Treatment for multiple myeloma

Abstract

This specification provides a method for treating cancer, particularly multiple myeloma, using an anti-Fc receptor-like 5 (FcRH5) / anti-differentiation antigen 3 (CD3) bispecific antibody in combination with an anti-B cell maturation factor (BCMA) / anti-CD3 bispecific antibody.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 509,612, filed on 22 June 2023, and U.S. Provisional Patent Application No. 63 / 600,286, filed on 17 November 2023, the entire contents of which are incorporated herein by reference.

[0002] Sequence List This application contains a sequence listing submitted electronically in XML format, the entirety of which is incorporated herein by reference. The XML copy, created on June 20, 2024, is named "00B206_1440_seqlist.xml" and has a size of 65,545 bytes.

[0003] Field of Invention This application relates to the treatment of cancers such as B-cell proliferative disorders. More specifically, this application relates to the treatment of humans with multiple myeloma (MM) using anti-Fc receptor-like protein 5 (FcRH5) / anti-differentiation antigen 3 (CD3) bispecific antibodies and anti-B-cell maturation antigen (BCMA) / anti-CD3 bispecific antibodies. [Background technology]

[0004] background Cancer remains one of the most deadly threats to human health. In the United States, cancer affects more than 1.7 million new cases each year, is the second leading cause of death after heart disease, and kills approximately one in four people.

[0005] Hematological malignancies, in particular, are the second leading cause of cancer-related death. Hematological malignancies include multiple myeloma (MM), an incurable neoplasm characterized by the proliferation and accumulation of malignant plasma cells in the bone marrow, resulting in the overproduction of monoclonal proteins (M proteins) detectable in the blood or urine of most patients. Approximately 30,000 people are diagnosed with MM each year in the United States, and approximately 160,000 people are diagnosed with MM worldwide each year. Terminal organ damage resulting from MM includes hypercalcemia, renal failure, anemia, and osteolytic bone lesions. Despite advances in treatment, MM remains incurable, with a median estimated survival of 8–10 years for standard-risk cases and 2–3 years for high-risk myeloma, even with aggressive treatments such as autologous stem cell transplantation (SCT). Despite significant improvements in patient survival rates over the past 20 years, only 10–15% of patients achieve or exceed their expected survival compared to the corresponding general population.

[0006] Therefore, improved treatment regimens are needed for MM and other cancers (e.g., hematological cancers). [Overview of the project]

[0007] Summary of the Invention This specification provides, in particular, methods for treating subjects having cancer (e.g., MM), compositions for use, and related products.

[0008] In one embodiment, the present invention provides a method for treating a subject having multiple myeloma (MM), comprising administering to the subject an effective amount of a first bispecific antibody that specifically binds to Fc receptor-like protein 5 (FcRH5) and differentiation antigen 3 (CD3), and (ii) an effective amount of a second bispecific antibody that specifically binds to B cell maturation antigen (BCMA) and CD3.

[0009] In another aspect, a bispecific antibody that specifically binds to FcRH5 and CD3 for use in treating a subject having MM, wherein the treatment comprises administering to the subject a first bispecific antibody that specifically binds to FcRH5 and CD3 and a second bispecific antibody that specifically binds to BCMA and CD3, is provided herein.

[0010] In another aspect, a bispecific antibody that specifically binds to BCMA and CD3 for use in treating a subject having MM, wherein the treatment comprises administering to the subject a first bispecific antibody that specifically binds to FcRH5 and CD3 and a second bispecific antibody that specifically binds to BCMA and CD3, is provided herein.

[0011] In some aspects, the subject has relapsed or refractory (R / R) MM.

[0012] In some aspects, the subject has a diagnosis of R / R MM according to the International Myeloma Working Group (IMWG) criteria.

[0013] In some aspects, the first bispecific antibody and the second bispecific antibody are administered to the subject in a dosing regimen comprising (i) a first phase comprising one or more dosing cycles; (ii) a second phase comprising one or more dosing cycles; and optionally (iii) a third phase comprising one or more dosing cycles.

[0014] In some aspects, the dosing regimen comprises the first phase and the second phase, but does not comprise the third phase.

[0015] In some aspects, the dosing regimen comprises the first phase, the second phase, and the third phase.

[0016] In some aspects, each dosing cycle of the first phase, the second phase, and / or the third phase is a 14-day dosing cycle.

[0017] In some embodiments, the second phase is a 28-day dosing cycle. In some embodiments, the second bispecific antibody is administered to the subject at a target dose of 76 mg on day 1 of each dosing cycle in the second phase.

[0018] In some embodiments, the first phase includes drug delivery cycles C1 to C26, and the second phase includes drug delivery cycle C27 and beyond.

[0019] In some embodiments, each dosing cycle, approximately one year after the initial administration of the second bispecific antibody to the subject, is 28 days long.

[0020] In some embodiments, each dosing cycle of the second bispecific antibody administered to the subject from the 27th dosing cycle onward is 28 days long.

[0021] In some embodiments, each medication cycle in the first and second phases is a 14-day cycle, and each medication cycle in the third phase is a 28-day cycle.

[0022] In some embodiments, the second bispecific antibody is administered to the subject on day 1 and day 8 of each dosing cycle in the first phase, and / or on day 1 of each dosing cycle in the third phase. In some embodiments, the third phase begins approximately one year from the first target dose of the second bispecific antibody administered to the subject. In some embodiments, the 27th dosing cycle (C27) is the first dosing cycle of the third phase. In some embodiments, the method further includes a prephase comprising one or more dosing cycles prior to the first phase.

[0023] In some embodiments, the prephase includes one medication cycle (C1).

[0024] In some embodiments, prephase C1 is (i) a drug cycle of approximately 15 days, or (ii) a drug cycle of approximately 22 days.

[0025] In some embodiments, the pre-phase C1 is a medication cycle of approximately 15 days.

[0026] In some embodiments, the prephase includes administering a first bispecific antibody to the target on day 9, day 10, or day 11 of C1.

[0027] In some embodiments, the first bispecific antibody is administered to the subject in an escalating dose of 3.6 mg on day 9, 10, or 11 of C1. In some embodiments, the prephase includes administering the second bispecific antibody to the subject on (i) day 1, (ii) day 3, 4, or 5, and (iii) day 8.

[0028] In some embodiments, the prephase includes administering a second bispecific antibody to the subject on (i) day 1, (ii) day 4, and (iii) day 8. In some embodiments, the second bispecific antibody is administered to the subject on day 1 in a first escalating dose of 12 mg.

[0029] In some embodiments, the second bispecific antibody is administered to the subject at a second escalating dose of 32 mg on day 3, day 4, or day 5.

[0030] In some embodiments, a second bispecific antibody is administered to the subject on day 8 at a target dose of 76 mg.

[0031] In some embodiments, the pre-phase C1 is a medication cycle of approximately 22 days.

[0032] In some embodiments, the prephase includes administering a first bispecific antibody to the target on day 16, day 17, or day 18 of C1.

[0033] In some embodiments, the first bispecific antibody is administered to the subject at an increasing dose of 3.6 mg on day 16, day 17, or day 18 of C1.

[0034] In some embodiments, the prephase includes administering a second bispecific antibody to the target on (i) day 1, (ii) day 3, day 4 or 5, (iii) day 8, and (iv) day 15.

[0035] In some embodiments, the second bispecific antibody is administered to the subject on day 1 in a first escalating dose of 12 mg.

[0036] In some embodiments, the second bispecific antibody is administered to the subject at a second escalating dose of 32 mg on day 3, day 4, or day 5.

[0037] In some embodiments, a second bispecific antibody is administered to the subject on day 8 at a target dose of 76 mg.

[0038] In some embodiments, a second bispecific antibody is administered to the subject on day 15 at a target dose of 76 mg.

[0039] In some embodiments, the first phase includes at least one medication cycle, at least two medication cycles, at least three medication cycles, at least four medication cycles, or at least five medication cycles.

[0040] In some embodiments, the first phase includes a first 14-day medication cycle (C1).

[0041] In some embodiments, a target dose of the first bispecific antibody is administered to the subject during the first phase.

[0042] In some embodiments, the first phase includes administering a target dose of the first bispecific antibody to the target on day 2, day 3, or day 4 of C1.

[0043] In some embodiments, the target dose of the first bispecific antibody is 60 mg.

[0044] In some embodiments, the target dose of the first bispecific antibody is 60 mg administered over C1-C8 of the first phase Q2W, and thereafter, the target dose of the first bispecific antibody is 60 mg administered in Q4W.

[0045] In some embodiments, the target dose of the first bispecific antibody is 105 mg.

[0046] In some embodiments, the target dose of the first bispecific antibody is 105 mg administered over C1-C8 of the first phase Q2W, and thereafter, the target dose of the first bispecific antibody is 60 mg administered in Q4W.

[0047] In some embodiments, the target dose of the first bispecific antibody is 132 mg.

[0048] In some embodiments, the target dose of the second bispecific antibody is administered to the subject during the first phase.

[0049] In some embodiments, the first phase includes administering a target dose of a second bispecific antibody to the target on day 1 of C1.

[0050] In some embodiments, the first phase includes target administration of a second bispecific antibody at a target dose on days 1 and 8 of C1.

[0051] In some embodiments, the target dose of the second bispecific antibody is 76 mg.

[0052] In some embodiments, the target dose of the second bispecific antibody is 76 mg administered over C1-C8 of the first phase Q2W, and thereafter, the target dose of the second bispecific antibody is 76 mg administered in Q4W.

[0053] In some embodiments, the second phase includes at least one medication cycle, at least two medication cycles, at least three medication cycles, at least four medication cycles, at least five medication cycles, at least six medication cycles, at least seven medication cycles, at least eight medication cycles, at least nine medication cycles, at least ten medication cycles, at least eleven medication cycles, at least twelve medication cycles, at least thirteen medication cycles, at least fourteen medication cycles, at least fifteen medication cycles, at least sixteen medication cycles, at least seventeen medication cycles, at least eighteen medication cycles, at least nineteen medication cycles, at least twenty medication cycles, at least twenty-one medication cycles, at least twenty-two medication cycles, at least twenty-three medication cycles, at least twenty-four medication cycles, or at least twenty-five medication cycles.

[0054] In some embodiments, the second phase consists of the first medication cycle (C1), the second medication cycle (C2), the third medication cycle (C3), the fourth medication cycle (C4), the fifth medication cycle (C5), the sixth medication cycle (C6), the seventh medication cycle (C7), the eighth medication cycle (C8), the ninth medication cycle (C9), the tenth medication cycle (C10), the eleventh medication cycle (C11), the twelfth medication cycle (C12), and the thirteenth medication cycle. (C13), including the 14th medication cycle (C14), the 15th medication cycle (C15), the 16th medication cycle (C16), the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), the 24th medication cycle (C24), and the 25th medication cycle (C25).

[0055] In some embodiments, each medication cycle in the second phase is a 14-day medication cycle.

[0056] In some embodiments, the target dose of the first bispecific antibody is administered to the subject during the second phase.

[0057] In some embodiments, the second phase includes administering a target dose of the first bispecific antibody to the target on day 1 of each dosing cycle.

[0058] In some embodiments, the second phase includes targeting administration of a target dose of the first bispecific antibody on day 1 of the second phase, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and / or C25.

[0059] In some embodiments, the target dose of the first bispecific antibody is 60 mg.

[0060] In some embodiments, the target dose of the first bispecific antibody is 132 mg.

[0061] In some embodiments, the target dose of the first bispecific antibody is 105 mg.

[0062] In some embodiments, the target dose of the first bispecific antibody is 60 mg administered over C1-C8 of the second phase Q2W, and thereafter, the target dose of the first bispecific antibody is 60 mg administered in Q4W.

[0063] In some embodiments, the target dose of the first bispecific antibody is 105 mg administered over C1-C8 of the second phase Q2W, and thereafter, the target dose of the first bispecific antibody is 105 mg administered in Q4W.

[0064] In some embodiments, the target dose of the second bispecific antibody is administered to the subject during the second phase.

[0065] In some embodiments, the second phase includes administering a target dose of a second bispecific antibody to the target on day 1 of each dosing cycle.

[0066] In some embodiments, the second phase includes targeting administration of a target dose of a second bispecific antibody on day 1 of the second phase, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and / or C25.

[0067] In some embodiments, the second phase includes administering a target dose of a second bispecific antibody to the target patient on days 1 and 8 of each dosing cycle.

[0068] In some embodiments, the second phase includes targeting administration of a target dose of a second bispecific antibody on days 1 and 8 of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and / or C25 of the second phase.

[0069] In some embodiments, the subject achieves an IWMG response category of partial response (PR) or better with a response lasting for at least two months, and the frequency of administration of the second bispecific antibody is changed to every two weeks (Q2W).

[0070] In some embodiments, if the subject achieves a complete response (CR) in the IWMG response category after 6 months, the dosing frequency of the first and second bispecific antibodies is changed from every 2 weeks (Q2W) to every 4 weeks (Q4W).

[0071] In some embodiments, if a patient achieves a partial response (PR) in the IWMG response category with a response lasting at least two months, the dosing frequency of the second bispecific antibody is changed from every two weeks (Q2W) to every four weeks (Q4W).

[0072] In some embodiments, the subject subsequently has an increased disease burden that is not yet qualifies as a progressive disease according to the IWMG criteria, and the medication frequency is changed to weekly (QW).

[0073] In some embodiments, the second phase includes administering a target dose of a second bispecific antibody to the target patient on day 8 of each dosing cycle.

[0074] In some embodiments, the second phase includes targeting administration of a target dose of a second bispecific antibody on day 8 of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and / or C25.

[0075] In some embodiments, the target dose of the second bispecific antibody is 76 mg.

[0076] In some embodiments, the target dose of the second bispecific antibody is 76 mg administered over C1-C8 of the second phase Q2W, and thereafter, the target dose of the second bispecific antibody is 76 mg administered in Q4W.

[0077] In some embodiments, the method involves administering a first bispecific antibody to the target until disease progression, unacceptable toxicity, or up to 26 total drug cycles.

[0078] In some embodiments, the third phase includes one or more medication cycles.

[0079] In some embodiments, the third phase includes 1 to 130 medication cycles.

[0080] In some embodiments, each medication cycle in the third phase is a 14-day medication cycle.

[0081] In some embodiments, the target dose of the second bispecific antibody is administered to the subject during the third phase.

[0082] In some embodiments, the third phase includes administering a target dose of the second bispecific antibody to the target on day 1 of each dosing cycle of the third phase.

[0083] In some embodiments, the third phase includes administering a target dose of the second bispecific antibody to the target patient on days 1 and 8 of each dosing cycle in the third phase.

[0084] In some embodiments, the subject achieves an IWMG response category of partial response (PR) or better with a response lasting for at least two months, and the frequency of administration of the second bispecific antibody is changed to every two weeks (Q2W).

[0085] In some embodiments, if the subject subsequently has an increased disease burden that is not yet eligible as a progressive disease according to the IWMG criteria, the dosing frequency is changed to weekly (QW). In some embodiments, if the subject achieves a complete response (cr) IWMG response category after 6 months, the dosing frequency of the first and second bispecific antibodies is changed from every two weeks (q2w) to every four weeks (q4w).

[0086] In some embodiments, if a patient achieves a partial response (pr) IWMG response category with a response lasting for at least two months, the frequency of administration of the second bispecific antibody is changed from every two weeks (q2w) to every four weeks (q4w).

[0087] In some embodiments, the target dose of the second bispecific antibody is 76 mg.

[0088] In some embodiments, a second bispecific antibody is administered to the subject until disease progression or unacceptable toxicity occurs.

[0089] In some embodiments, the first bispecific antibody is administered intravenously to the subject.

[0090] In some embodiments, the second bispecific antibody is administered subcutaneously to the subject.

[0091] In some embodiments, the method further includes the step of administering a corticosteroid to a target.

[0092] In some embodiments, the method further includes administering a corticosteroid to the subject during the period of the first, second, and / or third phases.

[0093] In some embodiments, a corticosteroid is administered to the subject during the first phase, 1 hour (±15 minutes) before the administration of the first or second bispecific antibody.

[0094] In some embodiments, (i) the subject has experienced cytokine release syndrome (CRS) due to prior administration of a first bispecific antibody or a second bispecific antibody, and a corticosteroid is administered to the subject during the second phase, 1 hour (±15 minutes) before administration of the first bispecific antibody or the second bispecific antibody, and / or (ii) the subject has experienced CRS due to prior administration of a first bispecific antibody or a second bispecific antibody, and a corticosteroid is administered to the subject during the third phase, 1 hour (±15 minutes) before administration of the second bispecific antibody.

[0095] In some embodiments, the method further includes administering a corticosteroid to the subject during the prephase.

[0096] In some embodiments, corticosteroids are administered to subjects during the pre-phase C1 period, 1 hour (±15 minutes) before administration of the first or second bispecific antibody.

[0097] In some embodiments, the corticosteroid is dexamethasone or methylprednisolone.

[0098] In some aspects, the corticosteroid is dexamethasone.

[0099] In some embodiments, dexamethasone is administered to the subject at a dose of approximately 20 mg.

[0100] In some embodiments, methylprednisolone is administered to the subject at a dose of approximately 80 mg.

[0101] In some embodiments, corticosteroids are administered intravenously to the subject.

[0102] In some embodiments, the first bispecific antibody that specifically binds to FcRH5 and CD3 comprises the following six hypervariable regions (HVRs): (a) HVR-H1 containing the amino acid sequence of RFGVH (SEQ ID NO: 1); (b) HVR-H2 (SEQ ID NO: 2) containing the amino acid sequence of VIWRGGSTDYNAAFVS; (c) HVR-H3 (SEQ ID NO: 3) containing the amino acid sequence of HYYGSSDYALDN; (d) HVR-L1 containing the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) HVR-L2 (SEQ ID NO: 5) containing the amino acid sequence of SGSYRYS; and (f) HVR-L3 (SEQ ID NO: 6) containing the amino acid sequence of QQHYSPPYT, and an anti-FcRH5 arm containing a first binding domain.

[0103] In some embodiments, a first bispecific antibody that specifically binds to FcRH5 and CD3 comprises (a) a heavy chain variable (VH) domain containing an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain containing an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8; or (c) an anti-FcRH5 arm comprising a first binding domain containing the VH domain described in (a) and the VL domain described in (b).

[0104] In some embodiments, the first binding domain includes a VH domain containing the amino acid sequence of SEQ ID NO: 7 and a VL domain containing the amino acid sequence of SEQ ID NO: 8.

[0105] In some embodiments, a first bispecific antibody that specifically binds to FcRH5 and CD3 includes an anti-CD3 arm comprising a second binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

[0106] In some embodiments, a first bispecific antibody that specifically binds to FcRH5 and CD3 comprises (a) a VH domain containing an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15; (b) a VL domain containing an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16; or (c) an anti-CD3 arm containing a second binding domain comprising the VH domain described in (a) and the VL domain described in (b).

[0107] In some embodiments, the second binding domain includes a VH domain containing the amino acid sequence of SEQ ID NO: 15 and a VL domain containing the amino acid sequence of SEQ ID NO: 16.

[0108] In some embodiments, a first bispecific antibody that specifically binds to FcRH5 and CD3 comprises an anti-FcRH5 arm comprising a heavy-chain polypeptide (H1) and a light-chain polypeptide (L1), and an anti-CD3 arm comprising a heavy-chain polypeptide (H2) and a light-chain polypeptide (L2), wherein (a) H1 comprises the amino acid sequence of SEQ ID NO: 35, (b) L1 comprises the amino acid sequence of SEQ ID NO: 36, (c) H2 comprises the amino acid sequence of SEQ ID NO: 37, and (d) L2 comprises the amino acid sequence of SEQ ID NO: 38.

[0109] In some embodiments, the first bispecific antibody that specifically binds to FcRH5 and CD3 contains a nonglycosylation site mutation.

[0110] In some embodiments, non-glycosylation site mutations reduce the effector function of bispecific antibodies.

[0111] In some embodiments, nonglycosylation site mutations are substitution mutations.

[0112] In some embodiments, a first bispecific antibody that specifically binds to FcRH5 and CD3 contains a substitutional mutation in the Fc region that reduces effector function.

[0113] In some embodiments, the first bispecific antibody that specifically binds to FcRH5 and CD3 is a monoclonal antibody.

[0114] In some embodiments, the first bispecific antibody that specifically binds to FcRH5 and CD3 is a chimeric antibody.

[0115] In some embodiments, the first bispecific antibody that specifically binds to FcRH5 and CD3 is a humanized antibody.

[0116] In some embodiments, the first bispecific antibody that specifically binds to FcRH5 and CD3 is an antibody fragment that specifically binds to FcRH5 and CD3.

[0117] In some embodiments, the antibody fragment that specifically binds to FcRH5 and CD3 is selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments.

[0118] In some embodiments, the first bispecific antibody that specifically binds to FcRH5 and CD3 is a full-length antibody.

[0119] In some embodiments, the first bispecific antibody that specifically binds to FcRH5 and CD3 is an IgG antibody.

[0120] In some embodiments, the IgG antibody that specifically binds to FcRH5 and CD3 is an IgG1 antibody. In some embodiments, the first bispecific antibody that specifically binds to FcRH5 and CD3 comprises one or more heavy chain constant domains, the one or more heavy chain constant domains being selected from a first CH1(CH11) domain, a first CH2(CH21) domain, a first CH3(CH31) domain, a second CH1(CH12) domain, a second CH2(CH22) domain, and a second CH3(CH32) domain.

[0121] In some embodiments, at least one of the heavy chain constant domains is paired with another heavy chain constant domain.

[0122] In some embodiments, the CH31 domain and the CH32 domain each include projections or cavities, and the projections or cavities within the CH31 domain can be located within the cavities or projections within the CH32 domain, respectively.

[0123] In some embodiments, the CH31 domain and the CH32 domain are in contact at the interface between the protrusion and the cavity.

[0124] In some embodiments, the CH21 domain and the CH22 domain each include projections or cavities, and the projections or cavities of the CH21 domain can be positioned in the cavities or projections of the CH22 domain, respectively.

[0125] In some embodiments, the CH21 domain and the CH22 domain are in contact at the interface between the projection and the cavity.

[0126] In some embodiments, the anti-FcRH5 arm includes a projection, and the anti-CD3 arm includes a cavity.

[0127] In some embodiments, the CH3 domain of the anti-FcRH5 arm contains a protrusion containing the T366W amino acid substitution mutation (EU numbering), and the CH3 domain of the anti-CD3 arm contains cavities containing the T366S, L368A, and Y407V amino acid substitution mutations (EU numbering).

[0128] In some embodiments, the first bispecific antibody that specifically binds to FcRH5 and CD3 is cebostamab.

[0129] In some embodiments, the second bispecific antibody that specifically binds to BCMA and CD3 includes an anti-BCMA arm containing a first binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 40), SYPMS (SEQ ID NO: 39), or GFTFSSYPMS (SEQ ID NO: 41); (b) HVR-H2 comprising the amino acid sequence of GGSGGS (SEQ ID NO: 43) or AIGGSGGSLPYADIVKG (SEQ ID NO: 42); (c) HVR-H3 (SEQ ID NO: 44) comprising the amino acid sequence of YWPMDI; (d) HVR-L1 (SEQ ID NO: 45) comprising the amino acid sequence of RASQSVSSSYLA; (e) HVR-L2 (SEQ ID NO: 46) comprising the amino acid sequence of DASIRAT; and (f) HVR-L3 (SEQ ID NO: 47) comprising the amino acid sequence of QQYQSWPLT.

[0130] In some embodiments, a second bispecific antibody that specifically binds to BCMA and CD3 comprises (a) a VH domain containing an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 48; (b) a VL domain containing an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 49; or (c) an anti-BCMA arm containing a first binding domain comprising the VH domain described in (a) and the VL domain described in (b).

[0131] In some embodiments, the first binding domain of the second bispecific antibody includes a VH domain containing the amino acid sequence of SEQ ID NO: 48 and a VL domain containing the amino acid sequence of SEQ ID NO: 49.

[0132] In some embodiments, a second bispecific antibody that specifically binds to BCMA and CD3 includes an anti-CD3 arm comprising a second binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of GFTFSDY (SEQ ID NO: 53), DYYMT (SEQ ID NO: 52), or GFTFSDYYMT (SEQ ID NO: 54); (b) HVR-H2 comprising the amino acid sequence of RNRARGYT (SEQ ID NO: 56) or FIRNRARGYTSDHNPSVKG (SEQ ID NO: 55); (c) HVR-H3 comprising the amino acid sequence of DRPSYYVLDY (SEQ ID NO: 57); (d) HVR-L1 (SEQ ID NO: 58) comprising the amino acid sequence of KSSQSLFNVRSRKNYLA; (e) HVR-L2 (SEQ ID NO: 59) comprising the amino acid sequence of WASTRES; and (f) HVR-L3 (SEQ ID NO: 60) comprising the amino acid sequence of KQSYDLFT.

[0133] In some embodiments, a second bispecific antibody that specifically binds to BCMA and CD3 comprises (a) a VH domain containing an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 61; (b) a VL domain containing an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 62; or (c) an anti-CD3 arm containing a second binding domain comprising the VH domain described in (a) and the VL domain described in (b).

[0134] In some embodiments, the second binding domain of the second bispecific antibody includes a VH domain containing the amino acid sequence of SEQ ID NO: 61 and a VL domain containing the amino acid sequence of SEQ ID NO: 62.

[0135] In some embodiments, a bispecific antibody that specifically binds to BCMA and CD3 comprises an anti-BCMA arm comprising a heavy-chain polypeptide (H1) and a light-chain polypeptide (L1), and an anti-CD3 arm comprising a heavy-chain polypeptide (H2) and a light-chain polypeptide (L2), wherein (a) H1 comprises the amino acid sequence of SEQ ID NO: 50, (b) L1 comprises the amino acid sequence of SEQ ID NO: 51, (c) H2 comprises the amino acid sequence of SEQ ID NO: 63, and (d) L2 comprises the amino acid sequence of SEQ ID NO: 64.

[0136] In some embodiments, the second bispecific antibody contains a substitutional mutation in the Fc region that reduces effector function.

[0137] In some embodiments, the second bispecific antibody is a monoclonal antibody, a chimeric antibody, or a humanized antibody.

[0138] In some embodiments, the second bispecific antibody that specifically binds to BCMA and CD3 is an antibody fragment that specifically binds to BCMA and CD3.

[0139] In some embodiments, the antibody fragment that specifically binds to BCMA and CD3 is selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments.

[0140] In some embodiments, the second bispecific antibody is a full-length antibody.

[0141] In some embodiments, the second bispecific antibody is an IgG antibody.

[0142] In some embodiments, the IgG antibody is an IgG2 antibody.

[0143] In some embodiments, the second bispecific antibody comprises the first and second respective human IgG2 constant regions, each of which includes amino acid modifications at positions 223 and 228, or 223, 225 and 228, respectively, in the hinge region, and at positions 368 or 409, respectively, in the CH3 region (EU numbering).

[0144] In some embodiments, the first human IgG2 constant region includes amino acid substitution mutations (EU numbering) at C223E, P228E, and L368E.

[0145] In some embodiments, the second human IgG2 constant region includes amino acid substitution mutations (EU numbering) at C223R, E225R, P228R, and K409R.

[0146] In some embodiments, the second bispecific antibody that specifically binds to BCMA and CD3 is erlanatamab.

[0147] In some embodiments, the first bispecific antibody and / or the second bispecific antibody are administered to the subject simultaneously with one or more additional therapeutic agents.

[0148] In some embodiments, the first bispecific antibody and / or the second bispecific antibody are administered to the subject before the administration of one or more additional therapeutic agents.

[0149] In some embodiments, a first bispecific antibody and / or a second bispecific antibody are administered to the subject after administration of one or more additional therapeutic agents.

[0150] In some embodiments, one or more additional therapeutic agents include an effective amount of anti-IL-6 antibody.

[0151] In some embodiments, the anti-IL-6 antibody is tocilizumab.

[0152] In some embodiments, the subject has a CRS event, and the method further includes treating the symptoms of the CRS event while interrupting treatment with a first bispecific antibody and a second bispecific antibody.

[0153] In some embodiments, the method further includes administering an effective dose of tocilizumab to the subject to treat CRS events.

[0154] In some embodiments, the CRS event does not resolve or worsens within 24 hours of treatment of the symptoms of the CRS event, and the method further includes administering one or more additional doses of tocilizumab to the target to manage the CRS event.

[0155] In some embodiments, tocilizumab is administered to the subject by intravenous infusion.

[0156] In some embodiments, (a) the subject weighs 30 kg or more and is administered tocilizumab at a dose of 8 mg / kg, or (b) the subject weighs less than 30 kg and is administered tocilizumab at a dose of 12 mg / kg.

[0157] In some embodiments, tocilizumab is administered to the subject two hours before administration of the first bispecific antibody and / or the second bispecific antibody.

[0158] In some embodiments, one or more additional therapeutic agents include an effective amount of acetaminophen or paracetamol.

[0159] In some embodiments, acetaminophen or paracetamol is administered to the subject in doses of 500 mg to 1000 mg.

[0160] In some embodiments, acetaminophen or paracetamol is administered orally to the subject.

[0161] In some embodiments, one or more additional therapeutic agents include an effective amount of diphenhydramine.

[0162] In some embodiments, diphenhydramine is administered to the subject at a dose of 25 mg to 50 mg.

[0163] In some embodiments, diphenhydramine is administered orally to the subject.

[0164] In some embodiments, the method includes premedication with the following drugs before administering the first bispecific antibody and / or the second bispecific antibody to the target: (i) corticosteroid; (ii) acetaminophen or paracetamol; and / or (iii) diphenhydramine.

[0165] In some embodiments, the method comprises a prephase in which a corticosteroid is administered to the subject 1 hour (±15 minutes) before the administration of either the first bispecific antibody and / or the second bispecific antibody during the prephase.

[0166] In some embodiments, the method comprises a first phase in which a corticosteroid is administered to the subject 1 hour (±15 minutes) before the administration of either the first bispecific antibody and / or the second bispecific antibody during the first phase.

[0167] In some embodiments, the method comprises a second phase in which subjects have experienced CRS due to prior administration of a first bispecific antibody and / or a second bispecific antibody, and a corticosteroid is administered to the subjects 1 hour (±15 minutes) before the administration of either the first bispecific antibody and / or the second bispecific antibody during the second phase.

[0168] In some embodiments, the method comprises a third phase in which subjects have experienced CRS due to prior administration of a first bispecific antibody and / or a second bispecific antibody, and a corticosteroid is administered to the subjects 1 hour (±15 minutes) before the administration of either of the second bispecific antibodies in the third phase.

[0169] In some embodiments, the corticosteroid is dexamethasone or methylprednisolone.

[0170] In some aspects, the corticosteroid is dexamethasone.

[0171] In some embodiments, dexamethasone is administered to the subject at a dose of approximately 20 mg.

[0172] In some embodiments, methylprednisolone is administered to the subject at a dose of approximately 80 mg. In some embodiments, a corticosteroid is administered to the subject intravenously.

[0173] In some embodiments, acetaminophen or paracetamol is administered to the subject in doses of 500 mg to 1000 mg.

[0174] In some embodiments, acetaminophen or paracetamol is administered orally to the subject.

[0175] In some embodiments, diphenhydramine is administered to the subject at a dose of 25 mg to 50 mg.

[0176] In some embodiments, diphenhydramine is administered orally to the subject.

[0177] In another embodiment, a method for treating subjects having R / R MM is provided herein, the method comprising: (i) a prephase comprising a dosing cycle (C1) of approximately 15 days; (ii) a first phase following the prephase, comprising a first dosing cycle (C1), wherein C1 of the first phase is a dosing cycle of 14 days; and (iii) a first dosing cycle following the first phase. Cycle (C1), second medication cycle (C2), third medication cycle (C3), fourth medication cycle (C4), fifth medication cycle (C5), sixth medication cycle (C6), seventh medication cycle (C7), eighth medication cycle (C8), ninth medication cycle (C9), tenth medication cycle (C10), eleventh medication cycle (C11), twelfth medication cycle (C12), thirteenth medication cycle Cycle C13, 14th medication cycle (C14), 15th medication cycle (C15), 16th medication cycle (C16), 17th medication cycle (C17), 18th medication cycle (C18), 19th medication cycle (C19), 20th medication cycle (C20), 21st medication cycle (C21), 22nd medication cycle (C22), 23rd medication cycle (C23), 24th medication cycle (iv) The administration regimen to the subject includes a second phase comprising a second phase including a 25th medication cycle (C24) and a 25th medication cycle (C25), each medication cycle in the second phase being a 14-day medication cycle, and a third phase comprising one or more medication cycles following the second phase, with cebostamab administered to the subject at 3 doses on day 9, day 10, or day 11 of the prephase C1.The subjects were administered erlanatamab in an escalating dose of 6 mg, with a target dose of 60 mg on day 2, 3, or 4 of phase 1 C1, and a target dose of 60 mg on day 1 of phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and erlanatamab was administered in a first escalating dose of 12 mg on day 1 of prephase C1, and on day 3, 4, or 5 of prephase C1. The drug is administered to the patient in a second escalating dose of 32 mg, and also in a target dose of 76 mg on day 8 of prephase C1, a target dose of 76 mg on day 1 of phase 1 C1, a target dose of 76 mg on day 1 of phases C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 of phase 2, and a target dose of 76 mg on day 1 of each of one or more dosing cycles in phase 3.

[0178] In another embodiment, cebostamab for use in the treatment of subjects having R / R MM is provided herein, the treatment comprising: (i) a prephase comprising a dosing cycle (C1) of approximately 15 days; (ii) a first phase following the prephase, comprising a first dosing cycle (C1), wherein the C1 of the first phase is a dosing cycle of 14 days; and (iii) a second phase following the first phase. The first medication cycle (C1), the second medication cycle (C2), the third medication cycle (C3), the fourth medication cycle (C4), the fifth medication cycle (C5), the sixth medication cycle (C6), the seventh medication cycle (C7), the eighth medication cycle (C8), the ninth medication cycle (C9), the tenth medication cycle (C10), the eleventh medication cycle (C11), the twelfth medication cycle (C12), the thirteenth medication cycle (C12), and the thirteenth The medication cycle (C13), the 14th medication cycle (C14), the 15th medication cycle (C15), the 16th medication cycle (C16), the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), the 24th medication (iv) The administration regimen to the subject includes a second phase comprising cycle (C24) and a 25th medication cycle (C25), each medication cycle of the second phase being a 14-day medication cycle, and a third phase comprising one or more medication cycles following the second phase, with cebostamab administered at 3 doses on day 9, day 10, or day 11 of prephase C1.The subjects were administered erlanatamab in an escalating dose of 6 mg, with a target dose of 60 mg on day 2, 3, or 4 of phase 1 C1, and a target dose of 60 mg on day 1 of phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and erlanatamab was administered in a first escalating dose of 12 mg on day 1 of prephase C1, and on day 3, 4, or 5 of prephase C1. The drug is administered to the patient in a second escalating dose of 32 mg, and also in a target dose of 76 mg on day 8 of prephase C1, a target dose of 76 mg on day 1 of phase 1 C1, a target dose of 76 mg on day 1 of phases C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 of phase 2, and a target dose of 76 mg on day 1 of each of one or more dosing cycles in phase 3.

