Administration for treatment with anti-FcRH5 / anti-CD3 bispecific antibody

Abstract

The present invention provides a method of administering an anti-fragment crystallizable receptor-like 5 (FcRH5) / anti-cluster of differentiation 3 (CD3) bispecific antibody for the treatment of cancers such as multiple myeloma.

Description

Technical Field

[0001] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The name of the XML copy created on July 5, 2023, is 50474-297WO2_Sequence_Listing_7_5_23.xml, and the size is 41,770 bytes.

[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 crystallizable receptor-like 5 (FcRH5) / anti-cluster of differentiation 3 (CD3) bispecific antibody.

Background Art

[0003] Cancer remains one of the greatest threats to human health. In the United States, cancer affects over 1.7 million new patients each year, is the second most common cause of death after heart disease, and approximately 1 in 4 people die from it.

[0004] Blood cancer is, in particular, the second leading cause of cancer-related death. Blood 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 and has an estimated median survival of 8 - 10 years for standard-risk myeloma and 2 - 3 years for high-risk disease, even after autologous stem cell transplantation. Despite a significant improvement in patient survival over the past 20 years, only 10 - 15% of patients achieve or exceed the expected survival compared to the general population. The introduction of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (mAbs) has achieved an increase in survival. Nevertheless, most patients (if not all) ultimately relapse and become refractory, and the outcome of MM patients after relapse or refractoriness, or after they can no longer receive PIs or IMiDs, is very poor, with a survival of less than 1 year. Most late-stage patients have a median estimated overall survival (OS) of approximately 8 - 13 months and become refractory to PIs, IMiDs, and anti-CD38 mAbs (triple-class refractory).

[0005] Therefore, in particular, relapsed or refractory (R / R) MM still constitutes a significant unmet medical need, and new therapeutic agents and treatments are needed. SUMMARY OF THE INVENTION

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

[0007] In one aspect, the present invention features a method of treating a subject having relapsed or refractory (R / R) multiple myeloma (MM), wherein the subject has previously received a B cell maturation antigen (BCMA)-targeted therapeutic agent, and the method comprises administering to the subject a bispecific antibody that binds to Fc receptor homolog 5 (FcRH5) and cluster of differentiation 3 (CD3) in a dosing regimen comprising: (i) a first phase comprising administering the bispecific antibody to the subject in at least a first 21-day dosing cycle (C1), wherein the bispecific antibody is administered to the subject on (a) day 1 of C1; and (b) day 2, 3, or 4 of C1; and (ii) a second phase comprising one or more 21-day dosing cycles, wherein the bispecific antibody is administered to the subject every three weeks (Q3W).

[0008] In another aspect, the present invention is a method of treating a subject having R / R MM, the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first 21-day dosing cycle, wherein the first 21-day dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, C1D1 is from about 0.2 mg to about 0.4 mg and is administered to the subject on day 1 of the first dosing cycle, C1D2 is from about 3.1 mg to about 3.4 mg and is administered to the subject on day 2, 3, or 4 of the first dosing cycle, and C1D3 is greater than C1D2.

[0009] In another aspect, the present invention features a method of treating a subject having R / R MM, wherein the subject has triple-class refractory MM and has previously received a BCMA-targeted TDB antibody, and the method comprises administering to the subject a single-agent therapy with cevostamab in an administration regimen comprising: (i) a first phase comprising administering cevostamab to the subject in a first dosing cycle (C1); and (ii) a second phase comprising administering cevostamab to the subject every three weeks (Q3W), wherein each dosing cycle of the first and second phases is a 21-day dosing cycle, and cevostamab is administered to the subject: (i) during the first phase, at a first step-up dose of 0.3 mg on day 1 of C1 and as a second step-up dose of 3.3 mg on day 2, 3, or 4 of C1 during the first phase; (ii) during the first phase, at a target dose of 160 mg on day 8 of C1; and (iii) during the second phase, at a target dose of 160 mg on day 1 of each dosing cycle. In some embodiments, administration of the 160 mg target dose can be delayed to after day 9 of C1 in the first phase instead of day 8.

[0010] In another aspect, the present invention features a method of treating a subject having R / R MM, wherein the subject has triple-class refractory MM and has previously received a BCMA-targeted TDB antibody, and the method comprises administering to the subject a single-agent therapy with cevostamab in an administration regimen comprising: (i) a first phase comprising administering cevostamab to the subject in a first dosing cycle (C1); and (ii) a second phase comprising administering cevostamab to the subject every three weeks (Q3W), wherein each dosing cycle of the first and second phases is a 21-day dosing cycle, and cevostamab is administered to the subject: (i) during the first phase, at a first step-up dose of 0.3 mg on day 1 of C1 and as a second step-up dose of 3.3 mg on day 2, 3, or 4 of C1 during the first phase; (ii) during the first phase, at a target dose of 160 mg on day 8 of C1; and (iii) during the second phase, at a target dose of 160 mg on day 1 of each dosing cycle. In some embodiments, administration of the 160 mg target dose can be delayed to after day 9 of C1 in the first phase instead of day 8.

[0011] In another aspect, the present invention features a method of treating a subject having R / R MM, where the subject has triple-class refractory MM and has previously received BCMA-targeted CAR-T, and the method comprises administering to the subject a single-agent therapy of sevosetamab in an administration regimen comprising: (i) a first phase including administering sevosetamab to the subject at a first escalating dose of 0.3 mg on day 1 of C1 during a first administration cycle (C1); and (ii) a second phase including administering sevosetamab to the subject Q3W, wherein each administration cycle of the first and second phases is a 21-day administration cycle, and sevosetamab is administered to the subject: (i) during the first phase, at a second escalating dose of 3.3 mg on day 2, 3, or 4 of C1; (ii) during the first phase, at a target dose of 160 mg on day 8 of C1; and (iii) during the second phase, at a target dose of 160 mg on day 1 of each administration cycle. In some aspects, administration of the 160 mg target dose may be delayed to after day 9 of C1 of the first phase rather than on day 8.

[0012] In another aspect, the present invention features a method of treating a subject having R / R MM, wherein the subject has triple-class refractory MM and has previously received a BCMA-targeted ADC, and the method comprises administering to the subject a monotherapy of sevosetamab in an administration regimen comprising: (i) a first phase including administering sevosetamab to the subject at a first escalating dose of 0.3 mg on day 1 of C1 during a first dosing cycle (C1); and (ii) a second phase including administering sevosetamab to the subject Q3W, wherein each dosing cycle of the first and second phases is a 21-day dosing cycle, and sevosetamab is administered to the subject: (i) during the first phase, at a second escalating dose of 3.3 mg on day 2, 3, or 4 of C1 and at a target dose of 160 mg on day 8 of C1; and (iii) during the second phase, at a target dose of 160 mg on day 1 of each dosing cycle. In some embodiments, administration of the 160 mg target dose may be delayed to after day 9 of C1 in the first phase instead of day 8.

[0013] In another aspect, the present invention features a bispecific antibody that binds to FcRH5 and CD3 for use in treating a subject having R / R MM, wherein the subject has triple-class refractory MM and has previously received a BCMA-targeted therapeutic, and the treatment comprises administering to the subject the bispecific antibody in an administration regimen comprising: (i) a first phase including a first 21-day dosing cycle (C1) and including administering the bispecific antibody to the subject: (a) on day 1 of C1; (b) on day 2, 3, or 4 of C1; and (c) on day 8 (or after day 9) of C1; and (ii) a second phase including one or more 21-day dosing cycles and including administering the bispecific antibody to the subject Q3W.

[0014] In another aspect, the invention is a bispecific antibody that binds to FcRH5 and CD3 for use in the treatment of a subject having R / R MM, comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first 21-day dosing cycle, wherein the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, C1D1 is from about 0.2 mg to about 0.4 mg and is administered to the subject on day 1 of the first dosing cycle, C1D2 is from about 3.1 mg to about 3.4 mg and is administered to the subject on day 2, 3, or 4 of the first dosing cycle, and C1D3 is greater than C1D2.

[0015] In some aspects, the subject has triple-class refractory MM.

[0016] In some aspects, the BCMA-targeted therapeutic agent is selected from a BCMA-targeted T cell-dependent bispecific (TDB) antibody, a BCMA-targeted antibody-drug conjugate (ADC), or a chimeric antigen receptor T (CAR-T).

[0017] In some aspects, the BCMA-targeted therapeutic agent is a BCMA-targeted TDB antibody.

[0018] In some aspects, the method further comprises administering to the subject a bispecific antibody that binds to FcRH5 and CD3 on day 8 of C1 during a first phase.

[0019] In some aspects, the method further comprises administering to the subject a bispecific antibody that binds to FcRH5 and CD3 after day 9 of C1 during a first phase.

[0020] In some aspects, the first phase comprises administering to the subject a first step-up dose and a second step-up dose of the bispecific antibody that binds to FcRH5 and CD3.

[0021] In some embodiments, the first step-up dose is administered to the subject on day 1 of C1, and the second step-up dose is administered to the subject on day 2 of C1.

[0022] In some embodiments, (i) the first step-up dose is administered to the subject on day 1 of C1; (ii) the subject has a cytokine release syndrome (CRS) event after the first step-up dose; and (iii) the second step-up dose is administered to the subject on day 3 of C1 after resolution of the CRS event.

[0023] In some embodiments, (i) the first step-up dose is administered to the subject on day 1 of C1; (ii) the subject has a CRS event after the first step-up dose; and (iii) the second step-up dose is administered to the subject on day 4 of C1 after resolution of the CRS event.

[0024] In some embodiments, the first step-up dose is about 0.2% of the target dose, and the second step-up dose is about 2% of the target dose.

[0025] In some embodiments, the first step-up dose is about 0.3 mg, and the second step-up dose is about 3.3 mg.

[0026] In some embodiments, the target dose is administered to the subject on day 8 of C1.

[0027] In some embodiments, the target dose is administered to the subject on day 9 or later of C1.

[0028] In some embodiments, the first phase includes administering to the subject a first step-up dose of a bispecific antibody that binds to FcRH5 and CD3.

[0029] In some embodiments, the first step-up dose is administered to the subject on day 1 of C1.

[0030] In some embodiments, the first step-up dose is from about 0.2% to about 2.3% of the target dose.

[0031] In some embodiments, the first step-up dose is about 0.2% of the target dose.

[0032] In some embodiments, the first step-up dose is about 2% of the target dose.

[0033] In some embodiments, the first step-up dose is about 2.3% of the target dose.

[0034] In some embodiments, the first step-up dose is from about 0.3 mg to about 3.6 mg.

[0035] In some embodiments, the first step-up dose is 0.3 mg.

[0036] In some embodiments, the first step-up dose is 3.3 mg.

[0037] In some embodiments, the first step-up dose is 3.6 mg.

[0038] In some embodiments, the target dose is administered to the subject on days 2 and 8 of C1.

[0039] In some embodiments, the target dose is administered to the subject on day 2 of C1 and on and after day 9.

[0040] In some embodiments, (i) the subject has a CRS event after the first step-up dose; (ii) the target dose is administered to the subject on day 3 of C1 after resolution of the CRS event; and (iii) the target dose is administered to the subject on day 8 of C1.

[0041] In some embodiments, (i) the subject has a CRS event after the first step-up dose; (ii) the target dose is administered to the subject on day 4 of C1 after resolution of the CRS event; and (iii) the target dose is administered to the subject on day 8 of C1.

[0042] In some embodiments, (i) the subject has a CRS event after a first step-up dose; (ii) the target dose is administered to the subject on day 3 of C1 after resolution of the CRS event; and (iii) the target dose is administered to the subject on or after day 9 of C1.

[0043] In some embodiments, (i) the subject has a CRS event after a first step-up dose; (ii) the target dose is administered to the subject on day 4 of C1 after resolution of the CRS event; and (iii) the target dose is administered to the subject on or after day 9 of C1.

[0044] In some embodiments, the second phase comprises a method of at least 2 dosing cycles, at least 3 dosing cycles, at least 4 dosing cycles, at least 5 dosing cycles, at least 6 dosing cycles, at least 7 dosing cycles, at least 8 dosing cycles, at least 9 dosing cycles, at least 10 dosing cycles, at least 11 dosing cycles, at least 12 dosing cycles, or at least 13 dosing cycles.

[0045] In some embodiments, 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), a fifth dosing cycle (C5), a sixth dosing cycle (C6), a seventh dosing cycle (C7), an eighth dosing cycle (C8), a ninth dosing cycle (C9), a tenth dosing cycle (C10), an eleventh dosing cycle (C11), a twelfth dosing cycle (C12), and / or a thirteenth dosing cycle (C13).

[0046] In some embodiments, the second phase comprises administering to the subject a bispecific antibody that binds to FcRH5 and CD3 on day 1 of each dosing cycle.

[0047] In some embodiments, the second phase comprises C1, and day 1 of C1 in the second phase is at least 7 days after administration of the target dose of the bispecific antibody in the first phase.

[0048] In some embodiments, the target dose of the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject for each administration during the second phase.

[0049] In some embodiments, the second phase comprises administering the bispecific antibody that binds to FcRH5 and CD3 to the subject Q3W until the subject experiences disease progression, unacceptable toxicity, or death.

[0050] In some embodiments, the target dose is 160 mg.

[0051] In some embodiments, the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject as a monotherapy.

[0052] In some embodiments, the bispecific antibody that binds to FcRH5 and CD3 is administered intravenously to the subject.

[0053] In some embodiments, the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-FcRH5 arm comprising a first binding domain comprising the following six hypervariable regions (HVRs): (i) HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1); (ii) HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (iii) HVR-H3 comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO: 3); (iv) HVR-L1 comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (v) HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (vi) HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6).

[0054] In some embodiments, a bispecific antibody that binds to FcRH5 and CD3 comprises: (i) 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; (ii) 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 (iii) an anti-FcRH5 arm comprising a first binding domain comprising the VH domain described in (i) and the VL domain described in (ii).

[0055] 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.

[0056] In some embodiments, a bispecific antibody that binds to FcRH5 and CD3 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).

[0057] In some embodiments, a bispecific antibody that binds to FcRH5 and CD3 comprises: (i) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15; (ii) 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 (iii) an anti-CD3 arm comprising a second binding domain comprising the VH domain described in (i) and the VL domain described in (ii).

[0058] 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.

[0059] In some embodiments, a bispecific antibody that binds to FcRH5 and CD3 comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1) and a light chain polypeptide (L1), and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), wherein (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.

[0060] In some embodiments, a bispecific antibody that binds to FcRH5 and CD3 comprises an aglycosylation site mutation.

[0061] In some embodiments, the aglycosylation site mutation reduces the effector function of the bispecific antibody.

[0062] In some embodiments, the aglycosylation site mutation is a substitution mutation.

[0063] In some embodiments, a bispecific antibody that binds to FcRH5 and CD3 comprises a substitution mutation in the Fc region that reduces effector function.

[0064] In some embodiments, a bispecific antibody that binds to FcRH5 and CD3 is a monoclonal antibody.

[0065] In some embodiments, a bispecific antibody that binds to FcRH5 and CD3 is a humanized antibody.

[0066] In some embodiments, a bispecific antibody that binds to FcRH5 and CD3 is a chimeric antibody.

[0067] In some embodiments, the bispecific antibody that binds to FcRH5 and CD3 is an antibody fragment that binds to FcRH5 and CD3.

[0068] In some embodiments, the antibody fragment is selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments.

[0069] In some embodiments, the bispecific antibody that binds to FcRH5 and CD3 is a full-length antibody.

[0070] In some embodiments, the bispecific antibody that binds to FcRH5 and CD3 is an IgG antibody.

[0071] In some embodiments, the IgG antibody is an IgG1 antibody.

[0072] In some embodiments, the bispecific antibody that binds to FcRH5 and CD3 comprises one or more heavy chain constant domains, and the one or more heavy chain constant domains are selected from a first CH1 (CH11) domain, a first CH2 (CH21) domain, a first CH3 (CH31) domain, a second CH1 (CH12) domain, a second CH2 (CH22) domain, and a second CH3 (CH32) domain.

[0073] In some embodiments, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

[0074] In some embodiments, the CH31 domain and the CH32 domain each comprise a protrusion or a cavity, and the protrusion or cavity of the CH31 domain can be respectively arranged in the cavity or protrusion of the CH32 domain.

[0075] In some embodiments, the CH31 domain and the CH32 domain associate at the interface between the protrusion and the cavity.

[0076] In some embodiments, the CH21 domain and the CH22 domain each include a protrusion or a cavity, and the protrusion or cavity of the CH21 domain can be respectively disposed in the cavity or protrusion of the CH22 domain.

[0077] In other embodiments, the CH21 domain and the CH22 domain associate at the interface between the protrusion and the cavity.

[0078] In some embodiments, the anti-FcRH5 arm includes a protrusion and the anti-CD3 arm includes a cavity.

[0079] In some embodiments, the CH3 domain of the anti-FcRH5 arm includes a protrusion containing a T366W amino acid substitution mutation (EU numbering), and the CH3 domain of the anti-CD3 arm includes a cavity containing T366S, L368A, and Y407V amino acid substitution mutations (EU numbering).

[0080] In some embodiments, the bispecific antibody that binds to FcRH5 and CD3 is cevostamab.

[0081] In some embodiments, cevostamab is administered as a monotherapy.

[0082] In some embodiments, the bispecific antibody that binds to FcRH5 and CD3 is administered to a subject simultaneously with one or more additional therapeutic agents.

[0083] In some embodiments, the bispecific antibody that binds to FcRH5 and CD3 is administered to a subject prior to the administration of one or more additional therapeutic agents.

[0084] In some embodiments, the bispecific antibody that binds to FcRH5 and CD3 is administered to a subject after the administration of one or more additional therapeutic agents.

[0085] In some embodiments, one or more additional therapeutic agents include an effective amount of tocilizumab.

[0086] In some embodiments, tocilizumab is administered to a subject by intravenous infusion.

[0087] 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; or (ii) the subject weighs less than 30 kg and tocilizumab is administered to the subject at a dose of 12 mg / kg, and tocilizumab is administered to the subject at a dose not exceeding 800 mg.

[0088] In some embodiments, tocilizumab is administered to a subject 2 hours prior to administration of the bispecific antibody.

[0089] In some embodiments, one or more additional therapeutic agents comprise an effective amount of a BCMA-directed therapeutic agent.

[0090] In some embodiments, the subject has a CRS event and the method further comprises treating the symptoms of the CRS event while withholding treatment with a bispecific antibody that binds to FcRH5 and CD3.

[0091] In some embodiments, the method further comprises treating the symptoms of the CRS event.

[0092] In some embodiments, treating the symptoms of the CRS event comprises administering to the subject an effective amount of tocilizumab.

[0093] In some embodiments, tocilizumab is administered intravenously to the subject as a single dose of about 8 mg / kg.

[0094] In some embodiments, the CRS event does not resolve or worsens within 24 hours after treating the symptoms of the CRS event, and the method further comprises administering to the subject one or more additional doses of tocilizumab to manage the CRS event.

[0095] 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.

[0096] In some embodiments, one or more additional therapeutic agents comprise an effective amount of acetaminophen or paracetamol.

[0097] In some embodiments, acetaminophen or paracetamol is administered to the subject at a dose of about 500 mg to about 1000 mg.

[0098] In some embodiments, acetaminophen or paracetamol is administered orally to the subject.

[0099] In some embodiments, one or more additional therapeutic agents comprise an effective amount of diphenhydramine.

[0100] In some embodiments, diphenhydramine is administered to the subject at a dose of about 25 mg to about 50 mg.

[0101] In some embodiments, diphenhydramine is administered orally to the subject.

[0102] In some embodiments, the method comprises pre - dosing with the following agents: (i) a corticosteroid; (ii) acetaminophen or paracetamol; and / or (iii) diphenhydramine, before administering the bispecific antibody to the subject.

[0103] In some embodiments, the corticosteroid is administered to the subject 1 hour (± 15 minutes) before any administration of the bispecific antibody during the first phase.

[0104] In some embodiments, the subject has experienced CRS due to a prior administration of the bispecific antibody, and the corticosteroid is administered to the subject 1 hour (± 15 minutes) before any administration of the bispecific antibody during the second phase.

[0105] In some embodiments, the corticosteroid is administered to the subject 24 hours before any administration of the bispecific antibody during the first phase.

[0106] In some embodiments, the corticosteroid is dexamethasone or methylprednisolone.

[0107] In some embodiments, the corticosteroid is dexamethasone.

[0108] In some embodiments, dexamethasone is administered to the subject at a dose of about 20 mg.

[0109] In some embodiments, methylprednisolone is administered to the subject at a dose of about 80 mg.

[0110] In some embodiments, the corticosteroid is administered intravenously to the subject.

[0111] In some embodiments, acetaminophen or paracetamol is administered to the subject at a dose of 500 mg to 1000 mg.

[0112] In some embodiments, acetaminophen or paracetamol is administered orally to the subject.

[0113] In some embodiments, diphenhydramine is administered to the subject at a dose of 25 mg to 50 mg.

[0114] In some embodiments, diphenhydramine is administered orally to the subject.

[0115] In some embodiments, the subject has received at least four prior treatment lines for MM.

[0116] In some embodiments, the subject has been exposed to prior treatments including proteasome inhibitor (PI), IMiD, anti-CD38 therapeutic agent, and / or autologous stem cell transplantation (ASCT).

[0117] In some embodiments, the PI is bortezomib, carfilzomib or ixazomib.

[0118] In some embodiments, the IMiD is thalidomide, lenalidomide, or pomalidomide.

[0119] In some embodiments, the anti-CD38 therapeutic agent is an anti-CD38 antibody.

[0120] In some embodiments, the anti-CD38 antibody is daratumumab, MOR202, or isatuximab.

[0121] In some embodiments, the anti-CD38 antibody is daratumumab.

[0122] In some embodiments, the BCMA-targeted TDB antibody is teclistamab (JNJ-64007957), AM701, AMG 420, CC-93269, elranatamab, TNB-383B, linvoseltamab (REGN5458), arclatumumab (CC-93269), AFM26, or HPN217.

[0123] In some embodiments, the BCMA-targeted antibody-drug conjugate (ADC) is BLENREP® (belantamab mafodotin).

[0124] In some embodiments, the chimeric antigen receptor T (CAR-T) is selected from ABECMA® (idecabtagene vicleucel) and CARVYKTI® (cilta-cabtagene autoleucel). BRIEF DESCRIPTION OF THE DRAWINGS

[0125]

Figure 1

Modes for Carrying Out the Invention

[0126] I. Definitions As used herein, the term “about” refers to the normal error range of each value, which would be readily understood by one of ordinary skill in the art. References to “about” with respect to a value or parameter herein include (and describe) aspects directed to that value or parameter itself.

[0127] It is understood that the aspects of the invention described herein include “comprising,” “consisting of,” and “consisting essentially of” aspects.

[0128] The term "FcRH5" or "fragment crystallographic receptor-like 5" as used herein, unless otherwise indicated, refers to any native FcRH5 from any vertebrate, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), and encompasses "full-length," unprocessed FcRH5, as well as any form of FcRH5 that results from processing within a cell. The term also encompasses 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 in length.

[0129] 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 -13 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.

[0130] 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 processing within a cell. 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, which is 207 amino acids long (NCBI Reference SEQ ID NO: NP_000724), and the human CD3γ protein, which is 182 amino acids long (NCBI Reference SEQ ID NO: NP_000064).

[0131] 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.

[0132] For the purposes of this specification, "sevastamab" (also known as BFCR4350A or RO7187797) is an Fc-engineered humanized full-length non-glycosylated IgG1κ T cell-dependent bispecific antibody (TDB) that binds to FcRH5 and CD3 and comprises an anti-FcRH5 arm comprising the heavy chain polypeptide sequence of SEQ ID NO: 35 and the light chain polypeptide sequence of SEQ ID NO: 36, and an anti-CD3 arm comprising the heavy chain polypeptide sequence of SEQ ID NO: 37 and the light chain polypeptide sequence of SEQ ID NO: 38. Sevastamab contains an amino acid substitution of threonine to tryptophan (T366W) at position 366 on the heavy chain of the anti-FcRH5 arm using the EU numbering of Fc region amino acid residues, and three (tyrosine to valine at position 407, threonine to serine at position 366, and leucine to alanine at position 368) amino acid substitutions (Y407V, T366S, L368A) on the heavy chain of the anti-CD3 arm using the EU numbering of Fc region amino acid residues, which drive the heterodimerization of the two arms (half-antibodies). Sevastamab also contains an amino acid substitution (asparagine to glycine) at position 297 on each heavy chain (N297G) using the EU numbering of Fc region amino acid residues, resulting in a non-glycosylated antibody with minimal binding to Fc (Fcγ) receptors and thus interfering with Fc effector functions. Sevastamab is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Recommended INN: List 84, Vol. 34, No. 3 (issued in 2020) (see page 701).

[0133] The term "antibody" is used herein in the broadest sense and encompasses, without limitation, various antibody structures including 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.

[0134] "Affinity" refers to the total strength 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 the 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of molecule X for its partner Y can generally be represented by the dissociation constant (K D ). Affinity can be measured by common methods known in the art, including the methods described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

[0135] An "affinity matured" antibody refers to an antibody that has one or more modifications in one or more hypervariable regions (HVRs) compared to the parental antibody without such modifications, and such modifications improve the affinity of the antibody for the antigen.

[0136] With respect to the binding of an antibody to a target molecule, the terms "binds" or "binding" or "specifically binds" or "specific for" an epitope on a particular polypeptide or a particular polypeptide target mean a binding that is clearly distinct from non-specific interactions. Specific binding can be measured, for example, by determining the binding of a molecule compared to the binding of a control molecule. For example, specific binding can be determined by competition with a control molecule that is similar to the target, for example, with respect to an excess of unlabeled. In this case, specific binding is indicated when the binding of the labeled target to the probe is competitively inhibited by an excess of unlabeled target. As used herein, the expressions "binds" or "binding" or "specifically binds" or "specific" with respect to a particular polypeptide or an epitope on a particular polypeptide target mean, for example, 10 -4 M or less, alternatively 10 -5 M or less, alternatively 10 -6 M or less, alternatively 10 -7 M or less, alternatively 10-8 Less than M, alternatively 10 -9 Less than M, alternatively 10 -10 Less than M, alternatively 10 -11 Less than M, alternatively 10 -12 K for a target less than M D or 10 -4 From M to 10 -6 M or 10 -6 M to 10 -10 M or 10 -7 M to 10 -9 K in the range of M D can be represented by a molecule having. As will be understood by those skilled in the art, affinity and K D values are inversely correlated. High affinity for an antigen is measured by a low K D value. In one embodiment, the term "binding" refers to binding when a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope.

