Administration for treatment with anti-FCRH5 / anti-CD3 bispecific antibody

Abstract

The present invention provides methods of administering an anti-fragment crystalline receptor-like 5 (FcRH5) / anti-cluster of differentiation 3 (CD3) bispecific antibody for the treatment of cancer, such as multiple myeloma.

Description

[Technical field]

[0001] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format, the entire contents of which are incorporated herein by reference. The ASCII copy created on April 1, 2022 is titled "50474-277WO1_Sequence_Listing_4_1_22_ST25" and is 33,561 bytes in size.

[0002] The present invention relates to the treatment of cancer, such as B cell proliferative disorders. More specifically, the present invention relates to the treatment of human patients with multiple myeloma (MM) using an anti-fragment crystalline receptor-like 5 (FcRH5) / anti-cluster of differentiation 3 (CD3) bispecific antibody. [Background technology]

[0003] Cancer remains one of the greatest threats to human health. In the United States, cancer affects more than 1.7 million new cases each year and is the second leading cause of death after heart disease, accounting for approximately 1 in 4 deaths.

[0004] Hematological cancers, in particular, are the second leading cause of cancer-related deaths. Hematological cancers include multiple myeloma (MM), a neoplasm characterized by the proliferation and accumulation of malignant plasma cells. Worldwide, approximately 160,000 people are diagnosed with MM each year. MM remains incurable despite advances in treatment, with an estimated median survival of 8-10 years for standard-risk myeloma and 2-3 years for high-risk disease, despite receiving autologous stem cell transplantation. Despite significant improvements in patient survival over the past two decades, only 10-15% of patients achieve or exceed expected survival rates compared to the matched general population. Increased survival rates have been achieved with the introduction of proteasome inhibitors, immunomodulatory drugs (IMiDs), and monoclonal antibodies. Nevertheless, outcomes for MM patients are very poor, with survival times of less than one year for most (if not all) patients who eventually relapse, become refractory, or are no longer able to receive proteasome inhibitors or IMiDs.

[0005] Thus, relapsed or refractory (R / R) MM in particular still constitutes a significant unmet medical need, and new therapeutic agents and treatments are required. Summary of the Invention

[0006] Provided herein, inter alia, are methods of treating cancer (eg, B cell proliferative disorders, eg, MM), as well as related compositions for use(s) and articles of manufacture.

[0007] In one aspect, the invention features a method of treating a subject having multiple myeloma (MM), the method comprising administering to the subject a bispecific antibody that binds Fc receptor homolog 5 (FcRH5) and cluster of differentiation 3 (CD3) in a dosing regimen that includes: (i) a first phase comprising one or more dosing cycles, the first phase comprising administering the bispecific antibody to the subject every week (QW); (ii) a second phase comprising one or more dosing cycles, the second phase comprising administering the bispecific antibody to the subject every two weeks (Q2W); and (iii) a third phase comprising one or more dosing cycles, the third phase comprising administering the bispecific antibody to the subject every four weeks (Q4W).

[0008] In another aspect, the invention features a bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, the treatment comprising administration of the bispecific antibody to a subject in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, the first phase comprising administering the bispecific antibody to the subject every week (QW); (ii) a second phase comprising one or more dosing cycles, the second phase comprising administering the bispecific antibody to the subject every two weeks (Q2W); and (iii) a third phase comprising one or more dosing cycles, the third phase comprising administering the bispecific antibody to the subject every four weeks (Q4W).

[0009] In some embodiments, each dosing cycle is a 28 day dosing cycle.

[0010] In some embodiments, the first phase comprises at least two administration cycles.

[0011] In some embodiments, the first phase comprises a first administration cycle (C1) and a second administration cycle (C2).

[0012] In some embodiments, the first phase comprises administration of the bispecific antibody to the subject on days 1, 8, 15, and 22 of C1.

[0013] In some embodiments, the first phase comprises administration of the bispecific antibody to the subject on days 1, 8, 15, and 22 of C2.

[0014] In some embodiments, a target dose of the bispecific antibody is administered to the subject for each administration during the first phase.

[0015] In some embodiments, the first phase comprises administration of a first escalating dose of the bispecific antibody to the subject.

[0016] In some embodiments, the first escalation dose is administered to the subject on day 1 of C1.

[0017] In some embodiments, target doses are administered to the subject on days 8, 15, and 22 of C1.

[0018] In some embodiments, target doses are further administered to the subject on days 1, 8, 15, and 22 of C2.

[0019] In some embodiments, the first escalation dose is about 4% of the target dose.

[0020] In some embodiments, the first phase comprises administration of a first escalating dose and a second escalating dose of the bispecific antibody to the subject.

[0021] In some embodiments, a first escalation dose is administered to the subject on day 1 of C1, and a second escalation dose is administered to the subject on day 8 of C1.

[0022] In some embodiments, the target dose is administered to the subject on days 15 and 22 of C1.

[0023] In some embodiments, target doses are further administered to the subject on days 1, 8, 15, and 22 of C2.

[0024] In some embodiments, (i) the first escalation dose is 0.33% of the target dose, and (ii) the second escalation dose is about 4% of the target dose.

[0025] In some embodiments, the first escalation dose is 3.6 mg.

[0026] In some embodiments, the first escalation dose is 0.3 mg and the second escalation dose is 3.6 mg.

[0027] In some embodiments, the second phase comprises at least two administration cycles, at least three administration cycles, or at least four administration cycles.

[0028] In some embodiments, the second phase includes a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), and a fourth administration cycle (C4).

[0029] In some embodiments, the second phase comprises administration of the bispecific antibody to the subject on days 1 and 15 of C1, C2, C3 and / or C4.

[0030] In some embodiments, a target dose of the bispecific antibody is administered to the subject for each administration during the second phase.

[0031] In some embodiments, the third phase comprises at least two administration cycles, at least three administration cycles, at least four administration cycles, at least five administration cycles, at least six administration cycles, or at least seven administration cycles.

[0032] In some embodiments, the third phase includes a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), a sixth administration cycle (C6), and a seventh administration cycle (C7).

[0033] In some embodiments, the third phase comprises administering the bispecific antibody to the subject on day 1 of C1, C2, C3, C4, C5, C6, and / or C7.

[0034] In some embodiments, a target dose of the bispecific antibody is administered to the subject for each administration during the third phase.

[0035] In some embodiments, the target dose is 90 mg.

[0036] In some aspects, the bispecific antibody is administered to a subject as a monotherapy.

[0037] In some aspects, the bispecific antibody is administered intravenously to a subject.

[0038] In another aspect, the invention features a method of treating a subject with MM, the method comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 and an immunomodulatory drug (IMiD) in a dosing regimen that includes: (i) a first phase comprising one or more dosing cycles, the first phase comprising administering the bispecific antibody to the subject every two weeks (Q2W); and (ii) a second phase comprising one or more dosing cycles, the second phase comprising administering the bispecific antibody to the subject every four weeks (Q4W).

[0039] In another aspect, the invention features a bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, the treatment comprising administration of the bispecific antibody and an IMiD to a subject in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, the first phase comprising administering the bispecific antibody to the subject every two weeks (Q2W); and (ii) a second phase comprising one or more dosing cycles, the second phase comprising administering the bispecific antibody to the subject every four weeks (Q4W).

[0040] In some embodiments, each dosing cycle of the first phase and the second phase is a 28 day dosing cycle.

[0041] In some embodiments, the dosing regimen further comprises a pre-phase comprising one or more dosing cycles prior to the first phase, the pre-phase comprising administering the bispecific antibody to the subject weekly (QW).

[0042] In some embodiments, each dosing cycle of the prephase is a 21 day dosing cycle.

[0043] In some embodiments, the pre-phase comprises one administration cycle (C1).

[0044] In some embodiments, the pre-phase comprises administration of the bispecific antibody to the subject on days 1, 8, and 15 of C1.

[0045] In some embodiments, a target dose of the bispecific antibody is administered to the subject for each administration in the prephase.

[0046] In some embodiments, the pre-phase comprises administration of a first escalating dose of the bispecific antibody to the subject.

[0047] In some embodiments, the first escalation dose is administered to the subject on day 1 of C1.

[0048] In some embodiments, the target dose is administered to the subject on days 8 and 15 of C1.

[0049] In some embodiments, the first escalation dose is about 2.73% of the target dose.

[0050] In some embodiments, the pre-phase comprises administration of a first escalating dose and a second escalating dose of the bispecific antibody to the subject.

[0051] In some embodiments, a first escalation dose is administered to the subject on day 1 of C1, and a second escalation dose is administered to the subject on day 8 of C1.

[0052] In some embodiments, the target dose is administered to the subject on day 15 of C1.

[0053] In some embodiments, (i) the amount of the first escalation dose is 0.23% of the target dose, and (ii) the amount of the second escalation dose is about 2.73% of the target dose.

[0054] In some embodiments, the first escalation dose is 3.6 mg.

[0055] In some embodiments, the first escalation dose is 0.3 mg and the second escalation dose is 3.6 mg.

[0056] In some embodiments, the first phase comprises at least two administration cycles, at least three administration cycles, at least four administration cycles, at least five administration cycles, or at least six administration cycles.

[0057] In some embodiments, the first phase includes a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), and a sixth administration cycle (C6).

[0058] In some embodiments, the first phase comprises administration of the bispecific antibody to the subject on days 1 and 15 of C1, C2, C3, C4, C5, and / or C6.

[0059] In some embodiments, a target dose of the bispecific antibody is administered to the subject for each administration during the first phase.

[0060] In some embodiments, the second phase comprises at least two administration cycles, at least three administration cycles, at least four administration cycles, at least five administration cycles, at least six administration cycles, or at least seven administration cycles.

[0061] In some embodiments, the second phase includes a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), a sixth administration cycle (C6), and a seventh administration cycle (C7).

[0062] In some embodiments, the second phase comprises administration of the bispecific antibody on days C1, C2, C3, C4, C5, C6, and / or C7.

[0063] In some embodiments, a target dose of the bispecific antibody is administered to the subject for each administration during the second phase.

[0064] In some embodiments, the target dose is 132 mg.

[0065] In some aspects, the bispecific antibody is administered intravenously to a subject.

[0066] In some embodiments, an IMiD is administered to the subject on days 1-21 of each administration cycle in the first phase and / or the second phase.

[0067] In some embodiments, the IMiD is pomalidomide.

[0068] In some embodiments, pomalidomide is administered to the subject in a dosage of about 4 mg.

[0069] In some aspects, pomalidomide is administered orally to the subject.

[0070] In some embodiments, the dosing regimen further comprises administration of a corticosteroid to the subject during the pre-phase, the first phase, and / or the second phase.

[0071] In some embodiments, the corticosteroid is administered to the subject QW during the prephase, first phase, and / or second phase.

[0072] In some embodiments, the corticosteroid is administered to the subject intravenously or orally.

[0073] In some embodiments, a corticosteroid is administered to the subject during the prephase on days 1, 8, and 15 of C1.

[0074] In some embodiments, the corticosteroid is administered intravenously to the subject during the prephase on days 1, 8, and 15 of C1.

[0075] In some embodiments, a corticosteroid is administered to the subject during the first phase on days 1, 8, 15, and 22 of C1, C2, C3, and / or C4.

[0076] In some embodiments, a corticosteroid is administered to the subject (i) intravenously on days 1 and 15 of C1, C2, C3 and / or C4 during the first phase, and (ii) orally on days 8 and 22 of C1, C2, C3 and / or C4 during the first phase.

[0077] In some embodiments, a corticosteroid is further administered to the subject during the first phase on days 1, 8, 15 and / or 22 of C5 and / or C6.

[0078] In some embodiments, a corticosteroid is administered to the subject (i) intravenously on days 1 and / or 15 of C5 and / or C6 during the first phase, and (ii) orally on days 8 and / or 22 of C5 and / or C6 during the first phase.

[0079] In some embodiments, a corticosteroid is further administered to the subject during the second phase on days 1, 8, 15 and / or 22 of C1, C2, C3, C4, C5, C6 and / or C7.

[0080] In some embodiments, a corticosteroid is administered to the subject (i) intravenously on day 1 of C1, C2, C3, C4, C5, C6, and / or C7 during the second phase; and (ii) orally on days 8, 15, and / or 22 of C1, C2, C3, C4, C5, C6, and / or C7 during the second phase.

[0081] In some embodiments, the corticosteroid is administered intravenously to the subject prior to administration of the bispecific antibody.

[0082] In some embodiments, the corticosteroid is administered intravenously to the subject about 1 hour prior to administration of the bispecific antibody.

[0083] In some embodiments, the corticosteroid is dexamethasone or methylprednisolone.

[0084] In some embodiments, the corticosteroid is dexamethasone.

[0085] In some embodiments, dexamethasone is administered to the subject at a dosage of about 20 mg.

[0086] In some embodiments, methylprednisolone is administered to the subject at a dosage of about 80 mg.

[0087] In another aspect, the invention features a method of treating a subject with MM, the method comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 and an anti-cluster of differentiation 38 (CD38) antibody in a dosing regimen that includes: (i) a first phase comprising one or more dosing cycles, the first phase comprising administering the bispecific antibody to the subject every three weeks (Q3W); and (ii) a second phase comprising one or more dosing cycles, the second phase comprising administering the bispecific antibody to the subject every four weeks (Q4W).

[0088] In another aspect, the invention features a bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, the treatment comprising administering to the subject the bispecific antibody and an anti-CD38 antibody in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, the first phase comprising administering the bispecific antibody to the subject every three weeks (Q3W); and (ii) a second phase comprising one or more dosing cycles, the second phase comprising administering the bispecific antibody to the subject every four weeks (Q4W).

[0089] In some embodiments, the dosing regimen further comprises a run-in phase comprising one or more dosing cycles prior to the first phase, wherein the run-in phase comprises administering the bispecific antibody to the subject weekly (QW).

[0090] In some embodiments, each dosing cycle of the run-in phase is a 21 day dosing cycle.

[0091] In some embodiments, each dosing cycle of the first phase is a 21 day dosing cycle.

[0092] In some embodiments, each dosing cycle of the second phase is a 28 day dosing cycle.

[0093] In some embodiments, the run-in phase comprises one administration cycle (C1).

[0094] In some embodiments, the run-in phase comprises administering the bispecific antibody to the subject on: (i) days 2, 9, and 16 of C1; or (ii) days 3, 9, and 16 of C1.

[0095] In some embodiments, if the subject has an adverse reaction to the anti-CD38 antibody, the bispecific antibody is administered to the subject on days 3, 9, and 16 of C1.

[0096] In some embodiments, a target dose of the bispecific antibody is administered to the subject for each administration during the run-in phase.

[0097] In some embodiments, the run-in phase comprises administration of a first escalating dose of the bispecific antibody to a subject.

[0098] In some embodiments, the first escalation dose is administered to the subject on day 2 of C1 or day 3 of C1.

[0099] In some embodiments, the target dose is administered to the subject on days 9 and 16 of C1.

[0100] In some embodiments, the first escalation dose is about 2.25% of the target dose.

[0101] In some embodiments, the run-in phase comprises administration of a first escalating dose and a second escalating dose of the bispecific antibody to the subject.

[0102] In some embodiments, (i) a first escalation dose is administered to the subject on day 2 of C1 or day 3 of C1, and (ii) a second escalation dose is administered to the subject on day 9 of C1.

[0103] In some embodiments, the target dose is administered to the subject on day 16 of C1.

[0104] In some embodiments, (i) the first escalation dose is about 0.19% of the target dose, and (ii) the second escalation dose is about 2.25% of the target dose.

[0105] In some embodiments, the first escalation dose is 3.6 mg.

[0106] In some embodiments, the first escalation dose is 0.3 mg and the second escalation dose is 3.6 mg.

[0107] In some embodiments, the first phase comprises a first sub-phase and a second sub-phase.

[0108] In some embodiments, the first subphase of the first phase comprises at least two administration cycles.

[0109] In some embodiments, the first sub-phase of the first phase comprises a first administration cycle (C1) and a second administration cycle (C2).

[0110] In some embodiments, the first subphase of the first phase comprises administration of the bispecific antibody on days C1 and C2.

[0111] In some embodiments, a target dose of the bispecific antibody is administered to the subject for each administration during the first subphase of the first phase.

[0112] In some embodiments, the second sub-phase comprises at least two administration cycles, at least three administration cycles, at least four administration cycles, or at least five administration cycles.

[0113] In some embodiments, the second sub-phase of the first phase includes a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), and a fifth administration cycle (C5).

[0114] In some embodiments, the second subphase of the first phase comprises administration of the bispecific antibody on days C1, C2, C3, C4, and / or C5.

[0115] In some embodiments, a target dose of the bispecific antibody is administered to the subject for each administration during the second sub-phase of the first phase.

[0116] In some embodiments, the second phase comprises at least two administration cycles, at least three administration cycles, at least four administration cycles, or at least five administration cycles.

[0117] In some embodiments, the second phase includes a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), and a fifth administration cycle (C5).

[0118] In some embodiments, the second phase comprises administration of the bispecific antibody on days C1, C2, C3, C4, and / or C5.

[0119] In some embodiments, a target dose of the bispecific antibody is administered to the subject for each administration during the second phase.

[0120] In some embodiments, the target dose is 160 mg.

[0121] In some aspects, the bispecific antibody is administered intravenously to a subject.

[0122] In some embodiments, the anti-CD38 antibody is administered to the subject during a run-in phase.

[0123] In some embodiments, the run-in phase comprises a first administration cycle (C1), and an anti-CD38 antibody is administered to the subject during the run-in phase on days 1, 8, and 15 of C1.

[0124] In some embodiments, the anti-CD38 antibody is administered to the subject during the first subphase of the first phase.

[0125] In some embodiments, the anti-CD38 antibody is administered to the subject during the first subphase of the first phase on days 1, 8, and 15 of C1 and / or C2.

[0126] In some embodiments, the anti-CD38 antibody is administered to the subject during the second subphase of the first phase.

[0127] In some embodiments, the anti-CD38 antibody is administered to the subject during the second subphase of the first phase on day 1 of C1, C2, C3, C4, and / or C5.

[0128] In some embodiments, an anti-CD38 antibody is administered to the subject during the second phase.

[0129] In some embodiments, the anti-CD38 antibody is administered to the subject during the second phase on day 1 of C1, C2, C3, C4, and / or C5.

[0130] In some embodiments, the anti-CD38 antibody is administered subcutaneously (SC) to the subject.

[0131] In some embodiments, the anti-CD38 antibody is daratumumab or isatuximab.

[0132] In some embodiments, the anti-CD38 antibody is daratumumab.

[0133] In some embodiments, daratumumab is administered to the subject at a dosage of about 1800 mg.

[0134] In some embodiments, the dosing regimen further comprises administration of a corticosteroid to the subject during any dosing cycle within the run-in phase, the first phase, and / or the second phase.

[0135] In some embodiments, the corticosteroid is administered QW to the subject during the run-in phase.

[0136] In some embodiments, the run-in phase includes a first administration cycle (C1), and a corticosteroid is administered to the subject during the run-in phase on days 1, 8, and 15 of C1.

[0137] In some embodiments, a corticosteroid is further administered to the subject during the run-in phase on days 2, 9, and 16 of C1.

[0138] In some embodiments, the corticosteroid is administered QW to the subject during the first subphase of the first phase.

[0139] In some embodiments, a corticosteroid is administered to the subject during the first subphase of the first phase on days 1, 8, and 15 of C1 and C2.

[0140] In some embodiments, the corticosteroid is administered Q3W to the subject during the second sub-phase of the first phase.

[0141] In some embodiments, the corticosteroid is administered to the subject during the second subphase of the first phase on days C1, C2, C3, C4, and C5.

[0142] In some embodiments, the corticosteroid is administered Q4W to the subject during the second phase.

[0143] In some embodiments, a corticosteroid is administered to the subject during the second phase on days C1, C2, C3, C4, and / or C5.

[0144] In some embodiments, the corticosteroid is administered to the subject intravenously and / or orally.

[0145] In some embodiments, the corticosteroid is administered intravenously or orally to the subject: (i) on days 1, 8, and 15 of C1 during the run-in phase; (ii) on days 2, 9, and 16 of C1 during the run-in phase; (iii) on day 1 of C1 and C2 during the first sub-phase of the first phase; (iv) on day 1 of C1, C2, C3, C4, and C5 during the second sub-phase of the first phase; and (v) on days 8 and 15 of C1 and C2 during the first sub-phase of the first phase.

[0146] In some embodiments, a corticosteroid is further administered intravenously to the subject during the second phase on days C1, C2, C3, C4, and / or C5.

[0147] In some embodiments, the corticosteroid is administered intravenously to the subject as a premedication for the bispecific antibody.

[0148] In some embodiments, the corticosteroid is administered to the subject about 1 hour prior to administration of the bispecific antibody: (i) on days 2 or 3 of C1 during the run-in phase; (ii) on days 9 and 16 of C1 during the run-in phase; and (iii) on day 1 of C2 during the first sub-phase of the first phase.

[0149] In some embodiments, the corticosteroid is dexamethasone or methylprednisolone.

[0150] In some embodiments, the corticosteroid is dexamethasone.

[0151] In some embodiments, dexamethasone is administered to the subject at a dose of about 20 mg.

[0152] In some embodiments, methylprednisolone is administered to the subject at a dose of about 80 mg.

[0153] In some embodiments, the bispecific antibody comprises an anti-FcRH5 arm comprising a first binding domain comprising the following six hypervariable regions (HVRs): (i) an HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1); (ii) an HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (iii) an HVR-H3 comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO: 3); (iv) an HVR-L1 comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (v) an HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (vi) an HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6).

[0154] In some embodiments, the bispecific antibody comprises: (a) a heavy chain variable (VH) domain comprising 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 comprising 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 comprising the VH domain described in (a) and the VL domain described in (b).

[0155] In some embodiments, the first binding domain comprises 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.

[0156] In some embodiments, the bispecific antibody comprises an anti-CD3 arm having a second binding domain comprising the following six HVRs: (i) HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (ii) HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (iii) HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11); (iv) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (v) HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (vi) HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

[0157] In some embodiments, the bispecific antibody comprises an anti-CD3 arm comprising: (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising 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 comprising the VH domain described in (a) and the VL domain described in (b).

[0158] In some embodiments, the second binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO:15 and a VL domain comprising the amino acid sequence of SEQ ID NO:16.

[0159] In some embodiments, the bispecific antibody 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 (i) H1 comprises the amino acid sequence of SEQ ID NO: 35, (ii) L1 comprises the amino acid sequence of SEQ ID NO: 36, (iii) H2 comprises the amino acid sequence of SEQ ID NO: 37, and (iv) L2 comprises the amino acid sequence of SEQ ID NO: 38.

[0160] In some aspects, the bispecific antibody comprises an aglycosylation site mutation.

[0161] In some aspects, the aglycosylation site mutation reduces the effector function of the bispecific antibody.

[0162] In some embodiments, the aglycosylation site mutation is a substitution mutation.

[0163] In some embodiments, the bispecific antibody comprises substitution mutations in the Fc region that reduce effector function.

[0164] In some embodiments, the bispecific antibody is a monoclonal antibody.

[0165] In some embodiments, the bispecific antibody is a humanized antibody.

[0166] In some embodiments, the bispecific antibody is a chimeric antibody.

[0167] In some embodiments, the bispecific antibody is an antibody fragment that binds FcRH5 and CD3.

[0168] In some embodiments, antibody fragments include Fab, Fab'-SH, Fv, scFv, and (Fab') 2 The fragment is selected from the group consisting of:

[0169] In some embodiments, the bispecific antibody is a full-length antibody.

[0170] In some embodiments, the bispecific antibody is an IgG antibody.

[0171] In some embodiments, the IgG antibody is 1 It is an antibody.

[0172] In some embodiments, the bispecific antibody comprises one or more heavy chain constant domains, the one or more heavy chain constant domains comprising a first CH1 (CH1 1 ) domain, the first CH2 (CH2 1 ) domain, the first CH3 (CH31 ) domain, the second CH1 (CH1 2 ) domain, the second CH2 (CH2 2 ) domain, and the second CH3 (CH3 2 ) domain.

[0173] In some embodiments, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

[0174] In some embodiments, CH3 1 Domain and CH3 2 Each domain contains a protuberance or a cavity, and a CH3 1 The domain projection or cavity is CH3 2 They can be located in cavities or protrusions of the domain, respectively.

[0175] In some embodiments, CH3 1 Domain and CH3 2 The domains meet at the interface between the projections and the cavities.

[0176] In some embodiments, CH2 1 Domain and CH2 2 Each domain contains a protuberance or a cavity, and a CH2 1 The protrusion or cavity of the domain is CH2 2 They can be located in cavities or protrusions of the domain, respectively.

[0177] In other embodiments, CH2 1 Domain and CH2 2 The domains meet at the interface between the projections and the cavities.

[0178] In some embodiments, the anti-FcRH5 arm comprises a protrusion and the anti-CD3 arm comprises a cavity.

[0179] In some embodiments, the CH3 domain of the anti-FcRH5 arm comprises a protrusion comprising a T366W amino acid substitution mutation (EU numbering) and the CH3 domain of the anti-CD3 arm comprises a cavity comprising T366S, L368A, and Y407V amino acid substitution mutations (EU numbering).

[0180] In some embodiments, the bispecific antibody is cebostamab.

[0181] In some embodiments, the bispecific antibody is administered to a subject simultaneously with one or more additional therapeutic agents.

[0182] In some embodiments, the bispecific antibody is administered to a subject prior to the administration of one or more additional therapeutic agents.

[0183] In some embodiments, the bispecific antibody is administered to a subject following administration of one or more additional therapeutic agents.

[0184] In some embodiments, the one or more additional therapeutic agents comprises an effective amount of tocilizumab.

[0185] In some embodiments, tocilizumab is administered to the subject by intravenous infusion.

[0186] In some embodiments, (i) the subject weighs 30 kg or more and tocilizumab is administered to the subject at a dose of 8 mg / kg, (ii) the subject weighs less than 30 kg and tocilizumab is administered to the subject at a dose of 12 mg / kg, or (iii) the final dose administered does not exceed 800 mg.

[0187] In some embodiments, tocilizumab is administered to the subject 2 hours prior to administration of the bispecific antibody.

[0188] In some embodiments, the one or more additional therapeutic agents comprises an effective amount of a B-cell maturation antigen (BCMA)-directed therapy.

[0189] In some embodiments, the subject has a cytokine release syndrome (CRS) event and the method further comprises treating a symptom of the CRS event while pending treatment with the bispecific antibody.

[0190] In some embodiments, the methods further include administering to the subject an effective amount of tocilizumab to treat the CRS event.

[0191] In some embodiments, tocilizumab is administered intravenously to a subject as a single dose of about 8 mg / kg.

[0192] In some embodiments, the CRS event does not resolve or worsens within 24 hours of treating a symptom of the CRS event, and the method further comprises administering one or more additional doses of tocilizumab to the subject to manage the CRS event.

[0193] In some embodiments, the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 8 mg / kg.

[0194] In some embodiments, the one or more additional therapeutic agents comprises an effective amount of acetaminophen or paracetamol.

[0195] In some embodiments, acetaminophen or paracetamol is administered to a subject at a dose of about 500 mg to about 1000 mg.

[0196] In some embodiments, the acetaminophen or paracetamol is administered orally to the subject.

[0197] In some embodiments, the one or more additional therapeutic agents comprises an effective amount of diphenhydramine.

[0198] In some embodiments, diphenhydramine is administered to a subject at a dose of about 25 mg to about 50 mg.

[0199] In some embodiments, the diphenhydramine is administered orally to the subject.

[0200] In some embodiments, the MM is relapsed or refractory (R / R) MM.

[0201] In some embodiments, the subject has received at least three prior lines of treatment for MM.

[0202] In some embodiments, the subject has received at least four prior lines of treatment for MM.

[0203] In some embodiments, the subject has been exposed to a prior treatment including a proteasome inhibitor, an IMiD and / or an anti-CD38 therapeutic.

[0204] In some embodiments, the proteasome inhibitor is bortezomib, carfilzomib, or ixazomib.

[0205] In some embodiments, the IMiD is thalidomide, lenalidomide or pomalidomide.

[0206] In some embodiments, the anti-CD38 therapeutic is daratumumab, MOR202, or isatuximab.

[0207] In some embodiments, the anti-CD38 therapeutic is daratumumab.

[0208] In some embodiments, the subject has been exposed to prior treatment including autologous stem cell transplant (ASCT) or CAR-T cell therapy, and the CAR-T cell therapy was last administered at least 12 weeks prior to initiation of the method.

[0209] In another aspect, the invention features a method of treating a subject with MM, comprising administering to the subject cevostamab monotherapy in (i) a first phase including a first administration cycle (C1) and a second administration cycle (C2); (ii) a second phase including a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), and a fourth administration cycle (C4); and (iii) a second phase including a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), and a fourth administration cycle (C4). and a third phase including a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6) and a seventh dosing cycle (C7), wherein each dosing cycle of the first phase, second phase and third phase is a 28 day dosing cycle, and cevostamab is administered to the subject A) (i) at an escalation dose during the first phase on day 1 of C1, and (ii) at a target dose during the first phase on days 8, 15 of C1. (iii) at the target dose during the first phase, on days 1, 8, 15, and 22 of C2; (iv) at the target dose during the second phase, on days 1 and 15 of C1, C2, C3, and C4; and (v) at the target dose during the third phase, on day 1 of C1, C2, C3, C4, C5, C6, and C7; or B) (i) at the first escalation dose during the first phase, on day 1 of C1, and (ii) a target dose during the first phase is administered on days 15 and 22 of C1; (iii) a target dose during the first phase is administered on days 1, 8, 15, and 22 of C2; (iv) a target dose during the second phase is administered on days 1 and 15 of C1, C2, C3, and C4; and (v) a target dose during the third phase is administered on days 1 of C1, C2, C3, C4, C5, C6, and C7. In some embodiments, the escalation dose is 3.6 mg and the target dose is 90 mg. In some embodiments, the first escalation dose is 0.3 mg and the second escalation dose is 3.6 mg and the target dose is 90 mg.