[0179] In another embodiment, erranatamab for use in the treatment of subjects having R / R MM is provided herein, the treatment comprising: (i) a prephase comprising a dosing cycle (C1) of approximately 15 days; (ii) a first phase following the prephase, comprising a first dosing cycle (C1), wherein the C1 of the first phase is a dosing cycle of 14 days; and (iii) the first phase The following are the medication cycles: the first (C1), the second (C2), the third (C3), the fourth (C4), the fifth (C5), the sixth (C6), the seventh (C7), the eighth (C8), the ninth (C9), the tenth (C10), the eleventh (C11), the twelfth (C12), and the thirteenth. The medication cycle (C13), the 14th medication cycle (C14), the 15th medication cycle (C15), the 16th medication cycle (C16), the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), the 24th medication (iv) The administration regimen to the subject includes a second phase comprising cycle (C24) and a 25th medication cycle (C25), each medication cycle of the second phase being a 14-day medication cycle, and a third phase comprising one or more medication cycles following the second phase, with cebostamab administered at 3 doses on day 9, day 10, or day 11 of prephase C1.The subjects were administered erlanatamab in an escalating dose of 6 mg, with a target dose of 60 mg on day 2, 3, or 4 of phase 1 C1, and a target dose of 60 mg on day 1 of phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and erlanatamab was administered in a first escalating dose of 12 mg on day 1 of prephase C1, and on day 3, 4, or 5 of prephase C1. The drug is administered to the patient in a second escalating dose of 32 mg, and also in a target dose of 76 mg on day 8 of prephase C1, a target dose of 76 mg on day 1 of phase 1 C1, a target dose of 76 mg on day 1 of phases C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 of phase 2, and a target dose of 76 mg on day 1 of each of one or more dosing cycles in phase 3.

[0180] In another embodiment, a method for treating subjects having R / R MM is provided herein, the method comprising: (i) a prephase comprising a dosing cycle (C1) of approximately 22 days; (ii) a first phase following the prephase, comprising a first dosing cycle (C1), wherein C1 of the first phase is a dosing cycle of 14 days; and (iii) a first dosing cycle following the first phase. Cycle (C1), second medication cycle (C2), third medication cycle (C3), fourth medication cycle (C4), fifth medication cycle (C5), sixth medication cycle (C6), seventh medication cycle (C7), eighth medication cycle (C8), ninth medication cycle (C9), tenth medication cycle (C10), eleventh medication cycle (C11), twelfth medication cycle (C12), thirteenth medication cycle Cycle C13, 14th medication cycle (C14), 15th medication cycle (C15), 16th medication cycle (C16), 17th medication cycle (C17), 18th medication cycle (C18), 19th medication cycle (C19), 20th medication cycle (C20), 21st medication cycle (C21), 22nd medication cycle (C22), 23rd medication cycle (C23), 24th medication cycle (iv) The administration regimen to the subject includes a second phase comprising a second phase including a 25th medication cycle (C24) and a 25th medication cycle (C25), each medication cycle in the second phase being a 14-day medication cycle, and a third phase following the second phase comprising one or more medication cycles, with cebostamab administered to the subject on day 16, day 17, or day 18 of the prephase C1.The subjects were administered erranatamab in an escalating dose of 6 mg, with a target dose of 60 mg on day 2, 3, or 4 of Phase 1 C1, and a target dose of 60 mg on day 1 of Phase 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, respectively. Elranatamab was administered in a first escalating dose of 12 mg on day 1 of Prephase C1, and 32 mg on day 3, 4, or 5 of Prephase C1. The drug is administered to the subjects in the second escalating dose, as well as at a target dose of 76 mg on days 8 and 15 of prephase C1, at a target dose of 76 mg on day 1 of phase 1 C1, at a target dose of 76 mg on day 1 of phases C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 of phase 2, and at a target dose of 76 mg on day 1 of each of one or more dosing cycles in phase 3.

[0181] In another embodiment, cebostamab for use in the treatment of subjects having R / R MM is provided herein, the treatment comprising: (i) a prephase comprising a dosing cycle (C1) of approximately 22 days; (ii) a first phase following the prephase, comprising a first dosing cycle (C1), wherein the C1 of the first phase is a dosing cycle of 14 days; and (iii) a second phase following the first phase. The first medication cycle (C1), the second medication cycle (C2), the third medication cycle (C3), the fourth medication cycle (C4), the fifth medication cycle (C5), the sixth medication cycle (C6), the seventh medication cycle (C7), the eighth medication cycle (C8), the ninth medication cycle (C9), the tenth medication cycle (C10), the eleventh medication cycle (C11), the twelfth medication cycle (C12), the thirteenth Medication cycle (C13), 14th medication cycle (C14), 15th medication cycle (C15), 16th medication cycle (C16), 17th medication cycle (C17), 18th medication cycle (C18), 19th medication cycle (C19), 20th medication cycle (C20), 21st medication cycle (C21), 22nd medication cycle (C22), 23rd medication cycle (C23), 24th medication cycle (iv) The administration regimen to the subject includes a second phase comprising cycles (C24) and a 25th medication cycle (C25), each medication cycle of the second phase being a 14-day medication cycle, and a third phase comprising one or more medication cycles following the second phase, with cebostamab administered to the subject on day 16, day 17, or day 18 of the prephase C1.The subjects were administered erranatamab in an escalating dose of 6 mg, with a target dose of 60 mg on day 2, 3, or 4 of Phase 1 C1, and a target dose of 60 mg on day 1 of Phase 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, respectively. Elranatamab was administered in a first escalating dose of 12 mg on day 1 of Prephase C1, and 32 mg on day 3, 4, or 5 of Prephase C1. The drug is administered to the subjects in the second escalating dose, as well as at a target dose of 76 mg on days 8 and 15 of prephase C1, at a target dose of 76 mg on day 1 of phase 1 C1, at a target dose of 76 mg on day 1 of phases C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 of phase 2, and at a target dose of 76 mg on day 1 of each of one or more dosing cycles in phase 3.

[0182] In another embodiment, erranatamab for use in the treatment of subjects having R / R MM is provided herein, the treatment comprising: (i) a prephase comprising a dosing cycle (C1) of approximately 22 days; (ii) a first phase following the prephase, comprising a first dosing cycle (C1), wherein the C1 of the first phase is a dosing cycle of 14 days; and (iii) the first phase The following are the medication cycles: the first (C1), the second (C2), the third (C3), the fourth (C4), the fifth (C5), the sixth (C6), the seventh (C7), the eighth (C8), the ninth (C9), the tenth (C10), the eleventh (C11), the twelfth (C12), and the first 3rd medication cycle (C13), 14th medication cycle (C14), 15th medication cycle (C15), 16th medication cycle (C16), 17th medication cycle (C17), 18th medication cycle (C18), 19th medication cycle (C19), 20th medication cycle (C20), 21st medication cycle (C21), 22nd medication cycle (C22), 23rd medication cycle (C23), 24th medication cycle (iv) Administering cebostamab in a drug regimen comprising a second phase including drug cycle (C24) and a 25th drug cycle (C25), each drug cycle of the second phase being a 14-day drug cycle, and a third phase following the second phase, comprising one or more drug cycles, with 3 doses administered on day 16, day 17, or day 18 of prephase C1.The subjects were administered erranatamab in an escalating dose of 6 mg, with a target dose of 60 mg on day 2, 3, or 4 of Phase 1 C1, and a target dose of 60 mg on day 1 of Phase 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, respectively. Elranatamab was administered in a first escalating dose of 12 mg on day 1 of Prephase C1, and 32 mg on day 3, 4, or 5 of Prephase C1. The drug is administered to the subjects in the second escalating dose, as well as at a target dose of 76 mg on days 8 and 15 of prephase C1, at a target dose of 76 mg on day 1 of phase 1 C1, at a target dose of 76 mg on day 1 of phases C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 of phase 2, and at a target dose of 76 mg on day 1 of each of one or more dosing cycles in phase 3.

[0183] In another embodiment, a method for treating subjects having R / R MM is provided herein, the method comprising: (i) a first phase comprising a first dosing cycle (C1), wherein C1 of the first phase is a 14-day dosing cycle; and (ii) a second phase following the first phase, comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), a seventh dosing cycle (C7), and an eighth dosing cycle. C8, the 9th medication cycle (C9), the 10th medication cycle (C10), the 11th medication cycle (C11), the 12th medication cycle (C12), the 13th medication cycle (C13), the 14th medication cycle (C14), the 15th medication cycle (C15), the 16th medication cycle (C16), the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), (iii) administering to the subject in a drug regimen comprising a second phase, which includes a 24th drug cycle (C24) and a 25th drug cycle (C25), with each drug cycle in the second phase being a 14-day drug cycle, and a third phase following the second phase, which includes one or more drug cycles, wherein cebostamab is administered to the subject at a target dose of 60 mg, 105 mg, or 132 mg on day 2, 3, or 4 of C1 in the first phase, and on C1, C2, C3, C4, C5, C6, C7 in the second phase, In the first phase, erranatamab was administered to subjects at a target dose of 60 mg, 105 mg, or 132 mg on day 1 of C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and erranatamab was administered at a target dose of 76 mg on day 1 and day 8 of C1 in the first phase, and in the second phase, erranatamab was administered at a target dose of 76 mg on days 1 and 8 of C1 in the first phase, and on C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24,The drug is administered to the subjects at a target dose of 76 mg on days 1 and 8 of C25, and at a target dose of 76 mg on days 1 and 8 of each of at least one drug cycle in the third phase.

[0184] In another embodiment, cebostamab for use in the treatment of subjects having R / R MM is provided herein, the treatment comprising: (i) a first phase comprising a first dosing cycle (C1), wherein C1 of the first phase is a 14-day dosing cycle; and (ii) a second phase following the first phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), a seventh dosing cycle (C7), 8th medication cycle (C8), 9th medication cycle (C9), 10th medication cycle (C10), 11th medication cycle (C11), 12th medication cycle (C12), 13th medication cycle (C13), 14th medication cycle (C14), 15th medication cycle (C15), 16th medication cycle (C16), 17th medication cycle (C17), 18th medication cycle (C18), 19th medication cycle (C19), 20th medication cycle (C20), 21st medication cycle (C21), 22nd medication cycle (C22), 23rd medication cycle (C 23) A second phase comprising a 24th medication cycle (C24) and a 25th medication cycle (C25), where each medication cycle in the second phase is a 14-day medication cycle, and (iii) a third phase following the second phase, comprising one or more medication cycles, wherein cebostamab is administered to the subject in a medication regimen comprising a target dose of 60 mg, 105 mg, or 132 mg on day 2, 3, or 4 of C1 in the first phase, and C1, C2, C3, C4, C5, C6, C in the second phase. 7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 are administered to subjects at a target dose of 60 mg, 105 mg, or 132 mg, and erranatamab is administered at a target dose of 76 mg on days 1 and 8 of C1 in Phase 1, and on C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24,The drug is administered to the subjects at a target dose of 76 mg on days 1 and 8 of C25, and at a target dose of 76 mg on days 1 and 8 of each of at least one drug cycle in the third phase.

[0185] In another embodiment, erranatamab for use in the treatment of subjects having R / R MM is provided herein, the treatment comprising: (i) a first phase comprising a first dosing cycle (C1), wherein C1 of the first phase is a 14-day dosing cycle; and (ii) a second phase following the first phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7). ), the 8th medication cycle (C8), the 9th medication cycle (C9), the 10th medication cycle (C10), the 11th medication cycle (C11), the 12th medication cycle (C12), the 13th medication cycle (C13), the 14th medication cycle (C14), the 15th medication cycle (C15), the 16th medication cycle (C16), the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (iii) a third phase following the second phase, comprising administering cebostamab to the subject in a drug regimen comprising (iii) a second phase comprising a 24th drug cycle (C23), a 24th drug cycle (C24), and a 25th drug cycle (C25), where each drug cycle in the second phase is a 14-day drug cycle, and (iii) a third phase comprising one or more drug cycles, wherein cebostamab is administered to the subject in a drug regimen comprising a target dose of 60 mg, 105 mg, or 132 mg on day 2, 3, or 4 of C1 of the first phase, and C1, C2, C3, C4, C5, C 6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 are administered to the subjects at a target dose of 60 mg, 105 mg, or 132 mg, and erranatamab is administered at a target dose of 76 mg on days 1 and 8 of C1 in Phase 1, and on C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23,The target dose of 76 mg is administered to the subjects on days 1 and 8 of C24 and C25, and on days 1 and 8 of each of at least one medication cycle in the third phase.

[0186] In another embodiment, a method for treating subjects having R / R MM is provided herein, the method comprising: (i) a first phase comprising a first dosing cycle (C1), wherein C1 of the first phase is a 14-day dosing cycle; and (ii) a second phase following the first phase, comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), a seventh dosing cycle (C7), and an eighth dosing cycle. C8, the 9th medication cycle (C9), the 10th medication cycle (C10), the 11th medication cycle (C11), the 12th medication cycle (C12), the 13th medication cycle (C13), the 14th medication cycle (C14), the 15th medication cycle (C15), the 16th medication cycle (C16), the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), (iii) administering to the subject in a drug regimen comprising a second phase, which includes a 24th drug cycle (C24) and a 25th drug cycle (C25), with each drug cycle in the second phase being a 14-day drug cycle, and a third phase following the second phase, which includes one or more drug cycles, wherein cebostamab is administered to the subject at a target dose of 60 mg, 105 mg, or 132 mg on day 2, 3, or 4 of C1 in the first phase, and on C1, C2, C3, C4, C5, C6, C7 in the second phase, In the first phase, erranatamab was administered to subjects at a target dose of 60 mg, 105 mg, or 132 mg on day 1 of C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and erranatamab was administered at a target dose of 76 mg on day 1 and day 8 of C1 in the first phase, and in the second phase, erranatamab was administered at a target dose of 76 mg on days 1 and 8 of C1 in the first phase, and on C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24,The target dose of 76 mg is administered to the subjects on day 8 of C25, and on day 1 of each of at least one medication cycle in the third phase.

[0187] In another embodiment, cebostamab for use in the treatment of subjects having R / R MM is provided herein, the treatment comprising: (i) a first phase comprising a first dosing cycle (C1), wherein C1 of the first phase is a 14-day dosing cycle; and (ii) a second phase following the first phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), a seventh dosing cycle (C7), 8th medication cycle (C8), 9th medication cycle (C9), 10th medication cycle (C10), 11th medication cycle (C11), 12th medication cycle (C12), 13th medication cycle (C13), 14th medication cycle (C14), 15th medication cycle (C15), 16th medication cycle (C16), 17th medication cycle (C17), 18th medication cycle (C18), 19th medication cycle (C19), 20th medication cycle (C20), 21st medication cycle (C21), 22nd medication cycle (C22), 23rd medication cycle ( (iii) administering cebostamab to the subject in a drug regimen comprising a second phase, including a 24th drug cycle (C23), a 25th drug cycle (C24), and a 25th drug cycle (C25), where each drug cycle in the second phase is a 14-day drug cycle, and a third phase following the second phase, which comprises one or more drug cycles, with the target dose being 60 mg, 105 mg, or 132 mg on day 2, 3, or 4 of C1 in the first phase, and C1, C2, C3, C4, C5, C6, C in the second phase. 7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 are administered to subjects at a target dose of 60 mg, 105 mg, or 132 mg on day 1, and erranatamab is administered at a target dose of 76 mg on days 1 and 8 of C1 in Phase 1, and in Phase 2, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24,The target dose of 76 mg is administered to the subjects on day 8 of C25, and on day 1 of each of at least one medication cycle in the third phase.

[0188] In another embodiment, erranatamab for use in the treatment of subjects having R / R MM is provided herein, the treatment comprising: (i) a first phase comprising a first dosing cycle (C1), wherein C1 of the first phase is a 14-day dosing cycle; and (ii) a second phase following the first phase, comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7). , the 8th medication cycle (C8), the 9th medication cycle (C9), the 10th medication cycle (C10), the 11th medication cycle (C11), the 12th medication cycle (C12), the 13th medication cycle (C13), the 14th medication cycle (C14), the 15th medication cycle (C15), the 16th medication cycle (C16), the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (iii) a second phase comprising a 24th medication cycle (C23), a 25th medication cycle (C24), and a 25th medication cycle (C25), where each medication cycle in the second phase is a 14-day medication cycle, and (iii) a third phase following the second phase, comprising one or more medication cycles, wherein cebostamab is administered to the subject in a medication regimen comprising a target dose of 60 mg, 105 mg, or 132 mg on day 2, 3, or 4 of C1 in the first phase, and C1, C2, C3, C4, C5, C6 in the second phase, In the first phase, erranatamab was administered to subjects at a target dose of 60 mg, 105 mg, or 132 mg on day 1 of C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and erranatamab was administered at a target dose of 76 mg on day 1 and day 8 of C1 in the first phase, and in the second phase, erranatamab was administered at a target dose of 76 mg on days 1 and 8 of C1 in the first phase, and C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24,The target dose of 76 mg is administered to the subjects on day 8 of C25, and on day 1 of each of at least one medication cycle in the third phase.

[0189] In some embodiments, the method further includes a prephase before the first phase.

[0190] In some embodiments, the prephase comprises a drug cycle (C1) of approximately 15 days, in which cebostamab is administered to the subject at an escalating dose of 3.6 mg on day 9, 10, or 11 of prephase C1, and erranatamab is administered to the subject at a first escalating dose of 12 mg on day 1 of prephase C1, a second escalating dose of 32 mg on day 3, 4, or 5 of prephase C1, and a target dose of 76 mg on day 8 of prephase C1.

[0191] In some embodiments, the prephase comprises a dosing cycle (C1) of approximately 22 days, in which cebostamab is administered to the subject at an escalating dose of 3.6 mg on day 16, 17, or 18 of prephase C1, and erranatamab is administered to the subject at a first escalating dose of 12 mg on day 1 of prephase C1, at a second escalating dose of 32 mg on day 3, 4, or 5 of prephase C1, and at a target dose of 76 mg on days 8 and 15 of prephase C1.

[0192] In some aspects, the subject is a human subject. [Brief explanation of the drawing]

[0193] Brief explanation of the drawing [Figure 1] Figure 1 is a schematic diagram showing the overall design of the GO43979 study. DLT = Dose-Limiting Toxicity; ISC = Internal Safety Committee. [Figure 2] Figure 2 is a schematic diagram showing the initial research treatment medication schedule for GO43979 (option 1 in Figure 1). Cevos = cebostamab. [Figure 3]Figure 3 is a schematic diagram showing the GO43979 study treatment dosing schedule with prephase reduction (option 2 in Figure 1). [Figure 4] Figure 4 is a schematic diagram showing the GO43979 dosing schedule for target dose levels B and C (Figure 1). [Figure 5] Figure 5 is a schematic diagram showing the GO43979 dosing schedule at target dose level D (alternating dosing schedule) with target dose reduction. [Figure 6] Figure 6 is a schematic diagram showing the GO43979 study treatment drug schedule without escalating cebostamab doses (Option 3). [Figure 7] Figure 7 is a schematic diagram showing the GO43979 dosing schedule for target dose levels B and C (Figure 6). [Figure 8] Figure 8 is a schematic diagram showing the GO43979 dosing schedule at target dose level D (alternating dosing schedule) with target dose reduction. [Figure 9] Figure 9 is a schematic diagram showing the GO43979 dosing schedule at target dose level E. [Figure 10] Figure 10 is a schematic diagram showing the GO43979 dosing schedule for target dose levels F and G. [Modes for carrying out the invention]

[0194] Detailed description of the invention I. Definition As used herein, the term “about” refers to the normal range of error for each value, as readily understood by those skilled in the art. References of “about” to values ​​or parameters herein include (and describe) aspects directed toward the value or parameter itself.

[0195] It is understood that the embodiments of the present invention described herein include embodiments that "comprising," "consisting," and "consisting essentially of."

[0196] As used herein, the terms “FcRH5” or “Fc receptor-like protein 5” refer to any native FcRH5 from any vertebrate, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated, and are “full length” and encompass untreated FcRH5, as well as any form of FcRH5 resulting from intracellular processing. The term also encompasses naturally occurring variants of FcRH5, including, for example, splice variants or allele variants. FcRH5 includes, for example, the 977-amino acid-length human FcRH5 protein (UniProtKB / Swiss-Prot ID:Q96RD9.3).

[0197] The terms “anti-FcRH5 antibody,” “antibody that binds to FcRH5,” and “antibody that specifically binds to FcRH5” refer to antibodies that can bind to FcRH5 with sufficient affinity so that they are useful as diagnostic and / or therapeutic agents in targeting FcRH5. In one embodiment, the degree of binding of the anti-FcRH5 antibody to unrelated non-FcRH5 proteins is less than about 10% of the antibody's binding to FcRH5, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the antibody that binds to FcRH5 has an affinity of ≤1 μM, ≤250 nM, ≤100 nM, ≤15 nM, ≤10 nM, ≤6 nM, ≤4 nM, ≤2 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 -8 M or less, for example, 10 -8 M~10 -13 M, for example, 10 -9 M~10 -13 It has a dissociation constant (KD) of M). In certain embodiments, the anti-FcRH5 antibody binds to an epitope of FcRH5 that is conserved among FcRH5 from different species.

[0198] The term "differentiation antigen 3" or "CD3", as used herein, unless otherwise indicated, refers to any native CD3 derived from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), and includes, for example, CD3ε, CD3γ, CD3α, and CD3β chains. This term encompasses "full-length" unprocessed CD3 (e.g., unprocessed or unmodified CD3ε or CD3γ), as well as any form of CD3 obtained from intracellular processing. This term also encompasses naturally occurring variants of CD3, including, for example, splice variants or allelic variants. CD3 includes, for example, the human CD3ε protein, which is 207 amino acids long (NCBI reference sequence number NP_000724), and the human CD3γ protein, which is 182 amino acids long (NCBI reference sequence number NP_000064).

[0199] The terms "anti-CD3 antibody", "antibody that binds to CD3", and "antibody that specifically binds to CD3" refer to an antibody that can bind to CD3 with sufficient affinity to be useful as a diagnostic and / or therapeutic agent when the antibody targets CD3. In one embodiment, the degree of binding of the anti-CD3 antibody to an irrelevant non-CD3 protein is less than about 10% of the binding of the antibody to CD3, measured, for example, by radioimmunoassay (RIA). In certain embodiments, the antibody that binds to CD3 has a dissociation constant (KD) of ≦1 μM, ≦250 nM, ≦100 nM, ≦15 nM, ≦10 nM, ≦5 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., 10 -8 M or less, e.g., 10 -8 M to 10 -13 M, e.g., 10 -9 M to 10 -13 M). In certain embodiments, the anti-CD3 antibody binds to an epitope of CD3 that is conserved among CD3s from different species.

[0200] For the purposes of this specification, "cebostamab" (also known as BFCR4350A or RO7187797) is an Fc-engineered humanized full-length nonglycosylated IgG1 kappa T cell-dependent bispecificity (TDB) antibody that specifically binds to FcRH5 and CD3 and comprises an anti-FcRH5 arm containing the heavy chain polypeptide sequence of SEQ ID NO: 35 and the light chain polypeptide sequence of SEQ ID NO: 36, and an anti-CD3 arm containing the heavy chain polypeptide sequence of SEQ ID NO: 37 and the light chain polypeptide sequence of SEQ ID NO: 38. Sebostamab contains an amino acid substitution (T366W) at position 366 on the heavy chain of the anti-FcRH5 arm using EU numbering of Fc region amino acid residues, and three amino acid substitutions (Y407V, T366S, L368A) on the heavy chain of the anti-CD3 arm using EU numbering of Fc region amino acid residues (tyrosine to valine at position 407, threonine to serine at position 366, and leucine to alanine at position 368), driving heterodimerization of the two arms (half-antibodies). Sebostamab also contains an amino acid substitution (N297G) at position 297 of each heavy chain using EU numbering of Fc region amino acid residues, resulting in minimal binding to the Fc(Fcγ) receptor and consequently a non-glycosylated antibody that interferes with Fc effector function. Cebostamais is also listed in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Recommended INN: List 84, Vol. 34, No. 3, published 2020 (see page 701).

[0201] As used herein, the terms “B-cell maturation antigen” or “BCMA” refer to any naturally occurring BCMA from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. BCMA is also known in the art as a member of the tumor necrosis factor superfamily17. The term encompasses “full-length” unprocessed BCMA and any form of BCMA resulting from processing in cells. The term also encompasses naturally occurring variants of BCMA, including, for example, splice variants or allele variants. BCMA includes, for example, the human BCMA protein (NCBI RefSeq number NP_001183), which is 184 amino acids long.

[0202] The terms “anti-BCMA antibody,” “antibody that binds to BCMA,” and “antibody that specifically binds to BCMA” refer to antibodies that can bind to BCMA with sufficient affinity to be useful as a diagnostic and / or therapeutic agent when the antibody targets BCMA. In one embodiment, the degree of binding of an anti-BCMA antibody to unrelated non-BCMA proteins is less than about 10% of the binding of the antibody to BCMA, for example, when measured by RIA. In certain embodiments, the antibody that binds to BCMA is ≤1 μM, ≤250 nM, ≤100 nM, ≤15 nM, ≤10 nM, ≤6 nM, ≤4 nM, ≤2 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 -8 M or less, for example, 10 -8 M~10 -13 M, for example, 10 -9 M~10 -13 It has KD of M). In certain embodiments, the anti-BCMA antibody binds to BCMA epitopes that are conserved among BCMAs from different species.

[0203] For the purposes of this specification, “Eranatamab,” also known as PF-06863135, is a heterodimer humanized full-length bispecific IgG2 kappa TDB antibody that specifically binds to BCMA and CD3. Targeted T cell-mediated cytotoxicity follows the binding of one epitope of erranatamab to CD3-expressing T cells and a second epitope to BCMA-expressing cells (e.g., MM cells). Erranatamab is, for example, listed in Chemical Abstract Services (CAS) Registry Number 2408850-14-4, United States Adopted Names (USAN) File Number (HI-199), and WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Recommended INN: List 87, Vol. 36, No. 1, published 2022, pages As described in 100-103. In some cases, erranatamab comprises an anti-BCMA arm containing the heavy chain polypeptide sequence of SEQ ID NO: 50 and the light chain polypeptide sequence of SEQ ID NO: 51, and an anti-CD3 arm containing the heavy chain polypeptide sequence of SEQ ID NO: 63 and the light chain polypeptide sequence of SEQ ID NO: 64. In some cases, the heavy chain polypeptide sequence of the anti-BCMA arm of erranatamab may lack the C-terminal lysine residue present in SEQ ID NO: 50. In some cases, the heavy chain polypeptide sequence of the anti-CD3 arm of erranatamab may lack the C-terminal lysine residue present in SEQ ID NO: 63. In some cases, the heavy chain polypeptide sequence of the anti-BCMA arm of erranatamab may lack the C-terminal lysine residue present in SEQ ID NO: 50, and the heavy chain polypeptide sequence of the anti-CD3 arm of erranatamab may lack the C-terminal lysine residue present in SEQ ID NO: 63.

[0204] The term "antibody" as used herein is used in its broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies that specifically bind to FcRH5 and CD3, or bispecific antibodies that specifically bind to BCMA and CD3), and antibody fragments (e.g., bisFab), as long as they exhibit the desired antigen-binding activity.

[0205] "Affinity" refers to the sum of the non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects the 1:1 interaction between the binding pair's parts (e.g., antibody and antigen). The affinity of molecule X for its partner Y can generally be expressed by its dissociation constant (KD). Affinity can be measured by common methods known in the art, including the methods described herein. Specific descriptive and exemplary embodiments for measuring binding affinity are described below.

[0206] With respect to the binding of an antibody to a target molecule, the terms “binding,” “specific binding,” “specific to,” or “specific to” a particular polypeptide or epitope on a particular polypeptide target mean a binding that is measurably different from a nonspecific interaction. Specific binding can be determined, for example, by comparing the binding of a molecule to the binding of a control molecule. Specific binding can be determined, for example, by competition with a control molecule similar to the target, such as an excess of unlabeled targets. In this case, specific binding is indicated when the binding of a labeled target to a probe is competitively inhibited by an excess of unlabeled targets. As used herein, the terms “specific binding,” “specifically binding,” or “specific to” a particular polypeptide or epitope on a particular polypeptide target mean, for example, 10 -4 M or less, or 10 -5 M or less, or 10 -6 M or less, or 10 -7M or less, or 10 -8 M or less, or 10 -9 M or less, or 10 -10 M or less, or 10 -11 M or less, or 10 -12 KD against targets smaller than M, or 10 -4 M~10 -6 M or 10 -6 M~10 -10 M or 10 -7 M~10 -9 This can be indicated by molecules having a KD in the M range. As will be understood by those skilled in the art, affinity and KD values ​​are inversely correlated. High affinity for an antigen is measured by a low KD value. In one embodiment, the term “specific binding” refers to a binding in which a molecule binds to a particular polypeptide or an epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope.

[0207] An "affinity-mature" antibody refers to an antibody that, compared to a parent antibody without any modifications, has one or more modifications in one or more hypervariable regions (HVRs), and such modifications improve the antibody's affinity for the antigen.

[0208] The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used herein synonymously to refer to antibodies having a structure substantially similar to that of a native antibody or having a heavy chain containing an Fc region as defined herein.

[0209] An "antibody fragment" refers to a molecule other than an intact antibody, including a portion of the intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments, but not limited to, include bis-Fab;Fv;Fab;Fab, Fab'-SH;F(ab')2;diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv, ScFab); and multispecific antibodies formed from antibody fragments.

[0210] A "single-domain antibody" refers to an antibody fragment that contains all or part of the heavy chain variable domains or all or part of the light chain variable domains of an antibody. In certain embodiments, a single-domain antibody is a human single-domain antibody (see, for example, U.S. Patent No. 6,248,516, B1). Examples of single-domain antibodies include, but are not limited to, VHH.

[0211] The "Fab" fragment is an antigen-binding fragment produced by papain digestion of an antibody, consisting of the entire light chain, the variable region domain (VH) of the heavy chain, and the first constant domain (CH1) of a single heavy chain. Papain digestion of an antibody produces two identical Fab fragments. Pepsin treatment of an antibody produces a single large F(ab')2 fragment, which generally corresponds to two disulfide-linked Fab fragments with divalent antigen-binding activity and can still crosslink to an antigen. The Fab' fragment differs from the Fab fragment in that it has several additional residues at the carboxyl terminus of the CH1 domain, which contains one or more cysteines derived from the antibody hinge region. Fab'-SH is the herein name for Fab' fragments in which the cysteine ​​residue(s) of the constant domain have a free thiol group. The F(ab')2 antibody fragment was originally produced as a pair of Fab' fragments with hinge cysteines in between. Other chemical couplings of antibody fragments are also known.

[0212] "Fv" consists of a dimer in which one heavy chain and one light chain variable region domain are tightly bonded together. The folding of these two domains creates six hypervariable loops (three from the H chain and three from the L chain) that provide amino acid residues for antigen binding and confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of Fv containing only three antigen-specific CDRs) has the ability to recognize and bind to an antigen, although it often has lower affinity than the entire binding site.

[0213] In this specification, the term “Fc region” is used to define the C-terminal region of an immunoglobulin heavy chain, including native sequence Fc regions and variant Fc regions. While the boundaries of the Fc region of an immunoglobulin heavy chain can vary, the human IgG heavy chain Fc region is typically defined as extending from the amino acid residue at the Cys226 position or from Pro230 to its carboxyl terminus. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) can be removed, for example, during antibody production or purification, or by recombination of the nucleic acid encoding the antibody heavy chain. Thus, compositions of intact antibodies may include antibody populations in which all Lys447 residues have been removed, antibody populations in which Lys447 residues have not been removed, and antibody populations having a mixture of antibodies with and without Lys447 residues.

[0214] The "native sequence Fc region" contains the same amino acid sequence as the naturally occurring Fc region. The native sequence human Fc region includes the native sequence human IgG I Fc region (non-A and A allotypes); the native sequence human IgG2 Fc region; the native sequence human IgG3 Fc region; and the native sequence human IgG4 Fc region, as well as their naturally occurring variants.

[0215] A "variant Fc region" includes an amino acid sequence that differs from that of the native sequence Fc region by at least one amino acid modification, preferably one or more amino acid substitutions. Preferably, the variant Fc region has at least one amino acid substitution compared to the native sequence Fc region or the parent polypeptide Fc region, for example, about 1 to about 10 amino acid substitutions, preferably about 1 to about 5 amino acid substitutions, in the native sequence Fc region or the parent polypeptide Fc region. The variant Fc regions described herein will preferably have at least about 80% homology, preferably at least about 90% homology, or more preferably at least about 95% homology with the native sequence Fc region and / or the parent polypeptide Fc region.

[0216] As used herein, “Fc complex” means two CH3 domains of Fc regions that interact together to form a dimer, or, in a particular embodiment, two Fc regions that interact to form a dimer, and the cysteine ​​residues and / or CH3 domains of the hinge region interact by binding and / or force (e.g., van der Waals, hydrophobic force, hydrogen bond, electrostatic force, or disulfide bond).

[0217] As used herein, “Fc component” refers to the hinge region, CH2 domain, or CH3 domain of the Fc region.

[0218] The "hinge region" is generally defined as extending between approximately residues 216 to 230 of IgG (EU numbering), approximately residues 226 to 243 of IgG (Kabat numbering), or approximately residues 1 to 15 of IgG (IMGT specific numbering).

[0219] The "lower hinge region" of the Fc region is usually defined as the elongation of the residues immediately C-terminal to the hinge region, i.e., residues 233-239 (EU numbering) of the Fc region.

[0220] A "variant Fc region" includes an amino acid sequence that differs from that of the native sequence Fc region by at least one amino acid modification, preferably one or more amino acid substitutions. Preferably, the variant Fc region has at least one amino acid substitution compared to the native sequence Fc region or the parent polypeptide Fc region, for example, about 1 to about 10 amino acid substitutions, preferably about 1 to about 5 amino acid substitutions, in the native sequence Fc region or the parent polypeptide Fc region. The variant Fc region as described herein preferably has at least about 80% homology to the native sequence Fc region and / or the parent polypeptide Fc region, preferably at least about 90% homology, and more preferably at least about 95% homology.

[0221] "Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. The preferred FcR is the native human FcR sequence. Furthermore, preferred FcRs are those that bind to IgG antibodies (gamma receptors) and include the FcγRI, FcγRII, and FcγRIII subclass receptors, including allelic variants and, alternatively, splicing forms of these receptors. Examples of FcγRII receptors include FcγRIIA ("activating receptor") and FcγRIIB ("inhibiting receptor"), which have similar amino acid sequences, differing primarily in their cytoplasmic domains. The activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activating motif (ITAM) in its cytoplasmic domain. The inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain (see overview M. in Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are outlined in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those to be identified later, are encompassed herein by the term “FcR.” This term also includes the neonatal receptor FcRn, which is involved in the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)).

[0222] The terms “knob-into-hole” or “KnH” as used herein refer to techniques that direct the pairing of two polypeptides in vitro or in vivo by introducing a protrusion (knob) into one polypeptide and a cavity (hole) into the other polypeptide at the interface in which they interact. For example, KnH has been introduced at the Fc:Fc interaction interface, CL:CH1 interface, or VH / VL interface of antibodies (e.g., U.S. Patent Application Publication 2007 / 0178552, International Publication 96 / 027011, International Publication 98 / 050431, and Zhu et al. (1997) Protein Science 6:781-788). This is particularly useful for driving the pairing of two different heavy chains together during the production of multispecific antibodies. For example, a multispecific antibody having KnH in its Fc region may further constitute a single variable domain linked to each Fc region, or it may further constitute different heavy chain variable domains paired with identical, similar, or different light chain variable domains. KnH technology can also be used to combine two different receptor extracellular domains or to pair any other polypeptide sequences that constitute different target recognition sequences.

