about 6.0). Non-limiting examples of such Fc modifications are disclosed in US Patent Publication No.20150266966, incorporated herein in its entirety.

[0088] The present disclosure also includes bispecific antibodies comprising a first CH3 domain and a second Ig CH3 domain, wherein the first and second Ig CH3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bispecific antibody to Protein A as compared to a bi-specific antibody lacking the amino acid difference. In one embodiment, the first Ig CH3 domain binds Protein A and the second Ig CH3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering; H435R by EU numbering). The second CH3 may further comprise a Y96F modification (by IMGT; Y436F by EU). See, for example, US Patent No. 8,586,713. Further modifications that may be found within the second CH3 include: D16E, L18M, N44S, K52N, V57M, and V82I (by IMGT; D356E, L358M, N384S, K392N, V397M, and V422I by EU) in the case of IgG1 antibodies; N44S, K52N, and V82I (IMGT; N384S, K392N, and V422I by EU) in the case of IgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I by EU) in the case of IgG4 antibodies.

[0089] In certain embodiments, the Fc domain may be chimeric, combining Fc sequences derived from more than one immunoglobulin isotype. For example, a chimeric Fc domain can comprise part or all of a CH2 sequence derived from a human IgG1, human IgG2 or human IgG4 CH2 region, and part or all of a CH3 sequence derived from a human IgG1, human IgG2 or human IgG4. A chimeric Fc domain can also contain a chimeric hinge region. For example, a chimeric hinge may comprise an "upper hinge" sequence, derived from a human IgG1, a human IgG2 or a human IgG4 hinge region, combined with a "lower hinge" sequence, derived from a human IgG1, a human IgG2 or a human IgG4 hinge region. A particular example of a chimeric Fc domain that can be included in any of the antibodies set forth herein comprises, from N- to C-terminus: [IgG4 CH1]-[IgG4 upper hinge]- [IgG2 lower hinge]-[IgG4 CH2]-[IgG4 CH3]. Another example of a chimeric Fc domain that can be included in any of the antibodies set forth herein comprises, from N- to C-terminus: [IgG1 CH1]- [IgG1 upper hinge]-[IgG2 lower hinge]-[IgG4 CH2]-[IgG1 CH3]. These and other examples ofchimeric Fc domains or chimeric heavy chain constant regions that can be included in any of the antibodies of the present disclosure are described in US Patent Publication No.20140243504, which is herein incorporated in its entirety. Chimeric Fc domains and chimeric heavy chain constant regions having these general structural arrangements, and variants thereof, can have altered Fc receptor binding, which in turn affects Fc effector function.

[0090] According to certain exemplary embodiments of the present disclosure, the bispecific anti- BCMA / anti-CD3 antibody, or antigen-binding fragment thereof comprises heavy chain variable regions (A-HCVR and B-HCVR), light chain variable regions (A-LCVR and B-LCVR), and / or complementarity determining regions (CDRs) comprising any of the amino acid sequences of the bispecific anti-BCMA / anti-CD3 antibodies as set forth in WO 2020 / 018820. In certain exemplary embodiments, the bispecific anti-BCMA / anti-CD3 antibody or antigen-binding fragment thereof that can be used in the context of the methods of the present disclosure comprises: (a) a first antigen- binding arm that specifically binds BCMA comprising the heavy chain complementarity determining regions (A-HCDR1, A-HCDR2 and A-HCDR3) of a heavy chain variable region (A-HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and the light chain complementarity determining regions (A-LCDR1, A-LCDR2 and A-LCDR3) of a light chain variable region (A-LCVR) comprising the amino acid sequence of SEQ ID NO: 13; and (b) a second antigen-binding arm that specifically binds CD3 comprising the heavy chain CDRs (B-HCDR1, B-HCDR2 and B-HCDR3) of a HCVR (B-HCVR) comprising an amino acid sequence of SEQ ID NO: 5, and the light chain CDRs (B-LCDR1, B-LCDR2 and B-LCDR3) of a LCVR (B-LCVR) comprising the amino acid sequence of SEQ ID NO: 13. According to certain embodiments, the A-HCDR1 comprises the amino acid sequence of SEQ ID NO: 2; the A-HCDR2 comprises the amino acid sequence of SEQ ID NO: 3; the A-HCDR3 comprises the amino acid sequence of SEQ ID NO: 4; the A-LCDR1 comprises the amino acid sequence of SEQ ID NO: 14; the A-LCDR2 comprises the amino acid sequence of SEQ ID NO: 15; the A-LCDR3 comprises the amino acid sequence of SEQ ID NO: 16; the B-HCDR1 comprises the amino acid sequence of SEQ ID NO: 6; the B-HCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and the B-HCDR3 comprises the amino acid sequence of SEQ ID NO: 8; and the B-LCDR1 comprises the amino acid sequence of SEQ ID NO: 14; the B-LCDR2 comprises the amino acid sequence of SEQ ID NO: 15; the B-LCDR3 comprises the amino acid sequence of SEQ ID NO: 16. In yet other embodiments, the bispecific anti-BCMA / anti-CD3 antibody or antigen-binding fragment thereof comprises: (a) a first antigen-binding arm comprising a HCVR (A-HCVR) comprising SEQ ID NO: 1 and a LCVR (A-LCVR) comprising SEQ ID NO: 13; and (b) a second antigen-binding arm comprising a HCVR (B-HCVR) comprising SEQ ID NO: 5, and a LCVR (B-LCVR) comprising SEQ ID NO: 13. In certain exemplary embodiments, the bispecific anti-BCMA x CD3 antibody comprises a BCMA-binding arm comprising a heavy chain comprising the aminoacid sequence of SEQ ID NO: 17 and a light chain comprising the amino acid sequence of SEQ ID NO: 20, and a CD3-binding arm comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 18 and a light chain comprising the amino acid sequence of SEQ ID NO: 20.

[0091] In certain exemplary embodiments, the bispecific anti-BCMA / anti-CD3 antibody or antigen- binding fragment thereof that can be used in the context of the methods of the present disclosure comprises: (a) a first antigen-binding arm that specifically binds BCMA comprising the heavy chain complementarity determining regions (A-HCDR1, A-HCDR2 and A-HCDR3) of a heavy chain variable region (A-HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and the light chain complementarity determining regions (A-LCDR1, A-LCDR2 and A-LCDR3) of a light chain variable region (A-LCVR) comprising the amino acid sequence of SEQ ID NO: 13; and (b) a second antigen- binding arm that specifically binds CD3 comprising the heavy chain CDRs (B-HCDR1, B-HCDR2 and B-HCDR3) of a HCVR (B-HCVR) comprising an amino acid sequence of SEQ ID NO: 9, and the light chain CDRs (B-LCDR1, B-LCDR2 and B-LCDR3) of a LCVR (B-LCVR) comprising the amino acid sequence of SEQ ID NO: 13. According to certain embodiments, the A-HCDR1 comprises the amino acid sequence of SEQ ID NO: 2; the A-HCDR2 comprises the amino acid sequence of SEQ ID NO: 3; the A-HCDR3 comprises the amino acid sequence of SEQ ID NO: 4; the A-LCDR1 comprises the amino acid sequence of SEQ ID NO: 14; the A-LCDR2 comprises the amino acid sequence of SEQ ID NO: 15; the A-LCDR3 comprises the amino acid sequence of SEQ ID NO: 16; the B-HCDR1 comprises the amino acid sequence of SEQ ID NO: 10; the B-HCDR2 comprises the amino acid sequence of SEQ ID NO: 11; and the B-HCDR3 comprises the amino acid sequence of SEQ ID NO: 12; and the B-LCDR1 comprises the amino acid sequence of SEQ ID NO: 14; the B-LCDR2 comprises the amino acid sequence of SEQ ID NO: 15; the B-LCDR3 comprises the amino acid sequence of SEQ ID NO: 16. In yet other embodiments, the bispecific anti-BCMA / anti-CD3 antibody or antigen-binding fragment thereof comprises: (a) a first antigen- binding arm comprising a HCVR (A-HCVR) comprising SEQ ID NO: 1 and a LCVR (A-LCVR) comprising SEQ ID NO: 13; and (b) a second antigen-binding arm comprising a HCVR (B-HCVR) comprising SEQ ID NO: 9, and a LCVR (B-LCVR) comprising SEQ ID NO: 13. In certain exemplary embodiments, the bispecific anti-BCMA x CD3 antibody comprises a BCMA-binding arm comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 17 and a light chain comprising the amino acid sequence of SEQ ID NO: 20, and a CD3-binding arm comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and a light chain comprising the amino acid sequence of SEQ ID NO: 20.

