Methods of treating cancer

Abstract

Disclosed herein are methods of treating cancer with a combination of a BCMAxCD3 bispecific antibody, an anti-CD3 antibody, and an immunomodulatory drug. Also provided are pharmaceutical compositions comprising the same and methods for producing these antibodies of the disclosure.

Description

[0001] Reference sequence listing submitted electronically

[0002] This application contains a sequence listing that has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The XML copy, created on October 4, 2024, is named "258199061102_JBI6761WOPCT1_Sequence_Listing.xml" and is 65 kilobytes in size.

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 382,089, filed on November 2, 2022, which is incorporated herein by reference in its entirety. Technical Field

[0005] Disclosed are methods for treating cancer using BCMA x CD3 bispecific antibodies and combinations comprising a BCMA x CD3 bispecific antibody, an anti-CD38 antibody, and an immunomodulatory drug. Background Art

[0006] Multiple myeloma (MM) is a cancer of plasma cells. Mechanistically, MM is characterized by the production of a monoclonal protein (M protein) composed of pathological immunoglobulins or fragments of these pathological immunoglobulins that have lost their function. The proliferation of multiple myeloma cells leads to their subsequent displacement from the normal bone marrow niche, and excessive production of M protein causes characteristic lytic bone lesions, increased susceptibility to infection, hypercalcemia, renal insufficiency or failure, and neurologic complications.

[0007] Treatment options for multiple myeloma have improved over time and vary depending on the aggressiveness of the disease, underlying prognostic factors, the patient's performance status, and existing comorbidities. Treatment options include proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), alkylating agents, monoclonal antibodies (mAbs), antibody-drug conjugates, histone deacetylase inhibitors, nuclear protein export inhibitors, chimeric antigen receptor (CAR) T-cell therapy, and stem cell transplantation.

[0008] Despite these therapeutic gains, the disease relapses and is associated with additional risk factors (e.g., comorbidities or increasing age), thus warranting the need for novel therapeutic approaches, such as new doses and treatment regimens. Particularly in the elderly population, stem cell transplantation is often not a viable option, and in patients with refractory disease who have exhausted all available therapies, multiple myeloma remains an incurable malignancy and an unmet medical need, with significant morbidity and mortality. Summary of the Invention

[0009] In some embodiments, provided are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a BCMA x CD3 bispecific antibody, a therapeutically effective amount of an anti-CD3 antibody, and a therapeutically effective amount of an immunomodulatory drug (IMiD) for a time sufficient to treat the cancer.

[0010] In some embodiments, the BCMA x CD3 bispecific antibody comprises a BCMA binding domain comprising a heavy chain variable region (VH) comprising heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively, and a light chain variable region (VL) comprising light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11, respectively; and a CD3 binding domain comprising a VH comprising HCDR1, HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14, respectively, and a VL comprising LCDR1, LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17, respectively.

[0011] In some embodiments, the BCMA binding domain comprises a VH having the amino acid sequence of SEQ ID NO: 18 and a VL having the amino acid sequence of SEQ ID NO: 19; and the CD3 binding domain comprises a VH having the amino acid sequence of SEQ ID NO: 20 and a VL having the amino acid sequence of SEQ ID NO: 21.

[0012] In some embodiments, the BCMA x CD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 22, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 23, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 24, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 25, wherein HC1 associates with LC1 to form a first antigen-binding site that immunospecifically binds BCMA, and HC2 associates with LC2 to form a second antigen-binding site that immunospecifically binds CD3.

[0013] In some embodiments, the BCMA x CD3 bispecific antibody is teclistamab.

[0014] In some embodiments, the anti-CD38 antibody comprises a VH having HCDR1, HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NO:28, SEQ ID NO:29, and SEQ ID NO:30, respectively, and a VL having LCDR1, LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:33, respectively.

[0015] In some embodiments, the anti-CD38 antibody comprises a VH having the amino acid sequence of SEQ ID NO:34 and a VL having the amino acid sequence of SEQ ID NO:35.

[0016] In some embodiments, the anti-CD38 antibody comprises a HC having the amino acid sequence of SEQ ID NO:36 and a LC having the amino acid sequence of SEQ ID NO:37.

[0017] In some embodiments, the anti-CD38 antibody is daratumumab.

[0018] In some embodiments, the IMiD is selected from the group consisting of thalidomide, pomalidomide, lenalidomide, or any combination thereof.

[0019] In some embodiments, the IMiD is lenalidomide.

[0020] In some embodiments, the method further comprises administering a pretreatment to the subject.

[0021] In some embodiments, the pretreatment comprises administering a glucocorticoid, an antihistamine, an antipyretic, or a combination thereof.

[0022] In some embodiments, a method of treating cancer in a subject in need thereof is provided, comprising: i) administering one or more ascending doses of about 60 μg / kg, 240 μg / kg, or 300 μg / kg, or about 3 mg, 4 mg, 15 mg, 24 mg, or 25 mg of a BCMAxCD3 bispecific antibody to the subject subcutaneously; ii) administering, after the one or more ascending doses, a therapeutic dose of about 720 μg / kg, 1500 μg / kg, 3000 μg / kg, or 6000 μg / kg, or about 100 mg, 150 mg, 200 mg, 300 mg, or 450 mg of a BCMAxCD3 bispecific antibody to the subject subcutaneously; iii) administering a therapeutically effective amount of about 1200 mg to about 2400 mg of an anti-CD38 antibody to the subject subcutaneously; and iv) orally administering a therapeutically effective amount of about 15 mg to about 50 mg of an immunomodulatory drug (IMiD) to the subject; wherein the BCMAxCD3 bispecific antibody is administered to the subject. The CD3 bispecific antibody, anti-CD38 antibody, and IMiD are administered to the subject for a period of time sufficient to treat the cancer.

[0023] In some embodiments, a method of treating cancer in a subject in need thereof is provided, the method comprising: i) administering to the subject subcutaneously one or more ascending doses of 60 μg / kg, 240 μg / kg, or 300 μg / kg, or any combination thereof, or about 3 mg, 4 mg, 15 mg, 24 mg, or 25 mg, or any combination thereof, of a BCMA x CD3 bispecific antibody at a frequency selected from daily, every other day, or weekly; ii) administering to the subject subcutaneously, after the one or more ascending doses, a therapeutic dose of about 720 μg / kg, 1500 μg / kg, 3000 μg / kg, or 6000 μg / kg, or any combination thereof, or about 100 mg, 150 mg, 200 mg, 300 mg, or 450 mg, or any combination thereof, of a BCMA x CD3 bispecific antibody at a frequency selected from weekly, every two weeks, once every four weeks, or once monthly. The invention provides a method for treating cancer by administering a BCMA x CD3 bispecific antibody; iii) subcutaneously administering to the subject a therapeutically effective amount of about 1800 mg of an anti-CD38 antibody at a frequency selected from weekly, two weeks, four weeks, or monthly; and iv) orally administering to the subject a therapeutically effective amount of about 25 mg of an immunomodulatory drug (IMiD) at a frequency of daily or weekly; wherein the BCMA x CD3 bispecific antibody, the anti-CD38 antibody, and the IMiD are administered to the subject for a time sufficient to treat the cancer.

[0024] In some embodiments, a method of treating cancer in a subject in need thereof is provided, the method comprising: i) determining the subject's weight and assigning a BCMAxCD3 bispecific antibody treatment tier based on the weight, wherein if the subject's weight is less than or equal to a predetermined threshold, the subject is in tier 1, and wherein if the subject's weight is greater than the predetermined threshold, the subject is in tier 2; ii) subcutaneously administering one or more ascending doses of the BCMAxCD3 bispecific antibody to the subject; iii) following the one or more ascending doses, subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody to the subject; iv) subcutaneously administering a therapeutically effective amount of an anti-CD38 antibody to the subject; and v) orally administering a therapeutically effective amount of an immunomodulatory drug (IMiD) to the subject; wherein the BCMAxCD3 bispecific antibody, the anti-CD38 antibody, and the IMiD are administered to the subject for a time sufficient to treat the cancer.

[0025] In some embodiments, the predetermined weight threshold is selected from the group consisting of 50 kg, 55 kg, 60 kg, 65 kg, or 70 kg.

[0026] In some embodiments, a method of treating cancer in a subject in need thereof is provided, comprising: i) administering to the subject one or more ascending doses of terituzumab subcutaneously at 60 μg / kg, 240 μg / kg, or 300 μg / kg, or any combination thereof, or about 3 mg, 4 mg, 15 mg, 24 mg, or 25 mg, or any combination thereof, on days 2 and 4 after initiation of treatment; ii) administering to the subject subcutaneously about 720 μg / kg, 1500 μg / kg, or any combination thereof, at a frequency selected from weekly, every two weeks, every four weeks, or monthly, following the one or more ascending doses. , 3000 μg / kg, 6000 μg / kg, or any combination thereof, or a therapeutic dose of about 100 mg, 150 mg, 200 mg, 300 mg, 450 mg, or any combination thereof of terituzumab; iii) subcutaneously administering to the subject a therapeutically effective amount of about 1800 mg of daratumumab at a frequency selected from weekly, every two weeks, every four weeks, or monthly; iv) orally administering to the subject a therapeutically effective amount of about 25 mg of lenalidomide at a frequency of once daily; wherein terituzumab, daratumumab, and lenalidomide are administered to the subject for a time sufficient to treat the cancer.

[0027] In some embodiments, a method of treating cancer in a subject in need thereof is provided, the method comprising: i) administering to the subject a first ascending dose of 60 μg / kg of Terituzumab subcutaneously on day 2 of the treatment regimen, and administering to the subject a second ascending dose of 240 μg / kg or 300 μg / kg subcutaneously on day 4 of the treatment regimen; ii) after the first ascending dose and the second ascending dose, administering a therapeutic dose of Terituzumab based on a 28-day treatment cycle, the 28-day treatment cycle comprising a) administering to the subject a therapeutic dose of 720 μg / kg or 1500 μg / kg of Terituzumab subcutaneously on days 8, 15, and 22 of the first treatment cycle; b) administering to the subject a therapeutic dose of 720 μg / kg or 1500 μg / kg of Terituzumab subcutaneously weekly for each treatment cycle thereafter, wherein the weekly dose of 720 μg / kg is optionally The invention further provides the invention to: iii) administer 1800 mg of daratumumab subcutaneously to the subject in a 28-day treatment cycle, wherein daratumumab is administered weekly for the first and second treatment cycles, every two weeks for the third through sixth treatment cycles, and every four weeks for the seventh and subsequent treatment cycles; and iv) administer 25 mg of lenalidomide orally to the subject once daily for 21 days of a 28-day treatment cycle, wherein lenalidomide treatment is initiated in treatment cycle 2; and wherein terituzumab, daratumumab, and lenalidomide are administered to the subject for a time sufficient to treat the cancer.

[0028] In some embodiments, a method of treating cancer in a subject in need thereof is provided, the method comprising: i) administering to the subject subcutaneously a first escalating dose of terituzumab on day 2 of a first treatment cycle, and administering to the subject subcutaneously a second escalating dose of terituzumab on day 4 of the first treatment cycle, wherein if the subject weighs less than or equal to 60 kg, the first escalating dose is 3 mg of terituzumab and the second escalating dose is 15 mg of terituzumab, and wherein if the subject weighs greater than 60 kg, the first escalating dose is 4 mg of terituzumab and the second escalating dose is 24 mg or 25 mg of terituzumab; ii) administering to the subject subcutaneously a first escalating dose of terituzumab on day 2 of a first treatment cycle, and administering to the subject subcutaneously a second escalating dose of terituzumab on day 4 of the first treatment cycle, After the first escalating dose and the second escalating dose, a therapeutic dose of terituzumab is administered to the subject based on a 28-day treatment cycle, the administration comprising a) subcutaneously administering a therapeutic dose of terituzumab to the subject on days 8, 15, and 22 of the first treatment cycle, wherein if the subject weighs less than or equal to 60 kg, the therapeutic dose is 100 mg, and wherein if the subject weighs more than 60 kg, the therapeutic dose is 150 mg; and b) subcutaneously administering a therapeutic dose of terituzumab to the subject weekly for a second treatment cycle, wherein if the subject weighs less than or equal to 60 kg, the therapeutic dose is 100 mg, and wherein if the subject weighs more than 60 kg c) administering a therapeutic dose of terituzumab subcutaneously to the subject every two weeks for the third, fourth, fifth, and sixth treatment cycles, wherein if the subject weighs less than or equal to 60 kg, the therapeutic dose is 200 mg, and wherein if the subject weighs greater than 60 kg, the therapeutic dose is 300 mg; and d) administering a therapeutic dose of terituzumab subcutaneously to the subject once every four weeks for the seventh and subsequent treatment cycles, wherein if the subject weighs less than or equal to 60 kg, the therapeutic dose is 200 mg, optionally wherein the therapeutic dose is increased to 300 mg, and wherein if the subject weighs greater than 60 kg, The therapeutic dose is 300 mg, optionally wherein the therapeutic dose is escalated to 450 mg; iii) administering 1800 mg of daratumumab subcutaneously to the subject in a 28-day treatment cycle, wherein daratumumab is administered weekly for the first and second treatment cycles, every two weeks for the third through sixth treatment cycles, and once every four weeks for the seventh and subsequent treatment cycles; and iv) administering 25 mg of lenalidomide orally to the subject once daily for 21 days of a 28-day treatment cycle, wherein lenalidomide treatment is initiated in treatment cycle 2; and wherein terituzumab, daratumumab, and lenalidomide are administered to the subject for a time sufficient to treat the cancer.

[0029] In some embodiments, the methods provided herein also include administering a pre-treatment regimen. In some embodiments, the pre-treatment regimen includes i) intravenous or oral administration of a therapeutically effective amount of dexamethasone, wherein dexamethasone is administered at 20 mg on day 1 of the first treatment cycle, at 16 mg on day 2, 4, 8, 15, and 22 of the first treatment cycle, and at 20 mg or 40 mg weekly during each of the second, third, and fourth treatment cycles; ii) intravenous or oral administration of a therapeutically effective amount of diphenhydramine, wherein for all doses of daratumumab and all incremental doses and the first treatment dose of terituzumab, diphenhydramine is administered at 25 mg to 50 mg; and iii) intravenous or oral administration of a therapeutically effective amount of acetaminophen, wherein for all doses of daratumumab and all incremental doses and the first treatment dose of terituzumab, acetaminophen is administered at 650 mg to 1000 mg. In some embodiments, the pre-treatment regimen also includes administering montelukast at 10 mg. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the accompanying drawings.It should be understood that the invention is not limited to the precise embodiments shown in the drawings.

[0031] Figure 1 Schematic overview of the Phase 1 study of terituzumab administered in combination with daratumumab and lenalidomide (MajesTEC-2 Protocol E; NCT04722146) performed with solid phase extraction as of November 2022.

[0032] Figure 2 Description: Interleukin-6 profile of the cohort treated with terituzumab, daratumumab, and lenalidomide (MajesTEC-2 protocol E; NCT04722146) as of November 2022.

[0033] Figure 3 This is a schematic overview of the design of the initial Phase 3 study of terituzumab administered in combination with daratumumab and lenalidomide (terituzumab-DR) as compared with daratumumab and lenalidomide without terituzumab, as of November 2022 (MajesTEC-7; NCT05552222).

[0034] Figure 4 This is a schematic overview of the updated phase 3 study design (MajesTEC-7; NCT05552222) ending in October 2023 that includes three arms: terituzumab-DR, talquetamab-DR, and DRd. DETAILED DESCRIPTION

[0035] The methods disclosed herein may be more readily understood with reference to the following detailed description in conjunction with the accompanying drawings, which form a part of this disclosure. It should be understood that the methods disclosed herein are not limited to the specific methods described and / or illustrated herein, and that the terminology used herein is intended only to describe specific embodiments by way of example and is not intended to limit the methods protected by the claims. All patents, patent applications, and publications cited herein are incorporated by reference as if fully set forth herein.

[0036] Various terms related to various aspects of the specification are used throughout the specification and claims. Unless otherwise indicated, such terms are given their ordinary meaning in the art. Other specifically defined terms should be understood in a manner consistent with the definitions provided herein.

[0037] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes reference to two or more cells, and so forth.

[0038] Unless otherwise indicated, any numerical value, such as a concentration or concentration range described herein, is understood to be modified in all cases by the term "about". Thus, numerical values ​​generally include ±10% of the stated value. For example, a dose of 10 mg includes 9 mg to 11 mg. Unless the context clearly indicates otherwise, as used herein, a numerical range used explicitly includes all possible subranges, all individual values ​​within the range, including integers and fractions of these values ​​within such ranges.

[0039] When used with respect to a numerical range, a cutoff value, or a particular value, "about" means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. In the context of a particular assay, result, or embodiment, unless expressly stated otherwise in the examples or elsewhere in the specification, "about" means within one standard deviation or up to a range of 10%, whichever is greater, as is customary in the art.

[0040] "Antibody" in a broad sense refers to and includes immunoglobulin molecules, specifically monoclonal antibodies (including murine monoclonal antibodies, human monoclonal antibodies, humanized monoclonal antibodies and chimeric monoclonal antibodies), antigen-binding fragments, multispecific antibodies (such as bispecific antibodies, trispecific antibodies, tetraspecific antibodies, etc.), dimeric, tetrameric or multimeric antibodies, single-chain antibodies, domain antibodies, and any other modified configuration of immunoglobulin molecules that contain an antigen-binding site with the desired specificity. "Full-length antibodies" are composed of two heavy chains (HC) and two light chains (LC) interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region (composed of the domains CH1, hinge, CH2 and CH3). Each light chain is composed of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions can be further subdivided into hypervariable regions, which are called complementarity determining regions (CDRs) and are interspersed with framework regions (FRs). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Immunoglobulins can be assigned to five major classes based on the amino acid sequence of the heavy chain constant domain: IgA, IgD, IgE, IgG, and IgM. IgA and IgG are further subclassified into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. The light chains of antibodies from any vertebrate species can be assigned to one of two distinct classes, kappa and lambda, based on the amino acid sequence of their constant domains.

[0041] "Antigen-binding fragment" or "antigen-binding domain" refers to the portion of an immunoglobulin molecule that binds to an antigen. Antigen-binding fragments can be synthetic, enzymatically obtainable, or genetically engineered polypeptides and contain VH, VL, VH and VL, Fab, F(ab')2, Fd, and Fv fragments, domain antibodies (dAbs) consisting of one VH domain or one VL domain, shark variable IgNAR domains, humped VH domains, and minimal recognition units consisting of amino acid residues that mimic antibody CDRs, such as the FR3-CDR3-FR4 portion, HCDR1, HCDR2, and / or HCDR3, and LCDR1, LCDR2, and / or LCDR3. The VH and VL domains can be linked together via synthetic linkers to form various types of single-chain antibody designs, wherein the VH / VL domains can pair intramolecularly or intermolecularly to form a monovalent antigen-binding site, such as a single-chain Fv (scFv) or a diabody, in which the VH and VL domains are expressed by separate single-chain antibody constructs; for example, as described in International Patent Publication Nos. WO1998 / 44001, WO1988 / 01649, WO1994 / 13804, and WO1992 / 01047.

[0042] "BCMA" refers to human B-cell maturation antigen, also known as CD269 or TNFRSF17. Human BCMA (UniProtQ02223) contains the amino acid sequence of SEQ ID NO: 1. The extracellular domain of human BCMA encompasses residues 1-54 of SEQ ID NO: 1.

[0043] "Bispecific" refers to an antibody that specifically binds to two different antigens or two different epitopes within the same antigen. Bispecific antibodies may have cross-reactivity to other related antigens, for example, to the same antigen from another species (homologous), such as humans or monkeys, e.g., cynomolgus (cynomolgus, cyno) or chimpanzees (Pantroglodytes), or may bind to an epitope shared between two or more different antigens.

[0044] "Cancer" refers to a broad range of diseases characterized by the uncontrolled growth of abnormal cells in the body. Uncontrolled cell division and growth lead to the formation of malignant tumors that invade adjacent tissues and may also metastasize to distant parts of the body through the lymphatic system or bloodstream. "Cancer" or "cancerous tissue" can include tumors.

[0045] "CD3" refers to a human antigen expressed on T cells as part of a multimolecular T cell receptor (TCR) complex and composed of a homodimer or heterodimer formed by the association of two or four receptor chains: CD3ε, CD3δ, CD3ζ, and CD3γ. Human CD3ε comprises the amino acid sequence of SEQ ID NO: 2. SEQ ID NO: 3 shows the extracellular domain of CD3ε.

[0046] "CD38" refers to the CD38 protein (synonyms: ADP-ribosyl cyclase 1, cADPr hydrolase 1, cyclic ADP-ribose hydrolase 1). Human CD38 (UniProt Accession No. P28907) has the amino acid sequence set forth in SEQ ID NO: 4. CD38 is a single-pass type II transmembrane protein with amino acid residues 1-21 representing the cytoplasmic domain, amino acid residues 22-42 representing the transmembrane domain, and residues 43-300 representing the extracellular domain.

[0047] "CH3 region" or "CH3 domain" refers to the CH3 region of an immunoglobulin. The CH3 region of a human IgG1 antibody corresponds to amino acid residues 341-446. However, the CH3 region may also be of any of the other antibody isotypes described herein.

[0048] "Chimeric antigen receptor" or "CAR" refers to an engineered T cell receptor that is specifically transplanted to a ligand or antigen onto a T cell (e.g., a naive T cell, a central memory T cell, an effector memory T cell, or a combination thereof). CAR is also referred to as an artificial T cell receptor, a chimeric T cell receptor, or a chimeric immune receptor. CAR comprises an extracellular domain, a transmembrane domain, and at least one intracellular domain that can bind to an antigen. The CAR intracellular domain comprises a polypeptide that is known to be used as a transmission signal to cause activation or inhibition of a biological process in a cell. The transmembrane domain comprises any peptide or polypeptide that is known to span the cell membrane and can act to connect the extracellular domain and the signaling domain. The chimeric antigen receptor may optionally include a hinge domain that serves as a joint between the extracellular domain and the transmembrane domain.

[0049] "In combination" means that two or more therapeutic agents are administered to a subject together as a mixture, concurrently as single agents, or sequentially in any order. "Combination therapy" may refer to a therapeutically effective regimen that includes administering two or more anti-multiple myeloma agents to a subject to treat multiple myeloma.

[0050] A "complementarity determining region" (CDR) is a region of an antibody that binds to an antigen. CDRs can be defined using various descriptors, such as Kabat (Wu et al., J Exp Med 132:211-50, 1970) (Kabat et al., "Sequences of Proteins of Immunological Interest," 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al., J Mol Biol 196:901-17, 1987), IMGT (Lefranc et al., Dev Comp Immunol 27:55-77, 2003), and AbM (Martin and Thornton J Bmol Biol 263:800-15, 1996). The correspondence between various delineations and variable region numbering is described (see, e.g., Lefranc et al., Dev Comp Immunol 27:55-77, 2003; Honegger and Pluckthun, J Mol Biol 309:657-70, 2001; International Immunogenetics (IMGT) database; Web resource, http: / / www_imgt_org). Available programs (such as abYsis from UCL Business PLC) can be used to delineate CDRs. Unless otherwise expressly stated in the specification, as used herein, the terms "CDR," "HCDR1," "HCDR2," "HCDR3," "LCDR1," "LCDR2," and "LCDR3" include CDRs defined by any of the above methods (Kabat, Chothia, IMGT, or AbM). The correspondence between numbering systems, including, for example, Kabat numbering and the IMGT unique numbering system, is well known to those skilled in the art (see, e.g., Kabat; Chothia; Martin; Lefranc et al.).

[0051] Table 1. Kabat, IMGT, AbM, and Chothia numbering systems .

[0052]

[0053]

[0054] The term "comprising" is intended to include examples encompassed by the terms "consisting essentially of" and "consisting of; similarly, the term "consisting essentially of" is intended to include examples encompassed by the term "consisting of. Unless the context clearly requires otherwise, throughout the specification and claims, the words "comprising," "including," and the like are to be construed in an inclusive sense, rather than an exclusive or exhaustive sense; that is, in the sense of "including but not limited to."

[0055] "Enhancement" or "enhanced" refers to an enhancement of one or more functions of a test molecule when compared to a control molecule, or an enhancement of one or more functions of a combination of test molecules when compared to one or more control molecules. Exemplary functions that can be measured are tumor cell killing, T cell activation, relative or absolute T cell number, Fc-mediated effector function (e.g., ADCC, CDC, and / or ADCP), or binding to Fcγ receptors (FcγRs) or FcRn. "Enhanced" can be an enhancement of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more, or a statistically significant enhancement.

[0056] "Fcγ receptor" (FcγR) refers to the well-known FcγRI, FcγRIIa, FcγRIIb or FcγRIII. Activating FcγRs include FcγRI, FcγRIIa and FcγRIII.

[0057] A "fixed dose", also known as a "stable dose", refers to a dose that is administered to a subject without correcting for the subject's specific weight or body surface area. Thus, a fixed dose (sometimes called a smooth dose) is provided in absolute amounts of the drug (e.g., mg of drug) rather than in amounts based on weight (e.g., μg / kg or μg of drug / kg of body weight). For example, a subject weighing 65 kg may be administered the same smooth dose in milligrams as a subject weighing 85 kg. Stable doses may be administered according to predefined weight categories or types, but are not modified according to the subject's specific weight. For example, if the patient is greater than a predefined threshold weight (e.g., >60 kg), a "stable dose A" may be administered, while if the patient is less than or equal to a predefined threshold weight (e.g., ≤60 kg), a different "stable dose B" may be administered.

[0058] As used herein, "weight-based" refers to the administration of a dosage amount based on the specific weight of the subject; for example, 3 mg / kg refers to a dosage of 3 mg of antibody per kilogram of the subject's body weight. Unless otherwise indicated herein, when a dosage is described in units of "mg / kg" or "μg / kg," weight-based dosing is used.

[0059] Unless otherwise specified herein, BCMAxCD3 bispecific antibodies (such as terituzumab) are administered with a dosing schedule based on sequential 28-day treatment cycles, e.g., Cycle 1 starts on Day 1 of Cycle 1 and ends on Day 28 of Cycle 1, and then Day 1 of Cycle 2 starts the day after Day 28 of Cycle 1 and ends on Day 28 of Cycle 2, and then Day 1 of Cycle 3 starts the day after Day 28 of Cycle 2 and ends on Day 28 of Cycle 3, and so on. As used herein, with respect to treatment cycles, "C1" refers to Cycle 1, "C2" refers to Cycle 2, "C3" refers to Cycle 3, and so on. Multiple cycles may also be described, e.g., "C3-6" refers to Cycles 3-6 (Cycles 3, 4, 5, and 6). Cycle numbers with a "+" sign refer to that cycle and all subsequent cycles, e.g., "C3+" refers to starting with Cycle 3 and all subsequent cycles (i.e., C3, C4, C5, C6, C7, etc.).

[0060] According to certain embodiments, administration of the BCMAxCD3 bispecific antibody begins in cycle 1 of a therapeutically effective regimen. According to other embodiments in which the BCMAxCD3 antibody is administered as part of a combination therapy with one or more additional anti-multiple myeloma agents, administration of the BCMAxCD3 bispecific antibody may begin in cycle 2 or later, i.e., administration of one or more additional anti-multiple myeloma agents (but not the BCMAxCD3 bispecific antibody) may begin in cycle 1, and administration of the BCMAxCD3 bispecific antibody begins in cycle 2 or later. Thus, according to such embodiments, the first treatment cycle comprising administration of the BCMAxCD3 bispecific antibody is cycle 2 or later.

[0061] As used herein, "Q4W" means once every four weeks (i.e., once every 28 days), "Q2W" (also referred to as "bi-weekly" or "biweekly") means once every two weeks, and "QW" (also referred to as "weekly") means once a week. Q4W is also referred to herein as "monthly." The terms "Q4W" and "monthly" are used interchangeably and refer to once every 4 weeks or once every 28 days (e.g., in a sequential 28-day cycle, the first therapeutic dose occurs on Day 1 of Cycle 1, the second therapeutic dose occurs on Day 1 of Cycle 2, and so on). Administration of a therapeutic dose once a week (QW) is also referred to herein as a weekly dosing schedule; for example, a 28-day treatment cycle may have a weekly dosing schedule comprising four doses one week apart (e.g., on Days 1, 8, 15, and 22), or three doses one week apart (e.g., on Days 8, 15, and 22), or two doses one week apart (e.g., on Days 8 and 15). Administration of a therapeutic dose once every two weeks (Q2W) is also referred to herein as a biweekly dosing schedule. Administration of a therapeutic dose once every four weeks (Q4W) is also referred to herein as a monthly dosing schedule. Dosing regimens may be described herein in terms of dosage amount and frequency; for example, "C1: 1500 μg / kg QW" refers to the administration of 1500 μg / kg once a week in the first cycle of a therapeutically effective regimen, "C3-6: 3000 μg / kg Q2W" refers to the administration of 3000 μg / kg once every two weeks from the third cycle to the sixth cycle, "C3+: 3000 μg / kg Q4W" refers to the administration of 3000 μg / kg once every four weeks starting from the third cycle, and so on.

[0062] Additional abbreviations used herein include the following: CR, complete response; PR, partial response; Q2W, every 2 weeks; Q4W, every 4 weeks; QW, once weekly; RP2D, recommended phase 2 dose; SUD, escalating dose.

[0063] "Human antibody" refers to an antibody that is optimized to have a minimal immune response when administered to a human subject. The variable region of a human antibody is derived from a human immunoglobulin sequence. If a human antibody comprises a constant region or a portion of a constant region, the constant region is also derived from a human immunoglobulin sequence. If the variable region of a human antibody is obtained by using a system of human germline immunoglobulins or rearranged immunoglobulin genes, the human antibody comprises a heavy chain variable region and a light chain variable region "derived from" a sequence of human origin. Such exemplary systems are human immunoglobulin gene libraries displayed on phages, and transgenic non-human animals, such as mice or rats carrying human immunoglobulin loci. Because of the differences between the systems for obtaining human antibodies and human immunoglobulin loci, the introduction of somatic mutations or the intentional introduction of substitutions into the framework or CDR or both, "human antibodies" typically comprise amino acid differences compared to immunoglobulins expressed in humans. Typically, a "human antibody" has an amino acid sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence encoded by a human germline immunoglobulin gene or a rearranged immunoglobulin gene. In some cases, a "human antibody" may comprise a consensus framework sequence derived from human framework sequence analysis (e.g., as described in Knappik et al., (2000) J Mol Biol 296:57-86); or a synthetic HCDR3 bound to a human immunoglobulin gene library displayed on phage (e.g., as described in Shi et al., (2010) J Mol Biol 397:385-96 and International Patent Publication No. WO2009 / 085462). The definition of "human antibody" does not include antibodies in which at least one CDR is derived from a non-human species.

[0064] "Humanized antibody" refers to an antibody in which at least one CDR is derived from a non-human species and at least one framework is derived from a human immunoglobulin sequence. A humanized antibody may comprise substitutions in the framework such that the framework may not be an exact copy of an expressed human immunoglobulin or human immunoglobulin germline gene sequence.

[0065] As used herein, participants met the IMWG diagnostic criteria for multiple myeloma when they were diagnosed. The IMWG diagnostic criteria are known in the art. Multiple myeloma can be defined as ≥10% clonal BMPCs or biopsy-proven bone or extramedullary plasmacytoma. a and at least one of the following:

[0066] Evidence of end-organ damage, specifically:

[0067] -C: Hypercalcemia: Serum calcium above the ULN > 0.25 mmol / L (> 1 mg / dL)

[0068] or >2.75 mmol / L (>11 mg / dL)

[0069] -R: Renal insufficiency: Creatinine clearance <40 mL / min b or serum creatinine >177 μmol / L (>2 mg / dL)

[0070] -A: Anemia: Hemoglobin value is lower than the lower limit of normal by >20g / L or hemoglobin value is <100g / L

[0071] -B: Bone lesions: Skeletal radiography, CT, or PET-CT c,d One or more osteolytic lesions on

[0072] Any one or more of the following malignancy biomarkers:

[0073] - Clonal BMPC% a ≥60%

[0074] - Involved:uninvolved sFLC ratio e ≥100

[0075] ->1 MRI-studied lesion f

[0076] a. Clonality should be established by demonstrating kappa / lambda light chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. The bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in cases of discordance between aspirate and core biopsy, the highest value should be used.

[0077] b. Measured or estimated by validated equations.

[0078] c. If the bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to differentiate from solitary plasmacytoma with minimal bone marrow involvement.

[0079] d.PET-CT = 18F-fluorodeoxyglucose PET and CT.

[0080] e. These values ​​are based on the serum Freelite assay (The Binding Site Group, Birmingham, UK). Involved FLC must be ≥100 mg / Lf. Each lesion must be 5 mm or larger in size.

[0081] "Isolated" refers to a homogenous population of molecules (such as synthetic polynucleotides or proteins, such as antibodies) that have been substantially separated and / or purified from other components of the system (e.g., recombinant cells) in which the molecules are produced, as well as proteins that have been subjected to at least one purification or separation step. "Isolated antibody" refers to an antibody that is substantially free of other cellular material and / or chemicals, and encompasses antibodies isolated to higher purities, such as 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% purity.

[0082] "Monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibody molecules, i.e., the individual antibodies comprising the population are identical except for possible well-known changes (such as removal of the C-terminal lysine from the antibody heavy chain) or post-translational modifications (such as amino acid isomerization or deamidation, methionine oxidation, or asparagine or glutamine deamidation). Monoclonal antibodies generally bind to one antigenic epitope. Bispecific monoclonal antibodies bind to two different antigenic epitopes. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibodies may be monospecific or multispecific, such as bispecific, monovalent, bivalent, or multivalent.

[0083] "Mutation" refers to an engineered or naturally occurring change in a polypeptide or polynucleotide sequence compared to a reference sequence. The change can be a substitution, insertion, or deletion of one or more amino acids or polynucleotides.

[0084] "Non-fixed combination" refers to separate pharmaceutical compositions of the BCMAxCD3 bispecific antibody and the anti-CD38 antibody that are administered simultaneously, concurrently or sequentially as separate entities with no specific temporal constraints, wherein such administration provides effective levels of both compounds in the subject.

[0085] "Multispecific" refers to an antibody that specifically binds to at least two different antigens, or at least two different epitopes within the same antigen. A multispecific antibody can bind, for example, to two, three, four, or five different antigens or different epitopes within the same antigen.

[0086] "Pharmaceutical composition" refers to a composition comprising an active ingredient and a pharmaceutically acceptable carrier.

