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

Abstract

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

Description

[0001] Sequence Listing

[0002] This application contains a sequence listing, which has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy was created on May 9, 2022, is named 50474-278WO1_Sequence_Listing_5_9_22_ST25 and is 33,561 bytes in size. Technical Field

[0003] The present invention relates to the treatment of cancers 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-crystallizable fragment receptor-like 5 (FcRH5) / anti-cluster of differentiation 3 (CD3) bispecific antibody. Background Art

[0004] Cancer remains one of the most deadly threats to human health, striking more than 1.7 million new patients each year and being the second leading cause of death after heart disease in the United States, accounting for approximately one in four deaths.

[0005] In particular, blood cancers are the second leading cause of cancer-related death. Blood cancers include multiple myeloma (MM), a tumor characterized by the proliferation and accumulation of malignant plasma cells. Approximately 160,000 people are diagnosed with MM each year worldwide. Despite advances in treatment, MM remains incurable, with an estimated median survival of 8 to 10 years for standard-risk myeloma and 2 to 3 years for high-risk disease, even with autologous stem cell transplantation. Although patient survival has improved significantly over the past 20 years, only 10% to 15% of patients meet or exceed expected survival compared to the matched general population. Prolonged survival has been achieved with the introduction of proteasome inhibitors, immunomodulatory drugs (IMiDs), and monoclonal antibodies. However, most patients, if not all, eventually relapse, and patients with MM who become refractory or unsuitable for proteasome inhibitors or IMiDs have rather poor outcomes, with survival of less than 1 year.

[0006] Therefore, especially relapsed or refractory (R / R) MM remains a significant unmet medical need, and novel therapeutic agents and treatments are needed. Summary of the invention

[0007] Provided herein, inter alia, are methods of treating cancer (eg, B-cell proliferative disorders such as MM), as well as related compositions, uses, and articles of manufacture for use.

[0008] In one aspect, the invention features a method of treating a subject having multiple myeloma (MM), the method comprising subcutaneously administering to the subject a bispecific antibody that binds to Fc receptor homolog 5 (FcRH5) and cluster of differentiation 3 (CD3) at a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the subject every week (QW); (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the subject every two weeks (Q2W); and (iii) a third phase comprising one or more dosing cycles, wherein the third phase comprises administering the bispecific antibody to the subject every four weeks (Q4W).

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

[0010] In some aspects, the first phase comprises a first dosing cycle (C1).

[0011] In some aspects, the first stage consists of C1.

[0012] In some aspects, the first phase comprises administering the bispecific antibody to the subject on Day 1, Day 8, and Day 15 of C1.

[0013] In some aspects, the subject is administered a target dose of the bispecific antibody for each administration during the first stage.

[0014] In some aspects, the first phase comprises administering to the subject a first step-escalating dose of the bispecific antibody.

[0015] In some aspects, the subject is administered a first step-escalating dose on day 1 of C1.

[0016] In some aspects, the target dose is administered to the subject on Days 8 and 15 of C1.

[0017] In some aspects, the first step-escalation dose is about 1% to 30% of the target dose.

[0018] In some aspects, the first step-escalation dose is about 5% to 25% of the target dose.

[0019] In some aspects, the first step-escalation dose is 5% of the target dose.

[0020] In some aspects, the first step-escalation dose is 25% of the target dose.

[0021] In some aspects, the first stepped-up dose is 2 mg.

[0022] In some aspects, the first stepped-up dose is 10 mg.

[0023] In some aspects, the first phase comprises administering to the subject a first step-escalating dose and a second step-escalating dose of the bispecific antibody.

[0024] In some aspects, the subject is administered a first step-escalating dose on day 1 of C1 and the subject is administered a second step-escalating dose on day 8 of C1.

[0025] In some aspects, the target dose is administered to the subject on day 15 of C1.

[0026] In some aspects: (i) the first step-escalating dose is 1% to 10% of the target dose; and (ii) the second step-escalating dose is 15% to 45% of the target dose.

[0027] In some aspects: (i) the first step-escalating dose is 5% of the target dose; and (ii) the second step-escalating dose is 25% of the target dose.

[0028] In some aspects, the first stepped-up dose is 2 mg and the second stepped-up dose is 10 mg.

[0029] In some aspects, the bispecific antibody is not administered to the subject on day 22 of C1.

[0030] In some aspects, the bispecific antibody is administered to the subject a total of three times during C1.

[0031] In some aspects, the bispecific antibody is administered to the subject on day 22 of C1.

[0032] In some aspects, the second phase includes at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, or at least five dosing cycles.

[0033] In some aspects, the second phase includes a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5).

[0034] In some aspects, the second stage consists of C1, C2, C3, C4, and C5.

[0035] In some aspects, the second phase comprises administering the bispecific antibody to the subject on Day 1 and Day 15 of C1, C2, C3, C4, and / or C5.

[0036] In some aspects, the subject is administered a target dose of the bispecific antibody for each administration during the second stage.

[0037] In some aspects, the third phase includes at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, at least five dosing cycles, at least six dosing cycles, or at least seven dosing cycles.

[0038] In some aspects, the third phase includes a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7).

[0039] In some aspects, the third stage consists of C1, C2, C3, C4, C5, C6 and C7.

[0040] In some aspects, the third phase comprises administering the bispecific antibody to the subject on day 1 of C1, C2, C3, C4, C5, C6, and / or C7.

[0041] In some aspects, the subject is administered a target dose of the bispecific antibody for each administration during the third stage.

[0042] In some aspects, the dosing regimen further comprises a fourth phase comprising one or more dosing cycles.

[0043] In some aspects, the fourth phase comprises subcutaneously administering the bispecific antibody to the subject every week (QW), every two weeks (Q2W), every three weeks (Q3W), or every four weeks (Q4W).

[0044] In some aspects, the subject is administered a target dose of the bispecific antibody for each administration during the fourth stage.

[0045] In some aspects, the fourth phase comprises administering the bispecific antibody to the subject until disease progression.

[0046] In some aspects, the target dose is 40 mg.

[0047] In some aspects, the target dose is 120 mg.

[0048] In some aspects, the bispecific antibody is administered to a subject as a monotherapy.

[0049] In another aspect, the invention features a method of treating a subject having MM, the method comprising subcutaneously administering to the subject a bispecific antibody that binds to FcRH5 and CD3 at a dosing regimen comprising: (i) a first dose of between 0.1 mg and 10 mg of the bispecific antibody; (ii) a second dose of between 1 mg and 50 mg of the bispecific antibody; and (iii) a third dose of between 10 mg and 200 mg of the bispecific antibody.

[0050] In some aspects: (i) the first dose of the bispecific antibody is between 1 mg and 3 mg; (ii) the second dose of the bispecific antibody is between 8 mg and 12 mg; and (iii) the third dose of the bispecific antibody is between 35 mg and 45 mg.

[0051] In some aspects: (i) the first dose of the bispecific antibody is 2 mg; (ii) the second dose of the bispecific antibody is 10 mg; and (iii) the third dose of the bispecific antibody is 40 mg.

[0052] In some aspects: (i) the first dose of the bispecific antibody is 2 mg; (ii) the second dose of the bispecific antibody is 10 mg; and (iii) the third dose of the bispecific antibody is 120 mg.

[0053] In some aspects, the bispecific antibody is administered to the subcutaneous tissue of the abdomen.

[0054] In some aspects, the abdomen of the subject comprises four quadrants, and the bispecific antibody is administered to one of the four quadrants.

[0055] In some aspects, each sequential dose of the bispecific antibody is administered to a different member of the four quadrants in a rotating manner.

[0056] In some aspects, the bispecific antibody is administered to the thigh of the subject.

[0057] In some aspects, the bispecific antibody is administered subcutaneously by injection or by infusion.

[0058] In some aspects, the bispecific antibody is administered subcutaneously by injection.

[0059] In some aspects, the bispecific antibody is administered at an injection rate of about 0.25 mL / min to about 4 mL / min.

[0060] In some aspects, the bispecific antibody is administered at an injection rate of about 1 mL / min.

[0061] In some aspects, the bispecific antibody is administered by syringe.

[0062] In some aspects, the syringe is a prefilled syringe.

[0063] In some aspects, the bispecific antibody is administered by a pump.

[0064] In some aspects, the pump comprises a patch pump, a syringe pump, or an infusion pump.

[0065] In some aspects, the pump is a wearable pump.

[0066] In some aspects, the bispecific antibody 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).

[0067] In some aspects, the bispecific antibody comprises an anti-FcRH5 arm, which comprises a first binding domain, which comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:8; or (c) a VH domain as in (a) and a VL domain as in (b).

[0068] In some aspects, 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.

[0069] In some aspects, the bispecific antibody comprises an anti-CD3 arm comprising 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 (SEQID 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).

[0070] In some aspects, the bispecific antibody comprises an anti-CD3 arm comprising a second binding domain comprising: (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16; or (c) a VH domain as in (a) and a VL domain as in (b).

[0071] In some aspects, 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.

[0072] In some aspects, the bispecific antibody comprises: an anti-FcRH5 arm comprising a heavy chain polypeptide (H1) and a light chain polypeptide (L1); and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2); and 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.

[0073] In some aspects, the bispecific antibody comprises an aglycosylation site mutation.

[0074] In some aspects, the aglycosylation site mutation reduces the effector function of the bispecific antibody.

[0075] In some aspects, the aglycosylation site mutation is a substitution mutation.

[0076] In some aspects, the bispecific antibody comprises a substitution mutation in the Fc region that reduces effector function.

[0077] In some aspects, the bispecific antibodies are monoclonal antibodies.

[0078] In some aspects, the bispecific antibodies are humanized antibodies.

[0079] In some aspects, the bispecific antibodies are chimeric antibodies.

[0080] In some aspects, the bispecific antibody is an antibody fragment that binds FcRH5 and CD3.

[0081] In some aspects, the antibody fragment is selected from the group consisting of a Fab fragment, a Fab'-SH fragment, a Fv fragment, a scFv fragment, and a (Fab')2 Fragment.

[0082] In some aspects, the bispecific antibodies are full-length antibodies.

[0083] In some aspects, the bispecific antibody is an IgG antibody.

[0084] In some aspects, the IgG antibody is IgG 1 Antibody.

[0085] In some aspects, the bispecific antibody comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH1 1 ) domain, the first CH2 (CH2 1 ) domain, the first CH3 (CH3 1 ) domain, the second CH1 (CH1 2 ) domain, the second CH2 (CH2 2 ) domain and the second CH3 (CH3 2 ) domain.

[0086] In some aspects, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

[0087] In some aspects, CH3 1 Domain and CH3 2 The domains each contain a protrusion or a cavity, and wherein CH3 1 The protrusion or cavity in the domain can be located at the CH3 2 In a cavity or protrusion in a domain.

[0088] In some aspects, CH3 1 Domain and CH3 2 The domains meet at the interface between the protrusion and the cavity.

[0089] In some aspects, CH2 1 Domain and CH2 2 The domains each contain a protrusion or a cavity, and wherein CH2 1 The protrusion or cavity in the domain can be located at the CH2 2 In a cavity or protrusion in a domain.

[0090] In some aspects, CH2 1 Domain and CH2 2 The domains meet at the interface between the protrusion and the cavity.

[0091] In some aspects, the anti-FcRH5 arm comprises a protrusion and the anti-CD3 arm comprises a cavity.

[0092] In some aspects, the CH3 domain of the anti-FcRH5 arm comprises a protrusion comprising a T366W amino acid substitution mutation (EU numbering), and the CH3 domain of the anti-CD3 arm comprises a cavity comprising T366S, L368A, and Y407V amino acid substitution mutations (EU numbering).

[0093] In some aspects, the bispecific antibody is cevostamab.

[0094] In some aspects, the bispecific antibody and one or more additional therapeutic agents are administered to a subject simultaneously.

[0095] In some aspects, the bispecific antibody is administered to the subject prior to administration of one or more additional therapeutic agents.

[0096] In some aspects, the bispecific antibody is administered to the subject after administration of one or more additional therapeutic agents.

[0097] In some aspects, the one or more additional therapeutic agents comprises an effective amount of tocilizumab.

[0098] In some aspects, the subject experiences a cytokine release syndrome (CRS) event, and the method further comprises treating symptoms of the CRS event while suspending treatment with the bispecific antibody.

[0099] In some aspects, the method further comprises administering to the subject an effective amount of tocilizumab to treat the CRS event.

[0100] In some aspects, tocilizumab is administered to the subject by intravenous infusion.

[0101] In some aspects: (i) the subject weighs ≥30 kg and tocilizumab is administered to the subject at a dose of 8 mg / kg; (ii) the subject weighs <30 kg and tocilizumab is administered to the subject at a dose of 12 mg / kg; or (iii) the final dose administered does not exceed 800 mg.

[0102] In some aspects, if the CRS event does not resolve within 8 hours of treating symptoms of the CRS event, or worsens, the method further comprises administering one or more additional doses of tocilizumab to the subject to manage the CRS event.

[0103] In some aspects, the one or more additional therapeutic agents comprises an effective amount of a corticosteroid.

[0104] In some aspects, the corticosteroid is administered intravenously to the subject.

[0105] In some aspects, the corticosteroid is methylprednisolone.

[0106] In some aspects, methylprednisolone is administered at a dose of 80 mg.

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

[0108] In some aspects, dexamethasone is administered at a dose of 20 mg.

[0109] In some aspects, the corticosteroid is administered to the subject 45 minutes to 75 minutes prior to administration of the bispecific antibody.

[0110] In some aspects, the corticosteroid is administered to the subject 60 minutes prior to administering the bispecific antibody to the subject.

[0111] In some aspects, if the subject experienced CRS while previously being administered the bispecific antibody to the subject, a corticosteroid is administered to the subject prior to administering the bispecific antibody.

[0112] In some aspects, the one or more additional therapeutic agents comprises an effective amount of acetaminophen or paracetamol.

[0113] In some aspects, acetaminophen or paracetamol is administered in a dose of between 500 mg and 1000 mg.

[0114] In some aspects, acetaminophen or paracetamol is orally administered to the subject.

[0115] In some aspects, acetaminophen or paracetamol is administered to the subject prior to administering the bispecific antibody to the subject.

[0116] In some aspects, the one or more additional therapeutic agents comprises an effective amount of diphenhydramine.

[0117] In some aspects, diphenhydramine is administered in a dose of between 25 mg and 50 mg.

[0118] In some aspects, diphenhydramine is administered orally to the subject.

[0119] In some aspects, diphenhydramine is administered to the subject prior to administering the bispecific antibody to the subject.

[0120] In some aspects, the one or more additional therapeutic agents include an effective amount of an immunomodulatory agent (IMiD), a cluster of differentiation 38 (CD38)-directed therapy, or a B-cell maturation antigen (BCMA)-directed therapy.

[0121] In some aspects, the IMiD is pomalidomide.

[0122] In some aspects, the CD38-directed therapy is an anti-CD38 antibody.

[0123] In some aspects, the anti-CD38 antibody is daratumumab, MOR202, or isatuximab.

[0124] In some aspects, the anti-CD38 antibody is daratumumab.

[0125] In some aspects, the BCMA-directed therapy is an antibody-drug conjugate that targets BCMA.

[0126] In some aspects, the MM is relapsed or refractory (R / R) MM.

[0127] In some aspects, the subject: has been diagnosed with R / R MM, for whom no established therapy for MM is appropriate and available; or is intolerant to established therapy.

[0128] In some aspects, the subject has measurable disease defined as at least one of the following: (i) serum M-protein ≥ 0.5 g / dL; (ii) urine M-protein ≥ 200 mg / 24 h; or (iii) serum free light chain (SFLC) assay: SFLC involved ≥ 10 mg / dL, and abnormal SFLC ratio (< 0.26 or > 1.65).

[0129] In another aspect, the invention features a method of treating a subject with R / R MM, the method comprising subcutaneously administering sivostomumab to the subject at a dosing regimen comprising: (i) a first phase comprising a first dosing cycle (C1), wherein C1 is a 28-day dosing cycle, wherein the first phase comprises administering sivostomumab to the subject at a first step-escalating dose on day 1 of C1, at a second step-escalating dose on day 8 of C1, and at a target dose on day 15 of C1, and wherein the first step-escalating dose is 2 mg, the second step-escalating dose is 10 mg, and the target dose is 40 mg; (ii) a second phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5). Phase (C5), wherein each dosing cycle of the second phase is a 28-day dosing cycle, and wherein the second phase includes administering sivostomumab to the subjects at a target dose of 40 mg on Day 1 and Day 15 of C1, C2, C3, C4 and C5; and (iii) a third phase, which includes a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6) and a seventh dosing cycle (C7), wherein each dosing cycle of the third phase is a 28-day dosing cycle, and wherein the third phase includes administering sivostomumab at a target dose of 40 mg on Day 1 of C1, C2, C3, C4, C5, C6 and C7.

[0130] In another aspect, the invention features a subcutaneous administration device comprising a bispecific antibody that binds to FcRH5 and CD3, wherein the subcutaneous administration device comprises: (i) a first dose of the bispecific antibody between 0.5 mg and 8 mg; (ii) a second dose of the bispecific antibody between 2 mg and 40 mg; and / or (iii) a third dose of the bispecific antibody between 10 mg and 160 mg.

[0131] In some aspects: (i) the first dose of the bispecific antibody is between 1 mg and 3 mg; (ii) the second dose of the bispecific antibody is between 8 mg and 12 mg; and / or (iii) the third dose of the bispecific antibody is between 35 mg and 45 mg.

[0132] In some aspects: (i) the first dose of the bispecific antibody is 2 mg; (ii) the second dose of the bispecific antibody is 10 mg; and / or (iii) the third dose of the bispecific antibody is 40 mg.

[0133] In some aspects: (i) the first dose of the bispecific antibody is 2 mg; (ii) the second dose of the bispecific antibody is 10 mg; and (iii) the third dose of the bispecific antibody is 120 mg.

[0134] In some aspects, the subcutaneous administration device is a syringe.

[0135] In some aspects, the subcutaneous administration device is a prefilled syringe.

[0136] In some aspects, the subcutaneous administration device is a pump.

[0137] In some aspects, the pump comprises a patch pump, a syringe pump, or an infusion pump.

[0138] In some aspects, the pump is a wearable pump.

[0139] In some aspects, a subcutaneous administration device is used to treat MM.

[0140] In some aspects, the MM is an R / R MM.

[0141] In another aspect, the invention features a bispecific antibody that binds to FcRH5 and CD3 for use in the treatment of a subject with MM, wherein the treatment comprises subcutaneously administering the bispecific antibody to the subject in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the subject every week (QW); (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the subject every two weeks (Q2W); and (iii) a third phase comprising one or more dosing cycles, wherein the third phase comprises administering the bispecific antibody to the subject every four weeks (Q4W).

[0142] In another aspect, the invention features a bispecific antibody that binds to FcRH5 and CD3 for use in treating a subject with MM, wherein the treatment comprises subcutaneously administering the bispecific antibody to the subject at a dosing regimen comprising: (i) a first dose of between 0.5 mg and 8 mg of the bispecific antibody; (ii) a second dose of between 2 mg and 40 mg of the bispecific antibody; and (iii) a third dose of between 10 mg and 160 mg of the bispecific antibody.

[0143] In another aspect, the invention features sivosetumab for use in the treatment of a subject with R / R MM, wherein the treatment comprises subcutaneously administering sivosetumab to the subject at a dosing regimen comprising: (i) a first phase comprising a first dosing cycle (C1), wherein C1 is a 28-day dosing cycle, wherein the first phase comprises administering sivosetumab to the subject at a first step-escalating dose on day 1 of C1, at a second step-escalating dose on day 8 of C1, and at a target dose on day 15 of C1, and wherein the first step-escalating dose is 2 mg, the second step-escalating dose is 10 mg, and the target dose is 40 mg; (ii) a second phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5), wherein each dosing cycle of the second phase is a 28-day dosing cycle, and wherein the second phase includes administering sivostomumab to the subject at a target dose of 40 mg on Day 1 and Day 15 of C1, C2, C3, C4 and C5; and (iii) a third phase, which includes a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6) and a seventh dosing cycle (C7), wherein each dosing cycle of the third phase is a 28-day dosing cycle, and wherein the third phase includes administering sivostomumab at a target dose of 40 mg on Day 1 of C1, C2, C3, C4, C5, C6 and C7. BRIEF DESCRIPTION OF THE DRAWINGS

[0144] Figure 1 A schematic diagram of a 28-day dosing cycle schedule for subcutaneous administration of silvostomumab is shown. Briefly, in cycle 1, silvostomumab is administered starting with a step-up dose on days 1 and 8, followed by a target dose on day 15. In cycles 2 to 6, silvostomumab is administered Q2W at a target dose. In cycles 7 to 13, silvostomumab is administered Q4W at a target dose.