[0092] The methods of the present disclosure also encompass use of a bioequivalent to the bispecific antibodies discussed herein. The term "bioequivalent", as used herein, refers to antibodies or fragments thereof that are pharmaceutical equivalents or pharmaceutical alternativeswhose rate and / or extent of absorption do not show a significant difference with that of the bispecific antibodies discussed above when administered at the same molar dose under similar experimental conditions, either single dose or multiple dose. In the context of the disclosure, the term refers to antigen-binding proteins that bind to BCMA and CD3, which do not have clinically meaningful differences to the bispecific antibodies discussed herein in their safety, purity and / or potency. Combination Therapies

[0093] In certain embodiments, the methods of the present disclosure comprise administration of a second therapeutic agent or therapy, wherein the second therapeutic agent or therapy is an anti- cancer drug or anti-cancer therapy. In certain embodiments, the methods of the disclosure comprise administering an anti-BCMA / anti-CD3 bispecific antibody or antigen-binding fragment thereof in combination with radiation therapy, surgery or other anti-cancer therapy to generate long- term durable anti-tumor responses and / or enhance survival of patients with a BCMA-expressing cancer.

[0094] In some embodiments, the methods of the disclosure comprise administering radiation therapy prior to, concomitantly or after administering a bispecific anti-BCMA / anti-CD3 antibody or antigen-binding fragment thereof to a cancer patient. For example, radiation therapy may be administered in one or more doses to tumor lesions after administration of one or more doses of the antibodies. In some embodiments, radiation therapy may be administered locally to a tumor lesion to enhance the local immunogenicity of a patient's tumor (adjuvinating radiation) and / or to kill tumor cells (ablative radiation) after systemic administration of a bispecific anti-BCMA / anti-CD3 antibody or antigen-binding fragment thereof. Efficacy and Monitoring

[0095] The methods discussed in the present disclosure may further comprise tumor biopsies, imaging, and cytokine release syndrome (CRS) monitoring and management to evaluate efficacy and safety within individual subjects or populations of subjects.

[0096] CRS has been observed in connection with the administration of anti-BCMA x CD3 antibodies. Subcutaneous administration of bispecific antibodies in the dosing regimens discussed herein may be advantageous to reduce the incidence or severity of CRS because of a lower Cmax, delayed Tmax, and lower plasma cytokine levels compared to IV administration, as shown in the modeling illustrated in Figures 4A and 4B.

[0097] Corticosteroids or anti-IL-6 pathway therapies (e.g., sarilumab or tocilizumab) may be utilized in the management of CRS as discussed herein.Pharmaceutical Compositions and Administration

[0098] The present disclosure includes methods which comprise administering a bispecific anti- BCMA / anti-CD3 antibody or antigen-binding fragment thereof to a subject wherein the antibody (or fragment) is contained within a pharmaceutical composition. The pharmaceutical compositions of the disclosure may be formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTINTM), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in- oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238-311.

[0099] Various delivery systems are known and can be used to administer the pharmaceutical composition of the disclosure, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem.262: 4429-4432). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, or by injection, and may be administered together with other biologically active agents. In some cases, the antibodies are administered subcutaneously, or subcutaneously and intravenously.

[0100] A pharmaceutical composition of the present disclosure can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, with respect to subcutaneous delivery, a pen delivery device readily has applications in delivering a pharmaceutical composition of the present disclosure. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0101] Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of a pharmaceutical composition of the present disclosure. Examples include, but are not limited to AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25™ pen, HUMALOG™ pen, HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (sanofi-aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present disclosure include, but are not limited to the SOLOSTAR™ pen (sanofi-aventis), the FLEXPEN™ (Novo Nordisk), and the KWIKPEN™ (Eli Lilly), the SURECLICKTMAutoinjector (Amgen, Thousand Oaks, CA), the PENLETTM(Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L.P.), and the HUMIRATMPen (Abbott Labs, Abbott Park IL), to name only a few.

[0102] In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump may be used. In another embodiment, polymeric materials can be used; see, Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Fla. In yet another embodiment, a controlled release system can be placed in proximity of the composition's target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol.2, pp.115- 138). Other controlled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.

[0103] The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by known methods. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent. The injection thus prepared is preferably filled in an appropriate ampoule.

[0104] Advantageously, the pharmaceutical compositions for use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, a vial or a prefilled syringe.Administration Regimens

[0105] The present disclosure includes methods comprising administering to a subject a bispecific anti-BCMA x CD3 antibody or antigen-binding fragment thereof in a subcutaneous step- up dosing regimen. The step-up dosing regimen, combined with subcutaneous administration is designed to minimize the incidence or severity of adverse effects such as CRS, while maintaining therapeutic efficacy.

[0106] According to certain embodiments of the present disclosure, multiple doses of a bispecific anti-BCMA / anti-CD3 antibody or antigen-binding fragment thereof may be administered to a subject over a defined time course. The methods according to this aspect of the disclosure comprise administering to a subject multiple doses of a bispecific anti-BCMA / anti-CD3 antibody or antigen- binding fragment thereof. As used herein, "sequential administering" means that each dose of the antibody is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months). The present disclosure includes methods which comprise sequential administration to the patient a single initial dose of an antibody (or fragment), followed by one or more secondary doses of the antibody (or fragment), followed by one or more tertiary doses of the antibody (or fragment).

[0107] The terms "initial dose," "secondary doses," and "tertiary doses," refer to the temporal sequence of administration. Thus, the "initial dose" is the dose which is administered at the beginning of the treatment regimen (also referred to as the "baseline dose"); the "secondary doses" are the doses which are administered after the initial dose; and the "tertiary doses" are the doses which are administered after the secondary doses. The initial, secondary, and tertiary doses may each contain different amounts of the antibody or antigen-binding fragment thereof (e.g., the bispecific antibody).