[0223] The "framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The variable domain FR generally consists of four FR domains: FR1, FR2, FR3, and FR4. Therefore, the HVR and FR sequences generally appear in VH (or VL) in the following sequence: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0224] The "CH1 region" or "CH1 domain" includes extensions of residues from approximately residue 118 to 215 of IgG (EU numbering), approximately residues 114 to 223 of IgG (Kabat numbering), or approximately residues 1.4 to 121 of IgG (IMGT specific numbering) (Lefranc MP, Giudicelli V, Duroux P, Jabado-Michaloud J, Folch G, Aouinti S, Carillon E, Duvergey H, Houles A, Paysan-Lafosse T, Hadi-Saljoqi S, Sasorith S, Lefranc G, Kossida S. IMGT (trademark), the international ImMunoGeneTics information system (trademark) 25 years on. Nucleic Acids Res. 2015 Jan;43 (Database issue):D413-22).

[0225] The "CH2 domain" in the human IgG Fc region typically extends from approximately residues 244 to 360 (Kabat numbering), from approximately residues 231 to 340 (EU numbering), or from approximately 1.6 to 125 (IGMT-specific numbering). The CH2 domain is unique in that it is not closely paired with other domains. Rather, two N-linked branched carbohydrate chains interpose between the two CH2 domains of an intact native IgG molecule. It is hypothesized that the glycans act as a substitute for domain-to-domain pairing, contributing to the stabilization of the CH2 domain. (Burton, Molec. Immunol. 22:161-206 (1985)).

[0226] The "CH3 domain" includes an extension of the C-terminal residues of the CH2 domain in the Fc region (i.e., from approximately 361 to 478 amino acid residues in IgG (Kabat numbering), from approximately 341 to 447 amino acid residues in IgG (EU numbering), or from approximately 1.4 to 130 amino acid residues in IgG (IGMT-specific numbering)).

[0227] The "CL domain" or "constant light domain" includes an extension of the C-terminal residues of the light chain variable domain (VL). The antibody light chain may also be a kappa (κ) ("Cκ") or lambda (λ) ("Cλ") light chain region. The CK region generally extends from approximately 108 to 214 residues of IgG (Kabat or EU numbering) or from approximately 1.4 to 126 residues of IgG (IMGT specific numbering). The Cλ residue generally extends from approximately 107a to approximately 215 residues (Kabat numbering), or from approximately 1.5 residues to approximately 127 residues (IMGT-specific numbering) (Lefranc MP, Giudicelli V, Duroux P, Jabado-Michaloud J, Folch G, Aouinti S, Carillon E, Duvergey H, Houles A, Paysan-Lafosse T, Hadi-Saljoqi S, Sasorith S, Lefranc G, Kossida S. IMGT (trademark), the international ImMunoGeneTics information system (trademark) 25 years on. Nucleic Acids Res. 2015 Jan;43 (Database issue):D413-22).

[0228] Light chains (LCs) from any vertebrate species can be assigned to one of two distinct types, called kappa and lambda, based on the amino acid sequence of their constant domains. Depending on the amino acid sequence of the constant domains (CHs) of their heavy chains, immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, each with heavy chains called α, δ, γ, ε, and μ, respectively. The γ and α classes are further divided into subclasses based on relatively minor differences in CH sequences and function. For example, humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0229] The term "chimeric" antibody refers to an antibody in which part of the heavy chain and / or light chain originates from a specific source or species, while the rest of the heavy chain and / or light chain originates from a different source or species.

[0230] The "class" of an antibody refers to the type of constant domain or constant region held by its heavy chain. Antibodies have five major classes: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0231] A "human antibody" is defined as an antibody produced by a human or human cell, or an antibody having an amino acid sequence corresponding to a non-human antibody that utilizes a sequence encoding a human antibody, such as a human antibody repertoire. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage display libraries. (Hoogenboom and Winter, J. Mol. Biol. 227:381, 1991; Marks et al., J. Mol. Biol. 222:581, 1991.) The method described in Cole et al. Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p.77(1985); Boerner et al. J. Immunol., 147(1):86-95, 1991. See also van Dijk and van de Winkel. Curr. Opin. Pharmacol. 5:368-74, 2001 can also be used for the preparation of human monoclonal antibodies.

[0232] Human antibodies can be prepared by administering antigens to transgenic animals, such as immunized xenomouses, which have been modified to produce such antibodies in response to antigen challenge but whose endogenous gene locus has been deactivated (see, for example, U.S. Patents 6,075,181 and 6,150,584 relating to XENOMOUSE® technology). See also, for example, Li et al. Proc. Natl. Acad. Sci. USA. 103:3557-3562, 2006, relating to human antibodies produced by human B-cell hybridoma techniques.

[0233] The "Human Consensus Framework" is a framework representing the most commonly occurring amino acid residues in the selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from subgroups of variable domain sequences. Generally, the sequence subgroups are those described in Kabat et al. Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3. In one embodiment, for VL, the subgroup is subgroup Kappa I, as described in Kabat et al. above. In one embodiment, for VH, the subgroup is subgroup III, as described in Kabat et al. above.

[0234] A “humanized” antibody refers to a chimeric antibody containing amino acid residues derived from non-human HVR and amino acid residues derived from human FR. In certain embodiments, a humanized antibody contains substantially at least one, typically two, variable domains, where all or substantially all HVR (e.g., CDR) corresponds to that of a non-human antibody, and all or substantially all FRs correspond to those of a human antibody. In certain embodiments where all or substantially all FRs of the humanized antibody correspond to those of a human antibody, any of the FRs of the humanized antibody may contain one or more amino acid residues (e.g., one or more Vernier position residues of the FR) from a non-human FR. A humanized antibody may optionally contain at least a portion of the antibody constant region derived from a human antibody. The “humanized form” of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0235] A "variable region" or "variable domain" is a domain in the heavy or light chain of an antibody that is involved in the binding of the antibody to the antigen. The variable domains of the heavy and light chains of native antibodies (VH and VL, respectively) generally have similar structures, and each domain contains four conserved framework regions (FRs) and three hypervariable regions (HVRs). (e.g., Kindt et al. Kuby Immunology, 6) th See ed. WH. Freeman and Co., page 91 (2007). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind to a specific antigen can be isolated using the VH or VL domain of the antibody that binds to that antigen, and complementary libraries of VL or VH domains can be screened. See, for example, Portolano et al. J. Immunol. 150:880-887, 1993; Clarkson et al. Nature 352:624-628, 1991.

[0236] As used herein, the term “hypervariable region” or “HVR” refers to a region within the antibody variable domain whose sequence is hypervariable (“complementarity-determining region” or “CDR”). Generally, an antibody contains six CDRs, three in the VH region (CDR-H1, CDR-H2, CDR-H3) and three in the VL region (CDR-L1, CDR-L2, CDR-L3). Examples of CDRs used herein include: (a) CDRs present in amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917, 1987), (b) CDRs present at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al. Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)), and, (c) Antigen contact occurs at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J.Mol.Biol.262:732-745, 1996).

[0237] Unless otherwise indicated, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein in accordance with Kabat et al.

[0238] A "single-chain Fv," also abbreviated as "sFv" or "scFv," is an antibody fragment containing VH and VL antibody domains linked together in a single polypeptide chain. Preferably, the scFv polypeptide further includes a polypeptide linker between the VH and VL domains, which allows the scFv to form the desired structure for antigen binding. For an overview of scFv, see Pluckthun, The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994); Malmborg et al., J. Immunol. Methods 183: 7-13, 1995.

[0239] A "targeting domain" refers to a part of a compound or molecule that specifically binds to a target epitope, antigen, ligand, or receptor. Targeting domains include, but are not limited to, antibodies (e.g., monoclonal antibodies, polyclonal antibodies, recombinant antibodies, humanized antibodies, and chimeric antibodies), antibody fragments or parts thereof (e.g., bis-Fab fragments, Fab fragments, F(ab')2, scFab, scFv antibodies, SMIP, single-domain antibodies, diabodies, minibodies, scFv-Fc, aphibodies, nanobodies, and the VH and / or VL domains of antibodies), receptors, ligands, aptamers, peptide targeting domains (e.g., cysteine ​​knot protein (CKP), etc.), and other molecules with identified binding partners. A targeting domain can target, block, activate, or antagonize the antigen to which it binds.

[0240] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies constituting the population are identical and / or bound to the same epitope, except for variant antibodies, such as those containing naturally occurring mutations or those that may arise during the production of a monoclonal antibody preparation, the presence of such variants generally in trace amounts. In contrast to polyclonal antibody preparations, which typically contain various antibodies against various determinants (epitopes), each monoclonal antibody in a monoclonal antibody preparation is against a single determinant on an antigen. Therefore, the modifier “monoclonal” indicates the characteristic of an antibody obtained from a substantially homogeneous collection of antibodies and should not be interpreted as requiring antibody production by any particular method. For example, monoclonal antibodies used in accordance with the present invention may be prepared by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of a human immunoglobulin locus, and such and other exemplary methods for preparing monoclonal antibodies are described herein.

[0241] The term "multispecific antibody" is used in its broadest sense and particularly includes antibodies that possess polyepitope specificity. In one embodiment, a multispecific antibody binds to two different targets (e.g., a bispecific antibody). Examples of such multispecific antibodies include, but are not limited to, the following: antibodies containing a heavy chain variable domain (VH) and a light chain variable domain (VL) in which the VH / VL unit has polyepitope specificity; antibodies having two or more VL and VH domains, each VH / VL unit binding to a different epitope; antibodies having two or more single variable domains, each single variable domain binding to a different epitope; full-length antibodies; antibody fragments such as Fab, Fv, dsFv, scFv, diabodies, bispecific diabodies, and triabodies; and antibody fragments linked covalently or noncovalently. "Polyepitope specificity" refers to the ability to specifically bind to two or more different epitopes on the same or different target(s). "Single specificity" refers to the ability to bind to only one antigen. In one embodiment, a monospecific biepitope antibody binds to two different epitopes on the same target / antigen. In another embodiment, a monospecific polyepitope antibody binds to multiple different epitopes on the same target / antigen. According to one embodiment, a multispecific antibody is an IgG antibody that binds to each epitope with affinities of 5 μM to 0.001 pM, 3 μM to 0.001 pM, 1 μM to 0.001 pM, 0.5 μM to 0.001 pM, or 0.1 μM to 0.001 pM.

[0242] A "naked antibody" refers to an antibody that is not conjugated to a heterologous site (e.g., a cytotoxic site) or a radioactive label. Naked antibodies may be present in pharmaceutical formulations.

[0243] A "native antibody" refers to a native immunoglobulin molecule with various structures. For example, a native IgG antibody is a heterotetrameric glycoprotein of approximately 150,000 daltons, containing two identical light chains and two identical heavy chains linked by disulfide bonds. Each heavy chain from the N-terminus to the C-terminus has a variable region (VH), also called a variable heavy chain domain or heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also called a variable light chain domain or light chain variable domain, followed by a constant light chain (CL) domain. Based on the amino acid sequence of its constant domain, the light chains of an antibody can be assigned to one of two types called kappa (κ) or lambda (λ).

[0244] "Disorder" includes, but is not limited to, the pathological conditions that predispose a mammal to the disorder in question, including chronic and acute disorders or diseases, but any condition from which treatment would be beneficial. In one aspect, the disorder is cancer, for example, multiple myeloma (MM) (e.g., relapsed or refractory (R / R) MM).

[0245] The terms "proliferative disorder" and "proliferative disorder" refer to disorders associated with a certain degree of abnormal cell proliferation. In one aspect, a proliferative disorder is cancer. In another aspect, a proliferative disorder is a tumor.

[0246] As used herein, “tumor” refers to the growth and proliferation of all neoplastic cells, whether malignant or benign, as well as all precancerous and cancerous cells and tissues. The terms “cancer,” “cancerous,” “proliferative disorder,” “proliferative disorder,” and “tumor” are not mutually exclusive as used herein.

[0247] The terms “cancer” and “cancerous” refer to or describe a physiological condition in mammals characterized by uncontrolled cell growth / proliferation. Examples of cancer include solid tumor carcinomas and non-solid tumor carcinomas. Examples of cancer include, but are not limited to, B-cell proliferation disorders such as MM, which may be recurrent or refractory R / R MM.

[0248] The terms "B-cell proliferation disorder" or "B-cell malignancy" refer to disorders associated with a certain degree of abnormal B-cell proliferation.

[0249] "Effector function" refers to the biological activity resulting from the Fc region of an antibody, which varies depending on the antibody isotype. Examples of antibody effector functions include: C1q binding and complement-dependent cell-mediated cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, downregulation of cell surface receptors (e.g., B cell receptors), and B cell activation.

[0250] A "functional Fc region" possesses "effector function" of a native sequence Fc region. Such effector function generally requires the Fc region to be combined with a binding domain (e.g., an antibody-variable domain) and can be evaluated using various assays, such as those disclosed herein.

[0251] Complement-dependent cell injury, or CDC, refers to the lysis of target cells in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to an antibody (of the appropriate subclass) bound to a cognitive antigen. To assess complement activation, a CDC assay can be performed, for example, as described in Gazzano-Santoro et al., J.Immunol. Methods 202:163 (1996).

[0252] Antibody-dependent cell-mediated cytotoxicity (ADCC) is a form of cytotoxicity in which secreted immunoglobulin (Ig) bound to Fc receptors (FcRs) present on specific cytotoxic cells (e.g., natural killer (NK) cells, neutrophils, macrophages) allows these effector cells to specifically bind to target cells containing antigens, and subsequently kill those target cells with cytotoxic drugs. These antibodies "arm" the cytotoxic cells and are absolutely necessary for such death. While NK cells, the primary cells mediating ADCC, express only FcγRIII, monocytes express FcγRI, FcγRII, and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet. Annu. Rev. Immunol. 9:457-92, 1991. To evaluate the ADCC activity of a target molecule, an in vitro ADCC assay, such as those described in U.S. Patent No. 5,500,362 or No. 5,821,337, can be performed. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. Alternatively or additionally, the ADCC activity of a target molecule can be evaluated in vivo in animal models, such as those disclosed in Clynes et al. Proc. Natl. Acad. Sci. USA. 95:652-656, 1998.

[0253] As used herein, “complex” or “complex type” refers to the association of two or more molecules that interact with each other through bonds and / or forces other than peptide bonds (e.g., van der Waals forces, hydrophobic forces, hydrophilic forces). In one embodiment, the complex is a heteromultimer. As used herein, the terms “protein complex” or “polypeptide complex” should be understood to include complexes having non-protein entities (e.g., chemical molecules such as toxins or detection agents) conjugated to the protein in the protein complex.

[0254] As used herein, “delaying the progression” of a disorder or disease means delaying, hindering, slowing, stabilizing, and / or delaying the development of a disease or disorder (e.g., a cell proliferation disorder, e.g., cancer). This delay can be of varying lengths depending on the disease being treated and / or the individual’s medical history. As will be apparent to those skilled in the art, a sufficient or significant delay can effectively include prevention in that the individual does not develop the disease. For example, it can delay the development of terminal cancer, such as the occurrence of metastases.

[0255] The “effective dose” of a compound, for example, the anti-FcRH5 / anti-CD3 bispecific antibody (e.g., cebostamab) and / or anti-BCMA / anti-CD3 bispecific antibody (e.g., erranatamab) or a composition thereof (e.g., a pharmaceutical composition) is at least the minimum amount required to achieve the desired therapeutic or prophylactic outcome, e.g., a measurable improvement or prevention of a particular disorder (e.g., a cell proliferation disorder, e.g., cancer). The effective dose as used herein may vary depending on factors such as the patient’s disease state, age, sex, and weight, as well as the antibody’s ability to induce the desired response in the individual. The effective dose is also the amount at which the therapeutically beneficial effect outweighs any toxic or adverse effects of the treatment. For prophylactic use, beneficial or desirable outcomes include the elimination or reduction of risk, reduction of severity, or delay of disease onset, and include the biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that appear during the onset of the disease. In therapeutic use, beneficial or desired outcomes include clinical results such as a reduction in one or more symptoms caused by the disease, an improvement in the quality of life of the person affected, a reduction in the dose of other drugs required to treat the disease, an enhancement of the effect of another drug (e.g., by targeting), a delay in disease progression, and / or an extension of survival. In the case of cancer or tumors, an effective dose of the drug may have the effect of reducing the number of cancer cells, reducing tumor size, inhibiting (i.e., delaying to some extent, or preferably stopping) the invasion of cancer cells into peripheral organs, inhibiting (i.e., delaying to some extent, or preferably stopping) tumor metastasis, inhibiting tumor growth to some extent, and / or alleviating to some extent one or more of the symptoms associated with the disorder. An effective dose may be administered in one or more doses. For the purposes of the present invention, an effective dose of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve prophylactic treatment or therapeutic action. As understood in the clinical field, an effective dose of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition.Therefore, the “effective dose” may be considered in relation to the administration of one or more therapeutic agents, and a monotherapy agent may be considered to be given in an effective dose if, when combined with one or more other agents, the desired outcome can be achieved or is achieved.

[0256] As used herein, “objective response rate” (ORR) refers to the proportion of patients who have two consecutive stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response, as determined using the International Myeloma Working Group response criteria.

[0257] As used herein, “complete response” or “CR” refers to a response characterized by the absence of evidence of initial monoclonal protein isotype(s) for immunofixation of serum and urine, resolution of any soft tissue plasmacytoma, and plasma cells in the bone marrow (BM) being ≤5%. “Stringent complete response” or “sCR” refers to the absence of clonal cells in the BM by normal free light chain (FLC) ratio and immunohistochemistry (kappa / lambda ratio of ≤4:1 or ≥1:2 for kappa and lambda patients, respectively, after counting ≥100 plasma cells), in addition to the CR as defined above. In some examples, the CR / sCR rate is defined as the proportion of patients who achieve CR or sCR twice in a row.

[0258] As used herein, “very good partial response” or “VGPR” refers to a response characterized by a serum and urinary M-protein level detectable by immunofixation but not by electrophoresis; or a reduction of 90% or more in serum M-protein in addition to a urinary M-protein level of less than 100 mg / 24 hours. In some examples, the percentage of patients achieving VGPR or better is defined as the percentage of patients who achieve VGPR or better two consecutive times.

[0259] As used herein, “partial response” or “PR” refers to a response characterized by a ≥50% reduction in serum M protein and a ≥90% or <200 mg / 24 hour reduction in 24-hour urinary M protein. If serum and urinary M protein are unmeasurable, a ≥50% reduction in the difference between involved and uninvolved FLC levels may be determined instead of the M protein criterion. If serum and urinary M protein are unmeasurable and the serum FLC assay is also unmeasurable, a ≥50% reduction in plasma cells may be determined instead of M protein if the baseline BM plasmacytoma rate is ≥30%. Furthermore, if soft tissue plasmacytomia were present at baseline, a partial response includes a ≥50% reduction in soft tissue plasmacytoma size (SPD).

[0260] As used herein, “progression-free survival” (PFS) refers to the length of time during and after a treatment in which the treated disease (e.g., cancer) does not worsen. Progression-free survival may include the amount of time the patient experiences complete response (CR) or partial response (PR), as well as the amount of time the patient experiences stable disease. In some examples, PFS is defined as the time from the start of the study treatment to the first day of disease progression or death from any cause, whichever comes first.

[0261] As used herein, “Duration of Response” (DOR) is defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever comes first).

[0262] In some cases, DOR is defined as the number of days from the date of the first documented partial response (PR) or better to the date of disease progression or death from any cause, whichever comes first.

[0263] As used herein, the term “survival” means the period during which a patient is alive, and includes overall survival and progression-free survival.

[0264] As used herein, “overall survival” and “OS” refer to the length of time from the date of diagnosis or the date of commencement of treatment for the disease (e.g., cancer) during which the patient is still alive. For example, OS may be defined as the time from the commencement of the treatment to death from any cause.

[0265] The term "epitope" refers to a specific site on an antigen molecule to which an antibody binds. In some embodiments, the specific site on the antigen molecule to which the antibody binds is determined by the hydroxyl radical footprint. In some embodiments, the specific site on the antigen molecule to which the antibody binds is determined crystallographically.

[0266] The "subject" or "individual" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates, e.g., monkeys), rabbits, and rodents (e.g., mice and rats). In certain aspects, the subject or individual is a human.

[0267] An "isolated" protein or peptide is one that has been separated from its components in its natural environment. In some embodiments, the protein or peptide is purified to a purity of 95% or more than 99%, as determined, for example, by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse-phase HPLC).

[0268] "Isolated" nucleic acids refer to nucleic acid molecules separated from components of the natural environment. Isolated nucleic acids include nucleic acid molecules that are normally contained in cells that contain nucleic acid molecules, but the nucleic acid molecules are located outside of chromosomes or in chromosomal locations different from their natural chromosomal locations.

[0269] Unless otherwise specified, as used herein, the term “protein” refers to any native protein from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice, rats), unless otherwise specified. This term also includes any form of protein resulting from “full length,” untreated protein, and intracellular processing. This term also encompasses naturally occurring variants of proteins, such as splice variants or allele variants.

[0270] The "amino acid sequence identity percentage (%)" for a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence, after sequence alignment and, if necessary, introducing gaps to achieve the maximum possible sequence identity percentage, with no conservative substitutions considered as part of the sequence identity. Alignment for determining the amino acid sequence identity percentage can be obtained using various methods within the scope of the art, such as publicly available computer software like BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithm necessary to obtain the maximum alignment over the entire length of the sequences to be compared. However, for the purposes of this specification, the amino acid sequence identity % values ​​are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., and its source code, along with user documentation, has been filed with the U.S. Copyright Office, Washington DC, 20559, and is hereby registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc. (South San Francisco, California) or can be compiled from its source code. The ALIGN-2 program should be compiled for use on UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and remain unchanged.

[0271] In situations where ALIGN-2 is used for amino acid sequence comparison, the percent amino acid sequence identity of a given amino acid sequence A to, with, or against an amino acid sequence B (alternatively, described as a given amino acid sequence A that has or includes a particular percent amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 times the fraction X / Y, where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in the alignment of A and B by that program, and Y is the total number of amino acid residues in B. It will be appreciated that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, the percent amino acid sequence identity of A to B will not be equal to the percent amino acid sequence identity of B to A. Unless otherwise specified, all % amino acid sequence identity values used herein are obtained using the ALIGN-2 computer program as described in the immediately preceding paragraph.

[0272] The term "pharmaceutical preparation" refers to a preparation that is in a form such that the biological activity of the active ingredient contained therein is effective and that does not contain additional components that are toxic to an unacceptable degree to the subject to whom the preparation is administered.

[0273] "Pharmaceutically acceptable carrier" refers to a component in a pharmaceutical preparation other than the active ingredient that is non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0274] As used herein, "treatment" (and its grammatical variations, e.g., "treat" or "treating") refers to a clinical intervention in an attempt to alter the natural course of an individual being treated, which can be performed for prophylaxis or during the course of clinical pathology. Desired effects of treatment include, but are not limited to, preventing the onset or recurrence of a disease, alleviating symptoms, attenuating any direct or indirect pathological consequence of the disease, preventing metastasis, decreasing the rate of disease progression, improving or alleviating the condition, and remission or improvement of prognosis. In some aspects, the antibodies of the disclosure (e.g., the anti-FcRH5 / anti-CD3 TDB and / or anti-BCMA / anti-CD3 TDB of the disclosure) are used to delay the onset of a disease or to slow the progression of a disease.

[0275] "Reduce" or "inhibit" means, for example, the ability to cause an overall decrease of 20% or more, 50% or more, or 75%, 85%, 90%, 95%, or more. In certain aspects, reduction or inhibition can refer to the effector function of an antibody mediated by the antibody Fc region, and such effector functions specifically include complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cell phagocytosis (ADCP).

[0276] As used herein, “administer” means a method of giving a target a dose of a compound (e.g., the anti-FcRH5 / anti-CD3 bispecific antibody (e.g., cebostamab) and / or anti-BCMA / anti-CD3 bispecific antibody (e.g., erranatamab) of the present disclosure). The compositions used in the methods described herein may be administered, for example, intramuscularly, intravenously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intratracheally, intranasally, intravitreously, intravaginally, intrarectally, topically, intratumorally, intraperitoneally, subcutaneously, subconjunctivally, intravesically, intramucosaly, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, directly by local perfusion bath target cells, by catheter, by irrigation, in cream, or in lipid composition. In some embodiments, the compositions used in the methods described herein are administered intravenously. In some embodiments, the compositions used in the methods described herein are administered subcutaneously. The method of administration may vary depending on various factors (e.g., the compound or composition to be administered, and the severity of the symptom, disease, or disorder being treated).

[0277] II. Therapeutic methods and compositions for use This application is partially based on a method for treating subjects with cancer (e.g., multiple myeloma (MM) (e.g., R / R MM)) with an anti-Fc receptor-like protein 5 (FcRH5) / anti-differentiation antigen 3 (CD3) bispecific antibody (e.g., cebostamab) combined with an anti-B cell maturation antigen (BCMA) / anti-CD3 bispecific antibody, for example, using the fractionated dose escalation regimens disclosed herein. The anti-FcRH5 / anti-CD3 and anti-BCMA / anti-CD3 combination dosing regimens described herein are expected to improve and deepen therapeutic response, thereby increasing survival while maintaining quality of life in cancer subjects.

[0278] A. Medication regimen i. Medication regimens for cancer treatment This disclosure provides methods and compositions for treating cancer (e.g., hematological cancers (e.g., B-cell proliferative disorders (e.g., MM))).

[0279] For example, a method for treating a subject having cancer (e.g., hematological cancer (e.g., B-cell proliferative disorder (e.g., MM))) is provided herein, comprising administering to the subject an effective amount of a first bispecific antibody (e.g., cebostamab) that specifically binds to FcRH5 and CD3, and (ii) an effective amount of a second bispecific antibody (e.g., erlanatamab) that specifically binds to BCMA and CD3.

[0280] In another example, bispecific antibodies conjugating to FcRH5 and CD3 are provided herein for use in the treatment of subjects having cancer (e.g., hematological cancer (e.g., B-cell proliferative disorder (e.g., MM))), wherein the treatment comprises (ii) administering to the subject an effective amount of a first bispecific antibody (e.g., cebostamab) that specifically conjugates to FcRH5 and CD3, and (ii) an effective amount of a second bispecific antibody (e.g., erlanatamab) that specifically conjugates to BCMA and CD3.

[0281] In another example, the following bispecific antibodies are provided herein for use in the treatment of subjects having cancer (e.g., hematological cancer (e.g., B-cell proliferative disorder (e.g., MM))), wherein the treatment comprises (ii) administering to the subject an effective amount of a first bispecific antibody (e.g., cebostamab) that specifically binds to FcRH5 and CD3, and (ii) an effective amount of a second bispecific antibody (e.g., erlanatamab) that specifically binds to BCMA and CD3.

[0282] In some cases, the subjects have relapsed or refractory (R / R) myeloma. In some cases, the subjects have a diagnosis of R / R MM according to the International Myeloma Working Group (IMWG) criteria.

[0283] A first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) and a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) are administered to a subject in a drug regimen comprising a first phase comprising one or more drug cycles, a second phase comprising one or more drug cycles, and optionally, a third phase comprising one or more drug cycles. In some embodiments, the drug regimen comprises the first and second phases but does not include the third phase. In other embodiments, the drug regimen comprises the first, second, and third phases. Each drug cycle of the first, second, and / or third phases may have any appropriate length. In some examples, each drug cycle of the first, second, and / or third phases is a 14-day drug cycle. In some cases, the second or third phase of medication is a 28-day cycle.

[0284] With respect to the first phase, the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) may be administered in a dosing regimen that includes administering the first bispecific antibody to the subject on day 2, day 3, or day 4 of a dosing cycle having any preferred length as described herein. In some examples, each dosing cycle of the first phase is a 14-day dosing cycle. In some examples, the first phase includes or consists of a single 14-day dosing cycle (C1). In some examples, the first phase consists of a single 14-day dosing cycle (C1). In a particular example, the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) is administered to the subject on day 2 of the 14-day dosing cycle. In another example, the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) is administered to the subject on day 3 of the 14-day dosing cycle. In yet another example, the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) is administered to the subject on day 4 of a 14-day drug cycle.

[0285] With respect to the first phase, the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) may be administered in a dosing regimen that includes administering the second bispecific antibody to the subject on day 1 and / or day 8 of a dosing cycle having any preferred length as described herein. In some examples, each dosing cycle of the first phase is a 14-day dosing cycle. In some examples, the first phase includes or consists of a single 14-day dosing cycle (C1). In some examples, the first phase consists of a single 14-day dosing cycle (C1). In certain examples, the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on day 1 of the 14-day dosing cycle. In another example, a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on day 8 of a 14-day drug cycle. In yet another example, a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on days 1 and 8 of a 14-day drug cycle.

[0286] With respect to the second phase, the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) may be administered in a dosing regimen that includes administering the first bispecific antibody to the subject on day 1 of a dosing cycle having any preferred length as described herein. In some embodiments, each of the first and second dosing cycles is a 14-day dosing cycle. In a particular example, the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) is administered to the subject on day 1 of a 14-day dosing cycle.

[0287] With regard to the second phase, the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) may be administered in a dosing regimen that includes administering the second bispecific antibody to the subject on day 1 and / or day 8 of a dosing cycle having any preferred length as described herein. In some embodiments, each dosing cycle of the second phase is a 14-day dosing cycle. In a particular example, the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on day 1 of the 14-day dosing cycle. In another example, the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on day 8 of the 14-day dosing cycle. In yet another example, the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on day 1 and day 8 of the 14-day dosing cycle.

[0288] The first and second phases may comprise any appropriate number of drug administration cycles, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or more. In some embodiments, the first and / or second phases may continue until disease progression or unacceptable toxicity occurs, or up to one year of treatment.

[0289] In some cases, with respect to any third phase of the drug regimen, the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) is not administered.

[0290] With respect to any subsequent third phase, a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) may be administered in a dosing regimen that includes administering the second bispecific antibody to the subject on day 1 and / or day 8 of a dosing cycle having any preferred length as described herein. In some embodiments, each dosing cycle of the third phase is a 14-day dosing cycle. In a particular example, the second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on day 1 of the 14-day dosing cycle. In another example, the second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on days 1 and 8 of the 14-day dosing cycle.

[0291] The treatment method may further include a prephase comprising one or more drug-dosing cycles prior to the first phase, the prephase comprising administering a first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) and a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erlanatamab) to the subject in a drug-dosing regimen described herein.

[0292] Each prephase dosing cycle can have any appropriate length. In some cases, each prephase dosing cycle is approximately 15 days long. In some cases, the prephase consists of or includes a single 15-day dosing cycle. In some cases, the prephase consists of a single 15-day dosing cycle. In some cases, each prephase dosing cycle is approximately 22 days long. In some cases, the prephase consists of or includes a single 15-day dosing cycle. In some cases, the prephase consists of a single 22-day dosing cycle. In some cases, the prephase continues until the CRS event experienced in the prephase is resolved. In some cases, the prephase continues up to 7 days after the last dosing of the first bispecific antibody (e.g., cebostamab) in the prephase.

[0293] In some examples, the treatment method includes a prephase comprising one or more drug-dosing cycles prior to the first phase, the prephase comprising administering a first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) to the subject on day 9, day 10, or day 11 of a drug-dosing cycle having any preferred length as described herein. In some examples, the prephase comprises or comprises approximately 15 days. In a particular example, the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) is administered to the subject on day 9 of an approximately 15-day drug-dosing cycle in the prephase. In another example, the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) is administered on day 10 of an approximately 15-day drug-dosing cycle in the prephase. In yet another example, the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) is administered on day 11 of an approximately 15-day drug cycle in the prephase. The prephase may further include the administration of a second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the target. In a specific example, the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the target on days 1, 3, and 8 of an approximately 15-day drug cycle in the prephase. In yet another example, the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered on days 1, 4, and 8 of an approximately 15-day drug cycle in the prephase. In yet another example, a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered on days 1, 5, and 8 of an approximately 15-day drug cycle in the prephase.

[0294] In other examples, the treatment method includes a pre-phase that includes one or more dosing cycles before the first phase, and the pre-phase administers the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cevostamab) to the subject on the 16th, 17th, or 18th day of a dosing cycle having any suitable length described herein. In some examples, the pre-phase includes or consists of approximately 22 days. In a specific example, the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cevostamab) is administered to the subject on the 16th day of an approximately 22-day dosing cycle in the pre-phase. In another example, the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cevostamab) is administered to the subject on the 17th day of an approximately 22-day dosing cycle in the pre-phase. In yet another example, the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cevostamab) is administered to the subject on the 18th day of an approximately 22-day dosing cycle in the pre-phase. The pre-phase may further include administering a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., elranatamab) to the subject. In a specific example, the second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., elranatamab) is administered to the subject on the 1st, 3rd, 8th, and 15th days of an approximately 22-day dosing cycle in the pre-phase. In another example, the second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., elranatamab) is administered to the subject on the 1st, 4th, 8th, and 15th days of an approximately 22-day dosing cycle in the pre-phase. In yet another example, the second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., elranatamab) is administered to the subject on the 1st, 5th, 8th, and 15th days of an approximately 22-day dosing cycle in the pre-phase.

[0295] The pre-phase may include any suitable number of dosing cycles, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or more dosing cycles.

[0296] In certain cases, the prephase includes one medication cycle (C1).

[0297] In some cases, the target dose of the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) and / or the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the target patient for each dose in the prephase. In other words, the prephase may not utilize escalating dosing for the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) and / or the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab).

[0298] In other examples, the prephase involves administering escalating doses of a first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) and / or a second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the subject. The escalating doses of the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) and / or the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) may be administered to the subject on any appropriate day (or more) of the dosing cycle (e.g., C1).

[0299] For example, the dose escalation of the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) during the prephase is approximately 0.5 mg to approximately 19.9 mg (e.g., approximately 1 mg to approximately 18 mg, approximately 2 mg to approximately 15 mg, approximately 3 mg to approximately 10 mg, approximately 3.3 mg to approximately 6 mg, or approximately 3.4 mg to approximately 4 mg, e.g., approximately 3 mg, 3.2 mg, 3.3 mg, 3. 4mg, 3.6mg, 3.8mg, 4mg, 4.2mg, 4.4mg, 4.6mg, 4.8mg, 5mg, 5.2mg, 5.6mg, 5.8mg, 6mg, 6.2mg, 6.4m g, 6.6mg, 6.8mg, 7mg, 7.2mg, 7.4mg, 7.6mg, 7.8mg, 8mg, 8.2mg, 8.4mg, 8.6mg, 8.8mg, 9mg, 9.2mg, 9 .4mg, 9.6mg, 9.8mg, 10mg, 10.2mg, 10.4mg, 10.6mg, 10.8mg, 11mg, 11.2mg, 11.4mg, 11.6mg, 11.8 mg, 12mg, 12.2mg, 12.4mg, 12.6mg, 12.8mg, 13mg, 13.2mg, 13.4mg, 13.6mg, 13.8mg, 14mg, 14.2mg, The doses may be 14.4 mg, 14.6 mg, 14.8 mg, 15 mg, 15.2 mg, 15.4 mg, 15.6 mg, 15.8 mg, 16 mg, 16.2 mg, 16.4 mg, 16.6 mg, 16.8 mg, 17 mg, 18.2 mg, 18.4 mg, 18.6 mg, 18.8 mg, 19 mg, 19.2 mg, 19.4 mg, 19.6 mg, or 19.8 mg. In some cases, the escalating dose of the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) in the prephase is approximately 3.6 mg.