[0210] In another aspect, the invention features cevostamab for use in treating a subject with MM, the treatment comprising: (i) a first phase including a first administration cycle (C1) and a second administration cycle (C2); (ii) a second phase including a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), and a fourth administration cycle (C4); and (iii) a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), and a fourth administration cycle (C5). and a third phase including a fifth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6) and a seventh dosing cycle (C7), wherein each dosing cycle of the first phase, second phase and third phase is a 28-day dosing cycle, and cebostamab is administered to the subject: A) (i) on day 1 of C1 at an escalation dose during the first phase, and (ii) on day 8 of C1 at a target dose during the first phase. (iii) at the target dose during the first phase, on days 1, 8, 15, and 22 of C2; (iv) at the target dose during the second phase, on days 1 and 15 of C1, C2, C3, and C4; and (v) at the target dose during the third phase, on days 1 of C1, C2, C3, C4, C5, C6, and C7; or B) (i) at the first escalation dose during the first phase, on day 1 of C1 and on the first escalation dose during the first phase. (ii) during the first phase at a target dose on days 15 and 22 of C1, (iii) during the first phase at a target dose on days 1, 8, 15, and 22 of C2, (iv) during the second phase at a target dose on days 1 and 15 of C1, C2, C3, and C4, and (v) during the third phase at a target dose on days 1 of C1, C2, C3, C4, C5, C6, and C7. In some embodiments, the escalation dose is 3.6 mg and the target dose is 90 mg. In some embodiments, the first escalation dose is 0.3 mg and the second escalation dose is 3.6 mg and the target dose is 90 mg.

[0211] In another aspect, the invention features a method of treating a subject with MM, the method including administering cevostamab, pomalidomide, and dexamethasone to the subject in (i) a prephase including a 21 day administration cycle (C1); (ii) a first phase following the prephase including a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), and a sixth administration cycle (C6), wherein each administration cycle of the first phase is a 28 day administration cycle; and (iii) a second administration cycle (C7), a second phase following the first phase, the second phase including 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), each dosing cycle of the second phase being a 28 day dosing cycle, wherein cevostamab is administered to the subject (i) on day 1 of C1 as a first escalation dose during the pre-phase and on day 8 of C1 as a second escalation dose during the pre-phase;(ii) administered at a target dose on day 15 of C1 during the pre-phase, (iii) administered at a target dose on days 1 and 15 of C1, C2, C3, C4, C5, and C6 during the first phase, and (iv) administered at a target dose on day 1 of C1, C2, C3, C4, C5, C6, and C7 during the second phase; pomalidomide is administered to the subject (i) at a dose of about 4 mg on days 1-21 of C1, C2, C3, C4, C5, and C6 during the first phase, and (ii) at a dose of about 4 mg on days 1-21 of C1, C2, C3, C4, C5, C6, and C7 during the second phase; Samethasone is administered to the subject (i) at a dose of about 20 mg during the pre-phase on days 1, 8, and 15 of C1, and (ii) at a dose of about 20 mg during the first phase on days 1, 8, 15, and 22 of C1, C2, C3, and C4, and optionally dexamethasone is administered to the subject (iii) at a dose of about 20 mg during the first phase on days 1, 8, 15, and 22 of C5 and C6, and (iv) at a dose of about 20 mg during the second phase on days 1, 8, 15, and 22 of C1, C2, C3, C4, C5, C6, and C7. In some embodiments, the first escalation dose is 0.3 mg, the second escalation dose is 3.6 mg, and the target dose is 132 mg;

[0212] In another aspect, the invention features cebostamab for use in treating a subject having MM, the treatment comprising administering to the subject: cebostamab, pomalidomide, and dexamethasone; (i) a prephase comprising a 21-day administration cycle (C1); (ii) a first phase following the prephase comprising a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), and a sixth administration cycle (C6), wherein each administration cycle of the first phase is a 28-day administration cycle; and (iii) a second phase following the first phase, the second 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), each dosing cycle of the second phase being a 28 day dosing cycle, wherein cevostamab is administered to the subject (i) on day 1 of C1 as a first escalation dose during the pre-phase and on day 8 of C1 as a second escalation dose during the pre-phase;(ii) administered at a target dose on day 15 of C1 during the pre-phase, (iii) administered at a target dose on days 1 and 15 of C1, C2, C3, C4, C5, and C6 during the first phase, and (iv) administered at a target dose on day 1 of C1, C2, C3, C4, C5, C6, and C7 during the second phase; pomalidomide is administered to the subject (i) at a dose of about 4 mg on days 1-21 of C1, C2, C3, C4, C5, and C6 during the first phase, and (ii) at a dose of about 4 mg on days 1-21 of C1, C2, C3, C4, C5, C6, and C7 during the second phase; Samethasone is administered to the subject (i) at a dose of about 20 mg during the pre-phase on days 1, 8, and 15 of C1, and (ii) at a dose of about 20 mg during the first phase on days 1, 8, 15, and 22 of C1, C2, C3, and C4, and optionally dexamethasone is administered to the subject (iii) at a dose of about 20 mg during the first phase on days 1, 8, 15, and 22 of C5 and C6, and (iv) at a dose of about 20 mg during the second phase on days 1, 8, 15, and 22 of C1, C2, C3, C4, C5, C6, and C7. In some embodiments, the first escalation dose is 0.3 mg, the second escalation dose is 3.6 mg, and the target dose is 132 mg;

[0213] In another aspect, the invention features a method of treating a subject with MM, the method including administering cevostumab, daratumumab, and dexamethasone to the subject in: (i) a run-in phase including a 21-day administration cycle (C1); (ii) a first phase following the run-in phase including a first sub-phase and a second sub-phase, the first sub-phase including a first administration cycle (C1) and a second administration cycle (C2), the second ... (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), and a fifth administration cycle (C5), each administration cycle of the first phase being a 21-day administration cycle; and (iii) a second phase following the first phase, the second administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), and a fifth administration cycle (C5), each administration cycle of the first phase being a 21-day administration cycle. a second phase, each dosing cycle of the first phase being a 28 day dosing cycle, wherein the bispecific antibody is administered to the subject (i) on day 2 of C1 at a first step-up dose during the run-in phase and on day 9 of C1 as a second step-up dose during the run-in phase; (ii) on day 16 of C1 at a target dose during the run-in phase, (iii) on day 1 of each cycle at a target dose during the first phase, and (iv) on day 2 of C1 as a second step-up dose during the run-in phase. and (iii) during the second subphase of the first phase, daratumumab is administered to the subject at a dose of about 1800 mg on days 1, 8, and 15 of C1, during the run-in phase, at a dose of about 1800 mg on days 1, 8, and 15 of C1 and C2, and at a dose of about 1800 mg on days 1 of C1, C2, C3, C4, and C5;Dexamethasone is administered to the subject (i) at a dose of about 20 mg on days 1, 2, 8, 9, 15, and 16 of C1 during the run-in phase, (ii) at a dose of about 20 mg on days 1, 8, and 15 of C1 and C2 during the first sub-phase of the first phase, and (iii) at a dose of about 20 mg on day 1 of C1, C2, C3, C4, and C5 during the second sub-phase of the first phase, and optionally, dexamethasone is administered to the subject (iv) at a dose of about 20 mg on days 1 of C1, C2, C3, C4, and C5 during the second phase. In some embodiments, the first escalation dose is 0.3 mg, the second escalation dose is 3.6 mg, and the target dose is 160 mg;

[0214] In another aspect, the invention features cebostamab for use in treating a subject with MM, the treatment comprising administering to the subject (i) a run-in phase comprising a 21-day administration cycle (C1); (ii) a first phase following the run-in phase comprising a first sub-phase and a second sub-phase, the first sub-phase comprising a first administration cycle (C1) and a second administration cycle (C2), and the second sub-phase ... a first phase including a dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5), each dosing cycle of the first phase being a 21-day dosing cycle; and (iii) a second phase following the first phase including a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5). a second phase, each dosing cycle of the second phase being a 28 day dosing cycle, wherein the bispecific antibody is administered to the subject (i) on day 2 of C1 at a first escalation dose during the run-in phase and on day 9 of C1 as a second escalation dose during the run-in phase; (ii) on day 16 of C1 at a target dose during the run-in phase; (iii) on day 1 of each cycle at a target dose during the first phase; and (iv) on day 2 of C1 at a second escalation dose during the run-in phase. and (iii) during the second subphase of the first phase, daratumumab is administered to the subject at a dose of about 1800 mg on days 1, 8, and 15 of C1, during the run-in phase, (ii) during the first subphase of the first phase, daratumumab is administered to the subject at a dose of about 1800 mg on days 1, 8, and 15 of C1 and C2, and (iii) during the second subphase of the first phase, daratumumab is administered to the subject at a dose of about 1800 mg on days 1 of C1, C2, C3, C4, and C5;Dexamethasone is administered to the subject (i) at a dose of about 20 mg on days 1, 2, 8, 9, 15, and 16 of C1 during the run-in phase, (ii) at a dose of about 20 mg on days 1, 8, and 15 of C1 and C2 during the first sub-phase of the first phase, and (iii) at a dose of about 20 mg on day 1 of C1, C2, C3, C4, and C5 during the second sub-phase of the first phase, and optionally, dexamethasone is administered to the subject (iv) at a dose of about 20 mg on days 1 of C1, C2, C3, C4, and C5 during the second phase. In some embodiments, the first escalation dose is 0.3 mg, the second escalation dose is 3.6 mg, and the target dose is 160 mg; [Brief description of the drawings]

[0215] [Figure 1] FIG. 1 shows a schematic of the Arm A escalation dosing regimen of single-agent cevostamab (on a "modified weekly" schedule) from the CAMMA 1 Phase Ib clinical trial. "QW" refers to "weekly" dosing. "Q2W" refers to "every 2 weeks" dosing. "Q4W" refers to "every 4 weeks" dosing. [Diagram 2] FIG. 1 shows a schematic diagram of the Arm A two-step ascending dosing regimen of single-agent cevostamab (on a "modified weekly" schedule) from the CAMMA 1 Phase Ib clinical trial. [Diagram 3] FIG. 1 shows a schematic diagram of the Arm B two-step ascending dosing regimen for the combination of cevostamab, pomalidomide (P) and dexamethasone (d) from the CAMMA 1 Phase Ib clinical trial with a Q2W / Q4W cevostamab dosing schedule. "Pd" refers to the combination of pomalidomide and dexamethasone. [Figure 4] FIG. 1 shows a schematic diagram of the Arm C two-step ascending dosing regimen for the combination of cebostamab, daratumumab (D) and dexamethasone (d) from the CAMMA 1 Phase Ib clinical trial with a Q3W / Q4W cebostamab dosing schedule. "Dd" refers to the combination of daratumumab and dexamethasone. "Q3W" refers to dosing "every 3 weeks." [Diagram 5]Figure 1 shows a graph of a model simulating population pharmacokinetics (popPK) of the one-step escalation modified weekly dosing schedule described herein. Briefly, a preliminary popPK model was developed using available data (n=145) in the ongoing Phase I study GO39775, with doses ranging from 0.05mg / 0.15mg to 3.6mg / 160mg in arms A and C, and tested doses of 1.2mg / 3.6mg / 60mg to 0.3mg / 3.6mg / 160mg in arms B and D, on a Q3W schedule. Sevostamab serum concentration-time profiles were simulated at an escalation dose of 3.6mg, followed by 90mg weekly over the first two cycles (cycles 1-2), followed by Q2W dosing in cycles 3-6, and Q4W dosing from cycle 7 onwards (see Table 5 for additional details on these metrics). Each line is the geometric mean of 500 concentration-time simulations using the popPK model. The popPK model consists of a two-compartment model with linear and Michaelis-Menten clearance. [Figure 6]

[0036] Figure 1 shows a graph of a model simulating the popPK of the two-step ascending Q2W and Q3W dosing schedules described herein. Briefly, the model was performed to predict the exposure of 0.3mg / 3.6mg / 132mg of cevostamab in combination with Pd on a Q2W (cycles 1-6) and Q4W (cycles 7 onwards) schedule. Based on the favorable benefit-risk profile observed for the dose in the 0.3 mg / 3.6 mg / 160 mg Q3W regimen in the expansion cohort (arm D) of study GO39775, the exposure at this dose serves as a reference to ensure that the proposed cevostamab exposure for 0.3 mg / 3.6 mg / 132 ​​mg in the Q2W / Q4W regimen does not exceed the exposure previously tested in the 0.3 mg / 3.6 mg / 160 mg Q3W regimen using clinical data available as of the clinical cut-off date (CCOD) of March 2021 from the ongoing study GO39775 (see Table 5 for additional details on these metrics). Each line is the geometric mean of 500 concentration-time simulations using the popPK model. The popPK model consists of a two-compartment model with linear and Michaelis-Menten clearance. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0216] I. Definition The term "about" as used herein refers to the normal error range for the respective value, which is readily understood by one of ordinary skill in the art. Reference to "about" with respect to a value or parameter herein includes (and describes) aspects directed to the value or parameter itself.

[0217] It will be understood that the embodiments of the invention described herein include "comprising," "consisting of," and "consisting essentially of" embodiments.

[0218] The term "FcRH5" or "fragment crystallographic receptor-like 5" as used herein refers 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 includes "full-length" and unprocessed FcRH5, as well as any form of FcRH5 resulting from processing within a cell. This term also includes naturally occurring variants of FcRH5, including, for example, splice variants or allelic variants. FcRH5 includes, for example, the human FcRH5 protein (UniProtKB / Swiss-Prot ID: Q96RD9.3), which is 977 amino acids long.

[0219] The terms "anti-FcRH5 antibody" and "antibody that binds FcRH5" refer to an antibody that can bind FcRH5 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent targeting FcRH5. In one embodiment, the degree of binding of an anti-FcRH5 antibody to an unrelated, non-FcRH5 protein is less than about 10% of the binding of the antibody to FcRH5, e.g., as measured by radioimmunoassay (RIA). In certain embodiments, an antibody that binds 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, e.g. 10 -8 M~10 -1 M, for example 10 -9 M~10 -13 Dissociation constant (K D In certain embodiments, the anti-FcRH5 antibody binds to an epitope of FcRH5 that is conserved among FcRH5 from different species.

[0220] The term "cluster of differentiation 3" or "CD3", as used herein, unless otherwise indicated, refers to any native CD3 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), including, for example, CD3ε, CD3γ, CD3α, and CD3β chains. The term encompasses "full-length" unprocessed CD3 (e.g., unprocessed or unmodified CD3ε or CD3γ), as well as any form of CD3 resulting from intracellular processing. The term also encompasses naturally occurring variants of CD3, including, for example, splice variants or allelic variants. CD3 includes, for example, the human CD3ε protein (NCBI Reference SEQ ID NO: NP_000724), which is 207 amino acids long, and the human CD3γ protein (NCBI Reference SEQ ID NO: NP_000064), which is 182 amino acids long.

[0221] The terms "anti-CD3 antibody" and "antibody that binds to CD3" refer to an antibody that can bind to CD3 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent targeting CD3. In one embodiment, the degree of binding of an anti-CD3 antibody to an unrelated non-CD3 protein is less than about 10% of the binding of the antibody to CD3, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds to CD3 has an affinity 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~10 -13 M, for example 10 -9 M~10 -13 Dissociation constant (K D In certain embodiments, the anti-CD3 antibody binds to an epitope of CD3 that is conserved among CD3 from different species.

[0222] For purposes herein, "cebostamab" (also referred to as BFCR4350A or RO7187797) is an Fc-engineered humanized full-length aglycosylated IgG1κ T-cell-dependent bispecific antibody (TDB) that binds FcRH5 and CD3 and comprises an anti-FcRH5 arm comprising a heavy chain polypeptide sequence of SEQ ID NO: 35 and a light chain polypeptide sequence of SEQ ID NO: 36, and an anti-CD3 arm comprising a heavy chain polypeptide sequence of SEQ ID NO: 37 and a light chain polypeptide sequence of SEQ ID NO: 38. Sebostamab contains an amino acid substitution (T366W) from threonine to tryptophan 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) to drive heterodimerization of the two arms (half antibodies). Sebostamab also contains an amino acid substitution (N297G) at position 297 (asparagine to glycine) on each heavy chain using EU numbering of Fc region amino acid residues, resulting in an aglycosylated antibody with minimal binding to Fc (Fcγ) receptors and consequently preventing Fc effector function. Sebostamab is also listed in the WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Recommended INN:List 84, Vol. 34, No. 3 (published in 2020) (see page 701).

[0223] The term "antibody" is used herein in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments (e.g., bis-Fab), so long as they exhibit the desired antigen-binding activity.

[0224] "Affinity" refers to the strength of the sum of 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 a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y is generally determined by the dissociation constant (K D Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

[0225] An "affinity matured" antibody refers to an antibody that has one or more modifications in one or more hypervariable regions (HVRs), compared to a parent antibody that does not possess such modifications, which improve the affinity of the antibody for antigen.

[0226] The terms "full length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody having a heavy chain having a structure substantially similar to a native antibody structure or containing an Fc region as defined herein.

[0227] "Antibody fragment" refers to a molecule other than an intact antibody that contains a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, bis-Fab; Fv; Fab; Fab'-SH; F(ab') 2 including diabodies, linear antibodies, single chain antibody molecules (eg, scFv, ScFab), and multispecific antibodies formed from antibody fragments.

[0228] "Single domain antibody" refers to an antibody fragment that contains all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain embodiments, a single domain antibody is a human single domain antibody (see, e.g., U.S. Pat. No. 6,248,516 B1). Examples of single domain antibodies include, but are not limited to, VHHs.

[0229] A "Fab" fragment is an antigen-binding fragment produced by papain digestion of an antibody, consisting of the entire L chain, the variable region domain of the H chain (VH), and the first constant domain of one heavy chain (CH1). Papain digestion of an antibody produces two identical Fab fragments. Pepsin treatment of an antibody produces a single large F(ab') fragment. 2 The resulting fragment corresponds roughly to two disulfide-linked Fab fragments with divalent antigen-binding activity and is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments in that they have additional residues at the carboxy terminus of the CH1 domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine ​​residues of the constant domains bear a free thiol group. F(ab') 2 Antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0230] "Fv" consists of a dimer of one heavy chain and one light chain variable region domain in tight non-covalent association. The folding of these two domains results in six hypervariable loops (three loops each from the H chain and 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 an Fv containing only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although often with lower affinity than the entire binding site.

[0231] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain, including native sequence Fc regions and variant Fc regions. Although the boundaries of an immunoglobulin heavy chain Fc region can vary, the human IgG heavy chain Fc region is usually defined as extending from the amino acid residue at position Cys226 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 recombinantly engineering the nucleic acid encoding the antibody heavy chain. Thus, a composition of intact antibodies can include an antibody population with all Lys447 residues removed, an antibody population with no Lys447 residues removed, and an antibody population with a mixture of antibodies with and without the Lys447 residue.

[0232] A "functional Fc region" has an "effector function" of a native sequence Fc region. Exemplary "effector functions" include C1q binding, complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptor, BCR); B cell activation, and the like. Such effector functions generally require that the Fc region be combined with a binding domain (e.g., an antibody variable domain) and can be assessed using various assays, e.g., as disclosed in the definitions herein.

[0233] A "native sequence Fc region" comprises an amino acid sequence identical to that of an Fc region found in nature. Native sequence human Fc regions include native sequence human IgG1 Fc regions (non-A and A allotypes), native sequence human IgG2 Fc regions, native sequence human IgG3 Fc regions, and native sequence human IgG4 Fc regions, as well as naturally occurring variants thereof.

[0234] A "variant Fc region" comprises an amino acid sequence that differs from that of a 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 a native sequence Fc region or the Fc region of a parent polypeptide, e.g., 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 Fc region of a parent polypeptide. The variant Fc region 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 Fc region of the parent polypeptide.

[0235] As used herein, "Fc complex" refers to the CH3 domains of two Fc regions that interact together to form a dimer, or in certain embodiments, two Fc regions that interact to form a dimer, where cysteine ​​residues in the hinge region and / or the CH3 domains interact via bonds and / or forces (e.g., van der Waals, hydrophobic forces, hydrogen bonds, electrostatic forces, or disulfide bonds).

[0236] The "hinge region" is generally defined as extending between about residues 216 to about 230 of IgG (EU numbering), about residues 226 to about 243 of IgG (Kabat numbering), or about residues 1 to about 15 of IgG (IMGT unique numbering).

[0237] The "lower hinge region" of an Fc region is usually defined as the stretch of residues immediately C-terminal to the hinge region, ie, residues 233 to 239 (EU numbering) of the Fc region.

[0238] "Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. A preferred FcR is a native sequence human FcR. Additionally, a preferred FcR is one that binds IgG antibodies (gamma receptors), including receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. FcγRII receptors include FcγRIIA ("activating receptor") and FcγRIIB ("inhibiting receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain (see review M. in Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed 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 yet to be identified, are encompassed herein by the term "FcR". The 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)).

[0239] The term "knobs-into-holes" or "KnH" technology referred to herein refers to a technology that directs pairing of two polypeptides together in vitro or in vivo by introducing a protrusion (knob) into one polypeptide and a cavity (hole) into the other polypeptide at the interface where they interact. For example, KnH has been introduced into the Fc:Fc interaction interface, CL:CH1 interface or VH / VL interface of an antibody (e.g., US2007 / 0178552, WO96 / 027011, WO98 / 050431 and Zhu et al., (1997) Protein Science 6:781-788). This is particularly useful for driving pairing of two different heavy chains together during the production of multispecific antibodies. For example, a multispecific antibody with KnH in the Fc region may further comprise a single variable domain linked to each Fc region, or may further comprise a different heavy chain variable domain paired with an identical, similar or different light chain variable domain. The KnH technology can also be used to pair two different receptor extracellular domains together, or any other polypeptide sequence that comprises a different target recognition sequence.

[0240] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3 and FR4. Thus, the HVR and FR sequences generally appear in the following order in a VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0241] A "CH1 region" or "CH1 domain" comprises a stretch of residues from about residue 118 to residue 215 of IgG (EU numbering), from about residue 114 to residue 223 of IgG (Kabat numbering), or from about residue 1.4 to residue 121 of IgG (IMGT unique numbering) (Lefranc et al., IMGT®, the international ImMunoGeneTics information system® 25 years on. Nucleic Acids Res. 2015 Jan;43(Database issue):D413-22).

[0242] The "CH2 domain" of the human IgG Fc region typically spans from about residue 244 to about 360 of IgG (Kabat numbering), from about residue 231 to about 340 of IgG (EU numbering), or from about 1.6 to about 125 of IgG (IGMT unique numbering). The CH2 domain is unique in that it is not tightly paired with other domains. Rather, two N-linked branched carbohydrate chains are interposed between the two CH2 domains in intact native IgG molecules. It has been speculated that carbohydrates may provide an alternative for domain-domain pairing and help stabilize the CH2 domain. Burton, Molec. Immunol. 22:161-206 (1985).

[0243] The "CH3 domain" comprises the extension from the C-terminal residue of the Fc region into the CH2 domain (i.e., from about amino acid residue 361 to about 478 of IgG (Kabat numbering), from about amino acid residue 341 to about 447 of IgG (EU numbering), or from about amino acid residue 1.4 to about 130 of IgG (IGMT unique numbering)).

[0244] A "CL domain" or "constant light domain" comprises a stretch of residues C-terminal to the light chain variable domain (VL). The light chain (LC) of an antibody can be a kappa (κ) ("Cκ") or lambda (λ) ("Cλ") light chain region. The Cκ region generally extends from about residue 108 to about residue 214 of IgG (Kabat or EU numbering), or from about residue 1.4 to about residue 126 of IgG (IMGT unique numbering). The Cλ residues generally range from about residue 107a to residue 215 (Kabat numbering) or from about residue 1.5 to residue 127 (IMGT unique numbering) (Lefranc et al., supra).

[0245] The term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, and the remainder of the heavy and / or light chain is derived from a different source or species.

[0246] The "class" of an antibody refers to the type of constant domain or region carried by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these are further subdivided into subclasses (isotypes), e.g., IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 , and IgA 2 The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0247] A "human antibody" is an antibody having an amino acid sequence corresponding to an antibody produced by a human or human cell, or an antibody of non-human origin utilizing 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 generated using a variety of techniques known in the art, including phage display libraries. The methods described in Hoogenboom and Winter, J. Mol. Biol. 227:381, 1991; Marks et al., J. Mol. Biol. 222:581, 1991. Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p.77(1985); Boerner et al., J. Immunol., 147(1):86-95, 1991 can also be used to prepare human monoclonal antibodies. See also Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74, 2001. Human antibodies can be prepared by administering antigen to transgenic animals, e.g., immunized xenomouse, whose endogenous loci have been disabled but have been engineered to produce such antibodies in response to antigen exposure (see, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584 for XENOMOUSE™ technology). See, e.g., Li et al., Proc. Natl. Acad. Sci. USA. 103:3557-3562, 2006 for human antibodies generated via human B cell hybridoma technology.

[0248] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as 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., supra. In one embodiment, for VH, the subgroup is subgroup kappa III as described in Kabat et al., supra.

[0249] A "humanized" antibody refers to a chimeric antibody that comprises amino acid residues from a non-human HVR and amino acid residues from a human FR. In certain embodiments, a humanized antibody comprises substantially all of at least one, typically two, variable domains, with all or substantially all HVRs (e.g., CDRs) corresponding to those of a non-human antibody and all or substantially all FRs corresponding to those of a human antibody. In certain embodiments in which all or substantially all FRs of a humanized antibody correspond to those of a human antibody, any of the FRs of the humanized antibody may comprise one or more amino acid residues from a non-human FR(s) (e.g., one or more Vernier position residues of the FR). A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0250] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to an antigen. The variable domains of the heavy and light chains of native antibodies (VH and VL, respectively) generally have a similar structure, with each domain containing four conserved framework regions (FR) and three hypervariable regions (HVR). (See, e.g., Kindt et al., Kuby Immunology, 6 th (See, e.g., W.H. Freeman and Co., p. 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. Moreover, antibodies that bind to a specific antigen may be isolated by using the VH or VL domain of an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887, 1993; Clarkson et al. Nature 352:624-628, 1991.

[0251] The term "hypervariable region" or "HVR" as used herein refers to each region of an antibody variable domain that is hypervariable in sequence ("complementarity determining region" or "CDR"). Generally, an antibody contains six CDRs, three in the VH (CDR-H1, CDR-H2, CDR-H3) and three in the VL (CDR-L1, CDR-L2, CDR-L3). Exemplary CDRs herein include: (a) CDRs located at 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 located 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 contacts occurring 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).

[0252] Unless otherwise indicated, HVR residues and other residues in the variable domain (eg, FR residues) are numbered herein according to Kabat et al., supra.

[0253] "Single-chain Fv", also abbreviated as "sFv" or "scFv", is an antibody fragment comprising VH and VL antibody domains connected in a single polypeptide chain. Preferably, the scFv polypeptide further comprises a polypeptide linker between the VH and VL domains, which enables the scFv to form the desired structure for antigen binding. For a general description 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.

[0254] "Targeting domain" refers to a portion of a compound or molecule that specifically binds to a target epitope, antigen, ligand, or receptor. Targeting domains include antibodies (e.g., monoclonal antibodies, polyclonal antibodies, recombinant antibodies, humanized antibodies, and chimeric antibodies), antibody fragments or portions thereof (e.g., bis-Fab fragments, Fab fragments, F(ab') 2 Targeting domains include, but are not limited to, scFabs, scFv antibodies, SMIPs, single domain antibodies, diabodies, minibodies, scFv-Fc, affibodies, nanobodies, and VH and / or VL domains of antibodies), receptors, ligands, aptamers, peptide targeting domains (such as cysteine ​​knot proteins (CKPs)), and other molecules with identified binding partners. A targeting domain can target, block, agonize, or antagonize the antigen to which it binds.

[0255] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies constituting the population are identical and / or bind the same epitope, except for variant antibodies that may, for example, contain naturally occurring mutations or arise during the production of a monoclonal antibody preparation, such variants are generally present in minor amounts. In contrast to polyclonal antibody preparations, which typically contain different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies used in accordance with the present invention can be produced 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 the human immunoglobulin locus, and such methods and other exemplary methods for producing monoclonal antibodies are described herein.

[0256] The term "multispecific antibody" is used in the broadest sense and specifically encompasses antibodies with polyepitopic specificity. In one embodiment, a multispecific antibody binds to two different targets (e.g., bispecific antibodies). Such multispecific antibodies include, but are not limited to, antibodies comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), where the VH / VL unit has multiepitopic specificity, antibodies with two or more VL and VH domains, where each VH / VL unit binds a different epitope, antibodies with two or more single variable domains, where each single variable domain binds a different epitope, full-length antibodies, antibody fragments such as Fab, Fv, dsFv, scFv, diabodies, bispecific diabodies and triabodies, covalently or non-covalently linked antibody fragments. "Polyepitopic specificity" refers to the ability to specifically bind to two or more different epitopes on the same or different target(s). "Monospecificity" refers to the ability to bind to only one antigen. In one embodiment, a monospecific bi-epitope antibody binds two different epitopes on the same target / antigen. In one embodiment, a monospecific polyepitope antibody binds multiple different epitopes on the same target / antigen. According to one embodiment, the multispecific antibody is an IgG antibody that binds each epitope with an affinity 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.