[0137] The terms "full-length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody having a structure substantially similar to the native antibody structure or having a heavy chain containing an Fc region as defined herein.

[0138] "Antibody fragment" refers to a molecule other than an intact antibody that includes a portion of an intact antibody that binds an 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; diabody, linear antibody, single-chain antibody molecule (e.g., scFv, ScFab), and multispecific antibodies formed from antibody fragments.

[0139] "Single-domain antibody" refers to an antibody fragment that includes all or part of the heavy-chain variable domain of an antibody, or all or part of the light-chain variable domain. In certain embodiments, the single-domain antibody is a human single-domain antibody (see, e.g., U.S. Patent No. 6,248,516 B1). Examples of single-domain antibodies include, but are not limited to, VHH.

[0140] A "Fab" fragment is an antigen-binding fragment produced by papain digestion of an antibody and consists of the entire light chain and the variable region domain (VH) of the heavy chain and the first constant domain (CH1) of one heavy chain. Papain digestion of an antibody produces two identical Fab fragments. Pepsin treatment of an antibody yields a single large F(ab’)2 fragment, which corresponds approximately to two disulfide-linked Fab fragments with bivalent antigen-binding activity and can still cross-link antigens. A Fab’ fragment differs from a Fab fragment in having several additional residues at the carboxy terminus of the CH1 domain that include one or more cysteines from the antibody hinge region. Fab’-SH is the name herein for a Fab’ in which the cysteine residue of the constant domain has a free thiol group. The F(ab’)2 antibody fragment was originally produced as a pair of Fab’ fragments with an intervening hinge cysteine. Other chemical couplings of antibody fragments are also known.

[0141] "Fv" consists of a dimer in which one heavy-chain and one light-chain variable region domain make a firm non-covalent bond. Folding of these two domains gives rise to six hypervariable loops (three loops each from the H chain and the L chain) that provide amino acid residues for antigen binding and confer antigen-binding specificity on the antibody. However, even a single variable domain (or half of an Fv containing only the three CDRs specific for an antigen), although often having a lower affinity than the entire binding site, has the ability to recognize and bind an antigen.

[0142] As used herein, the term "Fc region" is used to define the C-terminal region of an immunoglobulin heavy chain, including the native sequence Fc region and variant Fc regions. The boundaries of the Fc region of an immunoglobulin heavy chain can vary, but the human IgG heavy chain Fc region is generally defined as extending from the amino acid residue at position Cys226 or 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 recombinant manipulation of the nucleic acid encoding the antibody heavy chain. Thus, a composition of intact antibodies can include a population of antibodies in which all Lys447 residues have been removed, a population of antibodies in which Lys447 residues have not been removed, and a population of antibodies that have a mixture of antibodies with and without Lys447 residues.

[0143] A "functional Fc region" has the "effector functions" of the native sequence Fc region. Exemplary "antibody 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 evaluated using a variety of assays as disclosed herein, for example.

[0144] A "native sequence Fc region" includes an amino acid sequence identical to the amino acid sequence of the 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 their naturally occurring variants.

[0145] The "variant Fc region" comprises an amino acid sequence that is different from that of the native sequence Fc region by at least one amino acid modification, preferably one or more amino acid substitutions. Preferably, the variant Fc region has at least one amino acid substitution as compared to the Fc region of the native sequence or the Fc region of the parent polypeptide, for example, having from about 1 to about 10 amino acid substitutions, preferably from about 1 to about 5 amino acid substitutions in the Fc region of the native sequence or the Fc region of the 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 Fc region of the native sequence and / or the Fc region of the parent polypeptide.

[0146] As used herein, "Fc complex" refers to the CH3 domains of two Fc regions that interact with each other to form a dimer, or in certain embodiments, two Fc regions interact to form a dimer, where the cysteine residues of 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).

[0147] The "hinge region" is generally defined as extending between about residues 216 to about 230 of IgG (EU numbering), between about residues 226 to about 243 of IgG (Kabat numbering), or between about residues 1 to about 15 of IgG (IMGT unique numbering).

[0148] The "lower hinge region" of the Fc region is typically defined as an extension of the residues immediately C-terminal to the hinge region, i.e., residues 233-239 (EU numbering) of the Fc region.

[0149] "Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. Preferred FcRs are native sequence human FcRs. Further preferred FcRs are those that bind to IgG antibodies (gamma receptors), including allelic variants and alternative splicing forms of these receptors, including receptors of the FcγRI, FcγRII, and FcγRIII subclasses. FcγRII receptors include FcγRIIA ("activating receptor") and FcγRIIB ("inhibitory receptor"), which have similar amino acid sequences that differ mainly in their cytoplasmic domains. The activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. The inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain (see review by 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 to be identified in the future, are encompassed by the term "FcR" herein. This term also includes the neonatal receptor FcRn, which is involved in the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)).

[0150] As used herein, the term "knob-into-hole" or "KnH" technology refers to a technique that directs the pairing of two polypeptides in vitro or in vivo by introducing a protrusion (knob) into one polypeptide and a cavity (hole) into the other polypeptide at the interface where they interact. For example, KnH has been introduced at the Fc:Fc interaction interface, the CL:CH1 interface, or the VH / VL interface of antibodies (e.g., US2007 / 0178552, WO96 / 027011, WO98 / 050431 and Zhu et al., (1997) Protein Science 6:781-788). This is particularly useful for driving the pairing of two different heavy chains together during the production of multispecific antibodies. For example, a multispecific antibody having KnH in the Fc region may further comprise a single variable domain linked to each Fc region, or may further comprise different heavy chain variable domains paired with the same, similar, or different light chain variable domains. KnH technology can also be used to pair two different receptor extracellular domains together, or any other polypeptide sequences that make up different target recognition sequences.

[0151] "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, HVR and FR sequences generally appear in the following sequences in VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0152] The "CH1 region" or "CH1 domain" includes the stretch of residues from approximately residue 118 to residue 215 of IgG (EU numbering), from approximately residue 114 to residue 223 of IgG (Kabat numbering), or from approximately 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).

[0153] The "CH2 domain" of the human IgG Fc region typically spans from approximately residue 244 to approximately 360 of IgG (Kabat numbering), from approximately residue 231 to approximately 340 of IgG (EU numbering), or from approximately 1.6 to approximately 125 of IgG (IGMT unique numbering). The CH2 domain is unique in that it is not closely paired with other domains. Rather, two N-linked branched carbohydrate chains intervene between the two CH2 domains of an intact native IgG molecule. It is speculated that the carbohydrate provides an alternative to domain-domain pairing and may help to stabilize the CH2 domain. Burton, Molec. Immunol. 22:161-206 (1985).

[0154] The "CH3 domain" includes the extension from the C-terminal residue of the Fc region to the CH2 domain (i.e., from approximately amino acid residue 361 to approximately 478 of IgG (Kabat numbering), from approximately amino acid residue 341 to approximately 447 of IgG (EU numbering), or from approximately amino acid residue 1.4 to approximately 130 of IgG (IGMT unique numbering)).

[0155] The "CL domain" or "constant light domain" includes a stretch of residues on the C-terminal side of the light chain variable domain (VL). The light chain (LC) of an antibody can be either a kappa (κ) ("Cκ") or a 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 span 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).

[0156] The term "chimeric" antibody refers to an antibody in which part of the heavy and / or light chain is derived from a particular source or species and the remaining part of the heavy and / or light chain is derived from a different source or species.

[0157] The "class" of an antibody refers to the type of constant domain or constant region carried by its heavy chain. There are five main classes of antibodies: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0158] "Human antibody" refers to an antibody produced by a human or human cell, or an antibody having an amino acid sequence corresponding to a non-human-derived antibody that utilizes a sequence encoding a human antibody such as a human antibody repertoire. This definition of a human antibody specifically excludes humanized antibodies containing non-human antigen-binding residues. Human antibodies can be generated using a variety of techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol. 227:381, 1991; Marks et al., J. Mol. Biol. 222:581, 1991. Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(1):86-95, 1991. The methods described therein can also be utilized for the preparation of human monoclonal antibodies. See also Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74, 2001. Human antibodies can be prepared, for example, by administering an antigen to a transgenic animal whose endogenous locus has been inactivated but which has been modified to generate such antibodies in response to antigen exposure, such as an immunized xenomouse (e.g., see U.S. Pat. Nos. 6,075,181 and 6,150,584 related to the XENOMOUSE technology). See also Li et al., Proc. Natl. Acad. Sci. USA. 103:3557-3562, 2006, regarding human antibodies generated by human B cell hybridoma technology. (商標) See U.S. Pat. Nos. 6,075,181 and 6,150,584 related to the technology. See also Li et al., Proc. Natl. Acad. Sci. USA. 103:3557-3562, 2006, regarding human antibodies generated by human B cell hybridoma technology.

[0159] The "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in the selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup such as those in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3. In one aspect, in the case of VL, the subgroup is subgroup kappa I as described in Kabat et al. above. In one aspect, in the case of VH, the subgroup is subgroup kappa III as in Kabat et al. above.

[0160] A "humanized" antibody refers to a chimeric antibody that contains amino acid residues derived from non-human HVRs and amino acid residues derived from human FRs. In certain aspects, a humanized antibody substantially includes at least one, typically two, variable domains, and all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to the FRs of a human antibody. In certain aspects where all or substantially all of the FRs of the humanized antibody correspond to the FRs of a human antibody, any of the FRs of the humanized antibody may contain one or more amino acid residues (e.g., one or more Vernier position residues of the FR) from a non-human FR(s). A humanized antibody may optionally include at least a portion of an antibody constant region derived from a human antibody. The "humanized form" of an antibody, e.g., a non-human antibody, refers to the antibody that has been humanized.

[0161] The term "variable region" or "variable domain" refers to the domain of an antibody heavy chain or antibody light chain that is involved in the binding of an antibody to an antigen. The variable domains of the heavy and light chains of a native antibody (VH and VL, respectively) generally have a similar structure, and each domain contains four conserved framework regions (FR) and three hypervariable regions (HVR). (See, e.g., Kindt et al., Kuby Immunology, 6 th ed. W.H. Freeman and Co., page 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. Further, an antibody that binds to a particular antigen may be isolated by using the VH or VL domain of the antibody that binds to 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.

[0162] As used herein, the term "hypervariable region" or "HVR" refers to the region (the "complementary determining region" or "CDR") of each region of an antibody variable domain where the sequence is hypervariable. Generally, an antibody contains six CDRs, three of which are in VH (CDR-H1, CDR-H2, CDR-H3) and three of which are in VL (CDR-L1, CDR-L2, CDR-L3). Exemplary CDRs herein include the following: (a) CDRs present 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 present in 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 in 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).

[0163] Unless otherwise indicated, HVR residues and other residues of the variable domains (e.g., FR residues) are numbered herein according to Kabat et al. supra.

[0164] A “single-chain Fv,” also abbreviated as “sFv” or “scFv,” is an antibody fragment that contains VH and VL antibody domains connected in a single polypeptide chain. Preferably, the scFv polypeptide further comprises a polypeptide linker between the VH domain and the VL domain, which enables the scFv to form the desired structure for antigen binding. For a review of scFv, see Pluckthun, The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenberg and Moore eds., Springer-Verlag, New York, pp. 269 - 315 (1994); Malmborg et al., J. Immunol. Methods 183:7 - 13, 1995.

[0165] The "targeting domain" refers to a compound or a part of a molecule that specifically binds to a target epitope, antigen, ligand, or receptor. Targeting domains include, but are not limited to, antibodies (e.g., monoclonal antibodies, polyclonal antibodies, recombinant antibodies, humanized antibodies, and chimeric antibodies), antibody fragments or parts thereof (e.g., bis-Fab fragments, Fab fragments, F(ab’)2, scFab, scFv antibodies, SMIP, single domain antibodies, diabodies, minibodies, scFv-Fc, affibodies, nanobodies, and VH and / or VL domains of antibodies), receptors, ligands, aptamers, peptide targeting domains (e.g., cysteine knot proteins (CKP), etc.), and other molecules having an identified binding partner. The targeting domain can target, block, activate, or antagonize the antigen to which it binds.

[0166] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind to the same epitope, except for variant antibodies that may be present in trace amounts, such as those containing naturally occurring mutations or arising during the production of the monoclonal antibody preparation. In contrast to polyclonal antibody preparations, which typically include 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 collection of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention can be made by a variety of techniques including, but not limited to, the hybridoma method, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals that contain all or part of the human immunoglobulin loci, and such methods and other exemplary methods for making monoclonal antibodies are described herein.

[0167] The term "multispecific antibody" is used in the broadest sense and encompasses antibodies having polyepitope specificity in particular. In one aspect, a multispecific antibody binds to two different targets (e.g., bispecific antibody). Such multispecific antibodies include, but are not limited to, the following. Antibodies containing heavy chain variable domains (VH) and light chain variable domains (VL), where the VH / VL unit has multi-epitope specificity; antibodies having two or more VL and VH domains, where each VH / VL unit binds to a different epitope; antibodies having two or more single variable domains, where each single variable domain binds to a different epitope; full-length antibodies, Fab, Fv, dsFv, scFv, diabodies, bispecific diabodies, and triabodies, such as antibody fragments; antibody fragments linked by covalent or non-covalent bonds. "Polyepitope 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 aspect, a monospecific bivalent antibody binds to two different epitopes on the same target / antigen. In one aspect, a monospecific polyepitope antibody binds to multiple different epitopes of the same target / antigen. According to one aspect, the multispecific antibody is an IgG antibody that binds to each epitope having 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.

[0168] A "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or a radiolabel. A naked antibody may be present in a pharmaceutical formulation.

[0169] "Native antibody" refers to naturally occurring immunoglobulin molecules having various structures. For example, native IgG antibodies are approximately 150,000 Dalton heterotetrameric glycoproteins composed of two identical light chains and two identical heavy chains that are disulfide-bonded. Each heavy chain from the N-terminus to the C-terminus has a variable region (VH), also called the 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 the variable light chain domain or light chain variable domain, followed by a constant light chain (CL) domain. The light chains of an antibody can be assigned to one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequence of their constant domains.

[0170] As used herein, the term "immunoadhesin" refers to a molecule that combines the binding specificity of a heterologous protein ("adhesin") and the effector functions of an immunoglobulin constant domain. Structurally, an immunoadhesin comprises an amino acid sequence having the desired binding specificity that is an amino acid sequence other than the antigen recognition binding site of an antibody (i.e., "heterologous" compared to the constant region of an antibody) and an immunoglobulin constant domain sequence (e.g., the CH2 and / or CH3 sequences of IgG), which are fused together. The adhesin and the immunoglobulin constant domain can optionally be separated by an amino acid spacer. Exemplary adhesin sequences include continuous amino acid sequences that include a portion of a receptor or ligand that binds to the protein of interest. The adhesin sequence can also be a sequence that binds to the protein of interest but is not a receptor or ligand sequence (e.g., the adhesin sequence in a peptibody). Such polypeptide sequences can be selected or identified by various methods including phage display techniques and high-throughput screening methods. The immunoglobulin constant domain sequence in an immunoadhesin can be obtained from any immunoglobulin such as IgG1, IgG2, IgG3, or IgG4 subtypes, IgA (including IgA1 and IgA2), IgE, IgD, or IgM.

[0171] "Chemotherapeutic agents" include chemical compounds useful for 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), sunitinib (SUTENT®, Pfizer / Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasanate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), lonafarnib (SCH66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, thiotepa and alkylating agents such as CYTOXAN® cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carbochromen, meturedopa and uredopa; ethyleneimines and methylmelamines including altretamine, triethylenemelamine, triethylenephosphamide, triethylenethiophosphamide and trimethylmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecin (including topotecan and irinotecan); bryostatin; calicheamicin; CC-1065 (including its synthetic analogs adozelesin, carzelesin and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); corticosteroids (including prednisone and prednisolone); cyproterone acetate;5α-reductases including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat, dacostatins; aldoxorubicin, talaromycin (synthetic analogs including KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chromafazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobenbitin, phenesterine, prednimustine, trofosfamide, uracil mustard, etc.; nitrosoureas such as carmustine, chloroozotocin, fotemustine, lomustine, nimustine, and ranimustine, etc.; antibiotics such as enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin γ1I and calicheamicin ω1I (Angew Chem.Intl.Ed.Engl. 1994 33:183-186); dynemicin including dynemicin A; bisphosphonates such as clodronate; esperamicin; similarly, neocarzinostatin chromophore and related chromophores enediyne antibiotic chromophores), aclacinomycins, actinomycins, authramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, cardinophilin, chromomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, adriamycin (registered trademark) (doxorubicin), morpholinodoxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolinodoxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, keramycin, rhodomycin, streptozocin, tubercidin, ubenimex, dinostatin, zorubicin; metabolic antagonists such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimethoprim, etc.;Purine analogs such as fludarabine, 6-mercaptopurine, thiampurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxyridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, drostanolone propionate, epithiostanol, mepitiostane, testolactone; anti-adrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; dexamethasone; diaziquone; elfomithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK (registered trademark) polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2”-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verrucarin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, for example, taxol (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE (registered trademark) (without cremophor), albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE (registered trademark) (paclitaxel, docetaxel; Sanofi-Aventis): chlorambucil, GEMZAR (registered trademark) (gemcitabine), 6-thioguanine, mercaptopurine;Methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE (registered trademark) (vinorelbine); nobandron; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA (registered trademark)); ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid, and pharmaceutically acceptable salts, acids and derivatives of any of the above are mentioned.;

[0172] In addition, examples of the chemotherapeutic agent include the following.(i) Anti-hormonal agents that act to modulate or inhibit the hormonal action on tumors, such as anti-estrogens and selective estrogen receptor modulators (SERMs), for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifene citrate); (ii) Aromatase inhibitors that inhibit the enzyme aromatase which regulates estrogen production in the adrenal glands, for example, 4(5)-imidazole, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestane, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), ARIMIDEX® (anastrozole; AstraZeneca), and other anti-androgenic agents, (iii) Anti-androgenic agents such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; buserelin, triptorelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all-trans retinoic acid, troxacitabine (1,3-dioxolane nucleoside cytosine analog) along with fenretinide; (iv) Protein kinase inhibitors; (v) Lipid kinase inhibitors; (vi) Antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, for example, PKC-α, Ralf, and H-Ras;; (vii) Ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) Gene therapy vaccines, for example, vaccines such as ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN®, rIL-2; topoisomerase 1 inhibitors such as LURTOTECAN®; ABARELIX® rmRH; and (ix) Pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0173] Chemotherapeutic agents 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 antibody-drug conjugates such as gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies having therapeutic potential as agents in combination with the compounds of the present invention include apolizumab, aselizumab, atorizumab, bapineuzumab, bevacizumab mertansine, canertinib mertansine, cedelizumab, certolizumab pegol, cidfostuximab, cidotuzumab, daclizumab, eclizumab, efalizumab, epratuzumab, elotuzumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labelizumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, norovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecificimab, pecilizumab, pecilizumab, ralivizumab, ranibizumab, reslizumab, reslizumab, reslizumab, rovelizumab, rupizumab, sibrotuzumab, siprilizumab, sonotuzumab, takatuzumab tetraxetan, tadoxizumab, talizumab, tefibazumab, tocilizumab, tralizumab, tucotuzumab celmoleukin, tucusituzumab, umabizumab, ultoxizumab, ustekinumab, visilizumab, and anti-interleukin-12 (ABT-874 / J695, Wyeth Research and Abbott Laboratories), a full-length IgG1λ antibody of only human sequence genetically engineered to recognize interleukin-12 p40 protein.

[0174] The chemotherapeutic agent also includes an "EGFR inhibitor", which refers to a compound that binds to EGFR or otherwise directly interacts with EGFR and inhibits or reduces the signaling activity of EGFR, and is alternatively referred to as an "EGFR antagonist". Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies that bind to EGFR include the following: MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see U.S. Patent No. 4,943,533) and variants thereof, such as chimerized 225 (C225 or cetuximab; ERBUTIX®) and reshaped human 225 (H225) (see International Publication No. 96 / 40210, Imclone Systems Inc.); fully human EGFR-targeted antibody IMC-11F8 (Imclone); antibody that binds to type II mutant EGFR (U.S. Patent No. 5,212,290); humanized and chimeric antibodies that bind to EGFR as described in U.S. Patent No. 5,891,996; and human antibodies that bind to EGFR such as ABX-EGF or Panitumumab (see International Publication No. 98 / 50433, Abgenix / Amgen); EMD 55900 (Stragliotto et al., Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab), a humanized EGFR antibody that competes with both EGF and TGF-α for EGFR binding (EMD / Merck); human EGFR antibody, HuMax-EGFR (GenMab); 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. Patent No. 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)).An anti-EGFR antibody can be conjugated to a cytotoxic agent, thereby generating an immunoconjugate (see, for example, EP 659,439, Merck Patent GmbH). EGFR antagonists include small molecules such as the compounds described in U.S. Pat. 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; 5,866,572; 6,399,602; 6,344,459; 6,602,863; 6,391,874; 6,344,455; 5,760,041; 6,002,008; and 5,747,498, as well as the following PCT publications: WO 98 / 14451; WO 98 / 50038; WO 99 / 09016; and WO 99 / 24037.Examples of specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA (registered trademark), 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 (registered trademark)) 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 (registered trademark), GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolineamine).

[0175] 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 (Pfizer and OSI), an oral selective inhibitor of ErbB2 receptor tyrosine kinase, dual HER inhibitors (such as EKB-569 (available from Wyeth) that preferentially binds to EGFR but inhibits both HER2- and EGFR-overexpressing cells), lapatinib (GSK572016, available from Glaxo-SmithKline), oral HER2 and EGFR tyrosine kinase inhibitors, PKI-166 (available from Novartis), pan-HER inhibitors (such as canertinib (CI-1033, Pharmacia)), Raf-1 inhibitors (such as the antisense agent ISIS-5132 available from ISIS Pharmaceuticals that inhibits Raf-1 signaling), 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 (such as batatinib (PTK787 / ZK222584, available from Novartis / Schering AG)), MAPK extracellular regulatory 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]pyrimidine, curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide), tilorone containing a nitrothiophene moiety, PD-0183805 (Warner-Lambert), antisense molecules (e.g., those that bind to HER-encoding nucleic acids), quinoxalines (U.S. Patent No. 5,804,396), trioxalen (U.S. Patent No. 5,804,396, ZD6474 (Astra Zeneca), PTK-787 (Novartis / Schering AG), pan-HER inhibitor (such as CI-1033 (Pfizer)), 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 (registered trademark)), or those described in any of the following patent publications: U.S. Patent No. 5,804,396, International Publication No. WO 99 / 09016 (American Cyanamid), WO 98 / 43960 (American Cyanamid), WO 97 / 38983 (Warner Lambert), WO 99 / 06378 (Warner Lambert), WO 99 / 06396 (Warner Lambert), WO 96 / 30347 (Pfizer, Inc), WO 96 / 33978 (Zeneca), WO 96 / 3397 (Zeneca), and WO 96 / 33980 (Zeneca).

[0176] Chemotherapeutic agents include dexamethasone, interferon, colchicine, methotrexate, 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 alpha-2a, interferon alpha-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nol fetumomab, oprelvekin, parifermin, pamidronate, pegademase, pegasparaginase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, tamoxifen, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and their pharmaceutically acceptable salts are also included.

[0177] Chemotherapeutic agents include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivoxate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fludrocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, acrometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasone-17-propionate, fludrocortolone caproate, fludrocortolone pivoxate, and fluprednidene acetate; immune-selective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-form (feG) (IMULAN BioTherapeutics, LLC); antirheumatic drugs such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, minocycline, sulfasalazine, tumor necrosis factor alpha (TNFα) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), 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 (registered trademark)); interleukin 13 (IL-13) blockers such as lebrikizumab; interferon alpha (IFN) blockers such as lonafarnib; beta7 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, theaflavin, flavanol, procyanidin, betulinic acid and its derivatives; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL (registered trademark)); beta-lapachone; lapachol; colchicine; betulinic acid; acetylcamptothecin, scoplectin, and 9-aminocamptothecin); podophyllotoxin; tegafur (UFTORAL (registered trademark)); bexarotene (TARGRETIN (registered trademark)); bisphosphonates such as clodronate (e.g., BONEFOS (registered trademark) or OSTAC (registered trademark)), etidronate (DIDROCAL (registered trademark)), NE-58095, zoledronic acid / zoledronate (ZOMETA (registered trademark)), alendronate (FOSAMAX (registered trademark)), pamidronate (AREDIA (registered trademark)), tiludronate (SKELID (registered trademark)), or risedronate (ACTONEL (registered trademark)); and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE (registered trademark) vaccine; perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteasome inhibitors (e.g., PS341); CCI-779; tipifarnib (R11577); olaphenib, ABT510; Bcl-2 inhibitors such as oblimersen sodium (GENASENSE (registered trademark)); pixantrone; farnesyltransferase inhibitors such as lonafarnib (SCH6636, SARASAR (trademark)); 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 using oxaliplatin (ELOXATIN (trademark)) in combination with 5-FU and leucovorin).

[0178] As chemotherapeutic agents, non-steroidal anti-inflammatory drugs having analgesic, antipyretic, and anti-inflammatory effects may also be mentioned. NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase. Specific examples of non-steroidal anti-inflammatory drugs include propionic acid derivatives such as aspirin, ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, naproxen, etc., acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, etc., enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, etc., fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, etc., and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, etc. The indications for NSAIDs can be symptomatic relief of rheumatoid arthritis, osteoarthritis, inflammatory arthropathy, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headache and migraine, postoperative pain, mild to moderate pain due to inflammation and tissue damage, fever, intestinal obstruction, and renal colic, etc.

[0179] As used herein, the term "cytotoxic agent" 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 212and radioisotopes 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, such as nucleolytic enzymes; antibiotics; toxins such as low molecular weight toxins or enzymatically active toxins derived from bacteria, fungi, plants or animals (including fragments and / or variants thereof); and various antitumor or anticancer agents disclosed below are included.

[0180] "Disorder" includes, but is not limited to, chronic and acute disorders or diseases, including those pathological conditions that predispose a mammal to the disorder in question, and any condition that would benefit from treatment. In one aspect, the disorder is cancer, such as a B cell proliferative disorder such as MM, such as relapsed or refractory MM.