[0087] A "pharmaceutically acceptable carrier" or "excipient" refers to an ingredient in a pharmaceutical composition, other than the active ingredient, that is non-toxic to the subject.

[0088] "Philadelphia chromosome" or "Ph" refers to the well-known chromosomal translocation between chromosomes 9 and 22, which results in the fusion of the oncogenic BCR-ABL gene with constitutively active tyrosine kinase activity. The translocation results in the fusion of a portion of the BCR gene from chromosome 22q11 with a portion of the ABL gene from chromosome 9q34 and is named t(9;22)(q34;q11) according to the International System for Human Cytogenetics Nomenclature (ISCN). Depending on the exact location of the fusion, the molecular weight of the resulting fusion protein can range from 185 kDa to 210 kDa. "Philadelphia chromosome" refers to all BCR-ABL fusion proteins formed due to the (9;22)(q34;q11) translocation.

[0089] "Recombinant" refers to DNA, antibodies and other proteins that are prepared, expressed, formed or isolated by recombinant means when fragments from different sources are joined to produce the recombinant DNA, antibody or protein.

[0090] "Reduction" or "reduced" refers to a decrease in one or more functions of a test molecule when compared to a control molecule, or a decrease in one or more functions of a combination of test molecules when compared to one or more control molecules. Exemplary functions that can be measured are tumor cell killing, T cell activation, relative or absolute T cell number, Fc-mediated effector function (e.g., ADCC, CDC and / or ADCP), or binding to Fc gamma receptors (FcγRs) or FcRn. "Reduced" can be a decrease of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more, or a statistically significant decrease.

[0091] "rHuPh20" refers to a recombinant human hyaluronidase having the amino acid sequence of SEQ ID NO: 5, which is a recombinant hyaluronidase described in International Patent Publication No. WO2004 / 078140 ( recombinant).

[0092] "Refractory to treatment" refers to a cancer that is not amenable to surgical intervention and does not initially respond to treatment.

[0093] "Recurrent" refers to cancer that responded to treatment but then came back.

[0094] "Ascending dose" refers to the dose of an active agent administered to a subject prior to a therapeutic dose. The escalating dose is lower than the therapeutic dose. To prevent or alleviate certain toxicities, such as cytokine release syndrome (CRS), a "priming" dosing strategy may include one or more lower escalating doses followed by a higher therapeutic dose.

[0095] "Turning-up phase" refers to the initial phase of a therapeutic regimen, in which at least one increasing dose of a therapeutic agent is administered to a subject. A turging phase can also include one or more therapeutic doses, i.e., a turging phase can include one or more increasing doses followed by one or more therapeutic doses; for example, a turging phase can include two increasing doses followed by two therapeutic doses. In specific embodiments, the turging phase is 28 days, i.e., the turging phase is a 28-day cycle of the therapeutic regimen.

[0096] "Subject" includes any human or non-human animal. "Non-human animals" include all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. Unless otherwise indicated, the terms "patient" and "subject" are used interchangeably.

[0097] A "BCMAxCD3 bispecific antibody" refers to a molecule containing two or more binding regions, one of which specifically binds to the cell surface antigen B-cell maturation antigen (BCMA) on target cells or tissues, and a second binding region of the molecule specifically binds to the T-cell antigen CD3. This dual-target / multi-target binding capability recruits T cells to target cells or tissues, thereby eradicating the target cells or tissues.

[0098] A "therapeutically effective amount" refers to an amount effective to achieve the desired therapeutic outcome at the dosage and for the period of time required. A therapeutically effective amount may vary according to factors such as the individual's disease state, age, sex, and weight, as well as the ability of the therapeutic agent or combination of therapeutic agents to elicit the desired response in the individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, improving the patient's health.

[0099] "Treatment" refers to both therapeutic treatment and preventive or defensive measures, wherein the goal is to prevent or slow down (mitigate) an undesirable physiological change or disorder. Beneficial or desired clinical outcomes include alleviation of symptoms, weakening of the extent of the disease, a stable (i.e., non-exacerbated) state of the disease, a delay or slowing of disease progression, an improvement or alleviation of the disease state, and relief (whether partial or complete), whether detectable or undetectable. "Treatment" may also mean extending survival compared to the expected survival of the subject if he or she is not receiving treatment. Individuals in need of treatment include individuals who already have a condition or disorder, as well as individuals who are susceptible to a condition or disorder, or individuals in whom a condition or disorder is to be prevented.

[0100] "Therapeutic dose" refers to the dose of an agent administered to a subject to treat a disease. A therapeutic dose can be administered on a repeated basis at regular dosing intervals (e.g., weekly, biweekly, monthly). A therapeutic dose can be preceded by one or more ascending doses.

[0101] "Tumor cell" or "cancer cell" refers to a cancerous, precancerous or transformed cell in vivo, in vitro or in tissue culture that has spontaneous or induced phenotypic changes. These changes do not necessarily involve the uptake of new genetic material. Although transformation can occur by infection with transforming viruses and the integration of new genomic nucleic acids, uptake of exogenous nucleic acids, or it can also occur spontaneously or after exposure to carcinogens, thereby mutating endogenous genes. Transformation / cancer is exemplified by morphological changes, cell immortality, abnormal growth control, lesion formation, proliferation, malignancy, regulation of tumor-specific marker levels, invasion, tumor growth in vitro, in vivo and in vitro in suitable animal hosts (such as nude mice, etc.).

[0102] Unless otherwise specifically stated, throughout the specification, the numbering of amino acid residues in the antibody constant region is performed according to the EU index as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD. (1991). Antibody constant chain numbering can be found, for example, on the ImMunoGeneTics website, IMGT Web Resources, IMGT Scientific Charts.

[0103] Substitutions in the CH3 region are represented as modified positions in the first CH3 domain of the first heavy chain / modified positions in the second CH3 domain of the second heavy chain. For example, F405L / K409R refers to an F405L mutation in the first CH3 region and a K09R mutation in the second CH3 region. L351Y_F405A_Y407V / T394W refers to L351Y, F405A, and Y407V mutations in the first CH3 region and a T394W mutation in the second CH3 region. D399FHKRQ / K409AGRH refers to a mutation in which D399 can be substituted with F, H, K, R, or Q, and K409 can be substituted with A, G, R, or H.

[0104] The conventional one-letter and three-letter amino acid codes as shown in Table 2 are used herein.

[0105] Table 2. Amino acid abbreviations

[0106] amino acids Three-letter code Single-letter code Alanine Ala A Arginine Arg R Asparagine Asn N Aspartic acid Asp D Cysteine Cys C glutamate Gln E Glutamine Glu Q Glycine Gly G Histidine His H Isoleucine Ile I Leucine Leu L Lysine Lys K Methionine Met M Phenylalanine Phe F Proline Pro P Serine Ser S Threonine Thr T Tryptophan Trp W Tyrosine Tyr Y Valine Val V

[0107] In one general aspect, the present disclosure relates to a method for treating cancer in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of a BCMA x CD3 bispecific antibody, an effective amount of an anti-CD38 antibody, and an effective amount of an immunomodulatory drug (IMiD) for a period of time sufficient to treat the cancer. In some embodiments, the method comprises administering any one of the BCMA x CD3 bispecific antibody, the anti-CD38 antibody, and the IMid, or any combination of the BCMA x CD3 bispecific antibody, the anti-CD38 antibody, and the IMid. In some embodiments, the method comprises administering to the subject an effective amount of a BCMA x CD3 bispecific antibody for a period of time sufficient to treat the cancer. In some embodiments, the method comprises administering to the subject an effective amount of an anti-CD38 antibody for a period of time sufficient to treat the cancer. In some embodiments, the method comprises administering to the subject an effective amount of an IMid for a period of time sufficient to treat the cancer. In some embodiments, the method comprises administering to the subject an effective amount of a BCMA x CD3 bispecific antibody and an effective amount of an anti-CD38 antibody for a period of time sufficient to treat the cancer. In some embodiments, the method comprises administering to the subject an effective amount of a BCMA x CD3 bispecific antibody and an effective amount of an IMiD for a period of time sufficient to treat the cancer. In some embodiments, the method comprises administering to the subject an effective amount of an anti-CD38 antibody and an effective amount of an IMiD for a time sufficient to treat the cancer. In some embodiments, the method comprises administering to the subject an effective amount of a BCMA x CD3 bispecific antibody, an effective amount of an anti-CD38 antibody, and an effective amount of an IMiD for a time sufficient to treat the cancer.

[0108] BCMA x CD3 bispecific antibody

[0109] B-cell maturation antigen (BCMA) is a member of the cell membrane-bound tumor necrosis factor receptor family that is involved in the differentiation of B cells into plasma cells. BCMA expression is restricted to the B-cell lineage, where it is primarily expressed in the interfollicular regions of germinal centers and on differentiated plasma cells and plasmablasts. BCMA is virtually absent on naive and memory B cells. The BCMA x CD3 bispecific antibody targets the CD3 receptor complex on T cells and BCMA on plasma cells. The dual binding sites allow the bispecific antibody to attract CD3+ T cells into close proximity with myeloma cells, regardless of T-cell receptor specificity or dependence on MHC class 1 molecules on the surface of antigen-presenting cells for activation, leading to cell death of BCMA-positive cells.

[0110] Any suitable BCMA x CD3 bispecific antibody can be used in any of the embodiments provided herein. Exemplary multispecific and / or bispecific formats include dual targeting molecules, including but not limited to dual targeting (DT)-Ig (GSK / Domantis), two-in-one antibody (Genetech) and mAb2 (F-Star), dual variable domain (DVD)-Ig (Abbott), Ts2Ab (MedImmune / AZ) and BsAb (Zymogenetics), HERCULES (Biogen Idec) and TvAb (Roche), ScFv / Fc fusion (Academic Institution), SCORPION (Emergent BioSolutions / Trubion, Zymogenetics / BMS) and dual affinity retargeting technology (Fc-DART) (MacroGenics), F(ab)2 (Megarex / AMGEN), bifunctional or Bis-Fab (Genetech), docking lock (DNL) (ImmunoMedics), bivalent bispecific (Biotecnol) and Fab-Fv (UCB-Celltech), bispecific T cell engager (BITE) (Micromet), tandem diabody (Tandab) (Affimend), dual affinity retargeting technology (DART) (MarcroGenics), single-chain diabody (Academic), TCR-like antibody (AIT, ReceptorLogics), human serum albumin ScFv fusion (Merrimack) and COMBODY (Epigen Biotech), dual-targeting nanobody (Ablynx) and dual-targeting heavy chain domain-only antibody. Various formats of bispecific antibodies have been described in, for example, Chames and Baty (2009) Curr Opin Drug Disc Dev 12:276 and Nunez-Prado et al. (2015) Drug Discovery Today 20(5):588-594.

[0111] In some embodiments, the BCMA x CD3 bispecific antibody is an antigen-binding fragment. Exemplary antigen-binding fragments are Fab, F(ab')2, Fd, and Fv fragments.

[0112] In some embodiments, the BCMA x CD3 bispecific antibody is chimeric, humanized, or human.

[0113] In some embodiments, the BCMA x CD3 bispecific antibody comprises: a BCMA binding domain comprising a VH having a HCDR1 of SEQ ID NO: 6, a HCDR2 of SEQ ID NO: 7, a HCDR3 of SEQ ID NO: 8, and a VL having a LCDR1 of SEQ ID NO: 9, a LCDR2 of SEQ ID NO: 10, and a LCDR3 of SEQ ID NO: 11; and a CD3 binding domain comprising a VH having a HCDR1 of SEQ ID NO: 12, a HCDR2 of SEQ ID NO: 13, a HCDR3 of SEQ ID NO: 14, and a VL having a LCDR1 of SEQ ID NO: 15, a LCDR2 of SEQ ID NO: 16, and a LCDR3 of SEQ ID NO: 17. The HCDRs and LCDRs of the BCMA x CD3 bispecific antibody are listed in Table 3 below:

[0114] Table 3: Exemplary CDRs of BCMAxCD3 bispecific antibodies

[0115]

[0116] The CDRs described in the above table belong to the Kabat numbering system. However, as provided herein, the CDRs of the present disclosure can be provided by any suitable numbering system, such as any of the Kabat, Chothia, IMGT or AbM numbering systems. Tables 4 to 6 below provide exemplary CDRs using the Chothia, AbM and IMGT numbering systems:

[0117] Table 4: Exemplary CDR-Chothia numbering system for BCMA x CD3 bispecific antibodies

[0118]

[0119]

[0120] Table 5: Exemplary CDR-AbM numbering system for BCMA x CD3 bispecific antibodies

[0121]

[0122] Table 6: Exemplary CDR-IMGT numbering system for BCMA x CD3 bispecific antibodies

[0123]

[0124] In some embodiments, the BCMA x CD3 bispecific antibody comprises a BCMA binding domain comprising a VH having a HCDR1 of SEQ ID NO:46, a HCDR2 of SEQ ID NO:47, a HCDR3 of SEQ ID NO:8, and a VL having a LCDR1 of SEQ ID NO:9, a LCDR2 of SEQ ID NO:10, and a LCDR3 of SEQ ID NO:11; and a CD3 binding domain comprising a VH having a HCDR1 of SEQ ID NO:48, a HCDR2 of SEQ ID NO:49, a HCDR3 of SEQ ID NO:14, and a VL having a LCDR1 of SEQ ID NO:15, a LCDR2 of SEQ ID NO:16, and a LCDR3 of SEQ ID NO:17.

[0125] In some embodiments, the BCMA x CD3 bispecific antibody comprises a BCMA binding domain comprising a VH having a HCDR1 of SEQ ID NO: 50, a HCDR2 of SEQ ID NO: 51, a HCDR3 of SEQ ID NO: 8, and a VL having a LCDR1 of SEQ ID NO: 9, a LCDR2 of SEQ ID NO: 10, and a LCDR3 of SEQ ID NO: 11; and a CD3 binding domain comprising a VH having a HCDR1 of SEQ ID NO: 52, a HCDR2 of SEQ ID NO: 53, a HCDR3 of SEQ ID NO: 14, and a VL having a LCDR1 of SEQ ID NO: 15, a LCDR2 of SEQ ID NO: 16, and a LCDR3 of SEQ ID NO: 17.

[0126] In some embodiments, the BCMA x CD3 bispecific antibody comprises: a BCMA binding domain comprising a VH having a HCDR1 of SEQ ID NO: 54, a HCDR2 of SEQ ID NO: 55, and a HCDR3 of SEQ ID NO: 56, and a VL having a LCDR1 of SEQ ID NO: 57, a LCDR2 having an amino acid sequence of DD, and a LCDR3 of SEQ ID NO: 11; and a CD3 binding domain comprising a VH having a HCDR1 of SEQ ID NO: 58, a HCDR2 of SEQ ID NO: 59, and a HCDR3 of SEQ ID NO: 60, and a VL having a LCDR1 of SEQ ID NO: 61, a LCDR2 having an amino acid sequence of GT, and a LCDR3 of SEQ ID NO: 17.

[0127] In some embodiments, the BCMA x CD3 bispecific antibody comprises: a BCMA binding domain comprising the VH of SEQ ID NO: 18 and the VL of SEQ ID NO: 19; and a CD3 binding domain comprising the VH of SEQ ID NO: 20 and the VL of SEQ ID NO: 21.

[0128] In some embodiments, the BCMA x CD3 bispecific antibody that binds BCMA comprises a first heavy chain (HC1) of SEQ ID NO: 22, a first light chain (LC1) of SEQ ID NO: 23, a second heavy chain (HC2) of SEQ ID NO: 24, and a second light chain (LC2) of SEQ ID NO: 25.

[0129] In some embodiments, the BCMA-binding arm of the BCMA x CD3 bispecific antibody and the CD3-binding arm of the BCMA x CD3 bispecific antibody comprise the amino acid sequences provided in Table 7a and Table 7b.

[0130] Table 7a: Sequences of the BCMA-binding arms of BCMA x CD3 bispecific antibodies .

[0131]

[0132] Table 7b: Sequences of the CD3 binding arms of BCMA x CD3 bispecific antibodies .

[0133]

[0134]

[0135] In some embodiments, the BCMA x CD3 bispecific antibody comprises a BCMA binding domain that binds to BCMA, the BCMA binding domain selected from the group consisting of BCMA binding domains of: Seattle Genetics' ACTR cancer therapy, AFM-26, ALLO-715, CRISPR Therapeutics' anti-BCMA allogeneic CAR-T cell therapy, Sorrento Therapeutics' anti-BCMA CAR-T therapy, Hrain Biotechnology's anti-CD19 / BCMACAR-T cell therapy, Chineo Med (Beijing)'s BCMACAR-T therapy, Triumvira Immunologics' BCMA TAC-T cell therapy, Shanghai Unicar-Therapy Biomed's BCMA-CAR T cell therapy, Regeneron's BCMA / CD3 antibody, NantKwest's CAR-NK cell therapy, CC-93629, CMD-505, CTX-4419, CYAD-211, HDP-101, HPN-217, P-BCMA-ALLO1, TNB-383B, bb-2121, AUTO-2, Pregene's BCMA chimeric antigen receptor therapy, Shanghai Bioray Laboratory's BCMA-CAR T cells, CARsgen Therapeutics' BCMA-CAR-T cells, Shenzhen BinDeBio's CAR-T / TCR-T cell immunotherapy, ET-140, P-BCMA-101, REGN-5458, AMG-701, Cellular Biomedicine Group's anti-BCMACAR-T cell therapy, bb-21217, BI-836909, CC-93269, Descartes-08, IM-21, JNJ-64007957, MEDI-2228, or PF-06863135.

[0136] In some embodiments, the BCMA x CD3 bispecific antibody can be, but is not limited to, elranatamab (also known as PF-06863135), teneobio (also known as TNB-383B), REGN5458, REGN5459, pavurutamab (also known as AMG-701), BI 836909, CC-93269, WVT078, or terituzumab (also known as JNJ-957 or JNJ-64007957). In some embodiments, the BCMA x CD3 bispecific antibody is elranatamab. In some embodiments, the BCMA x CD3 bispecific antibody is teneobio. In some embodiments, the BCMA x CD3 bispecific antibody is REGN5458. In some embodiments, the BCMA x CD3 bispecific antibody is REGN5459. In some embodiments, the BCMA x CD3 bispecific antibody is pavurutamab. In some embodiments, the BCMA x CD3 bispecific antibody is BI 836909. In some embodiments, the BCMA x CD3 bispecific antibody is CC-93269. In some embodiments, the BCMA x CD3 bispecific antibody is WVT078. In some embodiments, the BCMA x CD3 bispecific antibody is terituzumab.

[0137] In some embodiments, Terituzumab comprises a first heavy chain (HC1), a first light chain (LC1), a second heavy chain (HC2), and a second light chain (LC2), wherein HC1 associates with LC1 and HC2 associates with LC2, wherein HC1 and LC1 form a first antigen-binding site that immunospecifically binds to BCMA, and wherein HC2 and LC2 form a second antigen-binding site that immunospecifically binds to CD3. In some embodiments, Terituzumab comprises HC1 of SEQ ID NO: 22, LC1 of SEQ ID NO: 23, HC2 of SEQ ID NO: 24, and LC2 of SEQ ID NO: 25. In some embodiments, the BCMA arm and CD3 arm of Terituzumab form a functional bispecific antibody through the interaction of their respective Fc domains.

[0138] In some embodiments, the BCMA x CD3 bispecific antibody comprises any of the BCMA binding domains described in International Patent Publication No. WO2017 / 031104.

[0139] In some embodiments, the BCMA x CD3 bispecific antibody is of IgG1, IgG2, IgG3, or IgG4 isotype.

[0140] In some embodiments, the BCMA x CD3 bispecific antibody is of the IgG1 isotype.

[0141] In some embodiments, the BCMA x CD3 bispecific antibody is of the IgG2 isotype.

[0142] In some embodiments, the BCMA x CD3 bispecific antibody is of the IgG3 isotype.

[0143] In some embodiments, the BCMA x CD3 bispecific antibody is of the IgG4 isotype.

[0144] BCMA x CD3 bispecific antibodies can have any allotype. It is expected that the allotype has no effect on the properties of the BCMA x CD3 bispecific antibody, such as binding or Fc-mediated effector function. The immunogenicity of therapeutic antibodies is associated with an increased risk of infusion reactions and a reduced duration of therapeutic response (Baert et al., (2003) N Engl J Med 348:602-08). The extent to which a therapeutic antibody induces an immune response in the host can be determined in part by the antibody's allotype (Stickler et al., (2011) Genes and Immunity 12:213-21). Antibody allotypes are associated with amino acid sequence variations at specific positions in the constant region sequence of the antibody. Table 8 shows selected IgG1, IgG2, and IgG4 allotypes.

[0145] Table 8: IgG1, IgG2 and IgG4 allotypes.

[0146]

[0147] In some embodiments, the multispecific antibody comprises one or more Fc substitutions that reduce binding of the multispecific antibody to Fcγ receptors (FcγRs). Substitutions that reduce binding of the multispecific antibody to FcγRs reduce Fc effector functions such as ADCC, ADCP, and / or CDC of the multispecific antibody. Specific substitutions can be made compared to wild-type IgG1 of SEQ ID NO: 26 or wild-type IgG4 of SEQ ID NO: 27.

[0148] In some embodiments, the one or more Fc substitutions are selected from the group consisting of: F234A / L235A on IgG4, L234A / L235A on IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, K214T / E233P / L234V / L235A / G236 deletion / A327G / on IgG1. P331A / D365E / L358M on IgG2, H268Q / V309L / A330S / P331S on IgG2, S267E / L328F on IgG1, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236 deletion / G237A / P238S on IgG4, where residues are numbered according to the EU index.

[0149] In some embodiments, the one or more Fc substitutions are F234A / L235A on IgG4.

[0150] In some embodiments, the one or more Fc substitutions are L234A / L235A on IgG1.

[0151] In some embodiments, the one or more Fc substitutions are V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2.

[0152] In some embodiments, the one or more Fc substitutions are F234A / L235A on IgG4.

[0153] In some embodiments, the one or more Fc substitutions are S228P / F234A / L235A on IgG4.

[0154] In some embodiments, the one or more Fc substitutions is N297A on all Ig isotypes.

[0155] In some embodiments, the one or more Fc substitutions are V234A / G237A on IgG2.

[0156] In some embodiments, the one or more Fc substitutions are K214T / E233P / L234V / L235A / G236 deletion / A327G / P331A / D365E / L358M on IgG1.

[0157] In some embodiments, the one or more Fc substitutions are H268Q / V309L / A330S / P331S on IgG2.

[0158] In some embodiments, the one or more Fc substitutions are S267E / L328F on IgG1. In some embodiments, the one or more Fc substitutions are L234F / L235E / D265A on IgG1.

[0159] In some embodiments, the one or more Fc substitutions are L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1.

[0160] In some embodiments, the one or more Fc substitutions are S228P / F234A / L235A / G237A / P238S on IgG4 and S228P / F234A / L235A / G236 deletion / G237A / P238S on IgG4.

[0161] In some embodiments, the bispecific antibody further comprises an S228P substitution.

[0162] In some embodiments, the bispecific antibody comprises one or more asymmetric substitutions in the first CH3 domain or in the second CH3 domain, or in both the first CH3 domain and the second CH3 domain.

[0163] In some embodiments, the one or more asymmetric substitutions are selected from the group consisting of: F450L / K409R, wild type / F409L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V. V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F , L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F and T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0164] In some embodiments, one or more asymmetric substitutions are F450L / K409R. In some embodiments, one or more asymmetric substitutions are wild type / F409L_R409K. In some embodiments, one or more asymmetric substitutions are T366Y / F405A. In some embodiments, one or more asymmetric substitutions are T366W / F405W. In some embodiments, one or more asymmetric substitutions are F405W / Y407A. In some embodiments, one or more asymmetric substitutions are T394W / Y407T. In some embodiments, one or more asymmetric substitutions are T394S / Y407A. In some embodiments, one or more asymmetric substitutions are T366W / T394S. In some embodiments, one or more asymmetric substitutions are F405W / T394S. In some embodiments, one or more asymmetric substitutions are T366W / T366S_L368A_Y407V. In some embodiments, one or more asymmetric substitutions are L351Y_F405A_Y407V / T394W. In some embodiments, one or more asymmetric substitutions are T366I_K392M_T394W / F405A_Y407V. In some embodiments, one or more asymmetric substitutions are T366L_K392M_T394W / F405A_Y407V. In some embodiments, one or more asymmetric substitutions are L351Y_Y407A / T366A_K409F. In some embodiments, one or more asymmetric substitutions are L351Y_Y407A / T366V_K409F. In some embodiments, one or more asymmetric substitutions are Y407A / T366A_K409F. In some embodiments, the one or more asymmetric substitutions are T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0165] In some embodiments, the BCMA x CD3 bispecific antibody is of the IgG4 isotype and comprises a phenylalanine at position 405 and an arginine at position 409 in the first heavy chain (HC1), and a leucine at position 405 and a lysine at position 409 in the second heavy chain (HC2), where residue numbering is according to the EU index.

[0166] In some embodiments, the BCMA x CD3 bispecific antibody further comprises a proline at position 228, an alanine at position 234, and an alanine at position 235 in both HC1 and HC2.

[0167] This application describes various methods utilizing a BCMA x CD3 bispecific antibody. This can be any BCMA x CD3 bispecific antibody as provided herein, but it is understood that the antibody in any of the methods provided herein can be terituzumab.

[0168] anti-CD3 antibodies

[0169] CD38 is a multifunctional protein, whose function is manifested as receptor-mediated adhesion and signal transduction, and mediating calcium mobilization via its extracellular enzyme activity, catalyzing the formation of cyclic ADP ribose (cADPR) and ADPR. CD38 mediates the secretion of cytokines and the activation and proliferation of lymphocytes (Funaro et al., J Immunol 145:2390-6, 1990; Terhorst et al., Cell 771-80, 1981; Guse et al., Nature 398:70-3, 1999). CD38 also regulates extracellular NAD+ levels via its NAD glycohydrolase activity, which is involved in regulating regulatory T cell compartments (Adriouch et al., Microbes infect 14:1284-92, 2012; Chiarugi et al., Nature Reviews 12:741-52, 2012). In addition to signaling via Ca2+, CD38 signaling also occurs through interactions with antigen-receptor complexes or other types of receptor complexes on T and B cells, such as major histocompatibility complex (MHC) molecules, thereby participating not only in several cellular responses but also in the conversion and secretion of IgG1.

[0170] Any suitable anti-CD38 antibody can be used in the methods of the present application.

[0171] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:28, HCDR2 of SEQ ID NO:29, HCDR3 of SEQ ID NO:30, LCDR1 of SEQ ID NO:31, LCDR2 of SEQ ID NO:32, and LCDR3 of SEQ ID NO:33.

[0172] The CDRs listed above belong to the Kabat numbering system. However, as provided herein, the CDRs of the present disclosure can be provided by any suitable numbering system, such as any of the Kabat, Chothia, IMGT or AbM numbering systems. Table 9 below provides exemplary CDRs using the Kabat, Chothia, AbM and IMGT numbering systems:

[0173] Table 9: Exemplary CDRs of anti-CD38 antibodies .

[0174]

[0175] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:28, HCDR2 of SEQ ID NO:29, HCDR3 of SEQ ID NO:30, LCDR1 of SEQ ID NO:31, LCDR2 of SEQ ID NO:32, and LCDR3 of SEQ ID NO:33.

[0176] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:62, HCDR2 of SEQ ID NO:63, HCDR3 of SEQ ID NO:30, LCDR1 of SEQ ID NO:31, LCDR2 of SEQ ID NO:32, and LCDR3 of SEQ ID NO:33.

[0177] In some embodiments, the anti-CD38 antibody comprises a HCDR1 of SEQ ID NO:64, a HCDR2 of SEQ ID NO:65, a HCDR3 of SEQ ID NO:30, a LCDR1 of SEQ ID NO:31, a LCDR2 of SEQ ID NO:32, and a LCDR3 of SEQ ID NO:33.

[0178] In some embodiments, the anti-CD38 antibody comprises a HCDR1 of SEQ ID NO:66, a HCDR2 of SEQ ID NO:67, a HCDR3 of SEQ ID NO:68, a LCDR1 of SEQ ID NO:69, a LCDR2 comprising the amino acid sequence of DA, and a LCDR3 of SEQ ID NO:33.

[0179] In some embodiments, the anti-CD38 antibody comprises the VH of SEQ ID NO:34 and the VL of SEQ ID NO:35.

[0180] In some embodiments, the anti-CD38 antibody comprises the HC of SEQ ID NO:36 and the LC of SEQ ID NO:37.

[0181] Other anti-CD38 antibodies used in the methods of the present invention can be known antibodies, such as mAb003, described in U.S. Patent No. 7,829,673. The VH and VL of mAb003 can be expressed as IgG1 / κ; mAb024, described in U.S. Patent No. 7,829,673. The VH and VL of mAb024 can be expressed as IgG1 / κ; MOR-202 (MOR-03087), including those described in U.S. Patent No. 8,088,896. The VH and VL of MOR-202 can be expressed as IgG1 / κ; or isatuximab, described in U.S. Patent No. 8,153,765. The VH and VL of isatuximab can be expressed as IgG1 / κ. In some embodiments, the anti-CD38 antibody comprises a) a VH of SEQ ID NO: 38 and a VL of SEQ ID NO: 39; b) a VH of SEQ ID NO: 40 and a VL of SEQ ID NO: 41; c) a VH of SEQ ID NO: 42 and a VL of SEQ ID NO: 43; or d) a VH of SEQ ID NO: 44 and a VL of SEQ ID NO: 45.

[0182] In some embodiments, the anti-CD38 antibody is (daratumumab).

[0183] In some embodiments, daratumumab comprises the VH of SEQ ID NO:34 and the VL of SEQ ID NO:35.

[0184] In some embodiments, daratumumab comprises the HC of SEQ ID NO: 36 and the LC of SEQ ID NO: 37.

[0185] In some embodiments, the anti-CD38 antibody is chimeric, humanized, or human.

[0186] In some embodiments, the anti-CD38 antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0187] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0188] In some embodiments, the anti-CD38 antibody is an antigen-binding fragment. Exemplary antigen-binding fragments are Fab, F(ab')2, Fd, and Fv fragments.

[0189] This application describes various methods utilizing anti-CD38 antibodies. This can be any anti-CD38 antibody as provided herein, but it should be understood that the antibody in any of the methods provided herein can be daratumumab.

[0190] Immunomodulatory drugs (IMiDs)

[0191] Immunomodulatory drugs are known in the art, and any suitable immunomodulatory drug can be used in any embodiment provided herein. In some embodiments, the immunomodulatory drug is an immunomodulatory imide drug, such as but not limited to thalidomide, lenalidomide, pomalidomide, iberdomide and apremilast. In some embodiments, the immunomodulatory drug is thalidomide. In some embodiments, the immunomodulatory drug is lenalidomide. In some embodiments, the immunomodulatory drug is pomalidomide. In some embodiments, the immunomodulatory drug is iberdomide. In some embodiments, the immunomodulatory drug is apremilast.

[0192] This application describes various methods utilizing an IMiD, which can be any IMiD as provided herein, but it should be understood that the IMiD in any method provided herein can be lenalidomide.

[0193] BCMA x CD3 bispecific antibody administration

[0194] In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody is any amount administered for a sufficient time to treat cancer. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody is from about 60 μg / kg to about 6000 μg / kg, or any value or range therebetween, administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody is 60 μg / kg, administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody is 240 μg / kg, administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody is 300 μg / kg, administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 355 μg / kg administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 475 μg / kg administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 635 μg / kg administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 720 μg / kg administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 845 μg / kg administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 1125 μg / kg administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 1500 μg / kg administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 1685 μg / kg administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 2250 μg / kg administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 3000 μg / kg administered once daily, weekly, every two weeks, every three weeks, or every four weeks.In some embodiments, the therapeutically effective amount of the BCMAxCD3 bispecific antibody is 6000 μg / kg administered once daily, once weekly, every two weeks, every three weeks, or once every four weeks.

[0195] In some embodiments, the therapeutically effective amount of the BCMA x CD3 bispecific antibody is from about 3 mg to about 600 mg, or any value or range therebetween, administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 3 mg, administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 4 mg, administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 15 mg, administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 25 mg, administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 100 mg, administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the BCMAxCD3 bispecific antibody is 150 mg administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the BCMAxCD3 bispecific antibody is 200 mg administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the BCMAxCD3 bispecific antibody is 300 mg administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the BCMAxCD3 bispecific antibody is 450 mg administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the BCMAxCD3 bispecific antibody is any value including or between the values ​​provided herein.

[0196] In some embodiments, the therapeutically effective amount of the BCMAxCD3 bispecific antibody is determined based on the subject's weight. In some embodiments, the therapeutically effective amount of the BCMAxCD3 bispecific antibody is determined based on a predetermined weight threshold, wherein if the subject is at or below the predetermined weight threshold, the subject is in Tier 1 and a therapeutically effective amount of the BCMAxCD3 bispecific antibody is administered, and wherein if the subject is above the predetermined weight threshold, the subject is in Tier 2 and a therapeutically effective amount of the BCMAxCD3 bispecific antibody is administered, wherein the therapeutically effective amount of the BCMAxCD3 bispecific antibody for those subjects in Tier 1 and the therapeutically effective amount of the BCMAxCD3 bispecific antibody for those subjects in Tier 2 may be the same or different. In some embodiments, the therapeutically effective amount of the BCMAxCD3 bispecific antibody for those subjects in Tier 1 is the same as the effective amount of the BCMAxCD3 bispecific antibody for those subjects in Tier 2. In some embodiments, the effective amount of the BCMAxCD3 bispecific antibody for those subjects in Tier 1 is different from the effective amount of the BCMAxCD3 bispecific antibody for those subjects in Tier 2. In some embodiments, the predetermined weight threshold for determining an effective amount of the BCMA x CD3 bispecific antibody is any threshold value. In some embodiments, the predetermined weight threshold is 50 kg, 55 kg, 60 kg, 65 kg, 70 kg, greater than 70 kg, or any value therebetween.