[0257] "Naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel. The naked antibody may be present in a pharmaceutical formulation.

[0258] "Native antibodies" refer to naturally occurring immunoglobulin molecules with various structures. For example, native IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also called a variable heavy 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 domain or light chain variable domain, followed by a constant light chain (CL) domain. The light chain of an antibody may be assigned to one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[0259] As used herein, the term "immunoadhesin" refers to a molecule that combines the binding specificity of a heterologous protein ("adhesin") with the effector functions of an immunoglobulin constant domain. Structurally, an immunoadhesin comprises an amino acid sequence with the desired binding specificity that is an amino acid sequence other than the antigen recognition and binding site of an antibody (i.e., "heterologous" compared to the constant region of an antibody) fused to an immunoglobulin constant domain sequence (e.g., the CH2 and / or CH3 sequences of an IgG). The adhesin and the immunoglobulin constant domain may optionally be separated by an amino acid spacer. Exemplary adhesin sequences include contiguous amino acid sequences that include a portion of a receptor or ligand that binds to the protein of interest. An adhesin sequence may also be a sequence that binds to the protein of interest but is not a receptor or ligand sequence (e.g., an adhesin sequence in a peptibody). Such polypeptide sequences may be selected or identified by a variety of methods, including phage display techniques and high-throughput selection methods. The immunoglobulin constant domain sequences in the immunoadhesin may be obtained from any immunoglobulin, such as IgG1, IgG2, IgG3, or IgG4 subtypes, IgA (including IgA1 and IgA2), IgE, IgD, or IgM.

[0260] "Chemotherapeutic agent" includes chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech / OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer / Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN®, cyclosphosphamide; alkylsulfonates such as busulfan, improsulfan, piposulfan; aziridine compounds such as benzodopa, carboquone, metsudopa, uredopa; ethylenimines and methylamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (including topotecan and irinotecan); bryostatin; kallistatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (especially cryptophycin 1 and cryptophycin 8); corticosteroids (such as prednisone and prednisolone); cyproterone acetate;5α-reductase enzymes, including finasteride, dutasteride; vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatins; aldesleukin, talc ducarmycin (including synthetic analogs, KW-2189, CB1-TM1); eleutherobin; pancratistatin; sarcodictin; spongiostatins; chlorambucil, chromafazine, chlorophosphamide, estramustine, ifosfamide, Nitrogen mustards such as mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembitine, phenesterone, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γ1I and calicheamicin ω1I (Angew Chem. Intl. Ed. Engl. 1994) 33:183-186); dynemicins, including dynemicin A; bisphosphonates, such as clodronate; esperamicins; and neocarzinostatin chromophore and related chromoprotein enediine antibiotic chromophores), aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, schizomy ... anomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), mitomycins such as epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin C, mycophenolic acid, nogamicin, olivomycin, peplomycin, porfiromycin, puromycin, keramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate;Purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifuridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanol propionate, epithiostanol, mepitiosteine, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilosteine; folic acid supplements such as floric acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; etanercept; Niruracil; Amsacrine; Bestravcil; Bisantrene; Edatraxate; Defofamine; Demecolcine; Diaziquone; Elfomitin; Elliptinium acetate; Epothilone; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidynin; Maytansinoids such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidanor; Nitraerin; Pentostatin; Fenameth; Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK (registered trademark) polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; schizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veraculin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitractol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids such as taxol (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® (cremophor-free), albumin engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® (paclitaxel, docetaxel; Sanofi-Aventis): chlorambucil, GEMZAR® (gemcitabine), 6-thioguanine, mercaptopurine;methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); nobandrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; the topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid, as well as pharmaceutically acceptable salts, acids, and derivatives of any of the above;

[0261] Chemotherapeutic agents include the following:(i) antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), e.g., tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droxifene, iodoxyfene, 4-hydroxytamoxifen, trioxyfene, ketoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) agents that regulate estrogen production in the adrenal glands. aromatase inhibitors that inhibit the aromatase enzyme, for example, antiandrogens such as 4(5)-imidazole, aminoglutethimide, MEGASE® (megstrol acetate), AROMASIN® (exemestane; Pfizer), formestany, fadrozole, RIVISOR® (borzole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) flutamide, nilutamide, bicalutamide, lubricant, etc. antiandrogens such as alpha-prolide, and goserelin; buserelin, triplerin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all trans retinoic acid, fenretinide as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes involved in signal transduction pathways involved in abnormal cell proliferation, e.g., PKC-α, Ral f and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) gene therapy vaccines, such as ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN®, rIL-2; topoisomerase 1 inhibitors such as LURTOTECAN®; ABAREFIX® rmRH; and (ix) pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0262] Chemotherapeutic agents also include antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Imclone), panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody-drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include apolizumab, acelizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, celelizumab pegol, cidofusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, nat ... tuzumab, nimotuzumab, norobizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pexelizumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, reslizumab, rovelizumab, lupizumab, sibrotuzumab, siplizumab, sontuzumab, tacatatuzumab tetraxetan, tadoxizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab sermoreukin, tucotuzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and interleukin-12 and anti-interleukin-12 (ABT-874 / J695, Wyeth Research and Abbott Laboratories), a full-length, human sequence only IgG1λ antibody engineered to recognize the p40 protein.

[0263] Chemotherapeutic agents also include "EGFR inhibitors," which refer to compounds that bind to or otherwise directly interact with EGFR and inhibit or reduce the signaling activity of EGFR, alternatively referred to as "EGFR antagonists." Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies that bind to EGFR include: MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb225 (ATCC CRL8508), MAb528 (ATCC CRL8509) (see U.S. Pat. No. 4,943,533) and variants thereof, such as chimerized 225 (C225 or cetuximab; ERBUTIX®) and reshaped human 225 (H225) (WO 96 / 40210, Imclone Systems, Inc., 2002). Inc.); fully human EGFR-targeting antibody IMC-11F8 (Imclone); antibodies that bind type II mutant EGFR (U.S. Pat. No. 5,212,290); humanized and chimeric antibodies that bind EGFR, such as those described in U.S. Pat. No. 5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab (see WO 98 / 50433, Abgenix / Amgen); EMD 55900 (Stragliotto et al., Eur. J. Cancer 32A:636-640 (1996); EMD7200 (matuzumab), a humanized EGFR antibody against EGFR that competes with both EGF and TGF-α for EGFR binding (EMD / Merck); the human EGFR antibody, HuMax-EGFR (GenMab); the fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, and E7.6.3 and described in U.S. Pat. No. 6,235,883; MDX-447 (Medarex Inc); and mAb806 or humanized mAb806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)).Anti-EGFR antibodies can be conjugated to cytotoxic agents to generate immunoconjugates (see, for example, European Patent Application Publication No. 659,439, Merck Patent GmbH). EGFR antagonists can be conjugated to cytotoxic agents as described in U.S. Patent Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866, Nos. 5,760,041, 6,002,008, and 5,747,498, and the following PCT publications: WO 98 / 14451, WO 98 / 50038, WO 99 / 09016, and WO 99 / 24037.Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA®, Genentech / OSI Pharmaceuticals), PD183805 (CI1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.), ZD1839, gefitinib (IRESSA®) 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca), ZM105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca), BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim), PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol), (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine), CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide), EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7 -ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butynamide) (Wyeth), AG1478 (Pfizer), AG1571 (SU5271, Pfizer), and dual EGFR / HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2 methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).

[0264] Chemotherapeutic agents also include "tyrosine kinase inhibitors" (including the EGFR-targeted drugs described in the previous paragraph), small molecule HER2 tyrosine kinase inhibitors (such as TAK165 available from Takeda), CP-724,714, an oral selective inhibitor of ErbB2 receptor tyrosine kinase (Pfizer and OSI), dual HER inhibitors (such as EKB-569 (available from Wyeth) which preferentially binds to EGFR but inhibits both HER2 and EGFR overexpressing cells), lapatinib (GSK572016, available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor, PKI-166 (available from Novartis), pan-HER inhibitors (such as canertinib (CI-1033, Pharmacia)), Raf-1 inhibitors (such as ISIS, which inhibits Raf-1 signaling). antisense drug ISIS-5132 available from Novartis / Schering Pharmaceuticals), non-HER-targeted TK inhibitors (such as imatinib mesylate (GLEEVEC®, available from Glaxo SmithKline)), multi-targeted tyrosine kinase inhibitors (such as sunitinib (SUTENT®, available from Pfizer)), VEGF receptor tyrosine kinase inhibitors (vatalanib (PTK787 / ZK222584, available from Novartis / Schering Pharmaceuticals)), AG), the MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia), quinazolines (such as PD153035, 4-(3-chloroanilino)quinazoline), pyridopyrimidines, pyrimidopyrimidines, pyrrolopyrimidines (such as CGP59326, CGP60261, and CGP62706), pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidines, curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide), tyrphostins containing a nitrothiophene moiety, PD-0183805 (Warner-Lamber), antisense molecules (e.g., those that bind to HER-encoding nucleic acids), quinoxalines (U.S. Pat. No. 5,804,396), tryphostins (U.S. Pat. No. 5,804,No. 396), ZD6474 (AstraZeneca), PTK-787 (Novartis / Schering AG), pan-HER inhibitors (CI-1033 (Pfizer) etc.), Affinitac (ISIS3521, Isis / Lilly), imatinib mesylate (GLEEVEC (registered trademark)), PKI166 (Novartis), GW2016 (Glaxo SmithKline), CI-1033 (Pfizer), EKB-569 (Wyeth), semaxinib (Pfizer), ZD6474 (AstraZeneca), PTK-787 (Novartis / Schering AG), INC-1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE®), or any of the following patent publications: U.S. Pat. No. 5,804,396, WO 1999 / 09016 (American Cyanamid), WO 1998 / 43960 (American Cyanamid), WO 1997 / 38983 (Warner Lambert), WO 1999 / 06378 (Warner Lambert), WO 1999 / 06396 (Warner Lambert), WO 1996 / 30347 (Pfizer, Inc), WO 1996 / 33978 (Zeneca), WO 1996 / 3397 (Zeneca), and WO 1996 / 33980 (Zeneca).

[0265] Chemotherapeutic agents include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacizumab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, erlotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, and interferon alfa- 2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof.

[0266] Chemotherapeutic agents include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, and hydrocortisone-17- butyrate, hydrocortisone-17-valerate, aclomethasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasone-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate; phenylalanine-glutamine-glycine (FEG) and its D-form (feG) (IMULAN Immunoselective anti-inflammatory peptides (ImSAIDs) such as cyclosporine (cyclosporine A), D-penicillamine, gold salts, antirheumatic drugs such as hydroxychloroquine, leflunomide, minocycline, and sulfasalazine, etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), cetrizumab pegol (Cimzia), and golimumab (Simpson) tumor necrosis factor alpha (TNFα) blockers such as anakinra (Kineret), interleukin 1 (IL-1) blockers such as anakinra (Kineret), T cell costimulation blockers such as abatacept (Orencia), interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMRA®); interleukin 13 (IL-13) blockers such as lebrikizumab; interferon alpha (IFN) blockers such as rontalizumab; beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as anti-M1 prime; secreted homotrimeric LTa3 and membrane-bound heterotrimeric LTa1 / β2 blockers such as anti-lymphotoxin alpha (LTa); radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi212 、P 32 、Pb 212, and radioisotopes of Lu); various investigational drugs such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3, or farnesyltransferase inhibitors (L-739749, L-744832); polyphenols, such as quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavins, flavanols, procyanidins, betulinic acid and its derivatives; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); betulinic acid and its derivatives; tarlapachone; lapachol; colchicine; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin; podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); clodronate (e.g., BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid / zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate bisphosphonates, such as tirofinamide (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); as well as epidermal growth factor receptor (EGF-R); vaccines, such as the THERATOPE® vaccine; perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteosome inhibitors (e.g., PS341); CCI-779; tipifarnib (R11577); orafenib, ABT510; oblimersen sodium (GENASENSE®); pixantrone; farnesyltransferase inhibitors such as lonafarnib (SCH6636, SARASAR™); and pharmaceutically acceptable salts, acids, or derivatives of any of the above; and combinations of two or more of CHOP, an abbreviation for a combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone, and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin in combination with 5-FU and leucovorin (ELOXATIN™).

[0267] Chemotherapeutic agents may also include nonsteroidal anti-inflammatory drugs that have analgesic, antipyretic, and anti-inflammatory effects.NSAIDs include nonselective inhibitors of the enzyme cyclooxygenase.Specific examples of nonsteroidal anti-inflammatory drugs include propionic acid derivatives such as aspirin, ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, and naproxen, acetic acid derivatives such as indomethacin, sullindac, etodolac, and diclofenac, enolic acid derivatives such as piroxicam and meloxicam, fenamic acid derivatives such as tenoxicam, droxicam, lonoxicam, isoxicam, mefenamic acid, meclofenamic acid, flufenamic acid, and tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, and valdecoxib. Indications for NSAIDs may be symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathy, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headaches and migraines, post-operative pain, mild to moderate pain due to inflammation and tissue injury, fever, ileus, and renal colic.

[0268] The term "cytotoxic agent" as used herein refers to a substance that inhibits or prevents cell function and / or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212, and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, doxorubicin (ADRIAMYCIN®)), vinca alkaloids (vincristine, vinblastine, etoposide), melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitors; enzymes and fragments thereof, e.g., nucleases; antibiotics; toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof; and various anti-tumor or anti-cancer agents as disclosed below.

[0269] A "disorder" is any condition that would benefit from treatment, including, but not limited to, chronic and acute disorders or diseases, including those pathological conditions that predispose a mammal to the disorder in question. In one embodiment, the disorder is a cancer, e.g., a B-cell proliferative disorder such as MM, e.g., relapsed or refractory MM.

[0270] The terms "cell proliferative disorder" and "proliferative disorder" refer to disorders associated with some degree of abnormal cell proliferation. In one aspect, the cell proliferative disorder is cancer. In one aspect, the cell proliferative disorder is a tumor.

[0271] "Tumor," as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms "cancer," "cancerous," "cell proliferative disorder," "proliferative disorder," and "tumor" are not mutually exclusive as referred to herein.

[0272] The terms "cancer" and "cancerous" refer to or describe a physiological condition in a mammal that is typically characterized by uncontrolled cell growth / proliferation. Cancer aspects include solid tumor cancers and non-solid tumor cancers. Examples of cancer include, but are not limited to, B-cell proliferative disorders, such as MM, which may be relapsed or refractory MM. MM may be, for example, a typical MM (e.g., immunoglobulin G (IgG) MM, IgA MM, IgD MM, IgE MM, or IgM MM), a light chain MM (LCMM) (e.g., lambda light chain MM or kappa light chain MM), or a non-secretory MM. MM may have one or more cytogenetic features (e.g., high-risk cytogenetic features), such as t(4;14), t(11;14), t(14;16), and / or del(17p) (as described in Table 1 and the International Myeloma Working Group (IMWG) criteria provided in Sonneveld et al., Blood, 127(24):2955-2962, 2016) and / or 1q21 (as described in Chang et al., Bone Marrow Transplantation, 45:117-121, 2010). Cytogenetic features may be detected, for example, using fluorescent in situ hybridization (FISH).

[0273] [Table 1]

[0274] The term "B cell proliferative disorder" or "B cell malignancy" refers to disorders that are associated with some degree of abnormal B cell proliferation and include, for example, lymphoma, leukemia, myeloma, and myelodysplastic syndrome. In one embodiment, the B cell proliferative disorder is a lymphoma, such as, for example, non-Hodgkin's lymphoma (NHL), including, for example, diffuse large B cell lymphoma (DLBCL) (e.g., relapsed or refractory DLBCL). In another embodiment, the B cell proliferative disorder is a leukemia, such as chronic lymphocytic leukemia (CLL). Other specific examples of cancer include germinal center B cell-like (GCB) diffuse large B cell lymphoma (DLBCL), activated B cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenstrom's gammopathy (WM), central nervous system lymphoma (CNSL), Burkitt's lymphoma (BL), and B cell lymphoma. Prolymphocytic leukemia, Splenic marginal zone lymphoma, Hairy cell leukemia, Splenic lymphoma / leukemia, Unclassifiable, Diffuse red pulp small B-cell lymphoma, Hairy cell leukemia variant, Heavy chain disease, Alpha heavy chain disease, Gamma heavy chain disease, Mu heavy chain disease, Plasma cell myeloma, Isolated bone plasmacytoma, Extraosseous plasmacytoma, Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), Nodal marginal zone lymphoma, Childhood nodal marginal zone lymphoma, Childhood follicular lymphoma, Primary cutaneous follicle center lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, Primary CNS Includes DLBCL, primary cutaneous DLBCL, leg type, EBV-positive DLBCL of the elderly, chronic inflammation-associated DLBCL, lymphomatoid granulomatosis, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma due to HHV8-associated multicentric Castleman disease, primary effusion lymphoma: unclassifiable B-cell lymphoma with features intermediate between DLBCL and Burkitt lymphoma, and unclassifiable B-cell lymphoma with features intermediate between DLBCL and classical Hodgkin lymphoma.In addition, examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and lymphoid malignancies, including leukemia or B-cell lymphoma.More specific examples of such cancer include, but are not limited to, low-grade / follicular NHL; small lymphocytic (SL) NHL; intermediate-grade / follicular NHL; intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphocytic NHL; high-grade small non-dividing cell NHL; bulky mass disease NHL; AIDS-related lymphoma; and acute lymphocytic leukemia (ALL); chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD). Examples of solid tumors include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer, including small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous cell carcinoma of the lung; cancer of the peritoneum, hepatocellular carcinoma, gastric cancer, including gastrointestinal cancer, and gastrointestinal stromal cancer; cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, cancer of the urinary system, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatoma, anal carcinoma, penile carcinoma, melanoma, superficial spreading melanoma, lentigo maligna melanoma, acral lentigo melanoma, nodular melanoma, and abnormal blood vessel proliferation associated with nematoses, edema (such as that associated with brain tumors), Meigs syndrome, brain, and head and neck cancer, and associated metastases. In certain embodiments, cancers suitable for treatment with the antibodies of the invention include breast cancer, colorectal cancer, rectal cancer, non-small cell lung cancer, glioblastoma, non-Hodgkin's lymphoma (NHL), renal cell carcinoma, prostate cancer, liver cancer, pancreatic cancer, soft tissue sarcoma, Kaposi's sarcoma, carcinoid carcinoma, head and neck cancer, ovarian cancer, and mesothelioma.

[0275] "Complement-dependent cytotoxicity" 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 antibodies (of the appropriate subclass). To assess complement activation, assays such as those described in, for example, Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996) can be performed.

[0276] "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a form of cytotoxicity in which secreted Ig bound to Fc receptors (FcR) present on certain cytotoxic cells (e.g., natural killer (NK) cells, neutrophils, macrophages) enables these cytotoxic effector cells to specifically bind to target cells containing antigens and subsequently kill the target cells with cytotoxic agents. These antibodies "arm" the cytotoxic cells and are absolutely necessary for such killing. NK cells, the primary cells mediating ADCC, express only FcγRIII, while monocytes express FcγRI, FcγRII, and FcγRIII. Expression of FcR 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 the molecule of interest, in vitro ADCC assays such as those described in U.S. Patent No. 5,500,362 or 5,821,337 can be carried out.Effector cells useful for such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells.Alternatively or additionally, the ADCC activity of the molecule of interest can be evaluated in vivo, for example in animal models such as those disclosed in Clynes et al., Proc.Natl.Acad.Sci.USA.95:652-656,1998.

[0277] As used herein, "complex" or "complex type" refers to an association of two or more molecules that interact with each other through bonds and / or forces (e.g., van der Waals, hydrophobic, hydrophilic forces) that are not peptide bonds. In one embodiment, the complex is a heteromultimer. The term "protein complex" or "polypeptide complex" as used herein should be understood to include complexes having non-proteinaceous entities conjugated to proteins in the protein complex (e.g., including but not limited to chemical molecules such as toxins or detection agents).

[0278] As used herein, "delaying the progression" of a disorder or disease means to postpone, prevent, slow down, retard, stabilize, and / or delay the development of a disease or disorder (e.g., a cell proliferative disorder, such as cancer (e.g., MM)). This retardation can be of various durations depending on the history of the disease and / or the individual being treated. As will be apparent to one of skill in the art, a sufficient or significant retardation can, in effect, encompass prevention, in that the individual does not develop the disease. For example, late-stage cancer, such as the onset of metastasis, can be retarded.

[0279] An "effective amount" of a compound, e.g., an anti-FcRH5 / anti-CD3 T cell-dependent bispecific antibody (TDB) of the present invention or a composition thereof (e.g., a pharmaceutical composition), is at least the minimum amount necessary to achieve a desired therapeutic or prophylactic result, such as a measurable improvement or prevention of a particular disorder (e.g., a cell proliferative disorder, e.g., cancer). An effective amount herein may vary depending on factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in the individual. An effective amount is also one in which any toxic or adverse effects of the treatment are outweighed by the therapeutically beneficial effects. Beneficial or desired results for prophylactic use include results such as elimination or reduction of risk, reduction in severity, or delay in onset of disease, including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes manifested during the development of the disease. In the case of therapeutic use, the beneficial or desired result includes clinical results such as reduction of one or more symptoms caused by the disease, improvement of the quality of life of the person suffering from the disease, reduction of the dose of other drugs required for the treatment of the disease, enhancement of the effect of another drug (e.g., by targeting), delay of disease progression, and / or prolongation of survival. In the case of cancer or tumor, an effective amount of the drug can have the effect of reducing the number of cancer cells, reducing tumor size, inhibiting (i.e., slowing to some extent or desirably stopping) the invasion of cancer cells into peripheral organs, inhibiting (i.e., slowing to some extent or desirably 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 amount may be a single administration or multiple administrations. In the present invention, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve a prophylactic or therapeutic treatment. As understood in the clinical field, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" can be considered in the context of administration of one or more therapeutic agents, and a single agent can be viewed as being given in an effective amount if, in conjunction with one or more other agents, a desired result can be or is achieved.

[0280] As used herein, "overall survival" or "OS" refers to the percentage of individuals in a group who are likely to be surviving after a particular period of time.

[0281] As used herein, "objective response rate" (ORR) refers to the sum of stringent complete response (sCR) rate, complete response (CR) rate, very good partial response (VGPR) rate, and partial response (PR) rate as determined using the International Myeloma Working Group Response Criteria (see, e.g., Tables 9A and 9B in Example 1).

[0282] The term "epitope" refers to a specific site on an antigen molecule to which an antibody binds. In some embodiments, the specific site on an antigen molecule to which an antibody binds is determined by hydroxyl radical footprinting. In some embodiments, the specific site on an antigen molecule to which an antibody binds is determined crystallographically.

[0283] As used herein, a "growth inhibitor" refers to a compound or composition that inhibits cell growth in vitro or in vivo. In one embodiment, the growth inhibitor is a growth inhibitor antibody that inhibits or reduces the growth of cells expressing the antigen to which the antibody binds. In another embodiment, the growth inhibitor may significantly reduce the percentage of cells in S phase. Embodiments of growth inhibitors include agents that block cell cycle progression (at a place other than S phase), such as agents that induce G1 arrest or M-phase arrest. Classical M-phase blockers include vincas (vincristine and vinblastine), taxanes, and topoisomerase II inhibitors, such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. Agents that arrest G1, such as DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and araC, also extend to S-phase arrest. Further information can be found in Mendelsohn and Israel, eds., The Molecular Basis of Cancer, Chapter 1, entitled "Cell cycle regulation, oncogenes, and antitineoplastic drugs" (Murakami et al. (WB Saunders, Philadelphia, 1995)), e.g., p. 13. The taxanes (paclitaxel and docetaxel) are anticancer drugs, both derived from the yew tree. Docetaxel (TAXOTERE®, Rhone-Poulenc Rorer), derived from the European yew tree, is a semisynthetic analogue of paclitaxel (TAXOL®, Bristol-Myers Squibb). Paclitaxel and docetaxel promote the assembly of microtubules from tubulin dimers, stabilize microtubules by preventing depolymerization, and inhibit mitosis in cells.

[0284] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including, but not limited to, a cytotoxic agent.

[0285] The term "immunomodulatory agent" or "IMiD" refers to a class of molecules that modify immune system responses or immune system functions. Immunomodulatory agents include, but are not limited to, POMALYST® (pomalidomide), thalidomide (α-N-phthalimido-glutarimide) and its analogs, OTEZLA® (apremilast), REVLIMID® (lenalidomide) and PD-1 axis binding antagonists and pharma- ceutical acceptable salts or acids thereof.

[0286] A "subject" or "individual" is a mammal. Mammals include, but are not limited to, domestic animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the subject or individual is a human. The subject may be a patient.

[0287] An "isolated" protein or peptide is one that is separated from a component of its natural environment. In some embodiments, the protein or peptide is purified to greater than 95% or 99% purity, for example, as determined by electrophoresis (e.g., sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC).

[0288] An "isolated" nucleic acid refers to a nucleic acid molecule that is separated from components of its natural environment. Isolated nucleic acid includes a nucleic acid molecule contained within a cell that normally contains the nucleic acid molecule, but where the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0289] The term "PD-1 axis binding antagonist" refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with one or more of its binding partners to eliminate T cell dysfunction caused by signaling on the PD-1 signaling axis, thereby restoring or enhancing T cell function (e.g., proliferation, cytokine production, and / or target cell killing). As used herein, a PD-1 axis binding antagonist includes a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist. In some cases, the PD-1 axis binding antagonist includes a PD-L1 binding antagonist or a PD-1 binding antagonist. In a preferred embodiment, the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

[0290] The term "PD-L1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or prevents signaling resulting from the interaction of PD-L1 with any one or more of its binding partners, e.g., PD-1 and / or B7-1. In some cases, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In certain embodiments, a PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 and / or B7-1. In some cases, PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or prevent signaling resulting from the interaction of PD-L1 with one or more of its binding partners, e.g., PD-1 and / or B7-1. In one case, the PD-L1 binding antagonist reduces the negative costimulatory signal mediated by or through a cell surface protein expressed on T lymphocytes via signaling through PD-L1, so as to render dysfunctional T cells non-dysfunctional (e.g., enhance effector responses to antigen recognition). In some cases, the PD-L1 binding antagonist binds to PD-L1. In some cases, the PD-L1 binding antagonist is an anti-PD-L1 antibody (e.g., an anti-PD-L1 antagonist antibody). Exemplary anti-PD-L1 antagonist antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001, embafolimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636.In some embodiments, the anti-PD-L1 antibody is atezolizumab, MDX-1105, MEDI4736 (durvalumab), or MSB0010718C (avelumab). In one particular embodiment, the PD-L1 binding antagonist is MDX-1105. In another particular embodiment, the PD-L1 binding antagonist is MEDI4736 (durvalumab). In another particular embodiment, the PD-L1 binding antagonist is MSB0010718C (avelumab). In other embodiments, the PD-L1 binding antagonist may be a small molecule, such as GS-4224, INCB086550, MAX-10181, INCB090244, CA-170, or ABSK041, and in some cases may be administered orally. Other exemplary PD-L1 binding antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003 and JS-003. In a preferred embodiment, the PD-L1 binding antagonist is atezolizumab. Atezolizumab is also listed in HO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN:List 112, Vol.28, No.4, published January 16, 2015 (see page 485).

[0291] The term "PD-1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or prevents signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, e.g., PD-L1 and / or PD-L2. PD-1 (programmed death 1) is also referred to in the art as "programmed cell death 1," "PDCD1," "CD279," and "SLEB2." An exemplary human PD-1 is set forth in UniProtKB / Swiss-Prot Accession No. Q15116. In some cases, a PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In certain embodiments, a PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and / or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or interfere with signaling resulting from the interaction of PD-1 with PD-L1 and / or PD-L2. In one case, the PD-1 binding antagonist reduces the negative costimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes via signaling through PD-1, so as to render dysfunctional T cells non-dysfunctional (e.g., enhance effector responses to antigen recognition). In some cases, the PD-1 binding antagonist binds to PD-1. In some cases, the PD-1 binding antagonist is an anti-PD-1 antibody (e.g., an anti-PD-1 antagonist antibody).Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (cemiplimab), BGB-108, prorugolimab, canrelizumab, sintilimab, tislelizumab, toripalimab, dostarimab, retifanlimab, sasanlimab, penprimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimuzumab, BI 754091, cetrelimab, YBL-006, BAT1306, HX008, budicalimab, AMG404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103 and hAb21. In a particular embodiment, the PD-1 binding antagonist is MDX-1106 (nivolumab). In another particular embodiment, the PD-1 binding antagonist is MK-3475 (pembrolizumab). In another particular embodiment, the PD-1 binding antagonist is a PD-L2 Fc fusion protein, such as AMP-224. In another particular embodiment, the PD-1 binding antagonist is MED1-0680. In another particular embodiment, the PD-1 binding antagonist is PDR001 (spartalizumab). In another particular embodiment, the PD-1 binding antagonist is REGN2810 (cemiplimab). In another particular embodiment, the PD-1 binding antagonist is BGB-108. In another particular embodiment, the PD-1 binding antagonist is prorugolimab. In another particular embodiment, the PD-1 binding antagonist is canrelizumab. In another particular embodiment, the PD-1 binding antagonist is sintilimab. In another particular embodiment, the PD-1 binding antagonist is tislelizumab. In another particular embodiment, the PD-1 binding antagonist is toripalimab. Other additional exemplary PD-1 binding antagonists include BION-004, CB201, AUNP-012, ADG104, and LBL-006.