[0181] 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.

[0182] "Tumor", as used herein, refers to the growth and proliferation of all neoplastic cells, 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.

[0183] The terms "cancer" and "cancerous" refer to or describe physiological conditions in mammals that are typically characterized by uncontrolled cell growth / proliferation. Aspects of cancer 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 can be relapsed or refractory MM. MM can be, for example, typical MM (e.g., immunoglobulin G (IgG) MM, IgA MM, IgD MM, IgE MM, or IgM MM), light chain MM (LCMM) (e.g., lambda light chain MM or kappa light chain MM), or non-secretory MM. MM can have one or more cytogenetic features (e.g., high-risk cytogenetic features), for example, t(4;14), t(11;14), t(14;16), and / or del(17p) (described in the International Myeloma Working Group (IMWG) criteria provided in Table 1 and Sonneveld et al., Blood, 127(24):2955 - 2962, 2016) and / or 1q21 (described in Chang et al., Bone Marrow Transplantation, 45:117 - 121, 2010). Cytogenetic features can be detected, for example, using fluorescence in situ hybridization (FISH).

Table 1

[0184] The terms "B cell proliferative disorders" or "B cell malignancies" refer to disorders associated with abnormal B cell proliferation to some extent, including, for example, lymphoma, leukemia, myeloma, and myelodysplastic syndromes. In one embodiment, the B cell proliferative disorder is a lymphoma such as non-Hodgkin lymphoma (NHL), including, for example, diffuse large B cell lymphoma (DLBCL) (e.g., relapsed or refractory DLBCL). In other embodiments, 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), Waldenström macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt lymphoma (BL), B cell prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma / leukemia, unclassifiable, diffuse red pulp small B cell lymphoma of the spleen, hairy cell leukemia variant, heavy chain disease, alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasmacytic myeloma, solitary plasmacytoma of bone, extramedullary plasmacytoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), nodal marginal zone lymphoma, pediatric nodal marginal zone lymphoma, pediatric follicular lymphoma, primary cutaneous follicle center lymphoma, T cell / histiocyte-rich large B cell lymphoma, primary CNS DLBCL, primary cutaneous DLBCL, lower extremity type, EBV-positive DLBCL in the elderly, chronic inflammation-related DLBCL, lymphomatoid granulomatosis, mediastinal (thymic) primary B cell large 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 intermediate features between DLBCL and Burkitt lymphoma, and unclassifiable B cell lymphoma with intermediate features between DLBCL and classical Hodgkin lymphoma, and the like.Further examples of cancer include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and lymphatic malignancies including leukemia or B-cell lymphoma. Even more specific examples of such cancers include low grade / follicular NHL; small lymphocytic (SL) NHL; intermediate grade / follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphatic NHL; high grade small non-cleaved cell NHL; large tumor lesion NHL; AIDS-related lymphoma; and acute lymphocytic leukemia (ALL); chronic myelogenous leukemia; and post-transplant lymphoproliferative disorder (PTLD). Examples of solid tumors include squamous cell cancers (e.g., epithelial squamous cell cancers), small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and lung cancers including squamous carcinoma of the lung, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancers, and gastric cancer (gastric cancer) or stomach cancer including gastrointestinal stromal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urinary tract cancers, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial carcinoma or uterine carcinoma, salivary gland carcinoma, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer species, anal carcinoma, penile carcinoma, melanoma, superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanoma, nodular melanoma, as well as nevus syndromes, edema (such as those associated with brain tumors), Meigs syndrome, the brain, as well as head and neck cancers, and abnormal blood vessel growth associated with related 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 lymphoma (NHL), renal cell cancer, prostate cancer, liver cancer, pancreatic cancer, soft tissue sarcoma, Kaposi sarcoma, carcinoid carcinoma, head and neck cancer, ovarian cancer, and mesothelioma.

[0185] "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 an antibody (of the appropriate subclass). To evaluate complement activation, for example, an assay such as that described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996) can be performed.

[0186] "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a form of cytotoxicity in which secreted Ig bound to Fc receptors (FcRs) 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 the antigen and then kill the target cells with cytotoxic agents. The antibody "arms" the cytotoxic cells and is absolutely required for such killing. While NK cells, which are primary cells mediating ADCC, express only FcγRIII, monocytes express FcγRI, FcγRII, and FcγRIII. The expression of FcRs in hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet. Annu. Rev. Immunol. 9:457-92, 1991. To evaluate the ADCC activity of a molecule of interest, an in vitro ADCC assay such as that described in U.S. Patent No. 5,500,362 or 5,821,337 can be performed. Effector cells useful in such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. Alternatively or additionally, the ADCC activity of a molecule of interest can be evaluated in vivo, for example, in an animal model such as that disclosed in Clynes et al., Proc. Natl. Acad. Sci. USA. 95:652-656, 1998.

[0187] As used herein, "complex" or "complex form" refers to the association of two or more molecules that interact with each other via non-peptide bonds and / or forces (e.g., van der Waals, hydrophobic, hydrophilic forces). In one aspect, the complex is a heteromultimer. The terms "protein complex" or "polypeptide complex" as used herein are understood to include complexes having non-protein entities conjugated to the proteins in the protein complex (e.g., including, but not limited to, chemical molecules such as toxins or detection agents).

[0188] As used herein, "delaying the progression of" a disorder or disease means delaying, hindering, slowing, retarding, stabilizing, and / or postponing the development of a disease or disorder (e.g., a cell proliferative disorder such as cancer (e.g., MM)). This delay can be for varying lengths of time depending on the medical history and / or the individual being treated. As will be apparent to those skilled in the art, a sufficient or significant delay can in effect encompass prevention in that the individual does not develop the disease. For example, it can delay advanced cancers such as the occurrence of metastases.

[0189] 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 minimal 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). The effective amount herein may vary depending on factors such as the patient's disease state, age, gender, and weight, as well as the ability of the antibody to induce a desired response in the individual. An effective amount is also one in which the therapeutically beneficial effects outweigh any toxic or detrimental effects of the treatment. Beneficial or desired results for prophylactic use include removal or reduction of risk, reduction in severity, or delay in the onset of disease, including biochemical, histological and / or kinetic symptoms of the disease, its complications, and intermediate pathological phenotypes that appear during the development of the disease. For therapeutic use, beneficial or desired results include a decrease in one or more symptoms attributable to the disease, an improvement in the quality of life of the person suffering from the disease, a decrease in the dosage of other agents required for treatment of the disease, enhancement of the effect of another agent (e.g., by targeting), delay in the progression of the disease, and / or extension of survival time and other clinical outcomes. In the case of cancer or a tumor, an effective amount of the drug reduces the number of cancer cells, reduces tumor size, inhibits the invasion of cancer cells into peripheral organs (i.e., delays to some extent or preferably stops), inhibits tumor metastasis (i.e., delays to some extent or preferably stops), inhibits tumor growth to some extent, and / or may have the effect of reducing one or more of the symptoms associated with the disorder. An effective amount can be administered in one or more 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 art, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" can be considered in relation to the administration of one or more therapeutic agents, and a single agent can be considered to be administered in an effective amount if, alone or in combination with one or more other agents, a desired result can be achieved or is achieved.

[0190] As used herein, "overall survival" or "OS" refers to the percentage of individuals within a group likely to survive after a specified period of time.

[0191] As used herein, "objective response rate" (ORR) refers to the sum of the stringent complete response (sCR) rate, complete response (CR) rate, very good partial response (VGPR) rate, and partial response (PR) rate determined using the International Myeloma Working Group response criteria (see, e.g., Tables 6A and 6B of Example 1).

[0192] The term "epitope" refers to a specific site on an antigen molecule to which an antibody binds. In some embodiments, the specific site on the antigen molecule to which the antibody binds is determined by a hydroxyl radical footprint. In some embodiments, the specific site on the antigen molecule to which the antibody binds is determined crystallographically.

[0193] As used herein, "growth inhibitor" refers to a compound or composition that inhibits cell growth in vitro or in vivo. In one aspect, the growth inhibitor is a growth inhibitory antibody that inhibits or reduces the growth of cells expressing an antigen to which the antibody binds. In another aspect, the growth inhibitor may significantly reduce the proportion of cells in the S phase. Examples of growth inhibitors include agents that block the progression of the cell cycle (at locations other than the S phase), such as agents that induce G1 arrest or M arrest. Classical M phase blockers include vinca (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 like tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C, also affect 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 antineoplastic drugs" (Murakami et al. (W.B. Saunders, Philadelphia, 1995)), for example, on page 13. Taxanes (paclitaxel and docetaxel) are both anticancer drugs derived from yew. Docetaxel (TAXOTERE® from European yew, Rhone-Poulenc Rorer) is a semi-synthetic analogue of paclitaxel (TAXOL® from Bristol-Myers Squibb). Paclitaxel and docetaxel stabilize microtubules by promoting the assembly of microtubules from tubulin dimers and preventing depolymerization, thereby inhibiting mitosis in cells.

[0194] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including but not limited to a cytotoxic agent.

[0195] The term "immunomodulatory agent" or "IMiD" refers to a class of molecules that modify the response or function of the immune system. Immunomodulatory agents include, but are not limited to, POMALYST® (pomalidomide), thalidomide (α-N-phthalimidoglutarimide) and its analogs, OTEZLA® (apremilast), REVLIMID® (lenalidomide), and PD-1 axis-binding antagonists and their pharmaceutically acceptable salts or acids.

[0196] A "subject" or "individual" is a mammal. Mammals include, but are not limited to, farm 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. In some cases, the subject is an adult.

[0197] An "isolated" protein or peptide is separated from the components of its natural environment. In some embodiments, the protein or peptide is purified to a purity of 95% or more, or more than 99%, as determined by, for example, electrophoresis (e.g., sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), isoelectric focusing electrophoresis (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC).

[0198] An "isolated" nucleic acid refers to a nucleic acid molecule that has been separated from the components of its natural environment. Isolated nucleic acids include nucleic acid molecules contained within cells that normally contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location different from its natural chromosomal location.

[0199] The term "PD-1 axis-binding antagonist" refers to a molecule that inhibits the interaction between a PD-1 axis-binding partner and one or more of its binding partners in order to remove T cell dysfunction resulting from signaling on the PD-1 signaling axis, and as a result, restore or enhance T cell function (e.g., proliferation, cytokine production, and / or target cell killing). As used herein, PD-1 axis-binding antagonists include PD-L1-binding antagonists, PD-1-binding antagonists, and PD-L2-binding antagonists. In some cases, PD-1 axis-binding antagonists include PD-L1-binding antagonists or PD-1-binding antagonists. In a preferred embodiment, the PD-1 axis-binding antagonist is a PD-L1-binding antagonist.

[0200] The term "PD-L1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses, or interferes with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as 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 partner. In certain embodiments, the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 and / or B7-1. In some cases, the PD-L1 binding antagonist includes an anti-PD-L1 antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, and other molecules that reduce, block, inhibit, suppress, or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and / or B7-1. In one case, the PD-L1 binding antagonist reduces negative co-stimulatory signals mediated by or through cell surface proteins expressed on T lymphocytes via signal transduction through PD-L1 such that dysfunctional T cells are not rendered dysfunctional (e.g., enhancing 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, enoblituzumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosibelimab, rodaplimab, 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 a 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 can be a small molecule, such as GS-4224, INCB086550, MAX-10181, INCB090244, CA-170 or ABSK041, and in some cases can 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 described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN:List 112, Vol.28, No.4, published January 16, 2015 (see page 485).

[0201] The term "PD-1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses, or interferes with signaling resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and / or PD-L2. PD-1 (programmed death 1) is also known in the art as "programmed cell death 1", "PDCD1", "CD279", and "SLEB2". Exemplary human PD-1 is shown by UniProtKB / Swiss-Prot accession number 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, a PD-1 binding antagonist includes an anti-PD-1 antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, and other molecules that reduce, block, inhibit, suppress, or interfere with signaling resulting from the interaction of PD-1 with PD-L1 and / or PD-L2. In one case, a PD-1 binding antagonist reduces negative co-stimulatory signals mediated by or through cell surface proteins expressed on T lymphocytes via signaling through PD-1 such that dysfunctional T cells are prevented from becoming dysfunctional (e.g., enhancing effector responses to antigen recognition). In some cases, a PD-1 binding antagonist binds to PD-1. In some cases, a 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 (semiplimab), BGB-108, prorolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, pemprilimab, CS1003, HLX10, SCT-I10A, zinberelimab, balsilimab, genolimzumab, BI 754091, cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103 and hAb21. In certain embodiments, 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 (semiplimab). In another particular embodiment, the PD-1 binding antagonist is BGB-108. In another particular embodiment, the PD-1 binding antagonist is prorolimab. In another particular embodiment, the PD-1 binding antagonist is camrelizumab. 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.

[0202] The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses, or interferes with the signaling resulting from the interaction of PD-L2 with one or more of its binding partners, for example, 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". Exemplary human PD-L2 is shown by the UniProtKB / Swiss-Prot accession number 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, the 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, suppress, or interfere with the signaling resulting from the interaction of PD-L2 with one or more of its binding partners such as PD-1. In one embodiment, the PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes via signaling through PD-L2 such that dysfunctional T cells are not made dysfunctional (e.g., enhancing the effector response 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.

[0203] Unless otherwise indicated, as used herein, the term "protein" refers to any native protein from any vertebrate source, including, but not limited to, mammals such as primates (e.g., humans) and rodents (e.g., mice, rats), unless otherwise specified. The term includes any form of the "full-length", unprocessed protein and proteins resulting from intracellular processing. The term also encompasses naturally occurring variants of the protein, such as splice variants or allelic variants.

[0204] The "percent amino acid sequence identity" to a reference polypeptide sequence is defined, for purposes of alignment, as the percentage of amino acid residues in the candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence, after aligning the sequences to achieve the maximum percent sequence identity and introducing gaps, if necessary, and without considering any conservative substitutions as part of the sequence identity. Alignments for determining the percent amino acid sequence identity can be achieved in various ways within the skill of the art, e.g., using publicly available computer software such as BLAST, BLAST-2, Clustal W, Megalign (DNASTAR) software or the FASTA program package. One of ordinary skill in the art can determine appropriate parameters for sequence alignment, including any algorithms necessary to achieve the maximum alignment over the full length of the sequences being compared. Alternatively, the percent identity value can be generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., the source code of which has been filed in the user documentation of the U.S. Copyright Office (Washington D.C., 20559), registered under U.S. Copyright Registration No. TXU510087, and described in International Publication No. WO 2001 / 007611.

[0205] Unless otherwise indicated, for the purposes of this specification, the value of the percent amino acid sequence identity is 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 W.R. Pearson and D.J. Lipman (1988), "Improved Tools for Biological Sequence Analysis" PNAS 85:2444-2448; W.R. Pearson (1996) "Effective protein sequence comparison" Meth. Enzymol. 266:227-258; and Pearson et.al. (1997) Genomics 46:24-36, and is publicly available from www.fasta.bioch.virginia.edu / fasta_www2 / fasta_down.shtml or www.ebi.ac.uk / Tools / sss / fasta. Alternatively, the ggsearch (global protein:protein) program and default options (BLOSUM50; open: -10; ext: -2; Ktup = 2) can be used to compare sequences using a public server accessible at fasta.bioch.virginia.edu / fasta_www2 / index.cgi, ensuring a global rather than a local alignment is performed. The percent amino acid identity is shown in the output alignment header.

[0206] The term "pharmaceutical preparation" refers to a preparation in a form such that the biological activity of the active ingredient contained therein is effective and that does not contain additional components that are unacceptably toxic to the subject to which the preparation is administered.

[0207] "Pharmaceutically acceptable carrier" refers to components in a pharmaceutical preparation other than the active ingredient that are non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers or preservatives.

[0208] "Radiation therapy" means using directed gamma or beta rays to inflict sufficient damage on cells to limit their ability to function normally or to completely destroy them. It will be understood that there are many methods known in the art for determining dosage and treatment duration. A typical treatment is given as a single dose, and a typical dosage ranges from 10 to 200 units (gray) per day.

[0209] As used herein, "treatment" (and its grammatical variants, e.g., "treat" or "treating") refers to a clinical intervention in an attempt to alter the natural course of the individual being treated and can be done for prophylaxis or during the course of clinical pathology. Desired effects of treatment include preventing the onset or recurrence of a disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the disease progression rate, remission or palliation of the condition, and recovery or improved prognosis. In some embodiments, the antibodies of the disclosure (e.g., the anti-FcRH5 / anti-CD3 TDB of the disclosure) are used to delay the onset of a disease or to slow the progression of a disease.

[0210] "Reduce" or "inhibit" means, for example, the ability to cause an overall decrease of 20% or more, 50% or more, or 75%, 85%, 90%, 95%, or more. In certain embodiments, reduction or inhibition can refer to the effector function of an antibody mediated by the Fc region of the antibody, and such effector functions specifically include CDC, ADCC, and ADCP.

[0211] According to the present invention, the term "vaccine" relates to a pharmaceutical preparation (pharmaceutical composition) or product that induces an immune response, particularly a cellular immune response, upon administration and recognizes and attacks disease cells such as pathogens or 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 an immune response in a subject against cancer. A cancer vaccine typically consists of a source of a substance or cell (antigen) related to cancer, which is autologous (derived from the subject itself) or allogeneic (derived from others) to the subject, and is administered to the subject together with other components (e.g., adjuvants) for further stimulating and enhancing the immune response against the antigen. A cancer vaccine can result in stimulating the subject's immune system to produce antibodies against one or more specific antigens and / or producing killer T cells that attack cancer cells bearing those antigens.

[0212] As used herein, "administering" means a method of giving a dosage of a compound (e.g., anti-FcRH5 / anti-CD3 TDB, e.g., cevostamab, IMiD (e.g., pomalidomide), anti-CD38 antibody (e.g., daratumumab) or corticosteroid (e.g., dexamethasone)) to a subject. In some embodiments, the compositions utilized in the methods herein are administered intravenously. The compositions utilized in the methods described herein can be administered, for example, intramuscularly, intravenously, intradermally, transdermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrathoracically, intratracheally, intranasally, intravitreally, intravaginally, rectally, topically, intratumorally, intraperitoneally, subcutaneously, subconjunctivally, intravesicularly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, directly by a local perfusion bath target cell, by catheter, by perfusion, in a cream, or in a lipid composition. The method of administration can vary depending on various factors (e.g., the compound or composition being administered and the severity of the condition, disease, or disorder being treated).

[0213] 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 a higher level 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 intracellular processing. The term also encompasses naturally occurring variants of CD38, such as splice variants or allelic variants. CD38 is also known 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 human CD38 nucleic acid sequence is shown in NCBI reference sequence NM_001775.4 or SEQ ID NO: 33. The amino acid sequence of an exemplary human CD38 protein encoded by CD38 is shown in UniProt accession number P28907 or SEQ ID NO: 34.

[0214] The term "anti-CD38 antibody" is useful as a therapeutic agent when targeting cells expressing the antigen, and encompasses all antibodies that bind to CD38 with sufficient affinity so as not to significantly cross-react with other proteins such as negative control proteins in the assays described below. For example, anti-CD38 antibodies bind to CD38 on the surface of MM cells and mediate cell lysis through complement-dependent cytotoxicity, ADCC, antibody-dependent cell phagocytosis (ADCP), and activation of apoptosis mediated by Fc bridging, resulting in depletion of malignant cells and reduction of the overall cancer burden. Anti-CD38 antibodies can also regulate CD38 enzyme activity through inhibition of ribosyl cyclase enzyme activity and stimulation of the cyclic adenosine diphosphate ribose (cADPR) hydrolase activity of CD38. In certain embodiments, an anti-CD38 antibody that binds to CD38 has a dissociation constant (K D ) 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 to 10 -13 M, e.g., 10 -9 M to 10- -13 M). In certain embodiments, an anti-CD38 antibody can bind to both human CD38 and chimpanzee CD38. Anti-CD38 antibodies 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 includes functional fragments of the aforementioned antibodies. Examples of antibodies that bind to CD38 include daratumumab (DARZALEX®) (U.S. Patent No. 7,829,673 and U.S. Patent Publication No.: 20160067205A1); "MOR202" (U.S. Patent No. 8,263,746); and isatuximab (SAR-650984).

[0215] As used herein, "triple-class refractory" refers to patients (e.g., MM patients) who have been previously exposed to at least one proteasome inhibitor (PI; e.g., bortezomib, carfilzomib or ixazomib), at least one immunomodulatory agent (IMiD; e.g., thalidomide, lenalidomide or pomalidomide), and at least one anti-CD38 antibody (e.g., daratumumab, MOR202, or isatuximab) and are refractory to these agents.

[0216] II. Treatment Methods The present invention is based, in part, on a method of treating a subject having cancer (e.g., multiple myeloma (MM)) using a dosing regimen that includes a fractionated dose escalation regimen using an anti-fragment crystallizable receptor-like 5 (FcRH5) / anti-cluster of differentiation 3 (CD3) bispecific antibody. The dosing regimens described herein can be used in subjects having triple-class refractory MM who have previously received B-cell maturation antigen (BCMA)-targeted therapies such as T-cell dependent bispecific (TDB) antibodies. An exemplary dosing regimen described herein administers cevostamab on days 1, 2, and 8 for the first dosing cycle (C1) and then Q3W for each subsequent cycle. For example, a subject can be administered 0.3 mg of cevostamab on day 1, 3.3 mg of cevostamab on day 2, and the target dose (e.g., 160 mg) of cevostamab on day 8 for C1. This split 0.3 / 3.3 mg dosing regimen and / or the day 1 and 2 dosing is expected to reduce or inhibit undesirable treatment effects when delivering the target dose (e.g., 160 mg) including cytokine-driven toxicities (e.g., cytokine release syndrome (CRS)), infusion-related reactions (IRR), macrophage activation syndrome (MAS), neurotoxicity, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, and / or elevated liver enzymes. Further, administration of the split 0.3 / 3.3 mg dosing regimen and / or the day 1 and 2 dosing enables more tolerant earlier treatment delivery in rapidly progressing late-line relapsed / refractory (R / R) MM subjects. Accordingly, these methods are useful for treating a subject while achieving a more favorable benefit-risk profile.

[0217] In the case of undesirable treatment effects (e.g., CRS, IRR, MAS, or TLS), for example, the dosing regimen described herein may include administering sevosetamab on days 1, 3, and 8 for the first dosing cycle (C1) and then Q3W for each subsequent cycle. For example, the subject may be administered 0.3 mg of sevosetamab on day 1, 3.3 mg of sevosetamab on day 3, and the target dose (e.g., 160 mg) of sevosetamab on day 8 for C1. In another example, for example, the dosing regimen may include administering sevosetamab on days 1, 4, and 8 for the first dosing cycle (C1) and then Q3W for each subsequent cycle. For example, the subject may be administered 0.3 mg of sevosetamab on day 1, 3.3 mg of sevosetamab on day 4, and the target dose (e.g., 160 mg) of sevosetamab on day 8 for C1.

[0218] A. Dosing Regimen i. Step - up dosing regimen In some embodiments, the present invention provides a method of treating a subject having cancer (e.g., MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a step - up dosing regimen. In some examples, the subject has triple - class refractory MM and has previously received a BCMA - targeted therapeutic agent.

[0219] In some embodiments, the invention is a method of treating a subject having MM, comprising administering to the subject a bispecific antibody that binds to 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 C1D1 is from about 0.05 mg to about 180 mg (e.g., from about 0.1 mg to about 160 mg, from about 0.5 mg to about 140 mg, from about 1 mg to about 120 mg, from about 1.5 mg to about 100 mg, from about 2.0 mg to about 80 mg, from about 2.5 mg to about 50 mg, from about 3.0 mg to about 25 mg, from about 3.0 mg to about 15 mg, from about 3.0 mg to about 10 mg, or from about 3.0 mg to about 5 mg) and C1D2 is from about 0.15 mg to about 1000 mg (e.g., from about 0.5 mg to about 800 mg, from about 1 mg to about 700 mg, from about 5 mg to about 500 mg, from about 10 mg to about 400 mg, from about 25 mg to about 300 mg, from about 40 mg to about 200 mg, from about 50 mg to about 100 mg, from about 75 mg to about 100 mg, or from about 85 mg to about 100 mg). In some examples, C1D1 is administered on day 1 of the dosing cycle and C1D2 is administered on day 2 of the dosing cycle. In another example, C1D1 is administered on day 1 of the dosing cycle and C1D2 is administered on day 3 of the dosing cycle. In yet another example, C1D1 is administered on day 1 of the dosing cycle and C1D2 is administered on day 4 of the dosing cycle. The dosing cycle can have any suitable duration, e.g., 7 days, 14 days, 21 days, 28 days or longer.

[0220] In some aspects, the invention is a method of treating a subject having cancer (e.g., MM), comprising administering to the subject a bispecific antibody that binds to 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, C1D1 is from about 0.05 mg to about 180 mg (e.g., from about 0.1 mg to about 160 mg, from about 0.5 mg to about 140 mg, from about 1 mg to about 120 mg, from about 1.5 mg to about 100 mg, from about 2.0 mg to about 80 mg, from about 2.5 mg to about 50 mg, from about 3.0 mg to about 25 mg, from about 3.0 mg to about 15 mg, from about 3.0 mg to about 10 mg, or from about 3.0 mg to about 5 mg), and C1D2 is from about 0.15 mg to about 1000 mg (e.g., from about 0.5 mg to about 800 mg, from about 1 mg to about 700 mg, from about 5 mg to about 500 mg, from about 10 mg to about 400 mg, from about 25 mg to about 300 mg, from about 40 mg to about 200 mg, from about 50 mg to about 100 mg, from about 75 mg to about 100 mg, or from about 85 mg to about 100 mg), and (b) the second dosing cycle comprises a single dose of the bispecific antibody (C2D1; cycle 2, dose 1), C2D1 is greater than or equal to C1D2, and is from about 0.15 mg to about 1000 mg (e.g., from about 0.5 mg to about 800 mg, from about 1 mg to about 700 mg, from about 5 mg to about 500 mg, from about 10 mg to about 400 mg, from about 25 mg to about 300 mg, from about 40 mg to about 200 mg, from about 50 mg to about 100 mg, from about 75 mg to about 100 mg, or from about 85 mg to about 100 mg). In some examples, C1D1 is administered on day 1 of the dosing cycle and C1D2 is administered on day 2 of the dosing cycle. In another example, C1D1 is administered on day 1 of the dosing cycle and C1D2 is administered on day 3 of the dosing cycle. In yet another example, C1D1 is administered on day 1 of the dosing cycle and C1D2 is administered on day 4 of the dosing cycle. The dosing cycle can have any suitable period, e.g., 7 days, 14 days, 21 days, 28 days or a longer period.