[0197] In some embodiments, the predetermined weight threshold is 50 kg, wherein those subjects ≤ 50 kg are in Tier 1 and are administered a therapeutically effective amount of a BCMA x CD3 bispecific antibody, and those subjects > 50 kg are in Tier 2 and are administered a therapeutically effective amount of a BCMA x CD3 bispecific antibody, wherein the therapeutically effective amount of the BCMA x CD3 bispecific antibody for those subjects in Tier 1 and the therapeutically effective amount of the BCMA x CD3 bispecific antibody for those subjects in Tier 2 may be the same or different. In some embodiments, the predetermined weight threshold is 55 kg, wherein those subjects ≤ 55 kg are in Tier 1 and are administered a therapeutically effective amount of a BCMA x CD3 bispecific antibody, and those subjects > 55 kg are in Tier 2 and are administered a therapeutically effective amount of a BCMA x CD3 bispecific antibody, wherein the therapeutically effective amount of the BCMA x CD3 bispecific antibody for those subjects in Tier 1 and the therapeutically effective amount of the BCMA x CD3 bispecific antibody for those subjects in Tier 2 may be the same or different. In some embodiments, the predetermined weight threshold is 60 kg, wherein those subjects ≤ 60 kg are in Tier 1 and are administered a therapeutically effective amount of a BCMAxCD3 bispecific antibody, and those subjects > 60 kg are in Tier 2 and are administered a therapeutically effective amount of a BCMAxCD3 bispecific antibody, wherein the therapeutically effective amount of the BCMAxCD3 bispecific antibody for those subjects in Tier 1 and the therapeutically effective amount of the BCMAxCD3 bispecific antibody for those subjects in Tier 2 may be the same or different. In some embodiments, the predetermined weight threshold is 65 kg, wherein those subjects ≤ 65 kg are in Tier 1 and are administered a therapeutically effective amount of a BCMAxCD3 bispecific antibody, and those subjects > 65 kg are in Tier 2 and are administered a therapeutically effective amount of a BCMAxCD3 bispecific antibody, wherein the therapeutically effective amount of the BCMAxCD3 bispecific antibody for those subjects in Tier 1 and the therapeutically effective amount of the BCMAxCD3 bispecific antibody for those subjects in Tier 2 may be the same or different. In some embodiments, the predetermined weight threshold is 70 kg, wherein those subjects ≤ 70 kg are in Tier 1 and are administered a therapeutically effective amount of a BCMA x CD3 bispecific antibody, and those subjects > 70 kg are in Tier 2 and are administered a therapeutically effective amount of a BCMA x CD3 bispecific antibody, wherein the therapeutically effective amount of the BCMA x CD3 bispecific antibody for those subjects in Tier 1 and the therapeutically effective amount of the BCMA x CD3 bispecific antibody for those subjects in Tier 2 may be the same or different.

[0198] In some embodiments, the subject is in level 1 and the therapeutically effective amount of the BCMA x CD3 bispecific antibody is from about 3 mg to about 600 mg, or any value or range therebetween, administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 1 and the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 3 mg, or 4 mg, administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 1 and the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 15 mg, or 24 mg, administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 1 and the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 25 mg administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 1 and the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 100 mg administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 1 and the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 150 mg administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 1 and the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 200 mg administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 1 and the therapeutically effective amount of the BCMA x CD3 bispecific antibody is 300 mg administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in Tier 1 and the therapeutically effective amount of the BCMAxCD3 bispecific antibody is 450 mg administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in Tier 1 and the therapeutically effective amount of the BCMAxCD3 bispecific antibody is any value inclusive of or between the values ​​provided herein.

[0199] In some embodiments, the subject is in level 2 and the therapeutically effective amount of the BCMA x CD3 bispecific antibody is from about 3 mg to about 600 mg, or any value or range therebetween, administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 2 and the effective amount of the BCMA x CD3 bispecific antibody is 3 mg, administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 2 and the effective amount of the BCMA x CD3 bispecific antibody is 4 mg, administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 2 and the effective amount of the BCMA x CD3 bispecific antibody is 15 mg, administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 2 and the effective amount of the BCMA x CD3 bispecific antibody is 24 mg, administered once daily, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 2 and the effective amount of the BCMA x CD3 bispecific antibody is 25 mg administered once daily, weekly, every two weeks, every three weeks, or once every four weeks. In some embodiments, the subject is in level 2 and the effective amount of the BCMA x CD3 bispecific antibody is 100 mg administered once daily, weekly, every two weeks, every three weeks, or once every four weeks. In some embodiments, the subject is in level 2 and the effective amount of the BCMA x CD3 bispecific antibody is 150 mg administered once daily, weekly, every two weeks, every three weeks, or once every four weeks. In some embodiments, the subject is in level 2 and the effective amount of the BCMA x CD3 bispecific antibody is 200 mg administered once daily, weekly, every two weeks, every three weeks, or once every four weeks. In some embodiments, the subject is in level 2 and the effective amount of the BCMA x CD3 bispecific antibody is 300 mg administered once daily, weekly, every two weeks, every three weeks, or once every four weeks. In some embodiments, the subject is in Grade 2 and the effective amount of the BCMA x CD3 bispecific antibody is 450 mg administered once daily, once weekly, every two weeks, every three weeks, or once every four weeks. In some embodiments, the subject is in Grade 2 and the effective amount of the BCMA x CD3 bispecific antibody is any value inclusive of or between the values ​​provided herein.

[0200] In some embodiments, the BCMA x CD3 bispecific antibody is any BCMA x CD3 bispecific antibody as provided herein. In some embodiments, the BCMA x CD3 bispecific antibody is terituzumab. In some embodiments, terituzumab comprises an amino acid sequence as provided herein. In some embodiments, a therapeutically effective amount of terituzumab is any amount administered for a sufficient time to treat cancer. In some embodiments, a therapeutically effective amount of terituzumab is about 60 μg / kg to about 6000 μg / kg or any value or range therebetween, administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, a therapeutically effective amount of terituzumab is 60 μg / kg administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, a therapeutically effective amount of terituzumab is 240 μg / kg administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 300 μg / kg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 355 μg / kg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 475 μg / kg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 635 μg / kg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 720 μg / kg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 845 μg / kg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 1125 μg / kg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 1500 μg / kg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 1685 μg / kg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 2250 μg / kg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 3000 μg / kg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 6000 μg / kg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks.

[0201] In some embodiments, the therapeutically effective amount of terituzumab is about 3 mg to about 600 mg, or any value or range therebetween, administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 3 mg, administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 4 mg, administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 15 mg, administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 25 mg, administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 100 mg, administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 150 mg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 200 mg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 300 mg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is 450 mg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the therapeutically effective amount of terituzumab is any value including or between the values ​​provided herein.

[0202] In some embodiments, the therapeutically effective amount of terituzumab is determined based on the subject's weight. In some embodiments, the therapeutically effective amount of terituzumab is determined based on a predetermined weight threshold, wherein if the subject is equal to or below the predetermined weight threshold, the subject is in level 1 and a therapeutically effective amount of terituzumab is administered, and wherein if the subject is above the predetermined weight threshold, the subject is in level 2 and a therapeutically effective amount of terituzumab is administered, wherein the therapeutically effective amount of terituzumab for those subjects in level 1 and the therapeutically effective amount of terituzumab for those subjects in level 2 may be the same or different. In some embodiments, the therapeutically effective amount of terituzumab for those subjects in level 1 is the same as the effective amount of terituzumab for those subjects in level 2. In some embodiments, the effective amount of terituzumab for those subjects in level 1 is different from the effective amount of terituzumab for those subjects in level 2. In some embodiments, the predetermined weight threshold for determining the effective amount of terituzumab is any threshold. In some embodiments, the predetermined weight threshold is 50 kg, 55 kg, 60 kg, 65 kg, 70 kg, greater than 70 kg, or any value therebetween.

[0203] In some embodiments, the predetermined weight threshold is 50 kg, wherein those subjects ≤ 50 kg are in Tier 1 and are administered a therapeutically effective amount of Terituzumab, and those subjects > 50 kg are in Tier 2 and are administered a therapeutically effective amount of Terituzumab, wherein the therapeutically effective amount of Terituzumab for those subjects in Tier 1 and the therapeutically effective amount of Terituzumab for those subjects in Tier 2 may be the same or different. In some embodiments, the predetermined weight threshold is 55 kg, wherein those subjects ≤ 55 kg are in Tier 1 and are administered a therapeutically effective amount of Terituzumab, and those subjects > 55 kg are in Tier 2 and are administered a therapeutically effective amount of Terituzumab, wherein the therapeutically effective amount of Terituzumab for those subjects in Tier 1 and the therapeutically effective amount of Terituzumab for those subjects in Tier 2 may be the same or different. In some embodiments, the predetermined weight threshold is 60 kg, wherein those subjects ≤ 60 kg are in Tier 1 and are administered a therapeutically effective amount of Terituzumab, and those subjects > 60 kg are in Tier 2 and are administered a therapeutically effective amount of Terituzumab, wherein the therapeutically effective amount of Terituzumab for those subjects in Tier 1 and the therapeutically effective amount of Terituzumab for those subjects in Tier 2 may be the same or different. In some embodiments, the predetermined weight threshold is 65 kg, wherein those subjects ≤ 65 kg are in Tier 1 and are administered a therapeutically effective amount of Terituzumab, and those subjects > 65 kg are in Tier 2 and are administered a therapeutically effective amount of Terituzumab, wherein the therapeutically effective amount of Terituzumab for those subjects in Tier 1 and the therapeutically effective amount of Terituzumab for those subjects in Tier 2 may be the same or different. In some embodiments, the predetermined weight threshold is 70 kg, wherein those subjects ≤ 70 kg are in Grade 1 and are administered a therapeutically effective amount of terituzumab, and those subjects > 70 kg are in Grade 2 and are administered a therapeutically effective amount of terituzumab, wherein the therapeutically effective amount of terituzumab for those subjects in Grade 1 and the therapeutically effective amount of terituzumab for those subjects in Grade 2 may be the same or different.

[0204] In some embodiments, the subject is in level 1 and the therapeutically effective amount of terituzumab is about 3 mg to about 600 mg, or any value or range therebetween, administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 1 and the therapeutically effective amount of terituzumab is 3 mg, administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 1 and the therapeutically effective amount of terituzumab is 4 mg, administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 1 and the therapeutically effective amount of terituzumab is 15 mg, administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 1 and the therapeutically effective amount of terituzumab is 25 mg, administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 1 and the therapeutically effective amount of terituzumab is 100 mg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the subject is in level 1 and the therapeutically effective amount of terituzumab is 150 mg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the subject is in level 1 and the therapeutically effective amount of terituzumab is 200 mg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the subject is in level 1 and the therapeutically effective amount of terituzumab is 300 mg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the subject is in level 1 and the therapeutically effective amount of terituzumab is 450 mg administered once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the subject is in level 1 and the therapeutically effective amount of terituzumab is any value including or between the values ​​provided herein.

[0205] In some embodiments, the subject is in level 2 and the therapeutically effective amount of terituzumab is about 3 mg to about 600 mg, or any value or range therebetween, administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 2 and the effective amount of terituzumab is 3 mg, administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 2 and the effective amount of terituzumab is 4 mg, administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 2 and the effective amount of terituzumab is 15 mg, administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 2 and the effective amount of terituzumab is 24 mg, administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 2 and the effective amount of terituzumab is 25 mg, administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the subject is in level 2 and the effective amount of terituzumab is 100 mg once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the subject is in level 2 and the effective amount of terituzumab is 150 mg once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the subject is in level 2 and the effective amount of terituzumab is 200 mg once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the subject is in level 2 and the effective amount of terituzumab is 300 mg once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the subject is in level 2 and the effective amount of terituzumab is 450 mg once a day, once a week, every two weeks, every three weeks, or once every four weeks. In some embodiments, the subject is in level 2 and the effective amount of terituzumab is any value including the values ​​provided herein or between the values ​​provided herein.

[0206] This application describes various methods utilizing a BCMA x CD3 bispecific antibody. This can be any BCMA x CD3 bispecific antibody as provided herein, but it is understood that the antibody in any method can be terituzumab.

[0207] CD38 antibody administration

[0208] In some embodiments, the therapeutically effective amount of an anti-CD38 antibody is any amount administered for a sufficient time to treat the cancer. In some embodiments, the therapeutically effective amount of an anti-CD38 antibody is from about 1200 mg to about 2400 mg, or any value or range therebetween, administered once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of an anti-CD38 antibody is 1200 mg, administered once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of an anti-CD38 antibody is 1300 mg, administered once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of an anti-CD38 antibody is 1400 mg, administered once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of an anti-CD38 antibody is 1500 mg, administered once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of an anti-CD38 antibody is 1600 mg, administered once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the anti-CD38 antibody is 1700 mg administered once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the anti-CD38 antibody is 1800 mg administered once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the anti-CD38 antibody is 1900 mg administered once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the anti-CD38 antibody is 2000 mg administered once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the anti-CD38 antibody is 2100 mg administered once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the anti-CD38 antibody is 2200 mg administered once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the anti-CD38 antibody is 2300 mg administered once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of the anti-CD38 antibody is 2400 mg administered once a week, every two weeks, every three weeks, or once every four weeks.

[0209] In some embodiments, the anti-CD38 antibody is FDA-approved for clinical use. In some embodiments, the therapeutically effective amount of the anti-CD38 antibody is based on standard doses used in clinical practice for treating cancer. In some embodiments, the therapeutically effective amount of the anti-CD38 antibody is 1800 mg administered once a week, every two weeks, every three weeks, or once every four weeks.

[0210] In some embodiments, the anti-CD38 antibody can be any anti-CD38 antibody as provided herein. In some embodiments, the anti-CD38 antibody is daratumumab. In some embodiments, daratumumab comprises an amino acid sequence as provided herein. In some embodiments, the therapeutically effective amount of daratumumab is any amount administered for a sufficient time to treat the cancer. In some embodiments, the therapeutically effective amount of daratumumab is administered weekly, every two weeks, every three weeks, or every four weeks from about 1200 mg to about 2400 mg or any value or range therebetween. In some embodiments, the therapeutically effective amount of daratumumab is administered weekly, every two weeks, every three weeks, or every four weeks 1200 mg. In some embodiments, the therapeutically effective amount of daratumumab is administered weekly, every two weeks, every three weeks, or every four weeks 1300 mg. In some embodiments, the therapeutically effective amount of daratumumab is administered weekly, every two weeks, every three weeks, or every four weeks 1400 mg. In some embodiments, the therapeutically effective amount of daratumumab is 1500 mg administered once weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of daratumumab is 1600 mg administered once weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of daratumumab is 1700 mg administered once weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of daratumumab is 1800 mg administered once weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of daratumumab is 1900 mg administered once weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of daratumumab is 2000 mg administered once weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of daratumumab is 2100 mg administered once weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of daratumumab is 2200 mg administered once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of daratumumab is 2300 mg administered once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of daratumumab is 2400 mg administered once a week, every two weeks, every three weeks, or every four weeks.

[0211] In some embodiments, the therapeutically effective amount of daratumumab is based on standard doses used in clinical practice for treating cancer. In some embodiments, the therapeutically effective amount of daratumumab is 1800 mg administered once a week, every two weeks, every three weeks, or once every four weeks.

[0212] This application describes various methods utilizing an anti-CD38 antibody. This can be any anti-CD38 antibody as provided herein, but it should be understood that the antibody in any method can be daratumumab.

[0213] IMiD Dosage

[0214] In some embodiments, the therapeutically effective amount of an IMiD is any amount administered for a sufficient time to treat the cancer. In some embodiments, the effective amount of an IMiD is about 15 mg to about 50 mg, or any value or range therebetween, administered once a day, once a week, every two weeks, every three weeks, or every four weeks. In some embodiments, the therapeutically effective amount of an IMiD is 25 mg administered daily. In some embodiments, an IMiD is FDA-approved for clinical use. In some embodiments, the therapeutically effective amount of an IMiD is based on a standard dose used in clinical practice for treating cancer. In some embodiments, the therapeutically effective amount of an IMiD is 25 mg.

[0215] In some embodiments, the IMiD is an IMiD as provided herein. In some embodiments, the IMiD is lenalidomide. In some embodiments, the therapeutically effective amount of lenalidomide is any amount administered for a time sufficient to treat the cancer. In some embodiments, the effective amount of lenalidomide is administered once a day, once a week, every two weeks, every three weeks, or every four weeks, from about 15 mg to about 50 mg, or any value or range therebetween. In some embodiments, the therapeutically effective amount of lenalidomide is administered 25 mg daily. In some embodiments, the therapeutically effective amount of lenalidomide is based on the standard dose used in clinical practice for the treatment of cancer. In some embodiments, the therapeutically effective amount of lenalidomide is 25 mg.

[0216] Route of administration

[0217] The BCMA x CD3 bispecific antibodies, anti-CD38 antibodies, and IMiDs of the methods disclosed herein can be administered to a subject via any appropriate method of administration. Exemplary methods of administration include, but are not limited to, transarterial, subcutaneous, intradermal, intratumoral, intranodal, intramedullary, intramuscular, intravenous, intraperitoneal, intranasal, or intraosseous. In some embodiments, the BCMA x CD3 bispecific antibodies are administered intravenously or subcutaneously. In some embodiments, the BCMA x CD3 bispecific antibodies are administered intravenously (iv). In some embodiments, the BCMA x CD3 bispecific antibodies are administered subcutaneously (sc). In some embodiments, the anti-CD38 bispecific antibodies are administered intravenously or subcutaneously. In some embodiments, the anti-CD38 bispecific antibodies are administered intravenously (iv). In some embodiments, the anti-CD38 bispecific antibodies are administered subcutaneously (sc). In some embodiments, the IMiD bispecific antibodies are administered intravenously or orally. In some embodiments, the IMiD bispecific antibodies are administered intravenously (iv). In some embodiments, the IMiD bispecific antibodies are administered orally.

[0218] In some embodiments, the method comprises administering to the subject intravenously a therapeutically effective amount of a BCMA x CD3 bispecific antibody, intravenously administering a therapeutically effective amount of an anti-CD38 antibody, and intravenously administering a therapeutically effective amount of an immunomodulatory drug (IMiD) for a time sufficient to treat the cancer. In some embodiments, the method comprises administering to the subject subcutaneously a therapeutically effective amount of a BCMA x CD3 bispecific antibody, intravenously administering a therapeutically effective amount of an anti-CD38 antibody, and intravenously administering a therapeutically effective amount of an immunomodulatory drug (IMiD) for a time sufficient to treat the cancer. In some embodiments, the method comprises administering to the subject subcutaneously a therapeutically effective amount of a BCMA x CD3 bispecific antibody, intravenously administering a therapeutically effective amount of an anti-CD38 antibody, and orally administering a therapeutically effective amount of an immunomodulatory drug (IMiD) for a time sufficient to treat the cancer. In some embodiments, the method comprises administering to the subject intravenously a therapeutically effective amount of a BCMA x CD3 bispecific antibody, subcutaneously administering a therapeutically effective amount of an anti-CD38 antibody, and intravenously administering a therapeutically effective amount of an immunomodulatory drug (IMiD) for a time sufficient to treat the cancer. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a BCMA x CD3 bispecific antibody intravenously, administering a therapeutically effective amount of an anti-CD38 antibody subcutaneously, and orally administering a therapeutically effective amount of an immunomodulatory drug (IMiD) for a time sufficient to treat the cancer. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a BCMA x CD3 bispecific antibody subcutaneously, administering a therapeutically effective amount of an anti-CD38 antibody subcutaneously, and administering a therapeutically effective amount of an immunomodulatory drug (IMiD) intravenously for a time sufficient to treat the cancer. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a BCMA x CD3 bispecific antibody subcutaneously, administering a therapeutically effective amount of an anti-CD38 antibody subcutaneously, and orally administering a therapeutically effective amount of an immunomodulatory drug (IMiD) (orally) for a time sufficient to treat the cancer.

[0219] Dose timing

[0220] The components of the methods provided herein can be provided in any dose or frequency required to effectively treat cancer. In some embodiments, therapeutically effective amounts of the components of the methods provided herein can be provided in any frequency required to effectively treat cancer.

[0221] In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody is administered daily. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody is administered weekly. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody is administered every two weeks. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody is administered once every three weeks. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody is administered once every four weeks. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody is administered monthly. The frequency of administration of a therapeutically effective amount of a BCMA x CD3 bispecific antibody can be varied as needed to effectively treat cancer. For example, a therapeutically effective amount of a BCMA x CD3 bispecific antibody can be administered daily, weekly, every two weeks, every three weeks, every four weeks, monthly, or at any frequency in between any of the recited frequencies for a certain period of time, after which the therapeutically effective amount of a BCMA x CD3 bispecific antibody can be administered daily, weekly, every two weeks, every three weeks, every four weeks, monthly, or at any frequency in between any of the recited frequencies for a next period of time.

[0222] In some embodiments, a therapeutically effective amount of an anti-CD38 antibody is administered daily. In some embodiments, a therapeutically effective amount of an anti-CD38 antibody is administered weekly. In some embodiments, a therapeutically effective amount of an anti-CD38 antibody is administered every two weeks. In some embodiments, a therapeutically effective amount of an anti-CD38 antibody is administered once every three weeks. In some embodiments, a therapeutically effective amount of an anti-CD38 antibody is administered once every four weeks. In some embodiments, a therapeutically effective amount of an anti-CD38 antibody is administered once monthly. The frequency of administration of a therapeutically effective amount of an anti-CD38 antibody can be varied as needed to effectively treat cancer. For example, a therapeutically effective amount of an anti-CD38 antibody can be administered daily, weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or at any frequency between any of the frequencies described within a certain time period, after which time, a therapeutically effective amount of an anti-CD38 antibody can be administered daily, weekly, once every two weeks, once every three weeks, once every four weeks, monthly, or at any frequency between any of the frequencies described within the next time period.

[0223] In some embodiments, a therapeutically effective amount of an IMiD is administered daily. In some embodiments, a therapeutically effective amount of an IMiD is administered weekly. In some embodiments, a therapeutically effective amount of an IMiD is administered every two weeks. In some embodiments, a therapeutically effective amount of an IMiD is administered once every three weeks. In some embodiments, a therapeutically effective amount of an IMiD is administered once every four weeks. In some embodiments, a therapeutically effective amount of an IMiD is administered once monthly. The frequency of administration of a therapeutically effective amount of an IMiD can be varied as needed to effectively treat cancer. For example, a therapeutically effective amount of an IMiD can be administered daily, weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or at any frequency between any of the frequencies described within a certain time period, and after that time, a therapeutically effective amount of an IMiD can be administered daily, weekly, once every two weeks, once every three weeks, once every four weeks, monthly, or at any frequency between any of the frequencies described within the next time period.

[0224] In some embodiments, the therapeutically effective amount and frequency of the components of the method remain constant in the cyclic time period or cycle. In some embodiments, the duration of the treatment cycle can be any time period. In some embodiments, the treatment cycle can be sustainable 7, 8, 9, 10, 11, 12, 13, 14, 21, 28, 56, 112, 224, 365, more than 365 days or any number of days therebetween. In some embodiments, the treatment cycle lasts 28 days. It should be understood that the duration of the treatment cycle does not mean that the duration of treatment is limited in any way. Treatment can be any number of treatment cycles required for the sustainable treatment of cancer. In some embodiments, the components of the method provided herein can be applied to experimenter 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more than 20 treatment cycles, or the components of the method provided herein are applied to experimenter until cancer is treated. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody, an anti-CD38 antibody, and an IMiD is administered to a subject for one treatment cycle. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody, an anti-CD38 antibody, and an IMiD is administered to a subject for two treatment cycles. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody, an anti-CD38 antibody, and an IMiD is administered to a subject for three treatment cycles. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody, an anti-CD38 antibody, and an IMiD is administered to a subject for four treatment cycles. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody, an anti-CD38 antibody, and an IMiD is administered to a subject for five treatment cycles. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody, an anti-CD38 antibody, and an IMiD is administered to a subject for six treatment cycles. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody, an anti-CD38 antibody, and an IMiD is administered to a subject for seven treatment cycles. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody, an anti-CD38 antibody, and an IMiD is administered to a subject for more than seven treatment cycles. Furthermore, it should be understood that, as provided herein, the therapeutically effective amount or frequency of the components of the methods provided herein can be altered at the end of each treatment cycle. Thus, in some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody, an anti-CD38 antibody, and an IMiD is administered to a subject for one treatment cycle.In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody, an anti-CD38 antibody, and an IMiD is administered to a subject for two treatment cycles, wherein the therapeutically effective amount or frequency of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD may or may not be changed between each treatment cycle. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody, an anti-CD38 antibody, and an IMiD is administered to a subject for three treatment cycles, wherein the therapeutically effective amount or frequency of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD may or may not be changed between each treatment cycle. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody, an anti-CD38 antibody, and an IMiD is administered to a subject for four treatment cycles, wherein the therapeutically effective amount or frequency of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD may or may not be changed between each treatment cycle. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody, an anti-CD38 antibody, and an IMiD is administered to a subject for five treatment cycles, wherein the therapeutically effective amount or frequency of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD may or may not be changed between each treatment cycle. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody, an anti-CD38 antibody, and an IMiD is administered to a subject for six treatment cycles, wherein the therapeutically effective amount or frequency of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD may or may not be changed between each treatment cycle. In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody, an anti-CD38 antibody, and an IMiD is administered to a subject for seven treatment cycles, wherein the therapeutically effective amount or frequency of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD may or may not be changed between each treatment cycle. In some embodiments, therapeutically effective amounts of a BCMAxCD3 bispecific antibody, an anti-CD38 antibody, and an IMiD are administered to the subject for more than seven treatment cycles, wherein the therapeutically effective amount or frequency of the BCMAxCD3 bispecific antibody, anti-CD38 antibody, and IMiD can or can not be changed between each treatment cycle.

[0225] In some embodiments, a therapeutically effective amount of a BCMA x CD3 bispecific antibody is administered weekly for the first and second treatment cycles, every two weeks for the third, fourth, fifth, and sixth treatment cycles, and every four weeks for the seventh and subsequent treatment cycles. In some embodiments, a therapeutically effective amount of an anti-CD38 antibody is administered weekly for the first and second treatment cycles, every two weeks for the third, fourth, fifth, and sixth treatment cycles, and every four weeks for the seventh and subsequent treatment cycles. In some embodiments, a therapeutically effective amount of an IMiD is administered daily on days 1-21 of a 28-day treatment cycle. In some embodiments, a therapeutically effective amount of an IMiD is not administered in treatment cycle one. In some embodiments, a therapeutically effective amount of an IMiD is administered starting in treatment cycle two.

[0226] The duration of treatment in this method can be any amount of time required to treat the cancer. In some embodiments, the subject is treated with therapeutically effective amounts of BCMA x CD3 bispecific antibodies, anti-CD38 antibodies, and IMiDs for 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 104, 156, 208, 260, or more weeks, or any number of weeks therebetween. In some embodiments, the subject is treated with therapeutically effective amounts of BCMA x CD3 bispecific antibodies, anti-CD38 antibodies, and IMiDs for more than 260 weeks. In some embodiments, the subject is treated with therapeutically effective amounts of BCMA x CD3 bispecific antibodies, anti-CD38 antibodies, and IMiDs for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 36, 48, 60, or more months, or any number of months therebetween. In some embodiments, the subject is treated with therapeutically effective amounts of a BCMA x CD3 bispecific antibody, an anti-CD38 antibody, and an IMiD for more than 60 months. In some embodiments, the subject is treated with therapeutically effective amounts of a BCMA x CD3 bispecific antibody, an anti-CD38 antibody, and an IMiD for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more years, or any number of years therebetween. In some embodiments, the subject is treated with therapeutically effective amounts of a BCMA x CD3 bispecific antibody, an anti-CD38 antibody, and an IMiD for more than 10 years.

[0227] Loading and therapeutic dose

[0228] In some embodiments, the components of the methods provided herein may be provided as a loading dose, a therapeutic dose, or a combination thereof. In some embodiments, the components of the methods provided herein are provided in a therapeutic dose. In some embodiments, the components of the methods provided herein are provided in a loading dose followed by a therapeutic dose. In some embodiments, the loading dose comprises one or more ascending doses provided over a period of time. In some embodiments, one ascending dose is provided. In some embodiments, two ascending doses are provided. In some embodiments, three ascending doses are provided. In some embodiments, more than three ascending doses are provided. In some embodiments, any number of ascending doses may be provided as needed to provide the subject with an effective amount of the components required to treat the cancer.

[0229] In some embodiments, the BCMA x CD3 bispecific antibody may be administered as a loading dose followed by a therapeutic dose. In some embodiments, the loading dose comprises one or more ascending doses as provided herein. In some embodiments, the BCMA x CD3 bispecific antibody is administered as one ascending dose followed by a therapeutic dose. In some embodiments, the BCMA x CD3 bispecific antibody is administered as two ascending doses followed by a therapeutic dose. In some embodiments, the BCMA x CD3 bispecific antibody is administered as three ascending doses followed by a therapeutic dose. In some embodiments, the BCMA x CD3 bispecific antibody is administered as more than three ascending doses followed by a therapeutic dose.

[0230] In some embodiments, the first ascending dose of the BCMA x CD3 bispecific antibody is about 60 μg / kg to about 6000 μg / kg, or any value or range therebetween. In some embodiments, the first ascending dose of the BCMA x CD3 bispecific antibody is 60 μg / kg. In some embodiments, the first ascending dose of the BCMA x CD3 bispecific antibody is 240 μg / kg. In some embodiments, the first ascending dose of the BCMA x CD3 bispecific antibody is 300 μg / kg.

[0231] In some embodiments, the first ascending dose of the BCMA x CD3 bispecific antibody is about 3 mg to about 600 mg, or any value or range therebetween. In some embodiments, the first ascending dose of the BCMA x CD3 bispecific antibody is 3 mg. In some embodiments, the first ascending dose of the BCMA x CD3 bispecific antibody is 4 mg. In some embodiments, the first ascending dose of the BCMA x CD3 bispecific antibody is 15 mg. In some embodiments, the first ascending dose of the BCMA x CD3 bispecific antibody is 24 mg. In some embodiments, the first ascending dose of the BCMA x CD3 bispecific antibody is 25 mg.

[0232] In some embodiments, the first ascending dose of the BCMAxCD3 bispecific antibody is determined based on the subject's weight. In some embodiments, the first ascending dose of the BCMAxCD3 bispecific antibody is determined based on a predetermined weight threshold, wherein if the subject is at or below the predetermined weight threshold, the subject is in Tier 1 and the first ascending dose of the BCMAxCD3 bispecific antibody is administered, and wherein if the subject is above the predetermined weight threshold, the subject is in Tier 2 and the first ascending dose of the BCMAxCD3 bispecific antibody is administered, wherein the first ascending dose of the BCMAxCD3 bispecific antibody for those subjects in Tier 1 and the first ascending dose of the BCMAxCD3 bispecific antibody for those subjects in Tier 2 may be the same or different. In some embodiments, the first ascending dose of the BCMAxCD3 bispecific antibody for those subjects in Tier 1 is the same as the first ascending dose of the BCMAxCD3 bispecific antibody for those subjects in Tier 2. In some embodiments, the first ascending dose of the BCMAxCD3 bispecific antibody for those subjects in tier 1 is different than the first ascending dose of the BCMAxCD3 bispecific antibody for those subjects in tier 2. In some embodiments, the predetermined weight threshold used to determine the first ascending dose of the BCMAxCD3 bispecific antibody is as provided herein.

[0233] In some embodiments, the subject is in Tier 1 and the first ascending dose of the BCMA x CD3 bispecific antibody is from about 3 mg to about 600 mg, or any value or range therebetween. In some embodiments, the subject is in Tier 1 and the first ascending dose of the BCMA x CD3 bispecific antibody is 3 mg. In some embodiments, the subject is in Tier 1 and the first ascending dose of the BCMA x CD3 bispecific antibody is 4 mg. In some embodiments, the subject is in Tier 1 and the first ascending dose of the BCMA x CD3 bispecific antibody is 15 mg. In some embodiments, the subject is in Tier 1 and the first ascending dose of the BCMA x CD3 bispecific antibody is 24 mg. In some embodiments, the subject is in Tier 1 and the first ascending dose of the BCMA x CD3 bispecific antibody is 25 mg.

[0234] In some embodiments, the subject is in tier 2 and the first escalating dose of the BCMA x CD3 bispecific antibody is about 3 mg to about 600 mg, or any value or range therebetween. In some embodiments, the subject is in tier 2 and the first escalating dose of the BCMA x CD3 bispecific antibody is 3 mg. In some embodiments, the subject is in tier 2 and the first escalating dose of the BCMA x CD3 bispecific antibody is 4 mg. In some embodiments, the subject is in tier 2 and the first escalating dose of the BCMA x CD3 bispecific antibody is 15 mg. In some embodiments, the subject is in tier 2 and the first escalating dose of the BCMA x CD3 bispecific antibody is 24 mg. In some embodiments, the subject is in tier 2 and the first escalating dose of the BCMA x CD3 bispecific antibody is 25 mg.

[0235] In some embodiments, the second increasing dose of the BCMA x CD3 bispecific antibody is about 60 μg / kg to about 6000 μg / kg, or any value or range therebetween. In some embodiments, the second increasing dose of the BCMA x CD3 bispecific antibody is 60 μg / kg. In some embodiments, the second increasing dose of the BCMA x CD3 bispecific antibody is 240 μg / kg. In some embodiments, the second increasing dose of the BCMA x CD3 bispecific antibody is 300 μg / kg.

[0236] In some embodiments, the second ascending dose of the BCMA x CD3 bispecific antibody is about 3 mg to about 600 mg, or any value or range therebetween. In some embodiments, the second ascending dose of the BCMA x CD3 bispecific antibody is 3 mg. In some embodiments, the second ascending dose of the BCMA x CD3 bispecific antibody is 4 mg. In some embodiments, the second ascending dose of the BCMA x CD3 bispecific antibody is 15 mg. In some embodiments, the subject is in level 2 and the first ascending dose of the BCMA x CD3 bispecific antibody is 24 mg. In some embodiments, the second ascending dose of the BCMA x CD3 bispecific antibody is 25 mg.