[0145] Figure 2 Schematic diagram showing abdominal injection sites and rotation of injection sites. Sivosutumab can be administered subcutaneously to the patient into the subcutaneous tissue of the abdomen. The abdomen can be divided into 4 quadrants, and the injection sites can be rotated as shown. DETAILED DESCRIPTION

[0146] I. Definitions

[0147] As used herein, the term "about" refers to the common error range for the corresponding value that is readily known to those skilled in the art. Reference herein to "about" a value or parameter includes (and describes) aspects relating to the value or parameter itself.

[0148] It should be understood that aspects of the invention described herein include "comprising," "consisting of," and "consisting essentially of" aspects.

[0149] As used herein, the term "FcRH5" or "anti-crystallizable fragment receptor-like 5" refers to any native FcRH5 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated, and encompasses "full-length," unprocessed FcRH5, as well as any form of FcRH5 produced by processing in cells. The term also encompasses naturally occurring variants of FcRH5, including, for example, splice variants or allelic variants. FcRH5 includes, for example, human FcRH5 protein (UniProtKB / Swiss-Prot ID: Q96RD9.3), which is 977 amino acids in length.

[0150] The terms "anti-FcRH5 antibody" and "antibody that binds to FcRH5" refer to an antibody that is capable of binding to FcRH5 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent targeting FcRH5. In one embodiment, the extent of binding of an anti-FcRH5 antibody to an unrelated, non-FcRH5 protein is less than about 10% of the extent of binding of the antibody to FcRH5, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the antibody that binds to FcRH5 has a binding affinity of ≤1 μM, ≤250 nM, ≤100 nM, ≤15 nM, ≤10 nM, ≤6 nM, ≤4 nM, ≤2 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 -8 M or less, for example, 10 -8 M to 10 -13 M, for example, 10 -9 M to 10 -13 The 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.

[0151] Unless otherwise indicated, the term "cluster of differentiation 3" or "CD3" as used herein refers to any native CD3 from any vertebrate source, including, for example, 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 produced by processing in cells. The term also encompasses naturally occurring variants of CD3, including, for example, splice variants or allelic variants. CD3 includes, for example, a human CD3ε protein (NCBI RefSeq No. NP_000724) having a length of 207 amino acids and a human CD3γ protein (NCBI RefSeq No. NP_000064) having a length of 182 amino acids.

[0152] The terms "anti-CD3 antibody" and "antibody that binds to CD3" refer to an antibody that is capable of binding to CD3 with sufficient affinity such that the antibody can be used as a diagnostic and / or therapeutic agent targeting CD3. In one embodiment, the extent of binding of the anti-CD3 antibody to an unrelated, non-CD3 protein is less than about 10% of the extent of binding of the antibody to CD3, as measured, for example, by a radioimmunoassay (RIA). In certain embodiments, the antibody that binds to CD3 has a binding 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 smaller, e.g. 10 -8 M to 10 -13 M, for example 10 -9 M to 10 -13 The dissociation constant (K D In certain embodiments, the anti-CD3 antibody binds to an epitope of CD3 that is conserved in CD3 from different species.

[0153] For the purposes of this article, "Sivositumab" is also referred to as BFCR4350A or RO7187797, which is an Fc-engineered, humanized, full-length aglycosylated IgG1κ T cell-dependent bispecific antibody (TDB) that binds to FcRH5 and CD3 and comprises an anti-FcRH5 arm comprising a heavy chain polypeptide sequence of SEQ ID NO:35 and a light chain polypeptide sequence of SEQ ID NO:36, and an anti-CD3 arm comprising a heavy chain polypeptide sequence of SEQ ID NO:37 and a light chain polypeptide sequence of SEQ ID NO:38. Sivositumab contains an amino acid substitution of threonine to tryptophan at position 366 of the anti-FcRH5 arm (T366W) using EU numbering of amino acid residues in the Fc region, and three amino acid substitutions on the heavy chain of the anti-CD3 arm (Y407V, T366S, and L368A) using EU numbering of amino acid residues in the Fc region (a tyrosine to valine substitution at position 407, a threonine to serine substitution at position 366, and a leucine to alanine substitution at position 368) to drive heterodimerization of the two arms (half antibody). Sivositumab also contains an amino acid substitution (N297G) at position 297 on each heavy chain using EU numbering of amino acid residues in the Fc region, which results in a minimal aglycosylated antibody that binds to Fc (Fcγ) receptors and thereby prevents Fc effector function. Sivostomumab is also described in the following document: WHO Drug Information (International Nonproprietary Names), Proposed INN: List 84, Volume 34, Issue 3, published in 2020 (see page 701).

[0154] The term "antibody" herein is used in the broadest sense and covers various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) and antibody fragments (e.g., bis-Fab), so long as they exhibit the desired antigen-binding activity.

[0155] "Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y can generally be expressed by the dissociation constant (K D ) represents. Affinity can be measured by conventional methods known in the art, including those described herein. Specific illustrative and exemplary aspects for measuring binding affinity are described below.

[0156] An "affinity matured" antibody is one with one or more alterations in one or more hypervariable regions (HVRs) which result in an improvement in the affinity of the antibody for antigen, compared to a parent antibody which does not possess such alterations.

[0157] 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 a native antibody structure or having heavy chains that contain an Fc region as defined herein.

[0158] "Antibody fragment" refers to a molecule other than an intact antibody that contains a portion of an intact antibody and binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to: bis-Fab; Fv; Fab; Fab'-SH; F(ab') 2 ; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv, ScFab); and multispecific antibodies formed from antibody fragments.

[0159] "Single domain antibody" refers to an antibody fragment that contains all or part of the heavy chain variable domain or all or part of the light chain variable domain of an antibody. In certain aspects, a single domain antibody is a human single domain antibody (see, e.g., U.S. Patent No. 6,248,516B1). Examples of single domain antibodies include, but are not limited to, VHH.

[0160] The "Fab" fragment is an antigen-binding fragment produced by papain digestion of an antibody and consists of an intact L chain as well as the variable region domain of the H chain (VH) 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 produces a single large F(ab') 2 A fragment that is roughly equivalent to two Fab fragments connected by disulfide bonds with divalent antigen binding activity and still capable of cross-linking antigens. The difference between the Fab fragment and the Fab fragment is that the Fab fragment has some residues added to the carboxyl terminus of the CH1 domain, which contain one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine ​​residues of the constant domains carry free thiol groups. F(ab') 2 Antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them.Other chemical couplings of antibody fragments are also known.

[0161] "Fv" consists of a tight, non-covalently associated dimer of a heavy chain variable region domain and a light chain variable region domain. Six hypervariable loops (3 loops each from the H chain and L chain) are generated by the folding of these two domains, which contribute amino acid residues to achieve antigen binding and provide the antibody with antigen binding specificity. However, even a single variable domain (or half of an Fv, containing only three CDRs specific for an antigen) has the ability to recognize and bind to an antigen, although its affinity is often lower than that of the complete binding site.

[0162] The term "Fc region" herein is used to define the C-terminal region of an immunoglobulin heavy chain, which includes a native sequence Fc region and a variant Fc region. Although the boundaries of an immunoglobulin heavy chain Fc region may vary, the human IgG heavy chain Fc region is generally defined as extending from the amino acid residue at position Cys226 or from Pro230 to the carboxyl terminus of the heavy chain. The C-terminal lysine in the Fc region (residue 447 according to the EU numbering system) can be removed in, for example, the production or purification process of an antibody or by recombinantly designing a nucleic acid encoding an antibody heavy chain. Therefore, the composition of a complete antibody can include an antibody population removing all Lys447 residues, an antibody population not removing Lys447 residues, and an antibody population with and without an antibody mixture containing Lys447 residues.

[0163] A "functional Fc region" has the "effector functions" of a native sequence Fc region. Exemplary "effector functions" include C1q binding; complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptor; BCR); B cell activation, etc. Such effector functions generally require an Fc region in combination with a binding domain (e.g., an antibody variable domain), and can be assessed using various assays disclosed, for example, in the definitions herein.

[0164] A "native sequence Fc region" comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include native sequence human IgG1 Fc regions (non-A and A allotypes); native sequence human IgG2 Fc regions; native sequence human IgG3 Fc regions; and native sequence human IgG4 Fc regions and naturally occurring variants thereof.

[0165] A "variant Fc region" comprises an amino acid sequence that differs from a native sequence Fc region by virtue of at least one amino acid modification, preferably one or more amino acid substitutions. Preferably, the variant Fc region has at least one amino acid substitution compared to the native sequence Fc region or the Fc region of a parent polypeptide, for example, from about one to about ten amino acid substitutions in the native sequence Fc region or the Fc region of a parent polypeptide, and preferably from about one to about five amino acid substitutions. The variant Fc regions described herein preferably have at least about 80% homology with the native sequence Fc region and / or with the Fc region of a parent polypeptide, preferably at least about 90% homology therewith, or preferably at least about 95% homology therewith.

[0166] As used herein, "Fc complex" refers to the CH3 domains of two Fc regions interacting together to form a dimer, or in certain aspects, two Fc regions interacting to form a dimer, wherein the cysteine ​​residues in the hinge region and / or the CH3 domains interact through bonds and / or forces (e.g., van der Waals forces, hydrophobic forces, hydrogen bonds, electrostatic forces, or disulfide bonds).

[0167] The term "FcRH5 positive cells" refers to a cancer comprising cells expressing FcRH5 on their surface. For the purpose of determining whether a cell expresses FcRH5 on the surface, FcRH5 mRNA expression is considered to be associated with FcRH5 expression on the cell surface. In some embodiments, the expression of FcRH5 mRNA is determined by a method selected from in situ hybridization and RT-PCR (including quantitative RT-PCR). Alternatively, the expression of FcRH5 on the cell surface can be determined, for example, using antibodies against FcRH5 in methods such as immunohistochemistry, FACS, etc. In some embodiments, FcRH5 is one or more of FcRH5a, FcRH5b, FcRH5c, UniProt identifier Q96RD9-2 and / or FcRH5d. In some embodiments, FcRH5 is FcRH5c.

[0168] The "hinge region" is generally defined as stretching from about residues 216 to 230 of IgG (EU numbering), from about residues 226 to 243 of IgG (Kabat numbering), or from about residues 1 to 15 of IgG (IMGT unique numbering).

[0169] The "lower hinge region" of an Fc region is generally defined as the stretch of residues immediately C-terminal to the hinge region, ie, residues 233 to 239 (EU numbering) of the Fc region.

[0170] "Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. The preferred FcR is a native sequence human FcR. In addition, the preferred FcR is an FcR that binds to IgG antibodies (a gamma receptor), and includes receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. FcγRII receptors include FcγRIIA ("activating receptor") and FcγRIIB ("inhibiting receptor"), which have similar amino acid sequences, the main difference being 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 inhibition motif (ITIM) in its cytoplasmic domain (see Annu. Rev. Immunol. 15: 203-234, 1997 (M.). 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). The term "FcR" herein encompasses other FcRs, including those to be identified in the future. The term also includes the neonatal receptor FcRn, which is responsible for 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)).

[0171] As described herein, the term "knob-into-hole" or "KnH" technology refers to a technique for directing the pairing of two polypeptides together in vivo or in vitro by introducing a protrusion (knob) into one polypeptide and a cavity (hole) into the other polypeptide at their interactive interface. For example, KnH has been introduced into the Fc:Fc interaction interface, CL:CH1 interface, or VH / VL interface of antibodies (e.g., US2007 / 0178552, WO 96 / 027011, WO 98 / 050431, and Zhu et al., (1997) Protein Science 6:781-788). This is particularly useful for driving two different heavy chains to pair together during the preparation of multispecific antibodies. For example, a multispecific antibody having a KnH in its Fc region may further comprise a single variable domain connected to each Fc region, or 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 together two different receptor extracellular domains or any other polypeptide sequences containing different target recognition sequences.

[0172] "Framework" or "FR" refers to the variable domain residues other than the hypervariable region (HVR) residues. The FR of the variable domain is usually composed of the following four FR domains: FR1, FR2, FR3 and FR4. Therefore, HVR and FR sequences usually appear in the following sequence in VH (or VL): FR1-H1 (L1)-FR2-H2 (L2)-FR3-H3 (L3)-FR4.

[0173] A "CH1 region" or "CH1 domain" comprises a stretch of residues extending from about residue 118 to residue 215 of IgG (EU numbering), from about residue 114 to residue 223 of IgG (Kabat numbering), or from about residue 1.4 to residue 121 of IgG (IMGT unique numbering) (Lefranc et al., the international ImMunoGeneTics information 25yearson. Nucleic Acids Res. 2015 Jan;43(Database issue):D413-22).

[0174] The "CH2 domain" of the human IgG Fc region generally extends from about 244 to about 360 (Kabat numbering) of IgG, from about 231 to about 340 (EU numbering) of IgG, or from about 1.6 to about 125 (IGMT unique numbering) of IgG. The uniqueness of the CH2 domain is that it is not tightly paired with another domain. In contrast, two N-connected branched carbohydrate chains are between the two CH2 domains of the complete native IgG molecule. It is speculated that carbohydrates may provide alternatives for domain-domain pairing and help stabilize the CH2 domain. Burton, Molec. Immunol. 22: 161-206 (1985).

[0175] A “CH3 domain” comprises a stretch of residues extending C-terminally of the CH2 domain in the Fc region (i.e., from about amino acid residue 361 to about amino acid residue 478 of IgG (Kabat numbering), from about amino acid residue 341 to about amino acid residue 447 of IgG (EU numbering), or from about amino acid residue 1.4 to about amino acid residue 130 of IgG (IGMT unique numbering)).

[0176] The "CL domain" or "constant light domain" comprises a stretch of residues extending from the C-terminus of the light chain variable domain (VL). The light chain (LC) of an antibody can be a kappa (κ) ("Cκ") or lambda (λ) ("Cλ") light chain region. The Cκ region typically extends from about residue 108 to residue 214 of IgG (Kabat or EU numbering) or from about residue 1.4 to residue 126 of IgG (IMGT unique numbering). The Cλ residues typically extend 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).

[0177] The term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0178] The "class" of an antibody refers to the type of constant domain or region possessed by the heavy chain of the antibody. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these antibodies can be further divided into subclasses (isotypes), such as IgG 1 IgG 2 IgG 3 IgG 4 , IgA 1 and IgA 2 The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0179] A "human antibody" is an antibody having an amino acid sequence corresponding to the amino acid sequence of an antibody produced by a human or human cell, or derived from an antibody of non-human origin using a full repertoire of human antibodies or other human antibody coding sequences. This definition of a human antibody specifically excludes humanized antibodies comprising non-human antigen binding residues. Human antibodies can be produced using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol. 227: 381, 1991; Marks et al., J. Mol. Biol. 222: 581, 1991. Methods for preparing human monoclonal antibodies can also be described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147 (1): 86-95, 1991. See also van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74, 2001. Human antibodies can be prepared by administering an antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge but whose endogenous loci have been disabled, e.g., immunized xenogeneic mice (see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 for XENOMOUSE TM Technology). See also, e.g., Li et al., Proc. Natl. Acad. Sci. USA. 103:3557-3562, 2006 for human antibodies generated via human B cell hybridoma technology.

[0180] "Human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. In general, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. In general, the subgroup of sequences is a subgroup as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, NIH Publication 91-3242, Bethesda MD (1991), Volumes 1-3. In one aspect, for VL, the subgroup is subgroup κI as in Kabat et al. (supra). In one aspect, for VH, the subgroup is subgroup III as in Kabat et al. (supra).

[0181] "Humanized" antibody refers to such chimeric antibody, which includes amino acid residues from non-human HVR and amino acid residues from human FR. In some aspects, humanized antibody will substantially include all at least one, usually two variable domains, wherein all or substantially all HVR (e.g., CDR) correspond to the HVR of non-human antibodies, and all or substantially all FRs correspond to the FRs of human antibodies. In some aspects where all or substantially all FRs of humanized antibodies correspond to the FRs of human antibodies, any FR of humanized antibodies may contain one or more amino acid residues from non-human FRs (e.g., one or more vernier position residues of FR). Humanized antibodies may optionally include at least a portion of an antibody constant region derived from a human antibody. "Humanized form" antibodies, such as non-human antibodies, refer to antibodies that have undergone humanization.

[0182] The term "variable region" or "variable domain" refers to the domain of an antibody heavy chain or light chain that participates in the binding of an antibody to an antigen. The variable domains of the heavy and light chains of natural antibodies (VH and VL, respectively) generally have similar structures, wherein each domain comprises four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, e.g., Kindt et al., Kuby Immunology, 6th edition WH Freeman and Co., p. 91 (2007).) A single VH or VL domain may be sufficient to confer antigen binding specificity. In addition, antibodies that bind to a specific antigen may be separated using VH or VL domains from antibodies that bind to the antigen, respectively, to screen libraries of complementary VL or VH domains. See, e.g., Portolano et al., J. Immunol. 150: 880-887, 1993; Clarkson et al. Nature 352: 624-628, 1991.

[0183] As used herein, the term "hypervariable region" or "HVR" refers to each region of an antibody variable domain that is hypervariable in sequence (complementarity determining region or CDR). Typically, an antibody comprises six CDRs; three in VH (CDR-H1, CDR-H2, CDR-H3), and three in VL (CDR-L1, CDR-L2, CDR-L3). Exemplary CDRs herein include:

[0184] (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);

[0185] (b) CDRs occurring at the following 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

[0186] (c) Antigenic contact points occur at the following 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).

[0187] Unless otherwise indicated, HVR residues and other residues in the variable domain (eg, FR residues) are numbered herein according to Kabat et al., supra.

[0188] "Single-chain Fv", also abbreviated as "sFv" or "scFv", is an antibody fragment comprising VH and VL antibody domains linked into a single polypeptide chain. Preferably, the scFv polypeptide further comprises a polypeptide linker between the VH and VL domains, allowing the scFv to form a desired antigen binding structure. For a review of scFv, see Pluckthun, The Pharmacology of Monoclonal Antibodies, Vol. 113, Rosenburg and Moore, eds., Springer-Verlag, New York, pp. 269-315 (1994); Malmborg et al., J. Immunol. Methods 183:7-13, 1995.

[0189] "Targeting domain" means a portion of a compound or molecule that specifically binds to a target epitope, antigen, ligand, or receptor. Targeting domains include, but are not limited to, antibodies (e.g., monoclonal antibodies, polyclonal antibodies, recombinant antibodies, humanized antibodies, and chimeric antibodies), antibody fragments or portions thereof (e.g., bi-Fab fragments, Fab fragments, Fab' 2, scFab, scFv antibodies, SMIPs, single domain antibodies, diabodies, minibodies, scFv-Fc, affibodies, nanobodies, and VH and / or VL domains of antibodies), receptors, ligands, aptamers, peptide targeting domains (e.g., cysteine ​​knot proteins (CKPs)) and other molecules with identified binding partners. The targeting domain can target, block, agonize or antagonize the antigen bound to it.

[0190] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, that is, except for possible variant antibodies (e.g., containing naturally occurring mutations or produced during the production of monoclonal antibody preparations, such variants are usually present in small amounts), the single antibody comprising the population has identity and / or binds to the same epitope. Contrary to the polyclonal antibody preparations that generally include different antibodies for different determinants (epitopes), each monoclonal antibody in the monoclonal antibody preparation is directed to a single determinant on the antigen. Therefore, the modifier "monoclonal" represents that the feature of the antibody is obtained from a substantially homogeneous antibody population, and should not be interpreted as requiring antibody to be produced by any ad hoc method. For example, the monoclonal antibody to be used according to the present invention can be prepared by a variety of techniques, including but not limited to hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of human immunoglobulin loci, such methods and other exemplary methods for preparing monoclonal antibodies are described herein.

[0191] The term "multispecific antibody" is used in the broadest sense and specifically encompasses antibodies with multi-epitope specificity. In one aspect, a multispecific antibody binds to two different targets (e.g., a bispecific antibody). Such multispecific antibodies include, but are not limited to, antibodies comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH / VL unit has multi-epitope specificity; antibodies having two or more VL and VH domains, wherein each VH / VL unit binds to a different epitope; antibodies having two or more single variable domains, wherein each single variable domain binds to a different epitope; full-length antibodies; antibody fragments such as Fab, Fv, dsFv, scFv, diabodies, bispecific diabodies and triabodies, covalently or non-covalently linked antibody fragments. "Multi-epitope specificity" refers to the ability to specifically bind to two or more different epitopes on the same or different targets. "Monospecificity" refers to the ability to bind only one antigen. In one aspect, a monospecific bi-epitope antibody binds to two different epitopes on the same target / antigen. In one aspect, a monospecific multi-epitope antibody binds to multiple different epitopes of the same target / antigen. According to one aspect, a multispecific antibody is an IgG antibody that binds to each epitope with an affinity of 5 μM to 0.001 pM, 3 μM to 0.001 pM, 1 μM to 0.001 pM, 0.5 μM to 0.001 pM, or 0.1 μM to 0.001 pM.