[0221] 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, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.8 mg, 4 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 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, 10.4 mg, 10.6 mg, 10.8 mg, 11 mg, 11.2 mg, 11.4 mg, 11.6 mg, 11.8 mg, 12 mg, 12.2 mg, 12.4 mg, 12.6 mg, 12.8 mg, 13 mg, 13.2 mg, 13.4 mg, 13.6 mg, 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.is 8 mg, and (b) C1D2 is from about 20 mg to about 600 mg (e.g., from 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 mg, 25 mg, 30 mg, 35 mg, 40 mg, 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, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, or 600 mg).

[0222] In some embodiments, C1D1 is from about 1.2 mg to about 10.8 mg, and C1D2 is from 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 3.3 mg, and C1D2 is 40 mg. In some embodiments, C1D1 is 3.3 mg, and C1D2 is 90 mg. In some embodiments, C1D1 is 3.3 mg, and C1D2 is 120 mg. In some embodiments, C1D1 is 3.3 mg, and C1D2 is 132 mg. In some embodiments, C1D1 is 3.3 mg, and C1D2 is 160 mg. In some embodiments, C1D1 is 3.3 mg, and C1D2 is 198 mg. In some embodiments, C1D1 is 3.3 mg, and C1D2 is 252 mg. In some embodiments, C1D1 is 3.6 mg, and C1D2 is 40 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 120 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. In some embodiments, C1D1 is 3.6 mg, and C1D2 is 198 mg. In some embodiments, C1D1 is 3.6 mg, and C1D2 is 252 mg.

[0223] In some cases, these methods described above may include a first dosing cycle of 2 weeks or 14 days. In some cases, these methods described above may include a first dosing cycle of 3 weeks or 21 days. In some cases, these methods described above may include a first dosing cycle of 4 weeks or 28 days.

[0224] In some cases, these methods described above may include a first dosing cycle of 3 weeks or 21 days. In some cases, the method may include administering C1D1 and C1D2 to the subject on the first and second days, or on about those days, of the first dosing cycle.

[0225] In some cases, these methods described above may include a first dosing cycle of three weeks or 21 days. In some cases, the method may include administering C1D1 and C1D2 to the subject on days 1 and 3, respectively, of the first dosing cycle, or on or about those days (e.g., in the case of undesirable treatment effects such as CRS, IRR, MAS, or TLS). In other cases, the method may include administering C1D1 and C1D2 to the subject on days 1 and 4, respectively, of the first dosing cycle, or on or about those days (e.g., in the case of undesirable treatment effects such as CRS, IRR, MAS, or TLS).

[0226] ii. Two-step escalating dosing regimen In another aspect, the invention provides a method of treating a subject having cancer (e.g., MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a two-step escalating dosing regimen. In some examples, the subject has triple-class refractory MM and has previously received a BCMA-targeted therapeutic agent.

[0227] In some embodiments, the present disclosure provides a method of treating a subject having cancer (e.g., MM) comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen that includes at least a first dosing cycle, the first dosing cycle including 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 0.2 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), C1D2 is more than C1D1, and C1D3 is more than C1D2. In some embodiments, C1D1 is about 0.3 mg. In some examples, C1D1 is administered on day 1 of the dosing cycle and C1D2 is administered on day 2 of the dosing cycle. In some examples, C1D1 is administered on day 1 of the dosing cycle and C1D2 is administered on day 3 of the dosing cycle. In some examples, C1D1 is administered on day 1 of the dosing cycle and C1D2 is administered on day 4 of the dosing cycle. In some examples, C1D1 is administered on day 1 of the dosing cycle and C1D2 is administered on day 5 of the dosing cycle. In some examples, C1D1 is administered on day 1 of the dosing cycle and C1D2 is administered on day 6 of the dosing cycle. In some examples, C1D1 is administered on day 1 of the dosing cycle and C1D2 is administered on day 7 of the dosing cycle. The dosing cycle can have any suitable duration, e.g., 7 days, 14 days, 21 days, 28 days, or longer.

[0228] In some embodiments, C1D1 is from 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.

[0229] In some embodiments, the present disclosure provides a method of treating a subject having cancer (e.g., MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, the first dosing cycle comprising a first dose (C1D1) of the bispecific antibody, a second dose (C1D2) of the bispecific antibody, and a third dose (C1D3) of the bispecific antibody, 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. In some examples, C1D1 is administered on day 1 of the dosing cycle and C1D2 is administered on day 2 of the dosing cycle. In some examples, C1D1 is administered on day 1 of the dosing cycle and C1D2 is administered on day 3 of the dosing cycle. In some examples, C1D1 is administered on day 1 of the dosing cycle and C1D2 is administered on day 4 of the dosing cycle. The dosing cycle can have any suitable duration, e.g., 7 days, 14 days, 21 days, 28 days, or longer.

[0230] 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 to 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 (C1D1) of the bispecific antibody, a second dose (C1D2) of the bispecific antibody, and a third dose (C1D3) of the bispecific antibody, C1D1 and C1D2 are each less than C1D3, 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; (b) the second dosing cycle comprises a single dose (C2D1) of the bispecific antibody, C2D1 is greater than or equal to C1D3, and C2D1 is from about 20 mg to about 600 mg. In some examples, C1D1 is administered on day 1 of the dosing cycle and C1D2 is administered on day 2 of the dosing cycle. In some examples, C1D1 is administered on day 1 of the dosing cycle and C1D2 is administered on day 3 of the dosing cycle. In some examples, C1D1 is administered on day 1 of the dosing cycle and C1D2 is administered on day 4 of the dosing cycle. The dosing cycle can have any suitable duration, e.g., 7 days, 14 days, 21 days, 28 days, or longer.

[0231] In some embodiments, C1D1 is from about 0.05 mg to about 2.5 mg, from about 0.1 mg to about 2 mg, from about 0.2 mg to about 1 mg, or from 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.

[0232] In some embodiments, C1D1 is from 0.05 mg to 2.5 mg, from 0.1 mg to 2 mg, from 0.2 mg to 1 mg, or from 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.

[0233] In some embodiments, C1D2 is from about 3 mg to about 19.9 mg (e.g., from about 3 mg to about 18 mg, from about 3.1 mg to about 15 mg, from about 3.2 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, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 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, 10.4 mg, 10.6 mg, 10.8 mg, 11 mg, 11.2 mg, 11.4 mg, 11.6 mg, 11.8 mg, 12 mg, 12.2 mg, 12.4 mg, 12.6 mg, 12.8 mg, 13 mg, 13.2 mg, 13.4 mg, 13.6 mg, 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). In some embodiments, C1D2 is from about 3.2 mg to about 10 mg. In some embodiments, C1D2 is about 3.6 mg. In some embodiments, C1D2 is about 3.3 mg.

[0234] In some embodiments, C1D2 is from 3 mg to 19.9 mg (e.g., 3 mg to 18 mg, 3.1 mg to 15 mg, 3.2 mg to 10 mg, 3.3 mg to 6 mg, or 3.4 mg to 4 mg, e.g., 3 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 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, 10.4 mg, 10.6 mg, 10.8 mg, 11 mg, 11.2 mg, 11.4 mg, 11.6 mg, 11.8 mg, 12 mg, 12.2 mg, 12.4 mg, 12.6 mg, 12.8 mg, 13 mg, 13.2 mg, 13.4 mg, 13.6 mg, 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). In some embodiments, C1D2 is from 3.2 mg to 10 mg. In some embodiments, C1D2 is 3.6 mg. In some embodiments, C1D2 is about 3.3 mg.

[0235] In some embodiments, C1D3 is from about 20 mg to about 600 mg (e.g., from about 30 mg to about 500 mg, from about 40 mg to about 400 mg, from about 60 mg to about 350 mg, from about 80 mg to about 300 mg, from about 100 mg to about 200 mg, or from 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 from about 80 mg to about 300 mg. In some embodiments, C1D3 is about 90 mg. In some embodiments, C1D3 is about 132 mg. In some embodiments, C1D3 is about 160 mg.

[0236] In some embodiments, C1D3 is from 20 mg to 600 mg (e.g., from 30 mg to 500 mg, from 40 mg to 400 mg, from 60 mg to 350 mg, from 80 mg to 300 mg, from 100 mg to 200 mg, or from 140 mg to 180 mg, e.g., 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 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, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, or 600 mg). In some embodiments, C1D3 is from 80 mg to 300 mg. In some embodiments, C1D3 is 40 mg. In some embodiments, C1D3 is 90 mg. In some embodiments, C1D3 is 120 mg. In some embodiments, C1D3 is 132 mg. In some embodiments, C1D3 is 160 mg. In some embodiments, C1D3 is 198 mg. In some embodiments, C1D3 is 252 mg.

[0237] In some embodiments, the method comprises only a single administration cycle of the bispecific antibody (e.g., an administration cycle including C1D1, C1D2, and C1D3).

[0238] In other embodiments, the dosing regimen further comprises a second dosing cycle that includes at least a single dose (C2D1) of the bispecific antibody. In some embodiments, C2D1 is greater than or equal to C1D3 and is from about 20 mg to about 600 mg (e.g., from about 30 mg to about 500 mg, from about 40 mg to about 400 mg, from about 60 mg to about 350 mg, from about 80 mg to about 300 mg, from about 100 mg to about 200 mg, or from about 140 mg to about 180 mg, such as about 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 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, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, or 600 mg). In some embodiments, C2D1 is from about 80 mg to about 300 mg. In some embodiments, C2D1 is about 40 mg. In some embodiments, C2D1 is about 90 mg. In some embodiments, C2D1 is about 120 mg.In some embodiments, C2D1 is about 132 mg. In some embodiments, C2D1 is about 160 mg. In some embodiments, C2D1 is about 252 mg. In some embodiments, C2D1 is about 252 mg.

[0239] In some embodiments, C2D1 is from 20 mg to 600 mg (e.g., from 30 mg to 500 mg, from 40 mg to 400 mg, from 60 mg to 350 mg, from 80 mg to 300 mg, from 100 mg to 200 mg, or from 140 mg to 180 mg, e.g., 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 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, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, or 600 mg). In some embodiments, C2D1 is from 80 mg to 300 mg. In some embodiments, C2D1 is 40 mg. In some embodiments, C2D1 is 90 mg. In some embodiments, C2D1 is 120 mg. In some embodiments, C2D1 is 132 mg. In some embodiments, C2D1 is 160 mg. In some embodiments, C2D1 is 198 mg. In some embodiments, C2D1 is 252 mg.

[0240] Alternatively, in any of the above embodiments, C1D1 may be 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, such as about 0.3 mg, for example 0.3 mg), C1D2 may be from about 0.05 mg to about 180 mg (e.g., from about 0.1 mg to about 160 mg, from about 0.5 mg to about 140 mg, from about 1 mg to about 120 mg, from about 1.5 mg to about 100 mg, from about 2.0 mg to about 80 mg, from about 2.5 mg to about 50 mg, from about 3.0 mg to about 25 mg, from about 3.0 mg to about 15 mg, from about 3.0 mg to about 10 mg, from about 3.0 mg to about 5 mg, or from about 3.0 mg to about 4.0 mg, such as about 3.6 mg or about 3.3 mg, for example 3.6 mg or 3.3 mg), C1D3 may be from about 0.15 mg to about 1000 mg (e.g., from about 0.5 mg to about 800 mg, from about 1 mg to about 700 mg, from about 5 mg to about 500 mg, from about 10 mg to about 400 mg, from about 25 mg to about 300 mg, from about 40 mg to about 200 mg, from about 50 mg to about 190 mg, from about 140 mg to about 180 mg, or from about 150 mg to about 170 mg, such as about 160 mg, for example 160 mg), and in an embodiment including a second administration cycle, C2D1 may be from about 0.15 mg to about 1000 mg (e.g., from about 0.5 mg to about 800 mg, from about 1 mg to about 700 mg, from about 5 mg to about 500 mg, from about 10 mg to about 400 mg, from about 25 mg to about 300 mg, from about 40 mg to about 200 mg, from about 50 mg to about 190 mg, from about 140 mg to about 180 mg, or from about 150 mg to about 170 mg, such as about 160 mg, for example 160 mg).

[0241] In some cases, the length of the first dosing cycle is 1 week or 7 days. In some cases, the length of the first dosing cycle is 2 weeks or 14 days. In some cases, the length of the first dosing cycle is 3 weeks or 21 days. In some cases, the length of the first dosing cycle is 4 weeks or 28 days.

[0242] In any of the examples described herein, the first step-up dose and the second step-up dose may be administered approximately 1 day apart (e.g., approximately 20 hours apart, approximately 21 hours apart, approximately 23 hours apart, approximately 24 hours apart, approximately 25 hours apart, approximately 26 hours apart, approximately 27 hours apart, or approximately 28 hours apart), approximately 2 days apart (e.g., approximately 44 hours apart, approximately 45 hours apart, approximately 46 hours apart, approximately 47 hours apart, approximately 48 hours apart, approximately 49 hours apart, approximately 50 hours apart, approximately 51 hours apart, or approximately 52 hours apart), or approximately 3 days apart (e.g., approximately 68 hours apart, approximately 69 hours apart, approximately 70 hours apart, approximately 71 hours apart, or approximately 72 hours apart).

[0243] For example, in some cases, the method may include administering C1D1, C1D2, and C1D3 to a subject on days 1, 2, and 8, respectively, of the first dosing cycle, or on or about those days.

[0244] In other cases, the method may include administering C1D1, C1D2, and C1D3 to a subject on days 1, 3, and 8, respectively, of the first dosing cycle, or on or about those days (e.g., in the case of an undesirable treatment effect such as CRS, IRR, MAS, or TLS on day 1).

[0245] In other cases, the method may include administering C1D1, C1D2, and C1D3 to a subject on days 1, 4, and 8, respectively, of the first dosing cycle, or on or about those days (e.g., in the case of an undesirable treatment effect such as CRS, IRR, MAS, or TLS on day 1).

[0246] In some cases, the method may include administering C1D3 to the subject on or after the 9th day of the first dosing cycle (e.g., the 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, or 21st day).

[0247] In other cases, the method may include administering C1D1, C1D2, and C1D3 to the subject on the 1st, 2nd, and 9th days, respectively, of the first dosing cycle, or on or about those days (e.g., in the case of an undesirable treatment effect such as CRS, IRR, MAS, or TLS on the 1st day).

[0248] In other cases, the method may include administering C1D1, C1D2, and C1D3 to the subject on the 1st, 3rd, and 9th days, respectively, of the first dosing cycle, or on or about those days (e.g., in the case of an undesirable treatment effect such as CRS, IRR, MAS, or TLS on the 1st day).

[0249] In other cases, the method may include administering C1D1, C1D2, and C1D3 to the subject on the 1st, 4th, and 9th days, respectively, of the first dosing cycle, or on or about those days (e.g., in the case of an undesirable treatment effect such as CRS, IRR, MAS, or TLS on the 1st day).

[0250] In other cases, the method may include administering C1D1, C1D2, and C1D3 to the subject on the 1st, 5th, and 8th days, respectively, of the first dosing cycle, or on or about those days.

[0251] In other cases, the method may include administering C1D1, C1D2, and C1D3 to the subject on the 1st, 6th, and 8th days, respectively, of the first dosing cycle, or on or about those days.

[0252] In other cases, the method may include administering C1D1, C1D2, and C1D3 to the subject on the 1st, 7th, and 8th days, respectively, of the first dosing cycle, or on or about those days.

[0253] In still other cases, the method may include administering C1D1, C1D2, and C1D3 to the subject on the second, third, and eighth days, respectively, of the first dosing cycle, or on or about those days.

[0254] In other cases, the method may include administering C1D1, C1D2, and C1D3 to the subject on the third, fourth, and eighth days, respectively, of the first dosing cycle, or on or about those days.

[0255] iii. Further dosing cycles Any of the methods disclosed herein may include either of the one-step or two-step escalating dosing regimens disclosed above and may include any suitable number of further dosing cycles. In some cases, these methods as described above may include a second dosing cycle of one week or seven days. In some cases, these methods as described above may include a second dosing cycle of two weeks or fourteen days. In some cases, these methods as described above may include a second dosing cycle of three weeks or twenty-one days. In some cases, these methods as described above may include a second dosing cycle of four weeks or twenty-eight days. In some cases, the method may include administering C2D1 to the subject on the first day of the second dosing cycle, or on or about that day. In some cases, the method includes administering C2D1 to the subject at least one week (7 days) after administration of a previous dose of the bispecific antibody (e.g., C1D3).

[0256] In some cases where the method includes at least a second dosing cycle, the method may include one or more additional dosing cycles. In some cases, the dosing regimen may include from 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., from 1 to 3 additional dosing cycles, from 1 to 5 additional dosing cycles, from 3 to 8 additional dosing cycles, from 5 to 10 additional dosing cycles, from 8 to 12 additional dosing cycles, from 10 to 15 additional dosing cycles, from 12 to 17 additional dosing cycles, or from 15 to 17 additional dosing cycles, i.e., the dosing regimen may include one or more additional dosing cycles (plural) C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, and C19.

[0257] In some cases where the method includes at least a second dosing cycle, the method may include any suitable number of additional dosing cycles. For example, the additional dosing cycles may continue until the subject experiences disease progression, unacceptable toxicity, or death.

[0258] In some embodiments, the length of each of one or more additional dosing cycles is 7 days, 14 days, 21 days, or 28 days. In some embodiments, the length of each of one or more additional dosing cycles is from 5 days to 30 days, such as, for example, 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 one or more additional dosing cycles is 1 week or 7 days (e.g., Q1W). In some cases, the length of each of one or more additional dosing cycles is 2 weeks or 14 days (e.g., Q2W). In some cases, the length of each of one or more additional dosing cycles is 3 weeks or 21 days (e.g., Q3W). In some cases, the length of each of one or more additional dosing cycles is 4 weeks or 28 days (e.g., Q4W).

[0259] In some cases, each of one or more additional dosing cycles comprises a single dose of the bispecific antibody. In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is equal to C2D1, for example, 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 mg, 25 mg, 30 mg, 35 mg, 40 mg, 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, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, or 600 mg). In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is about 40 mg.In some embodiments, the dosage of the bispecific antibody in one or more additional dosing cycles is about 90 mg. In some embodiments, the dosage of the bispecific antibody in one or more additional dosing cycles is about 120 mg. In some embodiments, the dosage of the bispecific antibody in one or more additional dosing cycles is about 132 mg. In some embodiments, the dosage of the bispecific antibody in one or more additional dosing cycles is about 160 mg. In some embodiments, the dosage of the bispecific antibody in one or more additional dosing cycles is about 198 mg. In some embodiments, the dosage of the bispecific antibody in one or more additional dosing cycles is about 252 mg.

[0260] In some embodiments, the dosage of the bispecific antibody in one or more additional dosing cycles is equal to C2D1, for example, 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 mg, 25 mg, 30 mg, 35 mg, 40 mg, 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, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, or 600 mg). In some embodiments, the dosage of the bispecific antibody in one or more additional dosing cycles is 40 mg. In some embodiments, the dosage of the bispecific antibody in one or more additional dosing cycles is 90 mg. In some embodiments, the dosage of the bispecific antibody in one or more additional dosing cycles is 120 mg.In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is 132 mg. In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is about 160 mg. In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is 198 mg. In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is 252 mg.

[0261] In some cases, the method includes administering a single dose of the bispecific antibody to the subject on the first day of one or more additional dosing cycles, or about that day. In some cases, the method includes administering a single dose of the bispecific antibody to the subject on the first and fifteenth days of one or more additional dosing cycles, or about those days. In some cases, the method includes administering a single dose of the bispecific antibody to the subject on the first, eighth, fifteenth, and twenty-second days of one or more additional dosing cycles, or about those days.

[0262] In some embodiments, the bispecific antibody is administered to the subject every 7 days (QW) for up to 18 cycles, or until minimal residual disease (MRD) is detected, until progressive disease is detected. In some embodiments, the bispecific antibody is administered to the subject every 14 days (Q2W) for up to 18 cycles, or until minimal residual disease (MRD) is detected, until progressive disease is detected. In some embodiments, the bispecific antibody is administered to the subject every 21 days (Q3W) for up to 18 cycles, or until minimal residual disease (MRD) is detected, until progressive disease is detected. In some embodiments, the bispecific antibody is administered to the subject every 28 days (Q4W) for up to 18 cycles, or until minimal residual disease (MRD) is detected, until progressive disease is detected. In some embodiments, the bispecific antibody is administered to the subject QW, Q2W, Q3W, or Q4W until disease progression, unacceptable toxicity, or death is detected.

[0263] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to a subject as a monotherapy. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to a subject in combination with another therapeutic agent. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to a subject in combination with a corticosteroid. Exemplary corticosteroids used in combination therapy include dexamethasone and methylprednisolone.

[0264] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is sevosumab. In some cases, sevosumab is administered to a subject as a monotherapy. In some cases, sevosumab is administered to a subject in combination with a corticosteroid (e.g., dexamethasone and methylprednisolone).

[0265] B. Administration Regimen The present disclosure describes a method of treating a subject having cancer (e.g., multiple myeloma (MM)), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in an administration regimen described herein. In some examples, the subject has triple-class refractory MM and has previously received a BCMA-targeted therapeutic agent.

[0266] In some examples, the dosing regimen includes a first phase comprising one or more dosing cycles and a second phase comprising one or more dosing cycles. In some examples, each dosing cycle is a 7-day dosing cycle. In some examples, each dosing cycle is a 14-day dosing cycle. In some examples, each dosing cycle is a 21-day dosing cycle. In some examples, each dosing cycle is a 28-day dosing cycle. In one example, the first phase may include administering the bispecific antibody to the subject on days 1, 2, and 8 of each dosing cycle of the first phase, and the second phase may include administering the bispecific antibody to the subject QW, Q2W, Q3W, or Q4W. In other examples, the first phase may include administering the bispecific antibody to the subject on days 1, 3, and / or 8 of each dosing cycle of the first phase, and the second phase may include administering the bispecific antibody to the subject QW, Q2W, Q3W, or Q4W. In yet another example, the first phase may include administering the bispecific antibody to the subject on days 1, 4, and / or 8 of each dosing cycle of the first phase, and the second phase may include administering the bispecific antibody to the subject QW, Q2W, Q3W, or Q4W. In other examples, the first phase may include administering the bispecific antibody to the subject on days 1, 3, and / or 9 of each dosing cycle of the first phase, and the second phase may include administering the bispecific antibody to the subject QW, Q2W, Q3W, or Q4W. In yet another example, the first phase may include administering the bispecific antibody to the subject on days 1, 4, and / or 9 of each dosing cycle of the first phase, and the second phase may include administering the bispecific antibody to the subject QW, Q2W, Q3W, or Q4W.

[0267] For example, provided herein is a method of treating a subject having cancer (e.g., MM), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in an administration regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein in each dosing cycle of the first phase, the bispecific antibody is administered to the subject on (a) day 1, (b) day 2, 3, or 4, and / or (c) day 8 or 9; and (ii) a second phase comprising one or more dosing cycles, wherein the bispecific antibody is administered to the subject every three weeks (Q3W). In some examples, the administration regimen comprises the first phase. In some examples, the administration regimen comprises the second phase. In some examples, the administration regimen comprises the first and second phases.

[0268] In another example, provided herein is a bispecific antibody that binds to FcRH5 and CD3 for use in treating a subject having cancer (e.g., MM), the treatment comprising administering to the subject the bispecific antibody in an administration regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein in each dosing cycle of the first phase, the bispecific antibody is administered to the subject on (a) day 1, (b) day 2, 3, or 4, and / or (c) day 8 or 9; and (ii) a second phase comprising one or more dosing cycles, wherein the bispecific antibody is administered to the subject every three weeks (Q3W). In some examples, the administration regimen comprises the first phase. In some examples, the administration regimen comprises the second phase. In some examples, the administration regimen comprises the first and second phases.

[0269] In another example, the use of a bispecific antibody that binds to FcRH5 and CD3 in the manufacture of a medicament for the treatment of a subject having cancer (e.g., MM) is provided herein, 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, wherein in each dosing cycle of the first phase, the bispecific antibody is administered to the subject on (a) day 1, (b) day 2, 3, or 4, and / or (c) day 8 or 9; and (ii) a second phase comprising one or more dosing cycles, wherein the bispecific antibody is administered to the subject every three weeks (Q3W). 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 and second phases.

[0270] In another example, a method of treating a subject having cancer (e.g., MM) is provided herein, the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein in each dosing cycle of the first phase, the bispecific antibody is administered to the subject on (a) day 1, 2, 3, 4, 5, 6, and / or 7, and / or (b) day 8 or 9; and (ii) a second phase comprising one or more dosing cycles, wherein the bispecific antibody is administered to the subject every three weeks (Q3W). 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 and second phases. In some examples, during the first phase, if the subject experiences a CRS event after administration of a first escalating dose (e.g., 0.3 mg) on day 1 of C1, the administration of a second dose (e.g., 3.3 mg) can be delivered on day 2, 3, or 4 after the CRS has completely resolved.

[0271] In another example, bispecific antibodies that bind to FcRH5 and CD3 for use in the treatment of a subject having cancer (e.g., MM) are provided herein, and the treatment comprises administering the bispecific antibody to the subject in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein (a) on day 1, day 2, day 3, day 4, day 5, day 6, and / or day 7 of each dosing cycle of the first phase, and / or (b) on day 8 or day 9 of each dosing cycle of the first phase, the bispecific antibody is administered to the subject; and (ii) a second phase comprising one or more dosing cycles, wherein the bispecific antibody is administered to the subject every three weeks (Q3W). 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. In some examples, during the first phase, if the subject experiences a CRS event after administration of a first step-up dose (e.g., 0.3 mg) on day 1 of C1, administration of a second dose (e.g., 3.3 mg) can be delivered on day 2, day 3, or day 4 when the CRS has completely resolved.