[0237] In some embodiments, the second ascending dose of the BCMAxCD3 bispecific antibody is determined based on the subject's weight. In some embodiments, the second ascending dose of the BCMAxCD3 bispecific antibody is determined based on a predetermined weight threshold, wherein if the subject is at or below the predetermined weight threshold, the subject is in Tier 1 and the second ascending dose of the BCMAxCD3 bispecific antibody is administered, and wherein if the subject is above the predetermined weight threshold, the subject is in Tier 2 and the second ascending dose of the BCMAxCD3 bispecific antibody is administered, wherein the second ascending dose of the BCMAxCD3 bispecific antibody for those subjects in Tier 1 and the second ascending dose of the BCMAxCD3 bispecific antibody for those subjects in Tier 2 may be the same or different. In some embodiments, the second ascending dose of the BCMAxCD3 bispecific antibody for those subjects in Tier 1 is the same as the second ascending dose of the BCMAxCD3 bispecific antibody for those subjects in Tier 2. In some embodiments, the second ascending dose of the BCMAxCD3 bispecific antibody for those subjects in tier 1 is different than the second ascending dose of the BCMAxCD3 bispecific antibody for those subjects in tier 2. In some embodiments, the predetermined weight threshold used to determine the second ascending dose of the BCMAxCD3 bispecific antibody is as provided herein.

[0238] In some embodiments, the subject is in Tier 1 and the second escalating dose of the BCMA x CD3 bispecific antibody is from about 3 mg to about 600 mg, or any value or range therebetween. In some embodiments, the subject is in Tier 1 and the second escalating dose of the BCMA x CD3 bispecific antibody is 3 mg. In some embodiments, the subject is in Tier 1 and the second escalating dose of the BCMA x CD3 bispecific antibody is 4 mg. In some embodiments, the subject is in Tier 1 and the second escalating dose of the BCMA x CD3 bispecific antibody is 15 mg. In some embodiments, the subject is in Tier 1 and the second escalating dose of the BCMA x CD3 bispecific antibody is 24 mg. In some embodiments, the subject is in Tier 1 and the second escalating dose of the BCMA x CD3 bispecific antibody is 25 mg.

[0239] In some embodiments, the subject is in Tier 2 and the second escalating dose of the BCMA x CD3 bispecific antibody is from about 3 mg to about 600 mg, or any value or range therebetween. In some embodiments, the subject is in Tier 2 and the second escalating dose of the BCMA x CD3 bispecific antibody is 3 mg. In some embodiments, the subject is in Tier 2 and the second escalating dose of the BCMA x CD3 bispecific antibody is 4 mg. In some embodiments, the subject is in Tier 2 and the second escalating dose of the BCMA x CD3 bispecific antibody is 15 mg. In some embodiments, the subject is in Tier 2 and the second escalating dose of the BCMA x CD3 bispecific antibody is 24 mg. In some embodiments, the subject is in Tier 2 and the second escalating dose of the BCMA x CD3 bispecific antibody is 25 mg.

[0240] In some embodiments, the third or greater ascending dose of the BCMA x CD3 bispecific antibody is about 60 μg / kg to about 6000 μg / kg, or any value or range therebetween. In some embodiments, the third or greater ascending dose of the BCMA x CD3 bispecific antibody is 60 μg / kg. In some embodiments, the third or greater ascending dose of the BCMA x CD3 bispecific antibody is 240 μg / kg. In some embodiments, the third or greater ascending dose of the BCMA x CD3 bispecific antibody is 300 μg / kg.

[0241] In some embodiments, the third or greater ascending dose of the BCMA x CD3 bispecific antibody is about 3 mg to about 600 mg, or any value or range therebetween. In some embodiments, the third or greater ascending dose of the BCMA x CD3 bispecific antibody is 3 mg. In some embodiments, the third or greater ascending dose of the BCMA x CD3 bispecific antibody is 4 mg. In some embodiments, the third or greater ascending dose of the BCMA x CD3 bispecific antibody is 15 mg. In some embodiments, the third or greater ascending dose of the BCMA x CD3 bispecific antibody is 24 mg. In some embodiments, the third or greater ascending dose of the BCMA x CD3 bispecific antibody is 25 mg.

[0242] In some embodiments, the third or greater ascending dose of the BCMAxCD3 bispecific antibody is determined based on the subject's weight. In some embodiments, the third or greater ascending dose of the BCMAxCD3 bispecific antibody is determined based on a predetermined weight threshold, wherein if the subject is at or below the predetermined weight threshold, the subject is in Tier 1 and the third or greater ascending dose of the BCMAxCD3 bispecific antibody is administered, and wherein if the subject is above the predetermined weight threshold, the subject is in Tier 2 and the third or greater ascending dose of the BCMAxCD3 bispecific antibody is administered, wherein the third or greater ascending dose of the BCMAxCD3 bispecific antibody for those subjects in Tier 1 and the third or greater ascending dose of the BCMAxCD3 bispecific antibody for those subjects in Tier 2 may be the same or different. In some embodiments, the third or greater ascending dose of the BCMAxCD3 bispecific antibody for those subjects in Tier 1 is the same as the third or greater ascending dose of the BCMAxCD3 bispecific antibody for those subjects in Tier 2. In some embodiments, the third or greater ascending dose of the BCMAxCD3 bispecific antibody for those subjects in Tier 1 is different than the third or greater ascending dose of the BCMAxCD3 bispecific antibody for those subjects in Tier 2. In some embodiments, the predetermined weight threshold for determining the third or greater ascending dose of the BCMAxCD3 bispecific antibody is as provided herein.

[0243] In some embodiments, the subject is in Tier 1 and the third or greater escalating dose of the BCMA x CD3 bispecific antibody is about 3 mg to about 600 mg, or any value or range therebetween. In some embodiments, the subject is in Tier 1 and the third or greater escalating dose of the BCMA x CD3 bispecific antibody is 3 mg. In some embodiments, the subject is in Tier 1 and the third or greater escalating dose of the BCMA x CD3 bispecific antibody is 4 mg. In some embodiments, the subject is in Tier 1 and the third or greater escalating dose of the BCMA x CD3 bispecific antibody is 15 mg. In some embodiments, the subject is in Tier 1 and the third or greater escalating dose of the BCMA x CD3 bispecific antibody is 24 mg. In some embodiments, the subject is in Tier 1 and the third or greater escalating dose of the BCMA x CD3 bispecific antibody is 25 mg.

[0244] In some embodiments, the subject is in Tier 2 and the third or greater escalating dose of the BCMA x CD3 bispecific antibody is about 3 mg to about 600 mg, or any value or range therebetween. In some embodiments, the subject is in Tier 2 and the third or greater escalating dose of the BCMA x CD3 bispecific antibody is 3 mg. In some embodiments, the subject is in Tier 2 and the third or greater escalating dose of the BCMA x CD3 bispecific antibody is 4 mg. In some embodiments, the subject is in Tier 2 and the third or greater escalating dose of the BCMA x CD3 bispecific antibody is 15 mg. In some embodiments, the subject is in Tier 2 and the third or greater escalating dose of the BCMA x CD3 bispecific antibody is 24 mg. In some embodiments, the subject is in Tier 2 and the third or greater escalating dose of the BCMA x CD3 bispecific antibody is 25 mg.

[0245] In some embodiments, the escalating doses of the BCMA x CD3 bispecific antibody may be designated as escalating dose A and include doses of about 60 μg / kg to about 150 μg / kg, or any value or range therebetween. In some embodiments, the escalating dose A of the BCMA x CD3 bispecific antibody is 60 μg / kg. In some embodiments, the escalating dose A of the BCMA x CD3 bispecific antibody is 70 μg / kg. In some embodiments, the escalating dose A of the BCMA x CD3 bispecific antibody is 80 μg / kg. In some embodiments, the escalating dose A of the BCMA x CD3 bispecific antibody is 90 μg / kg. In some embodiments, the escalating dose A of the BCMA x CD3 bispecific antibody is 100 μg / kg. In some embodiments, the escalating dose A of the BCMA x CD3 bispecific antibody is 125 μg / kg. In some embodiments, the escalating dose A of the BCMA x CD3 bispecific antibody is 150 μg / kg.

[0246] In some embodiments, the escalating dose of the BCMA x CD3 bispecific antibody may be designated as escalating dose B and include doses of about 150 μg / kg to about 250 μg / kg, or any value or range therebetween. In some embodiments, the escalating dose B of the BCMA x CD3 bispecific antibody is 150 μg / kg. In some embodiments, the escalating dose B of the BCMA x CD3 bispecific antibody is 160 μg / kg. In some embodiments, the escalating dose B of the BCMA x CD3 bispecific antibody is 170 μg / kg. In some embodiments, the escalating dose B of the BCMA x CD3 bispecific antibody is 180 μg / kg. In some embodiments, the escalating dose B of the BCMA x CD3 bispecific antibody is 190 μg / kg. In some embodiments, the escalating dose B of the BCMA x CD3 bispecific antibody is 200 μg / kg. In some embodiments, the escalating dose B of the BCMA x CD3 bispecific antibody is 210 μg / kg. In some embodiments, the escalating dose B of the BCMA x CD3 bispecific antibody is 220 μg / kg. In some embodiments, the escalating dose B of the BCMA x CD3 bispecific antibody is 230 μg / kg. In some embodiments, the escalating dose B of the BCMA x CD3 bispecific antibody is 240 μg / kg. In some embodiments, the escalating dose B of the BCMA x CD3 bispecific antibody is 250 μg / kg.

[0247] In some embodiments, the escalating dose of the BCMA x CD3 bispecific antibody may be designated as an escalating dose C and include doses of about 5 μg / kg to about 60 μg / kg, or any value or range therebetween. In some embodiments, the escalating dose C of the BCMA x CD3 bispecific antibody is 5 μg / kg. In some embodiments, the escalating dose C of the BCMA x CD3 bispecific antibody is 10 μg / kg. In some embodiments, the escalating dose C of the BCMA x CD3 bispecific antibody is 15 μg / kg. In some embodiments, the escalating dose C of the BCMA x CD3 bispecific antibody is 20 μg / kg. In some embodiments, the escalating dose C of the BCMA x CD3 bispecific antibody is 25 μg / kg. In some embodiments, the escalating dose C of the BCMA x CD3 bispecific antibody is 30 μg / kg.

[0248] In some embodiments, the escalating dose C of the BCMA x CD3 bispecific antibody is 40 μg / kg.

[0249] In some embodiments, the escalating dose C of the BCMA x CD3 bispecific antibody is 50 μg / kg.

[0250] In some embodiments, the escalating dose C of the BCMA x CD3 bispecific antibody is 60 μg / kg.

[0251] In some embodiments, the escalating dose of the BCMA x CD3 bispecific antibody may be designated as an escalating dose D and include doses of about 250 μg / kg to about 600 μg / kg, or any value or range therebetween. In some embodiments, the escalating dose D of the BCMA x CD3 bispecific antibody is 250 μg / kg. In some embodiments, the escalating dose D of the BCMA x CD3 bispecific antibody is 300 μg / kg. In some embodiments, the escalating dose D of the BCMA x CD3 bispecific antibody is 350 μg / kg. In some embodiments, the escalating dose D of the BCMA x CD3 bispecific antibody is 400 μg / kg. In some embodiments, the escalating dose D of the BCMA x CD3 bispecific antibody is 450 μg / kg. In some embodiments, the escalating dose D of the BCMA x CD3 bispecific antibody is 500 μg / kg. In some embodiments, the escalating dose D of the BCMA x CD3 bispecific antibody is 550 μg / kg. In some embodiments, the escalating dose D of the BCMA x CD3 bispecific antibody is 600 μg / kg.

[0252] In some embodiments, the loading dose of the BCMA x CD3 bispecific antibody of the methods provided herein may include one or more of any dose or range selected from ascending doses A, B, C, D, or any combination thereof. In some embodiments, the loading dose of the BCMA x CD3 bispecific antibody may include one or more ascending doses as provided in Table 10 below:

[0253] Table 10

[0254]

[0255]

[0256]

[0257] In some embodiments, the escalating dose of the BCMA x CD3 bispecific antibody can be designated as an escalating dose E and include doses of about 3 mg to about 12 mg, or any value or range therebetween. In some embodiments, the escalating dose E of the BCMA x CD3 bispecific antibody is 3 mg. In some embodiments, the escalating dose E of the BCMA x CD3 bispecific antibody is 4 mg.

[0258] In some embodiments, the escalating dose of the BCMA x CD3 bispecific antibody can be designated as escalating dose F and include doses of about 12 mg to about 20 mg, or any value or range therebetween. In some embodiments, the escalating dose F of the BCMA x CD3 bispecific antibody is 12 mg. In some embodiments, the escalating dose F of the BCMA x CD3 bispecific antibody is 15 mg. In some embodiments, the escalating dose F of the BCMA x CD3 bispecific antibody is 20 mg.

[0259] In some embodiments, the escalating dose of the BCMA x CD3 bispecific antibody can be designated as an escalating dose G and include doses of about 20 mg to about 30 mg, or any value or range therebetween. In some embodiments, the escalating dose G of the BCMA x CD3 bispecific antibody is 20 mg. In some embodiments, the escalating dose G of the BCMA x CD3 bispecific antibody is 24 mg. In some embodiments, the escalating dose G of the BCMA x CD3 bispecific antibody is 25 mg. In some embodiments, the escalating dose G of the BCMA x CD3 bispecific antibody is 30 mg.

[0260] In some embodiments, the escalating dose of the BCMA x CD3 bispecific antibody can be designated as an escalating dose H and include doses of about 30 mg to about 50 mg, or any value or range therebetween. In some embodiments, the escalating dose H of the BCMA x CD3 bispecific antibody is 30 mg. In some embodiments, the escalating dose H of the BCMA x CD3 bispecific antibody is 40 mg. In some embodiments, the escalating dose H of the BCMA x CD3 bispecific antibody is 50 mg.

[0261] In some embodiments, the loading dose of the BCMA x CD3 bispecific antibody of the methods provided herein may include one or more of any dose or range selected from ascending doses E, F, G, or H, or any combination thereof. In some embodiments, the loading dose of the BCMA x CD3 bispecific antibody may include one or more ascending doses as provided in Table 11 below:

[0262] Table 11

[0263]

[0264]

[0265] It should be understood that in embodiments where the BCMA x CD3 bispecific antibody is administered in more than one ascending dose, the current ascending dose and the subsequent ascending dose may comprise the same or different doses and may comprise the same or different frequencies. In some embodiments, the current ascending dose and the subsequent ascending dose comprise the same dose and the same frequency. In some embodiments, the current ascending dose and the subsequent ascending dose comprise the same dose and different frequencies. In some embodiments, the current ascending dose and the subsequent ascending dose comprise different doses and the same frequency. In some embodiments, the current ascending dose and the subsequent ascending dose comprise different doses and different frequencies.

[0266] In some embodiments, a loading dose of the BCMA x CD3 bispecific antibody is administered at a frequency as provided herein. In some embodiments, a loading dose of the BCMA x CD3 bispecific antibody is administered daily. In some embodiments, a loading dose of the BCMA x CD3 bispecific antibody is administered every other day. In some embodiments, a loading dose of the BCMA x CD3 bispecific antibody is administered weekly.

[0267] In some embodiments, the loading dose of the BCMA x CD3 bispecific antibody may include one or more ascending doses. Thus, in some embodiments, one or more ascending doses of the BCMA x CD3 bispecific antibody are administered at a frequency as provided herein. In some embodiments, one or more ascending doses of the BCMA x CD3 bispecific antibody are administered daily. In some embodiments, one or more ascending doses of the BCMA x CD3 bispecific antibody are administered every other day. In some embodiments, one or more ascending doses of the BCMA x CD3 bispecific antibody are administered weekly.

[0268] In some embodiments, the loading dose comprises one or more ascending doses, wherein the one or more ascending doses are administered at doses and combinations as outlined in Table 10. In some embodiments, one or more ascending doses selected from the ascending doses A, B, C, or D as provided herein are administered daily. In some embodiments, one or more ascending doses selected from the ascending doses A, B, C, or D as provided herein are administered every other day. In some embodiments, one or more ascending doses selected from the ascending doses A, B, C, or D as provided herein are administered weekly. When administered in combination, each ascending dose A, B, C, or D may be administered at any frequency as provided herein prior to administration of the second ascending dose, which may be administered at any frequency as provided herein. Thus, in some embodiments, a first ascending dose selected from A, B, C, or D as provided herein is administered at a frequency selected from daily, every other day, or weekly for a first time period, followed by administration of a second ascending dose selected from A, B, C, or D as provided herein for a second time period at a frequency selected from daily, every other day, or weekly, wherein the second ascending dose does not belong to the same group A, B, C, or D as the first ascending dose, and wherein the first and second time periods may be the same or different. In embodiments comprising a third ascending dose, a third ascending dose selected from A, B, C, or D as provided herein is administered at a frequency selected from daily, every other day, or weekly for a third time period, wherein the first, second, and third ascending doses do not belong to the same group A, B, C, or D, and wherein the first, second, and third time periods may be the same or different. In embodiments comprising a fourth ascending dose, a fourth ascending dose selected from A, B, C, or D as provided herein is administered at a frequency selected from daily, every other day, or weekly for a fourth time period, wherein the first, second, third, and fourth ascending doses all belong to unique groups A, B, C, or D, and wherein the first, second, third, and fourth time periods may be the same or different.

[0269] In some embodiments, the loading dose comprises one or more ascending doses, wherein the one or more ascending doses are administered at doses and combinations as outlined in Table 11. In some embodiments, one or more ascending doses selected from ascending doses of E, F, G, or H as provided herein are administered daily. In some embodiments, one or more ascending doses selected from ascending doses of E, F, G, or H as provided herein are administered every other day. In some embodiments, one or more ascending doses selected from ascending doses of E, F, G, or H as provided herein are administered weekly. When administered in combination, each ascending dose of E, F, G, or H may be administered at any frequency as provided herein prior to administration of the second ascending dose, which may be administered at any frequency as provided herein. Thus, in some embodiments, a first ascending dose selected from E, F, G, or H as provided herein is administered at a frequency selected from daily, every other day, or weekly for a first time period, followed by administration of a second ascending dose selected from E, F, G, or H as provided herein at a frequency selected from daily, every other day, or weekly for a second time period, wherein the second ascending dose does not belong to the same group E, F, G, or H as the first ascending dose, and wherein the first and second time periods may be the same or different. In embodiments comprising a third ascending dose, a third ascending dose selected from E, F, G, or H as provided herein is administered at a frequency selected from daily, every other day, or weekly for a third time period, wherein the first, second, and third ascending doses do not belong to the same group E, F, G, or H, and wherein the first, second, and third time periods may be the same or different. In embodiments comprising a fourth ascending dose, a fourth ascending dose selected from E, F, G, or H as provided herein is administered at a frequency selected from daily, every other day, or weekly for a fourth time period, wherein the first, second, third, and fourth ascending doses do not belong to the same group E, F, G, or H, and wherein the first, second, third, and fourth time periods may be the same or different.

[0270] In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is about 60 μg / kg to about 6000 μg / kg, or any value or range therebetween. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 60 μg / kg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 240 μg / kg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 300 μg / kg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 355 μg / kg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 475 μg / kg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 635 μg / kg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 720 μg / kg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 845 μg / kg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 1125 μg / kg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 1500 μg / kg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 1685 μg / kg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 2250 μg / kg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 3000 μg / kg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 6000 μg / kg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is any value including or between the values ​​provided herein.

[0271] In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is from about 3 mg to about 600 mg, or any value or range therebetween. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 3 mg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 4 mg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 15 mg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 25 mg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 100 mg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 150 mg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 200 mg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 300 mg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is 450 mg. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is any value inclusive of or between the values ​​provided herein.

[0272] In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is determined based on the subject's weight. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody is determined based on a predetermined weight threshold, wherein if the subject is at or below the predetermined weight threshold, the subject is in Tier 1 and a therapeutic dose of the BCMA x CD3 bispecific antibody is administered, and wherein if the subject is above the predetermined weight threshold, the subject is in Tier 2 and a therapeutic dose of the BCMA x CD3 bispecific antibody is administered, wherein the therapeutic dose of the BCMA x CD3 bispecific antibody for those subjects in Tier 1 and the therapeutic dose of the BCMA x CD3 bispecific antibody for those subjects in Tier 2 may be the same or different. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody for those subjects in Tier 1 is the same as the therapeutic dose of the BCMA x CD3 bispecific antibody for those subjects in Tier 2. In some embodiments, the therapeutic dose of the BCMA x CD3 bispecific antibody for those subjects in Tier 1 is different from the therapeutic dose of the BCMA x CD3 bispecific antibody for those subjects in Tier 2. In some embodiments, the predetermined weight threshold used to determine the therapeutic dose of the BCMA x CD3 bispecific antibody is as provided herein.

[0273] In some embodiments, the subject is in Tier 1 and the treatment dose of the BCMA x CD3 bispecific antibody is from about 3 mg to about 600 mg, or any value or range therebetween. In some embodiments, the subject is in Tier 1 and the treatment dose of the BCMA x CD3 bispecific antibody is 3 mg. In some embodiments, the subject is in Tier 1 and the treatment dose of the BCMA x CD3 bispecific antibody is 4 mg. In some embodiments, the subject is in Tier 1 and the treatment dose of the BCMA x CD3 bispecific antibody is 15 mg. In some embodiments, the treatment dose of the BCMA x CD3 bispecific antibody is 25 mg. In some embodiments, the subject is in Tier 1 and the treatment dose of the BCMA x CD3 bispecific antibody is 100 mg. In some embodiments, the subject is in Tier 1 and the treatment dose of the BCMA x CD3 bispecific antibody is 150 mg. In some embodiments, the subject is in Tier 1 and the treatment dose of the BCMA x CD3 bispecific antibody is 200 mg. In some embodiments, the subject is in Tier 1 and the treatment dose of the BCMA x CD3 bispecific antibody is 300 mg. In some embodiments, the subject is in Tier 1 and the therapeutic dose of the BCMA x CD3 bispecific antibody is 450 mg. In some embodiments, the subject is in Tier 1 and the therapeutic dose of the BCMA x CD3 bispecific antibody is any value including or between the values ​​provided herein.

[0274] In some embodiments, the subject is in level 2 and the treatment dose of the BCMA x CD3 bispecific antibody is from about 3 mg to about 600 mg, or any value or range therebetween. In some embodiments, the subject is in level 2 and the treatment dose of the BCMA x CD3 bispecific antibody is 3 mg. In some embodiments, the subject is in level 2 and the treatment dose of the BCMA x CD3 bispecific antibody is 4 mg. In some embodiments, the subject is in level 2 and the treatment dose of the BCMA x CD3 bispecific antibody is 15 mg. In some embodiments, the subject is in level 2 and the treatment dose of the BCMA x CD3 bispecific antibody is 25 mg. In some embodiments, the subject is in level 2 and the treatment dose of the BCMA x CD3 bispecific antibody is 100 mg. In some embodiments, the subject is in level 2 and the treatment dose of the BCMA x CD3 bispecific antibody is 150 mg. In some embodiments, the subject is in level 2 and the treatment dose of the BCMA x CD3 bispecific antibody is 200 mg. In some embodiments, the subject is in level 2 and the treatment dose of the BCMA x CD3 bispecific antibody is 300 mg. In some embodiments, the subject is in level 2 and the therapeutic dose of the BCMA x CD3 bispecific antibody is 450 mg. In some embodiments, the subject is in level 2 and the therapeutic dose of the BCMA x CD3 bispecific antibody is any value including or between the values ​​provided herein.

[0275] In some embodiments, a therapeutic dose of the BCMA x CD3 bispecific antibody is administered daily. In some embodiments, a therapeutic dose of the BCMA x CD3 bispecific antibody is administered weekly. In some embodiments, a therapeutic dose of the BCMA x CD3 bispecific antibody is administered every two weeks. In some embodiments, a therapeutic dose of the BCMA x CD3 bispecific antibody is administered once every three weeks. In some embodiments, a therapeutic dose of the BCMA x CD3 bispecific antibody is administered once every four weeks. In some embodiments, a therapeutic dose of the BCMA x CD3 bispecific antibody is administered monthly. The frequency of administration of the therapeutic dose of the BCMA x CD3 bispecific antibody can be varied as needed to treat cancer. For example, a therapeutic dose of the BCMA x CD3 bispecific antibody can be administered daily, weekly, every two weeks, every three weeks, every four weeks, monthly, or at any frequency in between any of the aforementioned frequencies for a certain period of time, after which the therapeutic dose of the BCMA x CD3 bispecific antibody can be administered daily, weekly, every two weeks, every three weeks, every four weeks, monthly, or at any frequency in between any of the aforementioned frequencies for a next period of time.

[0276] Co-treatment and pre-treatment

[0277] In some embodiments, the method of treating cancer comprising administering a therapeutically effective amount of a BCMA x CD3 bispecific antibody, a therapeutically effective amount of an anti-CD38 antibody, and a therapeutically effective amount of an immunomodulatory drug (IMiD) further comprises administering a pretreatment regimen, a co-treatment regimen, or a combination thereof to the subject for a time sufficient to treat the cancer. In some embodiments, the method comprising administering a therapeutically effective amount of a BCMA x CD3 bispecific antibody, a therapeutically effective amount of an anti-CD38 antibody, and a therapeutically effective amount of an immunomodulatory drug (IMiD) further comprises administering a pretreatment regimen. In some embodiments, the method comprising administering a therapeutically effective amount of a BCMA x CD3 bispecific antibody, a therapeutically effective amount of an anti-CD38 antibody, and a therapeutically effective amount of an immunomodulatory drug (IMiD) further comprises administering a co-treatment regimen. In some embodiments, the method comprising administering a therapeutically effective amount of a BCMA x CD3 bispecific antibody, a therapeutically effective amount of an anti-CD38 antibody, and a therapeutically effective amount of an immunomodulatory drug (IMiD) further comprises administering a pretreatment regimen and a co-treatment regimen. It should be understood that any method of the present disclosure may further comprise administering a pretreatment regimen, a co-treatment regimen, or a combination thereof to the subject for a time sufficient to treat the cancer. Therefore, in some embodiments, the method as provided herein further comprises administering to the subject a pre-treatment regimen, a co-treatment regimen, or a combination thereof for a time sufficient to treat the cancer. In some embodiments, the method as provided herein further comprises administering to the subject a pre-treatment regimen for a time sufficient to treat the cancer. In some embodiments, the method as provided herein further comprises administering to the subject a co-treatment regimen for a time sufficient to treat the cancer. In some embodiments, the method as provided herein further comprises administering to the subject a pre-treatment regimen and a co-treatment regimen for a time sufficient to treat the cancer.

[0278] It should be understood that, as used herein, a "pretreatment regimen" may refer to a regimen of pharmaceutical compounds, compositions, or formulations administered prior to the initiation of administration of a therapeutically effective amount of a BCMA x CD3 bispecific antibody, a therapeutically effective amount of an anti-CD38 antibody, and a therapeutically effective amount of an immunomodulatory drug (IMiD). A "pretreatment regimen" may also refer to a regimen of pharmaceutical compounds, compositions, or formulations administered during the administration of a therapeutically effective amount of a BCMA x CD3 bispecific antibody, a therapeutically effective amount of an anti-CD38 antibody, and a therapeutically effective amount of an immunomodulatory drug (IMiD), provided that the pretreatment regimen is administered prior to the administration of a therapeutically effective amount of a BCMA x CD3 bispecific antibody, a therapeutically effective amount of an anti-CD38 antibody, and a therapeutically effective amount of an immunomodulatory drug (IMiD), and that the administration is performed on the same day. Therefore, it should be understood that, as used herein, a "pretreatment regimen" does not exclude components of the pretreatment regimen administered during the administration of a therapeutically effective amount of a BCMA x CD3 bispecific antibody, a therapeutically effective amount of an anti-CD38 antibody, and a therapeutically effective amount of an immunomodulatory drug (IMiD).

[0279] In some embodiments, the pretreatment regimen comprises administering a therapeutically effective amount of a glucocorticoid, a therapeutically effective amount of an antihistamine, a therapeutically effective amount of an antipyretic, or any combination thereof. In some embodiments, the pretreatment regimen comprises administering a therapeutically effective amount of a glucocorticoid. In some embodiments, the pretreatment regimen comprises administering a therapeutically effective amount of an antihistamine. In some embodiments, the pretreatment regimen comprises administering a therapeutically effective amount of an antipyretic. In some embodiments, the pretreatment regimen comprises administering a therapeutically effective amount of a glucocorticoid and a therapeutically effective amount of an antihistamine. In some embodiments, the pretreatment regimen comprises administering a therapeutically effective amount of a glucocorticoid and a therapeutically effective amount of an antipyretic. In some embodiments, the pretreatment regimen comprises administering a therapeutically effective amount of an antihistamine and a therapeutically effective amount of an antipyretic. In some embodiments, the pretreatment regimen comprises administering a therapeutically effective amount of a glucocorticoid, a therapeutically effective amount of an antihistamine, and a therapeutically effective amount of an antipyretic.

[0280] In some embodiments, the co-treatment regimen comprises administering a therapeutically effective amount of a glucocorticoid, a therapeutically effective amount of an antihistamine, a therapeutically effective amount of an antipyretic, or any combination thereof. In some embodiments, the co-treatment regimen comprises administering a therapeutically effective amount of a glucocorticoid. In some embodiments, the co-treatment regimen comprises administering a therapeutically effective amount of an antihistamine. In some embodiments, the co-treatment regimen comprises administering a therapeutically effective amount of an antipyretic. In some embodiments, the co-treatment regimen comprises administering a therapeutically effective amount of a glucocorticoid and a therapeutically effective amount of an antihistamine. In some embodiments, the co-treatment regimen comprises administering a therapeutically effective amount of a glucocorticoid and a therapeutically effective amount of an antipyretic. In some embodiments, the co-treatment regimen comprises administering a therapeutically effective amount of an antihistamine and a therapeutically effective amount of an antipyretic. In some embodiments, the co-treatment regimen comprises administering a therapeutically effective amount of a glucocorticoid, a therapeutically effective amount of an antihistamine, and a therapeutically effective amount of an antipyretic.

[0281] Glucocorticoid administration

[0282] In some embodiments, the therapeutically effective amount of a glucocorticoid is any amount administered in combination with the treatment regimen for a sufficient time to treat the cancer. In some embodiments, the therapeutically effective amount of a glucocorticoid is from about 8 mg to about 50 mg, or any value or range therebetween. In some embodiments, the therapeutically effective amount of a glucocorticoid is 8 mg. In some embodiments, the therapeutically effective amount of a glucocorticoid is 10 mg. In some embodiments, the therapeutically effective amount of a glucocorticoid is 12 mg. In some embodiments, the therapeutically effective amount of a glucocorticoid is 14 mg. In some embodiments, the therapeutically effective amount of a glucocorticoid is 16 mg. In some embodiments, the therapeutically effective amount of a glucocorticoid is 18 mg. In some embodiments, the therapeutically effective amount of a glucocorticoid is 20 mg. In some embodiments, the therapeutically effective amount of a glucocorticoid is 25 mg. In some embodiments, the therapeutically effective amount of a glucocorticoid is 30 mg. In some embodiments, the therapeutically effective amount of a glucocorticoid is 35 mg. In some embodiments, the therapeutically effective amount of a glucocorticoid is 40 mg. In some embodiments, the therapeutically effective amount of a glucocorticoid is 45 mg. In some embodiments, the therapeutically effective amount of the glucocorticoid is 50 mg.

[0283] Antihistamine administration

[0284] In some embodiments, the therapeutically effective amount of an antihistamine is any amount administered in combination with the treatment regimen for a sufficient time to treat the cancer. In some embodiments, the therapeutically effective amount of an antihistamine is from about 25 mg to about 50 mg or any value or range therebetween. In some embodiments, the therapeutically effective amount of an antihistamine is 25 mg. In some embodiments, the therapeutically effective amount of an antihistamine is 30 mg. In some embodiments, the therapeutically effective amount of an antihistamine is 35 mg. In some embodiments, the therapeutically effective amount of an antihistamine is 40 mg. In some embodiments, the therapeutically effective amount of an antihistamine is 45 mg. In some embodiments, the therapeutically effective amount of an antihistamine is 50 mg.

[0285] antipyretics

[0286] In some embodiments, the therapeutically effective amount of the antipyretic is any amount that is administered in combination with the treatment regimen for a sufficient time to treat the cancer. In some embodiments, the therapeutically effective amount of the antipyretic is from about 500 mg to about 1000 mg, or any value or range therebetween. In some embodiments, the therapeutically effective amount of the antipyretic is 500 mg. In some embodiments, the therapeutically effective amount of the antipyretic is 550 mg. In some embodiments, the therapeutically effective amount of the antipyretic is 600 mg. In some embodiments, the therapeutically effective amount of the antipyretic is 650 mg. In some embodiments, the therapeutically effective amount of the antipyretic is 700 mg. In some embodiments, the therapeutically effective amount of the antipyretic is 750 mg. In some embodiments, the therapeutically effective amount of the antipyretic is 800 mg. In some embodiments, the therapeutically effective amount of the antipyretic is 850 mg. In some embodiments, the therapeutically effective amount of the antipyretic is 900 mg. In some embodiments, the therapeutically effective amount of the antipyretic is 950 mg. In some embodiments, the therapeutically effective amount of the antipyretic is 1000 mg.

[0287] Routes of administration of pretreatment and co-treatment regimens

[0288] The glucocorticoids, antihistamines and antipyretics of the methods disclosed herein can be administered to a subject by any appropriate method of administration. Exemplary methods of administration include, but are not limited to, transarterial, subcutaneous, intradermal, intratumoral, intranodal, intramedullary, intramuscular, intravenous, intraperitoneal, intranasal or intraosseous. In some embodiments, glucocorticoids are administered orally or intravenously (iv). In some embodiments, glucocorticoids are administered orally. In some embodiments, glucocorticoids are administered intravenously (iv). In some embodiments, antihistamines are administered orally or intravenously (iv). In some embodiments, antihistamines are administered orally. In some embodiments, antihistamines are administered intravenously (iv). In some embodiments, antipyretics are administered orally or intravenously (iv). In some embodiments, antipyretics are administered orally. In some embodiments, antipyretics are administered intravenously (iv).

[0289] Frequency of administration of pre-treatment and co-treatment regimens

[0290] The components of the pre-treatment and co-treatment regimens of the methods provided herein can be provided at any dose or frequency. In some embodiments, therapeutically effective amounts of pre-treatment and co-treatment regimens can be provided at any frequency.

[0291] In some embodiments, the glucocorticoid is applied every day. In some embodiments, the glucocorticoid of an effective amount is applied every other day. In some embodiments, the glucocorticoid of an effective amount is applied weekly. In some embodiments, the glucocorticoid of an effective amount is applied every two weeks. In some embodiments, the glucocorticoid of an effective amount is applied once every three weeks. In some embodiments, the glucocorticoid of an effective amount is applied once every four weeks. In some embodiments, the glucocorticoid of an effective amount is applied once monthly. The frequency of application of the glucocorticoid of an effective amount can be changed as needed to achieve the desired effect. For example, the glucocorticoid of an effective amount can be applied every day, every week, every two weeks, every three weeks, every four weeks, monthly, or at any frequency between any of the frequencies described in a certain time period, after which the glucocorticoid of an effective amount can be applied every day, every week, every two weeks, every three weeks, every four weeks, monthly, or at any frequency between any of the frequencies described in the next time period.