[0300] During the prephase (e.g., a prephase of approximately 15 days), escalating doses of the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) may be administered to the subject on day 9, 10, or 11 of C1. In a specific example, the escalating dose of the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) is administered to the subject on day 9 of C1. In another example, the escalating dose of the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) is administered to the subject on day 10 of C1. In yet another example, the escalating dose of the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) is administered to the subject on day 11 of C1.

[0301] During the prephase (e.g., a prephase of approximately 22 days), escalating doses of the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) may be administered to the subject on day 16, 17, or 18 of C1. In a specific case, the escalating dose of the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) is administered to the subject on day 16 of C1. In another case, the escalating dose of the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) is administered to the subject on day 17 of C1.

[0302] In yet another example, an escalating dose of the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) is administered to the subject on day 18 of C1.

[0303] In some cases, the prephase involves administering a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) in a first escalating dose and a second escalating dose.

[0304] The first and / or second escalating doses of a second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) may be administered to the subject on any appropriate day of the prephase dosing cycle (e.g., C1).

[0305] For example, during the prephase, the first escalating dose of the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on day 1 of C1, and the second escalating dose is administered to the subject on day 3 of C1. In another example, the first escalating dose of the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on day 1 of C1, and the second escalating dose of the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on day 4 of C1. In yet another example, the first escalating dose of the second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on day 1 of C1, and the second escalating dose of the second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on day 5 of C1.

[0306] In a dual escalation regimen, one or more target doses of a second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) may be administered on any appropriate day after the second escalation dose. In one specific example, the target dose of the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on day 8 of C1. In another example, the target dose of the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on days 8 and 15 of C1.

[0307] Any appropriate dose may be used for the first and second dose escalations. For example, the first dose escalation may be 12 mg and the second dose escalation may be 32 mg.

[0308] The first phase may include any appropriate number of medication cycles (e.g., one, two, three, or more). In some examples, the first phase includes one medication cycle (C1). In some examples, the first phase consists of one medication cycle (C1). In another example, the first phase includes a first medication cycle (C1) and a second medication cycle (C2). In yet another example, the first phase includes a first medication cycle (C1), a second medication cycle (C2), and a third medication cycle (C3).

[0309] During the first phase, the treatment method may include administering a first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) and / or a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the subject. In a specific example, the first phase may include administering the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) to the subject on day 2, 3, or 4 of C1, and administering the second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the subject on day 1 and / or day 8 of C1. In another example, the first phase includes administering a first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) to the subject on days 2, 3, or 4 of C1 and C2, and a second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the subject on days 1 and / or 8 of C1 and C2. In yet another example, the first phase includes administering a first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) to the subject on days 2, 3, or 4 of C1, C2, and C3, and a second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the subject on days 1 and / or 8 of C1, C2, and C3.

[0310] In some examples, the first phase includes administering a first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) to the subject on day 2 of C1 and a second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the subject on day 1 of C1. In some examples, the first phase includes administering a first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) to the subject on day 3 of C1 and a second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the subject on day 1 of C1. In some examples, the first phase involves administering a first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) to the subject on day 4 of C1 and a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erlanatamab) to the subject on day 1 of C1.

[0311] In some examples, the first phase includes administering a first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) to the subject on day 2 of C1 and a second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the subject on days 1 and 8 of C1. In some examples, the first phase includes administering a first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) to the subject on day 3 of C1 and a second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the subject on days 1 and 8 of C1. In some examples, the first phase involves administering a first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) to the subject on day 4 of C1, and a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erlanatamab) to the subject on days 1 and 8 of C1.

[0312] The second phase may include any appropriate number of medication cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more medication cycles). In some examples, the second phase may include the first medication cycle (C1), the second medication cycle (C2), the third medication cycle (C3), the fourth medication cycle (C4), the fifth medication cycle (C5), the sixth medication cycle (C6), the seventh medication cycle (C7), the eighth medication cycle (C8), the ninth medication cycle (C9), the tenth medication cycle (C10), the eleventh medication cycle (C11), the twelfth medication cycle (C12), the thirteenth medication cycle ( C13), including the 14th medication cycle (C14), the 15th medication cycle (C15), the 16th medication cycle (C16), the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), the 24th medication cycle (C24), and the 25th medication cycle (C25).

[0313] In some examples, the second phase includes administering a first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) to the subject on day 1 of C1, and a second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the subject on day 1 of C1. The second phase involves administering the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) on day 1 of C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24 and C25 of the second phase. Furthermore, this may further include administering a second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erlanatamab) to the target on day 1 of phase 2, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25.

[0314] In some examples, the second phase may involve administering a first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) to the subject on day 1 of C1 and a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the subject on days 1 and 8 of C1. In other words, in a 14-day dosing cycle, the second phase may involve administering the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) every two weeks (Q2W) and the second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) every week (QW). In some examples, the second phase may involve administering a first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) to the subject on day 1 of C1 and a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the subject on day 8 of C1. In other words, in a 14-day dosing cycle, the second phase may involve administering a first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) Q2W and a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) Q2W. Phase 2 involves administering the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) on day 1 of phases C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24 and C25 of Phase 2, and also involves administering the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) on day 1 of phase 2, and This may further include targeting a second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erlanatamab) on days 1 and 8 of phases 2 C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25.In other words, the second phase may further include administering a first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) Q2W and a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) QW.

[0315] Alternatively, the second phase involves administering the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) on day 1 of C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 of the second phase. The second phase may further include administering a second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the target on day 8 of C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24 and C25. In other words, the second phase may further include administering a first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) Q2W and a second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) Q2W. In certain embodiments, the second phase may further include administering a first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) Q4W instead of Q2W and a second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) Q4W instead of Q2W, for example, after achieving a complete response during the first six months of the first phase of administration. In certain embodiments, the second phase may further include administering a second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) Q4W instead of Q2W, for example, after achieving a partial response over at least two months of the first phase.

[0316] The third phase may include any appropriate number of medication cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130 or more medication cycles). In some cases, the third phase consists of the first medication cycle (C1), the second medication cycle (C2), the third medication cycle (C3), the fourth medication cycle (C4), the fifth medication cycle (C5), the sixth medication cycle (C6), the seventh medication cycle (C7), the eighth medication cycle (C8), the ninth medication cycle (C9), the tenth medication cycle (C10), the eleventh medication cycle (C11), the twelfth medication cycle (C12), the thirteenth medication cycle ( C13), including the 14th medication cycle (C14), the 15th medication cycle (C15), the 16th medication cycle (C16), the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), the 24th medication cycle (C24), and the 25th medication cycle (C25).

[0317] In some examples, the third phase includes administering a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the subject on day 1 of C1. The third phase may further include administering a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the subject on day 1 of C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24 and C25 of the third phase. In other words, the third phase may further include administering a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the target every two weeks (Q2W) on day 1 of each cycle of the third phase. In certain embodiments, the third phase may further include administering a first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) Q4W instead of Q2W and a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) Q4W instead of Q2W after achieving a complete response, for example, during the first six months of the second phase of administration. In certain embodiments, the third phase may further include administering a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) Q4W instead of Q2W after achieving a partial response, for example, over at least two months of the second phase.

[0318] In some examples, the third phase includes administering a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the subject on day 1 and / or day 8 of C1. The third phase may further include administering a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the subject on day 1 and / or day 8 of C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24 and C25 of the third phase.

[0319] In some cases, a target dose of the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) is administered to the subject during the prephase, first phase, second phase, and / or third phase.

[0320] For example, during the prephase period, the target dose of the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) may be administered to the subject on day 9 of the prephase dosing cycle. In another example, the target dose of the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) may be administered to the subject on day 10 of the prephase dosing cycle. In yet another example, the target dose of the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) may be administered to the subject on day 11 of the prephase dosing cycle.

[0321] During the first phase, the target dose of the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) may be administered to the subject on day 2, day 3, or day 4 of the first phase dosing cycle. In a specific example, the target dose of the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) may be administered to the subject on day 2 of the first phase dosing cycle. In another example, the target dose of the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) may be administered to the subject on day 3 of the first phase dosing cycle. In yet another example, the target dose of the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) may be administered to the subject on day 4 of the first phase dosing cycle.

[0322] During the second phase, the target dose of the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) may be administered to the subject on day 1 of the second phase dosing cycle.

[0323] In some embodiments, the method or treatment includes a third phase, the third phase not involving the administration of a first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) to the subject.

[0324] Any appropriate target dose for the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) may be used, including any dosages described herein. In some examples, the target dose is 20 mg to 600 mg (e.g., 30 mg to 500 mg, 40 mg to 400 mg, 60 mg to 350 mg, 80 mg to 300 mg, 100 mg to 200 mg, or 140 mg to 180 mg, e.g., 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some embodiments, the target dose is 40 mg to 80 mg (e.g., 50 mg to 70 mg, e.g., 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, or 80 mg). In some embodiments, the target dose is 80 mg to 300 mg. In some embodiments, the target dose is 120 mg to 150 mg (e.g., 130 mg to 140 mg, e.g., 120 mg, 125 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 145 mg, or 150 mg). In some embodiments, the target dose is approximately 60 mg. In some embodiments, the target dose is approximately 105 mg. In some embodiments, the target dose is approximately 132 mg.

[0325] In some cases, the target dose of the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on day 8 of the prephase dosing cycle (e.g., in a double escalation regimen). In other cases, the target dose of the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered on day 15 of the prephase dosing cycle (e.g., in a double escalation regimen). In yet another case, the target dose of the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered on days 8 and 15 of the prephase dosing cycle (e.g., in a double escalation regimen).

[0326] During the first phase, the treatment method may include administering a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the subject on day 1 and / or day 8 of the first phase dosing cycle. In a specific example, the second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on day 1 of the first phase dosing cycle. In another example, the second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on days 1 and 8 of the first phase dosing cycle.

[0327] During the second phase, the treatment method may include administering a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the subject on day 1 and / or day 8 of the second phase dosing cycle. In a specific example, the second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on day 1 of the second phase dosing cycle. In another example, the second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on day 8 of the second phase dosing cycle. In yet another example, the second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on day 1 and day 8 of the second phase dosing cycle.

[0328] During the third phase, the treatment method may include administering a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) to the subject on day 1 and / or day 8 of the third phase dosing cycle. In a specific example, the second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on day 1 of the third phase dosing cycle. In another example, the second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject on days 1 and 8 of the third phase dosing cycle.

[0329] Any appropriate escalating dose of a second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) may be used (e.g., approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 6 mg, approximately 7 mg, approximately 8 mg, approximately 9 mg, approximately 10 mg, approximately 11 mg, approximately 12 mg, approximately 13 mg, approximately 14 mg, approximately 15 mg, approximately 16 mg, approximately 17 mg, approximately 18 mg, approximately 19 mg, approximately 20 mg, approximately (21 mg, approximately 22 mg, approximately 23 mg, approximately 24 mg, approximately 25 mg, approximately 26 mg, approximately 27 mg, approximately 28 mg, approximately 29 mg, approximately 30 mg, approximately 31 mg, approximately 32 mg, approximately 33 mg, approximately 34 mg, approximately 35 mg, approximately 36 mg, approximately 37 mg, approximately 38 mg, approximately 39 mg, approximately 40 mg, approximately 41 mg, approximately 42 mg, approximately 43 mg, approximately 44 mg, approximately 45 mg, approximately 46 mg, approximately 47 mg, approximately 48 mg, or approximately 49 mg). In some cases, a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the patient in escalating doses of approximately 5 mg to 50 mg (e.g., approximately 10 mg to 40 mg, approximately 10 mg to 15 mg, approximately 12 mg to 22 mg, approximately 20 mg to 40 mg, approximately 30 mg to 35 mg, e.g., approximately 12 mg, approximately 13 mg, approximately 14 mg, approximately 15 mg, approximately 16 mg, approximately 17 mg, approximately 18 mg, approximately 19 mg, approximately 20 mg, approximately 21 mg, approximately 22 mg, approximately 23 mg, approximately 24 mg, approximately 25 mg, approximately 26 mg, approximately 27 mg, approximately 28 mg, approximately 29 mg, approximately 30 mg, approximately 31 mg, or approximately 32 mg).

[0330] In one example, the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject in a first escalating dose of approximately 4 mg to 25 mg (e.g., approximately 4 mg to 20 mg, approximately 10 mg to 20 mg, approximately 11 mg to 15 mg, e.g., approximately 12 mg). In a further example, the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject in a second escalating dose of approximately 25 mg to 45 mg (e.g., approximately 27 mg to 37 mg, approximately 30 mg to 34 mg, e.g., approximately 32 mg or approximately 44 mg). In yet another example, the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject in a first escalating dose of approximately 12 mg and a second escalating dose of approximately 32 mg. In further examples, a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject in escalating doses of approximately 32 mg or approximately 44 mg. After administration of the escalating dose(s), the target dose of the second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) may be administered to the subject as described herein.

[0331] Any appropriate target dose of a second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) may be used (e.g., approximately 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg) g, about 79mg, about 80mg, about 81mg, about 82mg, about 83mg, about 84mg, about 85mg, about 86mg, about 87mg, about 88mg, about 89mg, about 90mg, Approximately 91mg, approximately 92mg, approximately 93mg, approximately 94mg, approximately 95mg, approximately 96mg, approximately 97mg, approximately 98mg, approximately 99mg, approximately 100mg, approximately 101mg, approximately 102mg (Approximately 103mg, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg, 111mg, 112mg, 113mg, 114mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg). In some cases, the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject at a target dose of approximately 40 mg to 160 mg (e.g., approximately 40 mg to 120 mg, e.g., approximately 40 mg to 80 mg, e.g., approximately 44 mg to 80 mg, e.g., approximately 44 mg to 76 mg, e.g., approximately 60 mg to 80 mg, e.g., approximately 70 mg to 80 mg, e.g., approximately 74 mg to 78 mg, e.g., approximately 74 mg, approximately 75 mg, approximately 76 mg, approximately 77 mg, or approximately 78 mg). In some cases, the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject at a target dose of approximately 44 mg, approximately 76 mg, approximately 116 mg, or approximately 152 mg. In some cases, a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject at a target dose of approximately 76 mg.

[0332] During any dosing cycle of the dosing regimen described herein, a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) may be administered to the subject after administration of the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) (e.g., approximately 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours later). During any dosing cycle of the dosing regimen described herein, a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) may be administered to the subject before the administration of the first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) to the subject (e.g., approximately 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours prior).

[0333] The first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) and / or the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) may be administered by any suitable route of administration. In some cases, the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) and / or the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) are administered intravenously to the subject. In other cases, the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) and / or the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) are administered subcutaneously to the subject. In other cases, the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) is administered intravenously, and the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered subcutaneously to the subject.

[0334] In some cases, this method or procedure further includes administering a corticosteroid to the target. Any suitable corticosteroid, such as dexamethasone or methylprednisolone, may be used.

[0335] In some cases, the method or procedure further includes administering a corticosteroid to the subject during the prephase C1 period, 1 hour (±15 minutes) before administering a first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) and / or a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab). The corticosteroid may be administered on the same day as the first bispecific antibody and / or the second bispecific antibody, or on a different day (e.g., one or more days before or one or more days after the administration of any bispecific antibody).

[0336] In some cases, the treatment method further includes administering corticosteroids to the target during the prephase.

[0337] Corticosteroids can be administered on any appropriate day during the pre-phase medication cycle.

[0338] In some cases, the treatment method further includes administering corticosteroids to the target during the first phase.

[0339] Corticosteroids may be administered on any appropriate day during the first phase of the medication cycle.

[0340] Corticosteroids may be administered on any one or more days selected from the following: day 1, day 2, day 3, day 4 and / or day 8 of the first phase of the dosing cycle (e.g., during C1 of the first phase). In a particular example, corticosteroids are administered to the subject on day 1 of the dosing cycle of the first phase (e.g., before or after administration of the second bispecific antibody). In another example, corticosteroids are administered to the subject on day 2 of the dosing cycle of the first phase (e.g., before or after administration of the first bispecific antibody). In yet another example, corticosteroids are administered to the subject on day 3 of the dosing cycle of the first phase (e.g., before or after administration of the first bispecific antibody). In yet another example, corticosteroids are administered to the subject on day 4 of the dosing cycle of the first phase (e.g., before or after administration of the first bispecific antibody). In yet another example, corticosteroids are administered to the subject on day 8 of the first phase of the medication cycle (e.g., before or after administration of the second bispecific antibody).

[0341] In some cases, the treatment method further includes administering corticosteroids to the target during the second phase.

[0342] Corticosteroids may be administered on any appropriate day during the second phase of the medication cycle.

[0343] Corticosteroids may be administered on day 1 and / or day 8 of the dosing cycle in the second phase (e.g., during phase C1 of the second phase). In certain cases, corticosteroids are administered to the subject on day 1 of the dosing cycle in the second phase (e.g., before or after administration of any bispecific antibody). In other cases, corticosteroids are administered to the subject on day 8 of the dosing cycle in the second phase (e.g., before or after administration of any bispecific antibody).

[0344] In some cases, the treatment method further includes administering corticosteroids to the target during the third phase.

[0345] Corticosteroids may be administered on any appropriate day during the third phase of the medication cycle.

[0346] Corticosteroids may be administered on day 1 and / or day 8 of the third phase of the medication cycle (e.g., during phase C1 of the third phase). In certain cases, corticosteroids are administered to the subject on day 1 of the third phase of the medication cycle (e.g., before or after administration of any bispecific antibody). In other cases, corticosteroids are administered to the subject on day 8 of the third phase of the medication cycle (e.g., before or after administration of any bispecific antibody).

[0347] In some cases, corticosteroids are administered to subjects who have experienced cytokine release syndrome (CRS) at previous doses. In some cases, corticosteroids are administered to subjects in the prephase, first phase, second phase, and / or third phase if the subject has experienced CRS events at previous doses.

[0348] Corticosteroids can be administered by any appropriate route of administration. In some cases, corticosteroids are administered intravenously or orally to the subject. In some cases, corticosteroids are administered intravenously to the subject.

[0349] In some cases, corticosteroids are administered intravenously to subjects before the administration of any bispecific antibody. In some cases, corticosteroids are administered intravenously to subjects after the administration of any bispecific antibody.

[0350] Corticosteroids may be administered at any appropriate time before administration of a bispecific antibody, for example, approximately 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours before administration of any bispecific antibody. In some cases, corticosteroids are administered intravenously to the subject approximately 1 hour before administration of any bispecific antibody.

[0351] Corticosteroids may be administered at any appropriate time after administration of any bispecific antibody, for example, approximately 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or 8 days after administration of any bispecific antibody. In some cases, corticosteroids are administered intravenously to subjects approximately 24 hours after administration of any bispecific antibody. In some cases, corticosteroids are administered intravenously to subjects approximately 7 days after administration of any bispecific antibody. In some cases, corticosteroids are administered intravenously to subjects approximately 24 hours after administration of any bispecific antibody, and again approximately 7 days later.

[0352] In some cases, the corticosteroid is dexamethasone or methylprednisolone.

[0353] In some cases, the corticosteroid is dexamethasone.

[0354] Dexamethasone can be administered in any appropriate dose, for example, 1 mg to 100 mg. In some cases, dexamethasone is administered to subjects at a dose of approximately 20 mg to 40 mg. In some cases, dexamethasone is administered to subjects at a dose of approximately 20 mg.

[0355] Methylprednisolone can be administered in any appropriate dose, for example, from 1 mg to 400 mg. In some cases, methylprednisolone is administered to subjects at a dose of approximately 80 mg.

[0356] Any two suitable anti-FcRH5 / anti-CD3 and anti-BCMA / anti-CD3 bispecific antibodies may be used, for example, any bispecific antibodies disclosed herein (e.g., Section H below).

[0357] In some cases, the first bispecific antibody (e.g., anti-FcRH5 / anti-CD3 antibody) is cebostamab, and the second bispecific antibody (e.g., anti-BCMA / anti-CD3 antibody) is erlanatamab.

[0358] In some cases, a first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) and a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) are administered to the subject concurrently with one or more additional therapeutic agents. Any suitable additional therapeutic agent(s), including any of those disclosed herein, may be used.

[0359] In some cases, a first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) and / or a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject before the administration of one or more additional therapeutic agents.

[0360] In some cases, a first bispecific antibody (e.g., an anti-FcRH5 / anti-CD3 antibody, e.g., cebostamab) and / or a second bispecific antibody (e.g., an anti-BCMA / anti-CD3 antibody, e.g., erranatamab) is administered to the subject after the administration of one or more additional therapeutic agents.

[0361] In some cases, one or more additional therapeutic agents include an effective dose of tocilizumab.

[0362] In some cases, the subjects have a CRS event, and the method further includes treating the symptoms of the CRS event while discontinuing treatment with a bispecific antibody.

[0363] In some cases, this method or treatment further includes administering an effective dose of tocilizumab to treat CRS events.

[0364] In some cases, the CRS event does not resolve or worsens within 24 hours of treatment of the symptoms of the CRS event, and this method further includes administering one or more additional doses of tocilizumab to the target to manage the CRS event.

[0365] In some cases, tocilizumab is administered to the patient by intravenous infusion.

[0366] In some cases, (a) the subject weighs 30 kg or more and is administered tocilizumab at a dose of 8 mg / kg, or (b) the subject weighs less than 30 kg and is administered tocilizumab at a dose of 12 mg / kg.

[0367] In some cases, tocilizumab is administered to the subject two hours before the administration of any bispecific antibody.

[0368] In some cases, one or more additional therapeutic agents include an effective amount of acetaminophen or paracetamol.

[0369] Any appropriate dose of acetaminophen or paracetamol may be used. In some cases, acetaminophen or paracetamol is administered to the subject at doses of approximately 500 mg to 1000 mg.

[0370] Acetaminophen or paracetamol may be administered by any suitable route of administration, including any of the routes of administration disclosed herein. In some cases, acetaminophen or paracetamol is administered orally to the subject.

[0371] In some cases, one or more additional therapeutic agents include an effective amount of diphenhydramine.

[0372] Any appropriate dose of diphenhydramine may be used. In some cases, diphenhydramine is administered to subjects at doses ranging from approximately 25 mg to approximately 50 mg.

[0373] Diphenhydramine may be administered by any suitable route of administration, including any of the routes of administration disclosed herein. In some examples, diphenhydramine is administered orally to the subject.

[0374] In another example, a method for treating subjects having R / R MM is provided herein, comprising (i) a prephase comprising a dosing cycle (C1) of approximately 15 days, and (ii) a first phase comprising a first dosing cycle (C1) following the prephase. Phase 1 of the series is a 14-day medication cycle, (iii) Following Phase 1, there are the first medication cycle (C1), the second medication cycle (C2), the third medication cycle (C3), the fourth medication cycle (C4), the fifth medication cycle (C5), the sixth medication cycle (C6), the seventh medication cycle (C7), the eighth medication cycle (C8), the ninth medication cycle (C9), the tenth medication cycle (C10), and the eleventh medication cycle. C11, 12th medication cycle (C12), 13th medication cycle (C13), 14th medication cycle (C14), 15th medication cycle (C15), 16th medication cycle (C16), 17th medication cycle (C17), 18th medication cycle (C18), 19th medication cycle (C19), 20th medication cycle (C20), 21st medication cycle (C21), 22nd medication cycle (C22), 23rd medication cycle ( (iv) The drug regimen includes administering the subject to a drug regimen comprising a second phase, which includes a 24th drug cycle (C24) and a 25th drug cycle (C25), each of which is a 14-day drug cycle, and a third phase, which includes one or more drug cycles following the second phase, with the first bispecific antibody administered on day 9, day 10, or day 11 of the prephase C1.The target dose is 60 mg on day 2, 3, or 4 of phase 1 C1, and 60 mg on day 1 of phase 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, with the second bispecific antibody administered to the subjects in an escalating dose of 6 mg, and on day 1 of prephase C1, C2, C2, C2, C2, C2, and C25, C2, and C2, C2, C2, C2, C2, C2, C2, and C25, C2, C2, C2, C2, C2, C2, C2, and C25, C2, C2, C2, C2, C2, C2, C2, C2, and C25. The drug is administered to the subjects at a second escalating dose of 32 mg, a target dose of 76 mg on day 8 of prephase C1, a target dose of 76 mg on day 1 of phase 1 C1, a target dose of 76 mg on day 1 of phases C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 of phase 2, and a target dose of 76 mg on day 1 of each of one or more dosing cycles in phase 3.

[0375] In another example, a method for treating subjects having R / R MM is provided herein, comprising (i) a prephase comprising a dosing cycle (C1) of approximately 22 days, and (ii) a first phase comprising a first dosing cycle (C1) following the prephase. Phase 1 of the series is a 14-day medication cycle, (iii) Following Phase 1, there are the first medication cycle (C1), the second medication cycle (C2), the third medication cycle (C3), the fourth medication cycle (C4), the fifth medication cycle (C5), the sixth medication cycle (C6), the seventh medication cycle (C7), the eighth medication cycle (C8), the ninth medication cycle (C9), the tenth medication cycle (C10), and the eleventh medication cycle. C11, 12th medication cycle (C12), 13th medication cycle (C13), 14th medication cycle (C14), 15th medication cycle (C15), 16th medication cycle (C16), 17th medication cycle (C17), 18th medication cycle (C18), 19th medication cycle (C19), 20th medication cycle (C20), 21st medication cycle (C21), 22nd medication cycle (C22), 23rd medication cycle ( (iv) The drug regimen includes administering the subject to a drug regimen comprising a second phase, which includes a 24th drug cycle (C24) and a 25th drug cycle (C25), each of which is a 14-day drug cycle, and a third phase, which includes one or more drug cycles following the second phase, with the first bispecific antibody administered on day 16, day 17, or day 18 of the prephase C1.The subjects were administered a target dose of 60 mg on day 2, 3, or 4 of phase 1 C1 in an escalating dose of 6 mg, and a target dose of 60 mg on day 1 of phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, respectively, in an escalating dose of 6 mg. The second bispecific antibody was administered in a first escalating dose of 12 mg on day 1 of prephase C1, and 32 mg on day 3, 4, or 5 of prephase C1. The drug is administered to the subjects in a second escalating dose of mg, and with a target dose of 76 mg on days 8 and 15 of prephase C1, a target dose of 76 mg on day 1 of phase 1 C1, a target dose of 76 mg on day 1 of phases C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 of phase 2, and a target dose of 76 mg on day 1 of each of one or more dosing cycles in phase 3.

[0376] In another example, a method for treating a subject having R / R MM is provided herein, comprising: a first bispecific antibody that specifically binds to FcRH5 and CD3 (e.g., cebostamab); and a second bispecific antibody that specifically binds to BCMA and CD3 (e.g., erlanatamab), comprising: (i) a first phase including a first dosing cycle (C1), wherein C1 of the first phase is a 14-day dosing cycle; and (ii) a second phase following the first phase, comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle ( C3), the fourth medication cycle (C4), the fifth medication cycle (C5), the sixth medication cycle (C6), the seventh medication cycle (C7), the eighth medication cycle (C8), the ninth medication cycle (C9), the tenth medication cycle (C10), the eleventh medication cycle (C11), the twelfth medication cycle (C12), the thirteenth medication cycle (C13), the fourteenth medication cycle (C14), the fifteenth medication cycle (C15), the sixteenth medication cycle (C16), the seventeenth medication cycle (C17), the eighteenth medication cycle (C18), and the nineteenth medication cycle (C19). (iii) administering to the subject in a drug regimen comprising (iii) a third phase following the second phase, comprising one or more drug cycles, the first bispecific antibody on days 2 and 3 of C1 of the first phase The target dose of 60 mg, 105 mg, or 132 mg is administered to the subjects on day 1 or day 4 of Phase 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and the second bispecific antibody is administered to the subjects at a target dose of 76 mg on day 1 and day 8 of Phase 1 C1, and in Phase 2 C1, C2, C3, C4, C5, C6,The target dose of 76 mg is administered to the subjects on days 1 and 8 of C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and also on days 1 and 8 of each of the one or more drug cycles in Phase 3.

[0377] In another example, a method for treating a subject having R / R MM is provided herein, comprising: a first bispecific antibody that specifically binds to FcRH5 and CD3 (e.g., cebostamab); and a second bispecific antibody that specifically binds to BCMA and CD3 (e.g., erlanatamab), comprising: (i) a first phase including a first dosing cycle (C1), wherein C1 of the first phase is a 14-day dosing cycle; and (ii) a second phase following the first phase, comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle ( C3), the fourth medication cycle (C4), the fifth medication cycle (C5), the sixth medication cycle (C6), the seventh medication cycle (C7), the eighth medication cycle (C8), the ninth medication cycle (C9), the tenth medication cycle (C10), the eleventh medication cycle (C11), the twelfth medication cycle (C12), the thirteenth medication cycle (C13), the fourteenth medication cycle (C14), the fifteenth medication cycle (C15), the sixteenth medication cycle (C16), the seventeenth medication cycle (C17), the eighteenth medication cycle (C18), and the nineteenth medication cycle (C19). (iii) administering to the subject in a drug regimen comprising (iii) a third phase following the second phase, comprising one or more drug cycles, the first bispecific antibody on days 2 and 3 of C1 of the first phase On day 1 or day 4, the target dose of 60 mg, 105 mg, or 132 mg is administered to the subjects, and on day 1 of phase 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 is administered to the subjects, and the second bispecific antibody is administered to the subjects at a target dose of 76 mg on day 8 of phase 1 C1, and on day 2 C1, C2, C3, C4, C5, C6, C7, C8,The target dose of 76 mg is administered to the subjects on days 1 and 8 of C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and on day 8 of each of the one or more dosing cycles in Phase 3.

[0378] In some examples, administering a bispecific antibody containing an anti-FcRH5 arm having a first binding domain may include the following six HVRs: (a) HVR-H1 containing the amino acid sequence of RFGVH (SEQ ID NO: 1), (b) HVR-H2 containing the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2), (c) HVR-H3 containing the amino acid sequence of HYYGSSDYALDN (SEQ ID NO: 3), (d) HVR-L1 containing the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4), (e) HVR-L2 containing the amino acid sequence of SGSYRYS (SEQ ID NO: 5), and (f) HVR-L3 containing the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6).

[0379] In some examples, the first bispecific antibody comprises (a) a heavy chain variable (VH) domain containing an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain containing an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8; or (c) an anti-FcRH5 arm comprising a first binding domain containing the VH domain described in (a) and the VL domain described in (b). In some examples, the first binding domain comprises a VH domain containing the amino acid sequence of SEQ ID NO: 7 and a VL domain containing the amino acid sequence of SEQ ID NO: 8.

[0380] In some examples, the first bispecific antibody that specifically binds to FcRH5 and CD3 includes the following six HVRs: (a) HVR-H1 containing the amino acid sequence SYYIH (SEQ ID NO: 9), (b) HVR-H2 containing the amino acid sequence WIYPENDNTKYNEKFKD (SEQ ID NO: 10), (c) HVR-H3 containing the amino acid sequence DGYSRYYFDY (SEQ ID NO: 11), (d) HVR-L1 containing the amino acid sequence KSSQSLLNSRTRKNYLA (SEQ ID NO: 12), (e) HVR-L2 containing the amino acid sequence WTSTRKS (SEQ ID NO: 13), and (f) HVR-L3 containing the amino acid sequence KQSFILRT (SEQ ID NO: 14), and includes an anti-CD3 arm containing a second binding domain.

[0381] In some examples, a first bispecific antibody that specifically binds to FcRH5 and CD3 comprises an anti-CD3 arm comprising (a) a VH domain containing an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15; (b) a VL domain containing an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16; or (c) a second binding domain containing the VH domain described in (a) and the VL domain described in (b). In some examples, the second binding domain comprises a VH domain containing the amino acid sequence of SEQ ID NO: 15 and a VL domain containing the amino acid sequence of SEQ ID NO: 16.

[0382] In some cases, the first bispecific antibody is cebostamab.

[0383] In some examples, a second bispecific antibody that specifically binds to BCMA and CD3 includes an anti-BCMA arm having a first binding domain, comprising the following six HVRs: (a) HVR-H1 containing the amino acid sequence of GFTFSSY (SEQ ID NO: 40), SYPMS (SEQ ID NO: 39), or GFTFSSYPMS (SEQ ID NO: 41); (b) HVR-H2 containing the amino acid sequence of GGSGGS (SEQ ID NO: 43), or AIGGSGGSLPYADIVKG (SEQ ID NO: 42); (c) HVR-H3 (SEQ ID NO: 44) containing the amino acid sequence of YWPMDI; (d) HVR-L1 (SEQ ID NO: 45) containing the amino acid sequence of RASQSVSSSYLA; (e) HVR-L2 (SEQ ID NO: 46) containing the amino acid sequence of DASIRAT; and (f) HVR-L3 containing the amino acid sequence of QQYQSWPLT (SEQ ID NO: 47).

[0384] In some examples, a second bispecific antibody that specifically binds to BCMA and CD3 comprises (a) a VH domain containing an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 48; (b) a VL domain containing an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 49; or (c) an anti-BCMA arm comprising a first binding domain containing the VH domain described in (a) and the VL domain described in (b). In some examples, the first binding domain comprises a VH domain containing the amino acid sequence of SEQ ID NO: 48 and a VL domain containing the amino acid sequence of SEQ ID NO: 49.

[0385] In some examples, a second bispecific antibody that specifically binds to BCMA and CD3 includes an anti-CD3 arm containing a second binding domain, comprising the following six HVRs: (a) HVR-H1 containing the amino acid sequence of GFTFSDY (SEQ ID NO: 53), DYYMT (SEQ ID NO: 52), or GFTFSDYYMT (SEQ ID NO: 54); (b) HVR-H2 containing the amino acid sequence of RNRARGYT (SEQ ID NO: 56), or FIRNRARGYTSDHNPSVKG (SEQ ID NO: 55); (c) HVR-H3 containing the amino acid sequence of DRPSYYVLDY (SEQ ID NO: 57); (d) HVR-L1 (SEQ ID NO: 58) containing the amino acid sequence of KSSQSLFNVRSRKNYLA; (e) HVR-L2 (SEQ ID NO: 59) containing the amino acid sequence of WASTRES; and (f) HVR-L3 containing the amino acid sequence of KQSYDLFT (SEQ ID NO: 60).

[0386] In some examples, a second bispecific antibody that specifically binds to BCMA and CD3 comprises (a) a VH domain containing an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 61; (b) a VL domain containing an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 62; or (c) an anti-CD3 arm comprising a second binding domain containing the VH domain described in (a) and the VL domain described in (b). In some examples, the second binding domain comprises a VH domain containing the amino acid sequence of SEQ ID NO: 61 and a VL domain containing the amino acid sequence of SEQ ID NO: 62.

[0387] In some cases, the second bispecific antibody is erlanatamab.