[0272] In another example, provided herein is the use of a bispecific antibody that binds to FcRH5 and CD3 in the manufacture of a medicament for treating a subject having 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, wherein (a) on day 1, day 2, day 3, day 4, day 5, day 6, and / or day 7 of each dosing cycle of the first phase, and / or (b) on day 8 or day 9 of each dosing cycle of the first phase, the bispecific antibody is administered to the subject; and (ii) a second phase comprising one or more dosing cycles, wherein the bispecific antibody is administered to the subject every three weeks (Q3W). 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. In some examples, during the first phase, if the subject experiences a CRS event after administration of a first step-up dose (e.g., 0.3 mg) on day 1 of C1, the administration of a second dose (e.g., 3.3 mg) can be delivered on day 2, day 3, or day 4 when the CRS has completely resolved.

[0273] The first phase can include any suitable number of dosing cycles. For example, in some examples, the first phase can include 1 dosing cycle, at least 2 dosing cycles, at least 3 dosing cycles, at least 4 dosing cycles, at least 5 dosing cycles, at least 6 dosing cycles, at least 7 dosing cycles, at least 8 dosing cycles, at least 9 dosing cycles, at least 10 dosing cycles, at least 11 dosing cycles, at least 12 dosing cycles, at least 13 dosing cycles, or more.

[0274] In some examples, the first phase is the first administration cycle (C1); the first and second administration cycles (C2); the first, second, and third administration cycles (C3); the first, second, third, and fourth administration cycles (C4); the first, second, third, fourth, and fifth administration cycles (C5); the first, second, third, fourth, fifth, and sixth administration cycles (C6); the first, second, third, fourth, fifth, sixth, and seventh administration cycles (C7); the first, second, third, fourth, fifth, sixth, seventh, and eighth administration cycles (C8); the first, second, third, fourth, fifth, sixth, seventh, eighth, and ninth administration cycles (C9); the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, and tenth administration cycles (C10); the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, and eleventh administration cycles (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 (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), the twelfth administration cycle (C12), and the thirteenth administration cycle (C13).;

[0275] The bispecific antibody can be administered on any suitable day of a given administration cycle. For example, in the case of a 28-day administration cycle, the bispecific antibody can be administered on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, day 14, day 15, day 16, day 17, day 18, day 19, day 20, day 21, day 22, day 23, day 24, day 25, day 26, day 27, or day 28. In another example, in the case of a 21-day administration cycle, the bispecific antibody can be administered on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, day 14, day 15, day 16, day 17, day 18, day 19, day 20, or day 21. In another example, in the case of a 14-day administration cycle, the bispecific antibody can be administered on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, or day 14. In another example, in the case of a 7-day administration cycle, the bispecific antibody can be administered on day 1, day 2, day 3, day 4, day 5, day 6, or day 7.

[0276] In some examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 8 of C1. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 8 of C2. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 8 of C3. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 8 of C4. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 8 of C5. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 8 of C6. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 8 of C7. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 8 of C8. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 8 of C9. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 8 of C10. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 8 of C11. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 8 of C12. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 8 of C13.

[0277] In some examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 8 of C1. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 8 of C2. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 8 of C3. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 8 of C4. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 8 of C5. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 8 of C6. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 8 of C7. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 8 of C8. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 8 of C9. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 8 of C10. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 8 of C11. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 8 of C12. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 8 of C13.

[0278] In some examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 8 of C1. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 8 of C2. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 8 of C3. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 8 of C4. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 8 of C5. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 8 of C6. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 8 of C7. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 8 of C8. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 8 of C9. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 8 of C10. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 8 of C11. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 8 of C12. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 8 of C13.

[0279] In some examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 9 of C1. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 9 of C2. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 9 of C3. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 9 of C4. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 9 of C5. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 9 of C6. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 9 of C7. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 9 of C9. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 9 of C9. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 9 of C10. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 9 of C11. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 9 of C12. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 2, and / or day 9 of C13.

[0280] In some examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 9 of C1. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 9 of C2. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 9 of C3. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 9 of C4. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 9 of C5. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 9 of C6. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 9 of C7. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 9 of C9. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 9 of C9. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 9 of C10. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 9 of C11. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 9 of C12. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 3, and / or day 9 of C13.

[0281] In some examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 9 of C1. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 9 of C2. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 9 of C3. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 9 of C4. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 9 of C5. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 9 of C6. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 9 of C7. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 9 of C9. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 9 of C9. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 9 of C10. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 9 of C11. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 9 of C12. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 4, and / or day 9 of C13.

[0282] In some examples, the target dose of the bispecific antibody is administered to the subject after the 9th day of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, or C12 of the first phase. For example, in some cases, the target dose of the bispecific antibody is administered to the subject on the 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, or 21st day of C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, or C12 of the first phase.

[0283] In some examples, the target dose of the bispecific antibody is administered to the subject for each administration during the first phase.

[0284] In some examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, or 8th day of C1. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, or 8th day of C2. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, or 8th day of C3. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, or 8th day of C4. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, or 8th day of C5. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, or 8th day of C6. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, or 8th day of C7. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, or 8th day of C8. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, or 8th day of C9. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, or 8th day of C10. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, or 8th day of C11. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, or 8th day of C12.In a further example, the first phase includes administration of the bispecific antibody at the target dose to the subject on day 1, 2, 3, 4, 5, 6, 7, or 8 of C13.

[0285] In some examples, the first phase includes administration of the bispecific antibody at the first step-up dose and the target dose to the subject. The first step-up dose can be administered to the subject on day 1, day 2, day 3, day 4, day 5, day 6, or day 7 of C1 during the first phase. The target dose can be administered to the subject on day 8 of C1 during the first phase. In a further example, the target dose can be administered to the subject on day 1 of C2 during the first phase. In a further example, the target dose can be administered to the subject on day 1 of C3 during the first phase. In a further example, the target dose can be administered to the subject on day 1 of C4 during the first phase. In a further example, the target dose can be administered to the subject on day 1 of C5 during the first phase. In a further example, the target dose can be administered to the subject on day 1 of C6 during the first phase. In a further example, the target dose can be administered to the subject on day 1 of C7 during the first phase. In a further example, the target dose can be administered to the subject on day 1 of C8 during the first phase. In a further example, the target dose can be administered to the subject on day 1 of C9 during the first phase. In a further example, the target dose can be administered to the subject on day 1 of C10 during the first phase. In a further example, the target dose can be administered to the subject on day 1 of C11 during the first phase. In a further example, the target dose can be administered to the subject on day 1 of C12 during the first phase. In a further example, the target dose can be administered to the subject on day 1 of C13 during the first phase.

[0286] In some examples, the first-step escalating dose is from about 0.1% to about 8% of the target dose. In some examples, the first-step escalating dose is about 0.12%, about 0.13%, about 0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, about 0.19%, about 0.2%, about 0.21%, about 0.22%, about 0.23%, about 0.24%, about 0.25%, about 0.26%, about 0.27%, about 0.28%, about 0.29%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.03%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, 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.

[0287] In some examples, the first-step escalating dose is 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.03%, 2.1%, 2.2%, 2.3%, 2.4%, 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-step escalating dose is 4% of the target dose.

[0288] In some examples, the first-step escalating dose is about 3.3 mg. In some examples, the first-step escalating dose is about 3.6 mg. In some examples, the first-step escalating 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.

[0289] In some examples, the first step-up dose is 3.3 mg. In some examples, the first step-up dose is 3.6 mg. In some examples, the first step-up 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.

[0290] In some examples, the first phase includes administration of the bispecific antibody at the first step-up dose and the second step-up dose to the subject. In some examples, the first step-up dose is administered to the subject on day 1 of C1 during the first phase, and the second step-up dose is administered on day 2 of C1. In some examples, the first step-up dose is administered to the subject on day 1 of C1 during the first phase, and the second step-up dose is administered on day 3 of C1. In some examples, the first step-up dose is administered to the subject on day 1 of C1 during the first phase, and the second step-up dose is administered on day 4 of C1. In some examples, the first step-up dose is administered to the subject on day 1 of C1 during the first phase, and the second step-up dose is administered on day 5 of C1. In some examples, the first step-up dose is administered to the subject on day 1 of C1 during the first phase, and the second step-up dose is administered on day 6 of C1. In some examples, the first step-up dose is administered to the subject on day 1 of C1 during the first phase, and the second step-up dose is administered on day 7 of C1.

[0291] During the first phase, if the subject experiences a CRS event after administration of the first step-up dose (e.g., 0.3 mg) on day 1 of C1, the administration of the second dose (e.g., 3.3 mg) can be delivered on day 2, day 3, or day 4 when the CRS has completely resolved. Depending on the clinical symptoms of the CRS event, a delay in the additional dose (e.g., delivery of the second dose on day 5, day 6, or day 7) may be necessary. See the CRS management guidelines described in Tables 3A and 3B.

[0292] In further examples, the target dose is administered to the subject during the first phase after administration of the second step-up dose. In some examples, the target dose is administered to the subject on day 8 of C1. In some examples, the target dose is administered to the subject on day 9 of C1. In some examples, the target dose is administered to the subject on or after day 9 of C1 (e.g., day 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21).

[0293] In further examples, the target dose is further administered to the subject on day 1 of C2 during the first phase. In further examples, the target dose is administered to the subject on day 1 of C3 during the first phase. In further examples, the target dose is administered to the subject on day 1 of C4 during the first phase. In further examples, the target dose is administered to the subject on day 1 of C5 during the first phase. In further examples, the target dose is administered to the subject on day 1 of C6 during the first phase. In further examples, the target dose is administered to the subject on day 1 of C7 during the first phase. In further examples, the target dose is administered to the subject on day 1 of C8 during the first phase. In further examples, the target dose is administered to the subject on day 1 of C9 during the first phase. In further examples, the target dose is administered to the subject on day 1 of C10 during the first phase. In further examples, the target dose is administered to the subject on day 1 of C11 during the first phase. In further examples, the target dose is administered to the subject on day 1 of C12 during the first phase. In further examples, the target dose is administered to the subject on day 1 of C13 during the first phase.

[0294] In some examples, the first step-up dose is from about 0.1% to about 2% of the target dose, and the second step-up dose is from about 2% to about 8% of the target dose. In some examples, the first step-up dose is about 0.11%, about 0.12%, about 0.13%, about 0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, about 0.19%, about 0.2%, about 0.21%, about 0.22%, about 0.23%, about 0.24%, about 0.25%, about 0.26%, about 0.27%, about 0.28%, about 0.29%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, or about 2% of the target dose, and the second step-up dose is about 2%, about 2.03%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, 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 step-up dose is about 0.19% of the target dose and the second step-up dose is about 2.06% of the target dose. In some examples, the first step-up dose is about 0.19% of the target dose and the second step-up dose is about 2.3% of the target dose.

[0295] In some examples, the first step-up dose is 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, or 2% of the target dose, and the second step-up dose is 2%, 2.03%, 2.1%, 2.2%, 2.3%, 2.4%, 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 step-up dose is 0.19% of the target dose and the second step-up dose is 2.06% of the target dose. In some examples, the first step-up dose is about 0.19% of the target dose and the second step-up dose is about 2.3% of the target dose.

[0296] In some examples, the first step-up dose is about 0.3 mg and the second step-up dose is about 3.3 mg. In some examples, the first step-up dose is about 0.3 mg and the second step-up dose is about 3.6 mg. In some examples, the first step-up 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 step-up dose is about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.3 mg, about 3.5 mg, about 3.6 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.

[0297] In some examples, the first step-up dose is 0.3 mg and the second step-up dose is 3.3 mg. In some examples, the first step-up dose is 0.3 mg and the second step-up dose is 3.6 mg. In some examples, the first step-up 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 step-up dose is 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.3 mg, 3.5 mg, 3.6 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.

[0298] In any of the foregoing examples, the second phase may include at least 2 dosing cycles, at least 3 dosing cycles, or at least 4 dosing cycles, at least 5 dosing cycles, at least 6 dosing cycles, at least 7, at least 8 dosing cycles, at least 9 dosing cycles, at least 10 dosing cycles, at least 11 dosing cycles, at least 12 dosing cycles, or at least 13 dosing cycles, or more. For example, the second phase may continue until the subject experiences disease progression, unacceptable toxicity, or death.

[0299] The second phase can include any suitable number of dosing cycles. For example, in some instances, the second phase is the first dosing cycle (C1); the first dosing cycle and the second dosing cycle (C2); the first dosing cycle, the second dosing cycle (C2), and the third dosing cycle (C3); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), and the fourth dosing cycle (C4); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), and the fifth dosing cycle (C5); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), and the sixth dosing cycle (C6); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), and the seventh dosing cycle (C7); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), and the eighth dosing cycle (C8); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), and the ninth dosing cycle (C9); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), and the tenth dosing cycle (C10);The first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), and the eleventh dosing cycle (C11); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11), and the twelfth dosing cycle (C12); or the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), the tenth dosing cycle (C10), the eleventh dosing cycle (C11), the twelfth dosing cycle (C12), and the thirteenth dosing cycle (C13) may be included.;

[0300] In some examples, the target dose of the bispecific antibody can be administered to the subject on day 1 of C1 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 of C2 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 of C3 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 of C4 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 of C5 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 of C6 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 of C7 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 of C8 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 of C9 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 of C10 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 of C11 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 of C12 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 of C13 during the second phase. In any of the foregoing examples, the second phase includes C1, and day 1 of C1 of the second phase is at least 7 days after the administration of the target dose of the bispecific antibody in the first phase.

[0301] In some examples, the bispecific antibody at the target dose is administered to the subject for each administration during the second phase.

[0302] In any of the foregoing examples, the target dosage can be from about 45 mg to about 180 mg. In some examples, the target dosage is from about 50 mg to about 175 mg. In some examples, the target dosage is from about 55 mg to about 165 mg. In some examples, the target dosage is from about 60 mg to about 160 mg. In some examples, the target dosage is from about 65 mg to about 155 mg. In some examples, the target dosage is from about 70 mg to about 150 mg. In some examples, the target dosage is from about 75 mg to about 145 mg. In some examples, the target dosage is from about 80 mg to about 140 mg. In some examples, the target dosage is from about 85 mg to about 135 mg. In some examples, the target dosage is from about 90 mg to about 130 mg. In some examples, the target dosage is about 40 mg. In some examples, the target dosage is about 90 mg. In some examples, the target dosage is about 120 mg. In some examples, the target dosage is about 132 mg. In some examples, the target dosage is about 160 mg. In some examples, the target dosage is about 198 mg. In some examples, the target dosage is about 252 mg.

[0303] In some examples, the target dose is about 40 mg. 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. In some examples, the target dose is about 185 mg. In some examples, the target dose is about 189 mg. In some examples, the target dose is about 195 mg. In some examples, the target dose is about 198 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 252 mg. In some examples, the target dose is about 255 mg. In some examples, the target dose is about 260 mg.

[0304] In some examples, the target dose is 45 mg to 180 mg. In some examples, the target dose is 50 mg to 175 mg. In some examples, the target dose is 55 mg to 165 mg. In some examples, the target dose is 60 mg to 160 mg. In some examples, the target dose is 65 mg to 155 mg. In some examples, the target dose is 70 mg to 150 mg. In some examples, the target dose is 75 mg to 145 mg. In some examples, the target dose is 80 mg to 140 mg. In some examples, the target dose is 85 mg to 135 mg. In some examples, the target dose is 90 mg to 130 mg. In some examples, the target dose is 40 mg. In some examples, the target dose is 90 mg. In some examples, the target dose is 120 mg. In some examples, the target dose is 132 mg. In some examples, the target dose is 160 mg. In some examples, the target dose is 198 mg. In some examples, the target dose is 252 mg.

[0305] In some examples, the target dosage is 40 mg. In some examples, the target dosage is 45 mg. In some examples, the target dosage is 50 mg. In some examples, the target dosage is 55 mg. In some examples, the target dosage is 60 mg. In some examples, the target dosage is 65 mg. In some examples, the target dosage is 70 mg. In some examples, the target dosage is 75 mg. In some examples, the target dosage is 80 mg. In some examples, the target dosage is 85 mg. In some examples, the target dosage is 90 mg. In some examples, the target dosage is 95 mg. In some examples, the target dosage is 100 mg. In some examples, the target dosage is 105 mg. In some examples, the target dosage is 110 mg. In some examples, the target dosage is 115 mg. In some examples, the target dosage is 120 mg. In some examples, the target dosage is 125 mg. In some examples, the target dosage is 130 mg. In some examples, the target dosage is 132 mg. In some examples, the target dosage is 135 mg. In some examples, the target dosage is 140 mg. In some examples, the target dosage is 145 mg. In some examples, the target dosage is 150 mg. In some examples, the target dosage is 155 mg. In some examples, the target dosage is 160 mg. In some examples, the target dosage is 165 mg. In some examples, the target dosage is 170 mg. In some examples, the target dosage is 175 mg. In some examples, the target dosage is 180 mg. In some examples, the target dosage is 185 mg. In some examples, the target dosage is 189 mg. In some examples, the target dosage is 195 mg. In some examples, the target dosage is 198 mg. In some examples, the target dosage is 200 mg. In some examples, the target dosage is 205 mg. In some examples, the target dosage is 210 mg. In some examples, the target dosage is 215 mg. In some examples, the target dosage is 220 mg. In some examples, the target dosage is 225 mg. In some examples, the target dosage is 230 mg. In some examples, the target dosage 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 252 mg. In some examples, the target dose is 255 mg. In some examples, the target dose is 260 mg.

[0306] In some examples, the bispecific antibody is administered to the subject as a monotherapy.

[0307] In some examples, the bispecific antibody is administered intravenously to the subject. In some examples, the bispecific antibody is administered subcutaneously to the subject.

[0308] In any of the foregoing examples, the dosing regimen further comprises administration of a corticosteroid to the subject during the first phase and / or the second phase. For example, in some examples, the dosing regimen further comprises administration of a corticosteroid to the subject during a run-in phase. In another example, the dosing regimen further comprises administration of a corticosteroid to the subject during the first phase. In another example, the dosing regimen further comprises administration of a corticosteroid to the subject during the second phase. In other examples, the dosing regimen further comprises administration of a corticosteroid to the subject during the first phase and the second phase.

[0309] In some examples, the dosing regimens described herein are for treating a subject having R / R MM, and the subject is administered a bispecific antibody that binds to FcRH5 and CD3. In some examples, the bispecific antibody is administered in a dosing regimen that contains at least a first 7-day dosing cycle. In some examples, the bispecific antibody is administered in a dosing regimen that contains at least a first 14-day dosing cycle. In some examples, the bispecific antibody is administered in a dosing regimen that contains at least a first 21-day dosing cycle. In some examples, the bispecific antibody is administered in a dosing regimen that contains at least a first 28-day dosing cycle. In some examples, the dosing cycle (e.g., a 7-day, 14-day, 21-day, or 28-day dosing cycle) includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3). In some examples, C1D1 is from about 0.2 mg to about 0.4 mg (e.g., about 0.2 mg, about 0.3 mg, or about 0.4 mg), C1D2 is from about 3.1 mg to about 3.4 mg (e.g., about 3.1 mg, about 3.2 mg, about 3.3 mg, or about 3.4 mg), and C1D3 is in an amount greater than C1D2. In some examples, C1D1 is 0.2 mg to 0.4 mg (e.g., 0.2 mg, 0.3 mg, or about 0.4 mg), C1D2 is 3.1 mg to 3.4 mg (e.g., 3.1 mg, 3.2 mg, 3.3 mg, or 3.4 mg), and C1D3 is in an amount greater than C1D2.

[0310] In some examples, the dosing regimens described herein are for treating a subject having triple-class refractory MM, and the subject is administered sevosetamab monotherapy. In some examples, the subject may have previously received a BCMA-targeted TDB antibody. In some examples, the subject may have previously received BCMA-targeted CAR-T. In some examples, the subject may have previously received BCMA-targeted ADC. In some examples, the sevosetamab monotherapy is administered in a dosing regimen that contains a first phase and a second phase. In some examples, sevosetamab is administered to the subject in a first dosing cycle (C1) during the first phase. In some examples, sevosetamab is administered to the subject Q3W during the second phase until the subject experiences disease progression, unacceptable toxicity, or death. In some examples, each dosing cycle of the first phase and the second phase is a 21-day dosing cycle. In some examples, sevosetamab is administered to the subject at a first escalating dose of 0.3 mg on day 1 of C1 during the first phase and at a second escalating dose of 3.3 mg on day 2 of C1 during the first phase. In other examples, sevosetamab is administered to the subject at a first escalating dose of 0.3 mg on day 1 of C1 during the first phase and at a second escalating dose of 3.6 mg on day 2 of C1 during the first phase. In other examples, sevosetamab is administered to the subject at a first escalating dose of 0.3 mg on day 1 of C1 during the first phase and at a second escalating dose of 3.3 mg on day 3 of C1 during the first phase. In other examples, sevosetamab is administered to the subject at a first escalating dose of 0.3 mg on day 1 of C1 during the first phase and at a second escalating dose of 3.6 mg on day 3 of C1 during the first phase. In other examples, sevosetamab is administered to the subject at a first escalating dose of 0.3 mg on day 1 of C1 during the first phase and at a second escalating dose of 3.3 mg on day 4 of C1 during the first phase. In other examples, sevosetamab is administered to the subject at a first escalating dose of 0.3 mg on day 1 of C1 during the first phase and at a second escalating dose of 3.6 mg on day 4 of C1 during the first phase.In any of the foregoing examples, sevosumab is administered at a target dose of 160 mg on day 8 or 9 of C1 during the first phase and on day 1 of each dosing cycle during the second phase.

[0311] In some examples, the disclosure provides a bispecific antibody that binds to FcRH5 and CD3 for use in treating a subject having R / R MM, wherein the subject has triple-class refractory MM and has previously received a BCMA-targeted therapeutic agent. In some examples, the treatment comprises administering the bispecific antibody to the subject in a dosing regimen comprising a first phase and a second phase. In some examples, the first phase comprises a first 21-day dosing cycle (C1), and the administration of the bispecific antibody to the subject is performed on days 1, 2, and 8 of C1. In some examples, the first phase comprises a first 21-day dosing cycle (C1), and the administration of the bispecific antibody to the subject is performed on days 1, 3, and 8 of C1. In some examples, the first phase comprises a first 21-day dosing cycle (C1), and the administration of the bispecific antibody to the subject is performed on days 1, 4, and 8 of C1. In some examples, the first phase comprises a first 21-day dosing cycle (C1), and the administration of the bispecific antibody to the subject is performed on days 1, 2, and 9 of C1. In some examples, the first phase comprises a first 21-day dosing cycle (C1), and the administration of the bispecific antibody to the subject is performed on days 1, 3, and 9 of C1. In some examples, the first phase comprises a first 21-day dosing cycle (C1), and the administration of the bispecific antibody to the subject is performed on days 1, 4, and 9 of C1. In some examples, the second phase comprises one or more 21-day dosing cycles, and the administration of the bispecific antibody to the subject is performed Q3W.

[0312] In some examples, the disclosure provides bispecific antibodies that bind to FcRH5 and CD3 for use in treating subjects having R / R MM. In some examples, a subject is administered a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen that includes at least a first 21-day dosing cycle, and the first dosing cycle contains a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody. In some examples, C1D1 is from about 0.2 mg to about 0.4 mg (e.g., 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg) and is administered to the subject on day 1 of the first dosing cycle. In some examples, C1D2 is from about 3.1 mg to about 3.4 mg (e.g., 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, or 3.5 mg) and is administered to the subject on day 2 of the first dosing cycle. In some examples, C1D3 is more than C1D2.

[0313] C. Combination Therapy In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to a subject in combination therapy. For example, the bispecific anti-FcRH5 / anti-CD3 antibody can be administered concurrently with one or more additional therapeutic agents described herein.

[0314] i. Anti-CD38 Antibody In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to a subject in combination with an anti-CD38 antibody. The anti-CD38 antibody can be administered to the subject by any suitable route of administration, such as intravenously (IV) or subcutaneously (SC). In some embodiments, the anti-CD38 antibody is daratumumab (e.g., daratumumab / rHuPH20). Daratumumab can be administered to the subject at 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 1950 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, or about 3600 mg). Daratumumab can be administered to the subject at a dose of about 1800 mg. In some embodiments, daratumumab is administered by intravenous infusion (e.g., an infusion over 3-5 hours) at a dose of 16 mg / kg once a week, once every two weeks, or once every four weeks. In some embodiments, daratumumab is administered by intravenous infusion (e.g., an infusion over 3-5 hours) at a dose of 16 mg / kg. In other embodiments, the anti-CD38 antibody is isatuximab. In some embodiments, the anti-CD38 antibody (e.g., daratumumab or isatuximab) is administered to the subject prior to the administration of the bispecific anti-FcRH5 / anti-CD3 antibody, e.g., one day prior to the administration of the bispecific anti-FcRH5 / anti-CD3 antibody. In some embodiments, the anti-CD38 antibody (e.g., daratumumab or isatuximab) is administered to the subject simultaneously with the administration of the bispecific anti-FcRH5 / anti-CD3 antibody.

[0315] ii. Corticosteroid In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to a subject in combination with a corticosteroid. The corticosteroid can be administered orally to the subject. The corticosteroid can be administered to the subject by any suitable route of administration, for example, intravenously. Any suitable corticosteroid can be used, for example, dexamethasone, methylprednisolone, prednisone, prednisolone, betamethasone, hydrocortisone, etc. In some embodiments, the corticosteroid is methylprednisolone. Methylprednisolone can be administered to the subject at a dose of about 80 mg. In other embodiments, the corticosteroid is dexamethasone. Dexamethasone can be administered to the subject at a dose of about 20 mg. In some embodiments, the corticosteroid (e.g., methylprednisolone or dexamethasone) is administered to the subject prior to administration of the bispecific anti-FcRH5 / anti-CD3 antibody, for example, 1 hour prior to administration of the bispecific anti-FcRH5 / anti-CD3 antibody. In some embodiments, the corticosteroid (e.g., methylprednisolone or dexamethasone) is administered to the subject about 1 day prior to administration of the bispecific anti-FcRH5 / anti-CD3 antibody. In some embodiments, the corticosteroid (e.g., methylprednisolone or dexamethasone) is administered to the subject simultaneously with administration of the bispecific anti-FcRH5 / anti-CD3 antibody.

[0316] The corticosteroid can 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 can be administered intravenously or orally to the subject.

[0317] In some examples, the corticosteroid is administered intravenously to the subject prior to administration of the bispecific antibody. In some examples, the corticosteroid is administered intravenously to the subject about 1 hour prior to administration of the bispecific antibody.