[0192] A "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (eg, a cytotoxic moiety) or a radiolabel. Naked antibodies can be present in pharmaceutical preparations.

[0193] "Natural antibodies" refer to naturally occurring immunoglobulin molecules with different structures. For example, natural IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons, consisting of two identical light chains and two identical heavy chains bonded by disulfide bonds. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also referred to as a variable heavy chain domain or a 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 referred to as a variable light chain domain or a light chain variable domain, followed by a constant light chain (CL) domain. The light chain of an antibody can be classified into one of two types based on the amino acid sequence of its constant domain, which are called kappa (κ) and lambda (λ).

[0194] As used herein, the term "immunoadhesin" refers to a molecule that combines the binding specificity of a heterologous protein ("adhesin") with the effector function of an immunoglobulin constant domain. Structurally, an immunoadhesin comprises a fusion of an amino acid sequence with a desired binding specificity and an immunoglobulin constant domain sequence (e.g., CH2 and / or CH3 sequence of IgG), which is not an antigen recognition and binding site of an antibody (i.e., "heterologous" compared to the constant region of an antibody). Adhesin and immunoglobulin constant domains may optionally be separated by an amino acid spacer sequence. Exemplary adhesin sequences include continuous amino acid sequences that include a portion of a receptor or ligand that binds to a target protein. Adhesin sequences may also be sequences that bind to a target protein, but are not receptor or ligand sequences (e.g., adhesin sequences in peptibodies). Such polypeptide sequences may be selected or identified by various methods, including phage display technology and high-throughput sorting methods. The immunoglobulin constant domain sequences in the immunoadhesins may be obtained from any immunoglobulin, such as IgG1, IgG2, IgG3 or IgG4 subtypes, IgA (including IgA1 and IgA2), IgE, IgD or IgM.

[0195] "Chemotherapeutic agents" include chemical compounds that can be used to treat cancer. Examples of chemotherapeutic agents include erlotinib ( Genentech / OSI Pharm.), bortezomib ( MillenniumPharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant ( AstraZeneca), sunitinib ( Pfizer / Sugen), letrozole ( Novartis), imatinib mesylate ( Novartis、finasunate( Novartis), oxaliplatin ( Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (Sirolimus, Wyeth), lapatinib ( GSK572016, GlaxoSmith Kline), lonafamib (SCH 66336), sorafenib ( Bayer Labs), gefitinib ( AstraZeneca), AG1478, alkylating agents such as thiotepa andCyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethyleneimines and methylmelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylmelamine; annona lactones (especially bullatacin and bullatacinone); e)); camptothecins (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogs adolesin, carzelesin and biszelesin); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); adrenocortical steroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductase inhibitors (including finasteride and dutasteride); vorinostat, romidepsin, panbistat, valproic acid, moxifloxacin mocetinostat, dolastatin; aldesleukin, talcumin (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards, such as chlorambucil, chlomaphazine, clofosamide, estramustine , ifosfamide, mechlorethamine, mechlorethamine hydrochloride, melphalan, nebiquinol, phenamicin, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimnustine; antibiotics such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma 1I and calicheamicin omega 1I (Angew Chem. Intl. Ed. Engl.1994 33:183-186); dynemicins, including dynemicin A; bisphosphonates such as clodronate; esperamicins; and the neocarcinogens and related chromoprotein enediyne antibiotic chromophores), aclacinomycins, actinomycins, authramycins, azaserines, bleomycins, cactinomycins, carabicins, caminomycins, carzinophilins, chromomycins, dactinomycins, daunomycins, detorubicin, 6-diazo-5-oxo-L-norleucine, (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrroline-doxorubicin and deoxydoxorubicin), epirubicin, isorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogamycin, olivetomycin, peplomycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozotocin, tuberculin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluoro Uracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimesate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxefuroxime, enocitabine, floxuridine; androgens such as calutosterone, drostanolone propionate, cyclothiodine, melastosane, testolactone; antiadreners such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folinic acid (frolinic acid), leucovorin, doxycycline, cyclopentolone, doxycycline ... acid; aceglucuronide; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diazocine; elfomithine; elliptinium acetate; epothilone; etoglucone; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansines, such as maytansine and ansamitocin; mitoguanidine; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanamine; tenuisporic acid; triazoquinone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, mycloracin A, and anguidine); urethan; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulanol; pipobroman; gacytosine; cytarabine ("Ara-C"); cyclophosphamide; thiotepa; taxanes, such as TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), (without Cremophor), albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and (docetaxel, docetaxel; Sanofi-Aventis); chlorambucil; (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; (Changchunorelbine); Novantrone; Teniposide; Edatrexate; Daunorubicin; Aminopterin; Capecitabine Ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinols, such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.

[0196] Chemotherapeutic agents also include: (i) antihormonal agents that act to modulate or inhibit the effects of hormones on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including Tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and (toremifine citrate); (ii) aromatase inhibitors that inhibit aromatase, an enzyme that regulates estrogen production by the adrenal glands, such as, for example, 4(5)-imidazole, aminoglutethimide, (Megestrol acetate), (exemestane; Pfizer), formestanie, fadrozole, (vorozole), (letrozole; Novartis) and (anastrozole; AstraZeneca); (iii) antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all trans-retinoic acid, fenretinide, and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways associated with abnormal cell proliferation, such as, for example, PKC-α, Ralf, and H-Ras; (vii) ribozymes, such as inhibitors of VEGF expression (e.g., ) and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, e.g. and rIL-2; topoisomerase 1 inhibitors, such as rmRH; and (ix) any of the pharmaceutically acceptable salts, acids and derivatives of the foregoing.

[0197] Chemotherapeutic agents also include antibodies, such as alemtuzumab (Campath), bevacizumab ( Genentech; Cetuximab ( Imclone; Panitumumab ( Amgen), rituximab ( Genentech / Biogen Idec), Pertuzumab ( 2C4, Genentech), trastuzumab ( Genentech), tositumomab (Bexxar, Corixia) and antibody-drug conjugates, gemtuzumab ozogamicin ( Other humanized monoclonal antibodies with therapeutic potential for use as agents in combination with the compounds of the present invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedilizumab, certolizumab pegol-conjugated pegol), cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin), ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab umab), reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumabtetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumabcelmoleukin), tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and anti-IL-12 (ABT-874 / J695, Wyeth Research and Abbott Laboratories), a recombinant, fully human sequence-specific IgG1λ antibody genetically modified to recognize the IL-12p40 protein.

[0198] Chemotherapeutic agents also include "EGFR inhibitors", which refer to compounds that bind to or directly interact with EGFR and prevent or reduce its signaling activity, and are alternatively referred to as "EGFR antagonists". Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies that bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see U.S. Pat. No. 4,943,533) and variants thereof, such as chimeric 225 (C225 or cetuximab; ) and reshaped human 225 (H225) (see WO 96 / 40210, Imclone Systems Inc.); IMC-11F8, a fully human antibody targeting EGFR (Imclone); antibodies that bind to type II mutant EGFR (U.S. Pat. No. 5,212,290); humanized and chimeric antibodies that bind to EGFR as described in U.S. Pat. No. 5,891,996; and human antibodies that bind to EGFR, such as ABX-EGF or panitumumab (see WO 98 / 50433, Abgenix / Amgen); EMD 55900 (Stragliotto et al., Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab), a humanized EGFR antibody against EGFR that competes with both EGF and TGF-α for binding to EGFR (EMD / Merck); human EGFR antibody, HuMax-EGFR (GenMab); fully human antibodies referred to as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3 and described in US 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)). Anti-EGFR antibodies can be conjugated to cytotoxic agents to generate immunoconjugates (see, e.g., EP659,439A2, Merck Patent GmbH). EGFR antagonists include small molecules, such as 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, and the following PCT publications: WO98 / 14451, WO98 / 50038, WO99 / 09016 and WO99 / 24037. Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, Genentech / OSI Pharmaceuticals); PD 183805 (CI 1033, 2-acrylamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer); ZD1839, gefitinib 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 (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 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-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR / HER2 tyrosine kinase inhibitors such as lapatinib ( GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[(2-methylsulfonyl)ethyl]amino]methyl]-2-furyl]-4-quinazolinamine).

[0199] 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 Pharmaceuticals; CP-724,714, an oral selective inhibitor of ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual HER inhibitors, such as EKB-569 (available from Wyeth), which preferentially binds to EGFR but simultaneously inhibits cells overexpressing HER2 and EGFR; lapatinib (GSK572016; available from GlaxoSmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors, such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors, such as ISIS-5132, an antisense agent that inhibits Raf-1 signaling, available from ISIS Pharmaceuticals; non-HER targeted TK inhibitors, such as imatinib mesylate ( available from GlaxoSmithKline); multitargeted tyrosine kinase inhibitors such as sunitinib ( VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787 / ZK222584, available from Novartis / Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines such as PD153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines such as CGP59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; curcumin (difluoroformylmethane, 4,5-bis(4-fluoroanilino)phthalimide); tyrosine containing a nitrothiophene moiety; PD-0183805 (Warner-Lamber); antisense molecules (e.g., molecules that bind to HER encoding nucleic acids); quinoxalines (U.S. Pat. No. 5,804,396); tyrosine phosphorylation inhibitors (U.S. Pat. No. 5,804,396); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); pan-HER inhibitors, such as CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis / Lilly); imatinib mesylate PKI 166 (Novartis); GW2016 (GlaxoSmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); seramatinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering); INC-1C11 (Imclone), rapamycin (sirolimus, ); or any of the following patent publications: U.S. Pat. No. 5,804,396, WO 1999 / 09016 (American Cyanamid), WO 1998 / 43960 (American Cyanamid), WO 1997 / 38983 (Warner Lambert), WO 1999 / 06378 (Warner Lambert), WO 1999 / 06396 (Warner Lambert), WO 1996 / 30347 (Pfizer, Inc), WO 1996 / 33978 (Zeneca), WO 1996 / 3397 (Zeneca), and WO 1996 / 33980 (Zeneca).

[0200] Chemotherapeutic agents also include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, live BCG, bevacizumab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, erlotinib, filgrastim, histrelin acetate, acetate), ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium sodium), quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate and zoledronic acid and pharmaceutically acceptable salts thereof.

[0201] Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, thiocortisone pivalate, triamcinolone acetonide, triamcinolone acetonide alcohol, mometasone, amcinonide, budesonide, desonide, fluocortolone acetate, fluocinolone, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone hexanoate, fluocortolone valerate, and flupredniidine acetate; immunoselective anti-inflammatory peptides (ImSAIDs), such as phenylalanine-glutamine-glycine (FEG) and its D-isomer 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 Interleukin 13 (IL-13) blockers, such as lebrikizumab; interferon alpha (IFN) blockers, such as lonavirin; β7 integrin blockers, such as rhuMAb β7; IgE pathway blockers, such as anti-M1 primers; 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 、Bi 212 , P 32 , Pb 212and radioisotopes of Lu); various experimental agents such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3, or farnesyltransferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavins, flavanols, proanthocyanidins, betulinic acid and its derivatives; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, ); β-lapachone; lapachol; colchicine; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin); podophyllotoxin; tegafur Bexarotene Bisphosphonates, such as clodronate (e.g. or ), etidronate NE-58095, Zoledronic Acid / Zoledronate Alendronate Pamidronate Tirodronate Risedronate and epidermal growth factor receptor (EGF-R); vaccines such as Vaccines; Perifosine; COX-2 inhibitors (e.g., celecoxib or etoricoxib); proteosome inhibitors (e.g., PS341); CCI-779; Tipifarnib (R11577); Orafenib, ABT510; Bcl-2 inhibitors such as oblimersen sodium Pixantrone; farnesyl transferase inhibitors such as lonafarnib (SCH 6636, SARASAR TM ); and pharmaceutically acceptable salts, acids or derivatives of any of the above; and combinations of two or more of the above, such as CHOP (an abbreviation for combination therapy with cyclophosphamide, doxorubicin, vincristine and prednisolone); and FOLFOX (with oxaliplatin (ELOXATIN TM ) is an abbreviation for the treatment regimen of combining 5-FU and leucovorin).

[0202] Chemotherapeutic agents also include nonsteroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory effects.NSAID includes non-selective inhibitors of cyclooxygenase.Specific examples of NSAID include aspirin, propionic acid derivatives (such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen), acetic acid derivatives (such as indomethacin, sulindac, etodolac, diclofenac), enolic acid derivatives (such as piroxicam, meloxicam, tenoxicam, droxicam and lornoxicam), fenamic acid derivatives (such as mefenamic acid, meclofenamic acid, flufenamic acid, toluenesulfonic acid) and COX-2 inhibitors (such as celecoxib, etoricoxib, lumixib, parecoxib, rofecoxib and valdecoxib). NSAIDs may be useful for relieving symptoms of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthritis, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headaches and migraines, postoperative pain, mild to moderate pain due to inflammation and tissue damage, fever, intestinal obstruction, and renal colic.

[0203] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cellular function and / or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (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, doxorubicin 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 small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof; and various anti-tumor or anti-cancer drugs disclosed below.

[0204] A "disorder" is any condition that would benefit from treatment, including, but not limited to, chronic and acute conditions or diseases, including those pathological conditions that predispose a mammal to the disorder. In one aspect, the disorder is cancer, e.g., a B-cell proliferative disorder such as MM (e.g., relapsed or refractory MM).

[0205] The terms "cell proliferative disorder" and "proliferative disease" refer to conditions 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.

[0206] As used herein, the term "tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. The terms "cancer," "cancerous," "cell proliferative disorder," "proliferative disorder," and "tumor" are not mutually exclusive herein.

[0207] The terms "cancer" and "cancerous" refer to or describe a physiological condition in mammals that is generally 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 may be relapsed or refractory MM. MM may be, for example, classic MM (e.g., immunoglobulin G (IgG) MM, IgA MM, IgD MM, IgE MM, or IgM MM), light chain MM (LCMM) (e.g., λ light chain MM or κ light chain MM), or non-secretory MM. MM may 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) (as described in Table 1 and the International Myeloma Working Group (IMWG) criteria provided in Sonneveld et al., Blood, 127(24):2955-2962, 2016), and / or 1q21 (as described in Chang et al., Bone Marrow Transplantation, 45:117-121, 2010). Cytogenetic features can be detected, for example, using fluorescent in situ hybridization (FISH). Examples of solid tumors include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma), peritoneal cancer, hepatocellular carcinoma, gastric cancer (including gastrointestinal cancer and gastrointestinal stromal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urinary tract cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, anal cancer, penile cancer, melanoma, superficial spreading melanoma, tonsillar malignant melanoma, acral lentiginous melanoma, nodular melanoma, and abnormal vascular proliferation associated with nevus hamartomas, edema (such as associated with brain tumors), Meigs syndrome, brain cancer, and head and neck cancer and related metastases. In certain embodiments, cancers suitable for treatment by the antibodies of the invention include breast cancer, colorectal cancer, rectal cancer, non-small cell lung cancer, glioblastoma, non-Hodgkin lymphoma (NHL), renal cell carcinoma, prostate cancer, liver cancer, pancreatic cancer, soft tissue sarcoma, Kaposi's sarcoma, carcinoid cancer, head and neck cancer, ovarian cancer, and mesothelioma.

[0208] Table 1. Cytogenetic characteristics of MM

[0209]

[0210]

[0211] The term "B cell proliferative disorder" or "B cell malignancy" refers to a disorder associated with some degree of abnormal B cell proliferation, and includes, for example, lymphoma, leukemia, myeloma, and myelodysplastic syndrome. In one embodiment, the B cell proliferative disorder is a lymphoma, such as non-Hodgkin's lymphoma (NHL), including, for example, diffuse large B cell lymphoma (DLBCL) (e.g., relapsed or refractory DLBCL). In another embodiment, the B cell proliferative disorder is a leukemia, such as chronic lymphocytic leukemia (CLL). Other specific examples of cancer include germinal center B cell-like (GCB) diffuse large B cell lymphoma (DLBCL), activated B cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenstrom's macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt's lymphoma (BL), precursor B cell lymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma / leukemia (unclassifiable), splenic diffuse red pulp small B cell lymphoma, variant hairy cell leukemia, heavy chain disease (alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease), plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmacytoma, mucosal leukemia, Extranodal marginal zone lymphoma of 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 DLBCL of the CNS, primary cutaneous DLBCL (leg type), EBV-positive DLBCL of the elderly, DLBCL associated with chronic inflammation, lymphomatoid granuloma, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma due to HHV8-associated multicentric Castleman disease, primary effusion lymphoma: B-cell lymphoma (unclassifiable, with features intermediate between DLBCL and Burkitt's lymphoma), and B-cell lymphoma (unclassifiable, with features intermediate between DLBCL and classical Hodgkin's lymphoma). Other examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies, including 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 lymphoblastic NHL; high-grade small non-truncated cell NHL; bulky disease NHL; AIDS-related lymphoma; and acute lymphoblastic leukemia (ALL); chronic myeloid leukemia; and post-transplant lymphoproliferative disorder (PTLD).

[0212] "Complement-dependent cytotoxicity" or "CDC" refers to the lysis of target cells in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to antibodies (of the appropriate subclass) bound to its cognate antigen. To assess complement activation, a CDC assay may be performed, e.g., as described in Gazzano-Santoro et al., J. Immunol. Methods 202: 163 (1996).

[0213] "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a form of cytotoxicity in which secreted Ig binds to Fc receptors (FcRs) present on certain cytotoxic cells (e.g., natural killer (NK) cells, neutrophils, and macrophages), allowing these cytotoxic effector cells to specifically bind to target cells bearing antigens and subsequently kill the target cells with cytotoxic agents. Antibodies "arm" cytotoxic cells and are required for such killing. NK cells, the main cells that mediate ADCC, express only FcγRIII, while monocytes express FcγRI, FcγRII, and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 3 of Ravetch and Kinet.Annu.Rev.Immunol.9:457-92, 1991, page 464. To assess the ADCC activity of a target molecule, an in vitro ADCC assay, such as that described in U.S. Pat. No. 5,500,362 or 5,821,337, may be performed. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells. Alternatively or additionally, the ADCC activity of the target molecule can be assessed in vivo, for example, in an animal model (such as disclosed in Clynes et al., Proc. Natl. Acad. Sci. USA. 95: 652-656, 1998).

[0214] As used herein, "complex" or "complexed" refers to the association of two or more molecules that interact with each other through bonds and / or forces other than peptide bonds (e.g., van der Waals forces, hydrophobic forces, hydrophilic forces). In one aspect, the complex is a heteromultimer. It should be understood that the term "protein complex" or "polypeptide complex" as used herein includes complexes of non-protein entities (e.g., including but not limited to chemical molecules such as toxins or detection agents) conjugated to proteins in the protein complex.

[0215] As used herein, "delaying progression" of a disorder or disease means slowing, hindering, slowing, delaying, stabilizing, and / or postponing the development of a disease or disorder (e.g., a cell proliferative disorder, e.g., cancer (e.g., MM)). Such a delay may be of varying lengths of time, depending on the medical history and / or the individual to be treated. It will be apparent to one skilled in the art that a substantial or significant delay may actually encompass prevention, in that the individual will not develop the disease. For example, the development of an advanced cancer, such as metastasis, may be delayed.

[0216] An "effective amount" of a compound (e.g., an anti-FcRH5 / anti-CD3 T cell-dependent bispecific antibody (TDB) disclosed herein) or a composition thereof (e.g., a pharmaceutical composition) is at least the minimum amount required to achieve a desired therapeutic or preventive result, such as a measurable improvement or prevention of a particular disorder (e.g., a cell proliferative disorder, such as cancer). The effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in an individual. An effective amount is also an amount in which any toxic or deleterious effects of the treatment are outweighed by the beneficial effects of the treatment. For preventive uses, beneficial or expected results include, for example, elimination or reduction of risk, lessening of severity, or delay of disease onset, including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that occur during the course of disease progression. For therapeutic uses, beneficial or expected results include clinical results, such as reduction of one or more symptoms caused by the disease, improvement of the quality of life of the patient, reduction of the dose of other drugs required to treat the disease, enhancement of the effects of other drugs (such as by targeting, slowing disease progression, and / or prolonging survival). In the case of cancer or tumors, an effective amount of a drug may reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down or expect to stop to some extent) cancer cell infiltration into surrounding organs; inhibit (i.e., slow down and expect to stop to some extent) tumor metastasis; inhibit the growth of tumors to some extent; and / or alleviate one or more symptoms associated with the condition to some extent. An effective amount may be administered once or multiple times. For the purposes of the present invention, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to prevent or treat directly or indirectly. As understood in a clinical context, 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. Therefore, an "effective amount" may be considered in the context of administering one or more therapeutic agents, and if the desired result can be obtained or achieved in combination with one or more other agents, an effective amount of a single agent may be considered.