[0388] In one embodiment, a method for treating a subject having cancer (e.g., MM) is provided herein, the method comprising (i) administering to the subject an effective amount of a first bispecific antibody that specifically binds to FcRH5 and CD3, and (ii) an effective amount of a second bispecific antibody that specifically binds to BCMA and CD3, wherein the first bispecific antibody that specifically binds to FcRH5 and CD3 is one of the following six HVRs: (a) HVR-H1 (SEQ ID NO: 1) containing the amino acid sequence RFGVH; (b) HVR- containing the amino acid sequence VIWRGGSTDYNAAFVS The first bispecific antibody, which specifically binds to FcRH5 and CD3, comprises an anti-FcRH5 arm containing a first binding domain including the amino acid sequences of H2 (SEQ ID NO: 2), (c)HYYGSSDYALDN, HVR-H3 (SEQ ID NO: 3), (d)KASQDVRNLVV (SEQ ID NO: 4), (e)SGSYRYS, HVR-L2 (SEQ ID NO: 5), and (f)QQHYSPPYT, HVR-L3 (SEQ ID NO: 6), and contains the amino acid sequences of the following six HVRs: (a)SYYIH (b) HVR-H2 (SEQ ID NO: 10) containing the amino acid sequence of (c) WIYPENDNTKYNEKFKD; (d) HVR-L1 containing the amino acid sequence of (c) WIYPENDNTKYNEKFKD; (e) HVR-L2 (SEQ ID NO: 13) containing the amino acid sequence of (c) WIYPENDNTKYNEKFKD; (c) HVR-H3 (SEQ ID NO: 11) containing the amino acid sequence of (d) WIYPENDNTKYNEKFKD; (e) HVR-L3 (SEQ ID NO: 12) containing the amino acid sequence of (c) WIYPENDNTKYNEKFKD; (f) HVR-L3 containing the amino acid sequence of (c) WIYPENDNTKYNEKFKD; (c The second bispecific antibody that specifically binds to MA and CD3 is one of the following six HVRs: (a) HVR-H1 containing the amino acid sequence of GFTFSSY (SEQ ID NO: 40), SYPMS (SEQ ID NO: 39), or GFTFSSYPMS (SEQ ID NO: 41); (b) HVR-H2 containing the amino acid sequence of GGSGGS (SEQ ID NO: 43) or AIGGSGGSLPYADIVKG (SEQ ID NO: 42); (c) HVR-H3 (SEQ ID NO: 44) containing the amino acid sequence of YWPMDI; (d) HVR-L1 (SEQ ID NO: 45) containing the amino acid sequence of RASQSVSSSYLA;(e) HVR-L2 (SEQ ID NO: 46) containing the amino acid sequence of DASIRAT; and (f) HVR-L3 (SEQ ID NO: 47) containing the amino acid sequence of QQYQSWPLT; the second bispecific antibody that specifically binds to BCMA and CD3 includes an anti-BCMA arm containing a first binding domain, and is one of the following six HVRs: (a) HVR-H1 containing the amino acid sequences of GFTFSDY (SEQ ID NO: 53), DYYMT (SEQ ID NO: 52), or GFTFSDYYMT (SEQ ID NO: 54); (b) RNRARGYT (SEQ ID NO: 56) (c) HVR-H2 containing the amino acid sequence of (a) FIRNRARGYTSDHNPSVKG (SEQ ID NO: 55); (d) HVR-H3 containing the amino acid sequence of (c) DRPSYYVLDY (SEQ ID NO: 57); (d) HVR-L1 (SEQ ID NO: 58) containing the amino acid sequence of (a) KSSQSLFNVRSRKNYLA; (e) HVR-L2 (SEQ ID NO: 59) containing the amino acid sequence of (a) WASTRES; and (f) HVR-L3 containing the amino acid sequence of (a) KQSYDLFT (SEQ ID NO: 60), comprising an anti-CD3 arm containing a second binding domain.

[0389] In one embodiment, a bispecific antibody that specifically binds to FcRH5 and CD3 is provided herein for use in the treatment of a subject having cancer (e.g., MM), the treatment comprising administering to the subject (i) an effective amount of a first bispecific antibody that specifically binds to FcRH5 and CD3, and (ii) an effective amount of a second bispecific antibody that specifically binds to BCMA and CD3, wherein the first bispecific antibody that specifically binds to FcRH5 and CD3 is one of the following six HVRs: (a) HVR-H1 (SEQ ID NO: 1) containing the amino acid sequence RFGVH (b) HVR-H2 (SEQ ID NO: 2) containing the amino acid sequence VIWRGGSTDYNAAFVS; (c) HVR-H3 (SEQ ID NO: 3) containing the amino acid sequence HYYGSSDYALDN; (d) HVR-L1 containing the amino acid sequence KASQDVRNLVV (SEQ ID NO: 4); (e) HVR-L2 (SEQ ID NO: 5) containing the amino acid sequence SGSYRYS; and (f) HVR-L3 (SEQ ID NO: 6) containing the amino acid sequence QQHYSPPYT; comprising an anti-FcRH5 arm containing a first binding domain that specifically binds to FcRH5 and CD3. The bispecific antibodies are for the following six HVRs: (a) HVR-H1 (SEQ ID NO: 9) containing the amino acid sequence SYYIH; (b) HVR-H2 (SEQ ID NO: 10) containing the amino acid sequence WIYPENDNTKYNEKFKD; (c) HVR-H3 (SEQ ID NO: 11) containing the amino acid sequence DGYSRYYFDY; (d) HVR-L1 (SEQ ID NO: 12) containing the amino acid sequence KSSQSLLNSRTRKNYLA; (e) HVR-L2 (SEQ ID NO: 13) containing the amino acid sequence WTSTRKS; and (f) the amino acid sequence KQSFILRT (SEQ ID NO: 14). The second bispecific antibody, which includes an anti-CD3 arm containing a second binding domain including HVR-L3 and specifically binds to BCMA and CD3, is one of the following six HVRs: (a) HVR-H1 containing the amino acid sequence of GFTFSSY (SEQ ID NO: 40), SYPMS (SEQ ID NO: 39), or GFTFSSYPMS (SEQ ID NO: 41); (b) HVR-H2 containing the amino acid sequence of GGSGGS (SEQ ID NO: 43) or AIGGSGGSLPYADIVKG (SEQ ID NO: 42); (c) HVR-H3 (SEQ ID NO: 44) containing the amino acid sequence of YWPMDI;(d) HVR-L1 (SEQ ID NO: 45) containing the amino acid sequence of RASQSVSSSYLA; (e) HVR-L2 (SEQ ID NO: 46) containing the amino acid sequence of DASIRAT; and (f) HVR-L3 (SEQ ID NO: 47) containing the amino acid sequence of QQYQSWPLT; the second bispecific antibody that specifically binds to BCMA and CD3 is an anti-BCMA arm containing a first binding domain, and is one of the following six HVRs: (a) HVR-L2 (SEQ ID NO: 52) containing the amino acid sequence of GFTFSDY (SEQ ID NO: 53), DYYMT (SEQ ID NO: 52), or GFTFSDYYMT (SEQ ID NO: 54). 1; comprising an anti-CD3 arm containing a second binding domain, including (b) HVR-H2 containing the amino acid sequence of RNRARGYT (SEQ ID NO: 56) or FIRNRARGYTSDHNPSVKG (SEQ ID NO: 55); (c) HVR-H3 containing the amino acid sequence of DRPSYYVLDY (SEQ ID NO: 57); (d) HVR-L1 (SEQ ID NO: 58) containing the amino acid sequence of KSSQSLFNVRSRKNYLA; (e) HVR-L2 (SEQ ID NO: 59) containing the amino acid sequence of WASTRES; and (f) HVR-L3 containing the amino acid sequence of KQSYDLFT (SEQ ID NO: 60).

[0390] In one embodiment, a bispecific antibody that specifically binds to BCMA and CD3 is provided herein for use in the treatment of a subject having cancer (e.g., MM), the treatment comprising administering to the subject (i) an effective amount of a first bispecific antibody that specifically binds to FcRH5 and CD3, and (ii) an effective amount of a second bispecific antibody that specifically binds to BCMA and CD3, wherein the first bispecific antibody that specifically binds to FcRH5 and CD3 is one of the following six HVRs: (a) HVR-H1 (SEQ ID NO: 1) containing the amino acid sequence RFGVH; (b) HVR-H2 (SEQ ID NO: 2) containing the amino acid sequence of VIWRGGSTDYNAAFVS; (c) HVR-H3 (SEQ ID NO: 3) containing the amino acid sequence of HYYGSSDYALDN; (d) HVR-L1 containing the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) HVR-L2 (SEQ ID NO: 5) containing the amino acid sequence of SGSYRYS; and (f) HVR-L3 (SEQ ID NO: 6) containing the amino acid sequence of QQHYSPPYT, comprising an anti-FcRH5 arm containing a first binding domain, which specifically binds to FcRH5 and CD3. The bispecific antibodies are for the following six HVRs: (a) HVR-H1 (SEQ ID NO: 9) containing the amino acid sequence SYYIH; (b) HVR-H2 (SEQ ID NO: 10) containing the amino acid sequence WIYPENDNTKYNEKFKD; (c) HVR-H3 (SEQ ID NO: 11) containing the amino acid sequence DGYSRYYFDY; (d) HVR-L1 (SEQ ID NO: 12) containing the amino acid sequence KSSQSLLNSRTRKNYLA; (e) HVR-L2 (SEQ ID NO: 13) containing the amino acid sequence WTSTRKS; and (f) the amino acid sequence KQSFILRT (SEQ ID NO: 14). The second bispecific antibody, which includes an anti-CD3 arm containing a second binding domain including HVR-L3 and specifically binds to BCMA and CD3, is one of the following six HVRs: (a) HVR-H1 containing the amino acid sequence of GFTFSSY (SEQ ID NO: 40), SYPMS (SEQ ID NO: 39), or GFTFSSYPMS (SEQ ID NO: 41); (b) HVR-H2 containing the amino acid sequence of GGSGGS (SEQ ID NO: 43) or AIGGSGGSLPYADIVKG (SEQ ID NO: 42); (c) HVR-H3 (SEQ ID NO: 44) containing the amino acid sequence of YWPMDI;(d) HVR-L1 (SEQ ID NO: 45) containing the amino acid sequence of RASQSVSSSYLA; (e) HVR-L2 (SEQ ID NO: 46) containing the amino acid sequence of DASIRAT; and (f) HVR-L3 (SEQ ID NO: 47) containing the amino acid sequence of QQYQSWPLT; the second bispecific antibody that specifically binds to BCMA and CD3 is an anti-BCMA arm containing a first binding domain, and is one of the following six HVRs: (a) HVR-L2 (SEQ ID NO: 52) containing the amino acid sequence of GFTFSDY (SEQ ID NO: 53), DYYMT (SEQ ID NO: 52), or GFTFSDYYMT (SEQ ID NO: 54). 1; comprising an anti-CD3 arm containing a second binding domain, including (b) HVR-H2 containing the amino acid sequence of RNRARGYT (SEQ ID NO: 56) or FIRNRARGYTSDHNPSVKG (SEQ ID NO: 55); (c) HVR-H3 containing the amino acid sequence of DRPSYYVLDY (SEQ ID NO: 57); (d) HVR-L1 (SEQ ID NO: 58) containing the amino acid sequence of KSSQSLFNVRSRKNYLA; (e) HVR-L2 (SEQ ID NO: 59) containing the amino acid sequence of WASTRES; and (f) HVR-L3 containing the amino acid sequence of KQSYDLFT (SEQ ID NO: 60).

[0391] In one embodiment, a method for treating a subject having cancer (e.g., MM) is provided herein, the method comprising (i) administering to the subject an effective amount of a first bispecific antibody that specifically binds to FcRH5 and CD3, and (ii) an effective amount of a second bispecific antibody that specifically binds to BCMA and CD3, wherein the first bispecific antibody comprises an anti-FcRH5 arm comprising a first binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 7 and a VL domain comprising the amino acid sequence of SEQ ID NO: 8, and the first bispecific antibody that specifically binds to FcRH5 and CD3 comprises the amino acid sequence of SEQ ID NO: 15 A second bispecific antibody that specifically binds to BCMA and CD3 includes an anti-CD3 arm comprising a VH domain containing the amino acid sequence of SEQ ID NO: 16 and a second binding domain comprising a VL domain containing the amino acid sequence of SEQ ID NO: 46, and a second bispecific antibody that specifically binds to BCMA and CD3 includes an anti-BCMA arm comprising a first binding domain comprising a VH domain containing the amino acid sequence of SEQ ID NO: 48 and a VL domain containing the amino acid sequence of SEQ ID NO: 49, and a second bispecific antibody that specifically binds to BCMA and CD3 includes an anti-CD3 arm comprising a second binding domain comprising a VH domain containing the amino acid sequence of SEQ ID NO: 61 and a VL domain containing the amino acid sequence of SEQ ID NO: 62.

[0392] In one embodiment, a bispecific antibody that specifically binds to FcRH5 and CD3 is provided herein for use in the treatment of a subject having cancer (e.g., MM), the treatment comprising (i) administering to the subject an effective amount of a first bispecific antibody that specifically binds to FcRH5 and CD3, and (ii) administering to the subject an effective amount of a second bispecific antibody that specifically binds to BCMA and CD3, wherein the first bispecific antibody comprises an anti-FcRH5 arm comprising a first binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 7 and a VL domain comprising the amino acid sequence of SEQ ID NO: 8, and the first bispecific antibody that specifically binds to FcRH5 and CD3. The first bispecific antibody, which specifically binds to BCMA and CD3, comprises an anti-CD3 arm containing a VH domain containing the amino acid sequence of SEQ ID NO: 15 and a second binding domain containing a VL domain containing the amino acid sequence of SEQ ID NO: 16. The second bispecific antibody comprises an anti-BCMA arm containing a first binding domain containing a VH domain containing the amino acid sequence of SEQ ID NO: 48 and a VL domain containing the amino acid sequence of SEQ ID NO: 49. The second bispecific antibody, which specifically binds to BCMA and CD3, comprises an anti-CD3 arm containing a second binding domain containing a VH domain containing the amino acid sequence of SEQ ID NO: 61 and a VL domain containing the amino acid sequence of SEQ ID NO: 62.

[0393] In one embodiment, a bispecific antibody that specifically binds to BCMA and CD3 is provided herein for use in the treatment of a subject having cancer (e.g., MM), the treatment comprising administering to the subject (i) an effective amount of a first bispecific antibody that specifically binds to FcRH5 and CD3, and (ii) an effective amount of a second bispecific antibody that specifically binds to BCMA and CD3, wherein the first bispecific antibody comprises an anti-FcRH5 arm comprising a first binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 7 and a VL domain comprising the amino acid sequence of SEQ ID NO: 8, and the first bispecific antibody that specifically binds to FcRH5 and CD3. The first bispecific antibody, which specifically binds to BCMA and CD3, comprises an anti-CD3 arm containing a VH domain containing the amino acid sequence of SEQ ID NO: 15 and a second binding domain containing a VL domain containing the amino acid sequence of SEQ ID NO: 16. The second bispecific antibody comprises an anti-BCMA arm containing a first binding domain containing a VH domain containing the amino acid sequence of SEQ ID NO: 48 and a VL domain containing the amino acid sequence of SEQ ID NO: 49. The second bispecific antibody, which specifically binds to BCMA and CD3, comprises an anti-CD3 arm containing a second binding domain containing a VH domain containing the amino acid sequence of SEQ ID NO: 61 and a VL domain containing the amino acid sequence of SEQ ID NO: 62.

[0394] In another example, the present invention provides a method for treating a human subject having R / R MM, comprising administering an effective dose of cebostamab and an effective dose of erranatamab to the subject.

[0395] In another example, a method for treating human subjects having R / R MM is provided herein, the method comprising: (i) a prephase comprising a dosing cycle (C1) of approximately 15 days; (ii) a first phase following the prephase, comprising a first dosing cycle (C1), wherein the C1 of the first phase is a dosing cycle of 14 days; and (iii) a first phase following the first phase. Medication cycle (C1), second medication cycle (C2), third medication cycle (C3), fourth medication cycle (C4), fifth medication cycle (C5), sixth medication cycle (C6), seventh medication cycle (C7), eighth medication cycle (C8), ninth medication cycle (C9), tenth medication cycle (C10), eleventh medication cycle (C11), twelfth medication cycle (C12), thirteenth medication cycle Ikuru (C13), 14th medication cycle (C14), 15th medication cycle (C15), 16th medication cycle (C16), 17th medication cycle (C17), 18th medication cycle (C18), 19th medication cycle (C19), 20th medication cycle (C20), 21st medication cycle (C21), 22nd medication cycle (C22), 23rd medication cycle (C23), 24th medication cycle (iv) The administration regimen to the subject includes a second phase comprising cycles (C24) and the 25th medication cycle (C25), each medication cycle in the second phase being a 14-day medication cycle, and a third phase comprising one or more medication cycles following the second phase, with cebostamab administered to the subject on day 9, day 10, or day 11 of the prephase C1.The subjects were administered erlanatamab in an escalating dose of 6 mg, with a target dose of 60 mg on day 2, 3, or 4 of phase 1 C1, and a target dose of 60 mg on day 1 of phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and erlanatamab was administered in a first escalating dose of 12 mg on day 1 of prephase C1, and on day 3, 4, or 5 of prephase C1. The drug is administered to the patient in a second escalating dose of 32 mg, and also in a target dose of 76 mg on day 8 of prephase C1, a target dose of 76 mg on day 1 of phase 1 C1, a target dose of 76 mg on day 1 of phases C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 of phase 2, and a target dose of 76 mg on day 1 of each of one or more dosing cycles in phase 3.

[0396] In another example, a method for treating a human subject having R / R MM is provided herein, comprising: (i) an effective amount of a first bispecific antibody (e.g., cebostamab) that specifically binds to FcRH5 and CD3, and (ii) an effective amount of a second bispecific antibody (e.g., erlanatamab) that specifically binds to BCMA and CD3, comprising: (i) a prephase comprising a dosing cycle (C1) of approximately 15 days; (ii) a first phase following the prephase, comprising a first dosing cycle (C1), wherein C1 of the first phase is a dosing cycle of 14 days; and (iii) Following Phase 1, there are the first medication cycles (C1), the second medication cycle (C2), the third medication cycle (C3), the fourth medication cycle (C4), the fifth medication cycle (C5), the sixth medication cycle (C6), the seventh medication cycle (C7), the eighth medication cycle (C8), the ninth medication cycle (C9), the tenth medication cycle (C10), the eleventh medication cycle (C11), the twelfth medication cycle (C12), the thirteenth medication cycle (C13), the fourteenth medication cycle (C14), the fifteenth medication cycle (C15), and the sixteenth medication cycle (C16). (iv) a second phase comprising the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), the 24th medication cycle (C24), and the 25th medication cycle (C25), wherein each medication cycle in the second phase is a 14-day medication cycle, and (iv) a third phase comprising one or more medication cycles following the second phase. The treatment involves administering a first bispecific antibody that specifically binds to FcRH5 and CD3 to the subject using Dimen, with an escalating dose of 3.6 mg on day 9, 10, or 11 of prephase C1, a target dose of 60 mg on day 2, 3, or 4 of phase 1 C1, and a target dose of 60 mg on day 1 of phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25.A second bispecific antibody that specifically binds to BCMA and CD3 is administered as a first escalating dose of 12 mg on day 1 of prephase C1, a second escalating dose of 32 mg on day 3, 4, or 5 of prephase C1, and a target dose of 76 mg on day 8 of prephase C1, a target dose of 76 mg on day 1 of phase 1 C1, and phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23. The target dose is 76 mg on day 1 of C24 and C25, and on day 1 of each of the one or more dosing cycles of the third phase, and the first bispecific antibody that specifically binds to FcRH5 and CD3 is one of the following six HVRs: (a) HVR-H1 (SEQ ID NO: 1) containing the amino acid sequence RFGVH; (b) HVR-H2 (SEQ ID NO: 2) containing the amino acid sequence VIWRGGSTDYNAAFVS; (c) HVR-H3 (SEQ ID NO: 3) containing the amino acid sequence HYYGSSDYALDN; (d) KASQDVRNLVV The first bispecific antibody, which specifically binds to FcRH5 and CD3, comprises an anti-FcRH5 arm containing a first binding domain including (e) HVR-L1 containing the amino acid sequence of (SEQ ID NO: 4); (e) HVR-L2 containing the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (f) HVR-L3 containing the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6), and is specific to the following six HVRs: (a) HVR-H1 containing the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) HVR-H2 containing the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10). The second bispecific antibody, which specifically binds to BCMA and CD3, includes an anti-CD3 arm containing a second binding domain, comprising (c) HVR-H3 (SEQ ID NO: 11) containing the amino acid sequence DGYSRYYFDY; (d) HVR-L1 (SEQ ID NO: 12) containing the amino acid sequence KSSQSLLNSRTRKNYLA; (e) HVR-L2 (SEQ ID NO: 13) containing the amino acid sequence WTSTRKS; and (f) HVR-L3 (SEQ ID NO: 14) containing the amino acid sequence KQSFILRT; and is specific to the following six HVRs: (a) GFTFSSY (SEQ ID NO: 40),The second bispecific antibody, which specifically binds to BCMA and CD3, comprises an anti-BCMA arm containing a first binding domain including (b) HVR-H1 containing the amino acid sequence of SYPMS (SEQ ID NO: 39) or GFTFSSYPMS (SEQ ID NO: 41); (b) HVR-H2 containing the amino acid sequence of GGSGGS (SEQ ID NO: 43) or AIGGSGGSLPYADIVKG (SEQ ID NO: 42); (c) HVR-H3 (SEQ ID NO: 44) containing the amino acid sequence of YWPMDI; (d) HVR-L1 (SEQ ID NO: 45) containing the amino acid sequence of RASQSVSSSYLA; (e) HVR-L2 (SEQ ID NO: 46) containing the amino acid sequence of DASIRAT; and (f) HVR-L3 (SEQ ID NO: 47) containing the amino acid sequence of QQYQSWPLT, and is as follows: HVR-H1 comprising the amino acid sequence of (a) GFTFSDY (SEQ ID NO: 53), DYYMT (SEQ ID NO: 52), or GFTFSDYYMT (SEQ ID NO: 54); (b) HVR-H2 comprising the amino acid sequence of RNRARGYT (SEQ ID NO: 56) or FIRNRARGYTSDHNPSVKG (SEQ ID NO: 55); (c) HVR-H3 comprising the amino acid sequence of DRPSYYVLDY (SEQ ID NO: 57); (d) HVR-L1 (SEQ ID NO: 58) comprising the amino acid sequence of KSSQSLFNVRSRKNYLA; (e) HVR-L2 (SEQ ID NO: 59) comprising the amino acid sequence of WASTRES; and (f) HVR-L3 comprising the amino acid sequence of KQSYDLFT (SEQ ID NO: 60), comprising an anti-CD3 arm containing a second binding domain.

[0397] In another example, a method for treating a human subject having R / R MM is provided herein, comprising: (i) an effective amount of a first bispecific antibody (e.g., cebostamab) that specifically binds to FcRH5 and CD3, and (ii) an effective amount of a second bispecific antibody (e.g., erlanatamab) that specifically binds to BCMA and CD3, comprising: (i) a prephase comprising a dosing cycle (C1) of approximately 22 days; (ii) a first phase following the prephase, comprising a first dosing cycle (C1), wherein C1 of the first phase is a dosing cycle of 14 days; and (iii) Following Phase 1, there are the first medication cycle (C1), the second medication cycle (C2), the third medication cycle (C3), the fourth medication cycle (C4), the fifth medication cycle (C5), the sixth medication cycle (C6), the seventh medication cycle (C7), the eighth medication cycle (C8), the ninth medication cycle (C9), the tenth medication cycle (C10), the eleventh medication cycle (C11), the twelfth medication cycle (C12), the thirteenth medication cycle (C13), the fourteenth medication cycle (C14), the fifteenth medication cycle (C15), and the sixteenth medication cycle (C16). (iv) a medication regimen including a second phase comprising the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), the 24th medication cycle (C24), and the 25th medication cycle (C25), wherein each medication cycle in the second phase is a 14-day medication cycle, and (iv) a third phase following the second phase, comprising one or more medication cycles. The procedure involves administering a first bispecific antibody that specifically binds to FcRH5 and CD3 to the subjects in a menstrual cycle, with an escalating dose of 3.6 mg on day 16, 17, or 18 of prephase C1, a target dose of 60 mg on day 2, 3, or 4 of phase C1 in the first phase, and a target dose of 60 mg on day 1 of phases C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 in the second phase.A second bispecific antibody that specifically binds to BCMA and CD3 is administered as a first escalating dose of 12 mg on day 1 of prephase C1, a second escalating dose of 32 mg on days 3, 4, or 5 of prephase C1, and a target dose of 76 mg on days 8 and 15 of prephase C1, a target dose of 76 mg on day 1 of phase 1 C1, and phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C2 2. The target dose is 76 mg on day 1 of C23, C24, and C25, and on day 1 of each of the one or more drug cycles of the third phase, and the first bispecific antibody that specifically binds to FcRH5 and CD3 is one of the following six HVRs: (a) HVR-H1 (SEQ ID NO: 1) containing the amino acid sequence RFGVH; (b) HVR-H2 (SEQ ID NO: 2) containing the amino acid sequence VIWRGGSTDYNAAFVS; (c) HVR-H3 (SEQ ID NO: 3) containing the amino acid sequence HYYGSSDYALDN; (d) KASQDVRN The first bispecific antibody, which specifically binds to FcRH5 and CD3, comprises an anti-FcRH5 arm containing a first binding domain including (e) HVR-L1 containing the amino acid sequence of LVV (SEQ ID NO: 4); (e) HVR-L2 (SEQ ID NO: 5) containing the amino acid sequence of SGSYRYS; and (f) HVR-L3 (SEQ ID NO: 6) containing the amino acid sequence of QQHYSPPYT, and is compatible with the following six HVRs: (a) HVR-H1 (SEQ ID NO: 9) containing the amino acid sequence of SYYIH; (b) HVR-H2 (SEQ ID NO: 10) containing the amino acid sequence of WIYPENDNTKYNEKFKD The second bispecific antibody, which specifically binds to BCMA and CD3, includes an anti-CD3 arm containing a second binding domain, comprising (c) HVR-H3 (SEQ ID NO: 11) containing the amino acid sequence of DGYSRYYFDY; (d) HVR-L1 (SEQ ID NO: 12) containing the amino acid sequence of KSSQSLLNSRTRKNYLA; (e) HVR-L2 (SEQ ID NO: 13) containing the amino acid sequence of WTSTRKS; and (f) HVR-L3 (SEQ ID NO: 14) containing the amino acid sequence of KQSFILRT; and the following six HVRs: (a) GFTFSSY (SEQ ID NO: 40),The second bispecific antibody, which specifically binds to BCMA and CD3, comprises an anti-BCMA arm containing a first binding domain including (b) HVR-H1 containing the amino acid sequence of SYPMS (SEQ ID NO: 39) or GFTFSSYPMS (SEQ ID NO: 41); (b) HVR-H2 containing the amino acid sequence of GGSGGS (SEQ ID NO: 43) or AIGGSGGSLPYADIVKG (SEQ ID NO: 42); (c) HVR-H3 (SEQ ID NO: 44) containing the amino acid sequence of YWPMDI; (d) HVR-L1 (SEQ ID NO: 45) containing the amino acid sequence of RASQSVSSSYLA; (e) HVR-L2 (SEQ ID NO: 46) containing the amino acid sequence of DASIRAT; and (f) HVR-L3 (SEQ ID NO: 47) containing the amino acid sequence of QQYQSWPLT, and is as follows: HVR-H1 comprising the amino acid sequence of (a) GFTFSDY (SEQ ID NO: 53), DYYMT (SEQ ID NO: 52), or GFTFSDYYMT (SEQ ID NO: 54); (b) HVR-H2 comprising the amino acid sequence of RNRARGYT (SEQ ID NO: 56) or FIRNRARGYTSDHNPSVKG (SEQ ID NO: 55); (c) HVR-H3 comprising the amino acid sequence of DRPSYYVLDY (SEQ ID NO: 57); (d) HVR-L1 (SEQ ID NO: 58) comprising the amino acid sequence of KSSQSLFNVRSRKNYLA; (e) HVR-L2 (SEQ ID NO: 59) comprising the amino acid sequence of WASTRES; and (f) HVR-L3 comprising the amino acid sequence of KQSYDLFT (SEQ ID NO: 60), comprising an anti-CD3 arm containing a second binding domain.

[0398] In another example, a method for treating a human subject having R / R MM is provided herein, comprising (i) an effective amount of a first bispecific antibody (e.g., cebostamab) that specifically binds to FcRH5 and CD3, and (ii) an effective amount of a second bispecific antibody (e.g., erlanatamab) that specifically binds to BCMA and CD3, comprising (i) a first phase including a first dosing cycle (C1), wherein C1 of the first phase is a 14-day dosing cycle, and (ii) a second phase following the first phase, wherein the first dosing cycle (C1), the second dosing cycle C2, 3rd medication cycle (C3), 4th medication cycle (C4), 5th medication cycle (C5), 6th medication cycle (C6), 7th medication cycle (C7), 8th medication cycle (C8), 9th medication cycle (C9), 10th medication cycle (C10), 11th medication cycle (C11), 12th medication cycle (C12), 13th medication cycle (C13), 14th medication cycle (C14), 15th medication cycle (C15), 16th medication cycle (C16), 17th medication cycle (C17), 18th medication cycle (C1 8) a second phase comprising a 14-day medication cycle, including the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), the 24th medication cycle (C24), and the 25th medication cycle (C25), and (iii) a third phase following the second phase, comprising one or more medication cycles, administered to the subject in a medication regimen comprising FcRH5 and CD A first bispecific antibody that specifically binds to 3 is administered to the subjects at a target dose of 60 mg, 105 mg, or 132 mg on day 2, 3, or 4 of phase 1 C1, and at a target dose of 60 mg, 105 mg, or 132 mg on day 1 of phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and a second bispecific antibody that specifically binds to BCMA and CD3 is administered.In the first phase, the target dose of 76 mg was administered to the subjects on days 1 and 8 of C1, in the second phase, the target dose of 76 mg was administered to the subjects on days 1 and 8 of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and in the third phase, the target dose of 76 mg was administered to the subjects on days 1 and 8 of each of the one or more drug cycles, and FcRH5 and The first bispecific antibodies that specifically bind to CD3 are the following six HVRs: (a) HVR-H1 (SEQ ID NO: 1) containing the amino acid sequence RFGVH; (b) HVR-H2 (SEQ ID NO: 2) containing the amino acid sequence VIWRGGSTDYNAAFVS; (c) HVR-H3 (SEQ ID NO: 3) containing the amino acid sequence HYYGSSDYALDN; (d) HVR-L1 (SEQ ID NO: 4) containing the amino acid sequence KASQDVRNLVV; (e) HVR-L2 (SEQ ID NO: 4) containing the amino acid sequence SGSYRYS. The first bispecific antibody, which specifically binds to FcRH5 and CD3, includes an anti-FcRH5 arm containing a first binding domain including (5) and (f) HVR-L3 (SEQ ID NO: 6) containing the amino acid sequence QQHYSPPYT, and the following six HVRs: (a) HVR-H1 (SEQ ID NO: 9) containing the amino acid sequence SYYIH; (b) HVR-H2 (SEQ ID NO: 10) containing the amino acid sequence WIYPENDNTKYNEKFKD; (c) HVR containing the amino acid sequence DGYSRYYFDY The second bispecific antibody, which specifically binds to BCMA and CD3, includes an anti-CD3 arm containing a second binding domain, comprising HVR-L1 containing the amino acid sequence of -H3 (SEQ ID NO: 11); (d)KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e)WTSTRKS (SEQ ID NO: 13); and (f)KQSFILRT (SEQ ID NO: 14); and is specific to the following six HVRs: (a)GFTFSSY (SEQ ID NO: 40),The second bispecific antibody, which specifically binds to BCMA and CD3, comprises an anti-BCMA arm containing a first binding domain including (b) HVR-H1 containing the amino acid sequence of SYPMS (SEQ ID NO: 39) or GFTFSSYPMS (SEQ ID NO: 41); (b) HVR-H2 containing the amino acid sequence of GGSGGS (SEQ ID NO: 43) or AIGGSGGSLPYADIVKG (SEQ ID NO: 42); (c) HVR-H3 (SEQ ID NO: 44) containing the amino acid sequence of YWPMDI; (d) HVR-L1 (SEQ ID NO: 45) containing the amino acid sequence of RASQSVSSSYLA; (e) HVR-L2 (SEQ ID NO: 46) containing the amino acid sequence of DASIRAT; and (f) HVR-L3 (SEQ ID NO: 47) containing the amino acid sequence of QQYQSWPLT, and is as follows: HVRs include: (a) HVR-H1 containing the amino acid sequence of GFTFSDY (SEQ ID NO: 53), DYYMT (SEQ ID NO: 52), or GFTFSDYYMT (SEQ ID NO: 54); (b) HVR-H2 containing the amino acid sequence of RNRARGYT (SEQ ID NO: 56) or FIRNRARGYTSDHNPSVKG (SEQ ID NO: 55); (c) HVR-H3 containing the amino acid sequence of DRPSYYVLDY (SEQ ID NO: 57); (d) HVR-L1 (SEQ ID NO: 58) containing the amino acid sequence of KSSQSLFNVRSRKNYLA; (e) HVR-L2 (SEQ ID NO: 59) containing the amino acid sequence of WASTRES; and (f) HVR-L3 containing the amino acid sequence of KQSYDLFT (SEQ ID NO: 60), comprising an anti-CD3 arm with a second binding domain. In some cases, the prephase consists of approximately 15-day medication cycles (C1), with cebostamab administered to the subject at an escalating dose of 3.6 mg on day 9, 10, or 11 of prephase C1, and erranatamab administered to the subject at a first escalating dose of 12 mg on day 1 of prephase C1, a second escalating dose of 32 mg on day 3, 4, or 5 of prephase C1, and a target dose of 76 mg on day 8 of prephase C1. In other cases, the prephase consists of approximately 22-day medication cycles (C1), with cebostamab administered to the subject at an escalating dose of 3.6 mg on day 16, 17, or 18 of prephase C1, and erranatamab administered to the subject at a first escalating dose of 12 mg on day 1 of prephase C1, and on day 3 of prephase C1,Administer a second dose of 32 mg on day 4 or 5, and then administer the target dose of 76 mg on days 8 and 15 of the pre-phase C1.