[0318] In some examples, the corticosteroid is dexamethasone or methylprednisolone. In some examples, the corticosteroid is dexamethasone.

[0319] In some examples, dexamethasone is administered to the subject at a dosage of about 10 mg to about 40 mg. In some examples, dexamethasone is administered to the subject at 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 at a dosage of about 20 mg.

[0320] In some examples, dexamethasone is administered to the subject at a dosage of 10 mg to 40 mg. In some examples, dexamethasone is administered to the subject at 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 at a dosage of 20 mg.

[0321] 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.

[0322] In some examples, methylprednisolone is administered to a subject at a dosage of 40 mg to 160 mg. In some examples, methylprednisolone is administered to the subject at 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 at a dosage of 80 mg. iii. Immunomodulatory drug (IMiD)

[0323] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to a subject in combination with an immunomodulatory drug (IMiD). The IMiD can be administered to the subject by any suitable route of administration, for example, orally. The IMiD can be administered intravenously to the subject. In some embodiments, the IMiD is pomalidomide. Pomalidomide can be administered to the subject at a dose of about 4 mg. In other embodiments, the IMiD is lenalidomide. In some embodiments, the IMiD (e.g., pomalidomide or lenalidomide) is administered to the subject prior to the administration of the bispecific anti-FcRH5 / anti-CD3 antibody, for example, 1 hour before the administration of the bispecific anti-FcRH5 / anti-CD3 antibody. In some embodiments, the IMiD (e.g., pomalidomide or lenalidomide) is administered to the subject simultaneously with the administration of the bispecific anti-FcRH5 / anti-CD3 antibody. In some embodiments, the IMiD (e.g., pomalidomide or lenalidomide) is administered daily between doses of the bispecific anti-FcRH5 / anti-CD3 antibody.

[0324] iv. Tocilizumab and treatment of CRS In one case, the additional therapeutic agent is an effective amount of tocilizumab (ACTEMRA®). In some cases, the subject has a cytokine release syndrome (CRS) event (e.g., has a CRS event after treatment with a bispecific antibody, e.g., has a CRS event after C1D1, C1D2, C1D3, C2D1 of the bispecific antibody, or after an additional dose), and the method further includes treating the symptoms of the CRS event while withholding treatment with the bispecific antibody (e.g., treating the CRS event by administering an effective amount of tocilizumab to the subject). In some embodiments, tocilizumab is administered intravenously as a single dose of about 8 mg / kg to the subject. In some embodiments, the CRS event does not resolve or worsens within 24 hours after treating the symptoms of the CRS event, and the method further includes administering to the subject one or more additional doses of tocilizumab to manage the CRS event, e.g., intravenously administering one or more additional doses of tocilizumab to the subject at a dose of about 8 mg / kg.

[0325] In some embodiments, treating the symptoms of the CRS event further includes treatment with high-dose vasopressors (e.g., norepinephrine, dopamine, phenylephrine, epinephrine, or vasopressin and norepinephrine), as described, for example, in Tables 2A, 2B, and 8.

[0326] In other cases, tocilizumab is administered as a premedication, e.g., administered to the subject prior to administration of the bispecific anti-FcRH5 / anti-CD3 antibody. In some cases, tocilizumab is administered as a premedication in Cycle 1, e.g., prior to the first dose (C1D1) of the bispecific antibody, the second dose (C1D2) of the bispecific antibody, and / or the third dose (C1D3) of the bispecific anti-FcRH5 / anti-CD3 antibody. In some embodiments, tocilizumab is administered intravenously as a single dose of about 8 mg / kg to the subject.

[0327] v. Symptoms and Grading of CRS CRS can be graded according to the Modified Cytokine Release Syndrome Grading System established by Lee et al., Blood, 124:188 - 195, 2014, Biol Blood Marrow Transplant, 25(4):625 - 638, 2019, as described in Table 2A. In addition to the diagnostic criteria, recommendations for the management of CRS based on its severity, including early intervention with corticosteroids and / or anti - cytokine therapy, are provided and referenced in Tables 2A and 2B.

Table 2A

Table 2B

[0328] Mild to moderate symptoms of CRS and / or infusion - related reactions (IRR) can include symptoms such as fever, headache, and myalgia, and can be treated symptomatically with analgesics, antipyretics, and antihistamines as shown. Severe or life - threatening symptoms of CRS and / or IRR, such as hypotension, tachycardia, dyspnea or chest discomfort, should be actively treated with supportive and resuscitative therapies as shown, including the use of high - dose corticosteroids, IV fluids, admission to the intensive care unit, and other supportive therapies. Severe CRS can be associated with other clinical sequelae such as disseminated intravascular coagulation syndrome, capillary leak syndrome, or macrophage activation syndrome (MAS). The standard of care for severe or life - threatening CRS resulting from immune - based therapies has not been established; case reports and recommendations using anti - cytokine therapies such as tocilizumab have been published (Teachey et al., Blood, 121:5154 - 5157, 2013; Lee et al., Blood, 124:188 - 195, 2014; Maude et al., New Engl J Med, 371:1507 - 1517, 2014).

[0329] As shown in Table 2A, even moderate symptoms of CRS in subjects with a wide range of comorbidities should be closely monitored considering hospitalization in the intensive care unit and administration of tocilizumab.

[0330] vi. Administration of tocilizumab as a premedication In some embodiments, an effective amount of an interleukin-6 receptor (IL-6R) antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) is administered as a premedication (prophylaxis), e.g., to a subject prior to administration of a bispecific antibody (e.g., administered about 2 hours prior to administration of the bispecific antibody). Administration of tocilizumab as a premedication can reduce the frequency or severity of CRS. In some embodiments, tocilizumab is administered as a premedication in Cycle 1, e.g., prior to the first dose (C1D1; Cycle 1, Dose 1), the second dose (C1D2; Cycle 1, Dose 2), and / or the third dose (C1D3; Cycle 1, Dose 3) of the bispecific antibody. In some embodiments, tocilizumab is administered intravenously as a single dose of about 1 mg / kg to about 15 mg / kg, e.g., about 4 mg / kg to about 10 mg / kg, e.g., about 6 mg / kg to about 10 mg / kg, e.g., about 8 mg / kg, to a subject. In some embodiments, tocilizumab is administered intravenously as a single dose of about 8 mg / kg to a subject. In some embodiments, tocilizumab is administered intravenously to a subject as a single dose of about 8 mg / kg (maximum 800 mg) for patients weighing 30 kg or more, and as a dose of about 12 mg / kg for patients weighing less than 30 kg. Other anti-IL-6R antibodies that can be used in combination with tocilizumab include sarilumab, balilimumab (ALX-0061), SA-237, and variants thereof.

[0331] For example, in one aspect, the bispecific antibody is co-administered with tocilizumab (ACTEMRA® / ROACTEMRA®), and the subject is first administered tocilizumab (ACTEMRA® / ROACTEMRA®), and then the bispecific antibody is administered separately (e.g., the subject is pre-treated with tocilizumab (ACTEMRA® / ROACTEMRA®)).

[0332] In some aspects, the incidence of CRS (e.g., grade 1 CRS, grade 2 CRS, and / or grade 3+ CRS) is reduced in patients pre-treated with tocilizumab compared to patients not pre-treated with tocilizumab. In some aspects, compared to patients not pre-treated with tocilizumab, patients pre-treated with tocilizumab require fewer interventions to treat CRS (e.g., less need for additional tocilizumab, IV fluids, steroids, or O2). In some aspects, the CRS symptoms are less severe in patients pre-treated with tocilizumab compared to patients not pre-treated with tocilizumab (e.g., limited to fever and rigors).

[0333] vii. Tocilizumab administered to treat CRS In some aspects, the subject experiences a CRS event during treatment with the therapeutic bispecific antibody, and an effective amount of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) is administered to manage the CRS event.

[0334] In some aspects, the subject has a CRS event (e.g., has a CRS event after treatment with the bispecific antibody, e.g., has a CRS event after the first dose or a subsequent dose of the bispecific antibody), and the method further comprises treating the symptoms of the CRS event while interrupting treatment with the bispecific antibody.

[0335] In some embodiments, the subject experiences a CRS event, and the method further comprises administering to the subject an effective amount of an interleukin-6 receptor (IL-6R) antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to manage the CRS event while withholding treatment with the bispecific antibody. In some embodiments, the IL-6R antagonist (e.g., tocilizumab) is administered intravenously to the subject as a single dose of about 1 mg / kg to about 15 mg / kg, e.g., about 4 mg / kg to about 10 mg / kg, e.g., about 6 mg / kg to about 10 mg / kg, e.g., about 8 mg / kg. In some embodiments, tocilizumab is administered intravenously to the subject as a single dose of about 8 mg / kg. Other anti-IL-6R antibodies that can be used in combination with tocilizumab include sarilumab, balilixizumab (ALX-0061), SA-237, and variants thereof.

[0336] In some embodiments, the CRS event does not resolve or worsens within 24 hours after treating the symptoms of the CRS event, and the method further comprises administering to the subject one or more additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab) to manage the CRS event, e.g., administering one or more additional doses of tocilizumab intravenously to the subject at a dose of about 1 mg / kg to about 15 mg / kg, e.g., about 4 mg / kg to about 10 mg / kg, e.g., about 6 mg / kg to about 10 mg / kg, e.g., about 8 mg / kg. In some embodiments, one or more additional doses of tocilizumab are administered intravenously to the subject as a single dose of about 8 mg / kg.

[0337] In some embodiments, the method further comprises administering to the subject an effective amount of a corticosteroid. The corticosteroid can be administered intravenously to the subject. In some embodiments, the corticosteroid is methylprednisolone. In some cases, methylprednisolone is administered as a single dose of about 1 mg / kg per day to about 5 mg / kg per day, for example, about 2 mg / kg per day. In some cases, the corticosteroid is dexamethasone. In some cases, dexamethasone is administered at a dose of about 10 mg (e.g., a single intravenous dose of about 10 mg) or at a dose of about 0.5 mg / kg / day.

[0338] If CRS events are not managed by administration of an IL-6R antagonist (e.g., tocilizumab) alone, corticosteroids, such as methylprednisolone or dexamethasone, can be administered to the subject. In some embodiments, treating the symptoms of a CRS event further comprises treating with a high-dose vasopressor (e.g., norepinephrine, dopamine, phenylephrine, epinephrine, or vasopressin and norepinephrine), as described, for example, in Tables 2A, 2B, and 7. Tables 3A and 2A provide details regarding tocilizumab treatment of severe or life-threatening CRS.

[0339] viii. Management of CRS events by grade Management of CRS events can be tailored based on the grade of CRS (Tables 2A and 3A) and the presence of co-existing diseases. Table 3A provides recommendations for the management of CRS syndromes by grade. Table 3B provides recommendations for the management of IRR syndromes by grade. [Table 3A] TIFF2025523020000005.tif252170TIFF2025523020000006.tif242170 [Table 3B]

[0340] ix. Management of Grade 2 CRS Events If the subject has a Grade 2 CRS event (e.g., a Grade 2 CRS event in the absence or minimal presence of co - morbidities) after administration of a therapeutic bispecific antibody, the method may further comprise treating the symptoms of the Grade 2 CRS event while withholding treatment with the bispecific antibody. If, for at least 3 consecutive days, the Grade 2 CRS event resolves to a Grade ≤ 1 CRS event, the method can further comprise restarting treatment with the bispecific antibody without changing the dose. On the other hand, if the Grade 2 CRS event does not resolve within 24 hours after treating the symptoms of the Grade 2 CRS event or does not deteriorate to a Grade ≥ 3 event, the method can further comprise administering to the subject an effective amount of an interleukin - 6 receptor (IL - 6R) antagonist (e.g., an anti - IL - 6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to manage the Grade 2 or Grade ≥ 3 CRS event. In some cases, tocilizumab is administered intravenously as a single dose of about 8 mg / kg to the subject. Other anti - IL - 6R antibodies that can be used in combination with tocilizumab include sarilumab, baricitinib (ALX - 0061), SA - 237, and variants thereof.

[0341] If the subject has a Grade 2 CRS event in the presence of a wide range of complications after administration of a therapeutic bispecific antibody, the method can further comprise administering a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to the subject and managing the Grade 2 CRS event while withholding treatment with the bispecific antibody. In some cases, the first dose of tocilizumab is administered intravenously to the subject at a dose of about 8 mg / kg. Other anti-IL-6R antibodies that can be used in combination with tocilizumab include sarilumab, bovalizumab (ALX-0061), SA-237, and variants thereof. In some cases, if the Grade 2 CRS event resolves to a Grade ≤ 1 CRS event within two weeks, the method further comprises restarting treatment with the bispecific antibody at a reduced dose. In some cases, if the event occurs during or within 24 hours of the infusion, the reduced dose is 50% of the initial infusion rate of the previous cycle. On the other hand, if the Grade 2 CRS event does not resolve within 24 hours of treating the symptoms of the Grade 2 CRS event or does not deteriorate to a Grade ≥ 3 CRS event, the method can further comprise administering one or more (e.g., 1, 2, 3, 4, or 5 or more) additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab) to the subject to manage the Grade 2, or Grade ≥ 3 CRS event. In some specific examples, since the Grade 2 CRS event does not resolve within 24 hours of treating the symptoms of the Grade 2 CRS event or does not deteriorate to a Grade ≥ 3 CRS event, the method can further comprise administering one or more additional doses of tocilizumab to the subject to manage the Grade 2, or Grade ≥ 3 CRS event. In some cases, the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 1 mg / kg to about 15 mg / kg, e.g., about 4 mg / kg to about 10 mg / kg, e.g., about 6 mg / kg to about 10 mg / kg, e.g., about 8 mg / kg. In some cases, the method further comprises administering an effective amount of corticosteroid to the subject.Corticosteroids can be administered before, after, or concomitantly with one or more additional doses of tocilizumab or other anti-IL-6R antibodies. In some cases, corticosteroids are administered intravenously to the subject. In some cases, the corticosteroid is methylprednisolone. In some cases, methylprednisolone is administered as a single dose of from about 1 mg / kg per day to about 5 mg / kg per day, for example, about 2 mg / kg per day. In some cases, the corticosteroid is dexamethasone. In some cases, dexamethasone is administered at a dose of about 10 mg (for example, a single intravenous dose of about 10 mg) or at a dose of about 0.5 mg / kg / day.

[0342] x. Management of Grade 3 CRS Events If a subject has a grade 3 CRS event after administration of a therapeutic bispecific antibody, the method can further include administering a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to the subject and managing the grade 3 CRS event while withholding treatment with the bispecific antibody. In some cases, the first dose of tocilizumab is administered intravenously to the subject at a dose of about 8 mg / kg. Other anti-IL-6R antibodies that can be used in combination with tocilizumab include sarilumab, bobaliizumab (ALX-0061), SA-237, and variants thereof. In some cases, the subject recovers within 8 hours after treatment with the bispecific antibody (e.g., no fever, no pressor), and the method further includes restarting treatment with the bispecific antibody at a reduced dose. In some cases, if the event occurs during or within 24 hours of infusion, the reduced dose is 50% of the initial infusion rate of the previous cycle. In other cases, if the grade 3 CRS event does not resolve within 24 hours after treating the symptoms of the grade 3 CRS event or does not worsen to a grade 4 CRS event, the method can further include administering one or more (e.g., 1, 2, 3, 4, or 5 or more) additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab) to the subject to manage the grade 3 or grade 4 CRS event. In some specific examples, since the grade 3 CRS event does not resolve within 24 hours after treating the symptoms of the grade 3 CRS event or does not worsen to a grade 4 CRS event, the method further includes administering one or more additional doses of tocilizumab to the subject to manage the grade 3 or grade 4 CRS event. In some cases, the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 1 mg / kg to about 15 mg / kg, such as about 4 mg / kg to about 10 mg / kg, such as about 6 mg / kg to about 10 mg / kg, such as about 8 mg / kg. In some cases, the method further includes administering an effective amount of corticosteroid to the subject.Corticosteroids can be administered before, after, or simultaneously with one or more additional doses of tocilizumab or other anti-IL-6R antibodies. In some cases, corticosteroids are administered intravenously to the subject. In some cases, the corticosteroid is methylprednisolone. In some cases, methylprednisolone is administered as a single dose of from about 1 mg / kg per day to about 5 mg / kg per day, for example, about 2 mg / kg per day. In some cases, the corticosteroid is dexamethasone. In some cases, dexamethasone is administered at a dose of about 10 mg (for example, a single intravenous dose of about 10 mg) or at a dose of about 0.5 mg / kg / day.

[0343] xi. Management of Grade 4 CRS events If a subject has a grade 4 CRS event after administration of a therapeutic bispecific antibody, the method can further include administering a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to the subject to manage the grade 4 CRS event and to continuously discontinue treatment with the bispecific antibody. In some cases, the first dose of tocilizumab is administered intravenously to the subject at a dose of about 8 mg / kg. Other anti-IL-6R antibodies that can be used in combination with tocilizumab include sarilumab, bovalizumab (ALX-0061), SA-237, and variants thereof. The grade 4 CRS event can, in some cases, resolve within 24 hours after treating the symptoms of the grade 4 CRS event. If the grade 4 CRS event does not resolve within 24 hours after treating the symptoms of this grade 4 CRS event, the method can further include administering one or more additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to the subject to manage the grade 4 CRS event. In some specific examples, the grade 4 CRS event does not resolve within 24 hours after treating the symptoms of the grade 4 CRS event, and the method further includes administering one or more (e.g., 1, 2, 3, 4, or 5 or more) additional doses of tocilizumab to the subject to manage the grade 4 CRS event. In some cases, the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 1 mg / kg to about 15 mg / kg, such as about 4 mg / kg to about 10 mg / kg, such as about 6 mg / kg to about 10 mg / kg, such as about 8 mg / kg. In some cases, the method further includes administering an effective amount of a corticosteroid to the subject. The corticosteroid can be administered before, after, or simultaneously with one or more additional doses of tocilizumab or another anti-IL-6R antibody. In some cases, the corticosteroid is administered intravenously to the subject. In some cases, the corticosteroid is methylprednisolone.In some cases, methylprednisolone is administered at a single dose of about 1 mg / kg per day to about 5 mg / kg per day, for example, about 2 mg / kg per day. In some cases, the corticosteroid is dexamethasone. In some cases, dexamethasone is administered at a dose of about 10 mg (e.g., a single intravenous dose of about 10 mg) or at a dose of about 0.5 mg / kg / day.

[0344] xii. Acetaminophen or paracetamol In another example, the additional therapeutic agent is an effective amount of acetaminophen or paracetamol. Acetaminophen or paracetamol may be administered orally to the subject, for example, at a dose of about 500 mg to about 1000 mg. In some embodiments, acetaminophen or paracetamol is administered to the subject as a premedication, for example, prior to administration of the bispecific anti-FcRH5 / anti-CD3 antibody.

[0345] xiii. Diphenhydramine In another example, the additional therapeutic agent is an effective amount of diphenhydramine. Diphenhydramine may be administered orally to the subject, for example, at a dose of about 25 mg to about 50 mg. In some embodiments, diphenhydramine is administered to the subject as a premedication, for example, prior to administration of the bispecific anti-FcRH5 / anti-CD3 antibody.

[0346] xiv. Anti-myeloma agent In another example, the additional therapeutic agent is an effective amount of an anti-myeloma agent, for example, an anti-myeloma agent that enhances and / or complements T cell-mediated killing of myeloma cells. The anti-myeloma agent can be, for example, pomalidomide, daratumumab, and / or B cell maturation antigen (BCMA)-directed therapy (e.g., an antibody-drug conjugate (BCMA-ADC) that targets BCMA). In some embodiments, the anti-myeloma agent is administered in 4-week cycles.

[0347] xv. Pretreatment with corticosteroids, acetaminophen or paracetamol, and / or diphenhydramine Any of the methods or procedures disclosed herein may include pretreatment with corticosteroids prior to administration of the bispecific antibody to a subject.

[0348] Any of the methods or procedures disclosed herein may include pretreatment with acetaminophen or paracetamol prior to administration of the bispecific antibody to a subject.

[0349] Any of the methods or procedures disclosed herein may include pretreatment with diphenhydramine prior to administration of the bispecific antibody to a subject.

[0350] For example, any of the methods or procedures disclosed herein may include pretreatment with the following agents prior to administration of the bispecific antibody to a subject: (i) corticosteroids; (ii) acetaminophen or paracetamol; and / or (iii) diphenhydramine.

[0351] In some examples, the treatment method includes a first phase, and the corticosteroid is administered to the subject 1 hour (±15 minutes) before any administration of the bispecific antibody during the first phase.

[0352] In some examples, the treatment method includes a first phase, and the corticosteroid is administered to the subject 24 hours before any administration of the bispecific antibody during the first phase.

[0353] In some examples, the treatment method includes a second phase, the subject has experienced CRS due to prior administration of the bispecific, and the corticosteroid is administered to the subject 1 hour (±15 minutes) before any administration of the bispecific antibody during the second phase.

[0354] Any suitable corticosteroid may be used. In some examples, the corticosteroid is dexamethasone or methylprednisolone. In some examples, the corticosteroid is dexamethasone. In some examples, dexamethasone is administered to the subject at a dose of about 20 mg. In some examples, the corticosteroid is methylprednisolone. In some examples, methylprednisolone is administered to the subject at a dose of about 80 mg.

[0355] The corticosteroid may be administered by any suitable route. In some examples, the corticosteroid is administered intravenously to the subject.

[0356] In some examples, acetaminophen or paracetamol is administered to the subject at a dose of 500 mg to 1000 mg. In some examples, acetaminophen or paracetamol is administered orally to the subject.

[0357] In some examples, diphenhydramine is administered to the subject at a dose of 25 mg to 50 mg. In some examples, diphenhydramine is administered orally to the subject.

[0358] xvi. Other combination therapies In some embodiments, one or more additional therapeutic agents include a PD-1 axis-binding antagonist, an immunomodulator, an anti-tumor agent, a chemotherapeutic agent, a growth inhibitor, an anti-angiogenic agent, radiation therapy, a cytotoxic agent, a cell-based therapy, or a combination thereof.

[0359] xvii. PD-1 axis-binding antagonist In some embodiments, the additional therapeutic agent is a PD-1 axis-binding antagonist. The PD-1 axis-binding antagonist may include a PD-L1-binding antagonist, a PD-1-binding antagonist, and a PD-L2-binding antagonist. Any suitable PD-1 axis-binding antagonist may be used.

[0360] In some cases, a PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners. In other cases, a PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1. In still other cases, a PD-L1 binding antagonist inhibits the binding of PD-L1 to B7-1. In some cases, a PD-L1 binding antagonist inhibits the binding of PD-L1 to both PD-1 and B7-1. A PD-L1 binding antagonist may be, but is not limited to, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule. In some cases, a PD-L1 binding antagonist is a small molecule that inhibits PD-L1 (e.g., GS-4224, INCB086550, MAX-10181, INCB090244, CA-170, or ABSK041). In some cases, a PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and VISTA. In some cases, a PD-L1 binding antagonist is CA-170 (also known as AUPM-170). In some cases, a PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and TIM3. In some cases, the small molecule is a compound described in International Publication No. WO 2015 / 033301 and / or WO 2015 / 033299.

[0361] In some cases, the PD-L1 binding antagonist is an anti-PD-L1 antibody. A variety of anti-PD-L1 antibodies are contemplated and described herein. In any of the cases herein, the isolated anti-PD-L1 antibody can bind to human PD-L1, such as human PD-L1 as shown in UniProtKB / Swiss-Prot accession number Q9NZQ7-1, or a variant thereof. In some cases, the anti-PD-L1 antibody can inhibit the binding between PD-L1 and PD-1 and / or between PD-L1 and B7-1. In some cases, the anti-PD-L1 antibody is a monoclonal antibody. In some cases, the anti-PD-L1 antibody is an antibody fragment selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some cases, the anti-PD-L1 antibody is a humanized antibody. In some cases, the anti-PD-L1 antibody is a human antibody. Exemplary anti-PD-L1 antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001, enoblituzumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosibelimab, rodapolimab, 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 cases, the anti-PD-L1 antibody is atezolizumab. Examples of anti-PD-L1 antibodies useful in the methods of the invention and methods of making them are described in International Patent Application Publication No. 2010 / 077634 and U.S. Patent No. 8,217,149, each of which is incorporated herein by reference in its entirety.

[0362] In some cases, the anti-PD-L1 antibody is avelumab (CAS Registry Number: 1537032-82-8). Avelumab, also known as MSB0010718C, is a human monoclonal IgG1 anti-PD-L1 antibody (Merck KGaA, Pfizer).

[0363] In some cases, the anti-PD-L1 antibody is durvalumab (CAS Registry Number: 1428935-60-7). Durvalumab, also known as MEDI4736, is an Fc-optimized human monoclonal IgG1 kappa anti-PD-L1 antibody described in International Publication No. WO 2011 / 066389 and U.S. Patent Application Publication No. 2013 / 034559 (MedImmune, AstraZeneca).

[0364] In some cases, the anti-PD-L1 antibody is MDX-1105 (Bristol Myers Squibb). MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO2007 / 005874.

[0365] In some cases, the anti-PD-L1 antibody is LY3300054 (Eli Lilly).

[0366] In some cases, the anti-PD-L11 antibody is STI-A1014 (Sorrento). STI-A1014 is a human anti-PD-L11 antibody.

[0367] In some cases, the anti-PD-L11 antibody is KN035 (Suzhou Alphamab). KN035 is a single-domain antibody (dAB) generated from a camelid phage display library.

[0368] In some cases, the anti-PD-L1 antibody is composed of a cleavable site or linker that, when cleaved (e.g., by proteases in the tumor microenvironment), activates the antibody-antigen binding domain to enable binding to its antigen, e.g., by removing a non-binding steric site. In some cases, the anti-PD-L1 antibody is CX-072 (CytomX Therapeutics).

[0369] In some cases, the anti-PD-L1 antibody comprises six HVR sequences (e.g., three heavy chain HVRs and three light chain HVRs), and / or the heavy chain variable domain and the light chain variable domain from an anti-PD-L1 antibody described in U.S. Patent Application Publication No. 20160108123, International Publication No. 2016 / 000619, International Publication No. 2012 / 145493, U.S. Patent No. 9,205,148, International Publication No. 2013 / 181634, or International Publication No. 2016 / 061142.