[0292] The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or prevents signaling resulting from the interaction of PD-L2 with any one or more of its binding partners, e.g., PD-1. PD-L2 (programmed death ligand 2) is also referred to in the art as "programmed cell death 1 ligand 2," "PDCD1LG2," "CD273," "B7-DC," "Btdc," and "PDL2." An exemplary human PD-L2 is set forth in UniProtKB / Swiss-Prot Accession No. Q9BQ51. In some cases, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In certain embodiments, a PD-L2 binding antagonist inhibits the binding of PD-L2 to PD-1. Exemplary PD-L2 antagonists include anti-PD-L2 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or interfere with signaling resulting from the interaction of PD-L2 with any one or more of its binding partners, such as PD-1. In one embodiment, the PD-L2 binding antagonist reduces the negative costimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes via signaling through PD-L2, such that dysfunctional T cells are rendered non-dysfunctional (e.g., enhance effector responses to antigen recognition). In some embodiments, the PD-L2 binding antagonist binds to PD-L2. In some embodiments, the PD-L2 binding antagonist is an immunoadhesin. In other embodiments, the PD-L2 binding antagonist is an anti-PD-L2 antagonist antibody.

[0293] Unless otherwise specified, the term "protein" as used herein 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. The term also includes "full-length," unprocessed proteins, and any form of protein resulting from processing within a cell. The term also encompasses naturally occurring variants of the protein, such as splice variants or allelic variants.

[0294] "Percentage (%) amino acid sequence identity" to 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 a reference polypeptide sequence, after aligning the sequences and introducing gaps if necessary to achieve maximum percent sequence identity, without considering any conservative substitutions as part of sequence identity for alignment. Alignment for determining percent amino acid sequence identity can be achieved in various ways within the skill of the art, for example, using publicly available computer software, such as BLAST, BLAST-2, Clustal W, Megalign (DNASTAR) software or FASTA program package. Those skilled in the art can determine the appropriate parameters for sequence alignment, including any algorithms required to achieve maximum alignment over the entire length of the sequences to be compared. Alternatively, percent identity values ​​can be generated using sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was written by Genentech, Inc. and the source code is on file in the user documentation at the US Copyright Office, Washington DC, 20559, registered under US Copyright Registration No. TXU510087, and described in WO 2001 / 007611.

[0295] Unless otherwise indicated, for purposes herein, percent amino acid sequence identity values ​​are generated using the ggsearch program of the FASTA package version 36.3.8c, or the subsequent BLOSUM50 comparison matrix. The FASTA program package is described by WR Pearson and DJ Lipman (1988), "Improved Tools for Biological Sequence Analysis," PNAS 85:2444-2448; WR Pearson (1996) "Effective protein sequence comparison," Meth. Enzymol. 266:227-258; and Pearson et.al. (1997) Genomics 46:24-36, and is publicly available at www.fasta.bioch.virginia.edu / fasta_www2 / fasta_down.shtml or www.ebi.ac.uk / Tools / sss / fasta. Alternatively, sequences can be compared using the public server accessible at fasta.bioch.virginia.edu / fasta_www2 / index.cgi using the ggsearch(global protein:protein) program and default options (BLOSUM50; open:-10; ext:-2; Ktup=2), ensuring a global rather than local alignment. Percent amino acid identity is indicated in the output alignment header.

[0296] The term "pharmaceutical formulation" refers to a preparation that is in a form such that the biological activity of the active ingredients contained in the preparation is effective, and that does not contain additional components that are unacceptably toxic to the subject to which the formulation is administered.

[0297] "Pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0298] "Radiation therapy" refers to the use of directed gamma or beta radiation to inflict sufficient damage on cells to limit their ability to function normally or to destroy them completely. It will be appreciated that there are many methods known in the art for determining dosage and duration of treatment. A typical treatment is given as a single administration, with typical dosages ranging from 10 to 200 units (grays) per day.

[0299] As used herein, "treatment" (and grammatical variants thereof, e.g., "treat" or "treating") refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed for prophylaxis or during the course of clinical pathology. The desired effects of treatment include preventing the onset or recurrence of disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, remission or alleviation of disease symptoms, and improving or improving prognosis. In some embodiments, the antibodies of the present invention (e.g., the anti-FcRH5 / anti-CD3 TDB of the present invention) are used to delay the onset of disease or to slow the progression of disease.

[0300] "Reducing" or "inhibiting" refers to the ability to cause an overall decrease, for example, of 20% or more, 50% or more, or 75%, 85%, 90%, 95% or more. In certain embodiments, reducing or inhibiting can refer to antibody effector functions mediated by the antibody Fc region, such effector functions specifically include CDC, ADCC and ADCP.

[0301] According to the present invention, the term "vaccine" refers to a pharmaceutical preparation (pharmaceutical composition) or product that upon administration induces an immune response, particularly a cellular immune response, to recognize and attack a pathogen or diseased cells, such as cancer cells. Vaccines may be used for the prevention or treatment of diseases. The vaccine may be a cancer vaccine. As used herein, a "cancer vaccine" is a composition that stimulates a subject's immune response against cancer. Cancer vaccines typically consist of a source of cancer-related substances or cells (antigens), which are autologous (derived from the self) or allogeneic (derived from another person) to the subject, and are administered to the subject along with other components (e.g., adjuvants) to further stimulate and enhance the immune response against the antigens. Cancer vaccines may result in the stimulation of the subject's immune system to produce antibodies against one or more specific antigens and / or killer T cells to attack cancer cells bearing those antigens.

[0302] As used herein, "administering" refers to the method of giving a dose of a compound (e.g., an anti-FcRH5 / anti-CD3 TDB, e.g., cevostamab, an IMiD (e.g., pomalidomide), an anti-CD38 antibody (e.g., daratumumab) or a corticosteroid (e.g., dexamethasone)) to a subject. In some embodiments, the compositions utilized in the methods herein are administered intravenously. The composition utilized in the method described herein can be administered, for example, intramuscularly, intravenously, intradermally, transdermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctivally, intravesicularly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, by local perfusion bath target cell directly, by catheter, by perfusion, in cream or in lipid composition.The method of administration can vary according to various factors (e.g., the compound or composition to be administered and the severity of the symptom, disease or disorder to be treated).

[0303] As used herein, "CD38" refers to a glycoprotein found on the surface of many immune cells, including CD4+, CD8+, B lymphocytes, and natural killer (NK) cells, and includes any native CD38 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. CD38 is typically expressed at higher levels and more uniformly on myeloma cells compared to normal lymphoid and myeloid cells. The term encompasses "full-length," unprocessed CD38, and any form of CD38 resulting from processing within the cell. The term also encompasses naturally occurring variants of CD38, such as splice variants or allelic variants. CD38 is also referred to in the art as cluster of differentiation 38, ADP-ribosyl cyclase 1, cADPr hydrolase 1, and cyclic ADP-ribose hydrolase 1. CD38 is encoded by the CD38 gene. An exemplary nucleic acid sequence of human CD38 is set forth in NCBI reference sequence NM_001775.4 or SEQ ID NO: 33. An exemplary amino acid sequence of a human CD38 protein encoded by CD38 is set forth in UniProt Accession No. P28907 or SEQ ID NO: 34.

[0304] The term "anti-CD38 antibody" encompasses all antibodies that bind to CD38 with sufficient affinity such that the antibody is useful as a therapeutic agent in targeting cells expressing the antigen and does not significantly cross-react with other proteins, such as negative control proteins, in the assays described below. For example, anti-CD38 antibodies can bind to CD38 on the surface of MM cells and mediate cell lysis through activation of complement-dependent cytotoxicity, ADCC, antibody-dependent cellular phagocytosis (ADCP), and apoptosis mediated by Fc cross-linking, resulting in depletion of malignant cells and reduction in overall cancer burden. Anti-CD38 antibodies can also modulate CD38 enzyme activity through inhibition of ribosyl cyclase enzyme activity and stimulation of cyclic adenosine diphosphate ribose (cADPR) hydrolase activity of CD38. In certain embodiments, anti-CD38 antibodies that bind to CD38 have a binding affinity of ≦1 μM, ≦100 nM, ≦10 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~10 -13 M, for example 10 -9 M~10- -13 Dissociation constant (K D ). In certain embodiments, the anti-CD38 antibody can bind to both human CD38 and chimpanzee CD38. Anti-CD38 antibodies also include anti-CD38 antagonist antibodies. Bispecific antibodies, in which one arm of the antibody binds to CD38, are also contemplated. This definition of anti-CD38 antibodies also encompasses functional fragments of the aforementioned antibodies. Examples of antibodies that bind to CD38 include daratumumab (DARZALEX®) (U.S. Pat. No. 7,829,673 and U.S. Pat. Publication No.: 20160067205A1); "MOR202" (U.S. Pat. No. 8,263,746); and isatuximab (SAR-650984).

[0305] II. Treatment method The present invention is based in part on a method of treating a subject with cancer (e.g., multiple myeloma (MM)) with a dosing regimen that includes a fractionated dose escalation dosing regimen using an anti-fragment crystallinity receptor-like 5 (FcRH5) / anti-cluster of differentiation 3 (CD3) bispecific antibody. The present invention provides dosing regimens for cebostamab monotherapy, and combinations of cebostamab with 1) pomalidomide and dexamethasone (Pd), and 2) daratumumab and dexamethasone (Dd). Exemplary dosing regimens described herein are of cebostamab as a single agent in a dose-dense dosing regimen, where cebostamab is administered in 28-day cycles, and cebostamab is administered Q1W for the first two cycles (C1 and C2), Q2W for cycles 3-6, and Q4W for cycles 7-13. Another exemplary dosing regimen described herein is cebostamab administered with Pd in ​​28-day cycles, with cebostamab administered Q2W for the first 24 weeks (cycles 1-6) and then Q4W (cycles 7 onwards). Another exemplary dosing regimen described herein is also cebostamab administered with Dd in 21-day cycles, with cebostamab administered Q3W for the first 24 weeks (cycles 1-8) and then Q4W (cycles 9 onwards). The methods disclosed herein may, for example, facilitate alignment with the dosing schedule of combination therapy partners. The methods are expected to reduce or inhibit undesired treatment effects, including cytokine-driven toxicity (e.g., cytokine release syndrome (CRS)), infusion-related reactions (IRR), macrophage activation syndrome (MAS), neurotoxicity, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, and / or liver enzyme elevation. Thus, these methods are useful for treating subjects while achieving a more favorable benefit-risk profile.

[0306] The present invention provides methods useful for treating a subject with cancer (e.g., multiple myeloma), comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 (i.e., an anti-FcRH5 / anti-CD3 antibody), e.g., in a split, dose-escalating dosing regimen, either as monotherapy or in combination with one or more additional therapeutic agents (e.g., an IMiD (e.g., pomalidomide), an anti-CD38 antibody (e.g., daratumumab), a corticosteroid (e.g., dexamethasone), or a combination thereof).

[0307] A. Dosing Regimen i. Non-escalation dosing regimen In some embodiments, the invention provides a method of treating a subject with cancer (e.g., multiple myeloma (MM)), comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 in a dosing regimen that does not administer any escalating doses.

[0308] In some embodiments, the invention provides a method of treating a subject with MM, comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 in a dosing regimen comprising at least a first administration cycle, the first administration cycle comprising a first dose of the bispecific antibody (C1D1), wherein the C1D1 is about 0.15 mg to about 1000 mg (e.g., about 0.5 mg to about 800 mg, about 1 mg to about 700 mg, about 5 mg to about 500 mg, about 10 mg to about 400 mg, about 25 mg to about 300 mg, about 40 mg to about 200 mg, about 50 mg to about 100 mg, about 75 mg to about 100 mg, or about 85 mg to about 100 mg).

[0309] In some aspects, the invention provides a method of treating a subject having cancer (e.g., MM), comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 in a dosing regimen comprising at least a first administration cycle, the first administration cycle comprising a first dose (C1D1) of the bispecific antibody of about 0.15 mg to about 1000 mg (e.g., about 0.5 mg to about 800 mg, about 1 mg to about 700 mg, about 5 mg to about 500 mg, about 10 mg to about 400 mg, about 25 mg to about 300 mg, about 40 mg to about 200 mg, about 50 mg to about 100 mg, about 75 mg to about 100 mg, or about 85 mg to about 100 mg).

[0310] In some embodiments, C1D1 is about 20 mg to about 600 mg (e.g., about 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., about 20, 40, 60, 80, 90, 100, 120, 130, 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, C1D1 is 90 mg. In some embodiments, C1D1 is 132 mg. In some embodiments, C1D1 is 160 mg.

[0311] ii. One-step escalation dosing regimen In some embodiments, the invention provides a method of treating a subject having cancer (e.g., MM), comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 in an escalating dosing regimen.

[0312] In some embodiments, the invention provides a method of treating a subject having MM, comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, the first dosing cycle comprising a first dose of the bispecific antibody (C1D1) and a second dose of the bispecific antibody (C1D2), wherein the C1D1 is administered at a dose of about 0.05 mg to about 180 mg (e.g., about 0.1 mg to about 160 mg, about 0.5 mg to about 140 mg, about 1 mg to about 120 mg, about 1.5 mg to about 100 mg, about 2. and C1D2 is about 0.15 mg to about 1000 mg (e.g., about 0.5 mg to about 800 mg, about 1 mg to about 700 mg, about 5 mg to about 500 mg, about 10 mg to about 400 mg, about 25 mg to about 300 mg, about 40 mg to about 200 mg, about 50 mg to about 100 mg, about 75 mg to about 100 mg, or about 85 mg to about 100 mg).

[0313] In some embodiments, the invention provides a method of treating a subject having cancer (e.g., MM), comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein (a) the first dosing cycle comprises a first dose of the bispecific antibody (C1D1; cycle 1, dose 1) and a second dose of the bispecific antibody (C1D2; Cycle 1, dose 2), C1D1 is less than C1D2, and C1D1 is about 0.05 mg to about 180 mg (e.g., about 0.1 mg to about 160 mg, about 0.5 mg to about 140 mg, about 1 mg to about 120 mg, about 1.5 mg to about 100 mg, about 2.0 mg to about 80 mg, about 2.5 mg to about 50 mg, about 3.0 mg to about 25 mg, about 3.0 mg to about 15 mg, about 3.0 mg to about 10 mg, or about 3.0 mg to about 5 mg), C1D2 is about 0.15 mg to about 1000 mg (e.g., about 0.5 mg to about 800 mg, about 1 mg to about 700 mg, about 5 mg to about 500 mg, about 10 mg to about 400 mg, about 25 mg to about 300 mg, about 40 mg to about 200 mg, about 50 mg to about 100 mg, about 75 mg to about 100 mg, or about 85 mg to about 100 mg), and (b) the second administration cycle is a single dose of the bispecific antibody ( C2D1; cycle 2, dose 1), wherein C2D1 is equal to or greater than C1D2 and is about 0.15 mg to about 1000 mg (e.g., about 0.5 mg to about 800 mg, about 1 mg to about 700 mg, about 5 mg to about 500 mg, about 10 mg to about 400 mg, about 25 mg to about 300 mg, about 40 mg to about 200 mg, about 50 mg to about 100 mg, about 75 mg to about 100 mg, or about 85 mg to about 100 mg).

[0314] In some embodiments, (a) C1D1 is from about 0.5 mg to about 19.9 mg (e.g., from about 1 mg to about 18 mg, from about 2 mg to about 15 mg, from about 3 mg to about 10 mg, from about 3.3 mg to about 6 mg, or from about 3.4 mg to about 4 mg, e.g., about 3 mg, 3.2 mg, 3.4 mg, 3.6 mg, 3.8 mg, 4 mg, 4.2 mg, 4.4 mg, 4.6 mg, 4.8 mg, 5 mg, 5.2 mg, 5.6 mg, 5.8 mg, 6 mg, 6.2 mg, 6.4 mg, 6.6 mg, 6.8 mg, 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, 1 0.6mg, 10.8mg, 11mg, 11.2mg, 11.4mg, 11.6mg, 11.8mg, 12mg, 12.2mg, 12.4mg, 12.6mg, 12.8mg, 13mg, 13.2mg, 13.4mg, 13.6mg, 13.8 mg, 14 mg, 14.2 mg, 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), and (b) C1D2 is about 20 mg to about 600 mg (e.g., about 30 mg g 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, for example, about 20, 40, 60, 80, 90, 100, 120, 130, 132, 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).

[0315] In some embodiments, C1D1 is about 1.2 mg to about 10.8 mg, and C1D2 is about 80 mg to about 300 mg. In some embodiments, C1D1 is 1.2 mg to 10.8 mg, and C1D2 is 80 mg to 300 mg. In some embodiments, C1D1 is 3.6 mg, and C1D2 is 90 mg. In some embodiments, C1D1 is 3.6 mg, and C1D2 is 132 mg. In some embodiments, C1D1 is 3.6 mg, and C1D2 is 160 mg.

[0316] In some cases, the methods described above may include a first administration cycle of 4 weeks or 28 days. In some cases, the methods may include administering C1D1 and C1D2 to the subject on or about days 1 and 8, respectively, of the first administration cycle.

[0317] In some cases, the methods described above may include a first administration cycle of 3 weeks or 21 days. In some cases, the methods may include administering C1D1 and C1D2 to the subject on or about days 1 and 8, respectively, of the first administration cycle.

[0318] In some cases, the methods described above may include a first administration cycle of 3 weeks or 21 days. In some cases, the methods may include administering C1D1 and C1D2 to the subject on or about day 2 and day 9, respectively, of the first administration cycle.

[0319] In some cases, the methods described above may include a first administration cycle of 3 weeks or 21 days. In some cases, the methods may include administering C1D1 and C1D2 to the subject on or about day 3 and day 9, respectively, of the first administration cycle.

[0320] iii. Two-step ascending dosing regimen In another aspect, the invention provides a method of treating a subject having cancer (e.g., MM), comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 in a two-step ascending dosing regimen.

[0321] In some aspects, the disclosure provides a method of treating a subject having cancer (e.g., MM), comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, the first dosing cycle comprising a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3), wherein the C1D1 is about 0.2 mg to about 0.4 mg. (e.g., about 0.20 mg, 0.21 mg, 0.22 mg, 0.23 mg, 0.24 mg, 0.25 mg, 0.26 mg, 0.27 mg, 0.28 mg, 0.29 mg, 0.30 mg, 0.31 mg, 0.32 mg, 0.33 mg, 0.34 mg, 0.35 mg, 0.36 mg, 0.37 mg, 0.38 mg, 0.39 mg, or 0.40 mg), wherein C1D2 is greater than C1D1 and C1D3 is greater than C1D2. In some embodiments, C1D1 is about 0.3 mg.

[0322] In some embodiments, C1D1 is 0.2 mg to 0.4 mg (e.g., 0.20 mg, 0.21 mg, 0.22 mg, 0.23 mg, 0.24 mg, 0.25 mg, 0.26 mg, 0.27 mg, 0.28 mg, 0.29 mg, 0.30 mg, 0.31 mg, 0.32 mg, 0.33 mg, 0.34 mg, 0.35 mg, 0.36 mg, 0.37 mg, 0.38 mg, 0.39 mg, or 0.40 mg). In some embodiments, C1D1 is 0.3 mg.

[0323] In some aspects, the disclosure provides a method of treating a subject having cancer (e.g., MM), comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, the first dosing cycle comprising a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3), wherein C1D1 is from about 0.01 mg to about 2.9 mg, C1D2 is from about 3 mg to about 19.9 mg, and C1D3 is from about 20 mg to about 600 mg.

[0324] In some aspects, the invention provides a method of treating a subject having cancer (e.g., MM), comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 in a dosing regimen comprising at least a first administration cycle and a second administration cycle, wherein (a) the first administration cycle comprises a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2) and a third dose of the bispecific antibody (C1D3), wherein C1D1 and C1D2 are each less than C1D3, C1D1 being from about 0.01 mg to about 2.9 mg, C1D2 being from about 3 mg to about 19.9 mg, and C1D3 being from about 20 mg to about 600 mg; and (b) the second administration cycle comprises a single dose of the bispecific antibody (C2D1), wherein C2D1 is greater than or equal to C1D3 and is from about 20 mg to about 600 mg.

[0325] In some embodiments, C1D1 is about 0.05 mg to about 2.5 mg, about 0.1 mg to about 2 mg, about 0.2 mg to about 1 mg, or about 0.2 mg to about 0.4 mg (e.g., about 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, or 2.9 mg). In some embodiments, C1D1 is about 0.3 mg.

[0326] In some embodiments, C1D1 is 0.05 mg to 2.5 mg, 0.1 mg to 2 mg, 0.2 mg to 1 mg, or 0.2 mg to 0.4 mg (e.g., 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, or 2.9 mg). In some embodiments, C1D1 is 0.3 mg.

[0327] In some embodiments, C1D2 is about 3 mg to about 19.9 mg (e.g., about 3 mg to about 18 mg, about 3.1 mg to about 15 mg, about 3.2 mg to about 10 mg, about 3.3 mg to about 6 mg, or about 3.4 mg to about 4 mg, e.g., about 3 mg, 3.2 mg, 3.4 mg, 3.6 mg, 3.8 mg, 4 mg, 4.2 mg, 4.4 mg, 4.6 mg, 4.8 mg, 5 mg, 5.2 mg, 5.6 mg, 5.8 mg, 6 mg, 6.2 mg, 6.4 mg, 6.6 mg, 6.8 mg, 7 mg, 7.2 mg, 7.4 mg, 7.6 mg, 7.8 mg, 8 mg, 8.2 mg, 8.4 mg, 8.6 mg, 8.8 mg, 9 mg, 9.2 mg, 9.4 mg, 9.6 mg, 9.8 mg, 10 mg, 1 0.2mg, 10.4mg, 10.6mg, 10.8mg, 11mg, 11.2mg, 11.4mg, 11.6mg, 11.8mg, 12mg, 12.2mg, 12 .4mg, 12.6mg, 12.8mg, 13mg, 13.2mg, 13.4mg, 13.6mg, 13.8mg, 14mg, 14.2mg, 14.4mg, 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 embodiments, C1D2 is about 3.2 mg to about 10 mg. In some embodiments, C1D2 is about 3.6 mg.

[0328] In some embodiments, C1D2 is present in an amount between 3 mg and 19.9 mg (e.g., between 3 mg and 18 mg, between 3.1 mg and 15 mg, between 3.2 mg and 10 mg, between 3.3 mg and 6 mg, or between 3.4 mg and 4 mg, e.g., 3 mg, 3.2 mg, 3.4 mg, 3.6 mg, 3.8 mg, 4 mg, 4.2 mg, 4.4 mg, 4.6 mg, 4.8 mg, 5 mg, 5.2 mg, 5.6 mg, 5.8 mg, 6 mg, 6.2 mg, 6.4 mg, 6.6 mg, 6.8 mg, 7 mg, 7.2 mg, 7.4 mg, 7.6 mg, 7.8 mg, 8 mg, 8.2 mg, 8.4 mg, 8.6 mg, 8.8 mg, 9 mg, 9.2 mg, 9.4 mg, 9.6 mg, 9.8 mg, 10 mg, 10.2 mg, 1 0.4mg, 10.6mg, 10.8mg, 11mg, 11.2mg, 11.4mg, 11.6mg, 11.8mg, 12mg, 12.2mg, 12.4mg, 12.6mg, 12.8mg, 13mg, 13.2mg, 13.4mg, 13.6mg, 13.8mg, 14mg, 14.2mg, 14.4mg, 14.6mg, 14.8mg, 15mg, 15.2mg, 15.4mg, 15.6mg, 15.8mg, 16mg, 16.2mg, 16.4mg, 16.6mg, 16.8mg, 17mg, 18.2mg, 18.4mg, 18.6mg, 18.8mg, 19mg, 19.2mg, 19.4mg, 19.6mg, or 19.8mg). In some embodiments, C1D2 is between 3.2 mg and 10 mg. In some embodiments, C1D2 is 3.6 mg.

[0329] In some embodiments, C1D3 is about 20 mg to about 600 mg (e.g., about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 60 mg to about 350 mg, about 80 mg to about 300 mg, about 100 mg to about 200 mg, or about 140 mg to about 180 mg, e.g., about 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, C1D3 is about 80 mg to about 300 mg. In some embodiments, the C1D3 is about 90 mg. In some embodiments, the C1D3 is about 132 mg. In some embodiments, the C1D3 is about 160 mg.

[0330] In some embodiments, C1D3 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, C1D3 is 80 mg to 300 mg. In some embodiments, C1D3 is 90 mg. In some embodiments, the C1D3 is 132 mg. In some embodiments, the C1D3 is 160 mg.

[0331] In some embodiments, the method comprises only a single administration cycle of a bispecific antibody (eg, an administration cycle comprising C1D1, C1D2 and C1D3).

[0332] In other embodiments, the dosing regimen further comprises a second dosing cycle comprising at least a single dose of the bispecific antibody (C2D1). In some embodiments, C2D1 is greater than or equal to C1D3, and is about 20 mg to about 600 mg (e.g., about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 60 mg to about 350 mg, about 80 mg to about 300 mg, about 100 mg to about 200 mg, or about 140 mg to about 180 mg, e.g., about 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, C2D1 is about 80 mg to about 300 mg. In some embodiments, the C2D1 is about 90 mg. In some embodiments, the C2D1 is about 132 mg. In some embodiments, the C2D1 is about 160 mg.

[0333] In some embodiments, C2D1 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, C2D1 is 80 mg to 300 mg. In some embodiments, C2D1 is 90 mg. In some embodiments, the C2D1 is 132 mg. In some embodiments, the C2D1 is 160 mg.

[0334] Alternatively, in any of the above embodiments, C1D1 is from about 0.01 mg to about 60 mg (e.g., from about 0.05 mg to about 50 mg, from about 0.01 mg to about 40 mg, from about 0.1 mg to about 20 mg, from about 0.1 mg to about 10 mg, from about 0.1 mg to about 5 mg, from about 0.1 mg to about 2 mg, from about 0.1 mg to about 1.5 mg, from about 0.1 mg to about 1.2 mg, from about 0.1 mg to about 0.5 mg, or from about 0.2 mg to about 0.4 mg, for example, about 0.3 mg, C1D2 may be about 0.05 mg to about 180 mg (e.g., about 0.1 mg to about 160 mg, about 0.5 mg to about 140 mg, about 1 mg to about 120 mg, about 1.5 mg to about 100 mg, about 2.0 mg to about 80 mg, about 2.5 mg to about 50 mg, about 3.0 mg to about 25 mg, about 3.0 mg to about 15 mg, about 3.0 mg to about 10 mg, about 3.0 mg to about 5 mg, or about 3.0 mg to about 4.0 mg, for example, about 3.6 mg, for example, 3.6 mg), and C1D3 may be about 0.15 mg to about 1000 mg (for example, about 0.5 mg to about 800 mg, about 1 mg to about 700 mg, about 5 mg to about 500 mg, about 10 mg to about 400 mg, about 25 mg to about 300 mg, about 40 mg to about 200 mg, about 50 mg to about 190 mg, about 140 mg to about 180 mg, or about 150 mg to about 170 mg, for example, about 160 mg, for example, 160 mg). Preferably, in embodiments including a second administration cycle, C2D1 may be about 0.15 mg to about 1000 mg (e.g., about 0.5 mg to about 800 mg, about 1 mg to about 700 mg, about 5 mg to about 500 mg, about 10 mg to about 400 mg, about 25 mg to about 300 mg, about 40 mg to about 200 mg, about 50 mg to about 190 mg, about 140 mg to about 180 mg, or about 150 mg to about 170 mg, such as about 160 mg, e.g., 160 mg).

[0335] In some cases, the length of the first administration cycle is 3 weeks or 21 days. In some cases, the method may include administering C1D1, C1D2 and C1D3 to the subject on or about day 1, day 8 and day 15, respectively, of the first administration cycle.

[0336] In some cases, the length of the first administration cycle is 3 weeks or 21 days. In some cases, the method may include administering C1D1, C1D2 and C1D3 to the subject on or about day 1, day 8 and day 15, respectively, of the first administration cycle.

[0337] In some cases, the length of the first administration cycle is 3 weeks or 21 days. In some cases, the method may include administering C1D1, C1D2 and C1D3 to the subject on or about day 2, day 9 and day 16, respectively, of the first administration cycle.

[0338] In some cases, the length of the first administration cycle is 3 weeks or 21 days. In some cases, the method may include administering C1D1, C1D2 and C1D3 to the subject on or about day 3, day 9 and day 16, respectively, of the first administration cycle.

[0339] iv. Further cycles of treatment In some cases, the methods described above may include a second administration cycle of 3 weeks or 21 days. In some cases, the methods described above may include a second administration cycle of 4 weeks or 28 days. In some cases, the method may include administering C2D1 to the subject on or about day 1 of the second administration cycle.

[0340] In some cases where the method includes at least a second administration cycle, the method may include one or more additional administration cycles. In some cases, the dosing regimen includes 1 to 17 additional dosing cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 additional dosing cycles, e.g., 1 to 3 additional dosing cycles, 1 to 5 additional dosing cycles, 3 to 8 additional dosing cycles, 5 to 10 additional dosing cycles, 8 to 12 additional dosing cycles, 10 to 15 additional dosing cycles, 12 to 17 additional dosing cycles, or 15 to 17 additional dosing cycles, i.e., the dosing regimen includes one or more additional dosing cycle(s) C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, and C19.