[0399] In another example, a method for treating a human subject having R / R MM is provided herein, comprising (i) an effective amount of a first bispecific antibody (e.g., cebostamab) that specifically binds to FcRH5 and CD3, and (ii) an effective amount of a second bispecific antibody (e.g., erlanatamab) that specifically binds to BCMA and CD3, comprising (i) a first phase including a first dosing cycle (C1), wherein C1 of the first phase is a 14-day dosing cycle, and (ii) a second phase following the first phase, wherein the first dosing cycle (C1), the second dosing cycle C2, 3rd medication cycle (C3), 4th medication cycle (C4), 5th medication cycle (C5), 6th medication cycle (C6), 7th medication cycle (C7), 8th medication cycle (C8), 9th medication cycle (C9), 10th medication cycle (C10), 11th medication cycle (C11), 12th medication cycle (C12), 13th medication cycle (C13), 14th medication cycle (C14), 15th medication cycle (C15), 16th medication cycle (C16), 17th medication cycle (C17), 18th medication cycle (C1 8) a second phase comprising a 14-day medication cycle, including the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), the 24th medication cycle (C24), and the 25th medication cycle (C25), and (iii) a third phase following the second phase, comprising one or more medication cycles, administered to the subject in a medication regimen comprising FcRH5 and CD A first bispecific antibody that specifically binds to 3 is administered to the subjects at a target dose of 60 mg, 105 mg, or 132 mg on day 2, 3, or 4 of phase 1 C1, and at a target dose of 60 mg, 105 mg, or 132 mg on day 1 of phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and a second bispecific antibody that specifically binds to BCMA and CD3 is administered.The target dose of 76 mg was administered to the subjects on days 1 and 8 of C1 in Phase 1, on day 8 of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 in Phase 2, and on day 1 of each of one or more dosing cycles in Phase 3, specifically targeting FcRH5 and CD3. The first bispecific antibody to bind is one of the following six HVRs: (a) HVR-H1 (SEQ ID NO: 1) containing the amino acid sequence RFGVH; (b) HVR-H2 (SEQ ID NO: 2) containing the amino acid sequence VIWRGGSTDYNAAFVS; (c) HVR-H3 (SEQ ID NO: 3) containing the amino acid sequence HYYGSSDYALDN; (d) HVR-L1 (SEQ ID NO: 4) containing the amino acid sequence KASQDVRNLVV; (e) HVR-L2 (SEQ ID NO: 5) containing the amino acid sequence SGSYRYS; The first bispecific antibody, which specifically binds to FcRH5 and CD3, includes an anti-FcRH5 arm containing a first binding domain containing HVR-L3 (SEQ ID NO: 6) containing the amino acid sequence QQHYSPPYT, and is compatible with the following six HVRs: (a) HVR-H1 (SEQ ID NO: 9) containing the amino acid sequence SYYIH; (b) HVR-H2 (SEQ ID NO: 10) containing the amino acid sequence WIYPENDNTKYNEKFKD; (c) HVR-H3 containing the amino acid sequence DGYSRYYFDY The second bispecific antibody, which specifically binds to BCMA and CD3, includes an anti-CD3 arm containing a second binding domain, comprising (SEQ ID NO: 11); (d) HVR-L1 containing the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 containing the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) HVR-L3 containing the amino acid sequence of KQSFILRT (SEQ ID NO: 14), for the following six HVRs: (a) GFTFSSY (SEQ ID NO: 40),The second bispecific antibody, which specifically binds to BCMA and CD3, comprises an anti-BCMA arm containing a first binding domain including (b) HVR-H1 containing the amino acid sequence of SYPMS (SEQ ID NO: 39) or GFTFSSYPMS (SEQ ID NO: 41); (b) HVR-H2 containing the amino acid sequence of GGSGGS (SEQ ID NO: 43) or AIGGSGGSLPYADIVKG (SEQ ID NO: 42); (c) HVR-H3 (SEQ ID NO: 44) containing the amino acid sequence of YWPMDI; (d) HVR-L1 (SEQ ID NO: 45) containing the amino acid sequence of RASQSVSSSYLA; (e) HVR-L2 (SEQ ID NO: 46) containing the amino acid sequence of DASIRAT; and (f) HVR-L3 (SEQ ID NO: 47) containing the amino acid sequence of QQYQSWPLT, and is as follows: HVRs include: (a) HVR-H1 containing the amino acid sequence of GFTFSDY (SEQ ID NO: 53), DYYMT (SEQ ID NO: 52), or GFTFSDYYMT (SEQ ID NO: 54); (b) HVR-H2 containing the amino acid sequence of RNRARGYT (SEQ ID NO: 56) or FIRNRARGYTSDHNPSVKG (SEQ ID NO: 55); (c) HVR-H3 containing the amino acid sequence of DRPSYYVLDY (SEQ ID NO: 57); (d) HVR-L1 (SEQ ID NO: 58) containing the amino acid sequence of KSSQSLFNVRSRKNYLA; (e) HVR-L2 (SEQ ID NO: 59) containing the amino acid sequence of WASTRES; and (f) HVR-L3 containing the amino acid sequence of KQSYDLFT (SEQ ID NO: 60), comprising an anti-CD3 arm with a second binding domain. In some cases, the prephase consists of approximately 15-day medication cycles (C1), with cebostamab administered to the subject at an escalating dose of 3.6 mg on day 9, 10, or 11 of prephase C1, and erranatamab administered to the subject at a first escalating dose of 12 mg on day 1 of prephase C1, a second escalating dose of 32 mg on day 3, 4, or 5 of prephase C1, and a target dose of 76 mg on day 8 of prephase C1. In other cases, the prephase consists of approximately 22-day medication cycles (C1), with cebostamab administered to the subject at an escalating dose of 3.6 mg on day 16, 17, or 18 of prephase C1, and erranatamab administered to the subject at a first escalating dose of 12 mg on day 1 of prephase C1, and on day 3 of prephase C1,Administer a second dose of 32 mg on day 4 or 5, and then administer the target dose of 76 mg on days 8 and 15 of the pre-phase C1.

[0400] In another example, a method for treating a human subject having R / R MM is provided herein, comprising (i) an effective amount of a first bispecific antibody (e.g., cebostamab) that specifically binds to FcRH5 and CD3, and (ii) an effective amount of a second bispecific antibody (e.g., erlanatamab) that specifically binds to BCMA and CD3, comprising (i) a prephase comprising a dosing cycle (C1) of approximately 15 days, and (ii) a first phase following the prephase, wherein the first dosing cycle ( (iii) Phase 1, which includes C1), where C1 of Phase 1 is a 14-day medication cycle, (iii) Phase 2, which follows Phase 1, comprising: Phase 1 (C1), Phase 2 (C2), Phase 3 (C3), Phase 4 (C4), Phase 5 (C5), Phase 6 (C6), Phase 7 (C7), Phase 8 (C8), Phase 9 (C9), Phase 10 Cycle (C10), 11th medication cycle (C11), 12th medication cycle (C12), 13th medication cycle (C13), 14th medication cycle (C14), 15th medication cycle (C15), 16th medication cycle (C16), 17th medication cycle (C17), 18th medication cycle (C18), 19th medication cycle (C19), 20th medication cycle (C20), 21st medication cycle (C21), 22nd medication cycle (C22 (iv) a second phase comprising a 23rd drug cycle (C23), a 24th drug cycle (C24), and a 25th drug cycle (C25), each of which is a 14-day drug cycle, and a third phase comprising one or more drug cycles following the second phase, wherein a first bispecific antibody that specifically binds to FcRH5 and CD3 is administered on day 9, day 10, or day 11 of prephase C1.The subjects were administered a target dose of 60 mg on day 2, 3, or 4 of phase 1 C1 in an escalating dose of 6 mg, and a target dose of 60 mg on day 1 of each of phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, respectively, and a second bispecific antibody that specifically binds to BCMA and CD3 was administered on day 1 of prephase C1. The first dose escalation is 2 mg, followed by a second dose escalation of 32 mg on day 3, 4, or 5 of prephase C1, with a target dose of 76 mg on day 8 of prephase C1, with a target dose of 76 mg on day 1 of phase 1 C1, and with a target dose of 76 mg on day 1 of each of phases C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 of phase 2. Furthermore, the target dose of 76 mg is administered to the subjects on day 1 of each of one or more dosing cycles in Phase 3. The first bispecific antibody comprises an anti-FcRH5 arm containing a first binding domain with a VH domain containing the amino acid sequence of SEQ ID NO: 7 and a VL domain containing the amino acid sequence of SEQ ID NO: 8. The first bispecific antibody, which specifically binds to FcRH5 and CD3, comprises an anti-CD3 arm containing a second binding domain with a VH domain containing the amino acid sequence of SEQ ID NO: 15 and a VL domain containing the amino acid sequence of SEQ ID NO: 16. The second bispecific antibody, which specifically binds to BCMA and CD3, comprises an anti-BCMA arm containing a first binding domain with a VH domain containing the amino acid sequence of SEQ ID NO: 48 and a VL domain containing the amino acid sequence of SEQ ID NO: 49. The second bispecific antibody, which specifically binds to BCMA and CD3, comprises an anti-CD3 arm containing a second binding domain with a VH domain containing the amino acid sequence of SEQ ID NO: 61 and a VL domain containing the amino acid sequence of SEQ ID NO: 62.

[0401] In another example, a method for treating a human subject having R / R MM is provided herein, comprising (i) an effective amount of a first bispecific antibody (e.g., cebostamab) that specifically binds to FcRH5 and CD3, and (ii) an effective amount of a second bispecific antibody (e.g., erlanatamab) that specifically binds to BCMA and CD3, (i) a prephase comprising a dosing cycle (C1) of approximately 22 days, and (ii) a first phase following the prephase, wherein the first dosing cycle ( (iii) Phase 1, which includes C1), where C1 of Phase 1 is a 14-day medication cycle, (iii) Phase 2, which follows Phase 1, comprising: Phase 1 (C1), Phase 2 (C2), Phase 3 (C3), Phase 4 (C4), Phase 5 (C5), Phase 6 (C6), Phase 7 (C7), Phase 8 (C8), Phase 9 (C9), Phase 10 Cycle (C10), 11th medication cycle (C11), 12th medication cycle (C12), 13th medication cycle (C13), 14th medication cycle (C14), 15th medication cycle (C15), 16th medication cycle (C16), 17th medication cycle (C17), 18th medication cycle (C18), 19th medication cycle (C19), 20th medication cycle (C20), 21st medication cycle (C21), 22nd medication cycle (C22 (iv) a second phase comprising the 23rd (C23), the 24th (C24), and the 25th (C25) drug cycles, each of which is a 14-day drug cycle, and a third phase comprising one or more drug cycles following the second phase, wherein a first bispecific antibody that specifically binds to FcRH5 and CD3 is administered on day 16, day 17, or day 18 of prephase C1.The subjects were administered a target dose of 60 mg on day 2, 3, or 4 of Phase 1 C1 in an escalating dose of 6 mg, and a target dose of 60 mg on day 1 of each of Phase 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and a second bispecific antibody that specifically binds to BCMA and CD3 was administered at 12 mg on day 1 of Prephase C1. The first escalating dose of g is 32 mg on day 3, day 4, or day 5 of prephase C1. The second escalating dose is 76 mg on days 8 and 15 of prephase C1. The target dose is 76 mg on day 1 of phase 1 C1. The target dose is 76 mg on day 1 of each of phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25. Furthermore, the target dose of 76 mg is administered to the subject on day 1 of each of one or more dosing cycles in the third phase, wherein the first bispecific antibody comprises an anti-FcRH5 arm containing a first binding domain containing a VH domain with the amino acid sequence of SEQ ID NO: 7 and a VL domain with the amino acid sequence of SEQ ID NO: 8; the first bispecific antibody that specifically binds to FcRH5 and CD3 comprises an anti-CD3 arm containing a second binding domain containing a VH domain with the amino acid sequence of SEQ ID NO: 15 and a VL domain with the amino acid sequence of SEQ ID NO: 16; the second bispecific antibody that specifically binds to BCMA and CD3 comprises an anti-BCMA arm containing a first binding domain containing a VH domain with the amino acid sequence of SEQ ID NO: 48 and a VL domain with the amino acid sequence of SEQ ID NO: 49; and the second bispecific antibody that specifically binds to BCMA and CD3 comprises an anti-CD3 arm containing a second binding domain containing a VH domain with the amino acid sequence of SEQ ID NO: 61 and a VL domain with the amino acid sequence of SEQ ID NO: 62.

[0402] In another example, a method for treating a human subject having R / R MM is provided herein, comprising (i) an effective amount of a first bispecific antibody (e.g., cebostamab) that specifically binds to FcRH5 and CD3, and (ii) an effective amount of a second bispecific antibody (e.g., erlanatamab) that specifically binds to BCMA and CD3, comprising (i) a first phase including a first dosing cycle (C1), wherein C1 of the first phase is a 14-day dosing cycle, and (ii) a second phase following the first phase, wherein the first dosing cycle (C1), the second dosing cycle C2, 3rd medication cycle (C3), 4th medication cycle (C4), 5th medication cycle (C5), 6th medication cycle (C6), 7th medication cycle (C7), 8th medication cycle (C8), 9th medication cycle (C9), 10th medication cycle (C10), 11th medication cycle (C11), 12th medication cycle (C12), 13th medication cycle (C13), 14th medication cycle (C14), 15th medication cycle (C15), 16th medication cycle (C16), 17th medication cycle (C17), 18th medication cycle (C1 8) a second phase comprising a 14-day medication cycle, including the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), the 24th medication cycle (C24), and the 25th medication cycle (C25), and (iii) a third phase following the second phase, comprising one or more medication cycles, administered to the subject in a medication regimen comprising FcRH5 and CD A first bispecific antibody that specifically binds to 3 is administered to the subjects at a target dose of 60 mg, 105 mg, or 132 mg on day 2, 3, or 4 of phase 1 C1, and at a target dose of 60 mg, 105 mg, or 132 mg on day 1 of phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and a second bispecific antibody that specifically binds to BCMA and CD3 is administered.The target dose is 76 mg on days 1 and 8 of C1 in Phase 1, 76 mg on days 1 and 8 of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 in Phase 2, and 76 mg on days 1 and 8 of each of the one or more drug cycles in Phase 3. The first bispecific antibody contains an anti-FcRH5 arm containing a VH domain containing the amino acid sequence of SEQ ID NO: 7 and a VL domain containing the amino acid sequence of SEQ ID NO: 8, and targets FcRH5 and CD. The first bispecific antibody that specifically binds to 3 comprises an anti-CD3 arm comprising a VH domain containing the amino acid sequence of SEQ ID NO: 15 and a second binding domain comprising a VL domain containing the amino acid sequence of SEQ ID NO: 16; the second bispecific antibody that specifically binds to BCMA and CD3 comprises an anti-BCMA arm comprising a first binding domain comprising a VH domain containing the amino acid sequence of SEQ ID NO: 48 and a VL domain containing the amino acid sequence of SEQ ID NO: 49; and the second bispecific antibody that specifically binds to BCMA and CD3 comprises an anti-CD3 arm comprising a second binding domain comprising a VH domain containing the amino acid sequence of SEQ ID NO: 61 and a VL domain containing the amino acid sequence of SEQ ID NO: 62. In some examples, the method further comprises a prephase before the first phase. In some cases, the prephase consists of approximately 15-day medication cycles (C1), with cebostamab administered to the subject at an escalating dose of 3.6 mg on day 9, 10, or 11 of prephase C1, and erranatamab administered to the subject at a first escalating dose of 12 mg on day 1 of prephase C1, a second escalating dose of 32 mg on day 3, 4, or 5 of prephase C1, and a target dose of 76 mg on day 8 of prephase C1. In other cases, the prephase consists of approximately 22-day medication cycles (C1), with cebostamab administered to the subject at an escalating dose of 3.6 mg on day 16, 17, or 18 of prephase C1, and erranatamab administered to the subject at a first escalating dose of 12 mg on day 1 of prephase C1, and on days 3, 4,Alternatively, administer a second escalating dose of 32 mg on day 5, and the target dose of 76 mg on days 8 and 15 of the prephase C1.

[0403] In another example, a method for treating a human subject having R / R MM is provided herein, comprising (i) an effective amount of a first bispecific antibody (e.g., cebostamab) that specifically binds to FcRH5 and CD3, and (ii) an effective amount of a second bispecific antibody (e.g., erlanatamab) that specifically binds to BCMA and CD3, comprising (i) a first phase including a first dosing cycle (C1), wherein C1 of the first phase is a 14-day dosing cycle, and (ii) a second phase following the first phase, wherein the first dosing cycle (C1), the second dosing cycle C2, 3rd medication cycle (C3), 4th medication cycle (C4), 5th medication cycle (C5), 6th medication cycle (C6), 7th medication cycle (C7), 8th medication cycle (C8), 9th medication cycle (C9), 10th medication cycle (C10), 11th medication cycle (C11), 12th medication cycle (C12), 13th medication cycle (C13), 14th medication cycle (C14), 15th medication cycle (C15), 16th medication cycle (C16), 17th medication cycle (C17), 18th medication cycle (C1 8) a second phase comprising a 14-day medication cycle, including the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), the 24th medication cycle (C24), and the 25th medication cycle (C25), and (iii) a third phase following the second phase, comprising one or more medication cycles, administered to the subject in a medication regimen comprising FcRH5 and CD A first bispecific antibody that specifically binds to 3 is administered to the subjects at a target dose of 60 mg, 105 mg, or 132 mg on day 2, 3, or 4 of phase 1 C1, and at a target dose of 60 mg, 105 mg, or 132 mg on day 1 of phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and a second bispecific antibody that specifically binds to BCMA and CD3 is administered.The target dose is 76 mg on day 1 and day 8 of phase 1 (C1), 76 mg on day 8 of phases 2 (C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25), and 76 mg on day 1 of each of one or more dosing cycles in phase 3. The first bispecific antibody contains an anti-FcRH5 arm containing a VH domain containing the amino acid sequence of SEQ ID NO: 7 and a VL domain containing the amino acid sequence of SEQ ID NO: 8, and is specifically effective against FcRH5 and CD3. The first bispecific antibody that binds comprises an anti-CD3 arm comprising a VH domain containing the amino acid sequence of SEQ ID NO: 15 and a second binding domain comprising a VL domain containing the amino acid sequence of SEQ ID NO: 16. The second bispecific antibody that specifically binds to BCMA and CD3 comprises an anti-BCMA arm comprising a first binding domain comprising a VH domain containing the amino acid sequence of SEQ ID NO: 48 and a VL domain containing the amino acid sequence of SEQ ID NO: 49. The second bispecific antibody that specifically binds to BCMA and CD3 comprises an anti-CD3 arm comprising a second binding domain comprising a VH domain containing the amino acid sequence of SEQ ID NO: 61 and a VL domain containing the amino acid sequence of SEQ ID NO: 62. In some examples, the method further comprises a prephase before the first phase. In some cases, the prephase consists of approximately 15-day medication cycles (C1), with cebostamab administered to the subject at an escalating dose of 3.6 mg on day 9, 10, or 11 of prephase C1, and erranatamab administered to the subject at a first escalating dose of 12 mg on day 1 of prephase C1, a second escalating dose of 32 mg on day 3, 4, or 5 of prephase C1, and a target dose of 76 mg on day 8 of prephase C1. In other cases, the prephase consists of approximately 22-day medication cycles (C1), with cebostamab administered to the subject at an escalating dose of 3.6 mg on day 16, 17, or 18 of prephase C1, and erranatamab administered to the subject at a first escalating dose of 12 mg on day 1 of prephase C1, and on days 3, 4,Alternatively, administer a second escalating dose of 32 mg on day 5, and the target dose of 76 mg on days 8 and 15 of the prephase C1.

[0404] Another example is a method for treating human subjects with R / R MM, wherein the method involves administering cebostamab and erranatamab: (i) a prephase comprising a dosing cycle (C1) of approximately 22 days; (ii) a first phase following the prephase, comprising a first dosing cycle (C1), wherein C1 of the first phase is a 14-day dosing cycle; and (iii) a first dosing cycle following the first phase. Cycle C1, 2nd medication cycle C2, 3rd medication cycle C3, 4th medication cycle C4, 5th medication cycle C5, 6th medication cycle C6, 7th medication cycle C7, 8th medication cycle C8, 9th medication cycle C9, 10th medication cycle C10, 11th medication cycle C11, 12th medication cycle C12, 13th medication cycle Cycle 13 (C14), Cycle 15 (C15), Cycle 16 (C16), Cycle 17 (C17), Cycle 18 (C18), Cycle 19 (C19), Cycle 20 (C20), Cycle 21 (C21), Cycle 22 (C22), Cycle 23 (C23), Cycle 24 (iv) Administering cebostamab in a drug regimen comprising a second phase including cycles (C24) and the 25th drug cycle (C25), wherein each drug cycle in the second phase is a 14-day drug cycle, and a third phase following the second phase, comprising one or more drug cycles, with 3 doses administered on day 16, day 17, or day 18 of the prephase C1.The subjects were administered erranatamab in an escalating dose of 6 mg, with a target dose of 60 mg on day 2, 3, or 4 of Phase 1 C1, and a target dose of 60 mg on day 1 of Phase 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, respectively. Elranatamab was administered in a first escalating dose of 12 mg on day 1 of Prephase C1, and 32 mg on day 3, 4, or 5 of Prephase C1. The drug is administered to the subjects in the second escalating dose, as well as at a target dose of 76 mg on days 8 and 15 of prephase C1, at a target dose of 76 mg on day 1 of phase 1 C1, at a target dose of 76 mg on day 1 of phases C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 of phase 2, and at a target dose of 76 mg on day 1 of each of one or more dosing cycles in phase 3.

[0405] Another example is a method for treating human subjects with R / R MM, wherein the method involves administering cebostamab and erranatamab, (i) a first phase comprising a first dosing cycle (C1), wherein C1 of the first phase is a 14-day dosing cycle, and (ii) a second phase following the first phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), a seventh dosing cycle (C7), an eighth dosing cycle ( C8), the 9th medication cycle (C9), the 10th medication cycle (C10), the 11th medication cycle (C11), the 12th medication cycle (C12), the 13th medication cycle (C13), the 14th medication cycle (C14), the 15th medication cycle (C15), the 16th medication cycle (C16), the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), the 2 (iii) administering to the subject in a drug regimen comprising a second phase, which includes 4 drug cycles (C24) and 25 drug cycles (C25), with each drug cycle in the second phase being a 14-day drug cycle, and a third phase following the second phase, which includes one or more drug cycles, wherein cebostamab is administered to the subject at a target dose of 60 mg, 105 mg, or 132 mg on day 2, 3, or 4 of C1 in the first phase, and C1, C2, C3, C4, C5, C6, C7, C in the second phase. 8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 are administered to subjects at a target dose of 60 mg, 105 mg, or 132 mg, and erranatamab is administered at a target dose of 76 mg on days 1 and 8 of C1 in Phase 1, and on C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24,The drug is administered to the subjects at a target dose of 76 mg on days 1 and 8 of C25, and at a target dose of 76 mg on days 1 and 8 of each of at least one drug cycle in the third phase.

[0406] Another example is a method for treating human subjects with R / R MM, wherein the method involves administering cebostamab and erranatamab, (i) a first phase comprising a first dosing cycle (C1), where C1 of the first phase is a 14-day dosing cycle, and (ii) a second phase following the first phase, comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), a seventh dosing cycle (C7), and an eighth dosing cycle. (C8), the 9th medication cycle (C9), the 10th medication cycle (C10), the 11th medication cycle (C11), the 12th medication cycle (C12), the 13th medication cycle (C13), the 14th medication cycle (C14), the 15th medication cycle (C15), the 16th medication cycle (C16), the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), (iii) administering to the subject in a drug regimen comprising a second phase, which includes 24 drug cycles (C24) and a 25th drug cycle (C25), with each drug cycle in the second phase being a 14-day drug cycle, and a third phase following the second phase, which includes one or more drug cycles, wherein cebostamab is administered at a target dose of 60 mg, 105 mg, or 132 mg on day 2, 3, or 4 of C1 in the first phase, and C1, C2, C3, C4, C5, C6, C7, C in the second phase. In the first phase, subjects were administered erranatamab at a target dose of 60 mg, 105 mg, or 132 mg on day 1 of C1, C9, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and erranatamab was administered at a target dose of 76 mg on day 1 and day 8 of C1 in the first phase, and in the second phase, subjects were administered erranatamab at a target dose of 76 mg on days 1 and 8 of C1, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24,The target dose of 76 mg is administered to the subjects on day 8 of C25, and on day 1 of each of at least one medication cycle in the third phase.

[0407] In another example, bispecific antibodies that specifically bind to FcRH5 and CD3 are provided herein for use in treating subjects having MM, the treatment comprising administering to the subject a first bispecific antibody that specifically binds to FcRH5 and CD3 (e.g., cebostamab) and a second bispecific antibody that specifically binds to BCMA and CD3 (e.g., erlanatamab).

[0408] In another example, a bispecific antibody (e.g., cebostamab) that specifically binds to FcRH5 and CD3 is provided herein for use in the treatment of human subjects having R / R MM, wherein the treatment comprises (i) an effective amount of a first bispecific antibody (e.g., cebostamab) that specifically binds to FcRH5 and CD3, and (ii) an effective amount of a second bispecific antibody (e.g., erlanatamab) that specifically binds to BCMA and CD3, comprising (i) a prephase comprising a dosing cycle (C1) of approximately 15 days, and (ii) a first phase comprising a first dosing cycle (C1) following the prephase. Phase 1, where C1 of Phase 1 is a 14-day medication cycle, (iii) following Phase 1, the first medication cycle (C1), the second medication cycle (C2), the third medication cycle (C3), the fourth medication cycle (C4), the fifth medication cycle (C5), the sixth medication cycle (C6), the seventh medication cycle (C7), the eighth medication cycle (C8), the ninth medication cycle (C9), the tenth medication cycle (C10), the eleventh medication cycle (C11), the twelfth medication cycle (C12), and the thirteenth medication cycle (C13). The second phase includes the 14th medication cycle (C14), the 15th medication cycle (C15), the 16th medication cycle (C16), the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), the 24th medication cycle (C24), and the 25th medication cycle (C25), wherein each medication cycle in the second phase is a 14-day medication cycle. , and (iv) administering to subjects in a drug regimen comprising a third phase comprising one or more drug cycles following the second phase, a first bispecific antibody that specifically binds to FcRH5 and CD3, in an escalating dose of 3.6 mg on day 9, 10 or 11 of prephase C1, a target dose of 60 mg on day 2, 3 or 4 of phase C1 of the first phase, and C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 of the second phase,The subjects were administered a target dose of 60 mg on day 1 of phases C20, C21, C22, C23, C24, and C25, and a second bispecific antibody that specifically binds to BCMA and CD3 was administered as a first escalating dose of 12 mg on day 1 of prephase C1, a second escalating dose of 32 mg on day 3, 4, or 5 of prephase C1, and a target dose of 76 mg on day 8 of prephase C1, a target dose of 76 mg on day 1 of phase 1 C1, and phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, The target dose of 76 mg was administered to the subjects on day 1 of C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and on day 1 of each of the one or more dosing cycles of the third phase. The first bispecific antibody that specifically binds to FcRH5 and CD3 is one of the following six HVRs: (a) HVR-H1 (SEQ ID NO: 1) containing the amino acid sequence RFGVH; (b) HVR-H2 (SEQ ID NO: 2) containing the amino acid sequence VIWRGGSTDYNAAFVS; (c) HYYGSSDYALDN The first bispecific antibody, which specifically binds to FcRH5 and CD3, includes an anti-FcRH5 arm containing a first binding domain, comprising (a) HVR-H3 (SEQ ID NO: 3) containing the amino acid sequence of (d) KASQDVRNLVV (SEQ ID NO: 4); (e) HVR-L2 (SEQ ID NO: 5) containing the amino acid sequence of (g) SGSYRYS; and (f) HVR-L3 (SEQ ID NO: 6) containing the amino acid sequence of QQHYSPPYT, and is specific to the following six HVRs: (a) HVR-H1 (SEQ ID NO: 9) containing the amino acid sequence of SYYIH; (b) WIYPENDN A second bispecific antibody that specifically binds to BCMA and CD3 includes an anti-CD3 arm containing a second binding domain, comprising (c) HVR-H2 (SEQ ID NO: 10) containing the amino acid sequence of TKYNEKFKD; (d) HVR-H3 (SEQ ID NO: 11) containing the amino acid sequence of DGYSRYYFDY; (c) HVR-L1 (SEQ ID NO: 12) containing the amino acid sequence of KSSQSLLNSRTRKNYLA; (e) HVR-L2 (SEQ ID NO: 13) containing the amino acid sequence of WTSTRKS; and (f) HVR-L3 containing the amino acid sequence of KQSFILRT (SEQ ID NO: 14),The following six HVRs include: (a) HVR-H1 containing the amino acid sequence of GFTFSSY (SEQ ID NO: 40), SYPMS (SEQ ID NO: 39), or GFTFSSYPMS (SEQ ID NO: 41); (b) HVR-H2 containing the amino acid sequence of GGSGGS (SEQ ID NO: 43) or AIGGSGGSLPYADIVKG (SEQ ID NO: 42); (c) HVR-H3 (SEQ ID NO: 44) containing the amino acid sequence of YWPMDI; (d) HVR-L1 (SEQ ID NO: 45) containing the amino acid sequence of RASQSVSSSYLA; (e) HVR-L2 (SEQ ID NO: 46) containing the amino acid sequence of DASIRAT; and (f) HVR-L3 (SEQ ID NO: 47) containing the amino acid sequence of QQYQSWPLT, each containing an anti-BCMA arm with a first binding domain that specifically binds to BCMA and CD3. The bispecific antibody contains an anti-CD3 arm containing a second binding domain, including the following six HVRs: (a) HVR-H1 containing the amino acid sequence of GFTFSDY (SEQ ID NO: 53), DYYMT (SEQ ID NO: 52), or GFTFSDYYMT (SEQ ID NO: 54); (b) HVR-H2 containing the amino acid sequence of RNRARGYT (SEQ ID NO: 56) or FIRNRARGYTSDHNPSVKG (SEQ ID NO: 55); (c) HVR-H3 containing the amino acid sequence of DRPSYYVLDY (SEQ ID NO: 57); (d) HVR-L1 (SEQ ID NO: 58) containing the amino acid sequence of KSSQSLFNVRSRKNYLA; (e) HVR-L2 (SEQ ID NO: 59) containing the amino acid sequence of WASTRES; and (f) HVR-L3 containing the amino acid sequence of KQSYDLFT (SEQ ID NO: 60).

[0409] In another example, a bispecific antibody (e.g., cebostamab) that specifically binds to FcRH5 and CD3 is provided herein for use in the treatment of human subjects having R / R MM, wherein the treatment comprises (i) an effective amount of a first bispecific antibody (e.g., cebostamab) that specifically binds to FcRH5 and CD3, and (ii) an effective amount of a second bispecific antibody (e.g., erlanatamab) that specifically binds to BCMA and CD3, comprising (i) a prephase comprising a dosing cycle (C1) of approximately 22 days, and (ii) a first phase comprising a first dosing cycle (C1) following the prephase. Phase 1, where C1 of Phase 1 is a 14-day medication cycle, (iii) following Phase 1, the first medication cycle (C1), the second medication cycle (C2), the third medication cycle (C3), the fourth medication cycle (C4), the fifth medication cycle (C5), the sixth medication cycle (C6), the seventh medication cycle (C7), the eighth medication cycle (C8), the ninth medication cycle (C9), the tenth medication cycle (C10), the eleventh medication cycle (C11), the twelfth medication cycle (C12), and the thirteenth medication cycle (C13). The second phase includes the 14th medication cycle (C14), the 15th medication cycle (C15), the 16th medication cycle (C16), the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), the 24th medication cycle (C24), and the 25th medication cycle (C25), wherein each medication cycle in the second phase is a 14-day medication cycle. , and (iv) administering to subjects in a drug regimen comprising a third phase comprising one or more drug cycles following the second phase, a first bispecific antibody that specifically binds to FcRH5 and CD3, in an escalating dose of 3.6 mg on day 16, 17 or 18 of prephase C1, a target dose of 60 mg on day 2, 3 or 4 of phase C1 of the first phase, and C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 of the second phase,The subjects were administered a target dose of 60 mg on day 1 of phases C20, C21, C22, C23, C24, and C25, and a second bispecific antibody that specifically binds to BCMA and CD3 was administered as a first escalating dose of 12 mg on day 1 of prephase C1, a second escalating dose of 32 mg on day 3, 4, or 5 of prephase C1, and a target dose of 76 mg on days 8 and 15 of prephase C1, a target dose of 76 mg on day 1 of phase 1 C1, and phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, and C11. The target dose of 76 mg was administered to the subjects on day 1 of C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and on day 1 of each of the one or more dosing cycles of the third phase. The first bispecific antibody that specifically binds to FcRH5 and CD3 is one of the following six HVRs: (a) HVR-H1 (SEQ ID NO: 1) containing the amino acid sequence RFGVH; (b) HVR-H2 (SEQ ID NO: 2) containing the amino acid sequence VIWRGGSTDYNAAFVS; (c) HYYGSSDYA The first bispecific antibody, which specifically binds to FcRH5 and CD3, comprises an anti-FcRH5 arm containing a first binding domain including (d) HVR-H3 (SEQ ID NO: 3) containing the amino acid sequence of LDN; (e) HVR-L1 (SEQ ID NO: 5) containing the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (f) HVR-L3 (SEQ ID NO: 6) containing the amino acid sequence of QQHYSPPYT; and the following six HVRs: (a) HVR-H1 (SEQ ID NO: 9) containing the amino acid sequence of SYYIH; (b) WIYPEN A second bispecific antibody that specifically binds to BCMA and CD3 includes an anti-CD3 arm containing a second binding domain, comprising (c) HVR-H2 (SEQ ID NO: 10) containing the amino acid sequence of DNTKYNEKFKD; (d) HVR-H3 (SEQ ID NO: 11) containing the amino acid sequence of DGYSRYYFDY; (c) HVR-L1 (SEQ ID NO: 12) containing the amino acid sequence of KSSQSLLNSRTRKNYLA; (e) HVR-L2 (SEQ ID NO: 13) containing the amino acid sequence of WTSTRKS; and (f) HVR-L3 containing the amino acid sequence of KQSFILRT (SEQ ID NO: 14),The following six HVRs include: (a) HVR-H1 containing the amino acid sequence of GFTFSSY (SEQ ID NO: 40), SYPMS (SEQ ID NO: 39), or GFTFSSYPMS (SEQ ID NO: 41); (b) HVR-H2 containing the amino acid sequence of GGSGGS (SEQ ID NO: 43) or AIGGSGGSLPYADIVKG (SEQ ID NO: 42); (c) HVR-H3 (SEQ ID NO: 44) containing the amino acid sequence of YWPMDI; (d) HVR-L1 (SEQ ID NO: 45) containing the amino acid sequence of RASQSVSSSYLA; (e) HVR-L2 (SEQ ID NO: 46) containing the amino acid sequence of DASIRAT; and (f) HVR-L3 (SEQ ID NO: 47) containing the amino acid sequence of QQYQSWPLT, each containing an anti-BCMA arm with a first binding domain that specifically binds to BCMA and CD3. The bispecific antibody contains an anti-CD3 arm containing a second binding domain, including the following six HVRs: (a) HVR-H1 containing the amino acid sequence of GFTFSDY (SEQ ID NO: 53), DYYMT (SEQ ID NO: 52), or GFTFSDYYMT (SEQ ID NO: 54); (b) HVR-H2 containing the amino acid sequence of RNRARGYT (SEQ ID NO: 56) or FIRNRARGYTSDHNPSVKG (SEQ ID NO: 55); (c) HVR-H3 containing the amino acid sequence of DRPSYYVLDY (SEQ ID NO: 57); (d) HVR-L1 (SEQ ID NO: 58) containing the amino acid sequence of KSSQSLFNVRSRKNYLA; (e) HVR-L2 (SEQ ID NO: 59) containing the amino acid sequence of WASTRES; and (f) HVR-L3 containing the amino acid sequence of KQSYDLFT (SEQ ID NO: 60).