[0108] According to this aspect of the disclosure, a bispecific anti-BCMA / anti-CD3 antibody or antigen-binding fragment thereof may be administered to a subject in need thereof as part of a dosing regimen comprising: subcutaneously administering 3-7 mg (e.g., 4-6, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, or 7 mg) of the bispecific antibody or antigen-binding fragment thereof to the subject on a first day during week 1 of the dosing regimen; subcutaneously administering 20-30 mg (e.g., 23-27, 24- 26, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg) of the bispecific antibody or antigen-binding fragment thereof to the subject on a second day during week 1 of the dosing regimen; subcutaneously administering 50-400 mg (e.g., 90-110, 95-105, 190-210, 195-205, 300-360, 325- 350, 330-340, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385,390, 395, or 400 mg) of the bispecific antibody or antigen-binding fragment thereof to the subject during week 2 of the dosing regimen; subcutaneously administering 150-400 mg (e.g., 190-210, 195-205, 300-360, 325-350, 330-340, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg) of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 3 to 5 of the dosing regimen; administering 150-400 mg (e.g., 190-210, 195-205, 300-360, 325-350, 330-340, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg) of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 6 to 13 of the dosing regimen; administering 150-400 mg (e.g., 190-210, 195-205, 300-360, 325-350, 330-340, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg) of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) to the subject during weeks 14 to 25 of the dosing regimen; and administering 150-400 mg (e.g., 190-210, 195-205, 300-360, 325-350, 330-340, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg) of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) or once every four weeks (Q4W) to the subject in subsequent weeks of the dosing regimen. In any of these embodiments, the bispecific antibody or antigen-binding fragment thereof may be administered Q2W to the subject in the subsequent weeks of the dosing regimen, or the bispecific antibody or antigen-binding fragment thereof may be administered Q4W to the subject in the subsequent weeks of the dosing regimen. In any of these embodiments, the bispecific antibody or antigen-binding fragment thereof may be administered intravenously during weeks 6 to 13, weeks 14 to 25, and in the subsequent weeks of the dosing regimen, or the bispecific antibody or antigen-binding fragment thereof may be administered subcutaneously during weeks 6 to 13, weeks 14 to 25, and in the subsequent weeks of the dosing regimen. Dosage

[0109] The amount of bispecific anti-BCMA / anti-CD3 antibody or antigen-binding fragmentthereof administered to a subject according to the methods of the present disclosure is, generally, a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" means an amount of antibody (a bispecific anti-BCMA / anti-CD3 antibody or antigen-binding fragment thereof that results in one or more of: (a) a reduction in the severity or duration of a symptom of a cancer (e.g., RRMM); (b) inhibition of tumor growth, or an increase in tumor necrosis, tumor shrinkage and / or tumor disappearance; (c) delay in tumor growth and development; (d) inhibition or elimination of tumor metastasis; (e) prevention of recurrence of tumor growth; (f) increase in survival of a subject with cancer (e.g., RRMM); and / or (g) a reduction in the use or need for conventional anti-cancer therapy (e.g., reduced or eliminated use of chemotherapeutic or cytotoxic agents) as compared to an untreated subject.

[0110] In the case of a bispecific anti-BCMA / anti-CD3 antibody or antigen-binding fragment thereof, a therapeutically effective amount can be from about 1 milligram (mg) to about 1000 mg, e.g., about 1 mg, about 3 mg, about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 310 mg, about 320 mg, about 330, about 336, about 340, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg of the bispecific anti-BCMA / anti-CD3 antibody or antigen-binding fragment thereof. In certain embodiments, the bispecific antibodies or antigen-binding fragments are administered at doses of about 5 mg, about 25 mg, about 100 mg, about 200 mg, or about 336 mg in a dosing regimen to the subject to treat a BCMA-expressing cancer (e.g., RRMM).

[0111] A summary of the sequences and the corresponding SEQ ID NOs referenced herein is shown in Table 1, below. Table 1: Summary of Sequences SEQ ID NO: Description9 Anti-CD3 Heavy Chain Variable Region (REGN5459) 10 Anti-CD3 HCDR1 (REGN5459)EXAMPLES

[0112] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the present disclosure, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric. Example 1: Generation of Bispecific Antibodies that Bind B-Cell Maturation Antigen (BCMA) and CD3

[0113] Bispecific antibodies comprising an anti-BCMA-specific binding domain and an anti-CD3- specific binding domain were constructed using standard methodologies, wherein the anti-BCMA antigen binding domain and the anti-CD3 antigen binding domain each comprise different, distinct HCVRs paired with a common LCVR. In some instances the bispecific antibodies were constructed utilizing a heavy chain from an anti-CD3 antibody, a heavy chain from an anti-BCMA antibody, and a common light chain (see Table 2).

[0114] The bispecific antibodies created in accordance with the present Example comprise two separate antigen-binding domains (i.e., binding arms). The first antigen-binding domain comprises a heavy chain variable region derived from an anti-BCMA antibody ("BCMA-VH"), and the second antigen-binding domain comprises a heavy chain variable region derived from an anti-CD3 antibody("CD3-VH"). Both the anti-BCMA and the anti-CD3 binding domains share a common light chain. The BCMA-VH / CD3-VH pairing creates antigen-binding domains that specifically recognize CD3 on T cells and BCMA on tumor cells.

[0115] A summary of the component parts of the antigen-binding domains of the anti-BCMA x CD3 bispecific antibodies constructed is set forth in Table 2. The corresponding CDR sequences and full-length heavy and light chain sequences are identified in Table 1. Table 2: Summary of Component Parts of Anti-BCMA x Anti-CD3 Bispecific Antibodies Anti-BCMA Anti-CD3 Antigen-Binding Antigen-Binding Common nExample 2: Methods of Treating Multiple Myeloma with Anti-BCMA x Anti-CD3 Bispecific Antibodies

[0116] A phase 1 / 2 study of the safety, tolerability, anti-tumor activity, and pharmacokinetics (PK) of REGN5458 (anti-BCMA x anti-CD3 bispecific antibody) in patients with relapsed or refractory multiple myeloma who have exhausted all therapeutic options, including proteasome inhibitors, immunomodulatory drugs and anti-CD38 antibody treatments, is being conducted.

[0117] Patients with difficult-to-treat, advanced forms of multiple myeloma are being studied as part of the REGN5458 program, including those with cancerous plasma cells that are extra- medullary (outside of the bone marrow) and non-secretory (do not secrete detectable biomarkers).

[0118] In multiple myeloma clinical trials, treatment assessment is based on the reduction of myeloma protein levels, as well as the eradication of myeloma cells. Myeloma protein response assessment is based on the reduction of levels of monoclonal (M) protein, a biomarker that is found in the patient’s urine and blood and used to determine the extent of myeloma disease. A partial remission (PR) is defined as ≥50% reduction of serum / urine M-protein or a ≥50% decrease in the difference between involved and uninvolved free light chain (FLC) levels, and a ≥50% reduction of soft tissue plasmacytomas. A very good partial remission (VGPR) is defined as a ≥90% reductionof serum / urine M-protein or a ≥90% decrease in the difference between involved and uninvolved FLC levels, a ≥90% reduction of soft tissue plasmacytomas, and detection of M-protein by immunofixatoion but not by electrophoresis. A complete remission (CR) is defined as negative detection of M-protein by immunofixation in serum and urine, the disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow aspirates.. Stringent complete remissions are defined as a complete remission (as noted above) plus normal FLC ratio (ĸ / λ ratio ≤4:1 or ≥ 1:2 for ĸ and λ patients). Minimal residual disease (MRD), which reflects the eradication of myeloma cells, is measured separately from M protein, and MRD negativity is defined as the absence of cancer plasma cells within 100,000 bone marrow cells.

[0119] Objectives: Both primary and secondary endpoints will be explored.

[0120] The primary objectives of the study are to assess the safety, tolerability, dose-limiting toxicities (DLTs), and pharmacokinetic (PK) properties, and to determine a dosing regimen of subcutaneous (SC) REGN5458 monotherapy in patients with relapsed or refractory multiple myeloma (RRMM).