[0341] In some embodiments, the length of each of the one or more additional administration cycles is 7 days, 14 days, 21 days, or 28 days. In some embodiments, the length of each of the one or more additional administration cycles is 5 days to 30 days, e.g., 5 to 9 days, 7 to 11 days, 9 to 13 days, 11 to 15 days, 13 to 17 days, 15 to 19 days, 17 to 21 days, 19 to 23 days, 21 to 25 days, 23 to 27 days, or 25 to 30 days. In some cases, the length of each of the one or more additional administration cycles is 3 weeks or 21 days. In some cases, the length of each of the one or more additional administration cycles is 4 weeks or 28 days.

[0342] In some cases, each of the one or more additional administration cycles comprises a single dose of the bispecific antibody. In some embodiments, the dose of the bispecific antibody in one or more additional administration cycles is equal to C2D1, e.g., about 20 mg to about 600 mg (e.g., about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 60 mg to about 350 mg, about 80 mg to about 300 mg, about 100 mg to about 200 mg, or about 140 mg to about 180 mg, e.g., about 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 dose of the bispecific antibody in one or more additional cycles of administration is about 90 mg. In some embodiments, the dose of the bispecific antibody in one or more additional cycles of administration is about 132 mg. In some embodiments, the dose of the bispecific antibody in one or more additional cycles of administration is about 160 mg. In some embodiments, the dose of the bispecific antibody in one or more additional administration cycles is equal to C2D1, e.g., 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 dose of the bispecific antibody in one or more additional administration cycles is 90 mg. In some embodiments, the dose of the bispecific antibody in one or more additional administration cycles is 132 mg. In some embodiments, the dose of the bispecific antibody in one or more additional administration cycles is about 160 mg.

[0343] In some cases, the method includes administering to the subject a single dose of the bispecific antibody on, or about, day 1 of one or more additional administration cycles. In some cases, the method includes administering to the subject a single dose of the bispecific antibody on, or about, days 1 and 15 of one or more additional administration cycles. In some cases, the method includes administering to the subject a single dose of the bispecific antibody on, or about, days 1, 8, 15 and 22 of one or more additional administration cycles.

[0344] In some embodiments, the bispecific antibody is administered to the subject every 7 days (QW) until progressive disease is observed for up to 18 cycles or until minimal residual disease (MRD). In some embodiments, the bispecific antibody is administered to the subject every 14 days (Q2W) until progressive disease is observed for up to 18 cycles or until minimal residual disease (MRD). In some embodiments, the bispecific antibody is administered to the subject every 21 days (Q3W) until progressive disease is observed for up to 18 cycles or until minimal residual disease (MRD). In some embodiments, the bispecific antibody is administered to the subject every 28 days (Q4W) until progressive disease is observed for up to 18 cycles or until minimal residual disease (MRD).

[0345] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject as a monotherapy. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject in combination with another therapeutic agent. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject in combination with an anti-CD38 antibody. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject in combination with a corticosteroid. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject in combination with an immunomodulatory drug (IMiD). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject in combination with an anti-CD38 antibody and a corticosteroid. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject in combination with an IMiD and a corticosteroid. Exemplary anti-CD38 antibodies used in combination therapy include daratumumab and isatuximab. Exemplary corticosteroids used in combination therapy include dexamethasone and methylprednisolone. Exemplary IMiDs used in combination therapy include pomalidomide and lenalidomide.

[0346] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is cebostamab. In some cases, cebostamab is administered to the subject as monotherapy. In some cases, cebostamab is administered to the subject in combination with pomalidomide (P). In some cases, cebostamab is administered to the subject in combination with dexamethasone (d). In some cases, cebostamab is administered to the subject in combination with pomalidomide and dexamethasone (Pd). In some cases, cebostamab is administered to the subject in combination with daratumumab (D). In some cases, cebostamab is administered to the subject in combination with daratumumab and dexamethasone (Dd).

[0347] B. Dosing Regimen The present disclosure describes a method of treating a subject with cancer (e.g., multiple myeloma (MM)), comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 in a dosing regimen described herein. In some examples, the dosing regimen comprises a first phase comprising one or more dosing cycles, a second phase comprising one or more dosing cycles, and a third phase comprising one or more dosing cycles. In some examples, each dosing cycle is a 28-day dosing cycle. The first phase may comprise administering the bispecific antibody to the subject every week (QW), the second phase may comprise administering the bispecific antibody to the subject every two weeks (Q2W), and / or the third phase may comprise administering the bispecific antibody to the subject every four weeks (Q4W).

[0348] For example, provided herein is a method of treating a subject with cancer (e.g., MM), comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, the first phase comprising administering the bispecific antibody to the subject every week (QW); (ii) a second phase comprising one or more dosing cycles, the second phase comprising administering the bispecific antibody to the subject every two weeks (Q2W); and / or (iii) a third phase comprising one or more dosing cycles, the third phase comprising administering the bispecific antibody to the subject every four weeks (Q4W). In some examples, the dosing regimen comprises a first phase. In some examples, the dosing regimen comprises a second phase. In some examples, the dosing regimen comprises a third phase. In some examples, the dosing regimen comprises a first phase and a second phase. In some examples, the dosing regimen comprises a first phase and a third phase. In some instances, the dosing regimen includes a second phase and a third phase.

[0349] In another example, provided herein is a bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with cancer (e.g., MM), the treatment comprising administering the bispecific antibody to the subject in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, the first phase comprising administering the bispecific antibody to the subject every week (QW); (ii) a second phase comprising one or more dosing cycles, the second phase comprising administering the bispecific antibody to the subject every two weeks (Q2W); and / or (iii) a third phase comprising one or more dosing cycles, the third phase comprising administering the bispecific antibody to the subject every four weeks (Q4W). In some examples, the dosing regimen comprises the first phase. In some examples, the dosing regimen comprises the second phase. In some examples, the dosing regimen comprises the third phase. In some examples, the dosing regimen comprises the first phase and the second phase. In some examples, the dosing regimen comprises the first phase and the third phase. In some instances, the dosing regimen includes a second phase and a third phase.

[0350] In another example, provided herein is the use of a bispecific antibody that binds FcRH5 and CD3 in the manufacture of a medicament for the treatment of a subject with cancer (e.g., MM), the treatment comprising administering the bispecific antibody to a subject in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, the first phase comprising administering the bispecific antibody to the subject every week (QW); (ii) a second phase comprising one or more dosing cycles, the second phase comprising administering the bispecific antibody to the subject every two weeks (Q2W); and / or (iii) a third phase comprising one or more dosing cycles, the third phase comprising administering the bispecific antibody to the subject every four weeks (Q4W). In some examples, the dosing regimen comprises the first phase. In some examples, the dosing regimen comprises the second phase. In some examples, the dosing regimen comprises the third phase. In some examples, the dosing regimen comprises the first phase and the second phase. In some examples, the dosing regimen comprises the first phase and the third phase. In some instances, the dosing regimen includes a second phase and a third phase.

[0351] The first phase can include any suitable number of administration cycles. For example, in some examples, the first phase can include at least 2 administration cycles, at least 3 administration cycles, at least 4 administration cycles, at least 5 administration cycles, at least 6 administration cycles, at least 7, at least 8 administration cycles, at least 9 administration cycles, at least 10 administration cycles, at least 11 administration cycles, at least 12 administration cycles, or at least 13 administration cycles, or more.

[0352] In some examples, the first phase includes a first administration cycle (C1); a first administration cycle and a second administration cycle (C2); a first administration cycle, a second administration cycle (C2), and a third administration cycle (C3); a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), and a fourth administration cycle (C4); a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), and a fifth administration cycle (C5); a first administration cycle (C 1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), and sixth administration cycle (C6); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), and seventh administration cycle (C7); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), and eighth administration cycle (C8); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), and ninth administration cycle (C9); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), ninth administration cycle (C9), and tenth administration cycle (C10); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), ninth administration cycle (C9), tenth administration cycle (C10), and eleventh administration cycle (C11);the first administration cycle (C1), the second administration cycle (C2), the third administration cycle (C3), the fourth administration cycle (C4), the fifth administration cycle (C5), the sixth administration cycle (C6), the seventh administration cycle (C7), the eighth administration cycle (C8), the ninth administration cycle (C9), the tenth administration cycle (C10), the eleventh administration cycle (C11), and the twelfth administration cycle (C12); or the first administration cycle cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), a sixth administration cycle (C6), a seventh administration cycle (C7), an eighth administration cycle (C8), a ninth administration cycle (C9), a tenth administration cycle (C10), an eleventh administration cycle (C11), a twelfth administration cycle (C12), and a thirteenth administration cycle;

[0353] The bispecific antibody may be administered on any suitable day of a given administration cycle. For example, for a 28-day administration cycle, the bispecific antibody may be administered on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, or 28th day. In another example, for a 21-day administration cycle, the bispecific antibody may be administered on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, or 21st day. In another example, for a 14 day administration cycle, the bispecific antibody may be administered on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14. In another example, for a 7 day administration cycle, the bispecific antibody may be administered on day 1, 2, 3, 4, 5, 6, or 7.

[0354] In some examples, the first phase includes administering the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C1. In a further example, the first phase includes administering the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C2. In a further example, the first phase includes administering the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C3. In a further example, the first phase includes administering the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C4. In a further example, the first phase includes administering the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C5. In a further example, the first phase includes administering the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C6. In a further example, the first phase comprises administering the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C7. In a further example, the first phase comprises administering the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C8. In a further example, the first phase comprises administering the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C9. In a further example, the first phase comprises administering the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C10. In a further example, the first phase comprises administering the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C11. In a further example, the first phase comprises administering the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C12. In a further example, the first phase comprises administration of the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C13.

[0355] In some examples, a target dose of the bispecific antibody is administered to the subject for each administration during the first phase.

[0356] In some examples, the first phase includes administering a target dose of the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C1. In further examples, the first phase includes administering a target dose of the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C2. In further examples, the first phase includes administering a target dose of the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C3. In further examples, the first phase includes administering a target dose of the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C4. In further examples, the first phase includes administering a target dose of the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C5. In a further example, the first phase comprises administering a target dose of the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C6. In a further example, the first phase comprises administering a target dose of the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C7. In a further example, the first phase comprises administering a target dose of the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C8. In a further example, the first phase comprises administering a target dose of the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C9. In a further example, the first phase comprises administering a target dose of the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C10. In a further example, the first phase comprises administering a target dose of the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C11. In a further example, the first phase comprises administering a target dose of the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C12. In a further example, the first phase comprises administering a target dose of the bispecific antibody to the subject on days 1, 8, 15, and / or 22 of C13.

[0357] In some examples, the first phase includes administration of a first escalation dose and a target dose of the bispecific antibody to the subject. The first escalation dose may be administered to the subject on day 1 of C1, day 2 of C1, day 3 of C1, day 4 of C1, day 5 of C1, day 6 of C1, or day 7 of C1 during the first phase. The target dose may be administered to the subject on day 8, day 15, and / or day 22 of C1 during the first phase. In a further example, the target dose may be administered to the subject on day 1, day 8, day 15, and / or day 22 of C2 during the first phase. In a further example, the target dose may be administered to the subject on day 1, day 8, day 15, and / or day 22 of C3 during the first phase. In a further example, the target dose may be administered to the subject on day 1, day 8, day 15, and / or day 22 of C4 during the first phase. In a further example, the target dose may be administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C5. In a further example, the target dose may be administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C6. In a further example, the target dose may be administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C7. In a further example, the target dose may be administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C8. In a further example, the target dose may be administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C9. In a further example, the target dose may be administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C10. In a further example, a target dose may be administered to a subject during the first phase on days 1, 8, 15, and 22 of C11. In a further example, a target dose may be administered to a subject during the first phase on days 1, 8, 15, and / or 22 of C12. In a further example, a target dose may be administered to a subject during the first phase on days 1, 8, 15, and / or 22 of C13.

[0358] In some examples, the first escalation dose is about 1% to about 8% of the target dose. In some examples, the first escalation dose is about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, or about 8% of the target dose.

[0359] In some examples, the first escalation dose is 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, or 8% of the target dose. In some examples, the first escalation dose is 4% of the target dose.

[0360] In some examples, the first escalation dose is about 3.6 mg. In some examples, the first escalation dose is about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

[0361] In some examples, the first escalation dose is 3.6 mg. In some examples, the first escalation dose is 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg.

[0362] In some examples, the first phase includes administering a first escalation dose and a second escalation dose of the bispecific antibody to the subject. In some examples, the first escalation dose is administered to the subject during the first phase on day 1 of C1, and the second escalation dose is administered on day 8 of C1. In some examples, the first escalation dose is administered to the subject during the first phase on day 2 of C1, and the second escalation dose is administered on day 9 of C1. In some examples, the first escalation dose is administered to the subject during the first phase on day 3 of C1, and the second escalation dose is administered on day 10 of C1. In some examples, the first escalation dose is administered to the subject during the first phase on day 4 of C1, and the second escalation dose is administered on day 11 of C1. In some examples, the first escalation dose is administered to the subject during the first phase on day 5 of C1, and the second escalation dose is administered on day 12 of C1. In some examples, the first escalation dose is administered to the subject during the first phase on day 6 of C1, and the second escalation dose is administered on day 13 of C1. In some examples, the first escalation dose is administered to the subject during the first phase on day 7 of C1, and the second escalation dose is administered on day 14 of C1. In some examples, the first escalation dose is administered to the subject during the first phase on day 8 of C1, and the second escalation dose is administered on day 15 of C1. In some examples, the first escalation dose is administered to the subject during the first phase on day 9 of C1, and the second escalation dose is administered on day 16 of C1. In some examples, the first escalation dose is administered to the subject during the first phase on day 10 of C1, and the second escalation dose is administered on day 17 of C1. In some examples, a first escalation dose is administered to the subject during the first phase on day 11 of C1, and a second escalation dose is administered on day 18 of C1. In some examples, a first escalation dose is administered to the subject during the first phase on day 12 of C1, and a second escalation dose is administered on day 19 of C1. In some examples, a first escalation dose is administered to the subject during the first phase on day 13 of C1, and a second escalation dose is administered on day 20 of C1. In some examples, a first escalation dose is administered to the subject during the first phase on day 14 of C1, and a second escalation dose is administered on day 21 of C1.

[0363] In further examples, the target dose is administered to the subject during the first phase after administration of the second escalation dose. In some examples, the target dose is administered to the subject on day 15 and / or day 22 of C1. In some examples, the target dose is administered to the subject on day 16 and / or day 23 of C1. In some examples, the target dose is administered to the subject on day 17 and / or day 24 of C1. In some examples, the target dose is administered to the subject on day 18 and / or day 25 of C1. In some examples, the target dose is administered to the subject on day 19 and / or day 26 of C1. In some examples, the target dose is administered to the subject on day 20 and / or day 27 of C1. In some examples, the target dose is administered to the subject on day 21 and / or day 28 of C1.

[0364] In a further example, the target dose is further administered to the subject on days 1, 8, 15, and / or 22 of C2 during the first phase. In a further example, the target dose is administered to the subject on days 1, 8, 15, and / or 22 of C3 during the first phase. In a further example, the target dose is administered to the subject on days 1, 8, 15, and / or 22 of C4 during the first phase. In a further example, the target dose is administered to the subject on days 1, 8, 15, and / or 22 of C5 during the first phase. In a further example, the target dose is administered to the subject on days 1, 8, 15, and / or 22 of C6 during the first phase. In a further example, the target dose is administered to the subject on days 1, 8, 15, and 22 of C7 during the first phase. In a further example, the target dose is administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C8. In a further example, the target dose is administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C9. In a further example, the target dose is administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C10. In a further example, the target dose is administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C11. In a further example, the target dose is administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C12. In a further example, the target dose is administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C13.

[0365] In some examples, the first escalation dose is about 0.1% to about 2% of the target dose, and the second escalation dose is about 3% to about 8% of the target dose. In some examples, the first escalation dose is about 0.5%, about 1%, about 1.5%, or about 2% of the target dose, and the second escalation dose is about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, or about 8% of the target dose. In some examples, the first escalation dose is about 0.33% of the target dose, and the second escalation dose is about 4% of the target dose.

[0366] In some examples, the first escalation dose is 0.5%, 1%, 1.5% or 2% of the target dose and the second escalation dose is 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5% or 8% of the target dose. In some examples, the first escalation dose is 0.33% of the target dose and the second escalation dose is 4% of the target dose.

[0367] In some examples, the first escalation dose is about 0.3 mg and the second escalation dose is about 3.6 mg. In some examples, the first escalation dose is about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, or about 1 mg, and the second escalation dose is about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

[0368] In some examples, the first escalation dose is 0.3 mg and the second escalation dose is 3.6 mg. In some examples, the first escalation dose is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or 1 mg and the second escalation dose is 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg.

[0369] In any of the foregoing examples, the second phase may include at least 2 administration cycles, at least 3 administration cycles, or at least 4 administration cycles, at least 5 administration cycles, at least 6 administration cycles, at least 7, at least 8 administration cycles, at least 9 administration cycles, at least 10 administration cycles, at least 11 administration cycles, at least 12 administration cycles, or at least 13 administration cycles, or more.

[0370] The second phase may include any suitable number of administration cycles. For example, in some examples, the second phase may include a first administration cycle (C1); a first administration cycle and a second administration cycle (C2); a first administration cycle, a second administration cycle (C2), and a third administration cycle (C3); a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), and a fourth administration cycle (C4); a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), and a fourth administration cycle (C4). , a fourth administration cycle (C4), and a fifth administration cycle (C5); a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), and a sixth administration cycle (C6); a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), and a sixth administration cycle (C6); and the seventh administration cycle (C7); the first administration cycle (C1), the second administration cycle (C2), the third administration cycle (C3), the fourth administration cycle (C4), the fifth administration cycle (C5), the sixth administration cycle (C6), the seventh administration cycle (C7), and the eighth administration cycle (C8); the first administration cycle (C1), the second administration cycle (C2), the third administration cycle (C3), the fourth administration cycle (C4), the fifth administration cycle (C5), the the sixth administration cycle (C6), the seventh administration cycle (C7), the eighth administration cycle (C8), and the ninth administration cycle (C9); the first administration cycle (C1), the second administration cycle (C2), the third administration cycle (C3), the fourth administration cycle (C4), the fifth administration cycle (C5), the sixth administration cycle (C6), the seventh administration cycle (C7), the eighth administration cycle (C8), the ninth administration cycle (C9), and the tenth administration cycle (C10);a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), a sixth administration cycle (C6), a seventh administration cycle (C7), an eighth administration cycle (C8), a ninth administration cycle (C9), a tenth administration cycle (C10), and an eleventh administration cycle (C11); or a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), a sixth administration cycle (C6), a seventh administration cycle (C7), an eighth administration cycle (C8), a ninth administration cycle (C9), a tenth administration cycle (C10), an eleventh administration cycle (C11), a twelfth administration cycle (C12), and a thirteenth administration cycle;

[0371] In some examples, the bispecific antibody target dose may be administered to the subject on day 1 and / or day 15 of C1 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 and / or day 15 of C2 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 and / or day 15 of C3 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 and / or day 15 of C4 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 and / or day 15 of C5 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 and / or day 15 of C6 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 and / or day 15 of C7 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on days 1 and / or 15 of C8 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on days 1 and / or 15 of C9 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on days 1 and / or 15 of C10 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on days 1 and / or 15 of C11 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on days 1 and / or 15 of C12 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on days 1 and / or 15 of C13 during the second phase.

[0372] In some examples, a target dose of the bispecific antibody is administered to the subject for each administration during the second phase.

[0373] The pre-phase can include any suitable number of administration cycles.For example, in any of the above examples, the third phase can include at least 2 administration cycles, at least 3 administration cycles, at least 4 administration cycles, at least 5 administration cycles, at least 6 administration cycles, at least 7 administration cycles, at least 8 administration cycles, at least 9 administration cycles, at least 10 administration cycles, at least 11 administration cycles, at least 12 administration cycles, or at least 13 administration cycles, or more.

[0374] In some examples, the third phase includes a first administration cycle (C1); a first administration cycle and a second administration cycle (C2); a first administration cycle, a second administration cycle (C2), and a third administration cycle (C3); a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), and a fourth administration cycle (C4); a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), and a fifth administration cycle (C5); a first administration cycle (C 1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), and sixth administration cycle (C6); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), and seventh administration cycle (C7); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), and eighth administration cycle (C8); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), and ninth administration cycle (C9); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), ninth administration cycle (C9), and tenth administration cycle (C10); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), ninth administration cycle (C9), tenth administration cycle (C10), and eleventh administration cycle (C11);the first administration cycle (C1), the second administration cycle (C2), the third administration cycle (C3), the fourth administration cycle (C4), the fifth administration cycle (C5), the sixth administration cycle (C6), the seventh administration cycle (C7), the eighth administration cycle (C8), the ninth administration cycle (C9), the tenth administration cycle (C10), the eleventh administration cycle (C11), and the twelfth administration cycle (C12); or the first administration cycle cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), a sixth administration cycle (C6), a seventh administration cycle (C7), an eighth administration cycle (C8), a ninth administration cycle (C9), a tenth administration cycle (C10), an eleventh administration cycle (C11), a twelfth administration cycle (C12), and a thirteenth administration cycle;

[0375] In some examples, the third phase includes administering the bispecific antibody to the subject on day 1 of C1. In further examples, the third phase includes administering the bispecific antibody to the subject on day 1 of C2. In further examples, the third phase includes administering the bispecific antibody to the subject on day 1 of C3. In further examples, the third phase includes administering the bispecific antibody to the subject on day 1 of C4. In further examples, the third phase includes administering the bispecific antibody to the subject on day 1 of C5. In further examples, the third phase includes administering the bispecific antibody to the subject on day 1 of C6. In further examples, the third phase includes administering the bispecific antibody to the subject on day 1 of C7. In further examples, the third phase includes administering the bispecific antibody to the subject on day 1 of C8. In further examples, the third phase includes administering the bispecific antibody to the subject on day 1 of C9. In a further example, the third phase includes administering the bispecific antibody to the subject on day 1 of C10. In a further example, the third phase includes administering the bispecific antibody to the subject on day 1 of C11. In a further example, the third phase includes administering the bispecific antibody to the subject on day 1 of C12. In a further example, the third phase includes administering the bispecific antibody to the subject on day 1 of C13.

[0376] In some examples, a target dose of the bispecific antibody is administered to the subject for each administration during the third phase.

[0377] In any of the foregoing examples, the target dose may be about 45 mg to about 180 mg. In some examples, the target dose is about 50 mg to about 175 mg. In some examples, the target dose is about 55 mg to about 165 mg. In some examples, the target dose is about 60 mg to about 160 mg. In some examples, the target dose is about 65 mg to about 155 mg. In some examples, the target dose is about 70 mg to about 150 mg. In some examples, the target dose is about 75 mg to about 145 mg. In some examples, the target dose is about 80 mg to about 140 mg. In some examples, the target dose is about 85 mg to about 135 mg. In some examples, the target dose is about 90 mg to about 130 mg. In some examples, the target dose is about 90 mg. In some examples, the target dose is about 132 mg. In some examples, the target dose is about 160 mg.

[0378] In some examples, the target dose is about 45 mg. In some examples, the target dose is about 50 mg. In some examples, the target dose is about 55 mg. In some examples, the target dose is about 60 mg. In some examples, the target dose is about 65 mg. In some examples, the target dose is about 70 mg. In some examples, the target dose is about 75 mg. In some examples, the target dose is about 80 mg. In some examples, the target dose is about 85 mg. In some examples, the target dose is about 90 mg. In some examples, the target dose is about 95 mg. In some examples, the target dose is about 100 mg. In some examples, the target dose is about 105 mg. In some examples, the target dose is about 110 mg. In some examples, the target dose is about 115 mg. In some examples, the target dose is about 120 mg. In some examples, the target dose is about 125 mg. In some examples, the target dose is about 130 mg. In some examples, the target dose is about 132 mg. In some examples, the target dose is about 135 mg. In some examples, the target dose is about 140 mg. In some examples, the target dose is about 145 mg. In some examples, the target dose is about 150 mg. In some examples, the target dose is about 155 mg. In some examples, the target dose is about 160 mg. In some examples, the target dose is about 165 mg. In some examples, the target dose is about 170 mg. In some examples, the target dose is about 175 mg. In some examples, the target dose is about 180 mg.

[0379] In some examples, the target dose is between 45 mg and 180 mg. In some examples, the target dose is between 50 mg and 175 mg. In some examples, the target dose is between 55 mg and 165 mg. In some examples, the target dose is between 60 mg and 160 mg. In some examples, the target dose is between 65 mg and 155 mg. In some examples, the target dose is between 70 mg and 150 mg. In some examples, the target dose is between 75 mg and 145 mg. In some examples, the target dose is between 80 mg and 140 mg. In some examples, the target dose is between 85 mg and 135 mg. In some examples, the target dose is between 90 mg and 130 mg. In some examples, the target dose is 90 mg. In some examples, the target dose is 132 mg. In some examples, the target dose is 160 mg.

[0380] In some examples, the target dose is 45 mg. In some examples, the target dose is 50 mg. In some examples, the target dose is 55 mg. In some examples, the target dose is 60 mg. In some examples, the target dose is 65 mg. In some examples, the target dose is 70 mg. In some examples, the target dose is 75 mg. In some examples, the target dose is 80 mg. In some examples, the target dose is 85 mg. In some examples, the target dose is 90 mg. In some examples, the target dose is 95 mg. In some examples, the target dose is 100 mg. In some examples, the target dose is 105 mg. In some examples, the target dose is 110 mg. In some examples, the target dose is 115 mg. In some examples, the target dose is 120 mg. In some examples, the target dose is 125 mg. In some examples, the target dose is 130 mg. In some examples, the target dose is 132 mg. In some examples, the target dose is 135 mg. In some examples, the target dose is 140 mg. In some examples, the target dose is 145 mg. In some examples, the target dose is 150 mg. In some examples, the target dose is 155 mg. In some examples, the target dose is 160 mg. In some examples, the target dose is 165 mg. In some examples, the target dose is 170 mg. In some examples, the target dose is 175 mg. In some examples, the target dose is 180 mg.

[0381] In some examples, the bispecific antibody is administered to a subject as a monotherapy.

[0382] In some examples, the bispecific antibody is administered to the subject intravenously. In some examples, the bispecific antibody is administered to the subject subcutaneously.

[0383] In a second example, the disclosure describes a method of treating a subject with cancer (e.g., MM), comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 and an immunomodulatory drug (IMiD) in a dosing regimen described herein. The dosing regimen may include a pre-phase including one or more dosing cycles, a first phase including one or more dosing cycles, and / or a second phase including one or more dosing cycles. Each dosing cycle of the pre-phase may be a 21-day dosing cycle, and each dosing cycle of the first phase and the second phase may be a 28-day dosing cycle. The pre-phase may include administering the bispecific antibody to the subject weekly (QW). The first phase may include administering the bispecific antibody to the subject every two weeks (Q2W). The second phase may include administering the bispecific antibody to the subject every four weeks (Q4W).

[0384] For example, provided herein is a method of treating a subject with cancer (e.g., MM), the method comprising: (i) a first phase comprising one or more dosing cycles, the first phase comprising administering a bispecific antibody to the subject every two weeks (Q2W); and / or (ii) a second phase comprising one or more dosing cycles, the second phase comprising administering a bispecific antibody to the subject every four weeks (Q4W). In some examples, the dosing regimen comprises the first phase. In some examples, the dosing regimen comprises the second phase. In some examples, the dosing regimen comprises the first phase and the second phase.

[0385] In another example, provided herein is a bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with cancer (e.g., MM), the treatment comprising administering the bispecific antibody to a subject in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, the first phase comprising administering the bispecific antibody to the subject every two weeks (Q2W); and / or (ii) a second phase comprising one or more dosing cycles, the second phase comprising administering the bispecific antibody to the subject every four weeks (Q4W). In some examples, the dosing regimen comprises the first phase. In some examples, the dosing regimen comprises the second phase. In some examples, the dosing regimen comprises the first phase and the second phase.

[0386] In another example, provided herein is the use of a bispecific antibody that binds FcRH5 and CD3 in the manufacture of a medicament for the treatment of a subject with cancer (e.g., MM), the treatment comprising administering the bispecific antibody to a subject in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, the first phase comprising administering the bispecific antibody to the subject every two weeks (Q2W); and / or (ii) a second phase comprising one or more dosing cycles, the second phase comprising administering the bispecific antibody to the subject every four weeks (Q4W). In some examples, the dosing regimen comprises the first phase. In some examples, the dosing regimen comprises the second phase. In some examples, the dosing regimen comprises the first phase and the second phase.

[0387] The pre-phase can include any suitable number of administration cycles. For example, in some examples, the pre-phase can include at least one administration cycle, at least two administration cycles, at least three administration cycles, at least four administration cycles, at least five administration cycles, at least six administration cycles, at least seven, at least eight administration cycles, at least nine administration cycles, at least ten administration cycles, at least eleven administration cycles, at least twelve administration cycles, or at least thirteen administration cycles, or more.