[0410] In another example, a bispecific antibody that specifically conjugates to FcRH5 and CD3 (e.g., cebostamab) is provided herein for use in the treatment of human subjects having R / R MM, wherein the treatment involves (i) an effective amount of a first bispecific antibody that specifically conjugates to FcRH5 and CD3 (e.g., cebostamab), and (ii) an effective amount of a second bispecific antibody that specifically conjugates to BCMA and CD3 (e.g., erlanatamab), in a first phase comprising a first dosing cycle (C1), where C1 of the first phase is a 14-day dosing cycle. (ii) A second phase following the first phase, comprising the first medication cycle (C1), the second medication cycle (C2), the third medication cycle (C3), the fourth medication cycle (C4), the fifth medication cycle (C5), the sixth medication cycle (C6), the seventh medication cycle (C7), the eighth medication cycle (C8), the ninth medication cycle (C9), the tenth medication cycle (C10), the eleventh medication cycle (C11), the twelfth medication cycle (C12), the thirteenth medication cycle (C13), the fourteenth medication cycle (C14), the fifteenth medication cycle ( (iii) a third phase following the second phase, which includes the 16th medication cycle (C16), the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), the 24th medication cycle (C24), and the 25th medication cycle (C25), wherein each medication cycle in the second phase is a 14-day medication cycle, and (iii) one or more third phases following the second phase. The regimen includes administering to the subject in a third phase, including the following medication cycles, a first bispecific antibody that specifically binds to FcRH5 and CD3, at a target dose of 60 mg, 105 mg, or 132 mg on day 2, 3, or 4 of phase 1 C1, and at 60 mg, 105 mg, on day 1 of phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25.Alternatively, administer a target dose of 132 mg to the subject, and administer a second bispecific antibody that specifically binds to BCMA and CD3 at a target dose of 76 mg on days 1 and 8 of C1 in the first phase, and at a target dose of 76 mg on days 1 and 8 of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 in the second phase, and in one or more dosing cycles of the third phase. The first bispecific antibody, which specifically binds to FcRH5 and CD3, is administered to the subjects at a target dose of 76 mg on days 1 and 8, respectively. The six HVRs are: (a) HVR-H1 (SEQ ID NO: 1) containing the amino acid sequence RFGVH; (b) HVR-H2 (SEQ ID NO: 2) containing the amino acid sequence VIWRGGSTDYNAAFVS; (c) HVR-H3 (SEQ ID NO: 3) containing the amino acid sequence HYYGSSDYALDN; (d) HVR-L1 (SEQ ID NO: 4) containing the amino acid sequence KASQDVRNLVV; (e) The first bispecific antibody, which specifically binds to FcRH5 and CD3, contains an anti-FcRH5 arm containing a first binding domain including HVR-L2 (SEQ ID NO: 5) containing the amino acid sequence of SGSYRYS and HVR-L3 (SEQ ID NO: 6) containing the amino acid sequence of QQHYSPPYT, and is compatible with the following six HVRs: (a) HVR-H1 (SEQ ID NO: 9) containing the amino acid sequence of SYYIH; (b) HVR-H2 (SEQ ID NO: 10) containing the amino acid sequence of WIYPENDNTKYNEKFKD; (c) DGYSRYYFDY The second bispecific antibody, which specifically binds to BCMA and CD3, includes an anti-CD3 arm containing a second binding domain, comprising (a) HVR-H3 (SEQ ID NO: 11) containing the amino acid sequence of (d) KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 (SEQ ID NO: 13) containing the amino acid sequence of (wtstrks); and (f) HVR-L3 containing the amino acid sequence of KQSFILRT (SEQ ID NO: 14), and is used for the following six HVRs: (a) GFTFSSY (SEQ ID NO: 40),The second bispecific antibody, which specifically binds to BCMA and CD3, comprises an anti-BCMA arm containing a first binding domain including (b) HVR-H1 containing the amino acid sequence of SYPMS (SEQ ID NO: 39) or GFTFSSYPMS (SEQ ID NO: 41); (b) HVR-H2 containing the amino acid sequence of GGSGGS (SEQ ID NO: 43) or AIGGSGGSLPYADIVKG (SEQ ID NO: 42); (c) HVR-H3 (SEQ ID NO: 44) containing the amino acid sequence of YWPMDI; (d) HVR-L1 (SEQ ID NO: 45) containing the amino acid sequence of RASQSVSSSYLA; (e) HVR-L2 (SEQ ID NO: 46) containing the amino acid sequence of DASIRAT; and (f) HVR-L3 (SEQ ID NO: 47) containing the amino acid sequence of QQYQSWPLT, and is as follows: The HVRs include: (a) HVR-H1 containing the amino acid sequence of GFTFSDY (SEQ ID NO: 53), DYYMT (SEQ ID NO: 52), or GFTFSDYYMT (SEQ ID NO: 54); (b) HVR-H2 containing the amino acid sequence of RNRARGYT (SEQ ID NO: 56) or FIRNRARGYTSDHNPSVKG (SEQ ID NO: 55); (c) HVR-H3 containing the amino acid sequence of DRPSYYVLDY (SEQ ID NO: 57); (d) HVR-L1 (SEQ ID NO: 58) containing the amino acid sequence of KSSQSLFNVRSRKNYLA; (e) HVR-L2 (SEQ ID NO: 59) containing the amino acid sequence of WASTRES; and (f) HVR-L3 containing the amino acid sequence of KQSYDLFT (SEQ ID NO: 60), comprising an anti-CD3 arm with a second binding domain. In some examples, the treatment further includes a prephase before the first phase. In some cases, the prephase consists of approximately 15-day medication cycles (C1), with cebostamab administered to the subject at an escalating dose of 3.6 mg on day 9, 10, or 11 of prephase C1, and erranatamab administered to the subject at a first escalating dose of 12 mg on day 1 of prephase C1, a second escalating dose of 32 mg on day 3, 4, or 5 of prephase C1, and a target dose of 76 mg on day 8 of prephase C1. In other cases, the prephase consists of approximately 22-day medication cycles (C1), with cebostamab administered to the subject at an escalating dose of 3.6 mg on day 16, 17, or 18 of prephase C1, and erranatamab administered to the subject.The first dose escalation is administered to the target patient at 12 mg on day 1 of prephase C1, the second dose escalation is administered at 32 mg on days 3, 4, or 5 of prephase C1, and the target dose of 76 mg is administered on days 8 and 15 of prephase C1.

[0411] In another example, a bispecific antibody that specifically conjugates to FcRH5 and CD3 (e.g., cebostamab) is provided herein for use in the treatment of human subjects having R / R MM, wherein the treatment involves (i) an effective amount of a first bispecific antibody that specifically conjugates to FcRH5 and CD3 (e.g., cebostamab), and (ii) an effective amount of a second bispecific antibody that specifically conjugates to BCMA and CD3 (e.g., erlanatamab), in a first phase comprising a first dosing cycle (C1), where C1 of the first phase is a 14-day dosing cycle. (ii) A second phase following the first phase, comprising the first medication cycle (C1), the second medication cycle (C2), the third medication cycle (C3), the fourth medication cycle (C4), the fifth medication cycle (C5), the sixth medication cycle (C6), the seventh medication cycle (C7), the eighth medication cycle (C8), the ninth medication cycle (C9), the tenth medication cycle (C10), the eleventh medication cycle (C11), the twelfth medication cycle (C12), the thirteenth medication cycle (C13), the fourteenth medication cycle (C14), the fifteenth medication cycle ( (iii) a third phase following the second phase, which includes the 16th medication cycle (C16), the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), the 24th medication cycle (C24), and the 25th medication cycle (C25), wherein each medication cycle in the second phase is a 14-day medication cycle, and (iii) one or more third phases following the second phase. The regimen includes administering to the subject in a third phase, including the following medication cycles, a first bispecific antibody that specifically binds to FcRH5 and CD3, at a target dose of 60 mg, 105 mg, or 132 mg on day 2, 3, or 4 of phase 1 C1, and at 60 mg, 105 mg, on day 1 of phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25.Alternatively, administer to the subject at a target dose of 132 mg, and administer a second bispecific antibody that specifically binds to BCMA and CD3 at a target dose of 76 mg on days 1 and 8 of C1 in the first phase, and at a target dose of 76 mg on day 8 of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 in the second phase, and each of the following in one or more drug cycles of the third phase On day 1, the target dose of 76 mg was administered to the subjects. The first bispecific antibody that specifically binds to FcRH5 and CD3 is one of the following six HVRs: (a) HVR-H1 (SEQ ID NO: 1) containing the amino acid sequence RFGVH; (b) HVR-H2 (SEQ ID NO: 2) containing the amino acid sequence VIWRGGSTDYNAAFVS; (c) HVR-H3 (SEQ ID NO: 3) containing the amino acid sequence HYYGSSDYALDN; (d) HVR-L1 (SEQ ID NO: 4) containing the amino acid sequence KASQDVRNLVV; (e) SGSYRY The first bispecific antibody, which specifically binds to FcRH5 and CD3, contains an anti-FcRH5 arm containing a first binding domain including HVR-L2 (SEQ ID NO: 5) containing the amino acid sequence of (f) QQHYSPPYT and HVR-L3 (SEQ ID NO: 6), and specifically binds to the following six HVRs: (a) HVR-H1 (SEQ ID NO: 9) containing the amino acid sequence of SYYIH; (b) HVR-H2 (SEQ ID NO: 10) containing the amino acid sequence of WIYPENDNTKYNEKFKD; (c) DGYSRYYFDY The second bispecific antibody, which specifically binds to BCMA and CD3, includes an anti-CD3 arm containing a second binding domain, comprising (d) HVR-H3 containing the amino acid sequence of (e) KSSQSLLNSRTRKNYLA (SEQ ID NO. 12); (f) HVR-L3 containing the amino acid sequence of (e) WTSTRKS (SEQ ID NO. 13); and (g) HVR-L3 containing the amino acid sequence of KQSFILRT (SEQ ID NO. 14), and is used for the following six HVRs: (a) GFTFSSY (SEQ ID NO. 40),The second bispecific antibody, which specifically binds to BCMA and CD3, comprises an anti-BCMA arm containing a first binding domain including (b) HVR-H1 containing the amino acid sequence of SYPMS (SEQ ID NO: 39) or GFTFSSYPMS (SEQ ID NO: 41); (b) HVR-H2 containing the amino acid sequence of GGSGGS (SEQ ID NO: 43) or AIGGSGGSLPYADIVKG (SEQ ID NO: 42); (c) HVR-H3 (SEQ ID NO: 44) containing the amino acid sequence of YWPMDI; (d) HVR-L1 (SEQ ID NO: 45) containing the amino acid sequence of RASQSVSSSYLA; (e) HVR-L2 (SEQ ID NO: 46) containing the amino acid sequence of DASIRAT; and (f) HVR-L3 (SEQ ID NO: 47) containing the amino acid sequence of QQYQSWPLT, and is as follows: The HVRs include: (a) HVR-H1 containing the amino acid sequence of GFTFSDY (SEQ ID NO: 53), DYYMT (SEQ ID NO: 52), or GFTFSDYYMT (SEQ ID NO: 54); (b) HVR-H2 containing the amino acid sequence of RNRARGYT (SEQ ID NO: 56) or FIRNRARGYTSDHNPSVKG (SEQ ID NO: 55); (c) HVR-H3 containing the amino acid sequence of DRPSYYVLDY (SEQ ID NO: 57); (d) HVR-L1 (SEQ ID NO: 58) containing the amino acid sequence of KSSQSLFNVRSRKNYLA; (e) HVR-L2 (SEQ ID NO: 59) containing the amino acid sequence of WASTRES; and (f) HVR-L3 containing the amino acid sequence of KQSYDLFT (SEQ ID NO: 60), comprising an anti-CD3 arm with a second binding domain. In some examples, the treatment further includes a prephase before the first phase. In some cases, the prephase consists of approximately 15-day medication cycles (C1), with cebostamab administered to the subject at an escalating dose of 3.6 mg on day 9, 10, or 11 of prephase C1, and erranatamab administered to the subject at a first escalating dose of 12 mg on day 1 of prephase C1, a second escalating dose of 32 mg on day 3, 4, or 5 of prephase C1, and a target dose of 76 mg on day 8 of prephase C1. In other cases, the prephase consists of approximately 22-day medication cycles (C1), with cebostamab administered to the subject at an escalating dose of 3.6 mg on day 16, 17, or 18 of prephase C1, and erranatamab administered to the subject.The first dose escalation is administered to the target patient at 12 mg on day 1 of prephase C1, the second dose escalation is administered at 32 mg on days 3, 4, or 5 of prephase C1, and the target dose of 76 mg is administered on days 8 and 15 of prephase C1.

[0412] In another example, a bispecific antibody that specifically conjugates to FcRH5 and CD3 (e.g., cebostamab) is provided herein for use in the treatment of human subjects having R / R MM, wherein the treatment comprises (i) an effective amount of a first bispecific antibody that specifically conjugates to FcRH5 and CD3 (e.g., cebostamab), and (ii) an effective amount of a second bispecific antibody that specifically conjugates to BCMA and CD3 (e.g., erlanatamab), in a prephase including (i) a dosing cycle (C1) of approximately 15 days. (ii) A first phase following the prephase, comprising a first medication cycle (C1), wherein C1 of the first phase is a 14-day medication cycle; (iii) A second phase following the first phase, comprising a first medication cycle (C1), a second medication cycle (C2), a third medication cycle (C3), a fourth medication cycle (C4), a fifth medication cycle (C5), a sixth medication cycle (C6), a seventh medication cycle (C7), an eighth medication cycle ( C8), the 9th medication cycle (C9), the 10th medication cycle (C10), the 11th medication cycle (C11), the 12th medication cycle (C12), the 13th medication cycle (C13), the 14th medication cycle (C14), the 15th medication cycle (C15), the 16th medication cycle (C16), the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 2 A second phase comprising two drug cycles (C22), a 23rd drug cycle (C23), a 24th drug cycle (C24), and a 25th drug cycle (C25), each of which is a 14-day drug cycle, and a third phase comprising one or more drug cycles following the second phase, wherein a first bispecific antibody that specifically binds to FcRH5 and CD3 is administered on day 9, day 10, or day 11 of prephase C1.The subjects were administered a target dose of 60 mg on day 2, 3, or 4 of Phase 1 C1 in an escalating dose of 6 mg, and a target dose of 60 mg on day 1 of each of Phase 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and a second bispecific antibody that specifically binds to BCMA and CD3 was administered on day 1 of Prephase C1. The first dose escalation is 2 mg, followed by a second dose escalation of 32 mg on day 3, 4, or 5 of prephase C1, with a target dose of 76 mg on day 8 of prephase C1, with a target dose of 76 mg on day 1 of phase 1 C1, and with a target dose of 76 mg on day 1 of each of phases C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 of phase 2. Furthermore, the target dose of 76 mg is administered to the subjects on day 1 of each of one or more dosing cycles in Phase 3. The first bispecific antibody comprises an anti-FcRH5 arm containing a first binding domain with a VH domain containing the amino acid sequence of SEQ ID NO: 7 and a VL domain containing the amino acid sequence of SEQ ID NO: 8. The first bispecific antibody, which specifically binds to FcRH5 and CD3, comprises an anti-CD3 arm containing a second binding domain with a VH domain containing the amino acid sequence of SEQ ID NO: 15 and a VL domain containing the amino acid sequence of SEQ ID NO: 16. The second bispecific antibody, which specifically binds to BCMA and CD3, comprises an anti-BCMA arm containing a first binding domain with a VH domain containing the amino acid sequence of SEQ ID NO: 48 and a VL domain containing the amino acid sequence of SEQ ID NO: 49. The second bispecific antibody, which specifically binds to BCMA and CD3, comprises an anti-CD3 arm containing a second binding domain with a VH domain containing the amino acid sequence of SEQ ID NO: 61 and a VL domain containing the amino acid sequence of SEQ ID NO: 62.

[0413] In another example, a bispecific antibody that specifically conjugates to FcRH5 and CD3 (e.g., cebostamab) is provided herein for use in the treatment of human subjects having R / R MM, wherein the treatment comprises (i) an effective amount of a first bispecific antibody that specifically conjugates to FcRH5 and CD3 (e.g., cebostamab), and (ii) an effective amount of a second bispecific antibody that specifically conjugates to BCMA and CD3 (e.g., erlanatamab), in a prephase (i) dosing cycle (C1) of approximately 22 days. (ii) A first phase following the prephase, comprising a first medication cycle (C1), wherein C1 of the first phase is a 14-day medication cycle; (iii) A second phase following the first phase, comprising a first medication cycle (C1), a second medication cycle (C2), a third medication cycle (C3), a fourth medication cycle (C4), a fifth medication cycle (C5), a sixth medication cycle (C6), a seventh medication cycle (C7), an eighth medication cycle ( C8), the 9th medication cycle (C9), the 10th medication cycle (C10), the 11th medication cycle (C11), the 12th medication cycle (C12), the 13th medication cycle (C13), the 14th medication cycle (C14), the 15th medication cycle (C15), the 16th medication cycle (C16), the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 2 A second phase comprising two drug cycles (C22), a 23rd drug cycle (C23), a 24th drug cycle (C24), and a 25th drug cycle (C25), each of which is a 14-day drug cycle, and a third phase comprising one or more drug cycles following the second phase, wherein a first bispecific antibody that specifically binds to FcRH5 and CD3 is administered on day 16, day 17, or day 18 of the prephase C1.The subjects were administered a target dose of 60 mg on day 2, 3, or 4 of Phase 1 C1 in an escalating dose of 6 mg, and a target dose of 60 mg on day 1 of each of Phase 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and a second bispecific antibody that specifically binds to BCMA and CD3 was administered at 12 mg on day 1 of Prephase C1. The first escalating dose of g is 32 mg on day 3, day 4, or day 5 of prephase C1. The second escalating dose is 76 mg on days 8 and 15 of prephase C1. The target dose is 76 mg on day 1 of phase 1 C1. The target dose is 76 mg on day 1 of each of phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25. Furthermore, the target dose of 76 mg is administered to the subject on day 1 of each of one or more dosing cycles in the third phase, wherein the first bispecific antibody comprises an anti-FcRH5 arm containing a first binding domain containing a VH domain with the amino acid sequence of SEQ ID NO: 7 and a VL domain with the amino acid sequence of SEQ ID NO: 8; the first bispecific antibody that specifically binds to FcRH5 and CD3 comprises an anti-CD3 arm containing a second binding domain containing a VH domain with the amino acid sequence of SEQ ID NO: 15 and a VL domain with the amino acid sequence of SEQ ID NO: 16; the second bispecific antibody that specifically binds to BCMA and CD3 comprises an anti-BCMA arm containing a first binding domain containing a VH domain with the amino acid sequence of SEQ ID NO: 48 and a VL domain with the amino acid sequence of SEQ ID NO: 49; and the second bispecific antibody that specifically binds to BCMA and CD3 comprises an anti-CD3 arm containing a second binding domain containing a VH domain with the amino acid sequence of SEQ ID NO: 61 and a VL domain with the amino acid sequence of SEQ ID NO: 62.

[0414] In another example, a bispecific antibody that specifically conjugates to FcRH5 and CD3 (e.g., cebostamab) is provided herein for use in the treatment of human subjects having R / R MM, wherein the treatment involves (i) an effective amount of a first bispecific antibody that specifically conjugates to FcRH5 and CD3 (e.g., cebostamab), and (ii) an effective amount of a second bispecific antibody that specifically conjugates to BCMA and CD3 (e.g., erlanatamab), in a first phase comprising a first dosing cycle (C1), where C1 of the first phase is a 14-day dosing cycle. (ii) A second phase following the first phase, comprising the first medication cycle (C1), the second medication cycle (C2), the third medication cycle (C3), the fourth medication cycle (C4), the fifth medication cycle (C5), the sixth medication cycle (C6), the seventh medication cycle (C7), the eighth medication cycle (C8), the ninth medication cycle (C9), the tenth medication cycle (C10), the eleventh medication cycle (C11), the twelfth medication cycle (C12), the thirteenth medication cycle (C13), the fourteenth medication cycle (C14), the fifteenth medication cycle ( (iii) a third phase following the second phase, which includes the 16th medication cycle (C16), the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), the 24th medication cycle (C24), and the 25th medication cycle (C25), wherein each medication cycle in the second phase is a 14-day medication cycle, and (iii) one or more third phases following the second phase. The regimen includes administering to the subject in a third phase, including the following medication cycles, a first bispecific antibody that specifically binds to FcRH5 and CD3, at a target dose of 60 mg, 105 mg, or 132 mg on day 2, 3, or 4 of phase 1 C1, and at 60 mg, 105 mg, on day 1 of phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25.Alternatively, administer to the subject a target dose of 132 mg, and administer to the subject a second bispecific antibody that specifically binds to BCMA and CD3 at a target dose of 76 mg on days 1 and 8 of C1 in the first phase, at a target dose of 76 mg on days 1 and 8 of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 in the second phase, and at a target dose of 76 mg on days 1 and 8 of each of one or more dosing cycles in the third phase, wherein the first bispecific antibody has a first binding domain containing a VH domain containing the amino acid sequence of SEQ ID NO: 7 and a VL domain containing the amino acid sequence of SEQ ID NO: 8. The first bispecific antibody, which specifically binds to FcRH5 and CD3, includes an anti-FcRH5 arm containing an anti-CD3 arm containing a VH domain containing the amino acid sequence of SEQ ID NO: 15 and a VL domain containing the amino acid sequence of SEQ ID NO: 16. The second bispecific antibody, which specifically binds to BCMA and CD3, includes an anti-BCMA arm containing a first binding domain containing a VH domain containing the amino acid sequence of SEQ ID NO: 48 and a VL domain containing the amino acid sequence of SEQ ID NO: 49. The second bispecific antibody, which specifically binds to BCMA and CD3, includes an anti-CD3 arm containing a second binding domain containing a VH domain containing the amino acid sequence of SEQ ID NO: 61 and a VL domain containing the amino acid sequence of SEQ ID NO: 62.

[0415] In another example, a bispecific antibody that specifically conjugates to FcRH5 and CD3 (e.g., cebostamab) is provided herein for use in the treatment of human subjects having R / R MM, wherein the treatment involves (i) an effective amount of a first bispecific antibody that specifically conjugates to FcRH5 and CD3 (e.g., cebostamab), and (ii) an effective amount of a second bispecific antibody that specifically conjugates to BCMA and CD3 (e.g., erlanatamab), in a first phase comprising a first dosing cycle (C1), where C1 of the first phase is a 14-day dosing cycle. (ii) A second phase following the first phase, comprising the first medication cycle (C1), the second medication cycle (C2), the third medication cycle (C3), the fourth medication cycle (C4), the fifth medication cycle (C5), the sixth medication cycle (C6), the seventh medication cycle (C7), the eighth medication cycle (C8), the ninth medication cycle (C9), the tenth medication cycle (C10), the eleventh medication cycle (C11), the twelfth medication cycle (C12), the thirteenth medication cycle (C13), the fourteenth medication cycle (C14), the fifteenth medication cycle ( (iii) a third phase following the second phase, which includes the 16th medication cycle (C16), the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), the 24th medication cycle (C24), and the 25th medication cycle (C25), wherein each medication cycle in the second phase is a 14-day medication cycle, and (iii) one or more third phases following the second phase. The regimen includes administering to the subject in a third phase, including the following medication cycles, a first bispecific antibody that specifically binds to FcRH5 and CD3, at a target dose of 60 mg, 105 mg, or 132 mg on day 2, 3, or 4 of phase 1 C1, and at 60 mg, 105 mg, on day 1 of phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25.Alternatively, administer to the subject a target dose of 132 mg, and administer to the subject a second bispecific antibody that specifically binds to BCMA and CD3 at a target dose of 76 mg on days 1 and 8 of C1 in the first phase, at a target dose of 76 mg on day 8 of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 in the second phase, and at a target dose of 76 mg on day 1 of each of one or more dosing cycles in the third phase, wherein the first bispecific antibody contains an anti-Fc binding domain containing a VH domain containing the amino acid sequence of SEQ ID NO: 7 and a VL domain containing the amino acid sequence of SEQ ID NO: 8. The first bispecific antibody, comprising an RH5 arm and specifically binding to FcRH5 and CD3, comprises an anti-CD3 arm comprising a second binding domain comprising a VH domain containing the amino acid sequence of SEQ ID NO: 15 and a VL domain containing the amino acid sequence of SEQ ID NO: 16. The second bispecific antibody, specifically binding to BCMA and CD3, comprises an anti-BCMA arm comprising a first binding domain comprising a VH domain containing the amino acid sequence of SEQ ID NO: 48 and a VL domain containing the amino acid sequence of SEQ ID NO: 49. The second bispecific antibody, specifically binding to BCMA and CD3, comprises an anti-CD3 arm comprising a second binding domain comprising a VH domain containing the amino acid sequence of SEQ ID NO: 61 and a VL domain containing the amino acid sequence of SEQ ID NO: 62.

[0416] In another example, cebostamab for use in the treatment of subjects having R / R MM is provided herein, the treatment comprising: (i) a prephase comprising a dosing cycle (C1) of approximately 15 days; (ii) a first phase following the prephase, comprising a first dosing cycle (C1), wherein the C1 of the first phase is a dosing cycle of 14 days; and (iii) a second phase following the first phase. The first medication cycle (C1), the second medication cycle (C2), the third medication cycle (C3), the fourth medication cycle (C4), the fifth medication cycle (C5), the sixth medication cycle (C6), the seventh medication cycle (C7), the eighth medication cycle (C8), the ninth medication cycle (C9), the tenth medication cycle (C10), the eleventh medication cycle (C11), the twelfth medication cycle (C12), the thirteenth Medication cycle (C13), 14th medication cycle (C14), 15th medication cycle (C15), 16th medication cycle (C16), 17th medication cycle (C17), 18th medication cycle (C18), 19th medication cycle (C19), 20th medication cycle (C20), 21st medication cycle (C21), 22nd medication cycle (C22), 23rd medication cycle (C23), 24th medication cycle (iv) Administering cebostamab to human subjects in a drug regimen comprising a second phase including cycles (C24) and the 25th drug cycle (C25), each drug cycle in the second phase being a 14-day drug cycle, and a third phase following the second phase, comprising one or more drug cycles, with 3 doses administered on day 9, day 10, or day 11 of the prephase C1.The subjects were administered erlanatamab in an escalating dose of 6 mg, with a target dose of 60 mg on day 2, 3, or 4 of phase 1 C1, and a target dose of 60 mg on day 1 of phases 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, and erlanatamab was administered in a first escalating dose of 12 mg on day 1 of prephase C1, and on day 3, 4, or 5 of prephase C1. The drug is administered to the patient in a second escalating dose of 32 mg, and also in a target dose of 76 mg on day 8 of prephase C1, a target dose of 76 mg on day 1 of phase 1 C1, a target dose of 76 mg on day 1 of phases C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 of phase 2, and a target dose of 76 mg on day 1 of each of one or more dosing cycles in phase 3.

[0417] In another example, cebostamab for use in the treatment of subjects having R / R MM is provided herein, the treatment comprising: (i) a prephase comprising a dosing cycle (C1) of approximately 22 days; (ii) a first phase following the prephase, comprising a first dosing cycle (C1), wherein the C1 of the first phase is a dosing cycle of 14 days; and (iii) the first phase The following are the medication cycles: the first (C1), the second (C2), the third (C3), the fourth (C4), the fifth (C5), the sixth (C6), the seventh (C7), the eighth (C8), the ninth (C9), the tenth (C10), the eleventh (C11), the twelfth (C12), and the first 3rd medication cycle (C13), 14th medication cycle (C14), 15th medication cycle (C15), 16th medication cycle (C16), 17th medication cycle (C17), 18th medication cycle (C18), 19th medication cycle (C19), 20th medication cycle (C20), 21st medication cycle (C21), 22nd medication cycle (C22), 23rd medication cycle (C23), 24th medication cycle (iv) Administering cebostamab in a drug regimen comprising a second phase including drug cycle (C24) and a 25th drug cycle (C25), each drug cycle of the second phase being a 14-day drug cycle, and a third phase following the second phase, comprising one or more drug cycles, with 3 doses administered on day 16, day 17, or day 18 of prephase C1.The subjects were administered erranatamab in an escalating dose of 6 mg, with a target dose of 60 mg on day 2, 3, or 4 of Phase 1 C1, and a target dose of 60 mg on day 1 of Phase 2 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25, respectively. Elranatamab was administered in a first escalating dose of 12 mg on day 1 of Prephase C1, and 32 mg on day 3, 4, or 5 of Prephase C1. The drug is administered to the subjects in the second escalating dose, as well as at a target dose of 76 mg on days 8 and 15 of prephase C1, at a target dose of 76 mg on day 1 of phase 1 C1, at a target dose of 76 mg on day 1 of phases C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 of phase 2, and at a target dose of 76 mg on day 1 of each of one or more dosing cycles in phase 3.

[0418] In another example, cebostamab for use in the treatment of subjects having R / R MM is provided herein, the treatment comprising: (i) a first phase comprising a first dosing cycle (C1), wherein C1 of the first phase is a 14-day d...

Claims

1. A method for treating a subject having multiple myeloma (MM), comprising administering to the subject an effective amount of a first bispecific antibody that specifically binds to Fc receptor-like 5 (FcRH5) and differentiation antigen 3 (CD3), and an effective amount of a second bispecific antibody that specifically binds to B cell maturation antigen (BCMA) and CD3.

2. The method according to claim 1, wherein the subject has recurrent or refractory (R / R) MM.

3. The method according to claim 2, wherein the subject is diagnosed with R / R MM according to the International Myeloma Working Group (IMWG) criteria.

4. The first bispecific antibody and the second bispecific antibody are (i) A first phase including one or more medication cycles, (ii) A second phase including one or more medication cycles, Optionally, (iii) A third phase including one or more medication cycles and The method according to any one of claims 1 to 3, wherein the drug regimen is administered to the subject.

5. The method according to claim 4, wherein the drug regimen includes the first phase and the second phase, but does not include the third phase.

6. The method according to claim 4, wherein the drug regimen comprises the first phase, the second phase, and the third phase.

7. The method according to claim 4 or 6, wherein each of the first phase, the second phase, and / or the third phase is a 14-day medication cycle.

8. The method according to any one of claims 4 to 7, further comprising a prephase including one or more drug delivery cycles prior to the first phase.

9. The method according to claim 8, wherein the prephase comprises one drug administration cycle (C1).

10. The method according to claim 9, wherein the C1 of the prephase is (i) a drug administration cycle of approximately 15 days, or (ii) a drug administration cycle of approximately 22 days.

11. The method according to claim 10, wherein the C1 of the prephase is a drug administration cycle of approximately 15 days.

12. The method according to claim 11, wherein the prephase comprises administering a first bispecific antibody to the subject on the 9th, 10th, or 11th day of C1.

13. The method according to claim 12, wherein the first bispecific antibody is administered to the subject in an increasing dose of 3.6 mg on the 9th, 10th, or 11th day of C1.

14. The method according to any one of claims 11 to 13, wherein the prephase comprises administering the second bispecific antibody to the subject on (i) day 1, (ii) day 3, day 4 or 5, and (iii) day 8.

15. The method according to claim 14, wherein the second bispecific antibody is administered to the subject on day 1 in a first escalating dose of 12 mg.

16. The method according to claim 14 or 15, wherein the second bispecific antibody is administered to the subject in a second escalating dose of 32 mg on the third, fourth, or fifth day.

17. The method according to any one of claims 14 to 16, wherein the second bispecific antibody is administered to the subject on the 8th day at a target dose of 76 mg.

18. The method according to claim 10, wherein the C1 of the prephase is a drug administration cycle of approximately 22 days.

19. The method according to claim 18, wherein the prephase comprises administering a first bispecific antibody to the subject on the 16th, 17th, or 18th day of C1.

20. The method according to claim 19, wherein the first bispecific antibody is administered to the subject in an increasing dose of 3.6 mg on the 16th, 17th, or 18th day of C1.

21. The method according to any one of claims 18 to 20, wherein the prephase comprises administering the second bispecific antibody to the subject on (i) day 1, (ii) day 3, day 4 or 5, (iii) day 8, and (iv) day 15.

22. The method according to claim 21, wherein the second bispecific antibody is administered to the subject on day 1 in a first escalating dose of 12 mg.

23. The method according to claim 21 or 22, wherein the second bispecific antibody is administered to the subject in a second escalating dose of 32 mg on the third, fourth, or fifth day.

24. The method according to any one of claims 21 to 23, wherein the second bispecific antibody is administered to the subject on the 8th day at a target dose of 76 mg.

25. The method according to any one of claims 21 to 24, wherein the second bispecific antibody is administered to the subject on day 15 at a target dose of 76 mg.

26. The method according to any one of claims 6 to 25, wherein the first phase comprises at least one drug delivery cycle, at least two drug delivery cycles, at least three drug delivery cycles, at least four drug delivery cycles, or at least five drug delivery cycles.

27. The method according to claim 26, wherein the first phase comprises a first 14-day medication cycle (C1).

28. The method according to claim 27, wherein the target dose of the first bispecific antibody is administered to the subject during the first phase.

29. The method according to claim 28, wherein the first phase comprises administering the target dose of the first bispecific antibody to the subject on the second, third, or fourth day of C1.

30. The method according to claim 28 or 29, wherein the target dose of the first bispecific antibody is 60 mg.

31. The method according to claim 28 or 29, wherein the target dose of the first bispecific antibody is 60 mg administered every two weeks (Q2W) over C1 to C8 of the first phase, and thereafter the target dose of the first bispecific antibody is 60 mg administered every four weeks (Q4W).

32. The method according to claim 28 or 29, wherein the target dose of the first bispecific antibody is 105 mg.

33. The method according to claim 28 or 29, wherein the target dose of the first bispecific antibody is 105 mg administered at Q2W over C1 to C8 of the first phase, and thereafter the target dose of the first bispecific antibody is 60 mg administered at Q4W.

34. The method according to claim 28 or 29, wherein the target dose of the first bispecific antibody is 132 mg.

35. The method according to any one of claims 27 to 34, wherein the target dose of the second bispecific antibody is administered to the subject during the first phase.

36. The method according to claim 35, wherein the first phase comprises administering the target dose of the second bispecific antibody to the subject on day 1 of C1.

37. The method according to claim 35 or 36, wherein the first phase comprises administering the target dose of the second bispecific antibody to the subject on day 1 and day 8 of C1.

38. The method according to any one of claims 35 to 37, wherein the target dose of the second bispecific antibody is 76 mg.

39. The method according to claim 35 or 36, wherein the target dose of the second bispecific antibody is 76 mg administered at Q2W over C1 to C8 of the first phase, and thereafter the target dose of the second bispecific antibody is 76 mg administered at Q4W.

40. The method according to any one of claims 6 to 39, wherein the second phase includes at least one medication cycle, at least two medication cycles, at least three medication cycles, at least four medication cycles, at least five medication cycles, at least six medication cycles, at least seven medication cycles, at least eight medication cycles, at least nine medication cycles, at least ten medication cycles, at least eleven medication cycles, at least twelve medication cycles, at least thirteen medication cycles, at least fourteen medication cycles, at least fifteen medication cycles, at least sixteen medication cycles, at least seventeen medication cycles, at least eighteen medication cycles, at least nineteen medication cycles, at least twenty medication cycles, at least twenty-one medication cycles, at least twenty-two medication cycles, at least twenty-three medication cycles, at least twenty-four medication cycles, or at least twenty-five medication cycles.