[0121] The secondary objectives of the study are to assess the preliminary anti-tumor activity of SC REGN5458 as measured by objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), rate of minimal residual disease (MRD) status, and overall survival (OS); and to characterize the immunogenicity of SC REGN5458.

[0122] Study Design: The study has three parts, part A, part B, and part C, discussed below.

[0123] Part A: Phase 1 part A will enroll maximum 16 patients and focus on: (1) characterizing the PK of REGN5458 and determination of bioavailability following SC administration in RRMM patients following a modified step-up dosing regimen: 5 mg SC (D1), 25 mg SC (D4), an intermediate dose of 100 mg SC (D8), followed by 200 mg SC (D15); (2) Assessment of safety and tolerability of a modified step up dosing regimen. Between 8-16 patients will receive a total of 6 SC doses through the end of cycle 1. Starting in cycle 2 all subsequent doses of REGN5458 will be 200 mg IV. Patients will receive weekly dosing in cycles 2-3 followed by biweekly dosing in cycles 4-6. For patients who achieve a very good partial response (VGPR) or better and have received a minimum of 26 weeks of treatment on the study, the frequency of study drug administration will be decreased from Q2W to Q4W intervals.

[0124] Part B: If part A is tolerable, phase 1 part B will enroll maximum 16 patients and will be similar to part A with the following change: the 100 mg step-up dose on D8 will be eliminated and, instead, the 200 mg SC dose will be administered on D8. Patients will receive a total of 6 SC doses through the end of cycle 1. Starting in cycle 2 (week 6) all additional doses of REGN5458 will be 200 mg IV. Patients will receive weekly dosing in cycles 2-3 followed by biweekly dosing in cycles 4-6. For patients who achieve a VGPR or better and have received a minimum of 26 weeks oftreatment on the study, the frequency of study drug administration will be decreased from Q2W to Q4W intervals.

[0125] Part C: Following parts A and B, the estimated SC bioavailability will be used to inform a full dose of REGN5458 in part C (336 mg). Part C will enable evaluation of the SC dose of REGN5458 needed to achieve a similar steady-state Ctrough and area under the curve (AUC) as that obtained following IV administration, as well as further assess safety, tolerability, and efficacy of REGN5458 delivered via SC administration. Part C will enroll 24 patients that will receive the step- up regimen of D1 (5 mg SC), D4 (25 mg SC), followed by the first full dose on D8 (336 mg SC), and all subsequent doses as 336 mg SC. Starting at cycle 1 week 2, QW treatment is administered SC in 28-day cycles for 3 cycles. Starting at cycle 4, Q2W treatment is administered SC until disease progression or until any criterion of study drug discontinuation is met. For patients who achieve a VGPR or better and have received a minimum of 26 weeks of treatment on the study, the frequency of study drug administration will be decreased from Q2W to Q4W intervals.

[0126] Study Duration: The planned duration of the study for each patient may vary, and will include a screening period (up to 28 days), followed by: - Treatment period in part A and B: Variable duration, comprised of SC administration of step- up doses in week 1 (D1, D4) followed by SC administration in week 2 (D8) and continuing through cycle 1 week 5. Starting at cycle 2, QW treatment is administered IV in 28-day cycles for 2 cycles. Starting at cycle 4, Q2W treatment is administered IV until disease progression or until any criterion of study drug discontinuation is met. For patients who achieve VGPR or better and have received a minimum of 26 weeks of treatment on the study, the frequency of IV study drug administration will be decreased from Q2W to Q4W intervals. - Treatment period in part C: Variable duration, comprised of SC administration of step-up doses in week 1 (D1, D4) followed by weekly SC administration through the end of cycle 3. Starting at cycle 4, Q2W treatment is administered SC until disease progression or until any criterion of study drug discontinuation is met. For patients who achieve VGPR or better and have received a minimum of 26 weeks of treatment on the study, the frequency of SC study drug administration will be decreased from Q2W to Q4W intervals. - Follow-up period (Parts A-C): variable duration. The follow-up period consists of a safety follow-up period (approximately 12 weeks [i.e., 90 days]), an efficacy follow-up period (until disease progression, start of subsequent MM therapy, death, or another discontinuation criterion is met), and confirmation of survival status (until death or study termination). - An additional cohort with full dose of 200 mg IV has also been initiated with prophylactic use of anti-IL-6R therapy to decrease the incidence and severity of cytokine release syndrome.A single dose of tocilizumab, an anti-IL-6R therapy, will be administered prior to the first IV dose of REGN5458. Approximately 40 patients evaluable for safety and efficacy are being enrolled and will receive REGN5458 IV monotherapy, administered as an infusion, at a dose of 5 mg at week 1 (initial dose), 25 mg at week 2 (intermediate dose), and 200 mg (full dose) at week 3 and thereafter until disease progression or another discontinuation criterion is met. If a patient has received at least 24 weeks of treatment with REGN5458 and has also achieved VGPR or better, then the frequency of study drug administration at 200 mg will be decreased from Q2W to Q4W intervals. In this cohort, patients who relapse after a BCMA CAR-T cellular therapy will be eligible to receive REGN5458 following the same dose and schedule. Twelve patients who relapse after receiving BCMA CAR-T cellular therapy will be enrolled.

[0127] Study Population: Up to 56 patients are planned, and the study will enroll patients with multiple myeloma who have progressed on or after 3 prior lines of therapy, or who are triple- refractory (defined as refractory to a PI, IMiD, and anti-CD38 monoclonal antibody). Refractory disease is defined as progression during treatment or within 60 days after completion of therapy, or less than a 25% response to therapy.

[0128] Inclusion Criteria - A patient must meet the following criteria to be eligible for inclusion in the study: 1. Age 18 years or greater 2. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 Individual cases of patients with ECOG 2 performance status, whose ECOG status is expected to improve as a consequence of effective therapy, may be discussed with the medical monitor for potential enrollment. 3. Confirmed diagnosis of active MM by International Myeloma Working Group (IMWG) diagnostic criteria. 4. Patients must have myeloma that is response evaluable according to the 2016 IMWG response criteria. Measurable disease is defined as 1 or more of the following: a. Serum M-protein ≥1 g / dL, b. Urine M-protein ≥200 mg / 24-hr, and / or c. FLC assay with involved FLC level ≥10 mg / dL with an abnormal serum FLC ratio d. A patient with Immunoglobulin A (IgA) myeloma but without measurable M-protein may be enrolled if quantitative IgA levels are greater than or equal to 400 mg / dL and can be followed longitudinally e. A patient with non-secretory MM may be considered for enrollment. 5. Patients with MM whose disease meets the following criteria:a. Progression on or after at least 3 prior lines of therapy including a PI, IMiD, and anti- CD38 antibody, OR b. Patients must be triple- refractory, defined as being refractory to prior treatment with at least 1 PI, 1 IMiD, and an anti-CD38 antibody. Refractory disease is defined as progression during treatment or within 60 days after completion of therapy, or <25% response to therapy, AND c. if the patient has relapsed after a BCMA-directed CAR-T cellular therapy, then: • Treatment with a CAR-T must have been associated with a response of PR or better, and • If CAR-T cellular therapy was the most recent prior therapy, excluding corticosteroids, then treatment must have been a minimum of 60 days prior to treatment with REGN5458. Adequate hematologic function before dosing as measured by: a. Platelet count > 50 x 109 / L. A patient may not have received a platelet transfusion within 7 days in order to meet this platelet eligibility requirement. b. ANC > 1.0 x 109 / L. A patient may not have received granulocyte colony stimulating factor (G-CSF) within 2 days in order to meet this absolute neutrophil count eligibility requirement. c. Hemoglobin > 8.0 g / dL Adequate renal and hepatic function, defined as: a. Total bilirubin ≤1.5 x ULN b. Transaminase (ALT, AST) ≤2.5 x ULN c. Alkaline phosphatase ≤2.5 x ULN − Patients with Gilbert syndrome do not need to meet this total bilirubin requirement provided that the total bilirubin is unchanged from the baseline value. Serum creatinine clearance by Cockcroft-Gault >30 mL / min − A patient with a creatinine clearance by Cockcroft-Gault who does not meet eligibility criteria may be considered for enrollment if a measured creatinine clearance (based on 24-hour urine collection or other reliable method) is >30 mL / min. If previously treated with CAR T therapy or any gene therapy products, patients must have recovered from the toxicities of this therapy Life expectancy of at least 6 months Willing and able to comply with clinic visits and study-related procedures, including serial bone marrow evaluations according to the protocol schedule− A bone marrow aspirate and biopsy, or other tissue infiltrated with malignant plasma cells, must be provided at screening for evaluation of BCMA levels in malignant cells, but demonstration of BCMA levels will not be required prior to enrollment. 12. Provide informed consent signed by the study patient 13. Able to understand and complete study-related questionnaire.