[0292] In some embodiments, the antihistamine is administered daily. In some embodiments, an effective amount of an antihistamine is administered every other day. In some embodiments, an effective amount of an antihistamine is administered weekly. In some embodiments, an effective amount of an antihistamine is administered every two weeks. In some embodiments, an effective amount of an antihistamine is administered once every three weeks. In some embodiments, an effective amount of an antihistamine is administered once every four weeks. In some embodiments, an effective amount of an antihistamine is administered once monthly. The frequency of administration of an effective amount of an antihistamine can be changed as needed to achieve the desired effect. For example, an effective amount of an antihistamine can be administered daily, weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or at any frequency between any of the frequencies described within a certain time period, after which an effective amount of an antihistamine can be administered daily, weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or at any frequency between any of the frequencies described within the next time period.

[0293] In some embodiments, the antipyretic is applied every day. In some embodiments, the antipyretic of an effective amount is applied every other day. In some embodiments, the antipyretic of an effective amount is applied weekly. In some embodiments, the antipyretic of an effective amount is applied every two weeks. In some embodiments, the antipyretic of an effective amount is applied once every three weeks. In some embodiments, the antipyretic of an effective amount is applied once every four weeks. In some embodiments, the antipyretic of an effective amount is applied once monthly. The frequency of application of the antipyretic of an effective amount can be changed as needed to achieve the desired effect. For example, the antipyretic of an effective amount can be applied every day, every week, every two weeks, every three weeks, every four weeks, once a month, or at any frequency between any of the frequencies described in a certain time period, after which the antipyretic of an effective amount can be applied every day, every week, every two weeks, every three weeks, every four weeks, once a month, or at any frequency between any of the frequencies described in the next time period.

[0294] In some embodiments, the therapeutically effective amount and frequency of the components of the method remain constant in the cycle time period or cycle. In some embodiments, the duration of the treatment cycle can be any time period. In some embodiments, the treatment cycle can be sustainable 7, 8, 9, 10, 11, 12, 13, 14, 21, 28, 56, 112, 224, 365, more than 365 days or any number of days therebetween. In some embodiments, the treatment cycle lasts 28 days. It should be understood that the duration of the treatment cycle does not mean that the duration of treatment is limited in any way. Treatment can be any number of treatment cycles required for the sustainable treatment of cancer. In some embodiments, the components of the method provided herein can be applied to experimenter 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more than 20 treatment cycles, or the components of the method provided herein are applied to experimenter until cancer is treated. In some embodiments, the glucocorticoid, antihistamine and antipyretic of the treatment effective amount are applied to the experimenter for a treatment cycle. In some embodiments, the subject is administered a therapeutically effective amount of a glucocorticoid, an antihistamine, and an antipyretic for two treatment cycles. In some embodiments, the subject is administered a therapeutically effective amount of a glucocorticoid, an antihistamine, and an antipyretic for three treatment cycles. In some embodiments, the subject is administered a therapeutically effective amount of a glucocorticoid, an antihistamine, and an antipyretic for four treatment cycles. In some embodiments, the subject is administered a therapeutically effective amount of a glucocorticoid, an antihistamine, and an antipyretic for five treatment cycles. In some embodiments, the subject is administered a therapeutically effective amount of a glucocorticoid, an antihistamine, and an antipyretic for six treatment cycles. In some embodiments, the subject is administered a therapeutically effective amount of a glucocorticoid, an antihistamine, and an antipyretic for seven treatment cycles. In some embodiments, the subject is administered a therapeutically effective amount of a glucocorticoid, an antihistamine, and an antipyretic for more than seven treatment cycles.

[0295] Should be understood that any component herein may or may not be used in any treatment cycle described herein.For example, in some embodiments, the glucocorticoid of therapeutically effective amount can be used as provided herein for the treatment cycle of first quantity, the antihistamine of therapeutically effective amount can be used for the treatment cycle of second quantity, and the antipyretic of therapeutically effective amount can be used for the treatment cycle of third quantity, wherein the treatment cycles of first, second and third quantity can be identical or different.

[0296] In addition, it should be understood that as provided herein, the effective amount or frequency of the component of the method provided herein can change at the end of each treatment cycle.Therefore, in some embodiments, glucocorticoid, antihistamine and antipyretic of treatment effective dose are applied to the experimenter and continue a treatment cycle.In some embodiments, glucocorticoid, antihistamine and antipyretic of treatment effective dose are applied to the experimenter and continue two treatment cycles, wherein the treatment effective amount or frequency of glucocorticoid, antihistamine and antipyretic can change or can not change between each treatment cycle.In some embodiments, glucocorticoid, antihistamine and antipyretic of treatment effective dose are applied to the experimenter and continue three treatment cycles, wherein the treatment effective amount or frequency of glucocorticoid, antihistamine and antipyretic can change or can not change between each treatment cycle.In some embodiments, glucocorticoid, antihistamine and antipyretic of treatment effective dose are applied to the experimenter and continue four treatment cycles, wherein the treatment effective amount or frequency of glucocorticoid, antihistamine and antipyretic can change or can not change between each treatment cycle. In some embodiments, the glucocorticoid, antihistamine and antipyretic of therapeutically effective amount are applied to the subject for five treatment cycles, wherein the therapeutically effective amount or frequency of glucocorticoid, antihistamine and antipyretic can be changed or can not be changed between each treatment cycle. In some embodiments, the glucocorticoid, antihistamine and antipyretic of therapeutically effective amount are applied to the subject for six treatment cycles, wherein the therapeutically effective amount or frequency of glucocorticoid, antihistamine and antipyretic can be changed or can not be changed between each treatment cycle. In some embodiments, the glucocorticoid, antihistamine and antipyretic of therapeutically effective amount are applied to the subject for seven treatment cycles, wherein the therapeutically effective amount or frequency of glucocorticoid, antihistamine and antipyretic can be changed or can not be changed between each treatment cycle. In some embodiments, the glucocorticoid, antihistamine and antipyretic of therapeutically effective amount are applied to the subject for more than seven treatment cycles, wherein the therapeutically effective amount or frequency of glucocorticoid, antihistamine and antipyretic can be changed or can not be changed between each treatment cycle.

[0297] In some embodiments, a therapeutically effective amount of a glucocorticoid is administered on days 1, 2, 4, and 8 of the first treatment cycle, and then weekly for the second, third, and fourth treatment cycles. In some embodiments, a therapeutically effective amount of an antihistamine is administered weekly for the first and second treatment cycles, and then biweekly for the third, fourth, fifth, and sixth treatment cycles. In some embodiments, a therapeutically effective amount of an antipyretic is administered weekly for the first and second treatment cycles, and then biweekly for the third, fourth, fifth, and sixth treatment cycles.

[0298] In some embodiments, a therapeutically effective amount of a glucocorticoid is administered on all days of administration of an anti-CD38 antibody and / or a BCMAxCD3 bispecific antibody for the first, second, third, and fourth treatment cycles. In some embodiments, a therapeutically effective amount of a glucocorticoid is further administered after a reaction associated with the administration of an anti-CD38 antibody. In some embodiments, a therapeutically effective amount of a glucocorticoid is further administered after a reaction associated with the administration of a BCMAxCD3 bispecific antibody or a cytokine release syndrome caused by a BCMAxCD3 bispecific antibody. In some embodiments, a therapeutically effective amount of an antihistamine is administered on all days of administration of an anti-CD38 antibody and / or a BCMAxCD3 bispecific antibody. In some embodiments, a therapeutically effective amount of an antihistamine is further administered after a reaction associated with the administration of an anti-CD38 antibody. In some embodiments, a therapeutically effective amount of an antihistamine is further administered after a reaction associated with the administration of a BCMAxCD3 bispecific antibody or a cytokine release syndrome caused by a BCMAxCD3 bispecific antibody. In some embodiments, a therapeutically effective amount of an antipyretic is administered on all days of administration of an anti-CD38 antibody and / or BCMAxCD3 bispecific antibody. In some embodiments, a therapeutically effective amount of an antipyretic is further administered following an administration-related reaction to an anti-CD38 antibody. In some embodiments, a therapeutically effective amount of an antipyretic is further administered following an administration-related reaction to a BCMAxCD3 bispecific antibody or a cytokine release syndrome caused by a BCMAxCD3 bispecific antibody.

[0299] The treatment duration of the method can be any time amount required for sustainable treatment of cancer. In some embodiments, with an effective amount of glucocorticoid, antihistamine and antipyretic treatment experimenter 1,2,3,4,5,6,7,8,12,16,20,24,28,32,36,40,44,48,52,104,156,208,260 or more weeks, or any weeks therebetween. In some embodiments, with an effective amount of glucocorticoid, antihistamine and antipyretic treatment experimenter more than 260 weeks. In some embodiments, with an effective amount of glucocorticoid, antihistamine and antipyretic treatment experimenter 1,2,3,4,5,6,7,8,9,10,11,12,24,36,48,60 or more months, or any months therebetween. In some embodiments, with an effective amount of glucocorticoid, antihistamine and antipyretic treatment experimenter more than 60 months. In some embodiments, the subject is treated with an effective amount of a glucocorticoid, an antihistamine, and an antipyretic for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more years, or any number of years therebetween. In some embodiments, the subject is treated with an effective amount of a glucocorticoid, an antihistamine, and an antipyretic for more than 10 years.

[0300] Loading and therapeutic dose

[0301] In some embodiments, the components of the methods provided herein may be provided as a loading dose, a therapeutic dose, or a combination thereof. In some embodiments, the components of the methods provided herein are provided in a therapeutic dose. In some embodiments, the components of the methods provided herein are provided in a loading dose followed by a therapeutic dose. In some embodiments, the loading dose comprises one or more ascending doses provided over a period of time. In some embodiments, one ascending dose is provided. In some embodiments, two ascending doses are provided. In some embodiments, three ascending doses are provided. In some embodiments, four ascending doses are provided. In some embodiments, more than four ascending doses are provided.

[0302] In some embodiments, glucocorticoid can be used as a loading dose followed by a therapeutic dose. In some embodiments, the loading dose includes one or more ascending doses as provided herein. In some embodiments, glucocorticoid is used as an ascending dose followed by a therapeutic dose. In some embodiments, glucocorticoid is used as two ascending doses followed by a therapeutic dose. In some embodiments, glucocorticoid is used as three ascending doses followed by a therapeutic dose. In some embodiments, glucocorticoid is used as four ascending doses followed by a therapeutic dose.

[0303] In some embodiments, the first ascending dose of a glucocorticoid is any amount administered in combination with the treatment regimen for a sufficient time to treat the cancer. In some embodiments, the first ascending dose of a glucocorticoid is from about 8 mg to about 50 mg, or any value or range therebetween. In some embodiments, the first ascending dose of a glucocorticoid is 8 mg. In some embodiments, the first ascending dose of a glucocorticoid is 10 mg. In some embodiments, the first ascending dose of a glucocorticoid is 12 mg. In some embodiments, the first ascending dose of a glucocorticoid is 14 mg. In some embodiments, the first ascending dose of a glucocorticoid is 16 mg. In some embodiments, the first ascending dose of a glucocorticoid is 18 mg. In some embodiments, the first ascending dose of a glucocorticoid is 20 mg. In some embodiments, the first ascending dose of a glucocorticoid is 25 mg. In some embodiments, the first ascending dose of a glucocorticoid is 30 mg. In some embodiments, the first ascending dose of a glucocorticoid is 35 mg. In some embodiments, the first ascending dose of a glucocorticoid is 40 mg. In some embodiments, the first ascending dose of a glucocorticoid is 45 mg. In some embodiments, the first ascending dose of glucocorticoid is 50 mg.

[0304] In some embodiments, the second ascending dose of the glucocorticoid is any amount administered in combination with the treatment regimen for a sufficient time to treat the cancer. In some embodiments, the second ascending dose of the glucocorticoid is from about 8 mg to about 50 mg, or any value or range therebetween. In some embodiments, the second ascending dose of the glucocorticoid is 8 mg. In some embodiments, the second ascending dose of the glucocorticoid is 10 mg. In some embodiments, the second ascending dose of the glucocorticoid is 12 mg. In some embodiments, the second ascending dose of the glucocorticoid is 14 mg. In some embodiments, the second ascending dose of the glucocorticoid is 16 mg. In some embodiments, the second ascending dose of the glucocorticoid is 18 mg. In some embodiments, the second ascending dose of the glucocorticoid is 20 mg. In some embodiments, the second ascending dose of the glucocorticoid is 25 mg. In some embodiments, the second ascending dose of the glucocorticoid is 30 mg. In some embodiments, the second ascending dose of the glucocorticoid is 35 mg. In some embodiments, the second ascending dose of the glucocorticoid is 40 mg. In some embodiments, the second ascending dose of the glucocorticoid is 45 mg. In some embodiments, the second escalating dose of glucocorticoid is 50 mg.

[0305] In some embodiments, the third, fourth or greater incremental dose of a glucocorticoid is any amount administered in combination with a treatment regimen for a time sufficient to treat the cancer. In some embodiments, the third, fourth or greater incremental dose of a glucocorticoid is from about 8 mg to about 50 mg or any value or range therebetween. In some embodiments, the third, fourth or greater incremental dose of a glucocorticoid is 8 mg. In some embodiments, the third, fourth or greater incremental dose of a glucocorticoid is 10 mg. In some embodiments, the third, fourth or greater incremental dose of a glucocorticoid is 12 mg. In some embodiments, the third, fourth or greater incremental dose of a glucocorticoid is 14 mg. In some embodiments, the third, fourth or greater incremental dose of a glucocorticoid is 16 mg. In some embodiments, the third, fourth or greater incremental dose of a glucocorticoid is 18 mg. In some embodiments, the third, fourth or greater incremental dose of a glucocorticoid is 20 mg. In some embodiments, the third, fourth or greater incremental dose of a glucocorticoid is 25 mg. In some embodiments, the third, fourth, or greater incremental dose of a glucocorticoid is 30 mg. In some embodiments, the third, fourth, or greater incremental dose of a glucocorticoid is 35 mg. In some embodiments, the third, fourth, or greater incremental dose of a glucocorticoid is 40 mg. In some embodiments, the third, fourth, or greater incremental dose of a glucocorticoid is 45 mg. In some embodiments, the third, fourth, or greater incremental dose of a glucocorticoid is 50 mg.

[0306] In some embodiments, the incremental dose of the glucocorticoid may be designated as an incremental dose J and include doses of about 8 mg to about 12 mg or any value or range therebetween. In some embodiments, the incremental dose J of the glucocorticoid is 8 mg. In some embodiments, the incremental dose J of the glucocorticoid is 9 mg. In some embodiments, the incremental dose J of the glucocorticoid is 10 mg. In some embodiments, the incremental dose J of the glucocorticoid is 11 mg. In some embodiments, the incremental dose J of the glucocorticoid is 12 mg.

[0307] In some embodiments, the incremental dose of the glucocorticoid may be designated as an incremental dose K and include doses of about 12 mg to about 20 mg or any value or range therebetween. In some embodiments, the incremental dose K of the glucocorticoid is 12 mg. In some embodiments, the incremental dose K of the glucocorticoid is 14 mg. In some embodiments, the incremental dose K of the glucocorticoid is 16 mg. In some embodiments, the incremental dose K of the glucocorticoid is 18 mg. In some embodiments, the incremental dose K of the glucocorticoid is 20 mg.

[0308] In some embodiments, the incremental dose of a glucocorticoid can be designated as an incremental dose L and includes a dose of about 20 mg to about 50 mg or any value or range therebetween. In some embodiments, the incremental dose L of a glucocorticoid is 20 mg. In some embodiments, the incremental dose L of a glucocorticoid is 25 mg. In some embodiments, the incremental dose L of a glucocorticoid is 30 mg. In some embodiments, the incremental dose L of a glucocorticoid is 35 mg. In some embodiments, the incremental dose L of a glucocorticoid is 40 mg. In some embodiments, the incremental dose L of a glucocorticoid is 45 mg. In some embodiments, the incremental dose L of a glucocorticoid is 50 mg. In some embodiments, the incremental dose L of a glucocorticoid is 60 mg.

[0309] In some embodiments, the loading dose of the glucocorticoid of the methods provided herein may include one or more of any dose or range selected from ascending doses of J, K, L, or any combination thereof. In some embodiments, the loading dose of the glucocorticoid may include one or more ascending doses as provided in Table 12 below:

[0310] Table 12

[0311]

[0312]

[0313] It should be understood that in embodiments in which a glucocorticoid is administered with more than one incremental dose, the current incremental dose and subsequent incremental doses may comprise the same or different doses, and may comprise the same or different frequencies. In some embodiments, the current incremental dose and subsequent incremental doses comprise the same dose and the same frequency. In some embodiments, the current incremental dose and subsequent incremental doses comprise the same dose and different frequencies. In some embodiments, the current incremental dose and subsequent incremental doses comprise different doses and the same frequency. In some embodiments, the current incremental dose and subsequent incremental doses comprise different doses and different frequencies.

[0314] In some embodiments, the glucocorticoid of a loading dose is administered at a frequency as provided herein. In some embodiments, the glucocorticoid of a loading dose is administered daily. In some embodiments, the glucocorticoid of a loading dose is administered every other day. In some embodiments, the glucocorticoid of a loading dose is administered weekly.

[0315] In some embodiments, the loading dose of glucocorticoid may include one or more increasing doses. Therefore, in some embodiments, the glucocorticoid of one or more increasing doses is used with a frequency as provided herein. In some embodiments, the glucocorticoid of one or more increasing doses is used every day. In some embodiments, the glucocorticoid of one or more increasing doses is used every other day. In some embodiments, the glucocorticoid of one or more increasing doses is used weekly.

[0316] In some embodiments, the loading dose includes one or more ascending doses, wherein the one or more ascending doses are administered in the dosage and combination as outlined in Table 12. In some embodiments, one or more ascending doses selected from the ascending doses J, K or L as provided herein are administered daily. In some embodiments, one or more ascending doses selected from the ascending doses J, K or L as provided herein are administered every other day. In some embodiments, one or more ascending doses selected from the ascending doses J, K or L as provided herein are administered weekly. When administered in combination, each ascending dose J, K or L can be administered with any frequency as provided herein before administering the second ascending dose, and the second ascending dose can be administered with any frequency as provided herein. Therefore, in some embodiments, a first ascending dose selected from J, K or L as provided herein is administered at a frequency selected from daily, every other day or weekly for a first period of time, followed by a second ascending dose selected from J, K or L as provided herein for a second period of time at a frequency selected from daily, every other day or weekly, wherein the second ascending dose does not belong to the same group J, K or L as the first ascending dose, and wherein the first and second period of time may be the same or different. In embodiments comprising a third ascending dose, the third ascending dose selected from J, K or L as provided herein is administered at a frequency selected from daily, every other day or weekly for a third time period, wherein the first, second and third ascending doses do not belong to the same group J, K or L, and wherein the first, second and third time periods may be the same or different.

[0317] In some embodiments, the therapeutic dose of a glucocorticoid is from about 8 mg to about 50 mg, or any value or range therebetween. In some embodiments, the therapeutic dose of a glucocorticoid is 8 mg. In some embodiments, the therapeutic dose of a glucocorticoid is 10 mg. In some embodiments, the therapeutic dose of a glucocorticoid is 12 mg. In some embodiments, the therapeutic dose of a glucocorticoid is 14 mg. In some embodiments, the therapeutic dose of a glucocorticoid is 16 mg. In some embodiments, the therapeutic dose of a glucocorticoid is 18 mg. In some embodiments, the therapeutic dose of a glucocorticoid is 20 mg. In some embodiments, the therapeutic dose of a glucocorticoid is 25 mg. In some embodiments, the therapeutic dose of a glucocorticoid is 30 mg. In some embodiments, the therapeutic dose of a glucocorticoid is 35 mg. In some embodiments, the therapeutic dose of a glucocorticoid is 40 mg. In some embodiments, the therapeutic dose of a glucocorticoid is 45 mg. In some embodiments, the therapeutic dose of a glucocorticoid is 50 mg.

[0318] In some embodiments, the glucocorticoid of therapeutic dose is applied every day. In some embodiments, the glucocorticoid of therapeutic dose is applied weekly. In some embodiments, the glucocorticoid of therapeutic dose is applied every two weeks. In some embodiments, the glucocorticoid of therapeutic dose is applied once every three weeks. In some embodiments, the glucocorticoid of therapeutic dose is applied once every four weeks. In some embodiments, the glucocorticoid of therapeutic dose is applied once every two months. The frequency of application of the glucocorticoid of therapeutic dose can be changed as needed to achieve the desired effect. For example, the glucocorticoid of therapeutic dose can be applied every day, every week, every two weeks, every three weeks, every four weeks, every month or any frequency between any frequency described in a certain time period, after which the glucocorticoid of therapeutic dose can be applied every day, every week, every two weeks, every three weeks, every four weeks, every month or any frequency between any frequency described in the next time period.

[0319] Timing of administration of pre-treatment and co-treatment regimens

[0320] In some embodiments, the components of the pretreatment regimen or co-treatment regimen are administered prior to initiating administration of a therapeutically effective amount of a BCMA x CD3 bispecific antibody, a therapeutically effective amount of an anti-CD38 antibody, and a therapeutically effective amount of an immunomodulatory drug (IMiD). In some embodiments, the components of the pretreatment regimen or co-treatment regimen are administered concurrently with the therapeutically effective amount of a BCMA x CD3 bispecific antibody, a therapeutically effective amount of an anti-CD38 antibody, and a therapeutically effective amount of an immunomodulatory drug (IMiD).

[0321] In embodiments where a therapeutically effective amount of a glucocorticoid, an antihistamine, and an antipyretic is administered concurrently with a therapeutically effective amount of a BCMA x CD3 bispecific antibody, a therapeutically effective amount of an anti-CD38 antibody, and a therapeutically effective amount of an immunomodulatory drug (IMiD), the glucocorticoid, antihistamine, and antipyretic may be administered before, concurrently with, or after the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD. In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered before the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD. In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered concurrently with the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD. In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered after the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD.

[0322] In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered from about 1 minute to about 360 minutes prior to administration of the BCMAxCD3 bispecific antibody, anti-CD38 antibody, and IMiD, or any value or range therebetween. In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered 15 minutes prior to administration of the BCMAxCD3 bispecific antibody, anti-CD38 antibody, and IMiD. In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered 20 minutes prior to administration of the BCMAxCD3 bispecific antibody, anti-CD38 antibody, and IMiD. In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered 25 minutes prior to administration of the BCMAxCD3 bispecific antibody, anti-CD38 antibody, and IMiD. In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered 30 minutes prior to administration of the BCMAxCD3 bispecific antibody, anti-CD38 antibody, and IMiD. In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered 35 minutes prior to administration of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD. In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered 40 minutes prior to administration of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD. In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered 45 minutes prior to administration of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD. In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered 50 minutes prior to administration of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD. In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered 55 minutes prior to administration of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD. In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered 60 minutes prior to administration of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD. In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered 75 minutes prior to administration of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD. In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered 90 minutes prior to administration of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD. In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered 105 minutes prior to administration of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD. In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered 120 minutes prior to administration of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD.In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered 135 minutes prior to administration of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD. In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered 150 minutes prior to administration of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD. In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered 165 minutes prior to administration of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD. In some embodiments, the glucocorticoid, antihistamine, and antipyretic are administered 180 minutes prior to administration of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, and IMiD.

[0323] In some embodiments, the glucocorticoid is administered at a certain time before the anti-CD38 antibody. In some embodiments, the glucocorticoid is administered from about 1 minute to about 240 minutes before the anti-CD38 antibody is administered, or any value or range therebetween. In some embodiments, the glucocorticoid is administered 15 minutes before the anti-CD38 antibody is administered. In some embodiments, the glucocorticoid is administered 20 minutes before the anti-CD38 antibody is administered. In some embodiments, the glucocorticoid is administered 25 minutes before the anti-CD38 antibody is administered. In some embodiments, the glucocorticoid is administered 30 minutes before the anti-CD38 antibody is administered. In some embodiments, the glucocorticoid is administered 35 minutes before the anti-CD38 antibody is administered. In some embodiments, the glucocorticoid is administered 40 minutes before the anti-CD38 antibody is administered. In some embodiments, the glucocorticoid is administered 45 minutes before the anti-CD38 antibody is administered. In some embodiments, the glucocorticoid is administered 50 minutes before the anti-CD38 antibody is administered. In some embodiments, the glucocorticoid is administered 55 minutes before the anti-CD38 antibody is administered. In some embodiments, the glucocorticoid is administered 60 minutes before the administration of the anti-CD38 antibody. In some embodiments, the glucocorticoid is administered 75 minutes before the administration of the anti-CD38 antibody. In some embodiments, the glucocorticoid is administered 90 minutes before the administration of the anti-CD38 antibody. In some embodiments, the glucocorticoid is administered 105 minutes before the administration of the anti-CD38 antibody. In some embodiments, the glucocorticoid is administered 120 minutes before the administration of the anti-CD38 antibody. In some embodiments, the glucocorticoid is administered 135 minutes before the administration of the anti-CD38 antibody. In some embodiments, the glucocorticoid is administered 150 minutes before the administration of the anti-CD38 antibody. In some embodiments, the glucocorticoid is administered 165 minutes before the administration of the anti-CD38 antibody. In some embodiments, the glucocorticoid is administered 180 minutes before the administration of the anti-CD38 antibody. In some embodiments, the glucocorticoid is administered 210 minutes before the administration of the anti-CD38 antibody. In some embodiments, the glucocorticoid is administered 240 minutes before the administration of the anti-CD38 antibody.

[0324] Combination therapy with anti-CD3 antibodies

[0325] In some embodiments, a therapeutically effective amount of an anti-CD3 antibody is administered alone. It should be understood that "alone" does not necessarily mean that the anti-CD3 antibody is administered as a monotherapy, but rather that no other drug is administered simultaneously with the anti-CD3 antibody or in the same composition. In some embodiments, the anti-CD3 antibody is administered in combination with a substance that reduces the injection volume of the anti-CD3 antibody for subcutaneous administration. In some embodiments, the substance is a recombinant hyaluronidase. In some embodiments, the recombinant hyaluronidase is a recombinant human hyaluronidase PH20 (rHuPH20). In some embodiments, the hyaluronidase comprises the amino acid sequence of SEQ ID NO: 5. In some embodiments, the anti-CD3 antibody is administered in combination with a recombinant hyaluronidase as provided herein. In some embodiments, the anti-CD3 antibody is administered subcutaneously in combination with a recombinant hyaluronidase as provided herein. In some embodiments, the anti-CD3 antibody is administered in combination with a recombinant hyaluronidase comprising the amino acid sequence of SEQ ID NO: 5. In some embodiments, the anti-CD3 antibody is administered subcutaneously in combination with a recombinant hyaluronidase comprising the amino acid sequence of SEQ ID NO: 5.

[0326] Hyaluronidase can be used at any concentration required to achieve the desired effect. In some embodiments, hyaluronidase is used at a concentration of about 10,000U to about 50,000U or any value or scope therebetween. In some embodiments, hyaluronidase is used at a concentration of 10,000U. In some embodiments, hyaluronidase is used at a concentration of 20,000U. In some embodiments, hyaluronidase is used at a concentration of 30,000U. In some embodiments, hyaluronidase is used at a concentration of 40,000U. In some embodiments, hyaluronidase is used at a concentration of 50,000U.

[0327] Glucocorticoids, antihistamines, and antipyretics

[0328] Glucocorticoid is a class of corticosteroids, which is a part for immune system feedback mechanism, and plays the role of reducing the immune function of some aspects, such as the effect of inflammation.Glucocorticoid is known in the art, and any suitable glucocorticoid can be used in any embodiment provided herein.The non-limiting example of glucocorticoid includes cortisol, cortisone (cortisone), prednisone (prednisone), prednisolone (prednisolone), methylprednisolone (methylprednisolone), dexamethasone (dexamethasone), betamethasone (betamethasone), triamcinolone (triamcinolone), deflazacort (deflazacort), fludrocortisone acetate (fludrocortisoneacetate), deoxycorticosterone acetate (deoxycorticosterone acetate), aldosterone (aldosterone) and beclometasone (beclometasone). In some embodiments, glucocorticoid is dexamethasone.

[0329] Antihistamines are drugs that inhibit the swelling and vasodilation induced by histamine. Antihistamines are known in the art, and any suitable antihistamine can be used in any embodiment provided herein. Non-limiting examples of antihistamines include acrivastine, alimemazine, amitriptyline, amoxapine, azelastine, bilastine, bromodiphenhydramine, bromopheniramine, buclizine, carbinoxamine, cetirizine, chlorpheniramine ... orodiphenhydramine), chlorphemiramine, chlorpromazine, chlorprothixene, chloropyramine, cinnarizine, clemastine, clomipramine, clozapine, cyproheptadine, cyproheptadine, desloratadine, ne), dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimetindene, diphenhydramine, dosulepin, doxepin, doxylamine, ebastine, embramine, fexofenadine, hydroxyzine, imipramine (imipramine), levocabastine, levocetirizine, levomepromazine, loratadine, maprotiline, meclizine, mianserin, mirtazapine, olanzapine, olopatadine, orphenadrine, periciazine,Phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, quetiapine, rupatadine, trazodone, rupatadine, and tirprolidine. In some embodiments, the antihistamine is selected from the group including but not limited to bromdiphenhydramine, chlordiphenhydramine, diphenhydramine, orphenadrine, or any diphenhydramine equivalent. In some embodiments, the antihistamine is a diphenhydramine equivalent. In some embodiments, the antihistamine is diphenhydramine.

[0330] Antipyretics are drugs or substances that have an antipyretic effect. Antipyretics are known in the art, and any suitable antipyretic can be used in any embodiment provided herein. Non-limiting examples of antipyretics include ibuprofen, aspirin, acetaminophen, naproxen, nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, ketoprofen, flurbiprofen, nimesulide, diclofenac, and celecoxib. In some embodiments, the antipyretic is an NSAID or a salicylate. In some embodiments, the antipyretic is selected from the group including but not limited to ibuprofen, aspirin, acetaminophen, naproxen, ketoprofen, flurbiprofen, nimesulide, diclofenac, and celecoxib. In some embodiments, the antipyretic is ibuprofen. In some embodiments, the antipyretic is aspirin. In some embodiments, the antipyretic is acetaminophen. In some embodiments, the antipyretic is naproxen.

[0331] Exemplary Treatment Methods

[0332] The following treatment methods are exemplary and are not intended to be limiting in any way. In some embodiments, the method is provided in Table 13 below:

[0333] Table 13 - Exemplary Treatment Methods

[0334]

[0335]

[0336] a Can be increased to 1500 μg / kg QW or intermediate doses.b If previously increased to 1500 μg / kg QW, it can be further increased to 3000 μg / kg Q2W. c Can be increased to 6000 μg / kg Q4W. d 30,000 units of hyaluronidase were administered.

[0337] In some embodiments, the method comprises a tiered dosing regimen wherein the terituzumab dose is determined based on a subject weight threshold of 60 kg. In some embodiments, the method is as provided in Table 14 below:

[0338] Table 14 - Exemplary Treatment Methods

[0339]

[0340]

[0341] a If the Q2W dose is determined to be safe, it can be increased to 300 mg Q4W. b If the Q2W dose is determined to be safe,

[0342] The dose can be increased to 450mg Q4W. c 30,000 units of hyaluronidase were administered.

[0343] In some embodiments, the method further comprises a pre-treatment or co-treatment regimen. In some embodiments, the pre-treatment or co-treatment regimen is provided in Table 15 below:

[0344] Table 15 - Exemplary Pretreatment Methods

[0345]

[0346] a Also following administration of daratumumab for Grade 2 and ≥3 related reactions. b Also after a Grade ≥2 cytokine release syndrome or related reaction to terituzumab administration. c For subjects >75 years or ≤75 years with a BMI <18.5, dexamethasone may be administered at a dose of 20 mg. d Also after a Grade ≥2 cytokine release syndrome or related reaction to terituzumab administration. e Also after a Grade ≥2 cytokine release syndrome or related reaction to terituzumab administration.

[0347] In some embodiments, the pretreatment or co-treatment regimen is as provided in Table 16 below:

[0348] Table 16 - Exemplary Pretreatment Methods

[0349]

[0350] a Also following administration of daratumumab for Grade 2 and ≥3 related reactions. b Also after a Grade ≥2 cytokine release syndrome or related reaction to terituzumab administration. c For subjects >75 years or ≤75 years with a BMI <18.5, dexamethasone may be administered at a dose of 20 mg. d Also after a Grade ≥2 cytokine release syndrome or related reaction to terituzumab administration. e Also after a Grade ≥2 cytokine release syndrome or related reaction to terituzumab administration.

[0351] In some embodiments, the method comprises a treatment regimen of Table 13. In some embodiments, the method comprises a treatment regimen of Table 14. In some embodiments, the method comprises a treatment regimen of Table 13 and further comprises a pre-treatment or co-treatment regimen of Table 15. In some embodiments, the method comprises a treatment regimen of Table 13 and further comprises a pre-treatment or co-treatment regimen of Table 16. In some embodiments, the method comprises a treatment regimen of Table 14 and further comprises a pre-treatment or co-treatment regimen of Table 15. In some embodiments, the method comprises a treatment regimen of Table 14 and further comprises a pre-treatment or co-treatment regimen of Table 16.

[0352] Cancer type

[0353] In some embodiments, the cancer is a hematological malignancy or a solid tumor.

[0354] In some embodiments, the hematological malignancy is multiple myeloma, smoldering multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, plasma cell leukemia, light chain amyloidosis (AL), precursor B-cell lymphoblastic leukemia, precursor B-cell lymphoblastic leukemia, leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), B-cell malignancies, chronic myeloid leukemia (CML), hairy cell leukemia (HCL), blastic plasmacytoid dendritic cell neoplasm, Hodgkin lymphoma, non-Hodgkin lymphoma, marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma (MALT), plasma cell leukemia, anaplastic large cell lymphoma (ALCL), leukemia, or lymphoma.

[0355] In some embodiments, the hematological malignancy is multiple myeloma. In some embodiments, the multiple myeloma is newly diagnosed multiple myeloma. In some embodiments, the multiple myeloma is relapsed or refractory multiple myeloma (RRMM).