[0217] As used herein, "overall survival" or "OS" refers to the percentage of individuals in a group of individuals who are likely to survive after a specific period of time.

[0218] As used herein, "objective response rate" (ORR) refers to the sum of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) rates determined using the International Myeloma Working Group response criteria (e.g., see Tables 8A and 8B in Example 1).

[0219] The term "epitope" refers to a specific site on an antigen molecule to which an antibody binds. In some aspects, the specific site on an antigen molecule to which an antibody binds is determined by hydroxyl radical footprinting. In some aspects, the specific site on an antigen molecule to which an antibody binds is determined by crystallography.

[0220] As used herein, "growth inhibitor" refers to a compound or composition that inhibits cell growth in vitro or in vivo. In one aspect, a growth inhibitor is a growth inhibitory antibody that prevents or reduces the proliferation of cells expressing the antigen to which the antibody binds. On the other hand, a growth inhibitor can be an inhibitor that significantly reduces the percentage of cells in the S phase. Aspects of growth inhibitors include agents that block cell cycle progression (in places other than the S phase), such as agents that induce G1 arrest and M phase arrest. Classical M phase blockers include periwinkle (vincristine and vinblastine), taxanes, and topoisomerase II inhibitors (e.g., doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin). Those agents that block G1 also overflow into S phase arrest, such as DNA alkylating agents, such as tamoxifen, prednisone, dacarbazine, nitrogen mustard, cisplatin, methotrexate, 5-fluorouracil, and ara-C. Further information can be found in Chapter 1 by Murakami et al., entitled "Cell cycle regulation, oncogenes, and antineoplastic drugs" in Mendelsohn and Israel, eds., The Molecular Basis of Cancer (WB Saunders, Philadelphia, 1995), e.g., page 13. Taxanes (paclitaxel and docetaxel) are both anticancer drugs derived from yew. Docetaxel ( Rhone-PoulencRorer) is derived from European yew and is a semi-synthetic analog of paclitaxel ( Bristol-Myers Squibb). Paclitaxel and docetaxel promote microtubule assembly of tubulin dimers and stabilize microtubules by preventing depolymerization, thereby inhibiting cell mitosis.

[0221] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including but not limited to a cytotoxic agent.

[0222] The term "immunomodulator" or "IMiD" refers to a class of molecules that alter the immune system response or immune system function. Immunomodulators include but are not limited to (pomalidomide), thalidomide (α-N-phthalimide-glutarimide) and its analogs, (Apremilast), (lenalidomide) and PD-1 axis binding antagonists and their pharmaceutically acceptable salts or acids.

[0223] A "subject" or "individual" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain aspects, a subject or individual is a human. A subject can be a patient.

[0224] An "isolated" protein or peptide is one that has been separated from a component of its natural environment. In some aspects, the protein or peptide is purified to a purity greater than 95% or 99% as determined by, for example, electrophoresis (e.g., sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reversed phase HPLC).

[0225] An "isolated" nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that normally contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0226] The term "PD-1 axis binding antagonist" refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with one or more of its binding partners to eliminate T cell dysfunction caused by signaling on the PD-1 signaling axis, resulting in restoration or enhancement of 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 aspect, the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

[0227] The term "PD-L1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, eliminates or interferes with the signal transduction generated by the interaction of PD-L1 with one or more of its binding partners (such as PD-1 and / or B7-1). In some cases, the PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partner. In a specific aspect, 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 anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that reduce, block, inhibit, eliminate or interfere with the signal transduction generated by the interaction of PD-L1 with one or more of its binding partners (such as PD-1 and / or B7-1). In one instance, the PD-L1 binding antagonist reduces the negative co-stimulatory signal mediated by signaling through PD-L1 mediated by or through cell surface proteins expressed on T lymphocytes, thereby rendering the dysfunctional T cells less dysfunctional (e.g., improving the response of effectors to antigen recognition). In some instances, the PD-L1 binding antagonist binds to PD-L1. In some instances, 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, envafolimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001 , KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636. In some aspects, the anti-PD-L1 antibody is atezolizumab, MDX-1105, MEDI4736 (durvalumab), or MSB0010718C (avetumab). In one specific aspect, the PD-L1 binding antagonist is MDX-1105. In another specific aspect, the PD-L1 binding antagonist is MEDI4736 (durvalumab). In another specific aspect, the PD-L1 binding antagonist is MSB0010718C (avelumab).In other aspects, the PD-L1 binding antagonist can be a small molecule, for example, GS-4224, INCB086550, MAX-10181, INCB090244, CA-170 or ABSK041, which can be orally administered in some cases. Other exemplary PD-L1 binding antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003 and JS-003. In a preferred aspect, the PD-L1 binding antagonist is atezolizumab. Atezolizumab is also described in WHO Drug Information (International Nonproprietary Drug Name (Proposed INN)) List 112, Vol. 28, No. 4, 2014, p. 488.

[0228] The term "PD-1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, eliminates or interferes with the signal transduction generated by 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 referred to as "programmed cell death 1", "PDCD1", "CD279" and "SLEB2" in the art. Exemplary human PD-1 is shown in 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 a specific aspect, a PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and / or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies and antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that reduce, block, inhibit, eliminate or interfere with the signal transduction generated by the interaction of PD-1 with PD-L1 and / or PD-L2. In one instance, a PD-1 binding antagonist reduces negative co-stimulatory signals mediated by signaling through PD-1 mediated by or through cell surface proteins expressed on T lymphocytes, thereby rendering dysfunctional T cells less dysfunctional (e.g., improving effector responses to antigen recognition). In some instances, a PD-1 binding antagonist binds to PD-1. In some instances, 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 (cemiprilimab), BGB-108, palolizumab, carrelizumab, sintilimab, tislelizumab, toripalimab, dotalimumab, rivulimab, sazanlimab, penampalimab, CS1003, HLX10, SCT-I10A, sepalizumab, batilizumab, genoluzumab, BI 754091, silimumab, YBL-006, BAT1306, HX008, brigalimumab, AMG 404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103 and hAb21. In one specific aspect, the PD-1 binding antagonist is MDX-1106 (nivolumab). In another specific aspect, the PD-1 binding antagonist is MK-3475 (pembrolizumab). In another specific aspect, the PD-1 binding antagonist is a PD-L2 fusion protein, for example, AMP-224. In another specific aspect, the PD-1 binding antagonist is MED1-0680.In another specific aspect, the PD-1 binding antagonist is PDR001 (spartalizumab). In another specific aspect, the PD-1 binding antagonist is REGN2810 (simiprilimab). In another specific aspect, the PD-1 binding antagonist is BGB-108. In another specific aspect, the PD-1 binding antagonist is palolizumab. In another specific aspect, the PD-1 binding antagonist is carrelizumab. In another specific aspect, the PD-1 binding antagonist is sindilimab. In another specific aspect, the PD-1 binding antagonist is tislelizumab. In another specific aspect, the PD-1 binding antagonist is toripalizumab. Other additional exemplary PD-1 binding antagonists include BION-004, CB201, AUNP-012, ADG104, and LBL-006.

[0229] The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, eliminates or interferes with the signal transduction generated by the interaction of PD-L2 with one or more of its binding partners (such as PD-1). PD-L2 (programmed death ligand 2) is also referred to in the art as "programmed cell death 1 ligand 2", "PDCD1LG2", "CD273", "B7-DC", "Btdc" and "PDL2". An exemplary human PD-L2 is shown in 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 a specific aspect, a PD-L2 binding antagonist inhibits the binding of PD-L2 to PD-1. Exemplary PD-L2 antagonists include anti-PD-L2 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, eliminate, or interfere with the signal transduction generated by the interaction of one or more of PD-L2 and its binding partners (such as PD-1). On the one hand, the PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or expressed by the cell surface protein expressed on T lymphocytes, and the surface protein makes the dysfunctional T cell dysfunction less (e.g., improve the response of the effector to antigen recognition) through the signal transduction mediated by PD-L2. In some aspects, the PD-L2 binding antagonist binds to PD-L2. In some aspects, the PD-L2 binding antagonist is an immunoadhesin. In other aspects, the PD-L2 binding antagonist is an anti-PD-L2 antagonist antibody.

[0230] Unless otherwise indicated, the term "protein" as used herein refers to any native protein from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term includes "full-length" unprocessed proteins, as well as any form of proteins produced by processing in cells. The term also encompasses naturally occurring protein variants, such as splice variants or allelic variants.

[0231] "Amino acid sequence identity percentage (%)" relative to a reference polypeptide sequence is defined 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 candidate sequence with the reference polypeptide sequence and introducing spaces (if necessary) to achieve maximum sequence identity percentage, and for the purpose of alignment without considering any conservative substitutions as components of sequence identity. Alignment for determining amino acid sequence identity percentage can be achieved in various ways within the technical scope of the art, for example, using publicly available computer software, such as BLAST, BLAST-2, Clustal W, Megalign (DNASTAR) software or FASTA program package. Those skilled in the art can determine the appropriate parameters for aligning sequences, including any algorithm required for achieving maximum alignment over the full length of the compared sequence. Alternatively, the sequence comparison computer program ALIGN-2 can be used to generate identity percentage values. The ALIGN-2 sequence comparison computer program was written by Genentech, Inc. and the source code has been filed with user documentation in the US Copyright Office, Washington DC, 20559, where it is registered under US Copyright Registration No. TXU510087 and is described in WO 2001 / 007611.

[0232] Unless otherwise indicated, for the purposes of this article, the values ​​of percent amino acid sequence identity are generated using the BLOSUM50 comparison matrix using the ggsearch program of the FASTA package version 36.3.8c or higher. The FASTA package is 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 creation and can be obtained from www.fasta.bioch.virginia.edu / fasta_www2 / fasta_down.shtml or www.ebi.ac.uk / Tools / sss / fasta. Alternatively, sequences can be compared using a public server accessible at fasta.bioch.virginia.edu / fasta_www2 / index.cgi, using the ggsearch (global protein:protein) program and default options (BLOSUM50; open: -10; ext: -2; Ktup = 2) to ensure that a global rather than a local alignment is performed. The amino acid identity percentage is given in the output alignment header.

[0233] The term "pharmaceutical formulation" refers to a preparation that is in a form that permits the biological activity of the active ingredient contained therein to be effective, and that contains no additional components that are unacceptably toxic to a subject to which the preparation would be administered.

[0234] "Pharmaceutically acceptable carrier" refers to a component of a pharmaceutical preparation other than the active ingredient that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0235] "Radiotherapy" refers to the use of directed gamma or beta rays to induce sufficient damage to cells to limit the ability of the cells to function normally or to completely destroy the cells. It will be understood that there are many known methods in the art to determine the dosage and duration of treatment. Typical treatment is a single administration, with a typical dosage range of 10 to 200 units (Gray) per day.

[0236] As used herein, "treatment" (and grammatical variations such as "treat" or "treating") refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed for prevention or during the course of clinical pathology. Desired effects of treatment include, but are not limited to, preventing the occurrence or recurrence of disease, alleviating symptoms, diminishing any direct or indirect pathological consequences of disease, preventing metastasis, reducing the rate of disease progression, ameliorating or palliating the disease state, and alleviating or improving prognosis. In some aspects, the antibodies disclosed herein (e.g., the anti-FcRH5 / anti-CD3 TDB disclosed herein) are used to delay the development of disease or slow the progression of disease.

[0237] "Reduce" or "inhibit" means the ability to cause an overall reduction, for example, an overall reduction of 20% or more, 50% or more, or 75%, 85%, 90%, 95% or more. In certain aspects, reduction or inhibition can refer to the effector function of an antibody mediated by the Fc region of the antibody, and this effector function specifically includes CDC, ADCC and ADCP.

[0238] According to the present invention, the term "vaccine" refers to a pharmaceutical preparation (pharmaceutical composition) or product that induces an immune response after administration, particularly a cellular immune response that recognizes and attacks pathogens or diseased cells, such as cancer cells. Vaccines can be used to prevent or treat diseases. The vaccine can be a cancer vaccine. As used herein, a "cancer vaccine" is a composition that stimulates an immune response in a subject against cancer. Cancer vaccines are typically composed of cancer-related materials or cell (antigen) sources that may be autologous (from oneself) or allogeneic (from others) for the subject, together with other ingredients (e.g., adjuvants) to further stimulate and promote an immune response to the antigen. Cancer vaccines can result in stimulation of the subject's immune system to produce antibodies against one or more specific antigens, and / or produce killer T cells to attack cancer cells with those antigens.

[0239] As used herein, "administering" means a method of administering a dose of a compound (e.g., an anti-FcRH5 / anti-CD3 TDB, such as silvostomumab) to a subject. In some aspects, the composition used in the methods herein is administered intravenously. The composition used in the methods described herein can be administered, for example, intramuscularly, intravenously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctivally, intracapsularly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, topically, by inhalation, by injection, by infusion, by continuous infusion, by local perfusion directly irrigating target cells, by catheter, by lavage, in the form of an emulsion or in the form of a lipid composition. The method of administration can vary depending on a variety of factors (e.g., the compound or composition to be administered and the severity of the condition, disease or disorder to be treated).

[0240] Unless otherwise indicated, "CD38" as used herein 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). CD38 is typically expressed at higher and more uniform levels on myeloma cells than normal lymphoid and myeloid cells. The term includes "full-length" unprocessed CD38, as well as any form of CD38 produced by processing in cells. 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. The nucleic acid sequence of an exemplary human CD38 is set forth in the following NCBI Reference Sequence: NM_001775.4 or in SEQ ID NO: 33. The amino acid sequence of an exemplary human CD38 protein encoded by CD38 is set forth in UniProt Accession No. P28907 or in SEQ ID NO:34.

[0241] The term "anti-CD38 antibody" encompasses all antibodies that bind to CD38 with sufficient affinity so that the antibody can be used as a therapeutic agent targeting cells expressing the antigen and does not significantly cross-react with other proteins (such as negative control proteins) in the assays described below. For example, anti-CD38 antibodies can bind to CD38 on the surface of MM cells and mediate cell lysis by activating complement-dependent cytotoxicity, ADCC, antibody-dependent cellular phagocytosis (ADCP), and Fc cross-linking-mediated apoptosis, leading to the consumption of malignant cells and a reduction in the overall cancer burden. Anti-CD38 antibodies can also modulate CD38 enzymatic activity by inhibiting ribosyl cyclase activity and stimulating the cyclic adenosine diphosphate ribose (cADPR) hydrolase activity of CD38. In certain aspects, the dissociation constant (K) of an anti-CD38 antibody bound to CD38 is D ) is ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM or ≤0.001 nM (e.g., 10 -8 M or smaller, e.g. 10 -8 M to 10 -13 M, for example 10 -9 M to 10 - 13 M). In certain aspects, the anti-CD38 antibody can bind to both human CD38 and chimpanzee CD38. Anti-CD38 antibodies also include anti-CD38 antagonist antibodies. Bispecific antibodies in which one arm of the antibody binds CD38 are also contemplated. This definition of anti-CD38 antibodies also includes functional fragments of the foregoing antibodies. Examples of antibodies that bind to CD38 include: Daratumumab (U.S. Patent No.: 7,829,673 and U.S. Publication No.: 20160067205A1); "MOR202" (U.S. Patent No.: 8,263,746); and isatuximab (SAR-650984).

[0242] "Subcutaneous administration device" refers to a device suitable for or designed to administer a drug, such as a therapeutic antibody (e.g., an anti-FcRH5 / anti-CD3 bispecific antibody (e.g., silvostomumab)) or a drug formulation by a subcutaneous route. Exemplary subcutaneous administration devices include, but are not limited to, syringes (including prefilled syringes), injection devices, infusion pumps, injection pens, needle-free devices, and patch delivery systems. The subcutaneous administration device can administer a specific volume of a drug formulation, such as about 1.0 mL, about 1.25 mL, about 1.5 mL, about 1.75 mL, about 2.0 mL, about 2.5 mL, about 3 mL, about 3.5 mL, about 4 mL, about 5 mL, or more.

[0243] II. Treatment Methods

[0244] The present invention is based in part on a method of treating a subject with cancer (e.g., multiple myeloma (MM)) using a dosing regimen comprising a fractionated, dose-escalating dosing regimen comprising an anti-crystallizable fragment receptor-like 5 (FcRH5) / anti-cluster of differentiation 3 (CD3) bispecific antibody. The present invention provides a dosing regimen for silvositamab monotherapy in which silvositamab is administered subcutaneously to a subject. An exemplary dosing regimen described herein is a dosing regimen for silvositamab as a single agent in a subcutaneous dosing regimen in which silvositamab is administered in a 28-day cycle, wherein silvositamab is administered subcutaneously for the first cycle (C1) Q1W, silvositamab is administered subcutaneously for cycles 2 to 6 Q2W, and silvositamab is administered subcutaneously for cycles 7 to 13 Q4W. The methods disclosed herein can, for example, promote consistency with the dosing schedule of a combination therapy partner. Without wishing to be bound by theory, subcutaneous administration can, for example, reduce C1 compared to IV administration. 最大 and / or delayed reaching C compared with IV administration 最大 The time (t 最大 ). These methods are expected to reduce or inhibit unwanted therapeutic effects, including cytokine-driven toxicities (e.g., cytokine release syndrome (CRS)), infusion-related reactions (IRRs), macrophage activation syndrome (MAS), neurotoxicity, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, and / or elevated liver enzymes. Therefore, these methods can be used to treat subjects while achieving a more favorable benefit-risk profile.

[0245] The present invention provides methods useful for treating a subject having cancer (e.g., multiple myeloma), the method comprising subcutaneously administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (i.e., an anti-FcRH5 / anti-CD3 antibody), e.g., in a divided, dose-escalating dosing regimen, as a monotherapy or in combination with one or more additional therapeutic agents (e.g., an IMiD (e.g., pomalidomide), an anti-CD38 antibody (e.g., daratumumab, MOR202, or isatuximab), a corticosteroid (e.g., dexamethasone or methylprednisolone), acetaminophen, paracetamol, diphenhydramine, or a combination thereof).

[0246] A. Dosing regimens: no step-up, single step-up, and double step-up doses

[0247] i. Non-step-up dosing regimen

[0248] In some aspects, the invention provides 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 a dosing regimen that does not involve any step-up dosing.

[0249] In some aspects, the present invention provides a method of treating a subject having MM, the method comprising subcutaneously 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, wherein the first dosing cycle includes a first dose (C1D1) of the bispecific antibody, wherein C1D1 is between about 10 mg and about 1000 mg (e.g., between about 10 mg and about 70 mg, between about 15 mg and about 65 mg, between about 20 mg and about 60 mg, between about 25 mg and about 55 mg, between about 30 mg and about 50 mg, between about 35 mg and about 45 mg, between about 15 mg and about 225 mg, between about 20 mg and about 220 mg, between about From about 25 mg to about 215 mg, from about 30 mg to about 210 mg, from about 35 mg to about 205 mg, from about 40 mg to about 200 mg, from about 45 mg to about 195 mg, from about 50 mg to about 190 mg, from about 55 mg to about 185 mg, from about 60 mg to about 180 mg, from about 65 mg to about 175 mg, from about 70 mg to about 170 mg, from about 75 mg to about 165 mg, from about 80 mg to about 160 mg, from about 85 mg to about 155 mg, from about 90 mg to about 150 mg, from about 95 mg to about 145 mg, from about 100 mg to about 140 mg, from about 105 mg to about 1 about 150 mg to about 200 mg, about 175 mg to about 225 mg, about 200 mg to about 250 mg, about 225 mg to about 275 mg, about 250 mg to about 300 mg, about 275 mg to about 325 mg, about 300 mg to about 350 mg, about 325 mg to about 350 mg, about 325 mg to about 350 mg, about 350 ... about 375 mg, about 350 mg to about 400 mg, about 375 mg to about 425 mg, about 400 mg to about 450 mg, about 425 mg to about 475 mg, about 450 mg to about 500 mg, about 475 mg to about 525 mg, about 500 mg to about 550 mg, about 525 mg to about 575 mg, about 550 mg to about 600 mg, about 575 mg to about 625 mg, about 600 mg to about 650 mg, about 625 mg to about 675 mg, about 650 mg to about 700 mg, about 675 mg to about 725 mg, about 700 mg to about 750 mg,about 725 mg to about 775 mg, about 750 mg to about 800 mg, about 775 mg to about 825 mg, about 800 mg to about 850 mg, about 825 mg to about 875 mg, about 850 mg to about 900 mg, about 875 mg to about 925 mg, about 900 mg to about 950 mg, about 925 mg to about 975 mg, or about 950 mg to about 1000 mg).