[0129] Exclusion Criteria - A patient who meets any of the following criteria will be excluded from the study: 1. Diagnosis of plasma cell leukemia, primary systemic light-chain amyloidosis (excluding myeloma-associated amyloidosis), Waldenström macroglobulinemia (lymphoplasmacytic lymphoma), or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) 2. Patients with known MM brain lesions or meningeal involvement 3. History of neurodegenerative condition or CNS movement disorder, or patients with a history of seizure within 12 months prior to study enrollment are excluded 4. Cardiac ejection fraction <40% by echocardiogram or multi-gated acquisition scan (MUGA) 5. Continuous systemic corticosteroid treatment with more than 10 mg per day of prednisone or anti-inflammatory equivalent within 72 hours of start of study drug 6. Live or live attenuated vaccines with replicating potential within 28 days prior to first study drug administration. Has received a COVID-19 vaccination (initial series or booster) within 1 week of planned start of study medication or for which the planned COVID-19 vaccinations (initial series or booster) would not be completed 1 week prior to start of study drug 7. Treatment with any systemic standard or investigational anti-myeloma therapy within 5 half-lives or within 28 days prior to first administration of study drug, whichever is shorter 8. Prior treatment with BCMA-directed immunotherapies, including BCMA bispecific antibodies and BiTEs. Note: BCMA antibody-drug conjugates are not excluded, and BCMA-directed CAR-T treatment is not excluded 9. Any infection requiring hospitalization or treatment with IV anti-infectives within 2 weeks of first administration of study drug 10. Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) infection; or other uncontrolled infection a. Patients with HIV who have controlled infection (undetectable viral load and CD4 count above 350 cells / microliter either spontaneously or on a stable antiviral regimen) are permitted. b. Patients with hepatitis B (Hepatitis B Surface Antigen Test positive [HepBsAg+]) who have controlled infection (serum HBV DNA polymerase chain reaction [PCR] that isbelow the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted. c. Patients who are HCV antibody-positive (HCV Ab+) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted. 11. Has known allergy or hypersensitivity to components of REGN5458 12. Known hypersensitivity to both allopurinol and rasburicase 13. History of allogeneic stem cell transplantation at any time, or autologous stem cell transplantation within 12 weeks of the start of study treatment. 14. Another malignancy in the past 5 years, except for non-melanoma skin cancer that has undergone potentially curative therapy or in situ cancer, or any other tumor that has been deemed to be effectively treated with definitive local control and with curative intent 15. Is currently receiving treatment in another interventional study 16. Evidence of significant concurrent disease or medical condition that could interfere with the conduct of the study or put the patient at significant risk, including but not limited to, significant cardiovascular disease (eg, New York Heart Association class III or IV cardiac disease; myocardial infarction within the previous 6 months; unstable arrhythmias; unstable angina) and / or significant pulmonary disease (eg, prior history or ongoing complicated interstitial lung disease; obstructive pulmonary disease and history of symptomatic bronchospasm)

[0130] Treatment(s): REGN5458 for SC administration will be supplied as a liquid in sterile, single-use vials. Each vial will contain REGN5458 at a concentration of 10 mg / mL or 120 mg / mL.

[0131] SC administration of REGN5458 will vary: - Part A: SC administration is limited to step-up and cycle 1. Each patient will receive an initial dose of REGN54585 mg SC on D1, followed by 25 mg SC on D4, 100 mg SC on W2D1 (D8), followed by 200 mg SC doses on D15 / D22 / D28. Starting in cycle 2 each subsequent full dose of 200 mg will be administered IV. Patients will receive weekly IV infusion starting at the onset of cycle 2 week 6 for 2 cycles (4 weeks each), followed by Q2W infusion until progression or other discontinuation criteria are met. For patients who achieve VGPR or better and have received a minimum of 26 weeks of treatment on the study, the frequency of study drug administration will be decreased from Q2W to Q4W. Two hospitalizations are planned: 1) All patients in phase 1 part A will be hospitalized from the start of study treatment administration (C1D1) through D10, to ensure monitoring for 48 hours after the 100 mg SC dose of REGN5458 on D8.2) A second hospitalization period is implemented after the C1W3 dose (200 mg SC), to ensure monitoring for 48 hours after the 200 mg SCdose of REGN5458. Hospitalization beyond week 3 may be implemented at the discretion of the investigator. - Part B: SC administration is limited to step-up and cycle 1. Each patient will receive an initial dose of REGN54585 mg SC on D1, followed by 25 mg SC on D4, and 200 mg SC on W2D1 (D8), followed by 200 mg SC doses on D15 / D21 / D28. Starting in cycle 2 each subsequent full dose of 200 mg will be administered IV. Patients will receive weekly IV infusion starting in week 3 for 2 cycles (4 weeks each), followed by Q2W infusion until progression or other discontinuation criteria are met. For patients who achieve VGPR or better and have received a minimum of 26 weeks of treatment on the study, the frequency of study drug administration will be decreased from Q2W to Q4W. A single hospitalization is planned. All patients in phase 1 part B will be hospitalized from the start of study treatment administration (C1D1) through D10, to ensure monitoring for at 48 hours after the 200 mg SC dose of REGN5458 on D8. Hospitalization beyond week 2 may be implemented at the discretion of the investigator. - Part C: All doses of REGN5458 are SC. Each patient will receive an initial dose of REGN54585 mg SC on D1, followed by an intermediate dose of 25 mg SC on D4. The first full doses of REGN5458 (dose 336 mg) will be administered SC on cycle 1 week 2 (study D8). All subsequent doses (336 mg) will be administered SC. The dosing schedule will be weekly for cycles 1-3 cycles (4 weeks each), followed by Q2W infusion until progression or other discontinuation criteria are met. For patients who achieve VGPR or better and have received a minimum of 26 weeks of treatment on the study, the frequency of study drug administration will be decreased from Q2W to Q4W. The first 8 patients in part C will be hospitalized from the start of study treatment administration (C1D1) until 48 hours after the first full dose. Based on the overall rate of CRS / IRR events, hospitalization duration will be modified for subsequent patients. Hospitalization beyond week 1 may be implemented at the discretion of the investigator.