[0388] In some examples, the pre-phase includes a first administration cycle (C1); a first administration cycle and a second administration cycle (C2); a first administration cycle, a second administration cycle (C2), and a third administration cycle (C3); a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), and a fourth administration cycle (C4); a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), and a fifth administration cycle (C5); a first administration cycle (C1 ), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), and sixth administration cycle (C6); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), and seventh administration cycle (C7); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle ( C5), sixth administration cycle (C6), seventh administration cycle (C7), and eighth administration cycle (C8); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), and ninth administration cycle (C9); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), ninth administration cycle (C9), and tenth administration cycle (C10); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), ninth administration cycle (C9), tenth administration cycle (C10), and eleventh administration cycle (C11);the first administration cycle (C1), the second administration cycle (C2), the third administration cycle (C3), the fourth administration cycle (C4), the fifth administration cycle (C5), the sixth administration cycle (C6), the seventh administration cycle (C7), the eighth administration cycle (C8), the ninth administration cycle (C9), the tenth administration cycle (C10), the eleventh administration cycle (C11), and the twelfth administration cycle (C12); or the first administration cycle cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), a sixth administration cycle (C6), a seventh administration cycle (C7), an eighth administration cycle (C8), a ninth administration cycle (C9), a tenth administration cycle (C10), an eleventh administration cycle (C11), a twelfth administration cycle (C12), and a thirteenth administration cycle;

[0389] In some examples, the prephase includes administration of the bispecific antibody to the subject on days 1, 8, and / or 15 of C1. In further examples, the prephase includes administration of the bispecific antibody to the subject on days 1, 8, and / or 15 of C2. In further examples, the prephase includes administration of the bispecific antibody to the subject on days 1, 8, and / or 15 of C3. In further examples, the prephase includes administration of the bispecific antibody to the subject on days 1, 8, and / or 15 of C4. In further examples, the prephase includes administration of the bispecific antibody to the subject on days 1, 8, and / or 15 of C5. In further examples, the prephase includes administration of the bispecific antibody to the subject on days 1, 8, and / or 15 of C6. In further examples, the prephase includes administration of the bispecific antibody to the subject on days 1, 8, and / or 15 of C7. In a further example, the prephase includes administration of the bispecific antibody to the subject on days 1, 8, and / or 15 of C8. In a further example, the prephase includes administration of the bispecific antibody to the subject on days 1, 8, and / or 15 of C9. In a further example, the prephase includes administration of the bispecific antibody to the subject on days 1, 8, and / or 15 of C10. In a further example, the prephase includes administration of the bispecific antibody to the subject on days 1, 8, and / or 15 of C11. In a further example, the prephase includes administration of the bispecific antibody to the subject on days 1, 8, and / or 15 of C12. In a further example, the prephase includes administration of the bispecific antibody to the subject on days 1, 8, and / or 15 of C13. In some examples, a target dose of the bispecific antibody is administered to the subject for each administration in the prephase.

[0390] In some examples, the pre-phase includes administration of a target dose of the bispecific antibody to the subject on days 1, 8, and / or 15 of C1. In further examples, the pre-phase includes administration of a target dose of the bispecific antibody to the subject on days 1, 8, and / or 15 of C2. In further examples, the pre-phase includes administration of a target dose of the bispecific antibody to the subject on days 1, 8, and / or 15 of C3. In further examples, the pre-phase includes administration of a target dose of the bispecific antibody to the subject on days 1, 8, and / or 15 of C4. In further examples, the pre-phase includes administration of a target dose of the bispecific antibody to the subject on days 1, 8, and / or 15 of C5. In further examples, the pre-phase includes administration of a target dose of the bispecific antibody to the subject on days 1, 8, and / or 15 of C6. In a further example, the pre-phase comprises administering a target dose of the bispecific antibody to the subject on days 1, 8, and / or 15 of C7. In a further example, the pre-phase comprises administering a target dose of the bispecific antibody to the subject on days 1, 8, and / or 15 of C8. In a further example, the pre-phase comprises administering a target dose of the bispecific antibody to the subject on days 1, 8, and / or 15 of C9. In a further example, the pre-phase comprises administering a target dose of the bispecific antibody to the subject on days 1, 8, and / or 15 of C10. In a further example, the pre-phase comprises administering a target dose of the bispecific antibody to the subject on days 1, 8, and / or 15 of C11. In a further example, the pre-phase comprises administering a target dose of the bispecific antibody to the subject on days 1, 8, and / or 15 of C12. In a further example, the pre-phase comprises administration of a target dose of the bispecific antibody to the subject on days 1, 8, and / or 15 of C13.

[0391] In some examples, the prephase includes administration of a first escalation dose and a target dose of the bispecific antibody to the subject. The first escalation dose may be administered to the subject during the prephase on day 1 of C1, day 2 of C1, day 3 of C1, day 4 of C1, day 5 of C1, day 6 of C1, or day 7 of C1. The target dose may be administered to the subject during the prephase on day 8 and / or day 15 of C1. In a further example, the target dose may be administered to the subject during the prephase on day 1, day 8, and / or day 15 of C2. In a further example, the target dose may be administered to the subject during the prephase on day 1, day 8, and / or day 15 of C3. In a further example, the target dose may be administered to the subject during the prephase on day 1, day 8, and / or day 15 of C4. In a further example, the target dose may be administered to the subject during the prephase on day 1, day 8, and / or day 15 of C5. In a further example, the target dose may be administered to the subject during the prephase on days 1, 8, and / or 15 of C6. In a further example, the target dose may be administered to the subject during the prephase on days 1, 8, and / or 15 of C7. In a further example, the target dose may be administered to the subject during the prephase on days 1, 8, and / or 15 of C8. In a further example, the target dose may be administered to the subject during the prephase on days 1, 8, and / or 15 of C9. In a further example, the target dose may be administered to the subject during the prephase on days 1, 8, and / or 15 of C10. In a further example, the target dose may be administered to the subject during the prephase on days 1, 8, and / or 15 of C11. In a further example, the target dose may be administered to the subject during the prephase on days 1, 8, and / or 15 of C12. In a further example, the target dose may be administered to a subject during the pre-phase on days 1, 8, and / or 15 of C13.

[0392] In some examples, the first escalation dose is about 0.1% to about 10% of the target dose. In some examples, the first escalation dose is about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 2.73%, about 3%, about 3.5%, about 3.6%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% of the target dose.

[0393] In some examples, the first escalation dose is 0.1% to 10% of the target dose. In some examples, the first escalation dose is 0.5%, 1%, 2.73%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% of the target dose.

[0394] In some examples, the first escalation dose is about 3.6 mg. In some examples, the first escalation dose is about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

[0395] In some examples, the first escalation dose is 3.6 mg. In some examples, the first escalation dose is 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg.

[0396] In some examples, the prephase includes administering a first escalation dose and a second escalation dose of the bispecific antibody to the subject. In some examples, the first escalation dose is administered to the subject during the prephase on day 1 of C1, and the second escalation dose is administered on day 8 of C1. In some examples, the first escalation dose is administered to the subject during the prephase on day 2 of C1, and the second escalation dose is administered on day 9 of C1. In some examples, the first escalation dose is administered to the subject during the prephase on day 3 of C1, and the second escalation dose is administered on day 10 of C1. In some examples, the first escalation dose is administered to the subject during the prephase on day 4 of C1, and the second escalation dose is administered on day 11 of C1. In some examples, the first escalation dose is administered to the subject during the prephase on day 5 of C1, and the second escalation dose is administered on day 12 of C1. In some examples, a first escalation dose is administered to the subject during the pre-phase on day 6 of C1, and a second escalation dose is administered on day 13 of C1. In some examples, a first escalation dose is administered to the subject during the pre-phase on day 7 of C1, and a second escalation dose is administered on day 14 of C1. In some examples, a first escalation dose is administered to the subject during the pre-phase on day 8 of C1, and a second escalation dose is administered on day 15 of C1.

[0397] In further examples of the pre-phase, the target dose is administered to the subject during the pre-phase after administration of the second escalation dose. In some examples, the target dose is administered to the subject during the run-in phase on day 15, 16, 17, 18, 19, 20, or 21 of C1.

[0398] In a further example of the prephase, the target dose is further administered to the subject on days 1, 8, and / or 15 of C2 during the prephase. In a further example, the target dose is administered to the subject on days 1, 8, and / or 15 of C3 during the prephase. In a further example, the target dose is administered to the subject on days 1, 8, and / or 15 of C4 during the prephase. In a further example, the target dose is administered to the subject on days 1, 8, and / or 15 of C5 during the prephase. In a further example, the target dose is administered to the subject on days 1, 8, and / or 15 of C6 during the prephase. In a further example, the target dose is administered to the subject on days 1, 8, and / or 15 of C7 during the prephase. In a further example, the target dose is administered to the subject on days 1, 8, and / or 15 of C8 during the prephase. In a further example, the target dose is administered to the subject during the prephase on days 1, 8, and / or 15 of C9. In a further example, the target dose is administered to the subject during the prephase on days 1, 8, and / or 15 of C10. In a further example, the target dose is administered to the subject during the prephase on days 1, 8, and / or 15 of C11. In a further example, the target dose is administered to the subject during the prephase on days 1, 8, and / or 15 of C12. In a further example, the target dose is administered to the subject during the prephase on days 1, 8, and / or 15 of C13.

[0399] In some examples, the first step-up dose is about 0.1% to about 2% of the target dose, and the second step-up dose is about 3% to about 10% of the target dose. In some examples, the first step-up dose is about 0.23%, about 0.5%, about 1%, about 1.5%, or about 2% of the target dose, and the second step-up dose is about 2.5%, about 2.73%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, or about 8% of the target dose. In some examples, the first step-up dose is about 0.23% of the target dose, and the second step-up dose is about 2.73% of the target dose.

[0400] In some examples, the first escalation dose is 0.1%-2% of the target dose and the second escalation dose is 3%-10% of the target dose. In some examples, the first escalation dose is 0.23%, 0.5%, 1%, 1.5% or 2% of the target dose and the second escalation dose is 2.5%, 2.73%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5% or 8% of the target dose. In some examples, the first escalation dose is 0.23% of the target dose and the second escalation dose is 2.73% of the target dose.

[0401] In some examples, the first escalation dose is about 0.3 mg and the second escalation dose is about 3.6 mg. In some examples, the first escalation dose is about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, or about 1 mg, and the second escalation dose is about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

[0402] In some examples, the first escalation dose is 0.3 mg and the second escalation dose is 3.6 mg. In some examples, the first escalation dose is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or 1 mg and the second escalation dose is 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg.

[0403] The first phase may include any suitable number of administration cycles. For example, in any of the above examples, the first phase may include at least 2 administration cycles, at least 3 administration cycles, or at least 4 administration cycles, at least 5 administration cycles, at least 6 administration cycles, at least 7, at least 8 administration cycles, at least 9 administration cycles, at least 10 administration cycles, at least 11 administration cycles, at least 12 administration cycles, or at least 13 administration cycles, or more.

[0404] In some examples, the first phase includes a first administration cycle (C1); a first administration cycle and a second administration cycle (C2); a first administration cycle, a first administration cycle (C2), and a third administration cycle (C3); a first administration cycle (C1), a first administration cycle (C2), a third administration cycle (C3), and a fourth administration cycle (C4); a first administration cycle (C1), a first administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), and a fifth administration cycle (C5); a first administration cycle (C 1), first administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), and sixth administration cycle (C6); first administration cycle (C1), first administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), and seventh administration cycle (C7); first administration cycle (C1), first administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), and eighth administration cycle (C8); first administration cycle (C1), first administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), and ninth administration cycle (C9); first administration cycle (C1), first administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), ninth administration cycle (C9), and tenth administration cycle (C10); first administration cycle (C1), first administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), ninth administration cycle (C9), tenth administration cycle (C10), and eleventh administration cycle (C11);the first administration cycle (C1), the first administration cycle (C2), the third administration cycle (C3), the fourth administration cycle (C4), the fifth administration cycle (C5), the sixth administration cycle (C6), the seventh administration cycle (C7), the eighth administration cycle (C8), the ninth administration cycle (C9), the tenth administration cycle (C10), the eleventh administration cycle (C11), and the twelfth administration cycle (C12); or the first administration cycle cycle (C1), a first administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), a sixth administration cycle (C6), a seventh administration cycle (C7), an eighth administration cycle (C8), a ninth administration cycle (C9), a tenth administration cycle (C10), an eleventh administration cycle (C11), a twelfth administration cycle (C12), and a thirteenth administration cycle;

[0405] In some examples, the bispecific antibody target dose may be administered to the subject on day 1 and / or day 15 of C1 during the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 and / or day 15 of C2 during the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 and / or day 15 of C3 during the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 and / or day 15 of C4 during the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 and / or day 15 of C5 during the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 and / or day 15 of C6 during the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 and / or day 15 of C7 during the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on days 1 and / or 15 of C8 during the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on days 1 and / or 15 of C9 during the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on days 1 and / or 15 of C10 during the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on days 1 and / or 15 of C11 during the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on days 1 and / or 15 of C12 during the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on days 1 and / or 15 of C13 during the first phase.

[0406] In some examples, a target dose of the bispecific antibody is administered to the subject for each administration during the first phase.

[0407] In any of the foregoing examples, the second phase may include at least 2 administration cycles, at least 3 administration cycles, or at least 4 administration cycles, at least 5 administration cycles, at least 6 administration cycles, at least 7, at least 8 administration cycles, at least 9 administration cycles, at least 10 administration cycles, at least 11 administration cycles, at least 12 administration cycles, or at least 13 administration cycles, or more.

[0408] In some examples, the second phase includes a first administration cycle (C1); a first administration cycle and a second administration cycle (C2); a first administration cycle, a second administration cycle (C2), and a third administration cycle (C3); a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), and a fourth administration cycle (C4); a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), and a fifth administration cycle (C5); a first administration cycle (C 1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), and sixth administration cycle (C6); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), and seventh administration cycle (C7); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), and eighth administration cycle (C8); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), and ninth administration cycle (C9); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), ninth administration cycle (C9), and tenth administration cycle (C10); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), ninth administration cycle (C9), tenth administration cycle (C10), and eleventh administration cycle (C11);the first administration cycle (C1), the second administration cycle (C2), the third administration cycle (C3), the fourth administration cycle (C4), the fifth administration cycle (C5), the sixth administration cycle (C6), the seventh administration cycle (C7), the eighth administration cycle (C8), the ninth administration cycle (C9), the tenth administration cycle (C10), the eleventh administration cycle (C11), and the twelfth administration cycle (C12); or the first administration cycle cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), a sixth administration cycle (C6), a seventh administration cycle (C7), an eighth administration cycle (C8), a ninth administration cycle (C9), a tenth administration cycle (C10), an eleventh administration cycle (C11), a twelfth administration cycle (C12), and a thirteenth administration cycle;

[0409] In some examples, the bispecific antibody target dose may be administered to the subject on day 1 of C1 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C2 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C3 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C4 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C5 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C6 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C7 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C8 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C9 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C10 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C11 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C12 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C13 during the second phase.

[0410] In some examples, a target dose of the bispecific antibody is administered to the subject for each administration during the second phase.

[0411] In any of the foregoing examples, the target dose is about 65 mg to about 270 mg. In some examples, the target dose is about 75 mg to about 260 mg. In some examples, the target dose is about 85 mg to about 250 mg. In some examples, the target dose is about 95 mg to about 240 mg. In some examples, the target dose is about 95 mg to about 230 mg. In some examples, the target dose is about 95 mg to about 220 mg. In some examples, the target dose is about 105 mg to about 210 mg. In some examples, the target dose is about 115 mg to about 200 mg. In some examples, the target dose is about 125 mg to about 190 mg. In some examples, the target dose is about 130 mg to about 180 mg. In some examples, the target dose is about 90 mg. In some examples, the target dose is about 132 mg. In some examples, the target dose is about 160 mg.

[0412] In some examples, the target dose is about 65 mg. In some examples, the target dose is about 70 mg. In some examples, the target dose is about 75 mg. In some examples, the target dose is about 80 mg. In some examples, the target dose is about 85 mg. In some examples, the target dose is about 90 mg. In some examples, the target dose is about 95 mg. In some examples, the target dose is about 100 mg. In some examples, the target dose is about 105 mg. In some examples, the target dose is about 110 mg. In some examples, the target dose is about 115 mg. In some examples, the target dose is about 120 mg. In some examples, the target dose is about 125 mg. In some examples, the target dose is about 130 mg. In some examples, the target dose is about 132 mg. In some examples, the target dose is about 135 mg. In some examples, the target dose is about 140 mg. In some examples, the target dose is about 145 mg. In some examples, the target dose is about 150 mg. In some examples, the target dose is about 155 mg. In some examples, the target dose is about 160 mg. In some examples, the target dose is about 165 mg. In some examples, the target dose is about 170 mg. In some examples, the target dose is about 175 mg. In some examples, the target dose is about 180 mg. In some examples, the target dose is about 185 mg. In some examples, the target dose is about 190 mg. In some examples, the target dose is about 195 mg. In some examples, the target dose is about 200 mg. In some examples, the target dose is about 205 mg. In some examples, the target dose is about 210 mg. In some examples, the target dose is about 215 mg. In some examples, the target dose is about 220 mg. In some examples, the target dose is about 225 mg. In some examples, the target dose is about 230 mg. In some examples, the target dose is about 235 mg. In some examples, the target dose is about 240 mg. In some examples, the target dose is about 245 mg. In some examples, the target dose is about 250 mg. In some examples, the target dose is about 255 mg. In some examples, the target dose is about 260 mg.

[0413] In some examples, the target dose is between 65 mg and 270 mg. In some examples, the target dose is between 75 mg and 260 mg. In some examples, the target dose is between 85 mg and 250 mg. In some examples, the target dose is between 95 mg and 240 mg. In some examples, the target dose is between 95 mg and 230 mg. In some examples, the target dose is between 95 mg and 220 mg. In some examples, the target dose is between 105 mg and 210 mg. In some examples, the target dose is between 115 mg and 200 mg. In some examples, the target dose is between 125 mg and 190 mg. In some examples, the target dose is between 130 mg and 180 mg. In some examples, the target dose is 90 mg. In some examples, the target dose is 132 mg. In some examples, the target dose is 160 mg.

[0414] In some examples, the target dose is 65 mg. In some examples, the target dose is 70 mg. In some examples, the target dose is 75 mg. In some examples, the target dose is 80 mg. In some examples, the target dose is 85 mg. In some examples, the target dose is 90 mg. In some examples, the target dose is 95 mg. In some examples, the target dose is 100 mg. In some examples, the target dose is 105 mg. In some examples, the target dose is 110 mg. In some examples, the target dose is 115 mg. In some examples, the target dose is 120 mg. In some examples, the target dose is 125 mg. In some examples, the target dose is 130 mg. In some examples, the target dose is 132 mg. In some examples, the target dose is 135 mg. In some examples, the target dose is 140 mg. In some examples, the target dose is 145 mg. In some examples, the target dose is 150 mg. In some examples, the target dose is 155 mg. In some examples, the target dose is 160 mg. In some examples, the target dose is 165 mg. In some examples, the target dose is 170 mg. In some examples, the target dose is 175 mg. In some examples, the target dose is 180 mg. In some examples, the target dose is 185 mg. In some examples, the target dose is 190 mg. In some examples, the target dose is 195 mg. In some examples, the target dose is 200 mg. In some examples, the target dose is 205 mg. In some examples, the target dose is 210 mg. In some examples, the target dose is 215 mg. In some examples, the target dose is 220 mg. In some examples, the target dose is 225 mg. In some examples, the target dose is 230 mg. In some examples, the target dose is 235 mg. In some examples, the target dose is 240 mg. In some examples, the target dose is 245 mg. In some examples, the target dose is 250 mg. In some examples, the target dose is 255 mg. In some examples, the target dose is 260 mg.

[0415] The bispecific antibody may be administered by any suitable route of administration. In some examples, the bispecific antibody is administered to the subject intravenously. In some examples, the bispecific antibody is administered to the subject subcutaneously.

[0416] In any of the foregoing examples, the IMiD may be administered to the subject on any suitable day of any administration cycle. For example, in some examples, the IMiD is administered to the subject on days 1-21 of each administration cycle in the pre-phase. In some examples, the IMiD is administered to the subject on days 1-21 of each administration cycle in the first phase. In some examples, the IMiD is administered to the subject on days 1-21 of each administration cycle in the second phase. In some examples, the IMiD is administered to the subject on days 1-21 of each administration cycle in the pre-phase, the first phase, and the second phase. In some examples, the IMiD is administered to the subject on days 1-21 of each administration cycle in the first phase and the second phase.

[0417] The IMiD may be administered by any suitable route of administration. In some examples, the IMiD is administered orally to the subject. In some examples, the IMiD is administered intravenously to the subject.

[0418] In some examples, the IMiD is lenalidomide. In some examples, the IMiD is pomalidomide.

[0419] In some examples, pomalidomide is administered to the subject in a dosage of about 1 mg to about 8 mg. In some examples, pomalidomide is administered at about 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, or 8 mg. In some examples, pomalidomide is administered to the subject in a dosage of about 4 mg.

[0420] In some examples, pomalidomide is administered to the subject in a dosage of 1 mg to 8 mg. In some examples, pomalidomide is administered at 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, or 8 mg. In some examples, pomalidomide is administered to the subject in a dosage of 4 mg.

[0421] In any of the foregoing examples, the dosing regimen further comprises administering a corticosteroid to the subject during the pre-phase, the first phase, and / or the second phase. In some examples, the dosing regimen further comprises administering a corticosteroid to the subject during the pre-phase. In some examples, the dosing regimen further comprises administering a corticosteroid to the subject during the first phase. In some examples, the dosing regimen further comprises administering a corticosteroid to the subject during the second phase. In some examples, the dosing regimen further comprises administering a corticosteroid to the subject during the pre-phase and the first phase. In some examples, the dosing regimen further comprises administering a corticosteroid to the subject during the pre-phase and the second phase. In some examples, the dosing regimen further comprises administering a corticosteroid to the subject during the first phase and the second phase.

[0422] In some examples, the corticosteroid is administered to the subject QW, for example, during the prephase, first phase, and / or second phase.

[0423] The corticosteroid(s) may be administered by any suitable route of administration. In some examples, the corticosteroid is administered intravenously to the subject. In some examples, the corticosteroid is administered orally to the subject. In some examples, the corticosteroid may be administered intravenously or orally to the subject.

[0424] In some examples, the corticosteroid is administered to the subject during the prephase on days 1, 8, and / or 15 of C1. In further examples, the corticosteroid is administered to the subject during the prephase on days 1, 8, and / or 15 of C2. In further examples, the corticosteroid is administered to the subject during the prephase on days 1, 8, and / or 15 of C3. In further examples, the corticosteroid is administered to the subject during the prephase on days 1, 8, and / or 15 of C4. In further examples, the corticosteroid is administered to the subject during the prephase on days 1, 8, and / or 15 of C5. In further examples, the corticosteroid is administered to the subject during the prephase on days 1, 8, and / or 15 of C6. In further examples, the corticosteroid is administered to the subject during the prephase on days 1, 8, and / or 15 of C7. In a further example, the corticosteroid is administered to the subject during the prephase on days 1, 8, and / or 15 of C8. In a further example, the corticosteroid is administered to the subject during the prephase on days 1, 8, and / or 15 of C9. In a further example, the corticosteroid is administered to the subject during the prephase on days 1, 8, and / or 15 of C10. In a further example, the corticosteroid is administered to the subject during the prephase on days 1, 8, and / or 15 of C11. In a further example, the corticosteroid is administered to the subject during the prephase on days 1, 8, and / or 15 of C12. In a further example, the corticosteroid is administered to the subject during the prephase on days 1, 8, and / or 15 of C13.

[0425] In some examples, the corticosteroid is administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C1. In further examples, the corticosteroid is administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C2. In further examples, the corticosteroid is administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C3. In further examples, the corticosteroid is administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C4. In further examples, the corticosteroid is administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C5. In further examples, the corticosteroid is administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C6. In a further example, a corticosteroid is administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C7. In a further example, a corticosteroid is administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C8. In a further example, a corticosteroid is administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C9. In a further example, a corticosteroid is administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C10. In a further example, a corticosteroid is administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C11. In a further example, a corticosteroid is administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C12. In a further example, a corticosteroid is administered to the subject during the first phase on days 1, 8, 15, and / or 22 of C13.

[0426] In some examples, the corticosteroid is administered intravenously to the subject prior to administration of the bispecific antibody, hi some examples, the corticosteroid is administered intravenously to the subject about 1 hour prior to administration of the bispecific antibody.

[0427] Any suitable corticosteroid may be used, for example, any of the corticosteroids described herein. In some examples, the corticosteroid is dexamethasone or methylprednisolone. In some examples, the corticosteroid is dexamethasone.

[0428] In some examples, dexamethasone is administered to the subject in a dosage of about 10 mg to about 40 mg. In some examples, dexamethasone is administered to the subject in a dosage of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg. In some examples, dexamethasone is administered to the subject in a dosage of about 20 mg.

[0429] In some examples, dexamethasone is administered to the subject in a dosage of 10 mg to 40 mg. In some examples, dexamethasone is administered to the subject in a dosage of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg. In some examples, dexamethasone is administered to the subject in a dosage of 20 mg.

[0430] In some examples, methylprednisolone is administered to the subject at a dosage of about 40 mg to about 160 mg. In some examples, methylprednisolone is administered to the subject at a dosage of about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, or about 160 mg. In some examples, methylprednisolone is administered to the subject at a dosage of about 80 mg.

[0431] In some examples, methylprednisolone is administered to the subject in a dosage of 40 mg to 160 mg. In some examples, methylprednisolone is administered to the subject in a dosage of 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, or 160 mg. In some examples, methylprednisolone is administered to the subject in a dosage of 80 mg.

[0432] In a third example, the disclosure describes a method of treating a subject with cancer (e.g., MM), comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 and an anti-cluster of differentiation 38 (CD38) antibody in a dosing regimen described herein. The dosing regimen may include a run-in phase including one or more dosing cycles, a first phase including one or more dosing cycles (the first phase including a first sub-phase and a second sub-phase), and / or a second phase including one or more dosing cycles. Each dosing cycle of the run-in phase and the first phase may be a 21-day dosing cycle, and each dosing cycle of the second phase may be a 28-day dosing cycle. The run-in phase may include administering the bispecific antibody to the subject weekly (QW). The first phase may include administering the bispecific antibody to the subject every three weeks (Q3W). The second phase may include administering the bispecific antibody to the subject every four weeks (Q4W).

[0433] For example, provided herein is a method of treating a subject with cancer (e.g., MM), the method comprising: (i) a first phase comprising one or more dosing cycles, the first phase comprising administering a bispecific antibody to the subject every three weeks (Q3W); and / or (ii) a second phase comprising one or more dosing cycles, the second phase comprising administering a bispecific antibody to the subject every four weeks (Q4W). In some examples, the dosing regimen comprises the first phase. In some examples, the dosing regimen comprises the second phase. In some examples, the dosing regimen comprises the first phase and the second phase.

[0434] In another example, provided herein is a bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with cancer (e.g., MM), the treatment comprising administering the bispecific antibody to the subject in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, the first phase comprising administering the bispecific antibody to the subject every three weeks (Q3W); and / or (ii) a second phase comprising one or more dosing cycles, the second phase comprising administering the bispecific antibody to the subject every four weeks (Q4W). In some examples, the dosing regimen comprises the first phase. In some examples, the dosing regimen comprises the second phase. In some examples, the dosing regimen comprises the first phase and the second phase.

[0435] In another example, provided herein is the use of a bispecific antibody that binds FcRH5 and CD3 in the manufacture of a medicament for the treatment of a subject with cancer (e.g., MM), the treatment comprising administering the bispecific antibody to a subject in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, the first phase comprising administering the bispecific antibody to the subject every three weeks (Q3W); and / or (ii) a second phase comprising one or more dosing cycles, the second phase comprising administering the bispecific antibody to the subject every four weeks (Q4W). In some examples, the dosing regimen comprises the first phase. In some examples, the dosing regimen comprises the second phase. In some examples, the dosing regimen comprises the first phase and the second phase.

[0436] The first phase can include any suitable number of administration cycles. For example, in some examples, the run-in phase includes at least one administration cycle, at least two administration cycles, at least three administration cycles, at least four administration cycles, at least five administration cycles, at least six administration cycles, at least seven, at least eight administration cycles, at least nine administration cycles, at least ten administration cycles, at least eleven administration cycles, at least twelve administration cycles, or at least thirteen administration cycles, or more.

[0437] In some examples, the run-in phase may include a first administration cycle (C1); a first administration cycle and a second administration cycle (C2); a first administration cycle, a second administration cycle (C2), and a third administration cycle (C3); a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), and a fourth administration cycle (C4); a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), and a fifth administration cycle (C5); a first administration cycle ( C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), and sixth administration cycle (C6); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), and seventh administration cycle (C7); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), and eighth administration cycle (C8); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), and ninth administration cycle (C9); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), ninth administration cycle (C9), and tenth administration cycle (C10); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), ninth administration cycle (C9), tenth administration cycle (C10), and eleventh administration cycle (C11);the first administration cycle (C1), the second administration cycle (C2), the third administration cycle (C3), the fourth administration cycle (C4), the fifth administration cycle (C5), the sixth administration cycle (C6), the seventh administration cycle (C7), the eighth administration cycle (C8), the ninth administration cycle (C9), the tenth administration cycle (C10), the eleventh administration cycle (C11), and the twelfth administration cycle (C12); or the first administration cycle cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), a sixth administration cycle (C6), a seventh administration cycle (C7), an eighth administration cycle (C8), a ninth administration cycle (C9), a tenth administration cycle (C10), an eleventh administration cycle (C11), a twelfth administration cycle (C12), and a thirteenth administration cycle;

[0438] In some examples, the prephase includes administration of the bispecific antibody to the subject on days 2, 9, and / or 16 of C1. In some examples, the prephase includes administration of the bispecific antibody to the subject on days 3, 9, and / or 16 of C1. In a further example, the prephase includes administration of the bispecific antibody to the subject on days 2, 9, and / or 16 of C2. In a further example, the prephase includes administration of the bispecific antibody to the subject on days 2, 9, and / or 16 of C3. In a further example, the prephase includes administration of the bispecific antibody to the subject on days 2, 9, and / or 16 of C4. In a further example, the prephase includes administration of the bispecific antibody to the subject on days 2, 9, and / or 16 of C5. In a further example, the prephase includes administration of the bispecific antibody to the subject on days 2, 9, and / or 16 of C6. In a further example, the pre-phase comprises administering the bispecific antibody to the subject on days 2, 9, and / or 16 of C7. In a further example, the pre-phase comprises administering the bispecific antibody to the subject on days 2, 9, and / or 16 of C8. In a further example, the pre-phase comprises administering the bispecific antibody to the subject on days 2, 9, and / or 16 of C9. In a further example, the pre-phase comprises administering the bispecific antibody to the subject on days 2, 9, and / or 16 of C10. In a further example, the pre-phase comprises administering the bispecific antibody to the subject on days 2, 9, and / or 16 of C11. In a further example, the pre-phase comprises administering the bispecific antibody to the subject on days 2, 9, and / or 16 of C12. In a further example, the pre-phase comprises administering the bispecific antibody to the subject on days 2, 9, and / or 16 of C13. In some examples, a target dose of the bispecific antibody is administered to the subject for each administration in the prephase.