[0250] In some aspects, C1D1 is between about 10 mg and about 200 mg (e.g., between about 10 mg and about 170 mg, between about 11 mg and about 165 mg, between about 12 mg and about 160 mg, between about 13 mg and about 155 mg, between about 14 mg and about 150 mg, between about 15 mg and about 145 mg, between about 16 mg and about 140 mg, between about 17 mg and about 135 mg, between about 18 mg and about 130 mg, between about 19 mg and about 125 mg, between about 20 mg and about 120 mg, between about 21 mg and about 115 mg, between about 22 mg and about 110 mg, between about 23 mg and about 105 mg). about 24 mg to about 100 mg, about 25 mg to about 95 mg, about 26 mg to about 90 mg, about 27 mg to about 85 mg, about 28 mg to about 80 mg, about 29 mg to about 75 mg, about 30 mg to about 70 mg, about 31 mg to about 65 mg, about 32 mg to about 60 mg, about 33 mg to about 55 mg, about 34 mg to about 50 mg, about 35 mg to about 45 mg, about 40 mg to about 200 mg, about 45 mg to about 195 mg, about 50 mg to about 190 mg, about 55 mg to about 185 mg, about 6 0 mg to about 180 mg, about 65 mg to about 175 mg, about 70 mg to about 170 mg, about 75 mg to about 165 mg, about 80 mg to about 160 mg, about 85 mg to about 155 mg, about 90 mg to about 150 mg, about 95 mg to about 145 mg, about 100 mg to about 140 mg, about 105 mg to about 135 mg, about 110 mg to about 130 mg, about 115 mg to about 125 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about 50 mg or about 190 mg to about 200 mg).

[0251] In some aspects, C1D1 is between 10 mg and 1000 mg (e.g., between 10 mg and 70 mg, between 15 mg and 65 mg, between 20 mg and 60 mg, between 25 mg and 55 mg, between 30 mg and 50 mg, between 35 mg and 45 mg, between 15 mg and 225 mg, between 20 mg and 220 mg, between 25 mg and 215 mg, between 30 mg and 210 mg, between 35 mg and 205 mg, between 40 mg and 200 mg, between 45 mg and 195 mg, between 50 mg and 190 mg, between 55 mg and 185 mg, between 60 mg and 180 mg). , between 65mg and 175mg, between 70mg and 170mg, between 75mg and 165mg, between 80mg and 160mg, between 85mg and 155mg, between 90mg and 150mg, between 95mg and 145mg, between 100mg and 140mg, between 105mg and 135mg, between 110mg and 130mg, between 115mg and 125mg, between 10mg and 50mg, between 25mg and 75mg, between 50mg and 100mg, between 75mg and 125mg, between 100mg and 150mg, between 125mg and 175mg, 150mg Between 175mg and 225mg, between 200mg and 250mg, between 225mg and 275mg, between 250mg and 300mg, between 275mg and 325mg, between 300mg and 350mg, between 325mg and 375mg, between 350mg and 400mg, between 375mg and 425mg, between 400mg and 450mg, between 425mg and 475mg, between 450mg and 500mg, between 475mg and 525mg, between 500mg and 550mg, between 525mg and 575mg, between 550mg and 600mg g, 575 mg to 625 mg, 600 mg to 650 mg, 625 mg to 675 mg, 650 mg to 700 mg, 675 mg to 725 mg, 700 mg to 750 mg, 725 mg to 775 mg, 750 mg to 800 mg, 775 mg to 825 mg, 800 mg to 850 mg, 825 mg to 875 mg, 850 mg to 900 mg, 875 mg to 925 mg, 900 mg to 950 mg, 925 mg to 975 mg, or 950 mg to 1000 mg).

[0252] In some aspects, C1D1 is between 10 mg and 200 mg (e.g., between 10 mg and 170 mg, between 11 mg and 165 mg, between 12 mg and 160 mg, between 13 mg and 155 mg, between 14 mg and 150 mg, between 15 mg and 145 mg, between 16 mg and 140 mg, between 17 mg and 135 mg, between 18 mg and 130 mg, between 19 mg and 125 mg, between 20 mg and 120 mg, between 21 mg and 115 mg, between 22 mg and 110 mg, between 23 mg and 10 Between 5mg, 24mg and 100mg, 25mg and 95mg, 26mg and 90mg, 27mg and 85mg, 28mg and 80mg, 29mg and 75mg, 30mg and 70mg, 31mg and 65mg, 32mg and 60mg, 33mg and 55mg, 34mg and 50mg, 35mg and 45mg, 40mg and 200mg, 45mg and 195mg, 50mg and 190mg, 55mg and 185mg, 60 Between mg and 180mg, between 65mg and 175mg, between 70mg and 170mg, between 75mg and 165mg, between 80mg and 160mg, between 85mg and 155mg, between 90mg and 150mg, between 95mg and 145mg, between 100mg and 140mg, between 105mg and 135mg, between 110mg and 130mg, between 115mg and 125mg, between 10mg and 20mg, between 20mg and 30mg, between 30mg and 40mg, between 40mg and 50mg between 150mg and 160mg, between 160mg and 170mg, between 170mg and 180mg, between 180mg and 190mg, or between 190mg and 200mg).

[0253] In some aspects, the present invention provides a method of treating a subject having cancer (e.g., MM), the method comprising subcutaneously 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, wherein the first dosing cycle includes a first dose (C1D1) of the bispecific antibody of between about 10 mg to about 1000 mg (e.g., between about 10 mg to about 70 mg, between about 15 mg to about 65 mg, between about 20 mg to about 60 mg, between about 25 mg to about 55 mg, between about 30 mg to about 50 mg, between about 35 mg to about 45 mg, between about 15 mg to about 225 mg, between about 20 mg to about 220 mg) , about 25 mg to about 215 mg, about 30 mg to about 210 mg, about 35 mg to about 205 mg, about 40 mg to about 200 mg, about 45 mg to about 195 mg, about 50 mg to about 190 mg, about 55 mg to about 185 mg, about 60 mg to about 180 mg, about 65 mg to about 175 mg, about 70 mg to about 170 mg, about 75 mg to about 165 mg, about 80 mg to about 160 mg, about 85 mg to about 155 mg, about 90 mg to about 150 mg, about 95 mg to about 145 mg, about 100 mg to about 140 mg, about 105 mg to about about 135 mg, about 110 mg to about 130 mg, about 115 mg to about 125 mg, about 10 mg to about 50 mg, about 25 mg to about 75 mg, about 50 mg to about 100 mg, about 75 mg to about 125 mg, about 100 mg to about 150 mg, about 125 mg to about 175 mg, about 150 mg to about 200 mg, about 175 mg to about 225 mg, about 200 mg to about 250 mg, about 225 mg to about 275 mg, about 250 mg to about 300 mg, about 275 mg to about 325 mg, about 300 mg to about 350 mg, about 325 mg about 375 mg to about 375 mg, about 350 mg to about 400 mg, about 375 mg to about 425 mg, about 400 mg to about 450 mg, about 425 mg to about 475 mg, about 450 mg to about 500 mg, about 475 mg to about 525 mg, about 500 mg to about 550 mg, about 525 mg to about 575 mg, about 550 mg to about 600 mg, about 575 mg to about 625 mg, about 600 mg to about 650 mg, about 625 mg to about 675 mg, about 650 mg to about 700 mg, about 675 mg to about 725 mg, about 700 mg to about 750 mg,about 725 mg to about 775 mg, about 750 mg to about 800 mg, about 775 mg to about 825 mg, about 800 mg to about 850 mg, about 825 mg to about 875 mg, about 850 mg to about 900 mg, about 875 mg to about 925 mg, about 900 mg to about 950 mg, about 925 mg to about 975 mg, or about 950 mg to about 1000 mg).

[0254] In some aspects, C1D1 is between about 10 mg and about 200 mg (e.g., between about 10 mg and about 200 mg (e.g., between about 10 mg and about 170 mg, between about 11 mg and about 165 mg, between about 12 mg and about 160 mg, between about 13 mg and about 155 mg, between about 14 mg and about 150 mg, between about 15 mg and about 145 mg, between about 16 mg and about 140 mg, between about 17 mg and about 135 mg, between about 18 mg and about 130 mg, between about 19 mg and about 125 mg, between about 20 mg and about 120 mg, between about 21 mg and about 115 mg, between about 22 mg and about 110 mg). g, about 23 mg to about 105 mg, about 24 mg to about 100 mg, about 25 mg to about 95 mg, about 26 mg to about 90 mg, about 27 mg to about 85 mg, about 28 mg to about 80 mg, about 29 mg to about 75 mg, about 30 mg to about 70 mg, about 31 mg to about 65 mg, about 32 mg to about 60 mg, about 33 mg to about 55 mg, about 34 mg to about 50 mg, about 35 mg to about 45 mg, about 40 mg to about 200 mg, about 45 mg to about 195 mg, about 50 mg to about 190 mg, about 55 mg to about about 185 mg, about 60 mg to about 180 mg, about 65 mg to about 175 mg, about 70 mg to about 170 mg, about 75 mg to about 165 mg, about 80 mg to about 160 mg, about 85 mg to about 155 mg, about 90 mg to about 150 mg, about 95 mg to about 145 mg, about 100 mg to about 140 mg, about 105 mg to about 135 mg, about 110 mg to about 130 mg, about 115 mg to about 125 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about or about 190 mg to about 200 mg).

[0255] In some aspects, C1D1 is between 10 mg and 1000 mg (e.g., between 10 mg and 70 mg, between 15 mg and 65 mg, between 20 mg and 60 mg, between 25 mg and 55 mg, between 30 mg and 50 mg, between 35 mg and 45 mg, between 15 mg and 225 mg, between 20 mg and 220 mg, between 25 mg and 215 mg, between 30 mg and 210 mg, between 35 mg and 205 mg, between 40 mg and 200 mg, between 45 mg and 195 mg, between 50 mg and 190 mg, between 55 mg and 185 mg, between 60 mg and 180 mg). , between 65mg and 175mg, between 70mg and 170mg, between 75mg and 165mg, between 80mg and 160mg, between 85mg and 155mg, between 90mg and 150mg, between 95mg and 145mg, between 100mg and 140mg, between 105mg and 135mg, between 110mg and 130mg, between 115mg and 125mg, between 10mg and 50mg, between 25mg and 75mg, between 50mg and 100mg, between 75mg and 125mg, between 100mg and 150mg, between 125mg and 175mg, 150mg Between 175mg and 225mg, between 200mg and 250mg, between 225mg and 275mg, between 250mg and 300mg, between 275mg and 325mg, between 300mg and 350mg, between 325mg and 375mg, between 350mg and 400mg, between 375mg and 425mg, between 400mg and 450mg, between 425mg and 475mg, between 450mg and 500mg, between 475mg and 525mg, between 500mg and 550mg, between 525mg and 575mg, between 550mg and 600mg g, 575 mg to 625 mg, 600 mg to 650 mg, 625 mg to 675 mg, 650 mg to 700 mg, 675 mg to 725 mg, 700 mg to 750 mg, 725 mg to 775 mg, 750 mg to 800 mg, 775 mg to 825 mg, 800 mg to 850 mg, 825 mg to 875 mg, 850 mg to 900 mg, 875 mg to 925 mg, 900 mg to 950 mg, 925 mg to 975 mg, or 950 mg to 1000 mg).

[0256] In some aspects, C1D1 is between 10 mg and 200 mg (e.g., between 10 mg and 170 mg, between 11 mg and 165 mg, between 12 mg and 160 mg, between 13 mg and 155 mg, between 14 mg and 150 mg, between 15 mg and 145 mg, between 16 mg and 140 mg, between 17 mg and 135 mg, between 18 mg and 130 mg, between 19 mg and 125 mg, between 20 mg and 120 mg, between 21 mg and 115 mg, between 22 mg and 110 mg, between 23 mg and 10 Between 5mg, 24mg and 100mg, 25mg and 95mg, 26mg and 90mg, 27mg and 85mg, 28mg and 80mg, 29mg and 75mg, 30mg and 70mg, 31mg and 65mg, 32mg and 60mg, 33mg and 55mg, 34mg and 50mg, 35mg and 45mg, 40mg and 200mg, 45mg and 195mg, 50mg and 190mg, 55mg and 185mg, 60 Between mg and 180mg, between 65mg and 175mg, between 70mg and 170mg, between 75mg and 165mg, between 80mg and 160mg, between 85mg and 155mg, between 90mg and 150mg, between 95mg and 145mg, between 100mg and 140mg, between 105mg and 135mg, between 110mg and 130mg, between 115mg and 125mg, between 10mg and 20mg, between 20mg and 30mg, between 30mg and 40mg, between 40mg and 50mg between 150mg and 160mg, between 160mg and 170mg, between 170mg and 180mg, between 180mg and 190mg, or between 190mg and 200mg).

[0257] In some aspects, C1D1 is about 10 mg. In some aspects, C1D1 is about 15 mg. In some aspects, C1D1 is about 20 mg. In some aspects, C1D1 is about 25 mg. In some aspects, C1D1 is about 30 mg. In some aspects, C1D1 is about 35 mg. In some aspects, C1D1 is about 40 mg. In some aspects, C1D1 is about 45 mg. In some aspects, C1D1 is about 50 mg. In some aspects, C1D1 is about 55 mg. In some aspects, C1D1 is about 60 mg. In some aspects, C1D1 is about 65 mg. In some aspects, C1D1 is about 70 mg. In some aspects, C1D1 is about 75 mg. In some aspects, C1D1 is about 80 mg. In some aspects, C1D1 is about 85 mg. In some aspects, C1D1 is about 90 mg. In some aspects, C1D1 is about 95 mg. In some aspects, C1D1 is about 100 mg. In some aspects, C1D1 is about 105 mg. In some aspects, C1D1 is about 110 mg. In some aspects, C1D1 is about 115 mg. In some aspects, C1D1 is about 120 mg. In some aspects, C1D1 is about 125 mg. In some aspects, C1D1 is about 130 mg. In some aspects, C1D1 is about 135 mg. In some aspects, C1D1 is about 140 mg. In some aspects, C1D1 is about 145 mg. In some aspects, C1D1 is about 150 mg. In some aspects, C1D1 is about 155 mg. In some aspects, C1D1 is about 160 mg. In some aspects, C1D1 is about 165 mg. In some aspects, C1D1 is about 170 mg. In some aspects, C1D1 is about 175 mg. In some aspects, C1D1 is about 180 mg. In some aspects, C1D1 is about 185 mg. In some aspects, C1D1 is about 190 mg. In some aspects, C1D1 is about 195 mg. In some aspects, C1D1 is about 200 mg. In some aspects, C1D1 is about 205 mg. In some aspects, C1D1 is about 210 mg. In some aspects, C1D1 is about 215 mg. In some aspects, C1D1 is about 220 mg. In some aspects, C1D1 is about 225 mg. In some aspects, C1D1 is about 230 mg. In some aspects, C1D1 is about 235 mg. In some aspects, C1D1 is about 240 mg. In some aspects, C1D1 is about 245 mg. In some aspects, C1D1 is about 250 mg. In some aspects, C1D1 is about 255 mg. In some aspects, C1D1 is about 260 mg. In some aspects, C1D1 is about 265 mg. In some aspects, C1D1 is about 270 mg. In some aspects, C1D1 is about 275 mg. In some aspects, C1D1 is about 280 mg. In some aspects, C1D1 is about 285 mg.In some aspects, C1D1 is about 290 mg. In some aspects, C1D1 is about 295 mg. In some aspects, C1D1 is about 300 mg. In some aspects, C1D1 is about 305 mg. In some aspects, C1D1 is about 310 mg. In some aspects, C1D1 is about 315 mg. In some aspects, C1D1 is about 320 mg. In some aspects, C1D1 is about 325 mg. In some aspects, C1D1 is about 330 mg. In some aspects, C1D1 is about 335 mg. In some aspects, C1D1 is about 340 mg. In some aspects, C1D1 is about 345 mg. In some aspects, C1D1 is about 350 mg. In some aspects, C1D1 is about 355 mg. In some aspects, C1D1 is about 360 mg. In some aspects, C1D1 is about 365 mg. In some aspects, C1D1 is about 370 mg. In some aspects, C1D1 is about 375 mg. In some aspects, C1D1 is about 380 mg. In some aspects, C1D1 is about 385 mg. In some aspects, C1D1 is about 390 mg. In some aspects, C1D1 is about 395 mg. In some aspects, C1D1 is about 400 mg. In some aspects, C1D1 is about 405 mg. In some aspects, C1D1 is about 410 mg. In some aspects, C1D1 is about 415 mg. In some aspects, C1D1 is about 420 mg. In some aspects, C1D1 is about 425 mg. In some aspects, C1D1 is about 430 mg. In some aspects, C1D1 is about 435 mg. In some aspects, C1D1 is about 440 mg. In some aspects, C1D1 is about 445 mg. In some aspects, C1D1 is about 450 mg. In some aspects, C1D1 is about 455 mg. In some aspects, C1D1 is about 460 mg. In some aspects, C1D1 is about 465 mg. In some aspects, C1D1 is about 470 mg. In some aspects, C1D1 is about 475 mg. In some aspects, C1D1 is about 480 mg. In some aspects, C1D1 is about 485 mg. In some aspects, C1D1 is about 490 mg. In some aspects, C1D1 is about 495 mg. In some aspects, C1D1 is about 500 mg. In some aspects, C1D1 is about 505 mg. In some aspects, C1D1 is about 510 mg. In some aspects, C1D1 is about 515 mg. In some aspects, C1D1 is about 520 mg. In some aspects, C1D1 is about 525 mg. In some aspects, C1D1 is about 530 mg. In some aspects, C1D1 is about 535 mg. In some aspects, C1D1 is about 540 mg. In some aspects, C1D1 is about 545 mg. In some aspects, C1D1 is about 550 mg. In some aspects, C1D1 is about 555 mg. In some aspects, C1D1 is about 560 mg.In some aspects, C1D1 is about 565 mg. In some aspects, C1D1 is about 570 mg. In some aspects, C1D1 is about 575 mg. In some aspects, C1D1 is about 580 mg. In some aspects, C1D1 is about 585 mg. In some aspects, C1D1 is about 590 mg. In some aspects, C1D1 is about 595 mg. In some aspects, C1D1 is about 600 mg. In some aspects, C1D1 is about 605 mg. In some aspects, C1D1 is about 610 mg. In some aspects, C1D1 is about 615 mg. In some aspects, C1D1 is about 620 mg. In some aspects, C1D1 is about 625 mg. In some aspects, C1D1 is about 630 mg. In some aspects, C1D1 is about 635 mg. In some aspects, C1D1 is about 640 mg. In some aspects, C1D1 is about 645 mg. In some aspects, C1D1 is about 650 mg. In some aspects, C1D1 is about 655 mg. In some aspects, C1D1 is about 660 mg. In some aspects, C1D1 is about 665 mg. In some aspects, C1D1 is about 670 mg. In some aspects, C1D1 is about 675 mg. In some aspects, C1D1 is about 680 mg. In some aspects, C1D1 is about 685 mg. In some aspects, C1D1 is about 690 mg. In some aspects, C1D1 is about 695 mg. In some aspects, C1D1 is about 700 mg. In some aspects, C1D1 is about 705 mg. In some aspects, C1D1 is about 710 mg. In some aspects, C1D1 is about 715 mg. In some aspects, C1D1 is about 720 mg. In some aspects, C1D1 is about 725 mg. In some aspects, C1D1 is about 730 mg. In some aspects, C1D1 is about 735 mg. In some aspects, C1D1 is about 740 mg. In some aspects, C1D1 is about 745 mg. In some aspects, C1D1 is about 750 mg. In some aspects, C1D1 is about 755 mg. In some aspects, C1D1 is about 760 mg. In some aspects, C1D1 is about 765 mg. In some aspects, C1D1 is about 770 mg. In some aspects, C1D1 is about 775 mg. In some aspects, C1D1 is about 780 mg. In some aspects, C1D1 is about 785 mg. In some aspects, C1D1 is about 790 mg. In some aspects, C1D1 is about 795 mg. In some aspects, C1D1 is about 800 mg. In some aspects, C1D1 is about 805 mg. In some aspects, C1D1 is about 810 mg. In some aspects, C1D1 is about 815 mg. In some aspects, C1D1 is about 820 mg. In some aspects, C1D1 is about 825 mg. In some aspects, C1D1 is about 830 mg. In some aspects, C1D1 is about 835 mg.In some aspects, C1D1 is about 840 mg. In some aspects, C1D1 is about 845 mg. In some aspects, C1D1 is about 850 mg. In some aspects, C1D1 is about 855 mg. In some aspects, C1D1 is about 860 mg. In some aspects, C1D1 is about 865 mg. In some aspects, C1D1 is about 870 mg. In some aspects, C1D1 is about 875 mg. In some aspects, C1D1 is about 880 mg. In some aspects, C1D1 is about 885 mg. In some aspects, C1D1 is about 890 mg. In some aspects, C1D1 is about 895 mg. In some aspects, C1D1 is about 900 mg. In some aspects, C1D1 is about 905 mg. In some aspects, C1D1 is about 910 mg. In some aspects, C1D1 is about 915 mg. In some aspects, C1D1 is about 920 mg. In some aspects, C1D1 is about 925 mg. In some aspects, C1D1 is about 930 mg. In some aspects, C1D1 is about 935 mg. In some aspects, C1D1 is about 940 mg. In some aspects, C1D1 is about 945 mg. In some aspects, C1D1 is about 950 mg. In some aspects, C1D1 is about 955 mg. In some aspects, C1D1 is about 960 mg. In some aspects, C1D1 is about 965 mg. In some aspects, C1D1 is about 970 mg. In some aspects, C1D1 is about 975 mg. In some aspects, C1D1 is about 980 mg. In some aspects, C1D1 is about 985 mg. In some aspects, C1D1 is about 990 mg. In some aspects, C1D1 is about 995 mg. In some aspects, C1D1 is about 1000 mg.