[0132] Premedication with corticosteroids, antihistamines, and acetaminophen (paracetamol) may be used. Based on the slower kinetics of absorption with SC administration and taking into account the timing of CRS onset and duration with IV administration, the dose, route, and schedule of corticosteroid administration to prevent CRS / ICANS is predicted to differ. Dividing the total dose of dexamethasone over two days is implemented to mitigate CRS incidence and severity. The dosing guidelines for premedication in connection with SC antibody administration are listed below in Table 3.Table 3: Premedication Dosing Guidelines Premedication Dose Administration Dexamethasone 20 mg PO x 2 doses 1-3 hr prior to dose, andp , p p , g st full dose on week 4. In parts B and C, patients will receive premedication for each of the first 3 doses, through the first full dose on week 3. If the patient experiences CRS of any grade during the step-up dosing period through the first full dose, continue premedication and post-medication until the full dose is tolerated without experiencing CRS.

[0134] For patients in phase 1 parts B and C, if the first two step-up doses and the first full dose is tolerated without CRS of any grade, no further corticosteroid administration is needed. If the second step-up dose (25 mg) or the first full dose is accompanied by CRS of any grade, then additional corticosteroid administration may be used.

[0135] If continued corticosteroid administration is warranted, another intermediate or long-acting corticosteroid (e.g., methylprednisolone) may be substituted for dexamethasone. Anticytokine therapy (such as tocilizumab or sarilumab) may also be used.

[0136] Study Endpoint(s):

[0137] The primary endpoints in the study are: • The incidence of DLTs from the first dose through the end of the DLT observation period • The incidence and severity of treatment-emergent adverse events (TEAEs) and adverse events of special interest (AESI) with REGN5458 • Assessment of the PK of REGN5458 administered via SC injection.

[0138] The secondary endpoints in the study are: • Incidence and titer of anti-drug antibodies (ADAs) and incidence of neutralizing antibodies to REGN5458 over time • DOR using the international myeloma working group (IMWG) criteria • PFS as measured using the IMWG criteria • Rate of MRD negative status using the IMWG criteria • OS • ORR as measured using the IMWG criteria

[0139] Preliminary Results are discussed below.

[0140] Patient Demographic and Baseline Characteristics: Parts A and B included 13 patients with relapsed refractory multiple myeloma. The median age of the patients was 67 years, ranging from 57 to 82 years. The median weight of the patients was 68.3 kg, with a range from 46.2 to 85.7 kg. The racial composition was 53.8% Asian and 46.2% White. The gender distribution was balanced with 53.8% male and 46.2% female. The median soluble BCMA concentration was 0.385 mg / L (range 0.159 to 1.36 mg / L). The median albumin level was 39.7 g / L (range 29.3 to 46 g / L).

[0141] Soluble B-cell maturation antigen (sBCMA) is a biomarker linked to tumor burden in multiple myeloma. Monitoring sBCMA helps assess disease progression and response to treatment. Median baseline sBCMA levels were 0.302 mg / L and 0.526 mg / L in parts A and B. Linvoseltamab treatment initially increased sBCMA due to drug binding and slower clearance, peaking between weeks 4 and 6. Levels then sharply declined, falling below baseline by week 12, and reaching levels (<0.03 mg / L) in healthy individuals by week 23, indicating reduced tumor burden. In the phase 2 cohort findings with intravenous administration, which have more extensive follow-up, the concentration-time profiles of total sBCMA generally align with the initial trends observed in the phase 1 SC cohorts. The observed trends suggest the effectiveness of the SC dosing regimen followed by IV administrations in parts A and B. Monitoring of the SC dosing without transitioning to IV in part C is ongoing.

[0142] Safety Analysis: The study enrolled 13 patients (7 in part A and 6 in part B) and focused on assessing the safety profile of the treatment, particularly, common and serious adverse events. Notably, upon review of reported adverse events during the respective dose-limiting toxicities (DLT) periods for both part A and part B, it was determined that no DLTs occurred, indicating a manageable safety profile consistent with the clinical experience of intravenous linvoseltamab. The SC step-up regimen of 5 mg on day 1 and 25 mg on day 4 during week 1 followed by the full dose on day 8, is accelerated compared to the reference IV regimen where the step-up regimen during of 5 mg on day 1 and 25 mg on day 8 is administered. Initial findings from parts A and B demonstrate that the SC 5 / 25 mg step-up regimen is safe and tolerable. Both the full dose schedules in part A (SC 100 mg week 2 and 200 mg week 3, 4, and 5 prior to transition to IV 200 mg dose week 6) and part B (SC 200 mg week 2, 3, 4, and 5 prior to transition to IV 200 mg dose week 6) were also safe and tolerable.

[0143] Serum Cytokine Profiles: Preliminary analyses of cytokines in serum following SC dosing regimens in part A and B indicate cytokine elevations were notably lower post SC dosing to cytokine elevations observed post IV administration of linvoseltamab. Specifically, peak concentrations assessed with the initial dose, intermediate dose(s), and first full dose (200 mg) were overall lower and peaked later in SC compared to IV for interferon (IFN)-gamma, interleukin (IL)-2, IL-6, IL-8, IL-10 and tumor necrosis factor-alpha. These initial findings suggest moremoderate changes in circulating cytokine levels with SC dosing compared to IV, supporting further evaluation of SC administration.

[0144] Descriptive Pharmacokinetics: For part A, following the 5 / 25 mg step-up doses, a 100 mg SC dose was administered, resulting in a mean peak total linvoseltamab concentration (Cmax) of 7.43 µg / mL, with a coefficient of variation (CV) of 18.4% and a range from 5.16 to 9.56 µg / mL. The median time to reach maximum concentration (Tmax) was 5.0 days, ranging between 1.9 to 7.0 days. In part B, following the 5 / 25 mg step-up doses, a 200 mg SC dose yielded a mean Cmax of 13.2 µg / mL, with a CV of 73.1% and a range from 5.14 to 31.8 µg / mL. The median Tmax was similarly 5.0 days, ranging from 3.0 to 7.0 days. Initial concentrations increased rapidly within the first few weeks following the step-up regimen. SC administration resulted in significantly lower peak exposure, approximately 4 to 5 times lower than the standard 200 mg IV regimen.

[0145] Conclusion: The SC dosing regimen of linvoseltamab, particularly exploration of the full dose of 336 mg, is expected to provide comparable safety and efficacy to the IV regimen in view of the present disclosure. Preliminary data suggests SC administration is a viable alternative dosing route. The comprehensive evidence, including additional pharmacokinetic data from parts A, B, and C, along with longer duration of safety and efficacy assessments of the SC dosing regimen, will be used to further inform development of the linvoseltamab SC dosing strategy. Example 3: Pharmacokinetic Modeling and Simulation

[0146] A population pharmacokinetic (PopPK) model was utilized based on data from 281 patients receiving intravenous linvoseltamab. Concentrations of linvoseltamab in serum were well described by a two-compartment disposition model with parallel linear and nonlinear (Michaelis Menten type) clearance processes. Key inter-individual variability (IIV) terms are incorporated for clearance (CL), volume at steady state (Vss), intercompartmental clearance (Q), and Vmax. The model also considers covariates such as baseline body weight on CL / Q, and time-varying albumin and immunoglobulin G (IgG) on linear CL. With the inclusion of SC data, the model was updated to incorporate first-order absorption, estimating bioavailability and absorption rate constants (KA) to accurately represent SC administration while fixing the disposition parameters (estimated from the IV data).