[0439] In some examples, if the subject has an adverse reaction to the anti-CD38 antibody, the bispecific antibody is administered to the subject on days 3, 9 and / or 16 of C1.

[0440] In some examples, a target dose of the bispecific antibody is administered to the subject for each administration during the run-in phase.

[0441] In some examples, the run-in phase includes administration of a target dose of a bispecific antibody to a subject on days 2, 9, and / or 16 of C1. In some examples, the run-in phase includes administration of a target dose of a bispecific antibody to a subject on days 3, 9, and / or 16 of C1. In further examples, the run-in phase includes administration of a target dose of a bispecific antibody to a subject on days 2, 9, and / or 16 of C2. In further examples, the run-in phase includes administration of a target dose of a bispecific antibody to a subject on days 2, 9, and / or 16 of C3. In further examples, the run-in phase includes administration of a target dose of a bispecific antibody to a subject on days 2, 9, and / or 16 of C4. In further examples, the run-in phase includes administration of a target dose of a bispecific antibody to a subject on days 2, 9, and / or 16 of C5. In a further example, the run-in phase includes administering a target dose of the bispecific antibody to the subject on days 2, 9, and / or 16 of C6. In a further example, the run-in phase includes administering a target dose of the bispecific antibody to the subject on days 2, 9, and / or 16 of C7. In a further example, the run-in phase includes administering a target dose of the bispecific antibody to the subject on days 2, 9, and / or 16 of C8. In a further example, the run-in phase includes administering a target dose of the bispecific antibody to the subject on days 2, 9, and / or 16 of C9. In a further example, the run-in phase includes administering a target dose of the bispecific antibody to the subject on days 2, 9, and / or 16 of C10. In a further example, the run-in phase includes administering a target dose of the bispecific antibody to the subject on days 2, 9, and / or 16 of C11. In a further example, the run-in phase comprises administering a target dose of a bispecific antibody to a subject on days 2, 9, and / or 16 of C12. In a further example, the run-in phase comprises administering a target dose of a bispecific antibody to a subject on days 2, 9, and 16 of C13.

[0442] In some examples, the run-in phase includes administration of a first step-up dose and a target dose of the bispecific antibody to the subject. The first step-up dose may be administered to the subject on day 1 of C1, day 2 of C1, day 3 of C1, day 4 of C1, day 5 of C1, day 6 of C1, day 7 of C1, or day 8 of C1 during the run-in phase. The target dose may be administered to the subject on day 9 and / or day 16 of C1 during the run-in phase. In a further example, the target dose may be administered to the subject on day 2, day 9, and / or day 16 of C2 during the run-in phase. In a further example, the target dose may be administered to the subject on day 2, day 9, and / or day 16 of C3 during the run-in phase. In a further example, the target dose may be administered to the subject on day 2, day 9, and / or day 16 of C4 during the run-in phase. In a further example, the target dose may be administered to the subject during the run-in phase on days 2, 9, and / or 16 of C5. In a further example, the target dose may be administered to the subject during the run-in phase on days 2, 9, and / or 16 of C6. In a further example, the target dose may be administered to the subject during the run-in phase on days 2, 9, and / or 16 of C7. In a further example, the target dose may be administered to the subject during the run-in phase on days 2, 9, and / or 16 of C8. In a further example, the target dose may be administered to the subject during the run-in phase on days 2, 9, and / or 16 of C9. In a further example, the target dose may be administered to the subject during the run-in phase on days 2, 9, and / or 16 of C10. In a further example, the target dose may be administered to the subject during the run-in phase on days 2, 9, and / or 16 of C11. In a further example, the target dose may be administered to a subject during the run-in phase on days 2, 9, and / or 16 of C12. In a further example, the target dose may be administered to a subject during the run-in phase on days 2, 9, and / or 16 of C13.

[0443] In some examples, the first escalation dose is about 0.1% to about 10% of the target dose. In some examples of the run-in phase, the first escalation dose is about 0.5%, about 1%, about 1.5%, about 2%, about 2.25%, about 2.5%, about 3%, about 3.5%, about 3.6%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% of the target dose. In some examples, the first escalation dose is about 2.25% of the target dose.

[0444] In some examples, the first escalation dose is 0.1% to 10% of the target dose. In some examples of the run-in phase, the first escalation dose is 0.5%, 1%, 1.5%, 2%, 2.25%, 2.5%, 3%, 3.5%, 3.6%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% of the target dose. In some examples, the first escalation dose is 2.25% of the target dose.

[0445] In some examples, the first escalation dose is about 3.6 mg. In some examples of the run-in phase, the first escalation dose is about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

[0446] In some examples, the first escalation dose is 3.6 mg. In some examples of the run-in phase, the first escalation dose is 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg.

[0447] In some examples, the run-in phase includes administering a first step-up dose and a second step-up dose of the bispecific antibody to the subject. In some examples, the first step-up dose is administered to the subject on day 2 of C1 during the run-in phase, and the second step-up dose is administered on day 9 of C1. In some examples, the first step-up dose is administered to the subject on day 3 of C1 during the run-in phase, and the second step-up dose is administered on day 10 of C1. In some examples, the first step-up dose is administered to the subject on day 4 of C1 during the run-in phase, and the second step-up dose is administered on day 11 of C1. In some examples, the first step-up dose is administered to the subject on day 5 of C1 during the run-in phase, and the second step-up dose is administered on day 12 of C1. In some examples, the first step-up dose is administered to the subject on day 6 of C1 during the run-in phase, and the second step-up dose is administered on day 13 of C1. In some examples, the first step-up dose is administered to the subject during the run-in phase on day 7 of C1, and the second step-up dose is administered on day 14 of C1. In some examples, the first step-up dose is administered to the subject during the run-in phase on day 8 of C1, and the second step-up dose is administered on day 15 of C1.

[0448] In further examples, the target dose is administered to the subject during the run-in phase after administration of the second escalation dose. In some examples, the target dose is administered to the subject during the run-in phase on day 16, 17, 18, 19, 20, or 21 of C1.

[0449] In a further example, the target dose is further administered to the subject during the run-in phase on days 2, 9, and / or 16 of C2. In a further example, the target dose is administered to the subject during the run-in phase on days 2, 9, and / or 16 of C3. In a further example, the target dose is administered to the subject during the run-in phase on days 2, 9, and / or 16 of C4. In a further example, the target dose is administered to the subject during the run-in phase on days 2, 9, and / or 16 of C5. In a further example, the target dose is administered to the subject during the run-in phase on days 2, 9, and / or 16 of C6. In a further example, the target dose is administered to the subject during the run-in phase on days 2, 9, and / or 16 of C7. In a further example, the target dose is administered to the subject during the run-in phase on days 2, 9, and / or 16 of C8. In a further example, the target dose is administered to the subject during the run-in phase on days 2, 9, and / or 16 of C9. In a further example, the target dose is administered to the subject during the run-in phase on days 2, 9, and / or 16 of C10. In a further example, the target dose is administered to the subject during the run-in phase on days 2, 9, and / or 16 of C11. In a further example, the target dose is administered to the subject during the run-in phase on days 2, 9, and / or 16 of C12. In a further example, the target dose is administered to the subject during the run-in phase on days 2, 9, and / or 16 of C13.

[0450] In some examples of the run-in phase, the first step-up dose is about 0.1% to about 1% of the target dose, and the second step-up dose is about 2% to about 10% of the target dose. In some examples of the run-in phase, the first step-up dose is about 0.19%, about 0.5%, about 0.7%, about 1% of the target dose, and the second step-up dose is about 1.5%, about 2%, about 2.25%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% of the target dose. In some examples of the run-in phase, the first step-up dose is about 0.19% of the target dose, and the second step-up dose is about 2.25% of the target dose.

[0451] In some examples of the run-in phase, the first step-up dose is 0.1% to 1% of the target dose and the second step-up dose is 2% to 10% of the target dose. In some examples of the run-in phase, the first step-up dose is 0.19%, 0.5%, 0.7%, 1% of the target dose and the second step-up dose is 1.5%, 2%, 2.25%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% of the target dose. In some examples of the run-in phase, the first step-up dose is 0.19% of the target dose and the second step-up dose is 2.25% of the target dose.

[0452] In some examples of the run-in phase, the first escalation dose is about 0.3 mg and the second escalation dose is about 3.6 mg. In some examples, the first escalation dose is about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, or about 1 mg, and the second escalation dose is about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

[0453] In some examples of the run-in phase, the first escalation dose is 0.3 mg and the second escalation dose is 3.6 mg. In some examples, the first escalation dose is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or 1 mg and the second escalation dose is 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg.

[0454] In any of the foregoing examples, the first sub-phase of the first phase can include at least 2 administration cycles, at least 3 administration cycles, or at least 4 administration cycles, at least 5 administration cycles, at least 6 administration cycles, at least 7, at least 8 administration cycles, at least 9 administration cycles, at least 10 administration cycles, at least 11 administration cycles, at least 12 administration cycles, or at least 13 administration cycles, or more.

[0455] In some examples, a first sub-phase of a first phase includes a first administration cycle (C1); a first administration cycle and a second administration cycle (C2); a first administration cycle, a first administration cycle (C2), and a third administration cycle (C3); a first administration cycle (C1), a first administration cycle (C2), a third administration cycle (C3), and a fourth administration cycle (C4); a first administration cycle (C1), a first administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), and a fifth administration cycle (C5); a first administration cycle (C1), first administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), and sixth administration cycle (C6); first administration cycle (C1), first administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), and seventh administration cycle (C7); first administration cycle (C1), first administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C7), and seventh administration cycle (C8). a first administration cycle (C1), a first administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), a sixth administration cycle (C6), a seventh administration cycle (C7), an eighth administration cycle (C8), and a ninth administration cycle (C9); a first administration cycle (C1), a first administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), a sixth administration cycle (C6), a seventh administration cycle (C7), an eighth administration cycle (C8), and a ninth administration cycle (C9). cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), ninth administration cycle (C9), and tenth administration cycle (C10); first administration cycle (C1), first administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), ninth administration cycle (C9), tenth administration cycle (C10), and eleventh administration cycle (C11);the first administration cycle (C1), the first administration cycle (C2), the third administration cycle (C3), the fourth administration cycle (C4), the fifth administration cycle (C5), the sixth administration cycle (C6), the seventh administration cycle (C7), the eighth administration cycle (C8), the ninth administration cycle (C9), the tenth administration cycle (C10), the eleventh administration cycle (C11), and the twelfth administration cycle (C12); or the first administration cycle cycle (C1), a first administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), a sixth administration cycle (C6), a seventh administration cycle (C7), an eighth administration cycle (C8), a ninth administration cycle (C9), a tenth administration cycle (C10), an eleventh administration cycle (C11), a twelfth administration cycle (C12), and a thirteenth administration cycle;

[0456] In some examples, the bispecific antibody target dose may be administered to the subject on day 1 of C1 during the first subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C2 during the first subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C3 during the first subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C4 during the first subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C5 during the first subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C6 during the first subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C7 during the first subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C8 during the first subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C9 during the first subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C10 during the first subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C11 during the first subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C12 during the first subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C13 during the first subphase of the first phase.

[0457] In some examples, a target dose of the bispecific antibody is administered to the subject for each administration during the first sub-phase of the phase.

[0458] In any of the foregoing examples, the second sub-phase of the first phase can include at least 2 administration cycles, at least 3 administration cycles, or at least 4 administration cycles, at least 5 administration cycles, at least 6 administration cycles, at least 7, at least 8 administration cycles, at least 9 administration cycles, at least 10 administration cycles, at least 11 administration cycles, at least 12 administration cycles, or at least 13 administration cycles, or more.

[0459] In some examples, the second subphase of the first phase includes a first administration cycle (C1); a first administration cycle and a second administration cycle (C2); a first administration cycle, a first administration cycle (C2), and a third administration cycle (C3); a first administration cycle (C1), a first administration cycle (C2), a third administration cycle (C3), and a fourth administration cycle (C4); a first administration cycle (C1), a first administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), and a fifth administration cycle (C5). ; first administration cycle (C1), first administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), and sixth administration cycle (C6); first administration cycle (C1), first administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), and seventh administration cycle (C7); first administration cycle (C1), first administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C6), and seventh administration cycle (C7). the fifth administration cycle (C5), the sixth administration cycle (C6), the seventh administration cycle (C7), and the eighth administration cycle (C8); the first administration cycle (C1), the first administration cycle (C2), the third administration cycle (C3), the fourth administration cycle (C4), the fifth administration cycle (C5), the sixth administration cycle (C6), the seventh administration cycle (C7), the eighth administration cycle (C8), and the ninth administration cycle (C9); the first administration cycle (C1), the first administration cycle (C2), the third administration cycle (C3), the fourth administration cycle (C4), the fifth administration cycle (C5), the sixth administration cycle (C6), the seventh administration cycle (C7), the eighth administration cycle (C8), and the ninth administration cycle (C9). administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), ninth administration cycle (C9), and tenth administration cycle (C10); first administration cycle (C1), first administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), ninth administration cycle (C9), tenth administration cycle (C10), and eleventh administration cycle (C11);the first administration cycle (C1), the first administration cycle (C2), the third administration cycle (C3), the fourth administration cycle (C4), the fifth administration cycle (C5), the sixth administration cycle (C6), the seventh administration cycle (C7), the eighth administration cycle (C8), the ninth administration cycle (C9), the tenth administration cycle (C10), the eleventh administration cycle (C11), and the twelfth administration cycle (C12); or the first administration cycle cycle (C1), a first administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), a sixth administration cycle (C6), a seventh administration cycle (C7), an eighth administration cycle (C8), a ninth administration cycle (C9), a tenth administration cycle (C10), an eleventh administration cycle (C11), a twelfth administration cycle (C12), and a thirteenth administration cycle;

[0460] In some examples, the bispecific antibody target dose may be administered to the subject on day 1 of C1 during the second subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C2 during the second subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C3 during the second subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C4 during the second subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C5 during the second subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C6 during the second subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C7 during the second subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C8 during the second subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C9 during the second subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C10 during the second subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C11 during the second subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C12 during the second subphase of the first phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C13 during the second subphase of the first phase.

[0461] In some examples, a target dose of the bispecific antibody is administered to the subject for each administration during the second sub-phase of the phase.

[0462] In any of the foregoing examples, the second phase may include at least 2 administration cycles, at least 3 administration cycles, or at least 4 administration cycles, at least 5 administration cycles, at least 6 administration cycles, at least 7, at least 8 administration cycles, at least 9 administration cycles, at least 10 administration cycles, at least 11 administration cycles, at least 12 administration cycles, or at least 13 administration cycles, or more.

[0463] In some examples, the second phase includes a first administration cycle (C1); a first administration cycle and a second administration cycle (C2); a first administration cycle, a second administration cycle (C2), and a third administration cycle (C3); a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), and a fourth administration cycle (C4); a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), and a fifth administration cycle (C5); a first administration cycle (C 1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), and sixth administration cycle (C6); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), and seventh administration cycle (C7); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), and eighth administration cycle (C8); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), and ninth administration cycle (C9); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), ninth administration cycle (C9), and tenth administration cycle (C10); first administration cycle (C1), second administration cycle (C2), third administration cycle (C3), fourth administration cycle (C4), fifth administration cycle (C5), sixth administration cycle (C6), seventh administration cycle (C7), eighth administration cycle (C8), ninth administration cycle (C9), tenth administration cycle (C10), and eleventh administration cycle (C11);the first administration cycle (C1), the second administration cycle (C2), the third administration cycle (C3), the fourth administration cycle (C4), the fifth administration cycle (C5), the sixth administration cycle (C6), the seventh administration cycle (C7), the eighth administration cycle (C8), the ninth administration cycle (C9), the tenth administration cycle (C10), the eleventh administration cycle (C11), and the twelfth administration cycle (C12); or the first administration cycle cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), a sixth administration cycle (C6), a seventh administration cycle (C7), an eighth administration cycle (C8), a ninth administration cycle (C9), a tenth administration cycle (C10), an eleventh administration cycle (C11), a twelfth administration cycle (C12), and a thirteenth administration cycle;

[0464] In some examples, the bispecific antibody target dose may be administered to the subject on day 1 of C1 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C2 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C3 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C4 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C5 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C6 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C7 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C8 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C9 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C10 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C11 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C12 during the second phase. In a further example, the bispecific antibody target dose may be administered to the subject on day 1 of C13 during the second phase.

[0465] In some examples, a target dose of the bispecific antibody is administered to the subject for each administration during the second phase.

[0466] In any of the above examples, the target dose is about 75 mg to about 325 mg. In some examples, the target dose is about 80 mg to about 320 mg. In some examples, the target dose is about 85 mg to about 310 mg. In some examples, the target dose is about 95 mg to about 300 mg. In some examples, the target dose is about 105 mg to about 290 mg. In some examples, the target dose is about 110 mg to about 280 mg. In some examples, the target dose is about 115 mg to about 270 mg. In some examples, the target dose is about 125 mg to about 260 mg. In some examples, the target dose is about 135 mg to about 250 mg. In some examples, the target dose is about 145 mg to about 240 mg. In some examples, the target dose is about 155 mg to about 230 mg. In some examples, the target dose is about 160 mg to about 220 mg. In some examples, the target dose is about 160 mg to about 210 mg. In some examples, the target dose is about 160 mg to about 200 mg. In some examples, the target dose is about 90 mg. In some examples, the target dose is about 132 mg. In some examples, the target dose is about 160 mg.

[0467] In some examples, the target dose is about 65 mg. In some examples, the target dose is about 70 mg. In some examples, the target dose is about 75 mg. In some examples, the target dose is about 80 mg. In some examples, the target dose is about 85 mg. In some examples, the target dose is about 90 mg. In some examples, the target dose is about 95 mg. In some examples, the target dose is about 100 mg. In some examples, the target dose is about 105 mg. In some examples, the target dose is about 110 mg. In some examples, the target dose is about 115 mg. In some examples, the target dose is about 120 mg. In some examples, the target dose is about 125 mg. In some examples, the target dose is about 130 mg. In some examples, the target dose is about 132 mg. In some examples, the target dose is about 135 mg. In some examples, the target dose is about 140 mg. In some examples, the target dose is about 145 mg. In some examples, the target dose is about 150 mg. In some examples, the target dose is about 155 mg. In some examples, the target dose is about 160 mg. In some examples, the target dose is about 165 mg. In some examples, the target dose is about 170 mg. In some examples, the target dose is about 175 mg. In some examples, the target dose is about 180 mg. In some examples, the target dose is about 185 mg. In some examples, the target dose is about 190 mg. In some examples, the target dose is about 195 mg. In some examples, the target dose is about 200 mg. In some examples, the target dose is about 205 mg. In some examples, the target dose is about 210 mg. In some examples, the target dose is about 215 mg. In some examples, the target dose is about 220 mg. In some examples, the target dose is about 225 mg. In some examples, the target dose is about 230 mg. In some examples, the target dose is about 235 mg. In some examples, the target dose is about 240 mg. In some examples, the target dose is about 245 mg. In some examples, the target dose is about 250 mg. In some examples, the target dose is about 255 mg. In some examples, the target dose is about 260 mg. In some examples, the target dose is about 265 mg.In some examples, the target dose is about 270 mg. In some examples, the target dose is about 275 mg. In some examples, the target dose is about 280 mg. In some examples, the target dose is about 285 mg. In some examples, the target dose is about 290 mg. In some examples, the target dose is about 295 mg. In some examples, the target dose is about 300 mg. In some examples, the target dose is about 305 mg. In some examples, the target dose is about 310 mg. In some examples, the target dose is about 315 mg. In some examples, the target dose is about 320 mg. In some examples, the target dose is about 325 mg. In some examples, the target dose is about 330 mg. In some examples, the target dose is about 335 mg. In some examples, the target dose is about 340 mg. In some examples, the target dose is about 345 mg. In some examples, the target dose is about 350 mg. In some examples, the target dose is about 355 mg. In some examples, the target dose is about 360 mg.

[0468] In some examples, the target dose is 65 mg. In some examples, the target dose is 70 mg. In some examples, the target dose is 75 mg. In some examples, the target dose is 80 mg. In some examples, the target dose is 85 mg. In some examples, the target dose is 90 mg. In some examples, the target dose is 95 mg. In some examples, the target dose is 100 mg. In some examples, the target dose is 105 mg. In some examples, the target dose is 110 mg. In some examples, the target dose is 115 mg. In some examples, the target dose is 120 mg. In some examples, the target dose is 125 mg. In some examples, the target dose is 130 mg. In some examples, the target dose is 132 mg. In some examples, the target dose is 135 mg. In some examples, the target dose is 140 mg. In some examples, the target dose is 145 mg. In some examples, the target dose is 150 mg. In some examples, the target dose is 155 mg. In some examples, the target dose is 160 mg. In some examples, the target dose is 165 mg. In some examples, the target dose is 170 mg. In some examples, the target dose is 175 mg. In some examples, the target dose is 180 mg. In some examples, the target dose is 185 mg. In some examples, the target dose is 190 mg. In some examples, the target dose is 195 mg. In some examples, the target dose is 200 mg. In some examples, the target dose is 205 mg. In some examples, the target dose is 210 mg. In some examples, the target dose is 215 mg. In some examples, the target dose is 220 mg. In some examples, the target dose is 225 mg. In some examples, the target dose is 230 mg. In some examples, the target dose is 235 mg. In some examples, the target dose is 240 mg. In some examples, the target dose is 245 mg. In some examples, the target dose is 250 mg. In some examples, the target dose is 255 mg. In some examples, the target dose is 260 mg. In some instances, the target dose is 265 mg. In some instances, the target dose is 270 mg.In some examples, the target dose is 275 mg. In some examples, the target dose is 280 mg. In some examples, the target dose is 285 mg. In some examples, the target dose is 290 mg. In some examples, the target dose is 295 mg. In some examples, the target dose is 300 mg. In some examples, the target dose is 305 mg. In some examples, the target dose is 310 mg. In some examples, the target dose is 315 mg. In some examples, the target dose is 320 mg. In some examples, the target dose is 325 mg. In some examples, the target dose is 330 mg. In some examples, the target dose is 335 mg. In some examples, the target dose is 340 mg. In some examples, the target dose is 345 mg. In some examples, the target dose is 350 mg. In some examples, the target dose is 355 mg. In some examples, the target dose is 360 mg.

[0469] In some examples, a target dose of the bispecific antibody is administered to the subject for each administration during the second phase.

[0470] In some examples, the bispecific antibody is administered to the subject intravenously. In some examples, the bispecific antibody is administered to the subject subcutaneously.

[0471] In any of the foregoing examples, the anti-CD38 antibody is administered to the subject on days 1, 8, and / or 15 of each administration cycle in the run-in phase. In a further example, the anti-CD38 antibody is administered to the subject on days 1, 8, and / or 15 of each administration cycle in the first sub-phase of the first phase. In a further example, the anti-CD38 antibody is administered to the subject on day 1 of each administration cycle in the second sub-phase of the first phase. In a further example, the anti-CD38 antibody is administered to the subject on day 1 of each administration cycle in the second phase.

[0472] The anti-CD38 antibody may be administered by any suitable route of administration. In some examples, the anti-CD38 antibody is administered subcutaneously to the subject. In some examples, the anti-CD38 antibody is administered intravenously to the subject.

[0473] In some examples, the anti-CD38 antibody is daratumumab or isatuximab.

[0474] In some examples, the anti-CD38 antibody is daratumumab.

[0475] In some examples, daratumumab is administered in a dose of about 900 mg to about 3600 mg (e.g., about 900 mg, about 950 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg, about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, abou...

Claims

1. 1. A method of treating a subject with multiple myeloma (MM), comprising administering to the subject a bispecific antibody that binds Fc receptor homolog 5 (FcRH5) and cluster of differentiation 3 (CD3), (i) a first phase comprising one or more administration cycles, the first phase comprising administering the bispecific antibody to the subject weekly (QW); (ii) a second phase comprising one or more administration cycles, the second phase comprising administering the bispecific antibody to the subject every two weeks (Q2W); and (iii) a third phase comprising one or more administration cycles, wherein the third phase comprises administering the bispecific antibody to the subject every four weeks (Q4W).

2. 2. The method of claim 1, wherein each dosing cycle is a 28 day dosing cycle.

3. 3. The method of claim 2, wherein the first phase comprises at least two administration cycles.

4. 4. The method of claim 3, wherein the first phase comprises a first administration cycle (C1) and a second administration cycle (C2).

5. 5. The method of claim 4, wherein the first phase comprises administration of the bispecific antibody to the subject on days 1, 8, 15 and 22 of C1.

6. 6. The method of claim 4 or 5, wherein the first phase comprises administration of the bispecific antibody to the subject on days 1, 8, 15 and 22 of C2.

7. 7. The method of any one of claims 1 to 6, wherein a target dose of the bispecific antibody is administered to the subject for each administration during the first phase.

8. 7. The method of any one of claims 4 to 6, wherein the first phase comprises administration of a first escalating dose of the bispecific antibody to the subject.

9. 9. The method of claim 8, wherein the first escalation dose is administered to the subject on day 1 of C1.

10. 10. The method of claim 9, wherein target doses are administered to the subject on days 8, 15, and 22 of C1.

11. 11. The method of claim 10, wherein target doses are further administered to the subject on days 1, 8, 15, and 22 of C2.

12. 12. The method of claim 10 or 11, wherein the first escalation dose is about 4% of the target dose.

13. 7. The method of any one of claims 4 to 6, wherein the first phase comprises administration of a first escalating dose and a second escalating dose of the bispecific antibody to the subject.

14. 14. The method of claim 13, wherein the first escalation dose is administered to the subject on day 1 of C1 and the second escalation dose is administered to the subject on day 8 of C1.

15. 15. The method of claim 14, wherein a target dose is administered to the subject on days 15 and 22 of C1.

16. 16. The method of claim 15, wherein target doses are further administered to the subject on days 1, 8, 15, and 22 of C2.

17. 17. The method of claim 15 or 16, (a) the first escalation dose is 0.33% of the target dose; and (b) the second escalation dose is about 4% of the target dose.

18. 13. The method of any one of claims 8 to 12, wherein the first escalation dose is 3.6 mg.

19. 18. The method of any one of claims 13 to 17, wherein the first escalation dose is 0.3 mg and the second escalation dose is 3.6 mg.

20. 20. The method of any one of claims 2 to 19, wherein the second phase comprises at least two administration cycles, at least three administration cycles, or at least four administration cycles.

21. 21. The method of claim 20, wherein the second phase comprises a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), and a fourth dosing cycle (C4).

22. 22. The method of claim 21 , wherein the second phase comprises administration of the bispecific antibody to the subject on days 1 and 15 of C1, C2, C3, and / or C4.

23. 23. The method of any one of claims 20 to 22, wherein a target dose of the bispecific antibody is administered to the subject for each administration during the second phase.

24. 24. The method of any one of claims 2-23, wherein the third phase comprises at least two administration cycles, at least three administration cycles, at least four administration cycles, at least five administration cycles, at least six administration cycles, or at least seven administration cycles.

25. 25. The method of claim 24, wherein the third phase comprises a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), a sixth administration cycle (C6), and a seventh administration cycle (C7).

26. 26. The method of claim 25, wherein the third phase comprises administering the bispecific antibody to the subject on days C1, C2, C3, C4, C5, C6, and / or C7.

27. 27. The method of any one of claims 24 to 26, wherein a target dose of the bispecific antibody is administered to the subject for each administration during the third phase.

28. 30. The method of any one of claims 7, 10-12, 15-17, 23, and 27, wherein the target dose is 90 mg.

29. The method of any one of claims 1 to 28, wherein the bispecific antibody is administered to the subject as a monotherapy.

30. 30. The method of claim 29, wherein the bispecific antibody is administered intravenously to the subject.

31. 1. A method of treating a subject having MM, comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 and an immunomodulatory drug (IMiD); (i) a first phase comprising one or more administration cycles, the first phase comprising administering the bispecific antibody to the subject every two weeks (Q2W); and (ii) a second phase comprising one or more administration cycles, wherein the second phase comprises administering the bispecific antibody to the subject every four weeks (Q4W).

32. 32. The method of claim 31, wherein each dosing cycle of the first phase and the second phase is a 28 day dosing cycle.