[0258] In some aspects, C1D1 is 10 mg. In some aspects, C1D1 is 15 mg. In some aspects, C1D1 is 20 mg. In some aspects, C1D1 is 25 mg. In some aspects, C1D1 is 30 mg. In some aspects, C1D1 is 35 mg. In some aspects, C1D1 is 40 mg. In some aspects, C1D1 is 45 mg. In some aspects, C1D1 is 50 mg. In some aspects, C1D1 is 55 mg. In some aspects, C1D1 is 60 mg. In some aspects, C1D1 is 65 mg. In some aspects, C1D1 is 70 mg. In some aspects, C1D1 is 75 mg. In some aspects, C1D1 is 80 mg. In some aspects, C1D1 is 85 mg. In some aspects, C1D1 is 90 mg. In some aspects, C1D1 is 95 mg. In some aspects, C1D1 is 100 mg. In some aspects, C1D1 is 105 mg. In some aspects, C1D1 is 110 mg. In some aspects, C1D1 is 115 mg. In some aspects, C1D1 is 120 mg. In some aspects, C1D1 is 125 mg. In some aspects, C1D1 is 130 mg. In some aspects, C1D1 is 135 mg. In some aspects, C1D1 is 140 mg. In some aspects, C1D1 is 145 mg. In some aspects, C1D1 is 150 mg. In some aspects, C1D1 is 155 mg. In some aspects, C1D1 is 160 mg. In some aspects, C1D1 is 165 mg. In some aspects, C1D1 is 170 mg. In some aspects, C1D1 is 175 mg. In some aspects, C1D1 is 180 mg. In some aspects, C1D1 is 185 mg. In some aspects, C1D1 is 190 mg. In some aspects, C1D1 is 195 mg. In some aspects, C1D1 is 200 mg. In some aspects, C1D1 is 205 mg. In some aspects, C1D1 is 210 mg. In some aspects, C1D1 is 215 mg. In some aspects, C1D1 is 220 mg. In some aspects, C1D1 is 225 mg. In some aspects, C1D1 is 230 mg. In some aspects, C1D1 is 235 mg. In some aspects, C1D1 is 240 mg. In some aspects, C1D1 is 245 mg. In some aspects, C1D1 is 250 mg. In some aspects, C1D1 is 255 mg. In some aspects, C1D1 is 260 mg. In some aspects, C1D1 is 265 mg. In some aspects, C1D1 is 270 mg. In some aspects, C1D1 is 275 mg. In some aspects, C1D1 is 280 mg. In some aspects, C1D1 is 285 mg. In some aspects, C1D1 is 290 mg. In some aspects, C1D1 is 295 mg. In some aspects, C1D1 is 300 mg.In some aspects, C1D1 is 305 mg. In some aspects, C1D1 is 310 mg. In some aspects, C1D1 is 315 mg. In some aspects, C1D1 is 320 mg. In some aspects, C1D1 is 325 mg. In some aspects, C1D1 is 330 mg. In some aspects, C1D1 is 335 mg. In some aspects, C1D1 is 340 mg. In some aspects, C1D1 is 345 mg. In some aspects, C1D1 is 350 mg. In some aspects, C1D1 is 355 mg. In some aspects, C1D1 is 360 mg. In some aspects, C1D1 is 365 mg. In some aspects, C1D1 is 370 mg. In some aspects, C1D1 is 375 mg. In some aspects, C1D1 is 380 mg. In some aspects, C1D1 is 385 mg. In some aspects, C1D1 is 390 mg. In some aspects, C1D1 is 395 mg. In some aspects, C1D1 is 400 mg. In some aspects, C1D1 is 405 mg. In some aspects, C1D1 is 410 mg. In some aspects, C1D1 is 415 mg. In some aspects, C1D1 is 420 mg. In some aspects, C1D1 is 425 mg. In some aspects, C1D1 is 430 mg. In some aspects, C1D1 is 435 mg. In some aspects, C1D1 is 440 mg. In some aspects, C1D1 is 445 mg. In some aspects, C1D1 is 450 mg. In some aspects, C1D1 is 455 mg. In some aspects, C1D1 is 460 mg. In some aspects, C1D1 is 465 mg. In some aspects, C1D1 is 470 mg. In some aspects, C1D1 is 475 mg. In some aspects, C1D1 is 480 mg. In some aspects, C1D1 is 485 mg. In some aspects, C1D1 is 490 mg. In some aspects, C1D1 is 495 mg. In some aspects, C1D1 is 500 mg. In some aspects, C1D1 is 505 mg. In some aspects, C1D1 is 510 mg. In some aspects, C1D1 is 515 mg. In some aspects, C1D1 is 520 mg. In some aspects, C1D1 is 525 mg. In some aspects, C1D1 is 530 mg. In some aspects, C1D1 is 535 mg. In some aspects, C1D1 is 540 mg. In some aspects, C1D1 is 545 mg. In some aspects, C1D1 is 550 mg. In some aspects, C1D1 is 555 mg. In some aspects, C1D1 is 560 mg. In some aspects, C1D1 is 565 mg. In some aspects, C1D1 is 570 mg. In some aspects, C1D1 is 575 mg. In some aspects, C1D1 is 580 mg. In some aspects, C1D1 is 585 mg. In some aspects, C1D1 is 590 mg.In some aspects, C1D1 is 595 mg. In some aspects, C1D1 is 600 mg. In some aspects, C1D1 is 605 mg. In some aspects, C1D1 is 610 mg. In some aspects, C1D1 is 615 mg. In some aspects, C1D1 is 620 mg. In some aspects, C1D1 is 625 mg. In some aspects, C1D1 is 630 mg. In some aspects, C1D1 is 635 mg. In some aspects, C1D1 is 640 mg. In some aspects, C1D1 is 645 mg. In some aspects, C1D1 is 650 mg. In some aspects, C1D1 is 655 mg. In some aspects, C1D1 is 660 mg. In some aspects, C1D1 is 665 mg. In some aspects, C1D1 is 670 mg. In some aspects, C1D1 is 675 mg. In some aspects, C1D1 is 680 mg. In some aspects, C1D1 is 685 mg. In some aspects, C1D1 is 690 mg. In some aspects, C1D1 is 695 mg. In some aspects, C1D1 is 700 mg. In some aspects, C1D1 is 705 mg. In some aspects, C1D1 is 710 mg. In some aspects, C1D1 is 715 mg. In some aspects, C1D1 is 720 mg. In some aspects, C1D1 is 725 mg. In some aspects, C1D1 is 730 mg. In some aspects, C1D1 is 735 mg. In some aspects, C1D1 is 740 mg. In some aspects, C1D1 is 745 mg. In some aspects, C1D1 is 750 mg. In some aspects, C1D1 is 755 mg. In some aspects, C1D1 is 760 mg. In some aspects, C1D1 is 765 mg. In some aspects, C1D1 is 770 mg. In some aspects, C1D1 is 775 mg. In some aspects, C1D1 is 780 mg. In some aspects, C1D1 is 785 mg. In some aspects, C1D1 is 790 mg. In some aspects, C1D1 is 795 mg. In some aspects, C1D1 is 800 mg. In some aspects, C1D1 is 805 mg. In some aspects, C1D1 is 810 mg. In some aspects, C1D1 is 815 mg. In some aspects, C1D1 is 820 mg. In some aspects, C1D1 is 825 mg. In some aspects, C1D1 is 830 mg. In some aspects, C1D1 is 835 mg. In some aspects, C1D1 is 840 mg. In some aspects, C1D1 is 845 mg. In some aspects, C1D1 is 850 mg. In some aspects, C1D1 is 855 mg. In some aspects, C1D1 is 860 mg. In some aspects, C1D1 is 865 mg. In some aspects, C1D1 is 870 mg. In some aspects, C1D1 is 875 mg. In some aspects, C1D1 is 880 mg.In some aspects, C1D1 is 885 mg. In some aspects, C1D1 is 890 mg. In some aspects, C1D1 is 895 mg. In some aspects, C1D1 is 900 mg. In some aspects, C1D1 is 905 mg. In some aspects, C1D1 is 910 mg. In some aspects, C1D1 is 915 mg. In some aspects, C1D1 is 920 mg. In some aspects, C1D1 is 925 mg. In some aspects, C1D1 is 930 mg. In some aspects, C1D1 is 935 mg. In some aspects, C1D1 is 940 mg. In some aspects, C1D1 is 945 mg. In some aspects, C1D1 is 950 mg. In some aspects, C1D1 is 955 mg. In some aspects, C1D1 is 960 mg. In some aspects, C1D1 is 965 mg. In some aspects, C1D1 is 970 mg. In some aspects, C1D1 is 975 mg. In some aspects, C1D1 is 980 mg. In some aspects, C1D1 is 985 mg. In some aspects, C1D1 is 990 mg. In some aspects, C1D1 is 995 mg. In some aspects, C1D1 is 1000 mg.

[0259] ii. Single step-up dosing regimen

[0260] In some aspects, the invention provides a method of treating a subject having cancer (eg, MM), the method comprising subcutaneously administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a single step-up dosing regimen.

[0261] In some aspects, the present invention provides a method of treating a subject having MM, the method comprising subcutaneously 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, wherein the first dosing cycle includes a first dose (C1D1) of the bispecific antibody and a second dose (C1D2) of the bispecific antibody, wherein C1D1 is between about 0.1 mg and about 50 mg (e.g., between about 0.1 mg and about 9.5 mg, between about 0.2 mg and about 9 mg, between about 0.3 mg and about 8.5 mg, between about 0.4 mg and about 8 mg, between about 0.5 mg and about 7.5 mg, between about 0.6 mg and about 7 mg, between about 0.7 between about 1 mg and about 6.5 mg, between about 0.8 mg and about 6 mg, between about 0.9 mg and about 5.5 mg, between about 1 mg and about 5 mg, between about 1.1 mg and about 4.5 mg, between about 1.2 mg and about 4 mg, between about 1.3 mg and about 3.5 mg, between about 1.4 mg and about 3 mg, between about 1.5 mg and about 2.5 mg, between about 1 mg and about 3 mg, between about 0.2 mg and about 35 mg, between about 0.3 mg and about 30 mg, between about 0.4 mg and about 29 mg, between about 0.5 mg and about 28 mg, between about 1 mg and about 27 mg, between about 1.5 mg and about 26 mg, between about 2 mg and about 25 mg, about 2.5 From about 15 mg to about 24 mg, from about 3 mg to about 23 mg, from about 3.5 mg to about 22 mg, from about 4 mg to about 21 mg, from about 4.5 mg to about 20 mg, from about 5 mg to about 19 mg, from about 5.5 mg to about 18 mg, from about 6 mg to about 17 mg, from about 6.5 mg to about 16 mg, from about 7 mg to about 15 mg, from about 7.5 mg to about 14 mg, from about 8 mg to about 13 mg, from about 8 mg to about 12 mg, from about 8.5 mg to about 12 mg, from about 9 mg to about 11 mg, from about 0.1 mg to about 1 mg, from about 0.2 mg to about 1.5 mg, from about 0.3 mg to about 2 mg between about 0.4 mg and about 2.5 mg, between about 0.5 mg and about 3 mg, between about 0.6 mg and about 3.5 mg, between about 0.7 mg and about 4 mg, between about 0.8 mg and about 4.5 mg, between about 0.9 mg and about 5 mg, between about 1 mg and about 6 mg, between about 1.5 mg and about 6.5 mg, between about 2 mg and about 7 mg, between about 2.5 mg and about 7.5 mg, between about 3 mg and about 8 mg, between about 3.5 mg and about 8.5 mg, between about 4 mg and about 9 mg, between about 4.5 mg and about 9.5 mg, between about 5 mg and about 10 mg, between about 5.5 mg and about 10.5 mg, between about 6 mg and about 11 mg,about 6.5 mg to about 11.5 mg, about 7 mg to about 12 mg, about 7.5 mg to about 12.5 mg, about 8 mg to about 13 mg, about 8.5 mg to about 13.5 mg, about 9 mg to about 14 mg, about 9.5 mg to about 14.5 mg, about 10 mg to about 15 mg, about 11 mg to about 16 mg, about 12 mg to about 17 mg, about 13 mg to about 18 mg, about 14 mg to about 19 mg, about 15 mg to about 20 mg, about 16 mg to about 21 mg, about 17 mg to about 22 mg, about 18 mg to about 23 mg, about 19 mg to about 24 mg, about between about 20 mg to about 25 mg, between about 21 mg to about 26 mg, between about 22 mg to about 27 mg, between about 23 mg to about 28 mg, between about 24 mg to about 29 mg, between about 25 mg to about 30 mg, between about 26 mg to about 31 mg, between about 27 mg to about 32 mg, between about 28 mg to about 33 mg, between about 29 mg to about 34 mg, between about 30 mg to about 35 mg, between about 31 mg to about 36 mg, between about 32 mg to about 37 mg, between about 33 mg to about 38 mg, between about 34 mg to about 39 mg, between about 35 mg to about 40 mg, between about 36 mg to about 41 mg, between about 37 mg to about 42 mg between about 38 mg to about 43 mg, between about 39 mg to about 44 mg, between about 40 mg to about 45 mg, between about 41 mg to about 46 mg, between about 42 mg to about 47 mg, between about 43 mg to about 48 mg, between about 44 mg to about 49 mg, between about 45 mg to about 50 mg), and C1D2 is between about 10 mg to about 1000 mg (e.g., between about 10 mg to about 70 mg, between about 15 mg to about 65 mg, between about 20 mg to about 60 mg, between about 25 mg to about 55 mg, between about 30 mg to about 50 mg, between about 35 mg to about 45 mg, between about 15 mg to about 225 mg, between about 20 mg to about about 220 mg, about 25 mg to about 215 mg, about 30 mg to about 210 mg, about 35 mg to about 205 mg, about 40 mg to about 200 mg, about 45 mg to about 195 mg, about 50 mg to about 190 mg, about 55 mg to about 185 mg, about 60 mg to about 180 mg, about 65 mg to about 175 mg, about 70 mg to about 170 mg, about 75 mg to about 165 mg, about 80 mg to about 160 mg, about 85 mg to about 155 mg, about 90 mg to about 150 mg, about 95 mg to about 145 mg, about 100 mg to about 140 mg,Between about 105 mg and about 135 mg, between about 110 mg and about 130 mg, between about 115 mg and about 125 mg, between about 10 mg and about 50 mg, between about 25 mg and about 75 mg, between about 50 mg and about 100 mg, between about 75 mg and about 125 mg, between about 100 mg and about 150 mg, between about 125 mg and about 175 mg, between about 150 mg and about 200 mg, and between about 175 mg and about 225 mg between about 200 mg and about 250 mg, between about 225 mg and about 275 mg, between about 250 mg and about 300 mg, between about 275 mg and about 325 mg, between about 300 mg and about 350 mg, between about 325 mg and about 375 mg, between about 350 mg and about 400 mg, between about 375 mg and about 425 mg, between about 400 mg and about 450 mg, between about 425 mg and about 475 mg, between about 450 mg and about 475 mg, between about 480 mg and about 500 mg. From about 475 mg to about 525 mg, from about 500 mg to about 550 mg, from about 525 mg to about 575 mg, from about 550 mg to about 600 mg, from about 575 mg to about 625 mg, from about 600 mg to about 650 mg, from about 625 mg to about 675 mg, from about 650 mg to about 700 mg, from about 675 mg to about 725 mg, from about 700 mg to about 750 mg. From about 750 mg to about 800 mg, from about 775 mg to about 825 mg, from about 800 mg to about 850 mg, from about 825 mg to about 875 mg, from about 850 mg to about 900 mg, from about 875 mg to about 925 mg, from about 900 mg to about 950 mg, from about 925 mg to about 975 mg, or from about 950 mg to about 1000 mg).

[0262] In some aspects, C1D2 is between about 10 mg and about 200 mg (e.g., between 10 mg and about 170 mg, between about 11 mg and about 165 mg, between about 12 mg and about 160 mg, between about 13 mg and about 155 mg, between about 14 mg and about 150 mg, between about 15 mg and about 145 mg, between about 16 mg and about 140 mg, between about 17 mg and about 135 mg, between about 18 mg and about 130 mg, between about 19 mg and about 125 mg, between about 20 mg and about 120 mg, between about 21 mg and about 115 mg, between about 22 mg and about 110 mg, between about 23 mg and about 105 mg). g, about 24 mg to about 100 mg, about 25 mg to about 95 mg, about 26 mg to about 90 mg, about 27 mg to about 85 mg, about 28 mg to about 80 mg, about 29 mg to about 75 mg, about 30 mg to about 70 mg, about 31 mg to about 65 mg, about 32 mg to about 60 mg, about 33 mg to about 55 mg, about 34 mg to about 50 mg, about 35 mg to about 45 mg, about 40 mg to about 200 mg, about 45 mg to about 195 mg, about 50 mg to about 190 mg, about 55 mg to about 185 mg, about 6 0 mg to about 180 mg, about 65 mg to about 175 mg, about 70 mg to about 170 mg, about 75 mg to about 165 mg, about 80 mg to about 160 mg, about 85 mg to about 155 mg, about 90 mg to about 150 mg, about 95 mg to about 145 mg, about 100 mg to about 140 mg, about 105 mg to about 135 mg, about 110 mg to about 130 mg, about 115 mg to about 125 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about 50 mg or about 190 mg to about 200 mg).

[0263] In some aspects, C1D1 is between 0.1 mg and 50 mg (e.g., between 0.1 mg and 9.5 mg, between 0.2 mg and 9 mg, between 0.3 mg and 8.5 mg, between 0.4 mg and 8 mg, between 0.5 mg and 7.5 mg, between 0.6 mg and 7 mg, between 0.7 mg and 6.5 mg, between 0.8 mg and 6 mg, between 0.9 mg and 5.5 mg, between 1 mg and 5 mg, between 1.1 mg and 4.5 mg, between 1.2 mg and 4 mg, between 1.3 mg and 3.5 mg, between 1.4 mg and 3 mg, between 1.5 mg and 2.5 mg, between 1 mg and 3 mg, between 0.2 mg and 35 mg, between 0.3 mg and 5.5 mg). g to 30mg, 0.4mg to 29mg, 0.5mg to 28mg, 1mg to 27mg, 1.5mg to 26mg, 2mg to 25mg, 2.5mg to 24mg, 3mg to 23mg, 3.5mg to 22mg, 4mg to 21mg, 4.5mg to 20mg, 5mg to 19mg, 5.5mg to 18mg, 6mg to 17mg, 6.5mg to 16mg, 7mg to 15mg, 7.5mg to 14mg, 8mg to 13mg, 8mg to 12mg, 8.5mg to 12mg, 9mg to 11mg, 0.1mg to 1mg, 0.2mg to 1.5mg, 0.3mg to 2mg, 0.4mg to 2.5mg, 0.5mg to 3mg, 0.6mg to 3.5mg, 0.7mg to 4mg, 0.8mg to 4.5mg, 0.9mg to 5mg, 1mg to 6mg, 1.5mg to 6.5mg, 2mg to 7mg, 2.5mg to 7.5mg, 3mg to 8mg, 3.5mg to 8.5mg, 4mg to 9mg, 4.5mg to 9.5mg, 5mg to 10mg, 5.5mg to 10.5mg, 6mg to 11mg, Between 6.5mg and 11.5mg, between 7mg and 12mg, between 7.5mg and 12.5mg, between 8mg and 13mg, between 8.5mg and 13.5mg, between 9mg and 14mg, between 9.5mg and 14.5mg, between 10mg and 15mg, between 11mg and 16mg, between 12mg and 17mg, between 13mg and 18mg, between 14mg and 19mg, between 15mg and 20mg, between 16mg and 21mg, between 17mg and 22mg, between 18mg and 23mg, between 19mg and 24mg, between 20mg and 25mg, between 21mg and 26mg, between 22mg and 27mg,Between 23mg and 28mg, between 24mg and 29mg, between 25mg and 30mg, between 26mg and 31mg, between 27mg and 32mg, between 28mg and 33mg, between 29mg and 34mg, between 30mg and 35mg, between 31mg and 36mg, between 32mg and 37mg, between 33mg and 38mg, between 34mg and 39mg, between 35mg and 40mg, between 36mg and 41mg, between 37mg and 42mg, between 38mg and 43mg, between 39mg and 44mg, between 40mg and 45mg, between 41mg and 46mg, between 42mg and 47mg, between 43mg and 48mg g, 44 mg to 49 mg, 45 mg to 50 mg), and C1D2 is between 10 mg and 1000 mg (e.g., between 10 mg and 70 mg, between 15 mg and 65 mg, between 20 mg and 60 mg, between 25 mg and 55 mg, between 30 mg and 50 mg, between 35 mg and 45 mg, between 15 mg and 225 mg, between 20 mg and 220 mg, between 25 mg and 215 mg, between 30 mg and 210 mg, between 35 mg and 205 mg, between 40 mg and 200 mg, between 45 mg and 195 mg, between 50 mg and 190 mg, between 55 mg and 185 mg, between 60 mg and 1 Between 80mg, between 65mg and 175mg, between 70mg and 170mg, between 75mg and 165mg, between 80mg and 160mg, between 85mg and 155mg, between 90mg and 150mg, between 95mg and 145mg, between 100mg and 140mg, between 105mg and 135mg, between 110mg and 130mg, between 115mg and 125mg, between 10mg and 50mg, between 25mg and 75mg, between 50mg and 100mg, between 75mg and 125mg, between 100mg and 150mg, between 125mg and 175mg, between 150mg and 200mg, between 175 Between 200mg and 250mg, between 225mg and 275mg, between 250mg and 300mg, between 275mg and 325mg, between 300mg and 350mg, between 325mg and 375mg, between 350mg and 400mg, between 375mg and 425mg, between 400mg and 450mg, between 425mg and 475mg, between 450mg and 500mg, between 475mg and 525mg, between 500mg and 550mg, between 525mg and 575mg, between 550mg and 600mg, between 575mg and 625mg, between 600mg and 650mg,between 625mg and 675mg, between 650mg and 700mg, between 675mg and 725mg, between 700mg and 750mg, between 725mg and 775mg, between 750mg and 800mg, between 775mg and 825mg, between 800mg and 850mg, between 825mg and 875mg, between 850mg and 900mg, between 875mg and 925mg, between 900mg and 950mg, between 925mg and 975mg, or between 950mg and 1000mg).