[0370] In some cases, the PD-1 axis binding antagonist is a PD-1 binding antagonist. For example, in some cases, the PD-1 binding antagonist inhibits the binding of PD-1 to one or more of its ligand binding partners. In some cases, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1. In other cases, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L2. In still other cases, the PD-1 binding antagonist inhibits the binding of PD-1 to both PD-L1 and PD-L2. The PD-1 binding antagonist may be, but is not limited to, an antibody, its antigen-binding fragment, an immunoadhesin, a fusion protein, an oligopeptide or a small molecule. In some cases, the PD-1 binding antagonist is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., the Fc region of an immunoglobulin sequence)). For example, in some cases, the PD-1 binding antagonist is an Fc fusion protein. In some cases, the PD-1 binding antagonist is AMP-224. AMP-224, also known as B7-DCIg, is a PD-L2-Fc fusion soluble receptor described in WO 2010 / 027827 and WO 2011 / 066342. In some cases, the PD-1 binding antagonist is a peptide or a small molecule compound. In some cases, the PD-1 binding antagonist is AUNP-12 (Pierre Fabre / Aurigene). See, for example, WO 2012 / 168944, WO 2015 / 036927, WO 2015 / 044900, WO 2015 / 033303, WO 2013 / 144704, WO 2013 / 132317, and WO 2011 / 161699. In some cases, the PD-1 binding antagonist is a small molecule that inhibits PD-1.

[0371] In some cases, the PD-1 binding antagonist is an anti-PD-1 antibody. Various anti-PD-1 antibodies can be utilized in the methods and uses disclosed herein. In any of the examples herein, the PD-1 antibody can bind to human PD-1 or a variant thereof. In some cases, the anti-PD-1 antibody is a monoclonal antibody. In some cases, the anti-PD-1 antibody is an antibody fragment selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some cases, the anti-PD-1 antibody is a humanized antibody. In other cases, the anti-PD-1 antibody is a human antibody. Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (semiplimab), BGB-108, prorolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanelimab, pemprilimab, CS1003, HLX10, SCT-I10A, zinberelimab, balsilimab, genolimzumab, BI 754091, cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, and hAb21.

[0372] In some cases, the anti-PD-1 antibody is nivolumab (CAS Registry Number: 946414-94-4). Nivolumab (Bristol-Myers Squibb / Ono), also known as MDX-1106-04, MDX-1106, ONO-4538, BMS-936558, and OPDIVO® is an anti-PD-1 antibody described in International Publication No. WO 2006 / 121168.

[0373] In some cases, the anti-PD-1 antibody is pembrolizumab (CAS Registry Number: 1374853-91-4). Pembrolizumab (Merck) is also known as MK-3475, Merck 3475, lambrolizumab, KEYTRUDA®, and SCH-900475, and is the anti-PD-1 antibody described in International Publication No. WO 2009 / 114335.

[0374] In some cases, the anti-PD-1 antibody is MEDI-0680 (AMP-514; AstraZeneca). MEDI-0680 is a humanized IgG4 anti-PD-1 antibody.

[0375] In some cases, the anti-PD-1 antibody is PDR001 (CAS Registry Number 1859072-53-9; Novartis). PDR001 is a humanized IgG4 anti-PD-1 antibody that blocks the binding of PD-L1 and PD-L2 to PD-1.

[0376] In some cases, the anti-PD-1 antibody is REGN2810 (Regeneron). REGN2810 is a human anti-PD-1 antibody.

[0377] In some cases, the anti-PD-1 antibody is BGB-108 (BeiGene).

[0378] In some cases, the anti-PD-1 antibody is BGB-A317 (BeiGene).

[0379] In some cases, the anti-PD-1 antibody is JS-001 (Shanghai Junshi). JS-001 is a humanized anti-PD-1 antibody.

[0380] In some cases, the anti-PD-1 antibody is STI-A1110 (Sorrento). STI-A1110 is a human anti-PD-1 antibody.

[0381] In some cases, the anti-PD-1 antibody is INCSHR-1210 (Incyte). INCSHR-1210 is a human IgG4 anti-PD-1 antibody.

[0382] In some cases, the anti-PD-1 antibody is PF-06801591 (Pfizer).

[0383] In some cases, the anti-PD-1 antibody is TSR-042 (also known as ANB011; Tesaro / AnaptysBio).

[0384] In some cases, the anti-PD-1 antibody is AM0001 (ARMO Biosciences).

[0385] In some cases, the anti-PD-1 antibody is ENUM244C8 (Enumeral Biomedical Holdings). ENUM 244C8 is an anti-PD-1 antibody that inhibits PD-1 function without blocking the binding of PD-L1 to PD-1.

[0386] In some cases, the anti-PD-1 antibody is ENUM 388D4 (Enumeral Biomedical Holdings). ENUM 388D4 is an anti-PD-1 antibody that competitively inhibits the binding of PD-L1 to PD-1.

[0387] In some cases, the anti-PD-1 antibody comprises six HVR sequences (e.g., three heavy-chain HVRs and three light-chain HVRs) and / or the heavy-chain variable domain and the light-chain variable domain derived from an anti-PD-1 antibody described in WO 2015 / 112800, WO 2015 / 112805, WO 2015 / 112900, US 20150210769, WO 2016 / 089873, WO 2015 / 035606, WO 2015 / 085847, WO 2014 / 206107, WO 2012 / 145493, US 9,205,148, WO 2015 / 119930, WO 2015 / 119923, WO 2016 / 032927, WO 2014 / 179664, WO 2016 / 106160, and WO 2014 / 194302.

[0388] In some cases, the PD-1 axis-binding antagonist is a PD-L2-binding antagonist. In some cases, the PD-L2-binding antagonist is a molecule that inhibits the binding of PD-L2 to its ligand-binding partner. In certain embodiments, the PD-L2-binding ligand partner is PD-1. The PD-L2-binding antagonist may be, but is not limited to, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule.

[0389] In some cases, the PD-L2 binding antagonist is an anti-PD-L2 antibody. In any of the examples herein, the anti-PD-L2 antibody can bind to human PD-L2 or a variant thereof. In some cases, the anti-PD-L2 antibody is a monoclonal antibody. In some cases, the anti-PD-L2 antibody is an antibody fragment selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some cases, the anti-PD-L2 antibody is a humanized antibody. In other cases, the anti-PD-L2 antibody is a human antibody. In yet further specific embodiments, the anti-PD-L2 antibody has reduced or minimal effector function. In yet further specific embodiments, the minimal effector function is due to a "Fc mutation without effector" or a glycosylation mutation. In yet further cases, the Fc mutation without effector is an N297A or D265A / N297A substitution within the constant region. In some cases, the isolated anti-PD-L2 antibody is glycosylated.

[0390] xviii. Growth inhibitor In some embodiments, the additional therapeutic agent is a growth inhibitor. Exemplary growth inhibitors include agents that inhibit the progression of the cell cycle outside of the S phase, such as agents that induce G1 arrest (e.g., DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, or araC), or M phase arrest agents (e.g., vincristine, vinblastine, taxanes (e.g., paclitaxel and docetaxel), doxorubicin, epirubicin, daunorubicin, etoposide, or bleomycin).

[0391] xix. Radiation therapy In some embodiments, the additional therapeutic agent is radiation therapy. Radiation therapy involves using directed gamma or beta rays to induce sufficient damage to cells to limit their ability to function properly or to completely destroy the cells. A typical treatment is given as a single dose, and a typical dosage ranges from 10 to 200 units (gray) per day.

[0392] xx. Cytotoxic agents In some embodiments, the additional therapeutic agent is a cytotoxic agent, e.g., a substance that inhibits or prevents cell function and / or a substance that causes cell death or cell 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 radioisotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitors; enzymes and fragments thereof, e.g., nucleolytic enzymes; antibiotics; toxins such as low molecular weight toxins or enzymatically active toxins derived from bacteria, fungi, plants or animals (including fragments and / or variants thereof); and antitumor or anticancer agents.

[0393] xxi. Anticancer therapy In some cases, the method includes administering an anticancer therapy to the individual, in addition to or instead of the bispecific anti-FcRH5 / anti-CD3 antibody (e.g., antineoplastic agents, chemotherapeutic agents, growth inhibitors, anti-angiogenic agents, radiation therapy, or cytotoxic agents).

[0394] In some cases, the method further comprises administering to the patient an effective amount of an additional therapeutic agent. In some cases, the additional therapeutic agent is selected from the group consisting of anti-neoplastic agents, chemotherapeutic agents, growth inhibitors, anti-angiogenic agents, radiation therapy, cytotoxic agents, and combinations thereof. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with chemotherapy or a chemotherapeutic agent. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with a radiation therapy agent. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with a targeted therapy or a targeted therapeutic agent. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with immunotherapy or an immunotherapeutic agent, such as a monoclonal antibody. In some cases, the additional therapeutic agent is an agonist directed against a co-stimulatory molecule. In some cases, the additional therapeutic agent is an antagonist directed against a co-inhibitory molecule.

[0395] Although not wishing to be bound by theory, it is thought that enhancing T cell stimulation by promoting co-stimulatory molecules or inhibiting co-inhibitory molecules may promote tumor cell death and thereby treat or delay cancer progression. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an agonist directed against a co-stimulatory molecule. In some cases, the co-stimulatory molecules that are activated may include CD40, CD226, CD28, OX40, GITR, CD137, CD27, HVEM, or CD127. In some cases, the agonist for the co-stimulatory molecule is an agonist antibody that binds to CD40, CD226, CD28, OX40, GITR, CD137, CD27, HVEM, or CD127. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an antagonist directed against a co-inhibitory molecule. In some cases, the co-inhibitory molecules may include CTLA-4 (also known as CD152), TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO, TIGIT, MICA / B, or arginase. In some cases, the antagonist for the co-inhibitory molecule is an antagonist antibody that binds to CTLA-4, TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO, TIGIT, MICA / B, or arginase.

[0396] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody can be administered in combination with an antagonist directed against CTLA-4 (also known as CD152), e.g., a blocking antibody. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with ipilimumab (also known as MDX-010, MDX-101, or YERVOY®). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with tremelimumab (also known as ticilimumab or CP-675,206). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody can be administered in combination with an antagonist directed against B7-H3 (also known as CD276), e.g., a blocking antibody. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with MGA271. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody can be administered in combination with an antagonist directed against TGF-beta, e.g., metelimumab (also known as CAT-192), fresolimumab (also known as GC1008), or LY2157299.

[0397] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with a treatment that includes adoptive transfer of T cells expressing a chimeric antigen receptor (CAR), e.g., cytotoxic T cells or CTLs. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with a treatment that includes adoptive transfer of T cells that include a dominant negative TGF beta receptor, e.g., a dominant negative TGF beta type II receptor. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with a treatment that includes the HERCREEM protocol (see, e.g., ClinicalTrials.gov Identifier NCT00889954).

[0398] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an agonist directed against CD137 (also known as TNFRSF9, 4-1BB, or ILA), such as an activating antibody. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with urelumab (also known as BMS-663513). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an agonist directed against CD40, such as an activating antibody. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with CP-870893. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an agonist directed against OX40 (also known as CD134), such as an activating antibody. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an anti-OX40 antibody (e.g., AgonOX). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an agonist directed against CD27, such as an activating antibody. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with CDX-1127. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an antagonist against indoleamine-2,3-dioxygenase (IDO). In some cases, the IDO antagonist is 1-methyl-D-tryptophan (also known as 1-D-MT).

[0399] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an antibody-drug conjugate. In some cases, the antibody-drug conjugate comprises mertansine or monomethyl auristatin E (MMAE). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an anti-NaPi2b antibody-MMAE conjugate (also known as DNIB0600A or RG7599). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with trastuzumab emtansine (T-DM1, ado-trastuzumab emtansine, or KADCYLA®, also known as Genentech). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with DMUC5754A. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an antibody-drug conjugate that targets the endothelin B receptor (EDNBR), for example, an antibody directed against EDNBR conjugated to MMAE.

[0400] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an anti-angiogenic agent. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an antibody against VEGF, for example VEGF-A. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with bevacizumab (AVASTIN®, also known as Genentech). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an antibody against angiopoietin 2 (also known as Ang2). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with MEDI3617.

[0401] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an anti-neoplastic agent. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an agent that targets CSF-1R (also known as M-CSFR or CD115). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with anti-CSF-1R (also known as IMC-CS4). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an interferon, such as interferon alpha or interferon gamma. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with Roferon-A (also known as recombinant interferon alpha-2a). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with GM-CSF (also known as recombinant human granulocyte macrophage colony-stimulating factor, rhu GM-CSF, sargramostim, or LEUKINE®). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with IL-2 (also known as aldesleukin or PROLEUKIN®). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with IL-12. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an antibody that targets CD20. In some cases, the antibody that targets CD20 is obinutuzumab (also known as GA101 or GAZYVA®) or rituximab. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an antibody that targets GITR. In some cases, the antibody that targets GITR is TRX518.

[0402] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with a cancer vaccine. In some cases, the cancer vaccine is a peptide cancer vaccine, and in some cases, an individualized peptide vaccine. In some cases, the cancer peptide vaccine is a multivalent long peptide, a multipeptide, a peptide cocktail, a hybrid peptide, or a peptide-pulsed dendritic cell vaccine (see, e.g., Yamada et al., Cancer Sci. 104:14-21, 2013). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an adjuvant. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with a treatment comprising a TLR agonist, such as Poly-ICLC (also known as HILTONOL®), LPS, MPL, or CpG ODN. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with tumor necrosis factor (TNF) alpha. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with IL-1. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with HMGB1. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an IL-10 antagonist. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an IL-4 antagonist. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an IL-13 antagonist. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an HVEM antagonist. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an ICOS agonist, such as by administration of ICOS-L, or in combination with an agonist antibody directed against ICOS. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with a treatment that targets CX3CL1. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with a treatment that targets CXCL9.In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with a treatment that targets CXCL10. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with a treatment that targets CCL5. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an LFA-1 or ICAM1 agonist. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with a selectin agonist.

[0403] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with a targeted therapy. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an inhibitor of B-Raf. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with vemurafenib (also known as ZELBORAF®). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with dabrafenib (also known as TAFINLAR®). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with erlotinib (known as TARCEVA®). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an inhibitor of MEK, such as MEK1 (also known as MAP2K1) or MEK2 (also known as MAP2K2). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with cobimetinib (also known as GDC-0973 or XL-518). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with trametinib (also known as MEKINIST®). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an inhibitor of K-Ras. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an inhibitor of c-Met. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with ofatumumab (also known as MetMAb). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an inhibitor of Alk. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with AF802 (also known as CH5424802 or alectinib). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an inhibitor of phosphatidylinositol 3-kinase (PI3K). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with BKM120.In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with idelalisib (also known as GS-1101 or CAL-101). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with perifosine (also known as KRX-0401). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an inhibitor of Akt. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with MK2206. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with GSK690693. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with GDC-0941. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an inhibitor of mTOR. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with sirolimus (also known as rapamycin). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with temsirolimus (also known as CCI-779 or TORISEL®). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with everolimus (also known as RAD001). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with ridaforolimus (also known as AP-23573, MK-8669, or deforolimus). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with OSI-027. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with AZD8055. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with INK128. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with a dual PI3K / mTOR inhibitor. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with XL765. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with GDC-0980.In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with BEZ235 (also known as NVP-BEZ235). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with BGT226. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with GSK2126458. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with PF-04691502. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with PF-05212384 (also known as PKI-587).

[0404] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with a chemotherapeutic agent. A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer. Exemplary chemotherapeutic agents include erlotinib (TARCEVA®, Genentech / OSI Pharm.), antihormonal agents that act to regulate or inhibit the hormonal action on tumors such as antiestrogens and selective estrogen receptor modulators (SERMs), for example alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), or trastuzumab (HERCEPTIN®, Genentech) and other antibodies;, EGFR inhibitors (EGFR antagonists), tyrosine kinase inhibitors, but are not limited thereto, and chemotherapeutic agents also include non-steroidal anti-inflammatory drugs (NSAIDs) having analgesic, antipyretic and anti-inflammatory effects.

[0405] When the methods described herein involve combination therapies, such as the specific combination therapy described above, the combination therapy includes co - administration with one or more additional therapeutic agents of the bispecific anti - FcRH5 / anti - CD3 antibody, and such co - administration can be co - dosing (two or more therapeutic agents are included in the same formulation, or in separate formulations), or separate administrations. In this case, the administration of the bispecific anti - FcRH5 / anti - CD3 antibody can occur before, simultaneously with, and / or after the administration of the additional therapeutic agent(s). In one embodiment, the administration of the bispecific anti - FcRH5 / anti - CD3 antibody, and the administration of the additional therapeutic agent, or exposure to radiation therapy, can occur within about 1 month of each other, or within about 1 week, 2 weeks, or 3 weeks, or within about 1, 2, 3, 4, 5, or 6 days of each other.

[0406] In some aspects, the subject does not have an increased risk of CRS (e.g., has not experienced grade 3+ CRS during treatment with the bispecific antibody or CAR - T therapy; does not have detectable circulating plasma cells; and / or does not have extensive extramedullary disease).

[0407] D. Cancer Any of the methods of the invention described herein may be useful for the treatment of cancers such as B-cell proliferative disorders, including multiple myeloma (MM), which may be relapsed or refractory (R / R) MM. In some embodiments, the patient has received at least 3 prior lines of treatment for a B-cell proliferative disorder (e.g., MM), e.g., 3, 4, 5, 6 or more than 6 prior lines of treatment. In some embodiments, the patient has received at least 3 prior lines of treatment for a B-cell proliferative disorder, and the treatment is 4L+ treatment. For example, the patient may have been exposed to a proteasome inhibitor (P1), an immunomodulatory drug (IMiD), autologous stem cell transplantation (ASCT), anti-CD38 therapy (e.g., anti-CD38 antibody therapy, e.g., daratumumab therapy), CAR-T therapy, or a therapy comprising a bispecific antibody. In some cases, the patient has been exposed to all 3 of P1, IMiD and anti-CD38 therapy (i.e., triple-class refractory).Other examples of B cell proliferative disorders / malignancies that are amenable to treatment with bispecific anti-FcRH5 / anti-CD3 antibodies according to the methods described herein include non-Hodgkin lymphomas (NHL) such as diffuse large B cell lymphoma (DLBCL) which can be recurrent or refractory, and other cancers including, but not limited to, these other cancers are 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), Waldenström's macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt lymphoma (BL), B cell prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma / leukemia, unclassifiable, diffuse red pulp small B cell lymphoma, hairy cell leukemia variant, Waldenström's macroglobulinemia, heavy chain disease, alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasmacytic myeloma, solitary plasmacytoma of bone, extramedullary plasmacytoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), nodal marginal zone lymphoma, pediatric nodal marginal zone lymphoma, pediatric follicular lymphoma, primary cutaneous follicle center lymphoma, T cell / histiocyte-rich large B cell lymphoma, primary CNS DLBCL, primary cutaneous DLBCL, lower extremity type, EBV-positive DLBCL in the elderly, chronic inflammation-related DLBCL, lymphomatoid granulomatosis, mediastinal (thymic) primary B cell large cell lymphoma, intravascular large B cell lymphoma, ALK-positive large B cell lymphoma, plasmablastic lymphoma, large B cell lymphoma arising from HHV8-associated multicentric Castleman disease, primary effusion lymphoma: unclassifiable B cell lymphoma having intermediate characteristics between DLBCL and Burkitt lymphoma, and unclassifiable B cell lymphoma having intermediate characteristics between DLBCL and classical Hodgkin lymphoma, are included.Further examples of B cell proliferative disorders include, but are not limited to, multiple myeloma (MM); 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-cleaved cell NHL; large tumor lesion NHL; AIDS-related lymphoma; and acute lymphoblastic leukemia (ALL); chronic myelogenous leukemia; and post-transplant lymphoproliferative disorder (PTLD). Further examples of cancers include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and lymphoid malignancies including leukemia or B cell lymphoma. More specific examples of such cancers 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-cleaved cell NHL; large tumor lesion NHL; AIDS-related lymphoma; and acute lymphoblastic leukemia (ALL); chronic myelogenous leukemia; and post-transplant lymphoproliferative disorder (PTLD). Solid tumors that can be treated with bispecific anti-FcRH5 / anti-CD3 antibodies according to the methods described herein include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and lung cancer including squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular carcinoma, gastrointestinal cancer, and gastric cancer (gastric cancer) or stomach cancer including gastrointestinal stromal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urinary system cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial carcinoma or uterine carcinoma, salivary gland carcinoma, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer species, anal carcinoma, penile carcinoma, melanoma, superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanoma, nodular melanoma, as well as nevus syndrome, edema (such as those associated with brain tumors), Meigs syndrome, brain, as well as head and neck cancer, and abnormal blood vessel proliferation associated with related 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 lymphoma (NHL), renal cell cancer, prostate cancer, liver cancer, pancreatic cancer, soft tissue sarcoma, Kaposi sarcoma, carcinoid tumor, head and neck cancer, ovarian cancer, and mesothelioma.

[0408] E. Prior anticancer therapy In some embodiments, the subject has been previously treated for a B-cell proliferative disorder (e.g., MM). In some embodiments, the subject has received at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more treatment lines for a B-cell proliferative disorder. In some embodiments, the patient has received at least one prior treatment line for a B-cell proliferative disorder, e.g., the treatment is a 2L+, 3L+, 4L+, 5L+, 6L+, 7L+, 8L+, 9L+, 10L+, 11L+, 12L+, 13L+, 14L+, or 15L+ treatment. In some embodiments, the subject has received at least 3 prior treatment lines for a B-cell proliferative disorder (e.g., MM), e.g., the patient has received a 4L+ treatment, e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more treatment lines. In some embodiments, the subject has relapsed or refractory (R / R) multiple myeloma (MM), e.g., a patient with R / R MM who has received a 4L+ treatment for R / R MM. In some embodiments, the patient is triple-class refractory.

[0409] In some embodiments, the frontline treatment regimen includes one or more proteasome inhibitors (PIs) (e.g., bortezomib, carfilzomib or ixazomib); immunomodulatory drugs (IMiDs), such as thalidomide, lenalidomide or pomalidomide; autologous stem cell transplantation (ASCT); anti-CD38 agents, such as daratumumab (DARZALEX®) (U.S. Patent No. 7,829,673 and U.S. Patent Publication No.: 20160067205A1), "MOR202" (U.S. Patent No. 8,263,746), isatuximab (SAR-650984); CAR-T therapy; treatment involving bispecific antibodies; anti-SLAMF7 therapeutic agents (e.g., anti-SLAMF7 antibodies, such as elotuzumab); nuclear export inhibitors (e.g., selinexor); and histone deacetylase (HDAC) inhibitors (e.g., panobinostat). In some embodiments, the frontline treatment regimen includes antibody-drug conjugates (ADCs). In some embodiments, the frontline treatment regimen includes B cell maturation antigen (BCMA)-directed therapies, such as antibody-drug conjugates targeting BCMA (BCMA-ADCs). Exemplary BCMA-targeted TDB antibodies include teclistamab (JNJ-64007957), AM701, AMG 420 (BCMAxCD3 bispecific T cell engager, BiTE®, Amgen), CC-93269 (BCMAxCD3 bispecific antibody, Celgene), elranatamab (BCMAxCD3 bispecific antibody, Pfizer Inc.), TNB-383B (TeneoBio / AbbVie), linvoseltamab (REGN 5458 - BCMAxCD3 bispecific antibody, Regeneron), arclumab (CC-93269 - BMS), AFM26 (BCMAxCD16 tetravalent bispecific antibody, Affimed GmbH) and HPN217 (BCMAxALBxCD3 trispecific, Harpoon Therapeutics).

[0410] In some embodiments, the frontline treatment regimen includes all three of a proteasome inhibitor (PI), an IMiD, and an anti-CD38 agent (e.g., daratumumab). In some embodiments, the patient is refractory to the triple class.

[0411] In some embodiments, B cell proliferative disorders (e.g., MM) are refractory to treatment lines and, for example, refractory to one or more of daratumumab, PI, IMiD, ASCT, anti-CD38 agents, CAR-T therapy, treatment with bispecific antibodies, anti-SLAMF7 therapeutic agents, nuclear export inhibitors, HDAC inhibitors, ADCs or BCMA-directed therapies. In some embodiments, B cell proliferative disorders (e.g., MM) are refractory to daratumumab.

[0412] F. Risk-Benefit Profile The methods described herein can provide an improved benefit-risk profile for patients having cancer (e.g., multiple myeloma (MM), e.g., relapsed or refractory (R / R) MM), e.g., patients having R / R MM who are undergoing 4L+ treatment for R / R MM treated with a bispecific anti-FcRH5 / anti-CD3 antibody. In some cases, treatment using the methods described herein that result in administration of a bispecific anti-FcRH5 / anti-CD3 antibody according to a fractionated dose escalation regimen results in a reduction (by 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more) or complete inhibition (100% reduction) of unwanted events such as cytokine-driven toxicity (e.g., cytokine release syndrome (CRS)), infusion-related reaction (IRR), macrophage activation syndrome (MAS), neurotoxicity, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, elevated liver enzymes, and / or central nervous system (CNS) toxicity compared to treatment with a bispecific anti-FcRH5 / anti-CD3 antibody using an unfractionated dosing regimen, after treatment with a bispecific anti-FcRH5 / anti-CD3 antibody using the fractionated dose escalation regimen of the invention.

[0413] G. Safety and Efficacy i. Safety In some embodiments, less than 15% (e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%) of the patients treated using the methods described herein experience grade 3 or grade 4 cytokine release syndrome (CRS). In some embodiments, less than 5% of the patients treated using the methods described herein experience grade 3 or grade 4 CRS.

[0414] In some embodiments, less than 10% (e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%) of the patients treated using the methods described herein experience grade 4+ CRS. In some embodiments, less than 3% of the patients treated using the methods described herein experience grade 4+ CRS. In some embodiments, no patients experience grade 4+ CRS.

[0415] In some embodiments, less than 10% (e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%) of the patients treated using the methods described herein experience grade 3 CRS. In some embodiments, less than 5% of the patients treated using the methods described herein experience grade 3 CRS. In some embodiments, no patients experience grade 3 CRS.

[0416] In some embodiments, grade 2+ CRS events occur only in the first treatment cycle. In some embodiments, grade 2 CRS events occur only in the first treatment cycle. In some embodiments, no grade 2 CRS events occur.