[0356] In some embodiments, the multiple myeloma is a high-risk multiple myeloma. It is known that subjects with high-risk multiple myeloma relapse early and have a poor prognosis and outcome. A subject can be classified as having high-risk multiple myeloma if the subject has one or more of the following cytogenetic abnormalities: t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, 1qAmp, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p.

[0357] In some embodiments, the subject with high-risk multiple myeloma has one or more chromosomal abnormalities comprising: t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, 1qAmp, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p; or t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof.

[0358] Various qualitative and / or quantitative methods can be used to determine the relapse or refractory nature of the disease. Symptoms that may be associated are, for example, a decline or stabilization of the patient's health, or the re-emergence or worsening of various symptoms associated with solid tumors, and / or the spread of cancer cells from one site in the body to other organs, tissues, or cells.

[0359] Cytogenetic abnormalities can be detected, for example, by fluorescence in situ hybridization (FISH). In two chromosomal translocations, oncogenes are translocated to the IgH region on chromosome 14q32, resulting in these genes being dysregulated. t(4;14)(p16;q32) involves a translocation of fibroblast growth factor receptor 3 (FGFR3) and a protein containing multiple myeloma SET domain (MMSET) (also referred to as WHSC1 / NSD2), and t(14;16)(q32;q23) involves a translocation of the MAF transcription factor C-MAF. 17p deletion (del17p) involves the loss of the p53 locus.

[0360] In some embodiments, the multiple myeloma is relapsed or refractory to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0361] In some embodiments, the multiple myeloma is relapsed or refractory to treatment with an anti-CD38 antibody. In some embodiments, the multiple myeloma is relapsed or refractory to treatment with lenalidomide. In some embodiments, the multiple myeloma is relapsed or refractory to treatment with bortezomib. In some embodiments, the multiple myeloma is relapsed or refractory to treatment with pomalidomide. In some embodiments, the multiple myeloma is relapsed or refractory to treatment with carfilzomib. In some embodiments, the multiple myeloma is relapsed or refractory to treatment with elotuzumab. In some embodiments, the multiple myeloma is relapsed or refractory to treatment with ixazomib. In some embodiments, the multiple myeloma is relapsed or refractory to treatment with melphalan. In some embodiments, the multiple myeloma is relapsed or refractory to treatment with thalidomide.

[0362] In some embodiments, the hematological malignancy is AML.

[0363] In some embodiments, AML is AML with at least one genetic abnormality. In some embodiments, AML is AML with multilineage morbidity. In some embodiments, AML is therapy-related AML. In some embodiments, AML is undifferentiated AML. In some embodiments, AML is immature AML. In some embodiments, AML is mature AML. In some embodiments, AML is acute myelomonocytic leukemia. In some embodiments, AML is acute monocytic leukemia. In some embodiments, AML is acute erythroleukemia. In some embodiments, AML is acute megakaryocytic leukemia. In some embodiments, AML is acute basophilic leukemia. In some embodiments, AML is acute panmyelosis with fibrosis. In some embodiments, AML is myeloid sarcoma.

[0364] In some embodiments, the at least one genetic abnormality is a translocation between chromosomes 8 and 21, a translocation or inversion of chromosome 16, a translocation between chromosomes 15 and 17, a change in chromosome 11, or a mutation in fms-related tyrosine kinase 3 (FLT3), nucleolar phosphatidylserine (NPM1), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), DNA (cytosine-5)-methyltransferase 3 (DNMT3A), CCAAT / enhancer binding protein alpha (CEBPA), U2 small nuclear RNA accessory factor 1 (U2AF1), enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), maintenance of chromosome structure protein 1A (SMC1A), or maintenance of chromosome structure protein 3 (SMC3).

[0365] In some embodiments, the at least one genetic abnormality is a translocation between chromosomes 8 and 21. In some embodiments, the at least one genetic abnormality is a translocation or inversion of chromosome 16. In some embodiments, the at least one genetic abnormality is a translocation between chromosomes 15 and 17. In some embodiments, the at least one genetic abnormality is a change in chromosome 11. In some embodiments, the at least one genetic abnormality is a mutation in fms-related tyrosine kinase 3 (FLT3). In some embodiments, the at least one genetic abnormality is a mutation in nucleolar phosphatidylcholine (NPM1). In some embodiments, the at least one genetic abnormality is a mutation in isocitrate dehydrogenase 1 (IDH1). In some embodiments, the at least one genetic abnormality is a mutation in isocitrate dehydrogenase 2 (IDH2). In some embodiments, the at least one genetic abnormality is a mutation in DNA (cytosine-5)-methyltransferase 3 (DNMT3A). In some embodiments, the at least one genetic abnormality is a mutation in CCAAT / enhancer binding protein alpha (CEBPA). In some embodiments, the at least one genetic abnormality is a mutation in U2 small nuclear RNA accessory factor 1 (U2AF1). In some embodiments, at least one genetic abnormality is a mutation in enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2). In some embodiments, at least one genetic abnormality is a mutation in maintenance of chromosome structure protein 1A (SMC1A). In some embodiments, at least one genetic abnormality is a mutation in maintenance of chromosome structure protein 3 (SMC3).

[0366] In some embodiments, the at least one genetic abnormality is translocation t(8;21)(q22;q22), inversion inv(16)(p13;q22), translocation t(16;16)(p13;q22), translocation t(15;17)(q22;q12), mutation FLT3-ITD, mutation R132H or R100Q / R104V / F108L / R119Q / I130V of IDH1, or mutation R140Q or R172 of IDH2.

[0367] In some embodiments, at least one genetic abnormality is the translocation t(8;21)(q22;q22). In some embodiments, at least one genetic abnormality is the inversion inv(16)(p13;q22). In some embodiments, at least one genetic abnormality is the translocation t(16;16)(p13;q22). In some embodiments, at least one genetic abnormality is the translocation t(15;17)(q22;q12). In some embodiments, at least one genetic abnormality is the mutation FLT3-ITD. In some embodiments, at least one genetic abnormality is the mutation R132H of IDH1. In some embodiments, at least one genetic abnormality is the mutation R100Q / R104V / F108L / R119Q / I130V of IDH1. In some embodiments, at least one genetic abnormality is the mutation R140Q of IDH2. In some embodiments, at least one genetic abnormality is the mutation R172 of IDH2.

[0368] In some embodiments, the hematological malignancy is ALL.

[0369] In some embodiments, the ALL is B-cell lineage ALL, T-cell lineage ALL, adult ALL, or childhood ALL.

[0370] In some embodiments, ALL is B-cell lineage ALL. In some embodiments, ALL is T-cell lineage ALL. In some embodiments, ALL is adult ALL. In some embodiments, ALL is pediatric ALL.

[0371] In some embodiments, the subject with ALL has a Philadelphia chromosome or is resistant or has acquired resistance to treatment with a BCR-ABL kinase inhibitor.

[0372] In some embodiments, the subject with ALL has a Philadelphia chromosome. In some embodiments, the subject with ALL is resistant or has acquired resistance to treatment with a BCR-ABL kinase inhibitor.

[0373] Ph chromosome is present in about 20% of adults with ALL and a small part of children with ALL and is associated with poor prognosis. When relapse occurs, patients with Ph+ positive ALL can take tyrosine kinase inhibitor (TKI) regimens and therefore can become resistant to TKI. Therefore, anti-CD38 antibodies can be administered to subjects who have become resistant to selective or partially selective BCR-ABL inhibitors. Exemplary BCR-ABL inhibitors are, for example, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, barfitinib, sacatinib, tauzacer or daruseluting.

[0374] Other chromosomal rearrangements identified in patients with B-lineage ALL are t(v;11q23) (MLL rearrangement), t(1;19)(q23;p13.3); TCF3-PBX1 (E2A-PBX1), t(12;21)(p13;q22); ETV6-RUNX1 (TEL-AML1), and t(5;14)(q31;q32); IL3-IGH.

[0375] In some embodiments, the subject has ALL with t(v;11q23)(MLL rearrangement), t(1;19)(q23;p13.3); TCF3-PBX1(E2A-PBX1), t(12;21)(p13;q22); ETV6-RUNX1(TEL-AML1), or t(5;14)(q31;q32); IL3-IGH chromosomal rearrangement.

[0376] Chromosomal rearrangements can be identified using well-known methods, such as fluorescence in situ hybridization, karyotyping, pulsed-field gel electrophoresis, or sequencing.

[0377] In some embodiments, the hematological malignancy is smoldering multiple myeloma. In some embodiments, the hematological malignancy is MGUS. In some embodiments, the hematological malignancy is ALL. In some embodiments, the hematological malignancy is DLBLC. In some embodiments, the hematological malignancy is BL. In some embodiments, the hematological malignancy is FL. In some embodiments, the hematological malignancy is MCL. In some embodiments, the hematological malignancy is Waldenstrom's macroglobulinemia. In some embodiments, the hematological malignancy is plasma cell leukemia. In some embodiments, the hematological malignancy is AL. In some embodiments, the hematological malignancy is precursor B-cell lymphocytic leukemia. In some embodiments, the hematological malignancy is precursor B-cell lymphocytic leukemia. In some embodiments, the hematological malignancy is myelodysplastic syndrome (MDS). In some embodiments, the hematological malignancy is CLL. In some embodiments, the hematological malignancy is a B-cell malignancy. In some embodiments, the hematological malignancy is CML. In some embodiments, the hematological malignancy is HCL. In some embodiments, the hematological malignancy is blastic plasmacytoid dendritic cell neoplasm. In some embodiments, the hematological malignancy is Hodgkin lymphoma. In some embodiments, the hematological malignancy is non-Hodgkin lymphoma. In some embodiments, the hematological malignancy is MZL. In some embodiments, the hematological malignancy is MALT. In some embodiments, the hematological malignancy is plasma cell leukemia. In some embodiments, the hematological malignancy is ALCL. In some embodiments, the hematological malignancy is leukemia. In some embodiments, the hematological malignancy is lymphoma.

[0378] Subject population

[0379] In some embodiments, the subject is an adult 18 years of age or older. In some embodiments, the subject is about 18 to about 100 years of age, about 19 to 100 years of age, about 20 to 100 years of age, about 25 to 100 years of age, about 30 to 100 years of age, about 35 to 100 years of age, about 40 to 100 years of age, about 45 to 100 years of age, about 50 to 100 years of age, about 60 to 100 years of age, about 70 to 100 years of age, about 80 to 100 years of age, about 90 to 100 years of age, or any age or age range therebetween. In some embodiments, the subject is greater than 100 years of age. In some embodiments, the subject is from about 18 to about 100 years old, from about 18 to about 90 years old, from about 18 to about 80 years old, from about 18 to about 70 years old, from about 18 to about 60 years old, from about 18 to about 50 years old, from about 18 to about 45 years old, from about 18 to about 40 years old, from about 18 to about 35 years old, from about 18 to about 30 years old, from about 18 to about 25 years old, from about 18 to about 20 years old, from about 18 to about 19 years old, or any age or age range therebetween. In some embodiments, the subject is 18 years old or older.

[0380] In some embodiments, the subject is an adolescent between the ages of 12 and 17. In some embodiments, the subject is less than 18 years old. In some embodiments, the subject is 12 years old. In some embodiments, the subject is 13 years old. In some embodiments, the subject is 14 years old. In some embodiments, the subject is 15 years old. In some embodiments, the subject is 16 years old. In some embodiments, the subject is 16 years old.

[0381] In some embodiments, the subject has a primary diagnosis of multiple myeloma according to the International Myeloma Working Group (IMWG) diagnostic criteria.

[0382] In some embodiments, the subject has newly diagnosed multiple myeloma. In some embodiments, the subject has previously been diagnosed with multiple myeloma. In some embodiments, the subject previously diagnosed with multiple myeloma has received 1 to 3 previous therapy lines. In some embodiments, the subject previously diagnosed with multiple myeloma has received 1 previous therapy line. In some embodiments, the subject previously diagnosed with multiple myeloma has received 2 previous therapy lines. In some embodiments, the subject previously diagnosed with multiple myeloma has received 3 previous therapy lines. In some embodiments, the subject previously diagnosed with multiple myeloma and has received 1 to 3 previous therapy lines has received protease inhibitors (PIs), immunomodulatory drugs (IMiDs), or a combination thereof. In some embodiments, the subject previously diagnosed with multiple myeloma and has received 1 to 3 previous therapy lines has received protease inhibitors (PIs). In some embodiments, the subject previously diagnosed with multiple myeloma and has received 1 to 3 previous therapy lines has received immunomodulatory drugs (IMiDs). In some embodiments, the subject who has been previously diagnosed with multiple myeloma and has received 1 to 3 prior lines of therapy has received a protease inhibitor (PI) and an immunomodulatory drug (IMiD).

[0383] In some embodiments, the subject is newly diagnosed with multiple myeloma and is not considered a candidate for high-dose chemotherapy using autologous stem cell transplantation (ASCT). In some embodiments, the subject is not considered a candidate for high-dose chemotherapy using ASCT due to advanced age. In some embodiments, due to the presence of comorbid conditions that may have a negative impact on the tolerance to high-dose chemotherapy using ASCT, the subject is not considered a candidate for high-dose chemotherapy using ASCT. In some embodiments, due to the delay of high-dose chemotherapy using ASCT as initial treatment, the subject is not considered a candidate for high-dose chemotherapy using ASCT.

[0384] In some embodiments, the subject suffers from measurable disease before therapy begins.In some embodiments, measurable disease is defined as serum IgG free light chains (FLC) and abnormal serum Ig κ λ FLC ratios with serum M protein levels of ≥1.0g / dL, urine M protein levels of ≥200mg / 24 hours, serum IgG free light chains (FLC) and abnormal serum Ig κ λ FLC ratios of ≥10mg / dL, or a combination thereof.In some embodiments, measurable disease is defined as serum M protein levels with ≥1.0g / dL.In some embodiments, measurable disease is defined as urine M protein levels with ≥200mg / 24 hours.In some embodiments, measurable disease is defined as serum IgG free light chains (FLC) and abnormal serum Ig κ λ FLC ratios with ≥10mg / dL. In some embodiments, measurable disease is defined as having a serum M-protein level ≥1.0 g / dL, a urine M-protein level ≥200 mg / 24 hours, and serum IgG free light chains (FLC) ≥10 mg / dL and an abnormal serum IgκλFLC ratio.

[0385] IMWG diagnostic criteria

[0386] Multiple myeloma is defined as ≥10% clonal bone marrow plasma cells or biopsy-proven bone or extramedullary plasmacytoma and at least one of the following two criteria:

[0387] 1. Evidence of end-organ damage, specifically: C: hypercalcemia; R: renal insufficiency; A: anemia; and B: bone lesions. In some embodiments, hypercalcemia is defined as serum calcium >0.25 mmol / L (>1 mg / dL) above the upper limit of normal, or >2.75 mmol / L (>11 mg / dL). In some embodiments, hypercalcemia is defined as serum calcium >0.25 mmol / L (>1 mg / dL) above the upper limit of normal. In some embodiments, hypercalcemia is defined as serum calcium >2.75 mmol / L (>11 mg / dL). In some embodiments, renal insufficiency is defined as creatine clearance <40 mL / min or serum creatine >177 μmol / L (>2 mg / dL). In some embodiments, renal insufficiency is defined as creatine clearance <40 mL / min. In some embodiments, renal insufficiency is defined as serum creatine >177 μmol / L (>2 mg / dL). In some embodiments, anemia is defined as a hemoglobin value >20 g / L below the lower limit of normal, or a hemoglobin value <100 g / L. In some embodiments, anemia is defined as a hemoglobin value >20 g / L below the lower limit of normal. In some embodiments, anemia is defined as a hemoglobin value <100 g / L. In some embodiments, bone lesions are defined as one or more lytic bone lesions on skeletal radiography, CT, or PET-CT.

[0388] 2. Any one or more of the following biomarkers of malignancy: clonal bone marrow plasma cell percentage ≥60%, involved / uninvolved serum FLC ratio ≥100, and >1 focal lesion on MRI study.

[0389] ending

[0390] In some embodiments, the subject treated by the method provided herein has a partial response (PR) or a better response. In some embodiments, the subject treated by the method provided herein has a very good partial response (VGPR) or a better response. In some embodiments, the subject treated by the method provided herein has a complete response (CR) or a better response. In some embodiments, the subject treated by the method provided herein has a strict complete response (sCR) or a better response. Unless otherwise indicated herein, PR, VGPR, CR, sCR, stable disease (SD) and progressive disease (PD) are as defined by IMWG 2016 standards. IMWG (2016) response criteria are provided in Table A below.

[0391] Table A

[0392]

[0393]

[0394] CR = complete response; FLC = free light chain; IMWG = International Myeloma Working Group; M protein = monoclonal paraprotein; MR = minimal response; PC = plasma cell; PD = progressive disease; PR = partial response; sCR = stringent complete response; SD = stable disease; VGPR = very good partial response

[0395] a The presence / absence of clonal cells is based on the kappa / lambda ratio. Abnormal kappa / lambda ratio determined by immunohistochemistry or immunofluorescence

[0396] A minimum of 100 plasma cells is required for analysis. An abnormal ratio, reflecting the presence of an abnormal clone, is κ / λ > 4:1 or < 1:2. bIn some cases, the original M protein light chain isotype may still be detected upon immunofixation, but the accompanying heavy chain component has disappeared; this would not be considered a CR, even if the heavy chain component is undetectable, because the clone may have evolved into a light chain-only clone. Therefore, if a participant has an IgA lambda myeloma, in order to be considered a CR, there should be no detectable IgA upon immunofixation in serum or urine; if free lambda is detected without IgA, it must be accompanied by a different heavy chain isotype (IgG, IgM, etc.).

[0397] c Clarification of the criteria used to code disease progression: The bone marrow criteria for disease progression were used only for participants without measurable disease as measured by M-protein and FLC levels; the “25% increase” referred to M-protein and FLC, not to bone lesions or soft tissue plasmacytomas, and the “lowest response value” did not need to be a confirmed value.

[0398] *Explanation of the criteria used to code CR and VGPR in participants in whom the only measurable disease was by sFLC levels: In addition to the CR criteria listed above, CR in such participants indicates a normal FLC ratio of 0.26 to 1.65. VGPR in such participants requires a >90% reduction in the difference between affected and unaffected FLC levels.

[0399] In some embodiments, PR is defined as a reduction of serum M protein by more than 50% and a reduction of 24-hour urine M protein by >90% or to <200 mg / 24 hours. In some embodiments, VGPR is defined as serum and urine M protein levels detectable by immunofixation but not by electrophoresis, or a reduction of serum M protein by >90% plus a urine M protein level <100 mg / 24 hours. In some embodiments, CR is defined as negative serum and urine immunofixation, disappearance of any soft tissue plasmacytoma, and <5% plasma cells in the bone marrow. In some embodiments, sCR is defined as the above CR definition plus a normal FLC ratio and the absence of clonal cells in the bone marrow as determined by immunohistochemistry or immunofluorescence.

[0400] In some embodiments, the subject treated by the method provided herein will have a reduction in BCMA-expressing cells. In some embodiments, the subject treated by the method provided herein will have an increase in serum or plasma protein over time, such as, but not limited to, cytokines (such as IL-6, IFN-γ, IL-10, and IL-2Rα). In some embodiments, the subject treated by the method provided herein will have a pharmacodynamic marker indicating the mechanism of action of daratumumab, such as a reduction in CD38+NK cells or T reg cells in the periphery. In some embodiments, the subject treated by the method provided herein will have a reduction in minimal residual disease (MRD), as determined by bone marrow puncture DNA and next generation sequencing. In some embodiments, the subject treated by the method provided herein will have a continuous MRD- negative complete response (CR), wherein the subject is MRD- negative and continues to be greater than or equal to 12 months. The subject with continuous MRD- negative CR (≥12 months) is a subject with CR or better, who maintains MRD- negative status for at least 12 months, as determined by NGS with 10 -5 The sensitivity was determined without any test showing MRD-positive status or disease progression.

[0401] In some embodiments, subjects treated by the methods provided herein will have a greater positive response compared to other lines of therapy.

[0402] In some embodiments, subjects treated by the methods provided herein will maintain or improve on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30).

[0403] In some embodiments, subjects treated by the methods provided herein will maintain or improve on the Patient Reported Outcome version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).

[0404] In some embodiments, subjects treated by the methods provided herein will maintain or improve on the EuroQol 5-Dimension Questionnaire 5-Level (EQ-5D-5L).

[0405] In some embodiments, a subject treated by the methods provided herein will experience an improvement in one or more symptoms associated with a disease or disorder.

[0406] Pharmaceutical compositions and kits

[0407] The present invention also provides a pharmaceutical composition comprising the BCMAxCD3 bispecific antibody described herein and an anti-CD38 antibody. For example, the composition may comprise: a BCMA binding domain comprising a VH of SEQ ID NO: 18 and a VL of SEQ ID NO: 19; a CD3 binding domain comprising a VH of SEQ ID NO: 20 and a VL of SEQ ID NO: 21; and an anti-CD38 antibody comprising a VH of SEQ ID NO: 34 and a VL of SEQ ID NO: 35.

[0408] In some embodiments, the pharmaceutical composition comprises: a BCMAxCD3 bispecific antibody comprising HCl of SEQ ID NO: 22, LC1 of SEQ ID NO: 23, HC2 of SEQ ID NO: 24, LC2 of SEQ ID NO: 25; and an anti-CD38 antibody comprising HC of SEQ ID NO: 36 and LC of SEQ ID NO: 37. In some embodiments, the BCMAxCD3 bispecific antibody is of the IgG4 isotype and comprises a phenylalanine at position 405 and an arginine at position 409 in the first heavy chain (HCl), and a leucine at position 405 and a lysine at position 409 in the second heavy chain (HC2), wherein residue numbering is according to the EU index. In some embodiments, the BCMAxCD3 bispecific antibody further comprises a proline at position 228, an alanine at position 234, and an alanine at position 235 in both HCl and HC2.

[0409] The present disclosure also provides a kit or combination for use in the method of the present application, wherein the kit or combination comprises a BCMAxCD3 bispecific antibody and an anti-CD38 antibody.

[0410] Methods for producing antibodies used in the methods of the invention

[0411] Antibodies that bind to a specific antigen used in the methods of the invention can be re-selected, for example, from phage display libraries in which phage are engineered to express human immunoglobulins or portions thereof, such as Fab, single-chain antibodies (scFv), or unpaired or paired antibody variable regions (Knappik et al., J Mol Biol 296:57-86, 2000; Krebs et al., J Immunol Meth 254:67-84, 2001; Vaughan et al., Nature Biotechnology 14:309-14, 1996; Sheets et al., PITAS (USA) 95:6157-62, 1998; Hoogenboom and Winter, J Mol Biol 227:381, 1991; Marks et al., J Mol Biol 222:581, 1991). Phage display libraries express antibody heavy and light chain variable regions as fusion proteins with the phage pIX coat protein, as described in Shi et al. (2010) J. Mol. Biol. 397:385-96 and International Patent Publication No. WO2009 / 085462. Antibody libraries can be screened for binding to a desired antigen, such as BCMA, and positive clones obtained can be further characterized, and Fabs isolated from clone lysates can then be cloned as full-length antibodies. Such phage display methods for isolating human antibodies are well established in the art. See, e.g., U.S. Patent No. 5,223,409, U.S. Patent No. 5,403,484, U.S. Patent No. 5,571,698, U.S. Patent No. 5,427,908, U.S. Patent No. 5,580,717, U.S. Patent No. 5,969,108, U.S. Patent No. 6,172,197, U.S. Patent No. 5,885,793, U.S. Patent No. 6,521,404, U.S. Patent No. 6,544,731, U.S. Patent No. 6,555,313, U.S. Patent No. 6,582,915, and U.S. Patent No. 6,593,081.

[0412] T cell redirecting bispecific antibodies can be generated in vitro in a cell-free environment by the following process: according to the method described in International Patent Publication No. WO2011 / 131746, asymmetric mutations are introduced into the CH3 regions of two monospecific homodimeric antibodies, and a bispecific heterodimeric antibody is formed from the two parent monospecific homodimeric antibodies under reducing conditions that allow disulfide bond isomerization. In the method, two monospecific bivalent antibodies are engineered to have certain substitutions in the CH3 domain that promote heterodimer stability; these antibodies are incubated together under reducing conditions sufficient to cause disulfide bond isomerization of cysteines in the hinge region; thereby generating the bispecific antibody through Fab arm exchange. The incubation conditions can ideally be restored to non-reducing conditions. Exemplary reducing agents that can be used are 2-mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris(2-carboxyethyl)phosphine (TCEP), L-cysteine, and β-mercaptoethanol, preferably a reducing agent selected from the group consisting of 2-mercaptoethylamine, dithiothreitol, and tris(2-carboxyethyl)phosphine. For example, the following conditions can be used: in the presence of at least 25 mM 2-MEA or at least 0.5 mM dithiothreitol, at a pH of 5-8, such as pH 7.0 or pH 7.4, and at a temperature of at least 20°C, for incubation for at least 90 minutes.

[0413] Exemplary CH3 mutations that can be used in the first and second heavy chains of the bispecific antibody are K409R and / or F405L.

[0414] Additional CH3 mutations that may be used include, for example Technologies such as mutagenesis (Genmab), knob-hole mutagenesis (Genentech), electrostatic matching mutagenesis (Chugai, Amgen, NovoNordisk, Oncomed), strand exchange engineered domain body (SEEDbody) (EMD Serono), and other asymmetric mutagenesis (e.g., Zymeworks).

[0415] Mutations (Genmab) are disclosed in, for example, US9150663 and US2014 / 0303356, and include mutations F405L / K409R, wild type / F405L_R409K, T350I_K370T_F405L / K409R, K370W / K409R, D399AFGHILMNRSTVWY / K409R, T366ADEFGHILMQVY / K409R, L368ADEGHNRSTVQ / K409AGRH, D399FHKRQ / K409AGRH, F405IKLSTVW / K409AGRH, and Y407LWQ / K409AGRH.

[0416] Knob-hole mutations are disclosed, for example, in WO1996 / 027011 and include mutations at the CH3 interface, where amino acids with small side chains (holes) are introduced into the first CH3 domain, while amino acids with large side chains (knobs) are introduced into the second CH3 domain, resulting in preferential interactions between the first and second CH3 domains. Exemplary CH3 domain mutations that form knobs and holes are T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V.

[0417] The formation of heavy chain heterodimers can be promoted by using electrostatic interactions by replacing positively charged residues on the first CH3 region with negatively charged residues on the second CH3 region, as described in US2010 / 0015133, US2009 / 0182127, US2010 / 028637 or US2011 / 0123532.

[0418] Other asymmetric mutations that can be used to promote heavy chain heterodimerization are L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, or T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W, as described in US2012 / 0149876 or US2013 / 0195849.

[0419] SEEDbody mutations involve substitution of selected IgG residues for IgA residues to promote heavy chain heterodimerization as described in US20070287170.

[0420] Other exemplary mutations that can be used are R409D_K370E / D399K_E357K, S354C_T366W / Y349C_T366S_L368A_Y407V, Y349C_T366W / S354C_T366S_L368A_Y407V, T366K / L351D, L351K / Y349E, L351K / Y349D, L351K / L368E, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, K392D / D399K, K392D / E356K, K253E_D282K_K322D / D239K_E240K_K292D, K392D_K409D / D356K_D399K, as described in WO2007 / 147901, WO2011 / 143545, WO2013157954, WO2013096291 and US2018 / 0118849.

[0421] Additional bispecific or multispecific structures that can be used as BCMAxCD3 bispecific antibodies include dual variable domain immunoglobulins (DVDs) (International Patent Publication No. WO2009 / 134776; DVDs are full-length antibodies comprising a heavy chain having a VH1-linker-VH2-CH structure and a light chain having a VL1-linker-VL2-CL structure; the linker is optional), structures comprising a variety of dimerization domains to connect two antibody arms with different specificities such as leucine zippers or collagen dimerization domains (International Patent Publication No. WO2012 / 022811, U.S. Patent No. 5,932,448 and U.S. Patent No. 6,833,441), two or more domain antibodies (dAbs) conjugated together, bivalent antibodies, heavy chain-only antibodies such as camelid antibodies and engineered camelid antibodies, dual targeting (DT)-Ig (GSK / Domantis), two-in-one antibodies (Genentech), cross-linked Mabs (Karmanos Cancer Research Institute, Inc.), and antibodies. Center), mAb2 (F-Star) and CovX-host (CovX / Pfizer), IgG-like bispecific antibodies (InnClone / Eli Lilly), Ts2Ab (MedImmune / AZ) and BsAb (Zymogenetics), HERCULES (Biogen Idec) and TvAb (Roche), ScFv / Fc fusions (Academic Institution), SCORPION (Emergent BioSolutions / Trubion, Zymogenetics / BMS), dual affinity retargeting technology (Fc-DART) (MacroGenics) and bis(ScFv)2-Fab (National Research Center for Antibody Medicine--China), bifunctional or Bis-Fab (Genentech), dock-lock (DNL) (ImmunoMedics), bivalent bispecific (Biotecnol), and Fab-Fv (UCB-Celltech). ScFv-based, diabody-based domain antibodies include, but are not limited to, bispecific T-cell engager (BiTE) (Micromet), tandem diabody (Tandab) (Affimed), dual affinity retargeting technology (DART) (MacroGenics), single-chain diabody (Academic), TCR-like antibody (AIT, ReceptorLogics), human serum albumin ScFv fusion (Merrimack) and COMBODY (Epigen Biotech), dual-targeting nanobody (Ablynx), dual-targeting heavy chain domain-only antibody.

[0422] Antibody Fc engineering

[0423] The Fc region of a BCMAxCD3 bispecific antibody, such as a bispecific or multispecific antibody or an anti-CD38 antibody, may include at least one substitution in the Fc region that reduces binding of the BCMAxCD3 bispecific antibody to an activating Fcγ receptor (FcγR) and / or reduces Fc effector function, such as C1q binding, complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), or phagocytosis (ADCP).

[0424] The Fc positions that reduce Fc binding to activating FcγRs and subsequently reduce effector function are the following substitutions: L234A / L235A on IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, K214T / E233P / L234V / L235A / G236 deletion / A327G on IgG1 / P331A / D365E / L358M on IgG2, H268Q / V309L / A330S / P331S on IgG2, S267E / L328F on IgG1, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236 deletion / G237A / P238S on IgG4.

[0425] An Fc substitution that may be used to reduce CDC is the K322A substitution.

[0426] The well-known S228P substitution can also be made in IgG4 antibodies to enhance IgG4 stability.

[0427] An exemplary wild-type IgG1 comprises the amino acid sequence of SEQ ID NO: 16. An exemplary wild-type IgG4 comprises the amino acid sequence of SEQ ID NO: 17.

[0428] "Antibody-dependent cellular cytotoxicity," "antibody-dependent cell-mediated cytotoxicity," or "ADCC" is a mechanism of inducing cell death that relies on the interaction of antibody-coated target cells with effector cells with lytic activity, such as natural killer (NK) cells, monocytes, macrophages, and neutrophils, via Fcγ receptors (FcγRs) expressed on the effector cells. For example, NK cells express FcγRIIIa, while monocytes express FcγRI, FcγRII, and FcγRIIIa. The ADCC activity of an antibody can be assessed using an in vitro assay using cells expressing the protein to which the antibody binds as target cells and NK cells as effector cells. Cell lysis is detected based on the release of a marker (e.g., a radioactive substrate, a fluorescent dye, or a native intracellular protein) from the lysed cells. In an exemplary assay, target cells can be used at a ratio of 1 target cell to 4 effector cells. Target cells are pre-labeled with BATDA and mixed with effector cells and a test antibody. The sample is incubated for 2 hours, and the rate of cell lysis is measured by measuring the BATDA released into the supernatant. Data were normalized to maximal cytotoxicity using 0.67% Triton X-100 (Sigma Aldrich) and to a minimal control determined by spontaneous release of BATDA from target cells in the absence of any antibody.

[0429] "Antibody-dependent cellular phagocytosis" ("ADCP") refers to a mechanism by which antibody-coated target cells are eliminated by internalization by phagocytes, such as macrophages or dendritic cells. ADCP can be assessed by using monocyte-derived macrophages as effector cells and cells expressing the protein to which the antibody binds as target cells, which are also engineered to express GFP or another marker molecule. In an exemplary assay, the effector cell: target cell ratio can be, for example, 4:1. The effector cells can be incubated with the target cells for 4 hours with or without the antibodies of the invention. After incubation, the cells can be separated using accutase. Anti-CD11b and anti-CD14 antibodies coupled to fluorescent markers can be used to identify macrophages, and standard methods can be used to identify the macrophages based on CD11 expression. + CD14 + The percentage of phagocytosis was determined by the % GFP fluorescence in macrophages.

[0430] "Complement-dependent cytotoxicity" or "CDC" refers to a mechanism of cell death induction in which the Fc effector domain of a target-binding antibody binds to and activates the complement component C1q, which in turn activates the complement cascade, leading to target cell death. Activation of complement can also result in the deposition of complement components on the surface of target cells, which promote CDC by binding to complement receptors (e.g., CR3) on leukocytes. CDC of cells can be measured, for example, by: Daudi cells are plated at 1×10 5 Cells / well (50 μL / well) were seeded into RPMI-B (RPMI supplemented with 1% BSA), 50 μL of the test antibody was added to the well at a final concentration of 0 μg / mL to 100 μg / mL, the reaction was incubated at room temperature for 15 min, 11 μL of pooled human serum was added to the well, and the reaction was incubated at 37° C. for 45 min. The % of propidium iodide-stained cells can be detected in a FACS assay as the percentage (%) of lysed cells using standard methods.

[0431] Antibody binding to FcγR or FcRn can be assessed using flow cytometry on cells engineered to express each receptor. In an exemplary binding assay, 2×10 5 Individual cells / well were seeded into 96-well plates and blocked at 4°C for 30min in BSA staining buffer (BD Biosciences, San Jose, USA). Cells were incubated on ice at 4°C with test antibodies for 1.5 hours. After washing twice with BSA staining buffer, cells were incubated together at 4°C with R-PE labeled anti-human IgG secondary antibodies (Jackson Immunoresearch Laboratories) for 45min. Cells were washed twice in staining buffer and then resuspended in 150 μL of staining buffer (Cell Signaling Technology, Danvers, USA) containing 1:200 diluted DRAQ7 live / dead stain. B2 and B4 channels were used respectively to detect PE and DRAQ7 signals of stained cells by Miltenyi MACSQuant flow cytometer (Miltenyi Biotec, Auburn, USA). Live cells were gated according to the DRAQ7 exclusion method, and the geometric mean fluorescence signal of at least 10,000 live events collected was determined. Analyses were performed using FlowJo software (Tree Star). Data were plotted as the logarithm of antibody concentration versus mean fluorescence signal. Nonlinear regression analysis was performed.