[0147] The SC regimen for linvoseltamab is designed to achieve targeted PK profiles, with a recommended dosing approach starting with 5 mg on day 1 and 25 mg on day 4 of week 1. This is followed by a full treatment dose initially recommended as 330 mg (adjusted to 336 mg) weekly beginning on day 1 of week 2, transitioning to Q2W dosing from weeks 14 to 25, and subsequently, Q4W from week 26 for patients achieving ≥VGPR. The SC regimen assumes a bioavailability of 70% and aims for a comparable mean steady-state area under the curve (AUCτau, 24 weeks)relative to the registrational IV regimen. The expected geometric mean ratio (GMR) SC / IV for AUC is 1.03 at the beginning (week 3), 1.07 at the end of the QW dosing period (week 13), and 1.01 at the end of the biweekly dosing period (week 24). Similarly, for Ctrough, the expected GMR is 1.76 at the beginning (week 3), and 1.30 at both the end of the weekly dosing period (week 13) and the end of the Q2W dosing period (week 24). These aim to achieve non-inferiority, ensuring that the lower bound of the 90% confidence interval exceeds 0.8. The simulation results indicated comparable exposure metrics for the SC regimen compared to the IV regimen (Fig.5). The initial full dose recommendation was 330 mg (2.75 mL at 120 mg / mL). Operational considerations, including syringe graduation markings, require rounding to 2.80 mL, resulting in a 336 mg dose (<2% variance from 330 mg). Consequently, full doses of 336 mg will be administered.

[0148] The present disclosure is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the disclosure in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. Sequences SEQ ID NO: 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSNFWMTWVRQAPGKGLEWVANMNQDGSEKYYVDSVKGRFTISRD NAKSSLYLQMNSLRAEDTAVYYCARDREYCISTSCYDDFDYWGQGTLVTVSS SEQ ID NO: 2 GFTFSNFW SEQ ID NO: 3 MNQDGSEK SEQ ID NO: 4 ARDREYCISTSCYDDFDY SEQ ID NO: 5 EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYSMHWVRQAPGKGLEWVSGISWNSGSKGYADSVKGRFTISRD NAKNSLYLQMNSLRAEDTALYYCAKYGSGYGKFYHYGLDVWGQGTTVTVSS SEQ ID NO: 6 GFTFDDYS SEQ ID NO: 7 ISWNSGSK SEQ ID NO: 8 AKYGSGYGKFYHYGLDVSEQ ID NO: 9 EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYSMHWVRQAPGKGLEWVSGISWNSGSIGYADSVKGRFTISRD NAKNSLYLQMNSLRAEDTALYYCAKYGSGYGKFYYYGMDVWGQGTTVTVSS SEQ ID NO: 10 GFTFDDYS SEQ ID NO: 11 ISWNSGSI SEQ ID NO: 12 AKYGSGYGKFYYYGMDV SEQ ID NO: 13 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTL TISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK SEQ ID NO: 14 QSISSY SEQ ID NO: 15 AAS SEQ ID NO: 16 QQSYSTPPIT SEQ ID NO: 17 EVQLVESGGGLVQPGGSLRLSCAASGFTFSNFWMTWVRQAPGKGLEWVANMNQDGSEKYYVDSVKGRFTISRD NAKSSLYLQMNSLRAEDTAVYYCARDREYCISTSCYDDFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSES TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKV DKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHN HYTQKSLSLSLGK SEQ ID NO: 18 VQLVESGGGLVQPGRSLRLSCAASGFTFDDYSMHWVRQAPGKGLEWVSGISWNSGSKGYADSVKGRFTISRDN AKNSLYLQMNSLRAEDTALYYCAKYGSGYGKFYHYGLDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTA ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDK RVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTK PREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNRF TQKSLSLSPGK SEQ ID NO: 19 EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYSMHWVRQAPGKGLEWVSGISWNSGSIGYADSVKGRFTISRD NAKNSLYLQMNSLRAEDTALYYCAKYGSGYGKFYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSEST AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVD KRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKT KPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNR FTQKSLSLSPGKSEQ ID NO: 20 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTL TISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC *******

Claims

What is claimed is:

1. A method of treating multiple myeloma in a subject in need thereof, comprising administering to the subject a bispecific antibody or antigen-binding fragment thereof comprising a first antigen-binding domain that specifically binds a human B-cell maturation antigen (BCMA), and a second antigen-binding domain that specifically binds human CD3, wherein the bispecific antibody or antigen-binding fragment thereof is administered to the subject in a dosing regimen, wherein the dosing regimen comprises: subcutaneously administering 3-7 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on a first day during week 1 of the dosing regimen; subcutaneously administering 20-30 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on a second day during week 1 of the dosing regimen; subcutaneously administering 50-400 mg of the bispecific antibody or antigen-binding fragment thereof to the subject during week 2 of the dosing regimen; subcutaneously administering 150-400 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 3 to 5 of the dosing regimen; administering 150-400 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 6 to 13 of the dosing regimen; administering 150-400 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) to the subject during weeks 14 to 25 of the dosing regimen; and administering 150-400 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) or once every four weeks (Q4W) to the subject in subsequent weeks of the dosing regimen.

2. The method of claim 1, wherein the first day is day 1 of week 1, and the second day is day 4 of week 1 of the dosing regimen.

3. The method of claim 1 or 2, wherein the 3-7 mg of the bispecific antibody or antigen-binding fragment thereof is about 5 mg.

4. The method of any one of claims 1-3, wherein the 20-30 mg of the bispecific antibody or antigen-binding fragment thereof is about 25 mg.

5. The method of any one of claims 1-4, wherein the 50-400 mg of the bispecific antibody or antigen-binding fragment thereof is about 100 mg or about 200 mg.

6. The method of any one of claims 1-5, wherein the 150-400 mg of the bispecific antibody or antigen-binding fragment thereof is about 200 mg.

7. The method of any one of claims 1-4, wherein the 50-400 mg of the bispecific antibody or antigen-binding fragment is 300-360 mg, and the 150-400 mg of the bispecific antibody or antigen-binding fragment thereof is 300-360 mg.

8. The method of claim 7, wherein the 300-360 mg is 330-340 mg or about 336 mg.

9. The method of any one of claims 1-8, wherein the bispecific antibody or antigen-binding fragment thereof is administered Q2W to the subject in the subsequent weeks of the dosing regimen.

10. The method of any one of claims 1-8, wherein the bispecific antibody or antigen-binding fragment thereof is administered Q4W to the subject in the subsequent weeks of the dosing regimen.

11. The method of any one of claims 1-10, wherein the bispecific antibody or antigen-binding fragment thereof is administered intravenously during weeks 6 to 13, weeks 14 to 25, and in the subsequent weeks of the dosing regimen.

12. The method of any one of claims 1-10, wherein the bispecific antibody or antigen-binding fragment thereof is administered subcutaneously during weeks 6 to 13, weeks 14 to 25, and in the subsequent weeks of the dosing regimen.