[0417] In some embodiments, less than 3% of the patients treated using the methods described herein experience grade 4+ CRS, less than 5% of the patients treated using the methods described herein experience grade 3 CRS, and grade 2+ CRS events occur only in the first treatment cycle.

[0418] In some embodiments, grade 3+ CRS events do not occur, and grade 2 CRS events occur only in the first treatment cycle.

[0419] In some embodiments, the symptoms of immune effector cell-associated neurotoxicity syndrome (ICANS) are limited to confusion, disorientation, and expressive aphasia and resolve with steroids.

[0420] In some embodiments, less than 10% (e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%) of the patients treated using the methods described herein experience seizures or other grade 3+ neurological adverse events. In some embodiments, less than 5% of the patients experience seizures or other grade 3+ neurological adverse events. In some embodiments, no patients experience seizures or other grade 3+ neurological adverse events.

[0421] In some embodiments, all neurological symptoms are self-limiting or resolve with steroid and / or tocilizumab therapy.

[0422] ii. Efficacy In some embodiments, the overall response rate (ORR) for patients treated using the methods described herein is at least 25%, for example, at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100%. In some embodiments, the ORR is at least 40%. In some embodiments, the ORR is at least 45% (for example, at least 45%, 45.5%, 46%, 46.5%, 47%, 47.5%, 48%, 48.5%, 49%, 49.5%, or 50%), at least 55%, or at least 65%. In some embodiments, the ORR is at least 47.2%. In some embodiments, the ORR is about 47.2%. In some embodiments, the ORR is 75% or more. In some embodiments, at least 1% of the patients (for example, at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) have a complete response (CR) or a very good partial response (VGPR). In some embodiments, the ORR is 40% to 50%, and 10% to 20% of the patients have a CR or VGPR. In some embodiments, the ORR is at least 40%, and at least 20% of the patients have a CR or VGPR.

[0423] In some embodiments, the mean duration of response (DoR) for patients treated using the methods described herein is at least 2 months, for example, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 1 year, or greater than 1 year. In some embodiments, the mean DoR is at least 4 months. In some embodiments, the mean DoR is at least 5 months. In some embodiments, the mean DoR is at least 7 months.

[0424] In some embodiments, the 6-month progression-free survival (PFS) rate for patients treated using the methods described herein is at least 10%, for example, at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100%. In some embodiments, the 6-month PFS rate is at least 25%. In some embodiments, the 6-month PFS rate is at least 40%. In some embodiments, the 6-month PFS rate is at least 55%.

[0425] H. Administration Method The method can include administering the bispecific anti-FcRH5 / anti-CD3 antibody (and / or any additional therapeutic agent) by any suitable means including parenteral administration, intratracheal administration, and intranasal administration, and intralesional administration if desired for local treatment. Parenteral infusion includes intravenous, subcutaneous, intramuscular, intraarterial, and intraperitoneal administration routes. In some embodiments, the bispecific anti-FcRH5 / anti-CD3 antibody is administered by intravenous infusion. In other cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered subcutaneously.

[0426] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody administered by intravenous injection exhibits a lower toxic response (i.e., fewer unwanted effects) in patients than the same bispecific anti-FcRH5 / anti-CD3 antibody administered by subcutaneous injection, or vice versa.

[0427] In some embodiments, the bispecific anti-FcRH5 / anti-CD3 antibody is administered intravenously over 4 hours (±15 minutes), for example, the first dose of the antibody is administered over 4 hours ±15 minutes.

[0428] In some embodiments, the first dose and the second dose of the antibody are administered intravenously at a median infusion time of less than 4 hours (e.g., less than 3 hours, less than 2 hours, or less than 1 hour), and further doses of the antibody are administered intravenously at a median infusion time of less than 120 minutes (e.g., less than 90 minutes, less than 60 minutes, or less than 30 minutes).

[0429] In some embodiments, the first dose and the second dose of the antibody are administered intravenously with a median infusion time of less than 3 hours, and further doses of the antibody are administered intravenously with a median infusion time of less than 90 minutes.

[0430] In some embodiments, the first dose and the second dose of the antibody are administered intravenously with a median infusion time of less than 3 hours, and further doses of the antibody are administered intravenously with a median infusion time of less than 60 minutes. In some embodiments, the patient is hospitalized during the period of one or more administrations of the anti-FcRH5 / anti-CD3 antibody (e.g., hospitalization for 72 hours, 48 hours, 24 hours, or less than 24 hours), for example, hospitalized for C1D1 (cycle 1, dose 1) or C1D1 and C1D2 (cycle 1, dose 2). In some embodiments, the patient is hospitalized 72 hours after the administration of C1D1 and C1D2. In some embodiments, the patient is hospitalized 24 hours after the administration of C1D1 and C1D2. In some embodiments, the patient is not hospitalized after the administration of any dose of the anti-FcRH5 / anti-CD3 antibody.

[0431] For all of these methods described herein, the bispecific anti-FcRH5 / anti-CD3 antibody will be formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the dosing schedule, and other factors known to the medical practitioner. The bispecific anti-FcRH5 / anti-CD3 antibody may optionally, but not necessarily, be formulated with one or more drugs currently being used to prevent or treat the disorder in question. The effective amount of such other drugs will depend on the amount of bispecific anti-FcRH5 / anti-CD3 antibody present in the formulation, the type of disorder or treatment, and the other factors discussed above. The bispecific anti-FcRH5 / anti-CD3 antibody can be appropriately administered to the patient over a series of treatments.

[0432] Any of the dosages disclosed herein can be administered SC. Any suitable approach for SC administration can be used, including injection (e.g., bolus injection) or infusion. For example, the therapeutic agent (e.g., bispecific anti-FcRH5 / anti-CD3 antibody) can be administered SC using a pump (e.g., patch pump, syringe pump (e.g., syringe pump with an infusion set), or infusion pump (e.g., portable infusion pump or stationary infusion pump)), prefilled syringe, pen injector, or autoinjector.

[0433] For example, in any of the methods or uses disclosed herein, the therapeutic agent can be administered SC using a pump. In some examples, the pump can be used for patient or healthcare provider (HCP) convenience, an improved safety profile (e.g., with respect to the mechanism of action of the drug or the risk of IV-related infections), and / or combination therapy. Any suitable pump, e.g., a patch pump, syringe pump (e.g., a syringe pump with an infusion set), infusion pump (e.g., a portable infusion pump or a stationary infusion pump), or LVP can be used. In certain examples, the therapeutic agent can be administered SC using a patch pump. In some examples, the pump (e.g., a patch pump) can be a wearable or body-worn pump (e.g., a wearable or body-worn patch pump), e.g., an Enable ENFUSE® body injector or a West SMARTDOSE® wearable syringe (e.g., a West SMARTDOSE® 10 wearable syringe). In other examples, the therapeutic agent can be administered SC using a syringe pump (e.g., a syringe pump with an infusion set).

[0434] Other...

Claims

1. A method of treating a subject having relapsed or refractory (R / R) multiple myeloma (MM), wherein the subject has previously received a B-cell maturation antigen (BCMA)-targeted therapeutic agent, and the method comprises administering to the subject a bispecific antibody that binds to Fc receptor homolog 5 (FcRH5) and cluster of differentiation 3 (CD3), (i) a first phase comprising administering the bispecific antibody to the subject in at least a first 21-day dosing cycle (C1), wherein (a) on day 1 of C1; and (b) on day 2, 3, or 4 of C1, the bispecific antibody is administered to the subject, the first phase; and (ii) a second phase comprising one or more 21-day dosing cycles, wherein the bispecific antibody is administered to the subject every three weeks (Q3W), the second phase comprising administering in a dosing regimen comprising.

2. The method of claim 1, wherein the subject has triple-class refractory MM.

3. The method of claim 1, wherein the BCMA-targeted therapeutic agent is selected from a BCMA-targeted T cell-dependent bispecific (TDB) antibody, a BCMA-targeted antibody-drug conjugate (ADC), and a chimeric antigen receptor T (CAR-T).

4. The method according to any one of claims 1 to 3, wherein the BCMA-targeted therapeutic agent is a BCMA-targeted TDB antibody.

5. The method according to any one of claims 1 to 4, further comprising administering the bispecific antibody that binds to FcRH5 and CD3 to the subject on day 8 of C1 during the first phase.

6. The method according to any one of claims 1 to 4, further comprising administering the bispecific antibody that binds to FcRH5 and CD3 to the subject after day 9 of C1 during the first phase.

7. The method according to any one of claims 1 to 6, wherein the first phase comprises administering to the subject a first step-up dose and a second step-up dose of the bispecific antibody that binds to FcRH5 and CD3.

8. The method of claim 7, wherein the first step-up dose is administered to the subject on day 1 of C1 and the second step-up dose is administered to the subject on day 2 of C1.

9. The method according to claim 7, wherein (i) The first step-up dose is administered to the subject on the first day of C1; (ii) The subject has a cytokine release syndrome (CRS) event after the first step-up dose; and (iii) The second step-up dose is administered to the subject on the third day of C1 after the resolution of the CRS event, method.

10. The method according to claim 7, wherein (i) The first step-up dose is administered to the subject on the first day of C1; (ii) The subject has a CRS event after the first step-up dose; and (iii) The second step-up dose is administered to the subject on the fourth day of C1 after the resolution of the CRS event, method.

11. The method according to any one of claims 7 to 10, wherein the first step-up dose is about 0.2% of the target dose and the second step-up dose is about 2% of the target dose.

12. The method according to any one of claims 7 to 11, wherein the first step-up dose is about 0.3 mg and the second step-up dose is about 3.3 mg.

13. The method according to claim 11 or 12, wherein the target dose is administered to the subject on the eighth day of C1.

14. The method according to claim 11 or 12, wherein the target dose is administered to the subject on the ninth day or later of C1.

15. The method according to any one of claims 1 to 14, wherein the second phase includes at least 2 dosing cycles, at least 3 dosing cycles, at least 4 dosing cycles, at least 5 dosing cycles, at least 6 dosing cycles, at least 7 dosing cycles, at least 8 dosing cycles, at least 9 dosing cycles, at least 10 dosing cycles, at least 11 dosing cycles, at least 12 dosing cycles, or at least 13 dosing cycles.

16. The method according to claim 15, wherein the second phase includes a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), and a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), a seventh dosing cycle (C7), an eighth dosing cycle (C8), a ninth dosing cycle (C9), a tenth dosing cycle (C10), an eleventh dosing cycle (C11), a twelfth dosing cycle (C12), and / or a thirteenth dosing cycle (C13).

17. The method according to claim 15 or 16, wherein the second phase comprises administering to the subject the bispecific antibody that binds to FcRH5 and CD3 on the first day of each dosing cycle.

18. The method according to claim 17, wherein the second phase comprises C1, and the first day of C1 in the second phase is at least 7 days after administration of the target dose of the bispecific antibody in the first phase.

19. The method according to any one of claims 15 to 18, wherein the target dose of the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject for each administration during the second phase.

20. The method according to any one of claims 1 to 19, wherein the second phase comprises administering to the subject the bispecific antibody that binds to FcRH5 and CD3 at Q3W until the subject experiences disease progression, unacceptable toxicity or death.

21. The method according to any one of claims 11, 13, 18, and 19, wherein the target dose is 160 mg.

22. The method according to any one of claims 1 to 21, wherein the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject as a monotherapy.

23. The method according to claim 22, wherein the bispecific antibody that binds to FcRH5 and CD3 is administered intravenously to the subject.

24. The method according to any one of claims 1 to 23, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises the following six hypervariable regions (HVRs): (i) HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1); (ii) HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (iii) HVR-H3 comprising the amino acid sequence of HYYGS SDYALD N (SEQ ID NO: 3); (iv) HVR-L1 comprising the amino acid sequence of KASQDVRNL VV (SEQ ID NO: 4); (v) HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (vi) HVR-L3 comprising the amino acid sequence of QQHYS PPYT (SEQ ID NO: 6) and comprises an anti-FcRH5 arm comprising a first binding domain.

25. The method according to any one of claims 1 to 24, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises: (i) 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; (ii) 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 (iii) an anti-FcRH5 arm comprising a first binding domain comprising the VH domain described in (i) and the VL domain described in (ii).

26. The method according to claim 25, 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.

27. The method according to any one of claims 1 to 26, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises 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 WIYPE ndNTKYNEKFKD (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 KSSQSL LNSRTRKNYLA (SEQ ID NO: 12); (v) HVR-L2 comprising the amino acid sequence of WTS TRKS (SEQ ID NO: 13); and (vi) HVR-L3 comprising the amino acid sequence of KQS FILRT (SEQ ID NO: 14) and an anti-CD3 arm comprising a second binding domain.

28. The method according to any one of claims 1 to 27, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises: (i) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15; (ii) 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 (iii) an anti-CD3 arm comprising a second binding domain comprising the VH domain described in (i) and the VL domain described in (ii).

29. The method according to claim 28, 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.

30. The method according to any one of claims 1 to 29, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1) and a light chain polypeptide (L1), and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), (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, method.

31. The method according to any one of claims 1 to 30, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an aglycosylation site mutation.

32. The method according to claim 31, wherein the aglycosylation site mutation reduces the effector function of the bispecific antibody.

33. The method according to claim 32, wherein the aglycosylation site mutation is a substitution mutation.

34. The method according to claim 33, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises a substitution mutation in the Fc region that reduces the effector function.

35. The method according to any one of claims 1 to 34, wherein the bispecific antibody that binds to FcRH5 and CD3 is a monoclonal antibody.

36. The method according to any one of claims 1 to 35, wherein the bispecific antibody that binds to FcRH5 and CD3 is a humanized antibody.

37. The method according to any one of claims 1 to 36, wherein the bispecific antibody that binds to FcRH5 and CD3 is a chimeric antibody.

38. The method according to any one of claims 1 to 29 and 31 to 37, wherein the bispecific antibody that binds to FcRH5 and CD3 is an antibody fragment that binds to FcRH5 and CD3.

39. The method according to claim 38, wherein the antibody fragment is selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab') ２ fragment.

40. The method according to any one of claims 1 to 37, wherein the bispecific antibody that binds to FcRH5 and CD3 is a full-length antibody.

41. The method according to any one of claims 1 to 40, wherein the bispecific antibody that binds to FcRH5 and CD3 is an IgG antibody.

42. The method according to claim 41, wherein the IgG antibody is an IgG1 antibody.

43. The bispecific antibody that binds to FcRH5 and CD3 comprises one or more heavy chain constant domains, and the one or more heavy chain constant domains are a first CH1 (CH1 １ ), a first CH2 (CH2 １ ), a first CH3 (CH3 １ ), a second CH1 (CH1 ２ ), a second CH2 (CH2 ２ ), and a second CH3 (CH3 ２ ), the method according to any one of claims 1 to 42.

44. The method according to claim 43, wherein at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

45. said CH3 １ domain and said CH3 ２ domains each contain a protrusion or a cavity, and the said CH3 １ protrusion or cavity of the said CH3 ２ The method according to claim 44, wherein the said cavity or protrusion of the said CH3 domain can be respectively arranged in the said protrusion or cavity of the said CH3

46. said CH3 １ domain and said CH3 ２ The method according to claim 45, wherein the domain and the domain meet at an interface between the protrusion and the cavity.

47. said CH2 １ domain and said CH2 ２ domains each contain a protrusion or a cavity, and the １ protrusion or cavity of said CH2 ２ method according to any one of claims 43 to 46, wherein the cavity or protrusion of said CH2 domain can be respectively disposed in the protrusion or cavity of said CH2 domain.

48. said CH2 １ domain and said CH2 ２ The method according to claim 47, wherein the domain and the CH2 domain meet at the interface between the protrusion and the cavity.

49. The method according to claim 48, wherein the anti-FcRH5 arm comprises the protrusion and the anti-CD3 arm comprises the cavity.

50. The method according to claim 49, wherein the CH3 domain of the anti-FcRH5 arm comprises a protrusion containing a T366W amino acid substitution mutation (EU numbering), and the CH3 domain of the anti-CD3 arm comprises a cavity containing T366S, L368A, and Y407V amino acid substitution mutations (EU numbering).

51. The method according to any one of claims 1 to 37 and 40 to 50, wherein the bispecific antibody that binds to FcRH5 and CD3 is cevostamab.

52. The method according to claim 51, wherein the cevostamab is administered as a monotherapy.

53. The method according to any one of claims 1 to 52, wherein the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject simultaneously with one or more additional therapeutic agents.

54. The method according to any one of claims 1 to 52, wherein the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject prior to the administration of one or more additional therapeutic agents.

55. The method according to any one of claims 1 to 52, wherein the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject after the administration of one or more additional therapeutic agents.

56. The method according to claims 53 to 55, wherein the one or more additional therapeutic agents comprise an effective amount of tocilizumab.

57. The method according to claim 56, wherein tocilizumab is administered to the subject by intravenous infusion.

58. The method according to claim 57, (i) the weight of the subject is 30 kg or more, and tocilizumab is administered to the subject at a dose of 8 mg / kg; or (ii) the weight of the subject is less than 30 kg, and tocilizumab is administered to the subject at a dose of 12 mg / kg, and the tocilizumab is administered to the subject at a dose not exceeding 800 mg.

59. The method according to any one of claims 56 to 58, wherein tocilizumab is administered to the subject 2 hours before the administration of the bispecific antibody.

60. The method according to any one of claims 53 to 59, wherein the one or more additional therapeutic agents comprise an effective amount of a BCMA-directed therapeutic agent. **Claim 61** The method according to any one of claims 1 to 8 and 11 to 60, further comprising treating the symptoms of the CRS event while withholding treatment with the bispecific antibody that binds to FcRH5 and CD3, wherein the subject has a CRS event. **Claim 62** The method according to claim 9 or 10, further comprising treating the symptoms of the CRS event. **Claim 63** The method according to claim 61 or 62, wherein treating the symptoms of the CRS event comprises administering to the subject an effective amount of tocilizumab. **Claim 64** The method according to claim 63, wherein tocilizumab is administered intravenously to the subject as a single dose of about 8 mg / kg. **Claim 65** The method according to claim 64, wherein the CRS event does not resolve or worsens within 24 hours after treating the symptoms of the CRS event, and the method further comprises administering to the subject one or more additional doses of tocilizumab to manage the CRS event. **Claim 66** The method according to claim 65, wherein the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 8 mg / kg. **Claim 67** The method according to any one of claims 53 to 66, wherein the one or more additional therapeutic agents comprise an effective amount of acetaminophen or paracetamol. **Claim 68** The method according to claim 67, wherein acetaminophen or paracetamol is administered to the subject at a dose of about 500 mg to about 1000 mg. **Claim 69** The method according to claim 68, wherein acetaminophen or paracetamol is administered orally to the subject. **Claim 70** The method according to any one of claims 53 to 69, wherein the one or more additional therapeutic agents comprise an effective amount of diphenhydramine. **Claim 71** The method according to claim 70, wherein diphenhydramine is administered to the subject at a dose of about 25 mg to about 50 mg. **Claim 72** The method according to claim 71, wherein diphenhydramine is administered orally to the subject. **Claim 73** The method according to any one of claims 1 to 52, wherein the method comprises pre - dosing with the following agents: (i) corticosteroid; (ii) acetaminophen or paracetamol; and / or (iii) diphenhydramine before administering the bispecific antibody to the subject.

74. The method according to claim 73, wherein the corticosteroid is administered to the subject 1 hour (± 15 minutes) before any administration of the bispecific antibody during the first phase.

75. The method according to claim 73, wherein the corticosteroid is administered to the subject 24 hours before any administration of the bispecific antibody during the first phase.

76. The method according to any one of claims 73 to 75, wherein the subject has experienced CRS due to a prior administration of the bispecific antibody, and the corticosteroid is administered to the subject 1 hour (± 15 minutes) before any administration of the bispecific antibody during the second phase.

77. The method according to any one of claims 73 to 76, wherein the corticosteroid is dexamethasone or methylprednisolone.

78. The method according to claim 77, wherein the corticosteroid is dexamethasone.

79. The method according to claim 77 or 78, wherein the dexamethasone is administered to the subject at a dose of about 20 mg.

80. The method according to claim 77, wherein the methylprednisolone is administered to the subject at a dose of about 80 mg.

81. The method according to any one of claims 73 to 80, wherein the corticosteroid is administered intravenously to the subject.

82. The method according to any one of claims 73 to 81, wherein acetaminophen or paracetamol is administered to the subject at a dose of 500 mg to 1000 mg.

83. The method according to any one of claims 73 to 82, wherein acetaminophen or paracetamol is administered orally to the subject.

84. The method according to any one of claims 73 to 83, wherein diphenhydramine is administered to the subject at a dose of 25 mg to 50 mg.

85. The method according to any one of claims 73 to 84, wherein diphenhydramine is administered orally to the subject.

86. The method according to any one of claims 1 to 85, wherein the subject has received at least four prior treatment lines for the MM. **Claim 87** The method according to any one of claims 1 to 86, wherein the subject has been exposed to prior treatments including a proteasome inhibitor (PI), an IMiD, an anti-CD38 therapeutic agent, and / or autologous stem cell transplantation (ASCT). **Claim 88** The method according to claim 87, wherein the PI is bortezomib, carfilzomib or ixazomib. **Claim 89** The method according to claim 87, wherein the IMiD is thalidomide, lenalidomide or pomalidomide. **Claim 90** The method according to claim 87, wherein the anti-CD38 therapeutic agent is an anti-CD38 antibody. **Claim 91** The method according to claim 90, wherein the anti-CD38 antibody is daratumumab, MOR202, or isatuximab. **Claim 92** The method according to claim 91, wherein the anti-CD38 antibody is daratumumab. **Claim 93** The method according to any one of claims 2 to 92, wherein the BCMA-targeted TDB antibody is teclistamab (JNJ-64007957), AM701, AMG420, CC-93269, elranatamab, TNB-383B, linvoseltamab (REGN5458), arclatumumab (CC-93269), AFM26, or HPN217. **Claim 94** The method according to any one of claims 3 and 5 to 92, wherein the BCMA-targeted antibody-drug conjugate (ADC) is BELENREP® (belantamab mafodotin). **Claim 95** The method according to any one of claims 3 and 5 to 92, wherein the chimeric antigen receptor T (CAR-T) is selected from ABECMA® (idecabtagene vicleucel) and CARVYKTI® (cilta-cabtagene autoleucel). **Claim 96** A method of treating a subject having R / R MM, comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first 21-day dosing cycle, wherein the first 21-day dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, wherein C1D1 is from about 0.2 mg to about 0.4 mg and is administered to the subject on day 1 of the first dosing cycle, wherein C1D2 is from about 3.1 mg to about 3.4 mg and is administered to the subject on day 2, 3, or 4 of the first dosing cycle, and wherein C1D3 is more than C1D2.

97. A method of treating a subject having R / R MM, wherein the subject has triple-class refractory MM and has previously received a BCMA-targeted TDB antibody, the method comprising administering to the subject a single-agent therapy of sevosumab, (i) a first phase comprising administering sevosumab to the subject in a first dosing cycle (C1); and (ii) a second phase comprising administering sevosumab to the subject every 3 weeks (Q3W), in a dosing regimen comprising each dosing cycle of the first phase and the second phase being a 21-day dosing cycle, and sevosumab being administered to the subject (i) during the first phase, at a first step-up dose of 0.3 mg on day 1 of C1 and at a second step-up dose of 3.3 mg on day 2, 3, or 4 of C1 during the first phase; (ii) during the first phase, at a target dose of 160 mg on day 8 of C1; and (iii) during the second phase, at the target dose of 160 mg on day 1 of each dosing cycle. Method.

98. A method of treating a subject having R / R MM, wherein the subject has triple-class refractory MM and has previously received a BCMA-targeted CAR-T, the method comprising administering to the subject a single-agent therapy of sevosumab, (i) a first phase comprising administering sevosumab to the subject in a first dosing cycle (C1); and (ii) a second phase comprising administering sevosumab to the subject Q3W, in a dosing regimen comprising each dosing cycle of the first phase and the second phase is a 21-day dosing cycle, and cevostamab is administered to the subject (i) during the first phase, at a first step-up dose of 0.3 mg on day 1 of C1, and during the first phase, at a second step-up dose of 3.3 mg on day 2, 3, or 4 of C1; (ii) during the first phase, at a target dose of 160 mg on day 8 of C1; and (iii) during the second phase, at the target dose of 160 mg on day 1 of each dosing cycle, method.

99. A method of treating a subject having R / R MM, wherein the subject has triple-class refractory MM and has previously received a BCMA-targeted ADC, the method comprising administering to the subject a single-agent therapy with cevostamab (i) a first phase comprising administering cevostamab to the subject in a first dosing cycle (C1); and (ii) a second phase comprising administering cevostamab to the subject Q3W, in a dosing regimen comprising each dosing cycle of the first phase and the second phase is a 21-day dosing cycle, and cevostamab is administered to the subject (i) during the first phase, at a first step-up dose of 0.3 mg on day 1 of C1, and during the first phase, at a second step-up dose of 3.3 mg on day 2, 3, or 4 of C1; (ii) during the first phase, at a target dose of 160 mg on day 8 of C1; and (iii) during the second phase, at the target dose of 160 mg on day 1 of each dosing cycle, method.

100. A bispecific antibody that binds to FcRH5 and CD3 for use in treating a subject having R / R MM, wherein the subject has triple-class refractory MM and has previously received a BCMA-targeted therapeutic agent, the treatment comprising administering the bispecific antibody to the subject (i) a first phase comprising a first 21-day dosing cycle (C1), comprising administering the bispecific antibody to the subject on (a) day 1 of C1; (b) day 2, 3, or 4 of C1; and (c) day 8 of C1; and (ii)A second phase comprising one or more 21-day dosing cycles, the second phase comprising administering the bispecific antibody to the subject Q3W A bispecific antibody, comprising administering in a dosing regimen comprising.

101. A bispecific antibody that binds to FcRH5 and CD3 for use in treating a subject having R / R MM, the bispecific antibody that binds to FcRH5 and CD3 being administered to the subject in a dosing regimen comprising at least a first 21-day dosing cycle, the first dosing cycle comprising a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, wherein the C1D1 is from about 0.2 mg to about 0.4 mg and is administered to the subject on day 1 of the first dosing cycle, the C1D2 is from about 3.1 mg to about 3.4 mg and is administered to the subject on day 2, 3, or 4 of the first dosing cycle, and the C1D3 is greater than the C1D2.

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