[0264] In some aspects, C1D2 is between 10 mg and 200 mg (e.g., between 10 mg and 170 mg, between 11 mg and 165 mg, between 12 mg and 160 mg, between 13 mg and 155 mg, between 14 mg and 150 mg, between 15 mg and 145 mg, between 16 mg and 140 mg, between 17 mg and 135 mg, between 18 mg and 130 mg, between 19 mg and 125 mg, between 20 mg and 120 mg, between 21 mg and 115 mg, between 22 mg and 110 mg, between 23 mg and 10 Between 5mg, 24mg and 100mg, 25mg and 95mg, 26mg and 90mg, 27mg and 85mg, 28mg and 80mg, 29mg and 75mg, 30mg and 70mg, 31mg and 65mg, 32mg and 60mg, 33mg and 55mg, 34mg and 50mg, 35mg and 45mg, 40mg and 200mg, 45mg and 195mg, 50mg and 190mg, 55mg and 185mg, 60 Between mg and 180mg, between 65mg and 175mg, between 70mg and 170mg, between 75mg and 165mg, between 80mg and 160mg, between 85mg and 155mg, between 90mg and 150mg, between 95mg and 145mg, between 100mg and 140mg, between 105mg and 135mg, between 110mg and 130mg, between 115mg and 125mg, between 10mg and 20mg, between 20mg and 30mg, between 30mg and 40mg, between 40mg and 50mg between 150mg and 160mg, between 160mg and 170mg, between 170mg and 180mg, between 180mg and 190mg, or between 190mg and 200mg).

[0265] In some aspects, the present invention provides a method of treating a subject having cancer (e.g., MM), the method comprising subcutaneously administering to the subject a bispecific antibody that binds to FcRH5 and CD3 at a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein 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), wherein C1D1 is less than C1D2, and wherein C1D1 is between about 0.1 mg and about 50 mg (e.g., between about 0.1 mg and about 9.5 mg, between about 0.2 mg and about 9 mg, between about 0.3 mg and about 8.5 mg, between about 0.4 mg to about 8 mg, about 0.5 mg to about 7.5 mg, about 0.6 mg to about 7 mg, about 0.7 mg to about 6.5 mg, about 0.8 mg to about 6 mg, about 0.9 mg to about 5.5 mg, about 1 mg to about 5 mg, about 1.1 mg to about 4.5 mg, about 1.2 mg to about 4 mg, about 1.3 mg to about 3.5 mg, about 1.4 mg to about 3 mg, about 1.5 mg to about 2.5 mg, about 1 mg to about 3 mg, about 0.2 mg to about 35 mg, about 0.3 mg to about 30 mg, about 0.4 mg to about 29 mg, about 0.5 mg to about 28 mg , between about 1 mg and about 27 mg, between about 1.5 mg and about 26 mg, between about 2 mg and about 25 mg, between about 2.5 mg and about 24 mg, between about 3 mg and about 23 mg, between about 3.5 mg and about 22 mg, between about 4 mg and about 21 mg, between about 4.5 mg and about 20 mg, between about 5 mg and about 19 mg, between about 5.5 mg and about 18 mg, between about 6 mg and about 17 mg, between about 6.5 mg and about 16 mg, between about 7 mg and about 15 mg, between about 7.5 mg and about 14 mg, between about 8 mg and about 13 mg, between about 8 mg and about 12 mg, between about 8.5 mg and about 12 mg, between about 9 mg and about 11 mg between about 0.1 mg to about 1 mg, between about 0.2 mg to about 1.5 mg, between about 0.3 mg to about 2 mg, between about 0.4 mg to about 2.5 mg, between about 0.5 mg to about 3 mg, between about 0.6 mg to about 3.5 mg, between about 0.7 mg to about 4 mg, between about 0.8 mg to about 4.5 mg, between about 0.9 mg to about 5 mg, between about 1 mg to about 6 mg, between about 1.5 mg to about 6.5 mg, between about 2 mg to about 7 mg, between about 2.5 mg to about 7.5 mg, between about 3 mg to about 8 mg, between about 3.5 mg to about 8.5 mg, between about 4 mg to about 9 mg, between about 4.5 mg to about 9.5 mg,Between about 5 mg and about 10 mg, between about 5.5 mg and about 10.5 mg, between about 6 mg and about 11 mg, between about 6.5 mg and about 11.5 mg, between about 7 mg and about 12 mg, between about 7.5 mg and about 12.5 mg, between about 8 mg and about 13 mg, between about 8.5 mg and about 13.5 mg, between about 9 mg and about 14 mg, between about 9.5 mg and about 14.5 mg, between about 10 mg and about 15 mg, between about 11 mg and about 16 mg, between about 12 mg and about 17 mg, between about 13 mg and about 18 mg, between about 14 mg and about 19 mg, between about 15 mg and about 20 mg, between about 16 mg and about 21 mg , between about 17 mg and about 22 mg, between about 18 mg and about 23 mg, between about 19 mg and about 24 mg, between about 20 mg and about 25 mg, between about 21 mg and about 26 mg, between about 22 mg and about 27 mg, between about 23 mg and about 28 mg, between about 24 mg and about 29 mg, between about 25 mg and about 30 mg, between about 26 mg and about 31 mg, between about 27 mg and about 32 mg, between about 28 mg and about 33 mg, between about 29 mg and about 34 mg, between about 30 mg and about 35 mg, between about 31 mg and about 36 mg, between about 32 mg and about 37 mg, between about 33 mg and about 38 mg, between about 34 mg and about 39 mg. The amount of C1D2 is between about 10 mg and about 1000 mg (e.g., between about 10 mg and about 70 mg, about 15 mg and about 65 mg, about 20 mg and about 60 mg, about 25 mg and about 55 mg, about 30 mg and about 50 mg), and the amount of C1D2 is between about 10 mg and about 1000 mg (e.g., between about 10 mg and about 70 mg, about 15 mg and about 65 mg, about 20 mg and about 60 mg, about 25 mg and about 55 mg, about 30 mg and about 50 mg). about 50 mg, about 35 mg to about 45 mg, about 15 mg to about 225 mg, about 20 mg to about 220 mg, about 25 mg to about 215 mg, about 30 mg to about 210 mg, about 35 mg to about 205 mg, about 40 mg to about 200 mg, about 45 mg to about 195 mg, about 50 mg to about 190 mg, about 55 mg to about 185 mg, about 60 mg to about 180 mg, about 65 mg to about 175 mg, about 70 mg to about 170 mg, about 75 mg to about 165 mg, about 80 mg to about 160 mg, about 85 mg to about 155 mg,about 90 mg to about 150 mg, about 95 mg to about 145 mg, about 100 mg to about 140 mg, about 105 mg to about 135 mg, about 110 mg to about 130 mg, about 115 mg to about 125 mg, about 10 mg to about 50 mg, about 25 mg to about 75 mg, about 50 mg to about 100 mg, about 75 mg to about 125 mg, about 100 mg to about 150 mg, about 125 mg to about 175 mg Between about 150 mg and about 200 mg, between about 175 mg and about 225 mg, between about 200 mg and about 250 mg, between about 225 mg and about 275 mg, between about 250 mg and about 300 mg, between about 275 mg and about 325 mg, between about 300 mg and about 350 mg, between about 325 mg and about 375 mg, between about 350 mg and about 400 mg, between about 375 mg and about 425 mg, and between about 400 mg and about 450 mg. between about 425 mg and about 475 mg, between about 450 mg and about 500 mg, between about 475 mg and about 525 mg, between about 500 mg and about 550 mg, between about 525 mg and about 575 mg, between about 550 mg and about 600 mg, between about 575 mg and about 625 mg, between about 600 mg and about 650 mg, between about 625 mg and about 675 mg, between about 650 mg and about 700 mg, between about 675 mg and about 725 mg, about 700 mg to about 750 mg, about 725 mg to about 775 mg, about 750 mg to about 800 mg, about 775 mg to about 825 mg, about 800 mg to about 850 mg, about 825 mg to about 875 mg, about 850 mg to about 900 mg, about 875 mg to about 925 mg, about 900 mg to about 950 mg, about 925 mg to about 975 mg, or about 950 mg to about 1000 mg).

[0266] In some aspects, C1D2 is between about 10 mg and about 200 mg (e.g., between 10 mg and about 170 mg, between about 11 mg and about 165 mg, between about 12 mg and about 160 mg, between about 13 mg and about 155 mg, between about 14 mg and about 150 mg, between about 15 mg and about 145 mg, between about 16 mg and about 140 mg, between about 17 mg and about 135 mg, between about 18 mg and about 130 mg, between about 19 mg and about 125 mg, between about 20 mg and about 120 mg, between about 21 mg and about 115 mg, between about 22 mg and about 110 mg, between about 23 mg and about 105 mg). g, about 24 mg to about 100 mg, about 25 mg to about 95 mg, about 26 mg to about 90 mg, about 27 mg to about 85 mg, about 28 mg to about 80 mg, about 29 mg to about 75 mg, about 30 mg to about 70 mg, about 31 mg to about 65 mg, about 32 mg to about 60 mg, about 33 mg to about 55 mg, about 34 mg to about 50 mg, about 35 mg to about 45 mg, about 40 mg to about 200 mg, about 45 mg to about 195 mg, about 50 mg to about 190 mg, about 55 mg to about 185 mg, about 6 0 mg to about 180 mg, about 65 mg to about 175 mg, about 70 mg to about 170 mg, about 75 mg to about 165 mg, about 80 mg to about 160 mg, about 85 mg to about 155 mg, about 90 mg to about 150 mg, about 95 mg to about 145 mg, about 100 mg to about 140 mg, about 105 mg to about 135 mg, about 110 mg to about 130 mg, about 115 mg to about 125 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about 50 mg or about 190 mg to about 200 mg).

[0267] In some aspects, C1D1 is between 0.1 mg and 50 mg (e.g., between 0.1 mg and 9.5 mg, between 0.2 mg and 9 mg, between 0.3 mg and 8.5 mg, between 0.4 mg and 8 mg, between 0.5 mg and 7.5 mg, between 0.6 mg and 7 mg, between 0.7 mg and 6.5 mg, between 0.8 mg and 6 mg, between 0.9 mg and 5.5 mg, between 1 mg and 5 mg, between 1.1 mg and 4.5 mg, between 1.2 mg and 4 mg, between 1.3 mg and 3.5 mg, between 1.4 mg and 3 mg, between 1.5 mg and 2.5 mg, between 1 mg and 3 mg, between 0.2 mg and 35 mg, between 0.3 mg and 5.5 mg). g to 30 mg, 0.4 mg to 29 mg, 0.5 mg to 28 mg, 1 mg to 27 mg, 1.5 mg to 26 mg, 2 mg to 25 mg, 2.5 mg to 24 mg, 3 mg to 23 mg, 3.5 mg to 22 mg, 4 mg to 21 mg, 4.5 mg to 20 mg, 5 mg to 19 mg, 5.5 mg to 18 mg, 6 mg to 17 mg, 6.5 mg to 16 mg, 7 mg to 15 mg, 7.5 mg to 14 mg, 8 mg to 13 mg, 8.5 mg to 12 mg, 9 mg to 11 mg, 0.1 mg to 1 mg , between 0.2mg and 1.5mg, between 0.3mg and 2mg, between 0.4mg and 2.5mg, between 0.5mg and 3mg, between 0.6mg and 3.5mg, between 0.7mg and 4mg, between 0.8mg and 4.5mg, between 0.9mg and 5mg, between 1mg and 6mg, between 1.5mg and 6.5mg, between 2mg and 7mg, between 2.5mg and 7.5mg, between 3mg and 8mg, between 3.5mg and 8.5mg, between 4mg and 9mg, between 4.5mg and 9.5mg, between 5mg and 10mg, between 5.5mg and 10.5mg, between 6mg and 11mg, between 6.5mg and 11.5mg g, between 7mg and 12mg, between 7.5mg and 12.5mg, between 8mg and 13mg, between 8mg and 12mg, between 8.5mg and 13.5mg, between 9mg and 14mg, between 9.5mg and 14.5mg, between 10mg and 15mg, between 11mg and 16mg, between 12mg and 17mg, between 13mg and 18mg, between 14mg and 19mg, between 15mg and 20mg, between 16mg and 21mg, between 17mg and 22mg, between 18mg and 23mg, between 19mg and 24mg, between 20mg and 25mg, between 21mg and 26mg, between 22mg and 27mg,Between 23mg and 28mg, between 24mg and 29mg, between 25mg and 30mg, between 26mg and 31mg, between 27mg and 32mg, between 28mg and 33mg, between 29mg and 34mg, between 30mg and 35mg, between 31mg and 36mg, between 32mg and 37mg, between 33mg and 38mg, between 34mg and 39mg, between 35mg and 40mg, between 36mg and 41mg, between 37mg and 42mg, between 38mg and 43mg, between 39mg and 44mg, between 40mg and 45mg, between 41mg and 46mg, between 42mg and 47mg, between 43mg and 48mg g, 44 mg to 49 mg, 45 mg to 50 mg), and C1D2 is between 10 mg and 1000 mg (e.g., between 10 mg and 70 mg, between 15 mg and 65 mg, between 20 mg and 60 mg, between 25 mg and 55 mg, between 30 mg and 50 mg, between 35 mg and 45 mg, between 15 mg and 225 mg, between 20 mg and 220 mg, between 25 mg and 215 mg, between 30 mg and 210 mg, between 35 mg and 205 mg, between 40 mg and 200 mg, between 45 mg and 195 mg, between 50 mg and 190 mg, between 55 mg and 185 mg, between 60 mg and 1 Between 80mg, between 65mg and 175mg, between 70mg and 170mg, between 75mg and 165mg, between 80mg and 160mg, between 85mg and 155mg, between 90mg and 150mg, between 95mg and 145mg, between 100mg and 140mg, between 105mg and 135mg, between 110mg and 130mg, between 115mg and 125mg, between 10mg and 50mg, between 25mg and 75mg, between 50mg and 100mg, between 75mg and 125mg, between 100mg and 150mg, between 125mg and 175mg, between 150mg and 200mg, between 175 Between 200mg and 250mg, between 225mg and 275mg, between 250mg and 300mg, between 275mg and 325mg, between 300mg and 350mg, between 325mg and 375mg, between 350mg and 400mg, between 375mg and 425mg, between 400mg and 450mg, between 425mg and 475mg, between 450mg and 500mg, between 475mg and 525mg, between 500mg and 550mg, between 525mg and 575mg, between 550mg and 600mg, between 575mg and 625mg, between 600mg and 650mg,between 625mg and 675mg, between 650mg and 700mg, between 675mg and 725mg, between 700mg and 750mg, between 725mg and 775mg, between 750mg and 800mg, between 775mg and 825mg, between 800mg and 850mg, between 825mg and 875mg, between 850mg and 900mg, between 875mg and 925mg, between 900mg and 950mg, between 925mg and 975mg, or between 950mg and 1000mg).

[0268] In some aspects, C1D2 is between 10 mg and 200 mg (e.g., between 10 mg and 170 mg, between 11 mg and 165 mg, between 12 mg and 160 mg, between 13 mg and 155 mg, between 14 mg and 150 mg, between 15 mg and 145 mg, between 16 mg and 140 mg, between 17 mg and 135 mg, between 18 mg and 130 mg, between 19 mg and 125 mg, between 20 mg and 120 mg, between 21 mg and 115 mg, between 22 mg and 110 mg, between 23 mg and 10 Between 5mg, 24mg and 100mg, 25mg and 95mg, 26mg and 90mg, 27mg and 85mg, 28mg and 80mg, 29mg and 75mg, 30mg and 70mg, 31mg and 65mg, 32mg and 60mg, 33mg and 55mg, 34mg and 50mg, 35mg and 45mg, 40mg and 200mg, 45mg and 195mg, 50mg and 190mg, 55mg and 185mg, 60 Between mg and 180mg, between 65mg and 175mg, between 70mg and 170mg, between 75mg and 165mg, between 80mg and 160mg, between 85mg and 155mg, between 90mg and 150mg, between 95mg and 145mg, between 100mg and 140mg, between 105mg and 135mg, between 110mg and 130mg, between 115mg and 125mg, between 10mg and 20mg, between 20mg and 30mg, between 30mg and 40mg, between 40mg and 50mg between 150mg and 160mg, between 160mg and 170mg, between 170mg and 180mg, between 180mg and 190mg, or between 190mg and 200mg).

[0269] In some aspects, C1D1 is about 1 mg. In some aspects, C1D1 is about 2 mg. In some aspects, C1D1 is about 3 mg. In some aspects, C1D1 is about 4 mg. In some aspects, C1D1 is about 5 mg. In some aspects, C1D1 is about 6 mg. In some aspects, C1D1 is about 7 mg. In some aspects, C1D1 is about 8 mg. In some aspects, C1D1 is about 9 mg. In some aspects, C1D1 is about 10 mg. In some aspects, C1D1 is about 11 mg. In some aspects, C1D1 is about 12 mg. In some aspects, C1D1 is about 13 mg. In some aspects, C1D1 is about 14 mg. In some aspects, C1D1 is about 15 mg. In some aspects, C1D1 is about 16 mg. In some aspects, C1D1 is about 17 mg. In some aspects, C1D1 is about 18 mg. In some aspects, C1D1 is about 19 mg. In some aspects, C1D1 is about 20 mg. In some aspects, C1D1 is about 21 mg. In some aspects, C1D1 is about 22 mg. In some aspects, C1D1 is about 23 mg. In some aspects, C1D1 is about 24 mg. In some aspects, C1D1 is about 25 mg. In some aspects, C1D1 is about 26 mg. In some aspects, C1D1 is about 27 mg. In some aspects, C1D1 is about 28 mg. In some aspects, C1D1 is about 29 mg. In some aspects, C1D1 is about 30 mg. In some aspects, C1D1 is about 31 mg. In some aspects, C1D1 is about 32 mg. In some aspects, C1D1 is about 33 mg. In some aspects, C1D1 is about 34 mg. In some aspects, C1D1 is about 35 mg. In some aspects, C1D1 is about 36 mg. In some aspects, C1D1 is about 37 mg. In some aspects, C1D1 is about 38 mg. In some aspects, C1D1 is about 39 mg. In some aspects, C1D1 is about 40 mg. In some aspects, C1D1 is about 41 mg. In some aspects, C1D1 is about 42 mg. In some aspects, C1D1 is about 43 mg. In some aspects, C1D1 is about 44 mg. In some aspects, C1D1 is about 45 mg. In some aspects, C1D1 is about 46 mg. In some aspects, C1D1 is about 47 mg. In some aspects, C1D1 is about 48 mg. In some aspects, C1D1 is about 49 mg. In some aspects, C1D1 is about 50 mg.