[0432] Chimeric Antigen Receptor (CAR)

[0433] Chimeric antigen receptor (CAR) is a genetically engineered receptor. These engineered receptors can be easily inserted into immune cells including T cells and expressed by them according to techniques known in the art. For CAR, a single receptor can be programmed to recognize a specific antigen, and when bound to the antigen, activates immune cells to attack and destroy cells carrying the antigen. When these antigens are present on tumor cells, immune cells expressing CAR can target and kill tumor cells.

[0434] A CAR typically comprises an extracellular domain that binds an antigen (e.g., a prostate neoantigen), an optional linker, a transmembrane domain, and a cytoplasmic domain comprising a costimulatory domain and / or a signaling domain.

[0435] The extracellular domain of CAR may contain any polypeptide that binds to a desired antigen (e.g., a prostate neoantigen or a B cell maturation antigen (BCMA)). The extracellular domain may include a portion of an scFv, an antibody, or an alternative scaffold. CAR may also be engineered to bind to two or more desired antigens, which may be arranged in series and separated by a linker sequence. For example, one or more domain antibodies, scFv, llama VHH antibodies, or other VH-only antibody fragments may be organized in series via a linker to provide bispecificity or multispecificity to CAR.

[0436] The transmembrane domain of the CAR can be derived from the transmembrane domain of the following: CD8, α, β or ζ chain of T cell receptor, CD28, CD3ε, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, LFA-1 (CD11), la, CD18), ICOS (CD278), 4-1BB (CD137), 4-1BBL, GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI) , CD160, CD19, IL2Rβ, IL2Rγ, IL7Ra, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDI Id, ITGAE, CD103, ITGAL, CDI la, LFA-1, ITGAM, CDI lb, ITGAX, CDI lc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, DNAM1(CD226), SLAMF4(CD244, 2B4), CD84, CD96(tactile), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD15 0, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, NKG2D and / or NKG2C.

[0437] The intracellular costimulatory domain of CAR can be derived from the intracellular domain of one or more costimulatory molecules.Costimulatory molecules are well-known cell surface molecules except antigen receptors or Fc receptors, which provide T lymphocytes for the effective activation and function of T lymphocytes when combined with antigens. The exemplary costimulatory domains that can be used for CAR are 4-1BB, CD2, CD7, CD27, CD28, CD30, CD40, CD54 (ICAM), CD83, CD134 (OX40), CD150 (SLAMF1), CD152 (CTLA4), CD223 (LAG3), CD270 (HVEM), CD278 (ICOS), DAP10, LAT, NKD2C SLP76, TRIM and ZAP70 intracellular domain.

[0438] The intracellular signaling domain of CAR can be derived from, for example, The signaling domain of CAR polypeptides is a signaling domain of CAR3ζ, CD3ε, CD22, CD79a, CD66d or CD39. "Intracellular signaling domain" refers to the portion of the CAR polypeptide that participates in transducing information about the binding of the effective CAR to the target antigen into the interior of the immune effector cell to trigger effector cell function, such as activation, cytokine production, proliferation and cytotoxic activity, including the release of cytotoxic factors to the target cell bound by the CAR, or other cellular responses triggered after the antigen binds to the extracellular CAR domain.

[0439] The optional linker of the CAR between the extracellular domain and the transmembrane domain can be a polypeptide with a length of about 2 to 100 amino acids. The linker may include flexible residues (such as glycine and serine) or be composed of the flexible residues so that adjacent protein domains can move freely relative to each other. When it is desired to ensure that two adjacent domains do not interfere with each other spatially, a longer linker can be used. The linker can be cleavable or non-cleavable. The example of a cleavable linker includes a 2A linker (such as T2A), a 2A-like linker or their functional equivalents, and a combination thereof. The linker can also be derived from the hinge region of any immunoglobulin or part of the hinge region.

[0440] Exemplary CARs that can be used are, for example, CARs that contain an extracellular domain that binds to a prostate neoantigen of the present invention, a CD8 transmembrane domain, and a CD3 ζ signaling domain. Other exemplary CARs contain an extracellular domain that binds to a prostate neoantigen of the present invention, a CD8 or CD28 transmembrane domain, a CD28, 41BB or OX40 costimulatory domain, and a CD3 ζ signaling domain.

[0441] CARs are generated by standard molecular biology techniques. The extracellular domain that binds to the desired antigen can be derived from an antibody or antigen-binding fragment thereof generated using the techniques described herein.

[0442] Exemplary Embodiments: Treatment Strategies for Newly Diagnosed Multiple Myeloma

[0443] The present inventors have developed a novel dosing regimen for treating multiple myeloma in subjects with newly diagnosed multiple myeloma who are ineligible for, or not contemplated for, autologous stem cell transplantation (ASCT) as initial therapy.

[0444] Newly diagnosed multiple myeloma patients can be broadly classified as either "transplant eligible" or "transplant ineligible." Eligibility for a transplant is typically based on age, health, and comorbidities. For both transplant-eligible and transplant-ineligible patients, systemic therapy, typically administered as a triple or quadruple drug regimen, is the mainstay of treatment. For those patients who are eligible, it is used in combination with ASCT. DRd (daratumumab, lenalidomide, and dexamethasone) or VRd (bortezomib, lenalidomide, and dexamethasone) are two key treatment options, the standard of care, for newly diagnosed patients with multiple myeloma who are not transplant eligible.

[0445] In clinical practice, the treatment of newly diagnosed patients with multiple myeloma is evolving. For some patients, high-dose therapy with ASCT is not feasible, primarily due to advanced age, comorbidities, or patient frailty. In the United States, approximately 40% of all transplant-eligible patients do not receive high-dose therapy and ASCT as initial treatment. This evolution is driven by both the availability of new induction regimens (e.g., DRd, VRd) without high-dose therapy and ASCT, as well as patient preference, and is expected to continue to increase. Recently reported and ongoing pivotal studies reflect this evolution and include (1) patients who were assessed as clinically ineligible for transplant and (2) patients who were clinically eligible for transplant but did not receive transplant as their first treatment option (transplant delay). Results from several studies have shown similar overall survival outcomes with upfront ASCT compared with novel agent-based approaches without ASCT, suggesting that delay of ASCT is not associated with adverse survival outcomes and may be a viable option for appropriate candidates. The IFM2009 study showed no OS benefit in participants randomized to VRd + early ASCT compared with participants who received VRd + delayed ASCT until after first relapse. Current NCCN guidelines support this approach and suggest that delayed ASCT after early stem cell collection and banking is an appropriate option (category 1 recommendation: NCCN 2023).

[0446] Despite numerous treatment options, multiple myeloma remains incurable for the vast majority of patients. With each successive relapse, symptoms return, quality of life worsens, and the duration of response often decreases. Recent reports suggest that dropout rates between first-line and second-line therapies in patients with multiple myeloma are as high as 50%, and the longest possible PFS-driven OS outcomes are achieved with first-line therapies. Therefore, there remains a significant and critical unmet need for new treatment options that target alternative mechanisms of action, provide better disease control, provide deeper and more durable responses, and result in better long-term outcomes, including maintenance of health-related quality of life.

[0447] In the field of oncology, even for drugs that already have established doses in specific indications, the Food and Drug Administration (FDA) recommends further clinical studies to identify the optimal dose for the new indication; otherwise, patients may be exposed to unreasonable and significant risks, as well as other potential drawbacks. (See, e.g., Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases; Draft Guidance for Industry; January 2023). The present inventors have developed a novel dosing regimen for BCMAxCD3 bispecific antibodies that provides an improved safety profile over currently approved regimens while achieving deep and lasting efficacy. In particular, the present inventors have developed a novel dosing regimen for a combination therapy comprising terituzumab, daratumumab, and lenalidomide that may provide a better safety profile than currently approved regimens while achieving deep and lasting efficacy.

[0448] Embodiments of the present invention provide a novel dosing regimen for treating multiple myeloma in a subject with newly diagnosed multiple myeloma, who do not meet autologous stem cell transplantation (ASCT) as initial therapy qualification or do not intend to perform ASCT as initial therapy. As used herein, newly diagnosed subjects are diagnosed as multiple myeloma according to IMWG diagnostic criteria, and have not yet received any previous multiple myeloma or smoldering myeloma therapy (but may have received short-term corticosteroids, no more than 40mg dexamethasone or equivalent per day, for up to 4 days, a total of 160mg dexamethasone or equivalent). Therefore, newly diagnosed subjects do not have relapsed / refractory multiple myeloma (RRMM), that is, they do not have relapse and / or refractory to previous multiple myeloma therapy (but may have received short-term corticosteroids, no more than 40mg dexamethasone or equivalent per day, for up to 4 days, a total of 160mg dexamethasone or equivalent).

[0449] Subjects who are not eligible for ASCT as initial therapy may be ineligible due to: (i) advanced age, or (ii) the presence of comorbid conditions that may negatively impact tolerance to high-dose chemotherapy with ASCT. Subjects who are "not planning" to undergo ASCT as initial therapy are clinically fit enough to undergo ASCT but have delayed this treatment option.

[0450] According to one embodiment, terituzumab, daratumumab, and lenalidomide ("Tec-DR") are administered as a combination therapy for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for, or not contemplated for, autologous stem cell transplantation as initial therapy. According to one embodiment, terituzumab, daratumumab, and lenalidomide are administered as a combination therapy for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for, or not contemplated for, autologous stem cell transplantation as initial therapy.

[0451] According to certain embodiments, Tec-DR improves PFS (progression-free survival) and / or sustained MRD-negative CR (≥12 months) rate compared to DRd in subjects with newly diagnosed multiple myeloma who are not eligible for or not contemplated for ASCT as initial therapy.

[0452] According to certain embodiments, the combination of terituzumab with daratumumab subcutaneously (SC) and lenalidomide provides an effective and safe approach with higher efficacy rates (e.g., mPFS, mOS, and MRD-negative rates) compared to the current standard of care of daratumumab, lenalidomide, and dexamethasone (DRd) and / or bortezomib, lenalidomide, and dexamethasone (VRd).

[0453] According to certain embodiments of the methods provided herein, terituzumab, daratumumab, and lenalidomide ("Tec-DR") are administered as a combination therapy according to the therapeutically effective regimen shown in Table B below for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for or not intended for autologous stem cell transplantation as initial therapy.

[0454] Table B - Exemplary Treatment Methods

[0455]

[0456] IV = intravenous; PO = oral; Q2W = every other week; SC = subcutaneous

[0457] According to alternative embodiments of the methods provided herein, terituzumab, daratumumab, and lenalidomide ("Tec-DR") are administered as a combination therapy according to the therapeutically effective regimen shown in Table C below for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for or not intended for autologous stem cell transplantation as initial therapy.

[0458] Table C - Exemplary Treatment Methods

[0459]

[0460]

[0461] *Lenalidomide dose may need to be adjusted for participants with renal impairment as determined by CrCl. IV = intravenous; Q2W = every 2 weeks; Q4W = every 4 weeks; SC = subcutaneous

[0462] In the regimen shown in Table C, terituzumab is administered after the DR lead-in period and at a reduced frequency (Q4W) after the ramp-up phase is complete. It is believed that the DR lead-in period and the early reduction in terituzumab frequency (Q4W dosing in cycle 3) can reduce infection rates compared to the regimen shown in Table B while still achieving robust efficacy.

[0463] According to one embodiment, a method for treating adult patients with newly diagnosed multiple myeloma who are ineligible for or not planning to undergo autologous stem cell transplantation as initial therapy comprises administering to the subject a therapeutically effective combination therapy comprising a BCMAxCD3 bispecific antibody (e.g., terituzumab), daratumumab, and lenalidomide according to a dosing schedule comprising sequential 28-day treatment cycles, wherein administration of daratumumab begins in cycle 1, administration of lenalidomide begins in cycle 1, and administration of the BCMAxCD3 bispecific antibody begins in cycle 2; and wherein one or more escalating doses and at least one therapeutic dose of the BCMAxCD3 bispecific antibody are subcutaneously administered to the subject during the escalation phase of cycle 2, and wherein a therapeutic dose of the BCMAxCD3 bispecific antibody is subcutaneously administered to the subject monthly (Q4W) starting in cycle 3. In certain embodiments, the regimen further comprises administering dexamethasone orally or intravenously to the subject only in cycles 1 and 2.

[0464] According to another embodiment, a method for treating adult patients with newly diagnosed multiple myeloma who are ineligible for, or not contemplated for, autologous stem cell transplantation as initial therapy comprises administering to the subject a therapeutically effective combination therapy comprising a BCMA x CD3 bispecific antibody (e.g., terituzumab), daratumumab, and lenalidomide according to a regimen comprising 28-day cycles, wherein the regimen comprises:

[0465] For BCMA x CD3 bispecific antibodies (e.g., terituzumab):

[0466] In cycle 2, a first ascending dose of 60 μg / kg (e.g., on day 1 or 2), a second ascending dose of 300 μg / kg (e.g., on day 3 or 4), and then a weekly (QW) dose of 1500 μg / kg (e.g., on days 8 and 15) is administered subcutaneously, and

[0467] In cycle 3 and all subsequent treatment cycles, administer 3000 μg / kg monthly (Q4W) doses subcutaneously (e.g., on day 1);

[0468] For daratumumab :

[0469] In cycles 1-2, 1800 mg subcutaneously weekly (QW) (e.g., on days 1, 8, 15, and 22)

[0470] In cycles 3-6, 1800 mg subcutaneously every two weeks (Q2W) (e.g., on days 1 and 15), and

[0471] 1800 mg subcutaneously monthly (Q4W) (e.g., on Day 1) during Cycle 7 and all subsequent treatment cycles; and

[0472] For lenalidomide :

[0473] In Cycle 1 and all subsequent treatment cycles, 25 mg is administered orally daily for the first 21 days of each 28-day cycle. In certain embodiments, the regimen further includes 20 mg of dexamethasone administered orally or intravenously weekly (QW) (e.g., on Days 1, 8, 15, and 22) during Cycles 1-2 only.

[0474] In certain embodiments, the method achieves a reduction in new infections over time in a population of subjects with newly diagnosed multiple myeloma compared to a population of subjects with newly diagnosed multiple myeloma treated with the combination therapy but receiving more frequent doses of the BCMAxCD3 bispecific antibody (e.g., QW and / or Q2W) in cycle 3 and all subsequent treatment cycles.

[0475] In certain embodiments, the method achieves a reduction in ≥ Grade 3 new infections over time in a population of subjects with newly diagnosed multiple myeloma compared to a population of subjects with newly diagnosed multiple myeloma treated with the combination therapy but receiving more frequent doses of the BCMAxCD3 bispecific antibody (e.g., QW and / or Q2W) in cycle 3 and all subsequent treatment cycles.

[0476] In certain embodiments, the clinical response achieved by the method in the subject is an sCR, CR, VGPR, or PR in the subject, as defined by the IMWG (2016) response criteria.

[0477] In certain embodiments, the method achieves a CR, VGPR, or PR in the subject as defined by the IMWG (2016) response criteria.

[0478] In certain embodiments, the method achieves a VGPR or PR in the subject as defined by the IMWG (2016) response criteria.

[0479] In certain embodiments, the method achieves a median progression-free survival (mPFS) of at least 80 months, or at least 90 months, or at least 100 months, or at least 110 months in a population of subjects with newly diagnosed multiple myeloma who are ineligible for or not intended for autologous stem cell transplantation (ASCT) as initial therapy.

[0480] In certain embodiments, the method achieves a CR or better (i.e., sCR or CR) as defined by the IMWG (2016) response criteria in at least 60%, or at least 65%, or at least 70% of subjects in a population with newly diagnosed multiple myeloma who are not eligible for or are not intended for autologous stem cell transplantation (ASCT) as initial therapy.

[0481] In certain embodiments, the method achieves a sustained MRD-negative CR (≥12 months) rate of at least about 18%, or at least about 20%, or at least about 22%, or at least about 24%, or at least about 26% in a population of subjects with newly diagnosed multiple myeloma who are ineligible for, or not contemplated for, autologous stem cell transplantation (ASCT) as initial therapy after about 50 months of treatment with the combination therapy.

[0482] In certain embodiments, the method achieves a median progression-free survival (mPFS) in a population of subjects with newly diagnosed multiple myeloma who are ineligible for, or not scheduled for, autologous stem cell transplant (ASCT) as initial therapy, wherein the mPFS is greater than a reference mPFS achieved in a reference population of subjects with newly diagnosed multiple myeloma who are ineligible for, or not scheduled for, ASCT as initial therapy who were administered daratumumab, lenalidomide, and dexamethasone (DRd) instead of a combination therapy comprising a BCMA x CD3 bispecific antibody (e.g., terituzumab), daratumumab, and lenalidomide.

[0483] In certain embodiments, the mPFS is at least about 10 months, or at least 20 months, or at least 30 months, or at least 40 months, or at least 50 months greater than the reference mPFS.

[0484] In certain embodiments, the method achieves a median overall survival (mOS) in a population of subjects with newly diagnosed multiple myeloma who are ineligible for, or not scheduled for, autologous stem cell transplant (ASCT) as initial therapy, wherein the mOS is greater than a reference mOS achieved in a reference population of subjects with newly diagnosed multiple myeloma who are ineligible for, or not scheduled for, ASCT as initial therapy who were administered daratumumab, lenalidomide, and dexamethasone (DRd) instead of a combination therapy comprising a BCMA x CD3 bispecific antibody (e.g., terituzumab), daratumumab, and lenalidomide.

[0485] In certain embodiments, the mOS is at least 1 year, or at least 2 years, or at least 3 years, or at least 4 years greater than the reference mOS.

[0486] In certain embodiments, the method achieves a sustained MRD-negative CR (≥12 months) rate in a population of subjects with newly diagnosed multiple myeloma who are ineligible for, or not scheduled for, autologous stem cell transplantation (ASCT) as initial therapy, wherein the sustained MRD-negative CR (≥12 months) rate is greater than a reference sustained MRD-negative CR (≥12 months) rate achieved in a reference population of subjects with newly diagnosed multiple myeloma who are ineligible for, or not scheduled for, ASCT as initial therapy who were administered daratumumab, lenalidomide, and dexamethasone (DRd) instead of a combination therapy comprising a BCMA x CD3 bispecific antibody (e.g., terituzumab), daratumumab, and lenalidomide.

[0487] In certain embodiments, after approximately 50 months of treatment, the sustained MRD-negative CR (≥12 months) rate is at least 4%, or at least 6%, or at least 8%, or at least 10%, or at least 12%, or at least 14% greater than the reference sustained MRD-negative CR (≥12 months) rate.

[0488] In certain embodiments, the reference population has been administered daratumumab, lenalidomide, and dexamethasone (DRd) according to the following schedule:

[0489] For daratumumab :

[0490] In cycles 1-2, 1800 mg subcutaneously weekly (QW) (e.g., on days 1, 8, 15, and 22)

[0491] In cycles 3-6, 1800 mg subcutaneously every two weeks (Q2W) (e.g., on days 1 and 15), and

[0492] 1800 mg subcutaneously monthly (Q4W) (e.g., on Day 1) during Cycle 7 and all subsequent treatment cycles; and

[0493] For lenalidomide :

[0494] 25 mg orally once daily for the first 21 days of each 28-day cycle during Cycle 1 and all subsequent treatment cycles; and

[0495] For dexamethasone: Administer 40 mg or 20 mg of dexamethasone orally or intravenously weekly (QW) (eg, on Days 1, 8, 15, and 22) during Cycle 1 and all subsequent treatment cycles.

[0496] Enumeration implementation

[0497] The following provides enumerated embodiments of the present invention. These embodiments are exemplary only and do not limit the scope of the present disclosure or the appended claims.

[0498] 1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a BCMA x CD3 bispecific antibody, a therapeutically effective amount of an anti-CD38 antibody, and a therapeutically effective amount of an immunomodulatory drug (IMiD) for a period of time sufficient to treat the cancer.

[0499] 2. The method according to embodiment 1, wherein the BCMA x CD3 bispecific antibody comprises:

[0500] (1) a BCMA-binding domain comprising a heavy chain variable region (VH) of heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively, and a light chain variable region (VL) of light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11, respectively, and

[0501] (2) a CD3 binding domain comprising VHs of HCDR1, HCDR2 and HCDR3 having the amino acid sequences of SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14, respectively, and VLs of LCDR1, LCDR2 and LCDR3 having the amino acid sequences of SEQ ID NO: 15, SEQ ID NO: 16 and SEQ ID NO: 17, respectively.

[0502] 3. The method of embodiment 1 or 2, wherein the BCMA binding domain comprises the VH having the amino acid sequence of SEQ ID NO: 18 and the VL having the amino acid sequence of SEQ ID NO: 19; and the CD3 binding domain comprises the VH having the amino acid sequence of SEQ ID NO: 20 and the VL having the amino acid sequence of SEQ ID NO: 21.

[0503] 4. The method of any one of embodiments 1 to 3, wherein the BCMA x CD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 22, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 23, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 24, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 25,

[0504] wherein HC1 associates with LC1 to form a first antigen-binding site that immunospecifically binds to BCMA, and wherein HC2 associates with LC2 to form a second antigen-binding site that immunospecifically binds to CD3.

[0505] 5. The method according to any one of embodiments 1 to 4, wherein the BCMA x CD3 diabody is terituzumab.

[0506] 6. The method according to any one of embodiments 1 to 5, wherein the therapeutically effective amount of the BCMA x CD3 bispecific antibody is about 60 μg / kg to about 6000 μg / kg.

[0507] 7. The method according to embodiment 6, wherein the therapeutically effective amount of the BCMA x CD3 bispecific antibody is selected from 60 μg / kg, 240 μg / kg, 300 μg / kg, 720 μg / kg, 1500 μg / kg, 3000 μg / kg or 6000 μg / kg.

[0508] 8. The method according to any one of embodiments 1 to 5, wherein the therapeutically effective amount of the BCMA x CD3 bispecific antibody is about 3 mg to about 600 mg μg / kg.

[0509] 9. The method according to embodiment 8, wherein the therapeutically effective amount of the BCMA x CD3 bispecific antibody is selected from 3 mg, 4 mg, 15 mg, 24 mg, 25 mg, 100 mg, 150 mg, 200 mg, 300 mg and 450 mg.

[0510] 10. The method according to any one of embodiments 1 to 9, wherein the therapeutically effective amount of the BCMA x CD3 bispecific antibody is administered at a frequency selected from daily, weekly, every two weeks, once every four weeks, or once monthly.

[0511] 11. The method according to any one of embodiments 1 to 10, wherein the method further comprises administering a loading dose of the BCMAxCD3 bispecific antibody prior to administering the therapeutically effective amount of the BCMAxCD3 bispecific antibody.

[0512] 12. The method of embodiment 11, wherein the loading dose comprises one or more ascending doses.

[0513] 13. The method of embodiment 11 or 12, wherein the loading dose comprises 1, 2, 3 or more than 3 ascending doses.

[0514] 14. The method according to embodiment 12 or 13, wherein the one or more ascending doses of the BCMA x CD3 bispecific antibody is about 60 μg / kg to about 6000 μg / kg.

[0515] 15. The method according to embodiment 14, wherein the one or more increasing doses of the BCMA x CD3 bispecific antibody are selected from 60 μg / kg, 240 μg / kg or 300 μg / kg.

[0516] 16. The method according to embodiment 12 or 13, wherein the one or more ascending doses of the BCMA x CD3 bispecific antibody are about 3 mg to about 600 mg.

[0517] 17. The method according to embodiment 16, wherein the one or more ascending doses of the BCMA x CD3 bispecific antibody are selected from 3 mg, 4 mg, 15 mg, 24 mg or 25 mg.

[0518] 18. The method according to embodiment 11 or 12, wherein the loading dose of the BCMAxCD3 bispecific antibody is administered at a frequency selected from daily, every other day, or weekly.

[0519] 19. The method according to any one of embodiments 12 to 17, wherein the one or more ascending doses of the BCMA x CD3 bispecific antibody are administered at a frequency selected from daily, every other day, or weekly.

[0520] 20. The method of any one of embodiments 1 to 19, wherein the anti-CD38 antibody comprises a VH having HCDR1, HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively, and a VL having LCDR1, LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NO: 31, SEQ ID NO: 32, and SEQ ID NO: 33, respectively.

[0521] 21. The method of any one of embodiments 1 to 20, wherein the anti-CD38 antibody comprises the VH having the amino acid sequence of SEQ ID NO: 34 and the VL having the amino acid sequence of SEQ ID NO: 35.

[0522] 22. The method of any one of embodiments 1 to 21, wherein the anti-CD38 antibody comprises a HC having the amino acid sequence of SEQ ID NO: 36 and a LC having the amino acid sequence of SEQ ID NO: 37.

[0523] 23. The method of any one of embodiments 1 to 22, wherein the anti-CD38 antibody is daratumumab.

[0524] 24. The method of any one of embodiments 1 to 23, wherein the therapeutically effective amount of the anti-CD38 antibody is about 1200 mg to about 2400 mg.

[0525] 25. The method of any one of embodiments 1 to 24, wherein the therapeutically effective amount of the anti-CD38 antibody is about 1800 mg.

[0526] 26. The method according to any one of embodiments 1 to 25, wherein the therapeutically effective amount of the anti-CD38 antibody is administered at a frequency selected from daily, weekly, every two weeks, once every four weeks, or monthly.

[0527] 27. The method according to any one of embodiments 1 to 26, wherein the IMiD is selected from the group consisting of thalidomide, pomalidomide, lenalidomide, or any combination thereof.

[0528] 28. The method of any one of embodiments 1 to 27, wherein the IMiD is lenalidomide.

[0529] 29. The method of any one of embodiments 1 to 28, wherein the therapeutically effective amount of the IMiD is about 15 mg to about 50 mg.

[0530] 30. The method of any one of embodiments 1 to 29, wherein the therapeutically effective amount of the IMiD is about 25 mg.

[0531] 31. The method of any one of embodiments 1 to 30, wherein the effective amount of the IMiD is administered at a frequency selected from daily or weekly.

[0532] 32. The method of any one of embodiments 1 to 31, wherein the BCMA x CD3 diabody is administered subcutaneously.

[0533] 33. The method of any one of embodiments 1 to 32, wherein the anti-CD38 antibody is administered subcutaneously.

[0534] 34. The method of any one of embodiments 1 to 33, wherein the IMiD is administered orally.

[0535] 35. The method of any one of embodiments 1 to 34, further comprising administering a pretreatment to the subject.

[0536] 36. The method according to embodiment 35, wherein the pretreatment comprises a glucocorticoid, an antihistamine, an antipyretic, or a combination thereof.

[0537] 37. The method according to embodiment 36, wherein the glucocorticoid is dexamethasone, the antihistamine is diphenhydramine, and the antipyretic is acetaminophen.

[0538] 38. The method of any one of embodiments 35 to 37, wherein the pretreatment regimen comprises administering 8 mg to 40 mg of dexamethasone, 25 mg to 50 mg of diphenhydramine, and 650 mg to 1000 mg of acetaminophen.

[0539] 39. The method of embodiment 38, wherein:

[0540] i) administration of dexamethasone on days 1, 2, 4, and 8 of the first treatment cycle, and weekly thereafter for the second, third, and fourth treatment cycles;

[0541] ii) administering the diphenhydramine for all doses of the anti-CD38 antibody and all escalating doses and the first treatment dose of the BCMAxCD3 bispecific antibody; and

[0542] iii) administering the acetaminophen for all doses of the anti-CD38 antibody and all escalating doses and the first treatment dose of the BCMAxCD3 bispecific antibody.

[0543] 40. The method of embodiment 38 or 39, wherein the pretreatment regimen further comprises montelukast administered at 10 mg.

[0544] 41. A method of treating cancer in a subject in need thereof, the method comprising:

[0545] i) administering subcutaneously to the subject one or more ascending doses of about 60 μg / kg, 240 μg / kg, or 300 μg / kg, or about 3 mg, 4 mg, 15 mg, 24 mg, or 25 mg of the BCMA x CD3 bispecific antibody;

[0546] ii) administering to the subject subcutaneously a therapeutic dose of about 720 μg / kg, 1500 μg / kg, 3000 μg / kg, or 6000 μg / kg, or about 100 mg, 150 mg, 200 mg, 300 mg, or 450 mg of the BCMAxCD3 bispecific antibody following the one or more escalating doses;

[0547] iii) subcutaneously administering to the subject a therapeutically effective amount of about 1200 mg to about 2400 mg of the anti-CD38 antibody; and

[0548] iv) orally administering to the subject a therapeutically effective amount of about 15 mg to about 50 mg of an immunomodulatory drug (IMiD);

[0549] wherein the BCMA x CD3 bispecific antibody, the anti-CD38 antibody, and the ImiD are administered to the subject for a time sufficient to treat the cancer.

[0550] 42. The method of embodiment 41, wherein the BCMA x CD3 bispecific antibody comprises:

[0551] (1) a BCMA-binding domain comprising a heavy chain variable region (VH) of heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively, and a light chain variable region (VL) of light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11, respectively, and

[0552] (2) a CD3 binding domain comprising a VH having HCDR1, HCDR2 and HCDR3 with the amino acid sequences of SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14, respectively, and a VH having HCDR2 and HCDR3 with the amino acid sequences of SEQ ID NO:

[0553] 15. LCDR1 of the amino acid sequence of SEQ ID NO: 16 and SEQ ID NO: 17,

[0554] VL of LCDR2 and LCDR3.

[0555] 43. The method of embodiment 41 or 42, wherein the BCMA binding domain comprises the VH having the amino acid sequence of SEQ ID NO: 18 and the VH having the amino acid sequence of SEQ ID NO:

[0556] The CD3 binding domain comprises the VH having the amino acid sequence of SEQ ID NO: 20 and the VL having the amino acid sequence of SEQ ID NO: 21.

[0557] 44. The method of any one of embodiments 41 to 43, wherein the BCMA x CD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 22, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 23, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 24, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 25,

[0558] wherein HC1 associates with LC1 to form a first antigen-binding site that immunospecifically binds to BCMA, and wherein HC2 associates with LC2 to form a second antigen-binding site that immunospecifically binds to CD3.

[0559] 45. The method of any one of embodiments 41 to 44, wherein the BCMA x CD3 diabody is terituzumab.

[0560] 46. ​​The method according to any one of embodiments 41 to 45, wherein the one or more ascending doses of the BCMA x CD3 bispecific antibody are selected from about 60 μg / kg, 240 μg / kg, 300 μg / kg, or any combination thereof.

[0561] 47. The method according to any one of embodiments 41 to 46, wherein the one or more ascending doses of the BCMA x CD3 bispecific antibody are selected from about 3 mg, 4 mg, 15 mg, 24 mg, 25 mg, or any combination thereof.

[0562] 48. The method of any one of embodiments 41 to 47, wherein the one or more ascending doses of the BCMAxCD3 bispecific antibody are administered at a frequency selected from daily, every other day, or weekly.

[0563] 49. The method according to any one of embodiments 41 to 48, wherein the therapeutic dose of the BCMA x CD3 bispecific antibody is selected from 720 μg / kg, 1500 μg / kg, 3000 μg / kg or 6000 μg / kg or any combination thereof.

[0564] 50. The method according to any one of embodiments 41 to 48, wherein the therapeutic dose of the BCMA x CD3 bispecific antibody is selected from 100 mg, 150 mg, 200 mg, 300 mg or 450 mg or any combination thereof.

[0565] 51. The method according to any one of embodiments 41 to 50, wherein the therapeutic dose of the BCMA x CD3 bispecific antibody is administered at a frequency selected from weekly, every two weeks, once every four weeks, or monthly.

[0566] 52. The method of any one of embodiments 41 to 51, wherein the anti-CD38 antibody comprises a VH having HCDR1, HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively, and a VL having LCDR1, LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NO: 31, SEQ ID NO: 32, and SEQ ID NO: 33, respectively.

[0567] 53. The method of any one of embodiments 41 to 52, wherein the anti-CD38 antibody comprises the VH having the amino acid sequence of SEQ ID NO: 34 and the VL having the amino acid sequence of SEQ ID NO: 35.

[0568] 54. The method of any one of embodiments 41 to 53, wherein the anti-CD38 antibody comprises a HC having the amino acid sequence of SEQ ID NO: 36 and a LC having the amino acid sequence of SEQ ID NO: 37.

[0569] 55. The method of any one of embodiments 41 to 54, wherein the anti-CD38 antibody is daratumumab.

[0570] 56. The method of any one of embodiments 41 to 55, wherein the therapeutically effective amount of the anti-CD38 antibody is about 1800 mg.

[0571] 57. The method of any one of embodiments 41 to 56, wherein the therapeutically effective amount of the anti-CD38 antibody is administered at a frequency selected from weekly, every two weeks, once every four weeks, or monthly.

[0572] 58. The method of any one of embodiments 41 to 57, wherein the IMiD is selected from the group consisting of thalidomide, pomalidomide, lenalidomide, or any combination thereof.

[0573] 59. The method of any one of embodiments 41 to 58, wherein the IMiD is lenalidomide.

[0574] 60. The method of any one of embodiments 41 to 59, wherein the therapeutically effective amount of the IMiD is about 25 mg.

[0575] 61. The method of any one of embodiments 41 to 60, wherein the therapeutically effective amount of the IMiD is administered at a frequency selected from daily or weekly.

[0576] 62. The method of any one of embodiments 41 to 61, further comprising administering a pretreatment to the subject.

[0577] 63. The method of embodiment 62, wherein the pretreatment regimen comprises administering 8 mg to 40 mg of dexamethasone, 25 mg to 50 mg of diphenhydramine, and 650 mg to 1000 mg of acetaminophen.

[0578] 64. The method of embodiment 63, wherein:

[0579] i) administration of dexamethasone on days 1, 2, 4, and 8 of the first treatment cycle, and weekly thereafter for the second, third, and fourth treatment cycles;

[0580] ii) administering the diphenhydramine for all doses of the anti-CD38 antibody and all escalating doses and the first treatment dose of the BCMAxCD3 bispecific antibody; and

[0581] iii) Administer acetaminophen for all doses of the anti-CD38 antibody and all escalating and first treatment doses of the BCMAxCD3 bispecific antibody.