33. 33. The method of claim 31 or 32, further comprising a pre-phase comprising one or more administration cycles prior to said first phase, said pre-phase comprising weekly (QW) administration of said bispecific antibody to said subject.

34. 34. The method of claim 33, wherein each dosing cycle of the prephase is a 21 day dosing cycle.

35. 35. The method of claim 34, wherein the prephase comprises one administration cycle (C1).

36. 36. The method of claim 35, wherein the pre-phase comprises administration of the bispecific antibody to the subject on days 1, 8, and 15 of C1.

37. The method of any one of claims 33 to 36, wherein a target dose of said bispecific antibody is administered to said subject for each administration in said prephase.

38. 37. The method of any one of claims 33 to 36, wherein the pre-phase comprises administration of a first escalating dose of the bispecific antibody to the subject.

39. 39. The method of claim 38, wherein the first escalation dose is administered to the subject on day 1 of C1.

40. 40. The method of claim 39, wherein a target dose is administered to the subject on days 8 and 15 of C1.

41. 41. The method of claim 39 or 40, wherein the first escalation dose is about 2.73% of the target dose.

42. 37. The method of any one of claims 33 to 36, wherein the pre-phase comprises administration of a first escalating dose and a second escalating dose of the bispecific antibody to the subject.

43. 43. The method of claim 42, wherein the first escalation dose is administered to the subject on day 1 of C1 and the second escalation dose is administered to the subject on day 8 of C1.

44. 44. The method of claim 43, wherein the target dose is administered to the subject on day 15 of C1.

45. 45. The method of claim 43 or 44, (a) the amount of the first escalation dose is 0.23% of the target dose; and (b) the amount of the second escalation dose is about 2.73% of the target dose.

46. 42. The method of any one of claims 38-41, wherein the first escalation dose is 3.6 mg.

47. 46. ​​The method of any one of claims 42-45, wherein the first escalation dose is 0.3 mg and the second escalation dose is 3.6 mg.

48. 48. The method of any one of claims 32-47, wherein the first phase comprises at least two administration cycles, at least three administration cycles, at least four administration cycles, at least five administration cycles, or at least six administration cycles.

49. 49. The method of claim 48, wherein the first phase comprises a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), and a sixth administration cycle (C6).

50. 50. The method of claim 49, wherein the first phase comprises administration of the bispecific antibody to the subject on days 1 and 15 of C1, C2, C3, C4, C5, and / or C6.

51. 51. The method of claim 50, wherein a target dose of the bispecific antibody is administered to the subject for each administration during the first phase.

52. 52. The method of any one of claims 32-51, wherein the second phase comprises at least two administration cycles, at least three administration cycles, at least four administration cycles, at least five administration cycles, at least six administration cycles, or at least seven administration cycles.

53. 53. The method of claim 52, wherein the second phase comprises a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), a sixth administration cycle (C6), and a seventh administration cycle (C7).

54. 54. The method of claim 53, wherein the second phase comprises administration of the bispecific antibody on days C1, C2, C3, C4, C5, C6, and / or C7.

55. 55. The method of claim 54, wherein a target dose of the bispecific antibody is administered to the subject for each administration during the second phase.

56. 56. The method of any one of claims 37, 40, 41, 44, 45, 51, and 55, wherein the target dose is 132 mg.

57. The method of any one of claims 32 to 56, wherein the bispecific antibody is administered intravenously to the subject.

58. 58. The method of any one of claims 32-57, wherein the IMiD is administered to the subject on days 1-21 of each administration cycle in the first phase and / or the second phase.

59. 59. The method of any one of claims 31 to 58, wherein the IMiD is pomalidomide.

60. 60. The method of claim 59, wherein pomalidomide is administered to the subject in a dosage of about 4 mg.

61. 61. The method of claim 59 or 60, wherein pomalidomide is administered orally to the subject.

62. 62. The method of any one of claims 34-61, further comprising administering a corticosteroid to the subject during the pre-phase, the first phase, and / or the second phase.

63. 63. The method of claim 62, wherein the corticosteroid is administered QW to the subject during the prephase, the first phase, and / or the second phase.

64. 64. The method of claim 62 or 63, wherein the corticosteroid is administered to the subject intravenously or orally.

65. 65. The method of any one of claims 62-64, wherein the corticosteroid is administered to the subject during the prephase on days 1, 8 and 15 of C1.

66. 66. The method of any one of claims 62-65, wherein the corticosteroid is administered intravenously to the subject during the prephase on days 1, 8 and 15 of C1.

67. 67. The method of any one of claims 62-66, wherein the corticosteroid is administered to the subject during the first phase on days 1, 8, 15, and 22 of C1, C2, C3, and / or C4.

68. 68. The method of claim 67, wherein the corticosteroid is administered to the subject: (a) administered intravenously on days 1 and 15 of C1, C2, C3, and / or C4 during said first phase; and (b) orally administered on days 8 and 22 of C1, C2, C3, and / or C4 during said first phase.

69. 69. The method of claim 67 or 68, wherein the corticosteroid is further administered to the subject during the first phase on days 1, 8, 15 and / or 22 of C5 and / or C6.

70. 70. The method of claim 69, wherein the corticosteroid is administered to the subject: (a) administered intravenously on days 1 and / or 15 of C5 and / or C6 during said first phase; and (b) orally administered on days 8 and / or 22 of C5 and / or C6 during said first phase.

71. 71. The method of claim 69 or 70, wherein the corticosteroid is further administered to the subject during the second phase on days 1, 8, 15 and / or 22 of C1, C2, C3, C4, C5, C6 and / or C7.

72. 72. The method of claim 71, wherein the corticosteroid is administered to the subject: (a) administered intravenously on days C1, C2, C3, C4, C5, C6, and / or C7 during the second phase; and (b) during said second phase, C1, C2, C3, C4, C5, C6, and / or C7 are orally administered on days 8, 15, and / or 22.

73. 73. The method of any one of claims 64-72, wherein the corticosteroid is administered intravenously to the subject prior to the administration of the bispecific antibody.

74. 74. The method of claim 73, wherein the corticosteroid is administered intravenously to the subject about 1 hour prior to the administration of the bispecific antibody.

75. 75. The method of any one of claims 62 to 74, wherein the corticosteroid is dexamethasone or methylprednisolone.

76. 76. The method of claim 75, wherein the corticosteroid is dexamethasone.

77. 77. The method of claim 75 or 76, wherein the dexamethasone is administered to the subject in a dosage of about 20 mg.

78. 76. The method of claim 75, wherein the methylprednisolone is administered to the subject in a dosage of about 80 mg.

79. 1. A method of treating a subject having MM, comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 and an anti-cluster of differentiation 38 (CD38) antibody; (i) a first phase comprising one or more administration cycles, the first phase comprising administering the bispecific antibody to the subject every three weeks (Q3W); and (ii) a second phase comprising one or more administration cycles, wherein the second phase comprises administering the bispecific antibody to the subject every four weeks (Q4W).

80. 80. The method of claim 79, further comprising a run-in phase comprising one or more administration cycles prior to said first phase, said run-in phase comprising administering said bispecific antibody to said subject weekly (QW).

81. 81. The method of claim 80, wherein each dosing cycle of the run-in phase is a 21 day dosing cycle.

82. 82. The method of any one of claims 79-81, wherein each dosing cycle of the first phase is a 21 day dosing cycle.

83. 83. The method of any one of claims 79-82, wherein each dosing cycle of the second phase is a 28 day dosing cycle.

84. 84. The method according to any one of claims 80 to 83, wherein the run-in phase comprises one administration cycle (C1).

85. 85. The method of claim 84, wherein the run-in phase comprises administering to the subject: (a) days 2, 9, and 16 of C1; or (b) A method comprising administration of C1 on days 3, 9, and 16.

86. 86. The method of claim 85, wherein the bispecific antibody is administered to the subject on days 3, 9 and 16 of C1 if the subject has an adverse reaction to the anti-CD38 antibody.

87. 87. The method of any one of claims 80-86, wherein a target dose of the bispecific antibody is administered to the subject for each administration during the run-in phase.

88. 87. The method of any one of claims 80-86, wherein the run-in phase comprises administration of a first escalating dose of the bispecific antibody to the subject.

89. 89. The method of claim 88, wherein the first escalation dose is administered to the subject on day 2 of C1 or day 3 of C1.

90. 90. The method of claim 89, wherein a target dose is administered to the subject on days 9 and 16 of C1.

91. 91. The method of claim 89 or 90, wherein the first escalation dose is about 2.25% of the target dose.

92. 92. The method of any one of claims 81-91, wherein the run-in phase comprises administration of a first escalating dose and a second escalating dose of the bispecific antibody to the subject.

93. 93. The method of claim 92, comprising: (a) the first escalation dose is administered to the subject on day 2 of C1 or day 3 of C1; and (b) the second escalation dose is administered to the subject on day 9 of C1.

94. 94. The method of claim 93, wherein the target dose is administered to the subject on day 16 of C1.

95. A method according to any one of claims 92 to 94, comprising the steps of: (a) the first escalation dose is about 0.19% of the target dose; and (b) the second escalation dose is about 2.25% of the target dose.

96. 92. The method of any one of claims 88-91, wherein the first escalation dose is 3.6 mg.

97. 96. The method of any one of claims 92-95, wherein the first escalation dose is 0.3 mg and the second escalation dose is 3.6 mg.

98. 98. The method of any one of claims 82 to 97, wherein the first phase comprises a first sub-phase and a second sub-phase.

99. 99. The method of claim 98, wherein the first subphase of the first phase comprises at least two administration cycles.

100. 100. The method of claim 98 or 99, wherein the first sub-phase of the first phase comprises a first administration cycle (C1) and a second administration cycle (C2).

101. 101. The method of claim 100, wherein the first subphase of the first phase comprises administration of the bispecific antibody on days C1 and C2.

102. 102. The method of any one of claims 98-101, wherein a target dose of said bispecific antibody is administered to said subject for each administration during the first subphase of said first phase.

103. 103. The method of any one of claims 98-102, wherein the second sub-phase comprises at least two administration cycles, at least three administration cycles, at least four administration cycles, or at least five administration cycles.

104. 104. The method of claim 103, wherein the second sub-phase of the first phase comprises a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), and a fifth administration cycle (C5).

105. 105. The method of claim 104, wherein the second subphase of the first phase comprises administration of the bispecific antibody on days C1, C2, C3, C4, and / or C5.

106. 106. The method of any one of claims 103 to 105, wherein a target dose of said bispecific antibody is administered to said subject for each administration during the second sub-phase of said first phase.

107. 107. The method of any one of claims 83-106, wherein the second phase comprises at least two administration cycles, at least three administration cycles, at least four administration cycles, or at least five administration cycles.

108. 108. The method of claim 107, wherein the second phase comprises a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), and a fifth administration cycle (C5).

109. 109. The method of claim 108, wherein the second phase comprises administration of the bispecific antibody on days C1, C2, C3, C4, and / or C5.

110. 110. The method of claim 109, wherein a target dose of the bispecific antibody is administered to the subject for each administration during the second phase.

111. 112. The method of any one of claims 87, 90, 91, 94, 95, 102, 106, and 110, wherein the target dose is 160 mg.

112. The method of any one of claims 79 to 111, wherein the bispecific antibody is administered intravenously to the subject.

113. The method of any one of claims 81-112, wherein the anti-CD38 antibody is administered to the subject during the run-in phase.

114. The method of claim 113, wherein the run-in phase comprises a first administration cycle (C1), and the anti-CD38 antibody is administered to the subject during the run-in phase on days 1, 8, and 15 of C1.

115. The method of any one of claims 101-114, wherein the anti-CD38 antibody is administered to the subject during the first subphase of the first phase.

116. The method of claim 115, wherein the anti-CD38 antibody is administered to the subject during the first subphase of the first phase on days 1, 8, and 15 of C1 and / or C2.

117. The method of any one of claims 105 to 116, wherein the anti-CD38 antibody is administered to the subject during the second subphase of the first phase.

118. The method of claim 117, wherein the anti-CD38 antibody is administered to the subject during the second subphase of the first phase on day 1 of C1, C2, C3, C4, and / or C5.

119. The method of any one of claims 109 to 118, wherein the anti-CD38 antibody is administered to the subject during the second phase.

120. 120. The method of claim 119, wherein the anti-CD38 antibody is administered to the subject during the second phase on day 1 of C1, C2, C3, C4, and / or C5.

121. The method of any one of claims 79 to 120, wherein the anti-CD38 antibody is administered subcutaneously (SC) to the subject.

122. The method of any one of claims 79 to 121, wherein the anti-CD38 antibody is daratumumab or isatuximab.

123. 123. The method of claim 122, wherein the anti-CD38 antibody is daratumumab.

124. 124. The method of claim 123, wherein the daratumumab is administered to the subject at a dosage of about 1800 mg.

125. 125. The method of any one of claims 81-124, further comprising administration of a corticosteroid to the subject during any administration cycle within the run-in phase, the first phase, and / or the second phase.

126. 126. The method of claim 125, wherein the corticosteroid is administered QW to the subject during the run-in phase.

127. 127. The method of claim 125 or 126, wherein the run-in phase comprises a first administration cycle (C1), and the corticosteroid is administered to the subject during the run-in phase on days 1, 8, and 15 of C1.

128. 128. The method of any one of claims 125-127, wherein the corticosteroid is further administered to the subject during the run-in phase on days 2, 9 and 16 of C1.

129. 129. The method of any one of claims 125-128, wherein the corticosteroid is administered QW to the subject during the first subphase of the first phase.

130. 130. The method of claim 129, wherein the corticosteroid is administered to the subject during the first subphase of the first phase on days 1, 8, and 15 of C1 and C2.

131. 131. The method of any one of claims 125-130, wherein the corticosteroid is administered Q3W to the subject during the second sub-phase of the first phase.

132. 132. The method of claim 131, wherein the corticosteroid is administered to the subject during the second subphase of the first phase on days C1, C2, C3, C4, and C5.

133. 133. The method of any one of claims 125-132, wherein the corticosteroid is administered Q4W to the subject during the second phase.

134. 134. The method of claim 133, wherein the corticosteroid is administered to the subject during the second phase on days C1, C2, C3, C4, and / or C5.

135. 135. The method of any one of claims 125-134, wherein the corticosteroid is administered to the subject intravenously and / or orally.

136. 136. The method of claim 135, wherein the corticosteroid is administered to the subject: (a) administered intravenously or orally on days 1, 8, and 15 of C1 during the run-in phase; (b) administered intravenously on days 2, 9, and 16 of C1 during the run-in phase; (c) administered intravenously on days C1 and C2 during the first subphase of the first phase; (d) administered intravenously on days C1, C2, C3, C4, and C5 during the second subphase of the first phase; and (e) administered intravenously or orally on days 8 and 15 of C1 and C2 during said first sub-phase of said first phase.

137. 137. The method of claim 136, wherein the corticosteroid is further administered intravenously to the subject during the second phase on days C1, C2, C3, C4, and / or C5.

138. 138. The method of any one of claims 125-137, wherein the corticosteroid is administered intravenously to the subject as a premedication for the bispecific antibody.

139. 139. The method of claim 138, wherein the corticosteroid is administered to the subject about 1 hour prior to the administration of the bispecific antibody. (a) during the run-in phase, on day 2 or day 3 of C1; (b) during the run-in phase, on days 9 and 16 of C1; and (c) administered on day 1 of C2 during said first sub-phase of said first phase.

140. 140. The method of any one of claims 125 to 139, wherein the corticosteroid is dexamethasone or methylprednisolone.

141. 141. The method of any one of claims 125 to 140, wherein the corticosteroid is dexamethasone.

142. 142. The method of claim 141, wherein the dexamethasone is administered to the subject at a dose of about 20 mg.

143. 141. The method of claim 140, wherein the methylprednisolone is administered to the subject at a dose of about 80 mg.

144. The method according to any one of claims 1 to 143, wherein the bispecific antibody comprises the following six hypervariable regions (HVRs): (a) HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) HVR-H3 comprising the amino acid sequence HYYGSSDYALDN (SEQ ID NO: 3); (d) HVR-L1 comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO:5); and (f) HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6) and an anti-FcRH5 arm comprising a first binding domain comprising:

145. The method of any one of claims 1 to 144, wherein the bispecific antibody comprises: (a) a heavy chain variable (VH) domain comprising 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 comprising 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 comprising the VH domain according to (a) and the VL domain according to (b).

146. The method of claim 145, wherein the first binding domain comprises 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.

147. 147. The method of any one of claims 1 to 146, wherein the bispecific antibody comprises 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) and an anti-CD3 arm comprising a second binding domain comprising:

148. The method of any one of claims 1 to 147, wherein the bispecific antibody comprises: (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising 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 comprising a second binding domain comprising the VH domain according to (a) and the VL domain according to (b).

149. The method of claim 148, wherein the second binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 15 and a VL domain comprising the amino acid sequence of SEQ ID NO:

16.

150. 150. The method according to any one of claims 1 to 149, wherein the bispecific antibody 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), (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) the method, wherein L2 comprises the amino acid sequence of SEQ ID NO:

38.

151. The method of any one of claims 1 to 150, wherein the bispecific antibody comprises an aglycosylation site mutation.

152. The method of claim 151 , wherein the aglycosylation site mutation reduces an effector function of the bispecific antibody.

153. 153. The method of claim 152, wherein the aglycosylation site mutation is a substitution mutation.

154. The method of claim 153, wherein the bispecific antibody comprises a substitution mutation in the Fc region that reduces effector function.

155. The method of any one of claims 1 to 154, wherein the bispecific antibody is a monoclonal antibody.

156. The method of any one of claims 1 to 155, wherein the bispecific antibody is a humanized antibody.

157. The method of any one of claims 1 to 156, wherein the bispecific antibody is a chimeric antibody.

158. The method of any one of claims 1-149 and 151-157, wherein the bispecific antibody is an antibody fragment that binds to FcRH5 and CD3.

159. The antibody fragments include Fab, Fab'-SH, Fv, scFv, and (Fab') ２ The method of claim 158, wherein the nucleic acid is selected from the group consisting of:

160. The method of any one of claims 1 to 157, wherein the bispecific antibody is a full-length antibody.

161. The method of any one of claims 1 to 160, wherein the bispecific antibody is an IgG antibody.

162. The IgG antibody is IgG １ The method of claim 161, which is an antibody.

163. The bispecific antibody comprises one or more heavy chain constant domains, the one or more heavy chain constant domains being a first CH1 (CH1 １ ) domain, the first CH2 (CH2 １ ) domain, the first CH3 (CH3 １ ) domain, a second CH1 (CH1 ２ ) domain, the second CH2 (CH2 ２ ) domain, and a second CH3 (CH3 ２ 163. The method of any one of claims 1 to 162, wherein the domain is selected from the group consisting of .

164. 164. The method of claim 163, wherein at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

165. CH3 １ Domain and the CH3 ２ Each of the domains comprises a protrusion or a cavity, and the CH3 １ The protrusion or cavity of the domain is ２ 165. The method of claim 164, wherein said cavity or protrusion of said domain is positionable, respectively.

166. CH3 １ Domain and the CH3 ２ 166. The method of claim 165, wherein the domains associate at an interface between the protrusion and the cavity.

167. CH2 １ Domain and the CH2 ２ Each of the domains comprises a protrusion or a cavity, and the CH2 １ The protrusion or cavity of the domain is ２ 167. The method of any one of claims 163 to 166, wherein said cavity or protrusion of said domain is positionable, respectively.

168. CH2 １ Domain and the CH2 ２ 168. The method of claim 167, wherein the domains associate at an interface between the protrusion and the cavity.

169. 169. The method of claim 168, wherein the anti-FcRH5 arm comprises the protrusion and the anti-CD3 arm comprises the cavity.

170. The method of claim 169, wherein the CH3 domain of the anti-FcRH5 arm comprises a protrusion comprising a T366W amino acid substitution mutation (EU numbering) and the CH3 domain of the anti-CD3 arm comprises a cavity comprising T366S, L368A, and Y407V amino acid substitution mutations (EU numbering).

171. The method of any one of claims 1 to 170, wherein the bispecific antibody is cebostamab.

172. The method of any one of claims 1-171, wherein the bispecific antibody is administered to the subject simultaneously with one or more additional therapeutic agents.

173. 173. The method of claim 172, wherein the bispecific antibody is administered to the subject prior to administration of one or more additional therapeutic agents.

174. 173. The method of claim 172, wherein the bispecific antibody is administered to the subject following administration of one or more additional therapeutic agents.

175. 175. The method of claim 173 or 174, wherein the one or more additional therapeutic agents comprises an effective amount of tocilizumab.

176. 176. The method of claim 175, wherein tocilizumab is administered to the subject by intravenous infusion.

177. 177. The method of claim 176, (a) the subject weighs 30 kg or more, and tocilizumab is administered to the subject at a dose of 8 mg / kg; or (b) the subject weighs less than 30 kg and tocilizumab is administered to the subject at a dose of 12 mg / kg; or (c) The method, wherein the final dose administered does not exceed 800 mg.

178. 178. The method of any one of claims 175-177, wherein tocilizumab is administered to the subject 2 hours prior to administration of the bispecific antibody.

179. The method of any one of claims 174-178, wherein the one or more additional therapeutic agents comprises an effective amount of a B-cell maturation antigen (BCMA) directed therapy.

180. 180. The method of any one of claims 1-179, wherein the subject has a cytokine release syndrome (CRS) event, and the method further comprises treating a symptom of the CRS event while pending treatment with the bispecific antibody.

181. The method of claim 180, further comprising administering an effective amount of tocilizumab to the subject to treat the CRS event.

182. 182. The method of claim 181, wherein tocilizumab is administered intravenously to the subject as a single dose of about 8 mg / kg.

183. The method of claim 182, wherein the CRS event does not resolve or worsens within 24 hours of treating the symptoms of the CRS event, the method further comprising administering one or more additional doses of tocilizumab to the subject to manage the CRS event.

184. 184. The method of claim 183, wherein the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 8 mg / kg.

185. 185. The method of any one of claims 172-184, wherein the one or more additional therapeutic agents comprises an effective amount of acetaminophen or paracetamol.

186. 186. The method of claim 185, wherein acetaminophen or paracetamol is administered to the subject in a dose of about 500 mg to about 1000 mg.

187. 187. The method of claim 186, wherein acetaminophen or paracetamol is administered orally to the subject.

188. 188. The method of any one of claims 172-187, wherein the one or more additional therapeutic agents comprises an effective amount of diphenhydramine.

189. 189. The method of claim 188, wherein diphenhydramine is administered to the subject in a dose of about 25 mg to about 50 mg.

190. 190. The method of claim 189, wherein diphenhydramine is administered orally to the subject.

191. The method of any one of claims 1 to 190, wherein the MM is relapsed or refractory (R / R) MM.

192. The method of claim 191, wherein the subject has received at least three prior lines of treatment for the MM.

193. The method of claim 192, wherein the subject has received at least four prior lines of treatment for the MM.

194. The method of any one of claims 1 to 193, wherein the subject has been exposed to a prior treatment comprising a proteasome inhibitor, an IMiD and / or an anti-CD38 therapeutic agent.

195. 195. The method of claim 194, wherein the proteasome inhibitor is bortezomib, carfilzomib or ixazomib.

196. The method of claim 194, wherein the IMiD is thalidomide, lenalidomide or pomalidomide.

197. 195. The method of claim 194, wherein the anti-CD38 therapeutic agent is daratumumab, MOR202, or isatuximab.

198. The method of claim 197, wherein the anti-CD38 therapeutic agent is daratumumab.

199. The method of any one of claims 1-198, wherein the subject has been exposed to a prior treatment comprising autologous stem cell transplant (ASCT) or CAR-T cell therapy, and the CAR-T cell therapy was last administered at least 12 weeks prior to initiation of the method.

200. 1. A method of treating a subject with MM comprising administering cevostamab monotherapy to the subject; (i) a first phase comprising a first administration cycle (C1) and a second administration cycle (C2); (ii) a second phase comprising a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3) and a fourth administration cycle (C4); and (iii) a third phase including 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); each dosing cycle of the first phase, the second phase, and the third phase is a 28 day dosing cycle, and cevostamab is administered to the subject; A) (i) administered on day 1 of C1 at escalating doses during said first phase; (ii) administered at target doses during said first phase on days 8, 15, and 22 of C1; (iii) administered at a target dose during said first phase on days 1, 8, 15, and 22 of C2; (iv) administered at target doses during the second phase on days 1 and 15 of C1, C2, C3, and C4; and (v) administered on days C1, C2, C3, C4, C5, C6, and C7 at the target dose during said third phase; or or B) (i) administered on day 1 of C1 as a first escalation dose during said first phase, and on day 8 of C1 as a second escalation dose during said first phase; (ii) administered on days 15 and 22 of C1 at a target dose during said first phase; (iii) administered at a target dose during said first phase on days 1, 8, 15, and 22 of C2; (iv) administered at target doses during the second phase on days 1 and 15 of C1, C2, C3, and C4; and (v) The method of claim 1, wherein C1, C2, C3, C4, C5, C6, and C7 are administered at target doses during said third phase on days 1.

201. 1. A method of treating a subject having MM, the method comprising administering to the subject cevostamab, pomalidomide, and dexamethasone; (i) a prephase comprising a 21-day administration cycle (C1); (ii) a first phase following the pre-phase, the first phase including a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), and a sixth administration cycle (C6), each administration cycle of the first phase being a 28-day administration cycle; and (iii) a second phase following the first phase, the second 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), each dosing cycle of the second phase being a 28 day dosing cycle; Sebostamab is administered to the subject, (i) administered on day 1 of C1 as a first escalation dose during said pre-phase and on day 8 of C1 as a second escalation dose during said pre-phase; (ii) administered on day 15 of C1 at a target dose during said prephase; (iii) administered on days 1 and 15 of C1, C2, C3, C4, C5, and C6 at target doses during the first phase; and (iv) administered on days C1, C2, C3, C4, C5, C6, and C7 at target doses during said second phase; administering to the subject: (i) administered at a dose of about 4 mg on days 1-21 of C1, C2, C3, C4, C5, and C6 during the first phase; and (ii) administered on days 1-21 of C1, C2, C3, C4, C5, C6, and C7 at a dose of about 4 mg during the second phase; and the dexamethasone is administered to the subject; (i) administered during said prephase at a dose of about 20 mg on days 1, 8, and 15 of C1; and (ii) a dose of about 20 mg is administered during the first phase on days 1, 8, 15, and 22 of C1, C2, C3, and C4, and optionally, the dexamethasone is administered to the subject; (iii) administered during said first phase at a dose of about 20 mg on days 1, 8, 15, and 22 of C5 and C6; and (iv) during said second phase, C1, C2, C3, C4, C5, C6, and C7 are administered at a dose of about 20 mg on days 1, 8, 15, and 22.

202. 1. A method of treating a subject having MM, the method comprising administering to the subject cebostumab, daratumumab, and dexamethasone; (i) a run-in phase comprising a 21-day dosing cycle (C1); (ii) a first phase following the run-in phase, the first phase including a first sub-phase and a second sub-phase, the first sub-phase including a first dosing cycle (C1) and a second dosing cycle (C2), the second sub-phase including a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5), each dosing cycle of the first phase being a 21-day dosing cycle; and (iii) a second phase following the first phase, the second phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5), each dosing cycle of the second phase being a 28 day dosing cycle; The bispecific antibody is administered to the subject. (i) administered on day 2 of C1 as a first escalation dose during the run-in phase and on day 9 of C1 as a second escalation dose during the run-in phase; (ii) administered on day 16 of C1 at the target dose during the run-in phase; (iii) administered on day 1 of each cycle at the target dose during said first phase; and (iv) administered on day 1 of each cycle at the target dose during said second phase; administering the daratumumab to the subject; (i) administered during the run-in phase at a dose of about 1800 mg on days 1, 8, and 15 of C1; (ii) administered on days 1, 8, and 15 of C1 and C2 at a dose of about 1800 mg during the first sub-phase of the first phase; (iii) administered on days C1, C2, C3, C4, and C5 at a dose of about 1800 mg during the second sub-phase of the first phase; and the dexamethasone is administered to the subject; (i) administered at a dose of about 20 mg during the run-in phase on days 1, 2, 8, 9, 15, and 16 of C1; (ii) administered at a dose of about 20 mg during the first subphase of the first phase on days 1, 8, and 15 of C1 and C2; and (iii) during the second sub-phase of the first phase, a dose of about 20 mg is administered on days C1, C2, C3, C4, and C5, and optionally, the dexamethasone is administered to the subject; (iv) about 20 mg administered on days C1, C2, C3, C4 and C5 during the second phase.

203. 1. A bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, said treatment comprising: (i) a first phase comprising one or more administration cycles, the first phase comprising administering the bispecific antibody to the subject weekly (QW); (ii) a second phase comprising one or more administration cycles, the second phase comprising administering the bispecific antibody to the subject every two weeks (Q2W); and (iii) a third phase comprising one or more administration cycles, the third phase comprising administering the bispecific antibody to the subject every four weeks (Q4W).

204. 1. A bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, said treatment comprising: (i) a first phase comprising one or more administration cycles, the first phase comprising administering the bispecific antibody to the subject every two weeks (Q2W); and (ii) a second phase comprising one or more administration cycles, the second phase comprising administering the bispecific antibody to the subject every four weeks (Q4W).

205. 1. A bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, said treatment comprising: (i) a first phase comprising one or more administration cycles, the first phase comprising administering the bispecific antibody to the subject every three weeks (Q3W); and (ii) a second phase comprising one or more administration cycles, the second phase comprising administering the bispecific antibody to the subject every four weeks (Q4W).

Images