41. The second phase is the first medication cycle (C1), the second medication cycle (C2), the third medication cycle (C3), the fourth medication cycle (C4), the fifth medication cycle (C5), the sixth medication cycle (C6), the seventh medication cycle (C7), the eighth medication cycle (C8), the ninth medication cycle (C9), the tenth medication cycle (C10), the eleventh medication cycle (C11), the twelfth medication cycle (C12), the thirteenth medication cycle (C13), the fourteenth The method according to claim 40, comprising a medication cycle (C14), a 15th medication cycle (C15), a 16th medication cycle (C16), a 17th medication cycle (C17), a 18th medication cycle (C18), a 19th medication cycle (C19), a 20th medication cycle (C20), a 21st medication cycle (C21), a 22nd medication cycle (C22), a 23rd medication cycle (C23), a 24th medication cycle (C24), and a 25th medication cycle (C25).

42. The method according to claim 40 or 41, wherein each drug administration cycle in the second phase is a 14-day drug administration cycle.

43. The method according to any one of claims 40 to 42, wherein a target dose of the first bispecific antibody is administered to the subject during the second phase.

44. The method according to any one of claims 40 to 43, wherein the second phase comprises administering a target dose of the first bispecific antibody to the subject on the first day of each drug cycle.

45. The method according to claim 42 or 43, wherein the second phase comprises administering a target dose of the first bispecific antibody to the subject on day 1 of the second phase C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and / or C25.

46. The method according to any one of claims 43 to 45, wherein the target dose is 60 mg.

47. The method according to any one of claims 43 to 45, wherein the target dose of the first bispecific antibody is 60 mg administered at Q2W over C1 to C8 of the second phase, and thereafter the target dose of the first bispecific antibody is 60 mg administered at Q4W.

48. The method according to any one of claims 43 to 45, wherein the target dose of the first bispecific antibody is 105 mg.

49. The method according to any one of claims 43 to 45, wherein the target dose of the first bispecific antibody is 105 mg administered at Q2W over C1 to C8 of the second phase, and thereafter the target dose of the first bispecific antibody is 60 mg administered at Q4W.

50. The method according to any one of claims 43 to 45, wherein the target dose is 132 mg.

51. The method according to any one of claims 40 to 50, wherein the target dose of the second bispecific antibody is administered to the subject during the second phase.

52. The method according to any one of claims 40 to 51, wherein the second phase comprises administering the target dose of the second bispecific antibody to the subject on the first day of each drug cycle.

53. The method according to claim 52, wherein the second phase comprises administering the target dose of the second bispecific antibody to the subject on day 1 of the second phase C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and / or C25.

54. The method according to any one of claims 40 to 51, wherein the second phase comprises administering a target dose of the second bispecific antibody to the subject on day 1 and day 8 of each drug delivery cycle.

55. The method according to claim 54, wherein the second phase comprises administering the target dose of the second bispecific antibody to the subject on day 1 and day 8 of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and / or C25 of the second phase.

56. The method according to claim 54 or 55, wherein the subject achieves an IWMG response category of partial response (PR) or higher with a response that lasts for at least two months, and the frequency of administration of the second bispecific antibody is changed to every two weeks (Q2W).

57. The method according to claim 56, wherein the subject subsequently has an increased disease burden that does not yet qualify as a progressive disease according to the IWMG criteria, and the frequency of medication is changed to weekly (QW).

58. The method according to claim 45 or 53, wherein if the subject achieves a complete response (CR) in the IWMG response category after six months, the dosing frequency of the first bispecific antibody and the second bispecific antibody is changed from every two weeks (Q2W) to every four weeks (Q4W).

59. The method according to claim 53, wherein the subject achieves an IWMG response category of partial response (PR) with a response lasting for at least two months, and the frequency of administration of the second bispecific antibody is changed from every two weeks (Q2W) to every four weeks (Q4W).

60. The method according to any one of claims 40 to 51, wherein the second phase comprises administering a target dose of the second bispecific antibody to the subject on the eighth day of each drug cycle.

61. The method according to claim 58, wherein the second phase comprises administering the target dose of the second bispecific antibody to the subject on the 8th day of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and / or C25.

62. The method according to any one of claims 51 to 61, wherein the target dose of the second bispecific antibody is 76 mg.

63. The method according to any one of claims 51 to 59, wherein the target dose of the second bispecific antibody is 76 mg administered at Q2W over C1 to C8 of the second phase, and thereafter the target dose of the second bispecific antibody is 76 mg administered at Q4W.

64. The method according to any one of claims 1 to 63, wherein the method comprises administering the first bispecific antibody to the subject until disease progression, unacceptable toxicity, or up to 26 total drug cycles.

65. The method according to any one of claims 4 and 46 to 56, wherein the third phase comprises one or more drug administration cycles.

66. The method according to claim 65, wherein the third phase comprises 1 to 130 drug administration cycles.

67. The method according to claim 65 or 66, wherein each drug administration cycle in the third phase is a 14-day drug administration cycle.

68. The method according to any one of claims 65 to 67, wherein the target dose of the second bispecific antibody is administered to the subject during the third phase.

69. The method according to claim 68, wherein the third phase comprises administering the target dose of the second bispecific antibody to the subject on the first day of each drug delivery cycle of the third phase.

70. The method according to claim 68, wherein the third phase comprises administering the target dose of the second bispecific antibody to the subject on the first and eighth days of each drug delivery cycle of the third phase.

71. The method according to claim 70, wherein the subject achieves an IWMG response category of partial response (PR) or higher with a response that lasts for at least two months, and the frequency of administration of the second bispecific antibody is changed to every two weeks (Q2W).

72. The method according to claim 69 or 71, wherein if the subject achieves a complete response (CR) in the IWMG response category after six months, the dosing frequency of the first bispecific antibody and the second bispecific antibody is changed from every two weeks (Q2W) to every four weeks (Q4W).

73. The method according to claim 69 or 71, wherein the subject achieves an IWMG response category of partial response (PR) with a response lasting for at least two months, and the frequency of administration of the second bispecific antibody is changed from every two weeks (Q2W) to every four weeks (Q4W).

74. The method according to claim 71, wherein the subject subsequently has an increased disease burden that does not yet qualify as a progressive disease according to the IWMG criteria, and the frequency of medication is changed to weekly (QW).

75. The method according to any one of claims 68 to 71, wherein the target dose of the second bispecific antibody is 76 mg.

76. The method according to any one of claims 1 to 75, wherein the second bispecific antibody is administered to the subject until disease progression or unacceptable toxicity occurs.

77. The method according to any one of claims 1 to 76, wherein the first bispecific antibody is administered intravenously to the subject.

78. The method according to any one of claims 1 to 77, wherein the second bispecific antibody is administered subcutaneously to the subject.

79. The method according to any one of claims 1 to 78, further comprising administering a corticosteroid to the subject.

80. The method according to any one of claims 6 to 79, further comprising administering a corticosteroid to the subject during the first phase, the second phase, and / or the third phase.

81. The method according to any one of claims 6 to 80, wherein a corticosteroid is administered to the subject during the first phase, one hour (±15 minutes) before the administration of the first bispecific antibody or the second bispecific antibody.

82. (i) The subject has experienced cytokine release syndrome (CRS) due to prior administration of the first bispecific antibody or the second bispecific antibody, and the corticosteroid is administered to the subject during the second phase, 1 hour (±15 minutes) before the administration of the first bispecific antibody or the second bispecific antibody; and / or (ii) The method according to any one of claims 6 to 81, wherein the subject has experienced CRS due to prior administration of the first bispecific antibody or the second bispecific antibody, and a corticosteroid is administered to the subject during the third phase, 1 hour (±15 minutes) before the administration of the second bispecific antibody.

83. The method according to any one of claims 8 to 82, further comprising administering a corticosteroid to the subject during the prephase.

84. The method according to any one of claims 11 to 83, wherein a corticosteroid is administered to the subject in the C1 of the prephase one hour (±15 minutes) before the administration of the first bispecific antibody or the second bispecific antibody.

85. The method according to any one of claims 79 to 84, wherein the corticosteroid is dexamethasone or methylprednisolone.

86. The method according to claim 85, wherein the corticosteroid is dexamethasone.

87. The method according to claim 85 or 86, wherein the dexamethasone is administered to the subject in a dose of approximately 20 mg.

88. The method according to claim 85, wherein the methylprednisolone is administered to the subject in a dose of approximately 80 mg.

89. The method according to any one of claims 79 to 88, wherein the corticosteroid is administered intravenously to the subject.

90. The first bispecific antibody, which specifically binds to FcRH5 and CD3, has the following six hypervariable regions (HVRs): (a) HVR-H1 containing the amino acid sequence of RFGVH (SEQ ID NO: 1), (b) HVR-H2 containing the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2) (c) HVR-H3 containing the amino acid sequence of HYYGSSDYALDN (SEQ ID NO: 3), (d) HVR-L1 containing the amino acid sequence of KASQDVRNLV (SEQ ID NO: 4), (e) HVR-L2 containing the amino acid sequence of SGSYRYS (SEQ ID NO: 5), and (f) HVR-L3 containing the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6) The method according to any one of claims 1 to 89 and 175 to 190, comprising an anti-FcRH5 arm comprising a first binding domain

91. The method according to any one of claims 1 to 78, wherein the first bispecific antibody that specifically binds to FcRH5 and CD3 comprises (a) a heavy chain variable (VH) domain having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 8; or (c) an anti-FcRH5 arm comprising a first binding domain comprising the VH domain described in (a) and the VL domain described in (b).

92. The method according to claim 91, wherein the first binding domain comprises a VH domain containing the amino acid sequence of SEQ ID NO: 7 and a VL domain containing the amino acid sequence of SEQ ID NO:

8.

93. The first bispecific antibody that specifically binds to FcRH5 and CD3 is one of the following six HVRs: (a) HVR-H1 containing the amino acid sequence of SYYIH (SEQ ID NO: 9), (b) HVR-H2 containing the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10), (c) HVR-H3 containing the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11) (d) HVR-L1 containing the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12), (e) HVR-L2 containing the amino acid sequence of WTSTRKS (SEQ ID NO: 13), (f) HVR-L3 containing the amino acid sequence of KQSFILRT (SEQ ID NO: 14) The method according to any one of claims 1 to 92 and 175 to 190, comprising an anti-CD3 arm including a second binding domain including the above.

94. The method according to any one of claims 1 to 93, wherein the first bispecific antibody that specifically binds to FcRH5 and CD3 comprises (a) a VH domain having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 15; (b) a VL domain having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 16; or (c) an anti-CD3 arm having a second binding domain comprising the VH domain described in (a) and the VL domain described in (b).

95. The method according to claim 94, wherein the second binding domain comprises a VH domain containing the amino acid sequence of SEQ ID NO: 15 and a VL domain containing the amino acid sequence of SEQ ID NO:

16.

96. The first bispecific antibody that specifically binds to FcRH5 and CD3 comprises an anti-FcRH5 arm containing a heavy chain polypeptide (H1) and a light chain polypeptide (L1), and an anti-CD3 arm containing a heavy chain polypeptide (H2) and a light chain polypeptide (L2), (a) H1 contains the amino acid sequence of SEQ ID NO: 35, (b) L1 contains the amino acid sequence of SEQ ID NO: 36, (c) H2 contains the amino acid sequence of SEQ ID NO: 37, (d) L2 contains the amino acid sequence of SEQ ID NO: 38, The method according to any one of claims 1 to 95 and 175 to 190.

97. The method according to any one of claims 1 to 96, wherein the first bispecific antibody that specifically binds to FcRH5 and CD3 comprises a nonglycosylation site mutation.

98. The method according to claim 97, wherein the nonglycosylation site mutation reduces the effector function of the bispecific antibody.

99. The method according to claim 98, wherein the non-glycosylation site mutation is a substitution mutation.

100. The method according to any one of claims 1 to 99, wherein the first bispecific antibody that specifically binds to FcRH5 and CD3 includes a substitutional mutation in the Fc region that reduces effector function.

101. The method according to any one of claims 1 to 100, wherein the first bispecific antibody that specifically binds to FcRH5 and CD3 is a monoclonal antibody.

102. The method according to any one of claims 1 to 101, wherein the first bispecific antibody that specifically binds to FcRH5 and CD3 is a chimeric antibody.

103. The method according to any one of claims 1 to 102, wherein the first bispecific antibody that specifically binds to FcRH5 and CD3 is a humanized antibody.

104. The method according to any one of claims 1 to 95 and 97 to 103, wherein the first bispecific antibody that specifically binds to FcRH5 and CD3 is an antibody fragment that specifically binds to FcRH5 and CD3.

105. The method according to claim 104, wherein the antibody fragment that specifically binds to FcRH5 and CD3 is selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments.

106. The method according to any one of claims 1 to 103, wherein the first bispecific antibody that specifically binds to FcRH5 and CD3 is a full-length antibody.

107. The method according to any one of claims 1 to 106, wherein the first bispecific antibody that specifically binds to FcRH5 and CD3 is an IgG antibody.

108. The method according to claim 107, wherein the IgG antibody that specifically binds to FcRH5 and CD3 is an IgG1 antibody.

109. The method according to any one of claims 1 to 108, wherein the first bispecific antibody that specifically binds to FcRH5 and CD3 comprises one or more heavy chain constant domains, the one or more heavy chain constant domains being selected from a first CH1 (CH11) domain, a first CH2 (CH21) domain, a first CH3 (CH31) domain, a second CH1 (CH12) domain, a second CH2 (CH22) domain, and a second CH3 (CH32) domain.

110. The method according to claim 109, wherein at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

111. The method according to claim 110, wherein the CH31 domain and the CH32 domain each have projections or cavities, and the projections or cavities in the CH31 domain can each be positioned in the cavities or projections in the CH32 domain.

112. The method according to claim 111, wherein the CH31 domain and the CH32 domain are in contact at the interface between the protrusion and the cavity.

113. The method according to any one of claims 109 to 112, wherein the CH21 domain and the CH22 domain each comprise a projection or cavity, and the projection or cavity within the CH21 domain is capable of being positioned in the cavity or projection within the CH22 domain.

114. The method according to claim 113, wherein the CH21 domain and the CH22 domain are in contact at the interface between the projection and the cavity.

115. The method according to claim 114, wherein the anti-FcRH5 arm is provided with the projection and the anti-CD3 arm is provided with the cavity.

116. The method according to claim 115, wherein the CH3 domain of the anti-FcRH5 arm comprises a projection containing the T366W amino acid substitution mutation (EU numbering), and the CH3 domain of the anti-CD3 arm comprises a cavity containing the T366S, L368A, and Y407V amino acid substitution mutations (EU numbering).

117. The method according to any one of claims 1 to 103 and 106 to 116, wherein the first bispecific antibody that specifically binds to FcRH5 and CD3 is cebostamab.

118. The second bispecific antibody that specifically binds to BCMA and CD3 is one of the following six HVRs: (a) HVR-H1 containing the amino acid sequence of GTFFSSY (SEQ ID NO: 40), SYPMS (SEQ ID NO: 39), or GTFFSSYPMS (SEQ ID NO: 41), (b) HVR-H2 containing the amino acid sequence of GGSGGS (SEQ ID NO: 43) or AIGGSGGSLPYADIVKG (SEQ ID NO: 42), (c) HVR-H3 containing the amino acid sequence of YWPMDI (SEQ ID NO: 44) (d) HVR-L1 containing the amino acid sequence of RASQSVSSSYLA (SEQ ID NO: 45) (e) HVR-L2 containing the amino acid sequence of DASIRAT (SEQ ID NO: 46), (f) HVR-L3 containing the amino acid sequence of QQYQSWPLT (SEQ ID NO: 47) The method according to any one of claims 1 to 117 and 175 to 190, comprising an anti-BCMA arm comprising a first binding domain

119. The method according to any one of claims 1 to 118, wherein the second bispecific antibody that specifically binds to BCMA and CD3 comprises (a) a VH domain having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 48; (b) a VL domain having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 49; or (c) an anti-BCMA arm having a first binding domain comprising the VH domain described in (a) and the VL domain described in (b).

120. The method according to claim 119, wherein the first binding domain of the second bispecific antibody comprises a VH domain containing the amino acid sequence of SEQ ID NO: 48 and a VL domain containing the amino acid sequence of SEQ ID NO:

49.

121. The second bispecific antibody that specifically binds to BCMA and CD3 is one of the following six HVRs: (a) HVR-H1 containing the amino acid sequence of GFTFSDY (SEQ ID NO: 53), DYYMT (SEQ ID NO: 52), or GFTFSDYYMT (SEQ ID NO: 54), (b) HVR-H2 containing the amino acid sequence of RNRAGYT (SEQ ID NO: 56) or FIRNRARGYTSDHNPSVKG (SEQ ID NO: 55), (c) HVR-H3 containing the amino acid sequence of DRPSYYVLDY (SEQ ID NO: 57), (d) HVR-L1 containing the amino acid sequence of KSSQSLFNVRSRKNYLA (SEQ ID NO: 58) (e) HVR-L2 containing the amino acid sequence of WASTRES (SEQ ID NO: 59), (f) HVR-L3 containing the amino acid sequence of KQSYDLFT (SEQ ID NO: 60) The method according to any one of claims 1 to 120 and 175 to 190, comprising an anti-CD3 arm including a second binding domain including the above.

122. The method according to any one of claims 1 to 121, wherein the second bispecific antibody that specifically binds to BCMA and CD3 comprises (a) a VH domain having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 61; (b) a VL domain having at least 95% sequence identity with respect to the amino acid sequence of SEQ ID NO: 62; or (c) an anti-CD3 arm having a second binding domain comprising the VH domain described in (a) and the VL domain described in (b).

123. The method according to claim 122, wherein the second binding domain of the second bispecific antibody comprises a VH domain containing the amino acid sequence of SEQ ID NO: 61 and a VL domain containing the amino acid sequence of SEQ ID NO:

62.

124. The bispecific antibody that specifically binds to BCMA and CD3 comprises an anti-BCMA arm containing a heavy chain polypeptide (H1) and a light chain polypeptide (L1), and an anti-CD3 arm containing a heavy chain polypeptide (H2) and a light chain polypeptide (L2), (a) H1 contains the amino acid sequence of SEQ ID NO: 50, (b) L1 contains the amino acid sequence of SEQ ID NO: 51, (c) H2 contains the amino acid sequence of SEQ ID NO: 63, (d) L2 contains the amino acid sequence of SEQ ID NO: 64, The method according to any one of claims 1 to 123 and 175 to 190.

125. The method according to any one of claims 1 to 124, wherein the second bispecific antibody includes a substitution mutation in the Fc region that reduces effector function.

126. The method according to any one of claims 1 to 125, wherein the second bispecific antibody is a monoclonal antibody, a chimeric antibody, or a humanized antibody.

127. The method according to any one of claims 1 to 123, 125, and 126, wherein the second bispecific antibody that specifically binds to BCMA and CD3 is an antibody fragment that specifically binds to BCMA and CD3.

128. The method according to claim 127, wherein the antibody fragment that specifically binds to BCMA and CD3 is selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments.

129. The method according to any one of claims 1 to 126, wherein the second bispecific antibody is a full-length antibody.

130. The method according to any one of claims 1 to 129, wherein the second bispecific antibody is an IgG antibody.

131. The method according to claim 130, wherein the IgG antibody is an IgG2 antibody.

132. The method according to any one of claims 1 to 123 and 125 to 131, wherein the second bispecific antibody comprises first and second human IgG2 constant regions, each comprising amino acid modifications at positions 223 and 228 in the hinge region, or 223, 225 and 228, respectively, and amino acid modifications at position 368 or 409 (EU numbering) in the CH3 region, respectively.

133. The method according to claim 132, wherein the first human IgG2 constant region comprises amino acid substitution mutations (EU numbering) of C223E, P228E and L368E.

134. The method according to claim 132 or 133, wherein the second human IgG2 constant region comprises amino acid substitution mutations (EU numbering) of C223R, E225R, P228R and K409R.

135. The method according to any one of claims 1 to 126 and 129 to 134, wherein the second bispecific antibody that specifically binds to BCMA and CD3 is erlanatamab.

136. The method according to any one of claims 1 to 135, wherein the first bispecific antibody and / or the second bispecific antibody are administered to the subject simultaneously with one or more additional therapeutic agents.

137. The method according to any one of claims 1 to 135, wherein the first bispecific antibody and / or the second bispecific antibody are administered to the subject prior to the administration of one or more additional therapeutic agents.

138. The method according to any one of claims 1 to 135, wherein the first bispecific antibody and / or the second bispecific antibody are administered to the subject after administration of one or more additional therapeutic agents.

139. The method according to any one of claims 136 to 138, wherein the one or more additional therapeutic agents comprise an effective amount of anti-IL-6 antibody.

140. The method according to claim 139, wherein the anti-IL-6 antibody is tocilizumab.

141. The method according to any one of claims 1 to 140, wherein the subject has a CRS event, and the method further comprises treating the symptoms of the CRS event while interrupting treatment with the first bispecific antibody and the second bispecific antibody.

142. The method according to claim 141, further comprising administering an effective amount of tocilizumab to the subject in order to treat the CRS event.

143. The method according to claim 142, wherein the CRS event does not disappear or worsen within 24 hours after treatment of the symptoms of the CRS event, and the method further comprises administering one or more additional doses of tocilizumab to the subject in order to manage the CRS event.

144. The method according to any one of claims 139, 140, 142, and 143, wherein tocilizumab is administered to the subject by intravenous infusion.

145. (a) The subject weighs 30 kg or more and is administered to the subject at a dose of 8 mg / kg, or (b) The method according to claim 144, wherein the subject weighs less than 30 kg and is administered to the subject at a dose of 12 mg / kg.

146. The method according to any one of claims 139, 140, 142, and 143, wherein tocilizumab is administered to the subject two hours prior to the administration of the first bispecific antibody and / or the second bispecific antibody.

147. The method according to any one of claims 136 to 146, wherein the one or more additional therapeutic agents comprise an effective amount of acetaminophen or paracetamol.

148. The method according to claim 139, wherein acetaminophen or paracetamol is administered to the subject in a dose of 500 mg to 1000 mg.

149. The method according to claim 139 or 140, wherein acetaminophen or paracetamol is administered orally to the subject.

150. The method according to any one of claims 136 to 146, wherein the one or more additional therapeutic agents comprise an effective amount of diphenhydramine.

151. The method according to claim 150, wherein diphenhydramine is administered to the subject in a dose of 25 mg to 50 mg.

152. The method according to claim 150 or 151, wherein diphenhydramine is orally administered to the subject.

153. The method according to any one of claims 138 to 146, comprising premedication with the following agents: (i) a corticosteroid, (ii) acetaminophen or paracetamol, and / or (iii) diphenhydramine, prior to administration of the first bispecific antibody and / or the second bispecific antibody to the subject.

154. A method according to claim 153, comprising a prephase, wherein the corticosteroid is administered to the subject 1 hour (±15 minutes) before the administration of either the first bispecific antibody and / or the second bispecific antibody during the prephase.

155. The method according to claim 153 or 154, comprising a first phase, wherein the corticosteroid is administered to the subject 1 hour (±15 minutes) prior to the administration of either the first bispecific antibody and / or the second bispecific antibody during the first phase.

156. A method according to any one of claims 153 to 155, comprising a second phase, wherein the subject has experienced CRS due to prior administration of the first bispecific antibody and / or the second bispecific antibody, and the corticosteroid is administered to the subject 1 hour (±15 minutes) before the administration of either the first bispecific antibody and / or the second bispecific antibody during the second phase.

157. A method according to any one of claims 153 to 156, comprising a third phase, wherein the subject has experienced CRS due to prior administration of the first bispecific antibody and / or the second bispecific antibody, and the corticosteroid is administered to the subject 1 hour (±15 minutes) before any administration of the second bispecific antibody in the third phase.

158. The method according to any one of claims 153 to 157, wherein the corticosteroid is dexamethasone or methylprednisolone.

159. The method according to claim 158, wherein the corticosteroid is dexamethasone.

160. The method according to claim 158 or 159, wherein the dexamethasone is administered to the subject in a dose of approximately 20 mg.

161. The method according to claim 158, wherein the methylprednisolone is administered to the subject in a dose of approximately 80 mg.

162. The method according to any one of claims 153 to 161, wherein the corticosteroid is administered intravenously to the subject.

163. The method according to any one of claims 153 to 162, wherein acetaminophen or paracetamol is administered to the subject in a dose of 500 mg to 1000 mg.

164. The method according to any one of claims 153 to 163, wherein acetaminophen or paracetamol is administered orally to the subject.

165. The method according to any one of claims 153 to 164, wherein diphenhydramine is administered to the subject at a dose of 25 mg to 50 mg.

166. The method according to claims 153 to 165, wherein diphenhydramine is orally administered to the subject.

167. A method for treating an object having R / R MM, (i) A prephase including a medication cycle of approximately 15 days (C1), (ii) A first phase following the prephase, comprising a first medication cycle (C1), wherein C1 is a 14-day medication cycle, (iii) A second phase following the first phase, comprising a first medication cycle (C1), a second medication cycle (C2), a third medication cycle (C3), a fourth medication cycle (C4), a fifth medication cycle (C5), a sixth medication cycle (C6), a seventh medication cycle (C7), an eighth medication cycle (C8), a ninth medication cycle (C9), a tenth medication cycle (C10), an eleventh medication cycle (C11), a twelfth medication cycle (C12), a thirteenth medication cycle (C13), and a fourteenth medication cycle. Phase 2 includes medication cycles (C14), 15th medication cycle (C15), 16th medication cycle (C16), 17th medication cycle (C17), 18th medication cycle (C18), 19th medication cycle (C19), 20th medication cycle (C20), 21st medication cycle (C21), 22nd medication cycle (C22), 23rd medication cycle (C23), 24th medication cycle (C24), and 25th medication cycle (C25), each of which is a 14-day medication cycle. (iv) A third phase, following the second phase, comprising one or more drug administration cycles. The regimen includes administering cebostamab and erranatamab to the subject, Cebostamad is used in the aforementioned subjects. The drug is administered at an increasing dose of 3.6 mg on the 9th, 10th, or 11th day of the prephase of C1, at a target dose of 60 mg on the 2nd, 3rd, or 4th day of the first phase of C1, and at a target dose of 60 mg on the 1st day of the second phase of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25. Elranatamab is used in the aforementioned subjects, The drug is administered at a first escalating dose of 12 mg on day 1 of the prephase C1, at a second escalating dose of 32 mg on day 3, day 4, or day 5 of the prephase C1, and at a target dose of 76 mg on day 8 of the prephase C1. The first phase C1 was administered at a target dose of 76 mg on day 1. A method comprising administering a target dose of 76 mg on day 1 of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 in the second phase, and administering a target dose of 76 mg on day 1 of each of one or more drug administration cycles in the third phase.

168. A method for treating an object having R / R MM, (i) A prephase including a medication cycle of approximately 22 days (C1), (ii) A first phase following the prephase, comprising a first medication cycle (C1), wherein C1 is a 14-day medication cycle, (iii) A second phase following the first phase, comprising a first medication cycle (C1), a second medication cycle (C2), a third medication cycle (C3), a fourth medication cycle (C4), a fifth medication cycle (C5), a sixth medication cycle (C6), a seventh medication cycle (C7), an eighth medication cycle (C8), a ninth medication cycle (C9), a tenth medication cycle (C10), an eleventh medication cycle (C11), a twelfth medication cycle (C12), a thirteenth medication cycle (C13), and a fourteenth medication cycle. The second phase includes (C14), the 15th medication cycle (C15), the 16th medication cycle (C16), the 17th medication cycle (C17), the 18th medication cycle (C18), the 19th medication cycle (C19), the 20th medication cycle (C20), the 21st medication cycle (C21), the 22nd medication cycle (C22), the 23rd medication cycle (C23), the 24th medication cycle (C24), and the 25th medication cycle (C25), wherein each medication cycle in the second phase is a 14-day medication cycle. (iv) A third phase following the second phase, comprising one or more medication cycles The regimen includes administering cebostamab and erranatamab to the subjects. fruit, Cebostamad is used in the aforementioned subjects. The drug is administered in an gradually increasing dose of 3.6 mg on the 16th, 17th, or 18th day of the prephase C1. The drug is administered at a target dose of 60 mg on the second, third, or fourth day of the first phase C1. In the second phase, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24 and C25 are administered at a target dose of 60 mg on day 1. Elranatamab is used in the aforementioned subjects, The drug is administered at a first escalating dose of 12 mg on day 1 of the prephase C1, at a second escalating dose of 32 mg on day 3, day 4, or day 5 of the prephase C1, and at a target dose of 76 mg on day 8 and day 15 of the prephase C1. The first phase is administered at a target dose of 76 mg on day 1 of C1, A method comprising administering a target dose of 76 mg on day 1 of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 in the second phase, and administering a target dose of 76 mg on day 1 of each of one or more drug administration cycles in the third phase.

169. A method for treating an object having R / R MM, (i) A first phase comprising a first medication cycle (C1), wherein C1 is a 14-day medication cycle, (ii) A second phase following the first phase, comprising a first medication cycle (C1), a second medication cycle (C2), a third medication cycle (C3), a fourth medication cycle (C4), a fifth medication cycle (C5), a sixth medication cycle (C6), a seventh medication cycle (C7), an eighth medication cycle (C8), a ninth medication cycle (C9), a tenth medication cycle (C10), an eleventh medication cycle (C11), a twelfth medication cycle (C12), a thirteenth medication cycle (C13), a fourteenth medication cycle ( A second phase comprising C14), a 15th medication cycle (C15), a 16th medication cycle (C16), a 17th medication cycle (C17), a 18th medication cycle (C18), a 19th medication cycle (C19), a 20th medication cycle (C20), a 21st medication cycle (C21), a 22nd medication cycle (C22), a 23rd medication cycle (C23), a 24th medication cycle (C24), and a 25th medication cycle (C25), wherein each medication cycle of the second phase is a 14-day medication cycle, (iii) A third phase following the second phase, comprising one or more medication cycles The regimen includes administering cebostamab and erranatamab to the subject, Cebostamad is used in the aforementioned subjects. The drug is administered at a target dose of 60 mg, 105 mg, or 132 mg on the second, third, or fourth day of the first phase C1. In the second phase, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 are administered at a target dose of 60 mg, 105 mg, or 132 mg on day 1. Elranatamab is used in the aforementioned subjects, The first phase C1 is administered at a target dose of 76 mg on days 1 and 8. A method comprising administering a target dose of 76 mg on days 1 and 8 of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24 and C25 in the second phase, and administering a target dose of 76 mg on days 1 and 8 of each of the one or more drug administration cycles in the third phase.

170. A method for treating an object having R / R MM, (i) A first phase comprising a first medication cycle (C1), wherein C1 is a 14-day medication cycle, (ii) A second phase following the first phase, comprising a first medication cycle (C1), a second medication cycle (C2), a third medication cycle (C3), a fourth medication cycle (C4), a fifth medication cycle (C5), a sixth medication cycle (C6), a seventh medication cycle (C7), an eighth medication cycle (C8), a ninth medication cycle (C9), a tenth medication cycle (C10), an eleventh medication cycle (C11), a twelfth medication cycle (C12), a thirteenth medication cycle (C13), a fourteenth medication cycle ( A second phase comprising C14), a 15th medication cycle (C15), a 16th medication cycle (C16), a 17th medication cycle (C17), a 18th medication cycle (C18), a 19th medication cycle (C19), a 20th medication cycle (C20), a 21st medication cycle (C21), a 22nd medication cycle (C22), a 23rd medication cycle (C23), a 24th medication cycle (C24), and a 25th medication cycle (C25), wherein each medication cycle of the second phase is a 14-day medication cycle, (iii) A third phase following the second phase, comprising one or more medication cycles The regimen includes administering cebostamab and erranatamab to the subject, Cebostamad is used in the aforementioned subjects. In the first phase, C1 is administered at a target dose of 60 mg, 105 mg, or 132 mg on the second, third, or fourth day, and in the second phase, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 is administered at a target dose of 60 mg, 105 mg, or 132 mg on the first day. Elranatamab is used in the aforementioned subjects, The first phase is administered at a target dose of 76 mg on days 1 and 8 of C1, A method comprising administering a target dose of 76 mg on the 8th day of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, and C25 of the second phase, and administering a target dose of 76 mg on the 1st day of each of one or more drug administration cycles of the third phase.

171. The method according to claim 169 or 170, further comprising a prephase prior to the first phase.

172. The aforementioned prephase includes a medication cycle (C1) of approximately 15 days. Sebostamab is administered to the subject at an increasing dose of 3.6 mg on day 9, 10, or 11 of the prephase C1. The method according to claim 171, wherein erranatamab is administered to the subject in a first escalating dose of 12 mg on day 1 of the prephase C1, in a second escalating dose of 32 mg on day 3, day 4, or day 5 of the prephase C1, and in a target dose of 76 mg on day 8 of the prephase C1.

173. The aforementioned prephase includes a medication cycle (C1) of approximately 22 days. The method according to claim 171, wherein cebostamab is administered to the subject in an escalating dose of 3.6 mg on day 16, day 17, or day 18 of the prephase C1, and erranatamab is administered to the subject in a first escalating dose of 12 mg on day 1 of the prephase C1, a second escalating dose of 32 mg on day 3, day 4, or day 5 of the prephase C1, and a target dose of 76 mg on days 8 and 15 of the prephase C1.

174. The method according to any one of claims 1 to 161 and 163 to 178, wherein the subject is a human subject.

175. The method according to claim 4 or 5, wherein each drug administration cycle (C) of the second phase is a 28-day drug administration cycle.

176. The method according to claim 175, wherein the drug administration cycle of the first phase is a 14-day drug administration cycle.

177. The method according to claim 175 or 176, wherein the first phase comprises drug delivery cycles C1 to C26, and the second phase comprises drug delivery cycle C27 and subsequent cycles.

178. The method according to claim 177, wherein the second bispecific antibody is administered to the subject at a target dose of 76 mg on the first day of each dosing cycle of the second phase.

179. The method according to any one of claims 1 to 3, wherein each administration cycle from approximately one year after the initial administration of the second bispecific antibody administered to the subject is 28 days long.

180. The method according to any one of claims 1 to 3, wherein each administration cycle of the second bispecific antibody administered to the subject from the 27th administration cycle onward is 28 days long.

181. The method according to claim 180, wherein each medication cycle C1 to C26 is a 14-day medication cycle.

182. The method according to claim 6, wherein each drug administration cycle in the first phase and the second phase is a 14-day drug administration cycle, and each drug administration cycle in the third phase is a 28-day drug administration cycle.

183. The method according to claim 182, wherein the second bispecific antibody is administered to the subject on day 1 and day 8 of each drug delivery cycle of the first phase.

184. The method according to claim 182, wherein the second bispecific antibody is administered to the subject on the first day of each drug cycle of the second phase.

185. The method according to claim 182, wherein the second bispecific antibody is administered to the subject on the first day of each drug cycle of the third phase.

186. The method according to claim 182, wherein the second bispecific antibody is administered to the subject on day 1 and day 8 of each drug cycle in the first phase, the second bispecific antibody is administered to the subject on day 1 of each drug cycle in the second phase, and the second bispecific antibody is administered to the subject on day 1 of each drug cycle in the third phase.

187. The method according to any one of claims 182 to 186, wherein each second bispecific antibody is administered to the subject at a target dose of 76 mg.

188. The method according to any one of claims 182 to 187, wherein the third phase is initiated approximately one year after the initial administration of a target dose of the second bispecific antibody administered to the subject.

189. The method according to any one of claims 182 to 187, wherein the 27th medication cycle (C27) is the first medication cycle of the third phase.

190. The method according to claim 8 or 14, wherein the prephase comprises administering the second bispecific antibody to the subject on (i) day 1, (ii) day 4, and (iii) day 8.

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