[0582] 65. The method according to embodiment 63 or 64, wherein the pretreatment regimen further comprises montelukast administered at 10 mg.

[0583] 66. A method of treating cancer in a subject in need thereof, the method comprising:

[0584] i) administering subcutaneously to the subject one or more ascending doses of 60 μg / kg, 240 μg / kg, or 300 μg / kg, or any combination thereof, or about 3 mg, 4 mg, 15 mg, 24 mg, or 25 mg, or any combination thereof, of the BCMA x CD3 bispecific antibody at a frequency selected from daily, every other day, or weekly;

[0585] ii) administering to the subject subcutaneously a therapeutic dose of about 720 μg / kg, 1500 μg / kg, 3000 μg / kg, or 6000 μg / kg, or any combination thereof, or about 100 mg, 150 mg, 200 mg, 300 mg, or 450 mg, or any combination thereof, of the BCMAxCD3 bispecific antibody at a frequency selected from weekly, every two weeks, once every four weeks, or monthly, following the one or more ascending doses;...

Claims

1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a BCMA x CD3 bispecific antibody, a therapeutically effective amount of an anti-CD38 antibody, and a therapeutically effective amount of an immunomodulatory drug (IMiD) for a time sufficient to treat the cancer.

2. The method according to claim 1, wherein the BCMA x CD3 bispecific antibody comprises: (1) a BCMA binding domain, the BCMA binding domain comprising a heavy chain variable region (VH) having heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 having amino acid sequences of SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, respectively, and a light chain variable region (VL) having light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3 having amino acid sequences of SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:11, respectively, and (2) a CD3 binding domain, the CD3 binding domain comprising a VH having HCDRs HCDR1, HCDR2, and HCDR3 having amino acid sequences of SEQ ID NO:12, SEQ ID NO:13, and SEQ ID NO:14, respectively, and a VL having LCDRs LCDR1, LCDR2, and LCDR3 having amino acid sequences of SEQ ID NO:15, SEQ ID NO:16, and SEQ ID NO:17, respectively.

3. The method according to claim 1 or 2, wherein the BCMA binding domain comprises the VH having the amino acid sequence of SEQ ID NO:18 and the VL having the amino acid sequence of SEQ ID NO:19; and the CD3 binding domain comprises the VH having the amino acid sequence of SEQ ID NO:20 and the VL having the amino acid sequence of SEQ ID NO:

21.

4. The method according to any one of claims 1 to 3, wherein the BCMA x CD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO:22, a first light chain (LC1) having the amino acid sequence of SEQ ID NO:23, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO:24, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO:25, wherein HC1 associates with LC1 to form a first antigen binding site that immunospecifically binds BCMA, and wherein HC2 associates with LC2 to form a second antigen binding site that immunospecifically binds CD3.

5. The method according to any one of claims 1 to 4, wherein the BCMA x CD3 bispecific antibody is teclistamab.

6. The method according to any one of claims 1 to 5, wherein the therapeutically effective amount of the BCMA x CD3 bispecific antibody is from about 60 μg / kg to about 6000 μg / kg.

7. The method according to claim 6, wherein the therapeutically effective amount of the BCMA x CD3 bispecific antibody is selected from 60 μg / kg, 240 μg / kg, 300 μg / kg, 720 μg / kg, 1500 μg / kg, 3000 μg / kg or 6000 μg / kg.

8. The method according to any one of claims 1 to 5, wherein the therapeutically effective amount of the BCMA x CD3 bispecific antibody is from about 3 mg to about 600 mg.

9. The method according to claim 8, wherein the therapeutically effective amount of the BCMA x CD3 bispecific antibody is selected from 3 mg, 4 mg, 15 mg, 25 mg, 100 mg, 150 mg, 200 mg, 300 mg and 450 mg.

10. The method according to any one of claims 1 to 9, wherein the therapeutically effective amount of the BCMA x CD3 bispecific antibody is administered at a frequency selected from daily, weekly, bi-weekly, every four weeks or monthly.

11. The method according to any one of claims 1 to 10, wherein the method further comprises administering a loading dose of the BCMA x CD3 bispecific antibody before administering the therapeutically effective amount of the BCMA x CD3 bispecific antibody.

12. The method according to claim 11, wherein the loading dose comprises one or more escalating doses.

13. The method according to claim 11 or 12, wherein the loading dose comprises 1, 2, 3 or more than 3 escalating doses.

14. The method according to claim 12 or 13, wherein the one or more escalating doses of the BCMA x CD3 bispecific antibody are from about 60 μg / kg to about 6000 μg / kg.

15. The method according to claim 14, wherein the one or more escalating doses of the BCMA x CD3 bispecific antibody are selected from 60 μg / kg, 240 μg / kg or 300 μg / kg.

16. The method according to claim 12 or 13, wherein the one or more escalating doses of the BCMA x CD3 bispecific antibody are from about 3 mg to about 600 mg.

17. The method according to claim 16, wherein the one or more escalating doses of the BCMA x CD3 bispecific antibody are selected from 3 mg, 4 mg, 15 mg, 24 mg or 25 mg.

18. The method according to claim 11 or 12, wherein the loading dose of the BCMA x CD3 bispecific antibody is administered at a frequency selected from daily, every other day or weekly.

19. The method according to any one of claims 12 to 17, wherein the one or more escalating doses of the BCMA x CD3 bispecific antibody are administered at a frequency selected from daily, every other day, or weekly.

20. The method according to any one of claims 1 to 19, wherein the anti-CD38 antibody comprises a VH having HCDR1, HCDR2, and HCDR3 with amino acid sequences of SEQ ID NO:28, SEQ ID NO:29, and SEQ ID NO:30, respectively, and a VL having LCDR1, LCDR2, and LCDR3 with amino acid sequences of SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:33, respectively.

21. The method according to any one of claims 1 to 20, wherein the anti-CD38 antibody comprises the VH having the amino acid sequence of SEQ ID NO:34 and the VL having the amino acid sequence of SEQ ID NO:

35.

22. The method according to any one of claims 1 to 21, wherein the anti-CD38 antibody comprises an HC having the amino acid sequence of SEQ ID NO:36 and an LC having the amino acid sequence of SEQ ID NO:

37.

23. The method according to any one of claims 1 to 22, wherein the anti-CD38 antibody is daratumumab.

24. The method according to any one of claims 1 to 23, wherein the therapeutically effective amount of the anti-CD38 antibody is from about 1200 mg to about 2400 mg.

25. The method according to any one of claims 1 to 24, wherein the therapeutically effective amount of the anti-CD38 antibody is about 1800 mg.

26. The method according to any one of claims 1 to 25, wherein the therapeutically effective amount of the anti-CD38 antibody is administered at a frequency selected from daily, weekly, every two weeks, once every four weeks, or monthly.

27. The method according to any one of claims 1 to 26, wherein the IMiD is selected from the group consisting of thalidomide, pomalidomide, lenalidomide, or any combination thereof.

28. The method according to any one of claims 1 to 27, wherein the IMiD is lenalidomide.

29. The method according to any one of claims 1 to 28, wherein the therapeutically effective amount of the IMiD is from about 15 mg to about 50 mg.

30. The method according to any one of claims 1 to 29, wherein the therapeutically effective amount of the IMiD is about 25 mg.

31. The method according to any one of claims 1 to 30, wherein the therapeutically effective amount of the IMiD is administered at a frequency selected from daily or weekly.

32. The method according to any one of claims 1 to 31, wherein the BCMA x CD3 bispecific antibody is administered subcutaneously.

33. The method according to any one of claims 1 to 32, wherein the anti-CD38 antibody is administered subcutaneously.

34. The method according to any one of claims 1 to 33, wherein the IMiD is administered orally.

35. The method according to any one of claims 1 to 34, wherein the method further comprises administering a pre-treatment to the subject.

36. The method according to claim 35, wherein the pre-treatment regimen comprises administering 8 mg to 40 mg of dexamethasone, 25 mg to 50 mg of diphenhydramine, and 650 mg to 1000 mg of acetaminophen.

37. The method according to claim 36, wherein: i) the dexamethasone is administered on days 1, 2, 4, and 8 of the first treatment cycle and thereafter weekly for the second, third, and fourth treatment cycles; ii) the diphenhydramine is administered for all doses of the anti-CD38 antibody and all escalating and first treatment doses of the BCMA x CD3 bispecific antibody; and iii) the acetaminophen is administered for all doses of the anti-CD38 antibody and all escalating and first treatment doses of the BCMA x CD3 bispecific antibody.

38. The method according to claim 36 or 37, wherein the pre-treatment regimen further comprises montelukast administered at 10 mg.

39. A method of treating cancer in a subject in need thereof, the method comprising: i) subcutaneously administering to the subject one or more escalating doses of about 60 μg / kg, 240 μg / kg, or 300 μg / kg, or about 3 mg, 4 mg, 15 mg, 24 mg, or 25 mg of a BCMA x CD3 bispecific antibody; ii) after the one or more escalating doses, subcutaneously administering to the subject a therapeutic dose of about 720 μg / kg, 1500 μg / kg, 3000 μg / kg, or 6000 μg / kg, or about 100 mg, 150 mg, 200 mg, 300 mg, or 450 mg of the BCMA x CD3 bispecific antibody; iii) subcutaneously administering to the subject a therapeutically effective amount of about 1200 mg to about 2400 mg of an anti-CD38 antibody; and iv) orally administering to the subject a therapeutically effective amount of about 15 mg to about 50 mg of an immunomodulatory drug (IMiD); wherein the BCMA x CD3 bispecific antibody, the anti-CD38 antibody, and the IMiD are administered to the subject for a time sufficient to treat the cancer.

40. The method according to claim 39, wherein the BCMA x CD3 bispecific antibody comprises: (1) A BCMA-binding domain, wherein the BCMA-binding domain comprises a heavy-chain variable region (VH) having heavy-chain complementarity-determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 with amino acid sequences of SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, respectively, and a light-chain variable region (VL) having light-chain complementarity-determining regions (LCDRs) LCDR1, LCDR2, and LCDR3 with amino acid sequences of SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:11, respectively, and (2) A CD3-binding domain, wherein the CD3-binding domain comprises a VH having HCDR1, HCDR2, and HCDR3 with amino acid sequences of SEQ ID NO:12, SEQ ID NO:13, and SEQ ID NO:14, respectively, and a VL having LCDR1, LCDR2, and LCDR3 with amino acid sequences of SEQ ID NO:15, SEQ ID NO:16, and SEQ ID NO:17, respectively.

41. The method according to claim 39 or 40, wherein the BCMA-binding domain comprises the VH having the amino acid sequence of SEQ ID NO:18 and the VL having the amino acid sequence of SEQ ID NO:19; and the CD3-binding domain comprises the VH having the amino acid sequence of SEQ ID NO:20 and the VL having the amino acid sequence of SEQ ID NO:

21.

42. The method according to any one of claims 39 to 41, wherein the BCMA x CD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO:22, a first light chain (LC1) having the amino acid sequence of SEQ ID NO:23, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO:24, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO:25, wherein HC1 associates with LC1 to form a first antigen-binding site that immunospecifically binds BCMA, and wherein HC2 associates with LC2 to form a second antigen-binding site that immunospecifically binds CD3.

43. The method according to any one of claims 39 to 42, wherein the BCMA x CD3 bispecific antibody is teclistamab.

44. The method according to any one of claims 39 to 43, wherein the one or more escalating doses of the BCMA x CD3 bispecific antibody are selected from about 60 μg / kg, 240 μg / kg, 300 μg / kg, or any combination thereof.

45. The method according to any one of claims 39 to 44, wherein the one or more escalating doses of the BCMA x CD3 bispecific antibody are selected from about 3 mg, 4 mg, 15 mg, 24 mg, 25 mg, or any combination thereof.

46. The method according to any one of claims 39 to 45, wherein the one or more escalating doses of the BCMA x CD3 bispecific antibody are administered at a frequency selected from daily, every other day, or weekly.

47. The method according to any one of claims 39 to 46, wherein the therapeutic dose of the BCMA x CD3 bispecific antibody is selected from 720 μg / kg, 1500 μg / kg, 3000 μg / kg, or 6000 μg / kg or any combination thereof.

48. The method according to any one of claims 39 to 46, wherein the therapeutic dose of the BCMA x CD3 bispecific antibody is selected from 100 mg, 150 mg, 200 mg, 300 mg, or 450 mg or any combination thereof.

49. The method according to any one of claims 39 to 48, wherein the therapeutic dose of the BCMA x CD3 bispecific antibody is administered at a frequency selected from weekly, bi-weekly, once every four weeks, or monthly.

50. The method according to any one of claims 39 to 49, wherein the anti-CD38 antibody comprises a VH having HCDR1, HCDR2, and HCDR3 with amino acid sequences of SEQ ID NO:28, SEQ ID NO:29, and SEQ ID NO:30 respectively, and a VL having LCDR1, LCDR2, and LCDR3 with amino acid sequences of SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:33 respectively.

51. The method according to any one of claims 39 to 50, wherein the anti-CD38 antibody comprises the VH having the amino acid sequence of SEQ ID NO:34 and the VL having the amino acid sequence of SEQ ID NO:

35.

52. The method according to any one of claims 39 to 51, wherein the anti-CD38 antibody comprises an HC having the amino acid sequence of SEQ ID NO:36 and an LC having the amino acid sequence of SEQ ID NO:

37.

53. The method according to any one of claims 39 to 52, wherein the anti-CD38 antibody is daratumumab.

54. The method according to any one of claims 39 to 53, wherein the therapeutically effective amount of the anti-CD38 antibody is about 1800 mg.

55. The method according to any one of claims 39 to 54, wherein the therapeutically effective amount of the anti-CD38 antibody is administered at a frequency selected from weekly, bi-weekly, once every four weeks, or monthly.

56. The method according to any one of claims 39 to 55, wherein the IMiD is selected from the group consisting of thalidomide, pomalidomide, lenalidomide, or any combination thereof.

57. The method according to any one of claims 39 to 56, wherein the IMiD is lenalidomide.

58. The method according to any one of claims 39 to 57, wherein the therapeutically effective amount of the IMiD is about 25 mg.

59. The method according to any one of claims 39 to 58, wherein the therapeutically effective amount of the IMiD is administered at a frequency selected from daily or weekly.

60. The method according to any one of claims 39 to 59, wherein the method further comprises administering a pre-treatment to the subject.

61. The method according to claim 60, wherein the pre-treatment regimen comprises administering 8 mg to 40 mg of dexamethasone, 25 mg to 50 mg of diphenhydramine, and 650 mg to 1000 mg of acetaminophen.

62. The method according to claim 61, wherein: i) the dexamethasone is administered on days 1, 2, 4, and 8 of the first treatment cycle and thereafter weekly for the second, third, and fourth treatment cycles; ii) the diphenhydramine is administered for all doses of the anti-CD38 antibody and all escalating doses and the first treatment dose of the BCMA x CD3 bispecific antibody; and iii) the acetaminophen is administered for all doses of the anti-CD38 antibody and all escalating doses and the first treatment dose of the BCMA x CD3 bispecific antibody.

63. The method according to claim 61 or 62, wherein the pre-treatment regimen further comprises administering montelukast at 10 mg.

64. A method of treating cancer in a subject in need thereof, the method comprising: i) subcutaneously administering to the subject one or more escalating doses of 60 μg / kg, 240 μg / kg, or 300 μg / kg or any combination thereof, or about 3 mg, 4 mg, 15 mg, 24 mg, or 25 mg or any combination thereof of a BCMA x CD3 bispecific antibody at a frequency selected from daily, every other day, or weekly; ii) after the one or more escalating doses, subcutaneously administering to the subject a therapeutic dose of about 720 μg / kg, 1500 μg / kg, 3000 μg / kg, or 6000 μg / kg or any combination thereof, or about 100 mg, 150 mg, 200 mg, 300 mg, or 450 mg or any combination thereof of the BCMA x CD3 bispecific antibody at a frequency selected from weekly, every two weeks, once every four weeks, or once a month; iii) subcutaneously administering to the subject a therapeutically effective amount of about 1800 mg of an anti-CD38 antibody at a frequency selected from weekly, every two weeks, once every four weeks, or once a month; and iv) orally administering to the subject a therapeutically effective amount of about 25 mg of an immunomodulatory drug (IMiD) at a frequency of daily or weekly; wherein the BCMA x CD3 bispecific antibody, the anti-CD38 antibody, and the IMiD are administered to the subject for a time sufficient to treat the cancer.

65. The method according to claim 64, wherein the BCMA x CD3 bispecific antibody comprises: (1) A BCMA-binding domain, wherein the BCMA-binding domain comprises a heavy-chain variable region (VH) having heavy-chain complementarity-determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 with amino acid sequences of SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, respectively, and a light-chain variable region (VL) having light-chain complementarity-determining regions (LCDRs) LCDR1, LCDR2, and LCDR3 with amino acid sequences of SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:11, respectively, and (2) A CD3-binding domain, wherein the CD3-binding domain comprises a VH having HCDR1, HCDR2, and HCDR3 with amino acid sequences of SEQ ID NO:12, SEQ ID NO:13, and SEQ ID NO:14, respectively, and a VL having LCDR1, LCDR2, and LCDR3 with amino acid sequences of SEQ ID NO:15, SEQ ID NO:16, and SEQ ID NO:17, respectively.

66. The method according to claim 64 or 65, wherein the BCMA-binding domain comprises the VH having the amino acid sequence of SEQ ID NO:18 and the VL having the amino acid sequence of SEQ ID NO:19; and the CD3-binding domain comprises the VH having the amino acid sequence of SEQ ID NO:20 and the VL having the amino acid sequence of SEQ ID NO:

21.

67. The method according to any one of claims 64 to 66, wherein the BCMA x CD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO:22, a first light chain (LC1) having the amino acid sequence of SEQ ID NO:23, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO:24, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO:25, wherein HC1 associates with LC1 to form a first antigen-binding site that immunospecifically binds BCMA, and wherein HC2 associates with LC2 to form a second antigen-binding site that immunospecifically binds CD3.

68. The method according to any one of claims 64 to 67, wherein the BCMA x CD3 bispecific antibody is teclistamab.

69. The method according to any one of claims 64 to 68, wherein the anti-CD38 antibody comprises a VH having HCDR1, HCDR2, and HCDR3 with amino acid sequences of SEQ ID NO:28, SEQ ID NO:29, and SEQ ID NO:30, respectively, and a VL having LCDR1, LCDR2, and LCDR3 with amino acid sequences of SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:33, respectively.

70. The method according to any one of claims 64 to 69, wherein the CD38 antibody comprises the VH having the amino acid sequence of SEQ ID NO: 34 and the VL having the amino acid sequence of SEQ ID NO:

35.

71. The method according to any one of claims 64 to 70, wherein the CD38 antibody comprises the HC having the amino acid sequence of SEQ ID NO: 36 and the LC having the amino acid sequence of SEQ ID NO:

37.

72. The method according to any one of claims 64 to 71, wherein the anti-CD38 antibody is daratumumab.

73. The method according to any one of claims 64 to 72, wherein the IMiD is selected from the group consisting of thalidomide, pomalidomide, lenalidomide, or any combination thereof.

74. The method according to any one of claims 64 to 73, wherein the IMiD is lenalidomide.

75. The method according to any one of claims 64 to 74, wherein the method further comprises administering a pre-treatment to the subject.

76. The method according to claim 75, wherein the pre-treatment regimen comprises administering 8 mg to 40 mg of dexamethasone, 25 mg to 50 mg of diphenhydramine, and 650 mg to 1000 mg of acetaminophen.

77. The method according to claim 76, wherein: i) the dexamethasone is administered on days 1, 2, 4, and 8 of the first treatment cycle and thereafter weekly for the second, third, and fourth treatment cycles; ii) the diphenhydramine is administered for all doses of the anti-CD38 antibody and all escalating and first treatment doses of the BCMA x CD3 bispecific antibody; and iii) the acetaminophen is administered for all doses of the anti-CD38 antibody and all escalating and first treatment doses of the BCMA x CD3 bispecific antibody.

78. The method according to claim 76 or 77, wherein the pre-treatment regimen further comprises montelukast administered at 10 mg.

79. A method of treating cancer in a subject in need thereof, the method comprising: i) determining the subject's body weight and assigning a BCMA x CD3 bispecific antibody treatment tier based on the body weight, wherein if the subject's body weight is less than or equal to a predetermined threshold, the subject is in tier 1, and wherein if the subject's body weight is greater than the predetermined threshold, the subject is in tier 2; ii) subcutaneously administering to the subject one or more escalating doses of a BCMA x CD3 bispecific antibody; iii) after the one or more escalating doses, subcutaneously administering to the subject a therapeutic dose of the BCMA x CD3 bispecific antibody; iv) subcutaneously administering to the subject a therapeutically effective amount of an anti-CD38 antibody; and v) orally administering to the subject a therapeutically effective amount of an immunomodulatory drug (IMiD); Wherein, the BCMA x CD3 bispecific antibody, the anti-CD38 antibody, and the IMiD are administered to the subject for a time sufficient to treat the cancer.

80. The method according to claim 79, wherein the predetermined body weight threshold is selected from the group consisting of 50 kg, 55 kg, 60 kg, 65 kg, or 70 kg.

81. The method according to claim 79 or 80, wherein the predetermined body weight threshold is 60 kg.

82. The method according to any one of claims 79 to 81, wherein the BCMA x CD3 bispecific antibody comprises: (1) a BCMA-binding domain, the BCMA-binding domain comprising a heavy chain variable region (VH) having heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 with amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively, and a light chain variable region (VL) having light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3 with amino acid sequences of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11, respectively, and (2) a CD3-binding domain, the CD3-binding domain comprising a VH having HCDRs HCDR1, HCDR2, and HCDR3 with amino acid sequences of SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14, respectively, and a VL having LCDRs LCDR1, LCDR2, and LCDR3 with amino acid sequences of SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17, respectively.

83. The method according to any one of claims 79 to 82, wherein the BCMA-binding domain comprises the VH having the amino acid sequence of SEQ ID NO: 18 and the VL having the amino acid sequence of SEQ ID NO: 19; and the CD3-binding domain comprises the VH having the amino acid sequence of SEQ ID NO: 20 and the VL having the amino acid sequence of SEQ ID NO:

21.

84. The method according to any one of claims 79 to 83, wherein the BCMA x CD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 22, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 23, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 24, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 25, wherein HC1 associates with LC1 to form a first antigen-binding site that immunospecifically binds BCMA, and wherein HC2 associates with LC2 to form a second antigen-binding site that immunospecifically binds CD3.

85. The method according to any one of claims 79 to 84, wherein the BCMA x CD3 bispecific antibody is talquetamab.

86. The method according to any one of claims 79 to 85, wherein the one or more escalating doses of the BCMA x CD3 bispecific antibody for a subject at level 1 or level 2 are selected from 3 mg, 4 mg, 15 mg, 24 mg, or 25 mg or any combination thereof.

87. The method according to claim 86, wherein the one or more escalating doses of the BCMA x CD3 bispecific antibody for a subject at level 1 can be different from or the same as the one or more escalating doses of the BCMA x CD3 bispecific antibody for a subject at level 2.

88. The method according to any one of claims 79 to 87, wherein the therapeutic dose of the BCMA x CD3 bispecific antibody for a subject at level 1 or level 2 is selected from 100 mg, 150 mg, 200 mg, 300 mg, or 450 mg or any combination thereof.

89. The method according to claim 88, wherein the therapeutic dose of the BCMA x CD3 bispecific antibody for a subject at level 1 can be different from or the same as the therapeutic dose of the BCMA x CD3 bispecific antibody for a subject at level 2.

90. The method according to any one of claims 79 to 89, wherein the one or more escalating doses of the BCMA x CD3 bispecific antibody are administered at a frequency selected from daily, every other day, or weekly.

91. The method according to any one of claims 79 to 90, wherein the therapeutic dose of the BCMA x CD3 bispecific antibody is administered at a frequency selected from weekly, every two weeks, once every four weeks, or monthly.

92. The method according to any one of claims 79 to 91, wherein the anti-CD38 antibody comprises a VH having HCDR1, HCDR2, and HCDR3 with amino acid sequences of SEQ ID NO:28, SEQ ID NO:29, and SEQ ID NO:30, respectively, and a VL having LCDR1, LCDR2, and LCDR3 with amino acid sequences of SEQ ID NO:31, SEQ ID NO:32, and SEQ ID NO:33, respectively.

93. The method according to any one of claims 79 to 92, wherein the CD38 antibody comprises the VH having the amino acid sequence of SEQ ID NO:34 and the VL having the amino acid sequence of SEQ ID NO:

35.

94. The method according to any one of claims 79 to 93, wherein the CD38 antibody comprises an HC having the amino acid sequence of SEQ ID NO:36 and an LC having the amino acid sequence of SEQ ID NO:

37.

95. The method according to any one of claims 79 to 94, wherein the anti-CD38 antibody is daratumumab.

96. The method according to any one of claims 79 to 95, wherein the therapeutically effective amount of the anti-CD38 antibody is from about 1200 mg to about 2400 mg.

97. The method according to any one of claims 79 to 96, wherein the therapeutically effective amount of the anti-CD38 antibody is about 1800 mg.

98. The method according to any one of claims 79 to 97, wherein the therapeutically effective amount of the anti-CD38 antibody is administered at a frequency selected from once a week, once every two weeks, once every four weeks or once a month.

99. The method according to any one of claims 79 to 98, wherein the IMiD is selected from the group consisting of thalidomide, pomalidomide, lenalidomide or any combination thereof.

100. The method according to any one of claims 79 to 99, wherein the IMiD is lenalidomide.

101. The method according to any one of claims 79 to 100, wherein the therapeutically effective amount of the IMiD is from about 15 mg to about 50 mg.

102. The method according to any one of claims 79 to 101, wherein the therapeutically effective amount of the IMiD is about 25 mg.

103. The method according to any one of claims 79 to 102, wherein the therapeutically effective amount of the IMiD is administered at a frequency selected from daily or weekly.

104. The method according to any one of claims 79 to 103, wherein the method further comprises administering a pre-treatment to the subject.

105. The method according to claim 104, wherein the pre-treatment regimen comprises administering 8 mg to 40 mg of dexamethasone, 25 mg to 50 mg of diphenhydramine and 650 mg to 1000 mg of acetaminophen.

106. The method according to claim 105, wherein: i) the dexamethasone is administered on days 1, 2, 4 and 8 of the first treatment cycle and thereafter weekly for the second, third and fourth treatment cycles; ii) the diphenhydramine is administered for all doses of the anti-CD38 antibody and all escalating and first treatment doses of the BCMA xCD3 bispecific antibody; and iii) the acetaminophen is administered for all doses of the anti-CD38 antibody and all escalating and first treatment doses of the BCMAx CD3 bispecific antibody.

107. The method according to claim 105 or 106, wherein the pre-treatment regimen further comprises montelukast administered at 10 mg.

108. The method according to any one of claims 1 to 107, wherein the BCMA x CD3 bispecific antibody, the anti-CD38 antibody and the IMiD are administered in 28-day treatment cycles.

109. The method according to claim 108, wherein the method further comprises treating the subject for 1, 2, 3, 4, 5, 6, 7 or more than 7 treatment cycles.

110. The method according to claim 108 or 109, wherein the frequency, dose, or combination thereof of the BCMA x CD3 bispecific antibody, anti-CD38 antibody, IMiD, or combination thereof can be changed or can remain unchanged between the current and subsequent treatment cycles.

111. The method according to any one of claims 1 to 110, wherein the anti-CD38 antibody is administered together with hyaluronidase or provided for administration together with hyaluronidase.

112. The method according to claim 111, wherein the hyaluronidase is rHuPH20.

113. The method according to claim 111 or 112, wherein the hyaluronidase is administered or provided at 30,000 U.

114. The method according to any one of claims 1 to 113, wherein the cancer is multiple myeloma.

115. A method of treating multiple myeloma in a subject in need thereof, the method comprising: i) administering subcutaneously to the subject one or more escalating doses of talquetamab at 60 μg / kg, 240 μg / kg, or 300 μg / kg, or any combination thereof, or about 3 mg, 4 mg, 15 mg, 24 mg, or 25 mg, or any combination thereof on days 2 and 4 after the start of treatment; ii) after the one or more escalating doses, administering subcutaneously to the subject a therapeutic dose of talquetamab at about 720 μg / kg, 1500 μg / kg, 3000 μg / kg, 6000 μg / kg, or any combination thereof, or about 100 mg, 150 mg, 200 mg, 300 mg, 450 mg, or any combination thereof at a frequency selected from once a week, once every two weeks, once every four weeks, or once a month; iii) administering subcutaneously to the subject a therapeutically effective amount of about 1800 mg of daratumumab at a frequency selected from once a week, once every two weeks, once every four weeks, or once a month; and iv) orally administering to the subject a therapeutically effective amount of about 25 mg of lenalidomide once daily; wherein talquetamab, daratumumab, and lenalidomide are administered to the subject for a time sufficient to treat the cancer.

116. A method of treating multiple myeloma in a subject in need thereof, the method comprising: i) administering subcutaneously to the subject a first escalating dose of talquetamab at 60 μg / kg on day 2 of the treatment regimen, and a second escalating dose of 240 μg / kg or 300 μg / kg subcutaneously to the subject on day 4 of the treatment regimen; ii) after the first escalating dose and the second escalating dose, administering a therapeutic dose of talquetamab based on a 28-day treatment cycle, the 28-day treatment cycle comprising: a) administering subcutaneously to the subject a therapeutic dose of talquetamab at 720 μg / kg or 1500 μg / kg on days 8, 15, and 22 of the first treatment cycle; b) Administering subcutaneously to the subject a therapeutic dose of talquetamab of 720 μg / kg or 1500 μg / kg weekly for each subsequent treatment cycle; wherein the 720 μg / kg weekly dose is optionally increased to 1500 μg / kg weekly; wherein the 1500 μg / kg weekly dose is optionally increased to 3000 μg / kg every two weeks starting from the third treatment cycle; and wherein the 3000 μg / kg every two weeks dose is optionally increased to 6000 μg / kg every four weeks starting from the seventh treatment cycle; iii) Administering subcutaneously to the subject 1800 mg of daratumumab in 28-day treatment cycles, wherein the daratumumab is administered weekly for the first and second treatment cycles, every two weeks for the third to sixth treatment cycles, and every four weeks for the seventh and subsequent treatment cycles; and iv) Administering orally to the subject 25 mg of lenalidomide once daily for 21 days of a 28-day treatment cycle, wherein the lenalidomide treatment starts at the second treatment cycle; wherein talquetamab, daratumumab, and lenalidomide are administered to the subject for a time sufficient to treat the cancer.

117. A method of treating multiple myeloma in a subject in need thereof, the method comprising: i) Administering subcutaneously to the subject a first escalating dose of talquetamab on day 2 of the first treatment cycle and a second escalating dose of talquetamab on day 4 of the first treatment cycle, wherein if the subject weighs less than or equal to 60 kg, the first escalating dose is 3 mg of talquetamab and the second escalating dose is 15 mg of talquetamab, wherein if the subject weighs more than 60 kg, the first escalating dose is 4 mg of talquetamab and the second escalating dose is 24 mg or 25 mg of talquetamab; ii) After the first and second escalating doses, administering a therapeutic dose of talquetamab based on a 28-day treatment cycle, the 28-day treatment cycle comprising: a) Administering subcutaneously to the subject a therapeutic dose of talquetamab on days 8, 15, and 22 of the first treatment cycle, wherein if the subject weighs less than or equal to 60 kg, the therapeutic dose is 100 mg, wherein if the subject weighs more than 60 kg, the therapeutic dose is 150 mg; b) Administering subcutaneously to the subject a therapeutic dose of talquetamab weekly for the second treatment cycle, wherein if the subject weighs less than or equal to 60 kg, the therapeutic dose is 100 mg, wherein if the subject weighs more than 60 kg, the therapeutic dose is 150 mg; c) Administering subcutaneously to the subject a therapeutic dose of talquetamab every two weeks for the third, fourth, fifth, and sixth treatment cycles, wherein if the subject weighs less than or equal to 60 kg, the therapeutic dose is 200 mg, wherein if the subject weighs more than 60 kg, the therapeutic dose is 300 mg; and d) subcutaneously administering a therapeutic dose of terelizumab to the subject once every four weeks for the seventh and subsequent treatment cycles, wherein if the subject weighs less than or equal to 60 kg, the therapeutic dose is 200 mg, optionally wherein the therapeutic dose is increased to 300 mg, and wherein if the subject weighs more than 60 kg, the therapeutic dose is 300 mg, optionally wherein the therapeutic dose is increased to 450 mg; iii) subcutaneously administering 1800 mg of daratumumab to the subject in 28-day treatment cycles, wherein the daratumumab is administered weekly for the first and second treatment cycles, bi-weekly for the third to sixth treatment cycles, and once every four weeks for the seventh and subsequent treatment cycles; and iv) orally administering 25 mg of lenalidomide to the subject once daily for 21 days of a 28-day treatment cycle, wherein the lenalidomide treatment starts at the second treatment cycle; wherein terelizumab, daratumumab, and lenalidomide are administered to the subject for a time sufficient to treat the cancer.

118. The method according to any one of claims 115 to 117, wherein the method further comprises administering a pretreatment regimen.

119. The method according to claim 118, wherein the pretreatment regimen comprises: i) intravenously or orally administering a therapeutically effective amount of dexamethasone, wherein the dexamethasone is administered at 20 mg on day 1 of the first treatment cycle, at 16 mg on days 2, 4, 8, 15, and 22 of the first treatment cycle, and weekly at 20 mg or 40 mg during each of the second, third, and fourth treatment cycles; ii) intravenously or orally administering a therapeutically effective amount of diphenhydramine, wherein the diphenhydramine is administered at 25 mg to 50 mg for all doses of daratumumab and all escalating doses and the first therapeutic dose of terelizumab; and iii) intravenously or orally administering a therapeutically effective amount of acetaminophen, wherein the acetaminophen is administered at 650 mg to 1000 mg for all doses of daratumumab and all escalating doses and the first therapeutic dose of terelizumab.

120. The method according to claim 119, wherein diphenhydramine and acetaminophen are further administered after any grade 2 or higher cytokine release syndrome or administration-related reaction to the terelizumab.

121. The method according to claim 119 or 120, wherein dexamethasone is further administered after any grade 2, 3, or greater than 3 administration-related reaction to the daratumumab and / or any grade 2 or higher cytokine release syndrome or administration-related reaction to the terelizumab.

122. The method according to any one of claims 118 to 121, wherein the pretreatment regimen further comprises administering montelukast at 10 mg.

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