13. The method of claim 1, wherein the dosing regimen comprises: subcutaneously administering 3-7 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on a first day during week 1 of the dosing regimen; subcutaneously administering 20-30 mg of the bispecific antibody or antigen-binding fragment thereof to the subject on a second day during week 1 of the dosing regimen; subcutaneously administering 325-350 mg of the bispecific antibody or antigen-binding fragment thereof to the subject during week 2 of the dosing regimen; subcutaneously administering 325-350 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 3 to 5 of the dosing regimen; subcutaneously administering 325-350 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 6 to 13 of the dosing regimen;subcutaneously administering 325-350 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) to the subject during weeks 14 to 25 of the dosing regimen; and subcutaneously administering 325-350 mg of the bispecific antibody or antigen- binding fragment thereof once every two weeks (Q2W) or once every four weeks (Q4W) to the subject in subsequent weeks of the dosing regimen.

14. The method of claim 13, wherein 3-7 mg is about 5 mg, 20-30 mg is about 25 mg, and 325-350 mg is about 336 mg.

15. The method of any one of claims 1-14, further comprising administering a second therapeutic agent or therapeutic regimen.

16. The method of claim 15, wherein the second therapeutic agent or therapeutic regimen comprises a chemotherapeutic drug, DNA alkylators, immunomodulators, proteasome inhibitors, histone deacetylase inhibitors, radiotherapy, a stem cell transplant, a different bispecific antibody that interacts with a different tumor cell surface antigen and a T cell or immune cell antigen, an antibody drug conjugate, a PD-1 antagonist, a PD-L1 antagonist, or CTLA-4 checkpoint inhibitor, or combinations thereof.

17. The method of any one of claims 1-16, wherein the subject has been previously treated with an anti-CD38 antibody therapy.

18. The method of claim 17, wherein the anti-CD38 antibody is daratumumab or isatuximab.

19. The method of any one of claims 1-18, wherein the subject has been previously treated with a proteasome inhibitor or an immunomodulatory drug.

20. The method of claim 19, wherein the proteasome inhibitor is bortezomib, carfilzomib or ixazomib.

21. The method of claim 19, wherein the immunomodulatory drug is lenalidomide or pomalidomide.

22. The method of any one of claims 1-21, wherein the subject has an extramedullary plasmacytoma.

23. The method of any one of claims 1-22, wherein the multiple myeloma is relapsed or refractory multiple myeloma.

24. The method of any one of claims 1-23, wherein the subject has previously received one to three lines of prior therapy to treat multiple myeloma.

25. The method of any one of claims 1-23, wherein the subject is at least triple- refractory to prior therapies.

26. The method of claim 25, wherein the subject is quad-refractory or penta- refractory to prior therapies.

27. The method of any one of claims 1-26, wherein the subject has been previously treated with a BCMA-directed CAR-T cellular therapy.

28. The methof of any one of claims 1-27, wherein the subject is eligible for a stem cell transplant.

29. The method of any one of claims 1-27, wherein the subject is ineligible for a stem cell transplant.

30. A method of treating multiple myeloma in a subject that has failed prior CAR-T therapy or is not responsive to prior CAR-T therapy to treat the multiple myeloma, comprising administering to the subject a bispecific antibody or antigen-binding fragment thereof comprising a first antigen-binding domain that specifically binds a human B-cell maturation antigen (BCMA), and a second antigen-binding domain that specifically binds human CD3.

31. The method of claim 30, wherein the bispecific antibody or antigen-binding fragment is administered to the subject in a dosing regimen, wherein the dosing regimen comprises: intravenously administering 3-7 mg of the bispecific antibody or antigen-binding fragment thereof to the subject during week 1 of the dosing regimen; intravenously administering 20-30 mg of the bispecific antibody or antigen-binding fragment thereof to the subject during week 2 of the dosing regimen; intravenously administering 150-250 mg of the bispecific antibody or antigen-binding fragment thereof once weekly (QW) to the subject during weeks 3 to 13 of the dosing regimen; intravenously administering 150-250 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) to the subject during weeks 14 to 25 of the dosing regimen; andintravenously administering 150-250 mg of the bispecific antibody or antigen-binding fragment thereof once every two weeks (Q2W) or once every four weeks (Q4W) to the subject in subsequent weeks of the dosing regimen.

32. The method of any one of claims 1-31, wherein the subject is administered a dose of an anti-IL-6R antibody prior to receiving a first dose of the bispecific antibody or antigen- binding fragment thereof.

33. The method of any one of claims 1-32, wherein the first antigen-binding domain comprises a heavy chain variable region (HCVR) comprising three heavy chain complementarity determining regions, HCDR1, HCDR2 and HCDR3, comprising the amino acid sequences of SEQ ID NOs: 2, 3 and 4, respectively, and a light chain variable region (LCVR) comprising three light chain complementarity determining regions, LCDR1, LCDR2 and LCDR3, comprising the amino acid sequences of SEQ ID NOs: 14, 15 and 16, respectively.

34. The method of claim 33, wherein the HCVR of the first antigen-binding domain comprises the amino acid sequence of SEQ ID NO: 1, and the LCVR of the first antigen-binding domain comprises the amino acid sequence of SEQ ID NO:

13.

35. The method of any one of claims 1-34, wherein the second antigen-binding domain comprises a heavy chain variable region (HCVR) comprising three heavy chain complementarity determining regions, HCDR1, HCDR2 and HCDR3, comprising the amino acid sequences of SEQ ID NOs: 6, 7 and 8, respectively, and a light chain variable region (LCVR) comprising three light chain complementarity determining regions, LCDR1, LCDR2 and LCDR3, comprising the amino acid sequences of SEQ ID NOs: 14, 15 and 16, respectively.

36. The method of claim 35, wherein the HCVR of the second antigen-binding domain comprises the amino acid sequence of SEQ ID NO: 5, and the LCVR of the first antigen- binding domain comprises the amino acid sequence of SEQ ID NO:

13.

37. The method of any one of claims 1-34, wherein the second antigen-binding domain comprises a heavy chain variable region (HCVR) comprising three heavy chain complementarity determining regions, HCDR1, HCDR2 and HCDR3, comprising the amino acid sequences of SEQ ID NOs: 10, 11 and 12, respectively, and a light chain variable region (LCVR) comprising three light chain complementarity determining regions, LCDR1, LCDR2 and LCDR3, comprising the amino acid sequences of SEQ ID NOs: 14, 15 and 16, respectively.

38. The method of claim 37, wherein the HCVR of the second antigen-binding domain comprises the amino acid sequence of SEQ ID NO: 9, and the LCVR of the first antigen- binding domain comprises the amino acid sequence of SEQ ID NO:

13.

39. The method of any one of claims 1-38, wherein the bispecific antibody comprises a human IgG heavy chain constant region.

40. The method of claim 39, wherein the human IgG heavy chain constant region is isotype IgG1.

41. The method of claim 39, wherein the human IgG heavy chain constant region is isotype IgG4.

42. The method of any one of claims 39-41, wherein the bispecific antibody comprises a chimeric hinge that reduces Fcɣ receptor binding relative to a wild-type hinge of the same isotype.

43. The method of any one of claims 39-42, wherein the bispecific antibody comprises a first heavy chain and a second heavy chain, and wherein the first heavy chain or the second heavy chain, but not both, comprises a CH3 domain comprising a H435R (EU numbering) modification and a Y436F (EU numbering) modification.

44. The method of any one of claims 1-32, wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 17, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 18, and a common light chain paired with each of the first heavy chain and second heavy chain, respectively, comprising the amino acid sequence of SEQ ID NO:

20.

45. The method of any one of claims 1-32, wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 17, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 19, and a common light chain paired with each of the first heavy chain and second heavy chain, respectively, comprising the amino acid sequence of SEQ ID NO: 20.

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