[0270] In some aspects, C1D2 is about 10 mg. In some aspects, C1D2 is about 15 mg. In some aspects, C1D2 is about 20 mg. In some aspects, C1D2 is about 25 mg. In some aspects, C1D2 is about 30 mg. In some aspects, C1D2 is about 35 mg. In some aspects, C1D2 is about 40 mg. In some aspects, C1D2 is about 45 mg. In some aspects, C1D2 is about 50 mg. In some aspects, C1D2 is about 55 mg. In some aspects, C1D2 is about 60 mg. In some aspects, C1D2 is about 65 mg. In some aspects, C1D2 is about 70 mg. In some aspects, C1D2 is about 75 mg. In some aspects, C1D2 is about 80 mg. In some aspects, C1D2 is about 85 mg. In some aspects, C1D2 is about 90 mg. In some aspects, C1D2 is about 95 mg. In some aspects, C1D2 is about 100 mg. In some aspects, C1D2 is about 105 mg. In some aspects, C1D2 is about 110 mg. In some aspects, C1D2 is about 115 mg. In some aspects, C1D2 is about 120 mg. In some aspects, C1D2 is about 125 mg. In some aspects, C1D2 is about 130 mg. In some aspects, C1D2 is about 135 mg. In some aspects, C1D2 is about 140 mg. In some aspects, C1D2 is about 145 mg. In some aspects, C1D2 is about 150 mg. In some aspects, C1D2 is about 155 mg. In some aspects, C1D2 is about 160 mg. In some aspects, C1D2 is about 165 mg. In some aspects, C1D2 is about 170 mg. In some aspects, C1D2 is about 175 mg. In some aspects, C1D2 is about 180 mg. In some aspects, C1D2 is about 185 mg. In some aspects, C1D2 is about 190 mg. In some aspects, C1D2 is about 195 mg. In some aspects, C1D2 is about 200 mg. In some aspects, C1D2 is about 205 mg. In some aspects, C1D2 is about 210 mg. In some aspects, C1D2 is about 215 mg. In some aspects, C1D2 is about 220 mg. In some aspects, C1D2 is about 225 mg. In some aspects, C1D2 is about 230 mg. In some aspects, C1D2 is about 235 mg. In some aspects, C1D2 is about 240 mg. In some aspects, C1D2 is about 245 mg. In some aspects, C1D2 is about 250 mg. In some aspects, C1D2 is about 255 mg. In some aspects, C1D2 is about 260 mg. In some aspects, C1D2 is about 265 mg. In some aspects, C1D2 is about 270 mg. In some aspects, C1D2 is about 275 mg. In some aspects, C1D2 is about 280 mg. In some aspects, C1D2 is about 285 mg.In some aspects, C1D2 is about 290 mg. In some aspects, C1D2 is about 295 mg. In some aspects, C1D2 is about 300 mg. In some aspects, C1D2 is about 305 mg. In some aspects, C1D2 is about 310 mg. In some aspects, C1D2 is about 315 mg. In some aspects, C1D2 is about 320 mg. In some aspects, C1D2 is about 325 mg. In some aspects, C1D2 is about 330 mg. In some aspects, C1D2 is about 335 mg. In some aspects, C1D2 is about 340 mg. In some aspects, C1D2 is about 345 mg. In some aspects, C1D2 is about 350 mg. In some aspects, C1D2 is about 355 mg. In some aspects, C1D2 is about 360 mg. In some aspects, C1D2 is about 365 mg. In some aspects, C1D2 is about 370 mg. In some aspects, C1D2 is about 375 mg. In some aspects, C1D2 is about 380 mg. In some aspects, C1D2 is about 385 mg. In some aspects, C1D2 is about 390 mg. In some aspects, C1D2 is about 395 mg. In some aspects, C1D2 is about 400 mg. In some aspects, C1D2 is about 405 mg. In some aspects, C1D2 is about 410 mg. In some aspects, C1D2 is about 415 mg. In some aspects, C1D2 is about 420 mg. In some aspects, C1D2 is about 425 mg. In some aspects, C1D2 is about 430 mg. In some aspects, C1D2 is about 435 mg. In some aspects, C1D2 is about 440 mg. In some aspects, C1D2 is about 445 mg. In some aspects, C1D2 is about 450 mg. In some aspects, C1D2 is about 455 mg. In some aspects, C1D2 is about 460 mg. In some aspects, C1D2 is about 465 mg. In some aspects, C1D2 is about 470 mg. In some aspects, C1D2 is about 475 mg. In some aspects, C1D2 is about 480 mg. In some aspects, C1D2 is about 485 mg. In some aspects, C1D2 is about 490 mg. In some aspects, C1D2 is about 495 mg. In some aspects, C1D2 is about 500 mg. In some aspects, C1D2 is about 505 mg. In some aspects, C1D2 is about 510 mg. In some aspects, C1D2 is about 515 mg. In some aspects, C1D2 is about 520 mg. In some aspects, C1D2 is about 525 mg. In some aspects, C1D2 is about 530 mg. In some aspects, C1D2 is about 535 mg. In some aspects, C1D2 is about 540 mg. In some aspects, C1D2 is about 545 mg. In some aspects, C1D2 is about 550 mg. In some aspects, C1D2 is about 555 mg. In some aspects, C1D2 is about 560 mg.In some aspects, C1D2 is about 565 mg. In some aspects, C1D2 is about 570 mg. In some aspects, C1D2 is about 575 mg. In some aspects, C1D2 is about 580 mg. In some aspects, C1D2 is about 585 mg. In some aspects, C1D2 is about 590 mg. In some aspects, C1D2 is about 595 mg. In some aspects, C1D2 is about 600 mg. In some aspects, C1D2 is about 605 mg. In some aspects, C1D2 is about 610 mg. In some aspects, C1D2 is about 615 mg. In some aspects, C1D2 is about 620 mg. In some aspects, C1D2 is about 625 mg. In some aspects, C1D2 is about 630 mg. In some aspects, C1D2 is about 635 mg. In some aspects, C1D2 is about 640 mg. In some aspects, C1D2 is about 645 mg. In some aspects, C1D2 is about 650 mg. In some aspects, C1D2 is about 655 mg. In some aspects, C1D2 is about 660 mg. In some aspects, C1D2 is about 665 mg. In some aspects, C1D2 is about 670 mg. In some aspects, C1D2 is about 675 mg. In some aspects, C1D2 is about 680 mg. In some aspects, C1D2 is about 685 mg. In some aspects, C1D2 is about 690 mg. In some aspects, C1D2 is about 695 mg. In some aspects, C1D2 is about 700 mg. In some aspects, C1D2 is about 705 mg. In some aspects, C1D2 is about 710 mg. In some aspects, C1D2 is about 715 mg. In some aspects, C1D2 is about 720 mg. In some aspects, C1D2 is about 725 mg. In some aspects, C1D2 is about 730 mg. In some aspects, C1D2 is about 735 mg. In some aspects, C1D2 is about 740 mg. In some aspects, C1D2 is about 745 mg. In some aspects, C1D2 is about 750 mg. In some aspects, C1D2 is about 755 mg. In some aspects, C1D2 is about 760 mg. In some aspects, C1D2 is about 765 mg. In some aspects, C1D2 is about 770 mg. In some aspects, C1D2 is about 775 mg. In some aspects, C1D2 is about 780 mg. In some aspects, C1D2 is about 785 mg. In some aspects, C1D2 is about 790 mg. In some aspects, C1D2 is about 795 mg. In some aspects, C1D2 is about 800 mg. In some aspects, C1D2 is about 805 mg. In some aspects, C1D2 is about 810 mg. In some aspects, C1D2 is about 815 mg. In some aspects, C1D2 is about 820 mg. In some aspects, C1D2 is about 825 mg. In some aspects, C1D2 is about 830 mg. In some aspects, C1D2 is about 835 mg.In some aspects, C1D2 is about 840 mg. In some aspects, C1D2 is about 845 mg. In some aspects, C1D2 is about 850 mg. In some aspects, C1D2 is about 855 mg. In some aspects, C1D2 is about 860 mg. In some aspects, C1D2 is about 865 mg. In some aspects, C1D2 is about 870 mg. In some aspects, C1D2 is about 875 mg. In some aspects, C1D2 is about 880 mg. In some aspects, C1D2 is about 885 mg. In some aspects, C1D2 is about 890 mg. In some aspects, C1D2 is about 895 mg. In some aspects, C1D2 is about 900 mg. In some aspects, C1D2 is about 905 mg. In some aspects, C1D2 is about 910 mg. In some aspects, C1D2 is about 915 mg. In some aspects, C1D2 is about 920 mg. In some aspects, C1D2 is about 925 mg. In some aspects, C1D2 is about 930 mg. In some aspects, C1D2 is about 935 mg. In some aspects, C1D2 is about 940 mg. In some aspects, C1D2 is about 945 mg. In some aspects, C1D2 is about 950 mg. In some aspects, C1D2 is about 955 mg. In some aspects, C1D2 is about 960 mg. In some aspects, C1D2 is about 965 mg. In some aspects, C1D2 is about 970 mg. In some aspects, C1D2 is about 975 mg. In some aspects, C1D2 is about 980 mg. In some aspects, C1D2 is about 985 mg. In some aspects, C1D2 is about 990 mg. In some aspects, C1D2 is about 995 mg. In some aspects, C1D2 is about 1000 mg.

[0271] In some aspects, C1D1 is 1 mg. In some aspects, C1D1 is 2 mg. In some aspects, C1D1 is 3 mg. In some aspects, C1D1 is 4 mg. In some aspects, C1D1 is 5 mg. In some aspects, C1D1 is 6 mg. In some aspects, C1D1 is 7 mg. In some aspects, C1D1 is 8 mg. In some aspects, C1D1 is 9 mg. In some aspects, C1D1 is 10 mg. In some aspects, C1D1 is 11 mg. In some aspects, C1D1 is 12 mg. In some aspects, C1D1 is 13 mg. In some aspects, C1D1 is 14 mg. In some aspects, C1D1 is 15 mg. In some aspects, C1D1 is 16 mg. In some aspects, C1D1 is 17 mg. In some aspects, C1D1 is 18 mg. In some aspects, C1D1 is 19 mg. In some aspects, C1D1 is 20 mg. In some aspects, C1D1 is 21 mg. In some aspects, C1D1 is 22 mg. In some aspects, C1D1 is 23 mg. In some aspects, C1D1 is 24 mg. In some aspects, C1D1 is 25 mg. In some aspects, C1D1 is 26 mg. In some aspects, C1D1 is 27 mg. In some aspects, C1D1 is 28 mg. In some aspects, C1D1 is 29 mg. In some aspects, C1D1 is 30 mg. In some aspects, C1D1 is 31 mg. In some aspects, C1D1 is 32 mg. In some aspects, C1D1 is 33 mg. In some aspects, C1D1 is 34 mg. In some aspects, C1D1 is 35 mg. In some aspects, C1D1 is 36 mg. In some aspects, C1D1 is 37 mg. In some aspects, C1D1 is 38 mg. In some aspects, C1D1 is 39 mg. In some aspects, C1D1 is 40 mg. In some aspects, C1D1 is 41 mg. In some aspects, C1D1 is 42 mg. In some aspects, C1D1 is 43 mg. In some aspects, C1D1 is 44 mg. In some aspects, C1D1 is 45 mg. In some aspects, C1D1 is 46 mg. In some aspects, C1D1 is 47 mg. In some aspects, C1D1 is 48 mg. In some aspects, C1D1 is 49 mg. In some aspects, C1D1 is 50 mg.

[0272] In some aspects, C1D2 is 10 mg. In some aspects, C1D2 is 15 mg. In some aspects, C1D2 is 20 mg. In some aspects, C1D2 is 25 mg. In some aspects, C1D2 is 30 mg. In some aspects, C1D2 is 35 mg. In some aspects, C1D2 is 40 mg. In some aspects, C1D2 is 45 mg. In some aspects, C1D2 is 50 mg. In some aspects, C1D2 is 55 mg. In some aspects, C1D2 is 60 mg. In some aspects, C1D2 is 65 mg. In some aspects, C1D2 is 70 mg. In some aspects, C1D2 is 75 mg. In some aspects, C1D2 is 80 mg. In some aspects, C1D2 is 85 mg. In some aspects, C1D2 is 90 mg. In some aspects, C1D2 is 95 mg. In some aspects, C1D2 is 100 mg. In some aspects, C1D2 is 105 mg. In some aspects, C1D2 is 110 mg. In some aspects, C1D2 is 115 mg. In some aspects, C1D2 is 120 mg. In some aspects, C1D2 is 125 mg. In some aspects, C1D2 is 130 mg. In some aspects, C1D2 is 135 mg. In some aspects, C1D2 is 140 mg. In some aspects, C1D2 is 145 mg. In some aspects, C1D2 is 150 mg. In some aspects, C1D2 is 155 mg. In some aspects, C1D2 is 160 mg. In some aspects, C1D2 is 165 mg. In some aspects, C1D2 is 170 mg. In some aspects, C1D2 is 175 mg. In some aspects, C1D2 is 180 mg. In some aspects, C1D2 is 185 mg. In some aspects, C1D2 is 190 mg. In some aspects, C1D2 is 195 mg. In some aspects, C1D2 is 200 mg. In some aspects, C1D2 is 205 mg. In some aspects, C1D2 is 210 mg. In some aspects, C1D2 is 215 mg. In some aspects, C1D2 is 220 mg. In some aspects, C1D2 is 225 mg. In some aspects, C1D2 is 230 mg. In some aspects, C1D2 is 235 mg. In some aspects, C1D2 is 240 mg. In some aspects, C1D2 is 245 mg. In some aspects, C1D2 is 250 mg. In some aspects, C1D2 is 255 mg. In some aspects, C1D2 is 260 mg. In some aspects, C1D2 is 265 mg. In some aspects, C1D2 is 270 mg. In some aspects, C1D2 is 275 mg. In some aspects, C1D2 is 280 mg. In some aspects, C1D2 is 285 mg. In some aspects, C1D2 is 290 mg. In some aspects, C1D2 is 295 mg. In some aspects, C1D2 is 300 mg.In some aspects, C1D2 is 305 mg. In some aspects, C1D2 is 310 mg. In some aspects, C1D2 is 315 mg. In some aspects, C1D2 is 320 mg. In some aspects, C1D2 is 325 mg. In some aspects, C1D2 is 330 mg. In some aspects, C1D2 is 335 mg. In some aspects, C1D2 is 340 mg. In some aspects, C1D2 is 345 mg. In some aspects, C1D2 is 350 mg. In some aspects, C1D2 is 355 mg. In some aspects, C1D2 is 360 mg. In some aspects, C1D2 is 365 mg. In some aspects, C1D2 is 370 mg. In some aspects, C1D2 is 375 mg. In some aspects, C1D2 is 380 mg. In some aspects, C1D2 is 385 mg. In some aspects, C1D2 is 390 mg. In some aspects, C1D2 is 395 mg. In some aspects, C1D2 is 400 mg. In some aspects, C1D2 is 405 mg. In some aspects, C1D2 is 410 mg. In some aspects, C1D2 is 415 mg. In some aspects, C1D2 is 420 mg. In some aspects, C1D2 is 425 mg. In some aspects, C1D2 is 430 mg. In some aspects, C1D2 is 435 mg. In some aspects, C1D2 is 440 mg. In some aspects, C1D2 is 445 mg. In some aspects, C1D2 is 450 mg. In some aspects, C1D2 is 455 mg. In some aspects, C1D2 is 460 mg. In some aspects, C1D2 is 465 mg. In some aspects, C1D2 is 470 mg. In some aspects, C1D2 is 475 mg. In some aspects, C1D2 is 480 mg. In some aspects, C1D2 is 485 mg. In some aspects, C1D2 is 490 mg. In some aspects, C1D2 is 495 mg. In some aspects, C1D2 is 500 mg. In some aspects, C1D2 is 505 mg. In some aspects, C1D2 is 510 mg. In some aspects, C1D2 is 515 mg. In some aspects, C1D2 is 520 mg. In some aspects, C1D2 is 525 mg. In some aspects, C1D2 is 530 mg. In some aspects, C1D2 is 535 mg. In some aspects, C1D2 is 540 mg. In some aspects, C1D2 is 545 mg. In some aspects, C1D2 is 550 mg. In some aspects, C1D2 is 555 mg. In some aspects, C1D2 is 560 mg. In some aspects, C1D2 is 565 mg. In some aspects, C1D2 is 570 mg. In some aspects, C1D2 is 575 mg. In some aspects, C1D2 is 580 mg. In some aspects, C1D2 is 585 mg. In some aspects, C1D2 is 590 mg.In some aspects, C1D2 is 595 mg. In some aspects, C1D2 is 600 mg. In some aspects, C1D2 is 605 mg. In some aspects, C1D2 is 610 mg. In some aspects, C1D2 is 615 mg. In some aspects, C1D2 is 620 mg. In some aspects, C1D2 is 625 mg. In some aspects, C1D2 is 630 mg. In some aspects, C1D2 is 635 mg. In some aspects, C1D2 is 640 mg. In some aspects, C1D2 is 645 mg. In some aspects, C1D2 is 650 mg. In some aspects, C1D2 is 655 mg. In some aspects, C1D2 is 660 mg. In some aspects, C1D2 is 665 mg. In some aspects, C1D2 is 670 mg. In some aspects, C1D2 is 675 mg. In some aspects, C1D2 is 680 mg. In some aspects, C1D2 is 685 mg. In some aspects, C1D2 is 690 mg. In some aspects, C1D2 is 695 mg. In some aspects, C1D2 is 700 mg. In some aspects, C1D2 is 705 mg. In some aspects, C1D2 is 710 mg. In some aspects, C1D2 is 715 mg. In some aspects, C1D2 is 720 mg. In some aspects, C1D2 is 725 mg. In some aspects, C1D2 is 730 mg. In some aspects, C1D2 is 735 mg. In some aspects, C1D2 is 740 mg. In some aspects, C1D2 is 745 mg. In some aspects, C1D2 is 750 mg. In some aspects, C1D2 is 755 mg. In some aspects, C1D2 is 760 mg. In some aspects, C1D2 is 765 mg. In some aspects, C1D2 is 770 mg. In some aspects, C1D2 is 775 mg. In some aspects, C1D2 is 780 mg. In some aspects, C1D2 is 785 mg. In some aspects, C1D2 is 790 mg. In some aspects, C1D2 is 795 mg. In some aspects, C1D2 is 800 mg. In some aspects, C1D2 is 805 mg. In some aspects, C1D2 is 810 mg. In some aspects, C1D2 is 815 mg. In some aspects, C1D2 is 820 mg. In some aspects, C1D2 is 825 mg. In some aspects, C1D2 is 830 mg. In some aspects, C1D2 is 835 mg. In some aspects, C1D2 is 840 mg. In some aspects, C1D2 is 845 mg. In some aspects, C1D2 is 850 mg. In some aspects, C1D2 is 855 mg. In some aspects, C1D2 is 860 mg. In some aspects, C1D2 is 865 mg. In some aspects, C1D2 is 870 mg. In some aspects, C1D2 is 875 mg. In some aspects, C1D2 is 880 mg.In some aspects, C1D2 is 885 mg. In some aspects, C1D2 is 890 mg. In some aspects, C1D2 is 895 mg. In some aspects, C1D2 is 900 mg. In some aspects, C1D2 is 905 mg. In some aspects, C1D2 is 910 mg. In some aspects, C1D2 is 915 mg. In some aspects, C1D2 is 920 mg. In some aspects, C1D2 is 925 mg. In some aspects, C1D2 is 930 mg. In some aspects, C1D2 is 935 mg. In some aspects, C1D2 is 940 mg. In some aspects, C1D2 is 945 mg. In some aspects, C1D2 is 950 mg. In some aspects, C1D2 is 955 mg. In some aspects, C1D2 is 960 mg. In some aspects, C1D2 is 965 mg. In some aspects, C1D2 is 970 mg. In some aspects, C1D2 is 975 mg. In some aspects, C1D2 is 980 mg. In some aspects, C1D2 is 985 mg. In some aspects, C1D2 is 990 mg. In some aspects, C1D2 is 995 mg. In some aspects, C1D2 is 1000 mg.

[0273] In some cases, the above methods may include a first dosing cycle of four weeks or 28 days. In some cases, the methods may include administering C1D1 and C1D2 to the subject on or around day 1 and day 8, respectively, of the first dosing cycle.

[0274] iii. Double step-up dosing regimen

[0275] In other aspects, the invention provides a method of treating a subject having cancer (eg, MM), the method comprising subcutaneously administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a double ascending dosing regimen.

[0276] In some aspects, the disclosure features a method of treating a subject having cancer (e.g., MM), the method comprising subcutaneously 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, wherein the first dosing cycle includes 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 between about 0.1 mg and about 10 mg (e.g., between about 0.1 mg and about 2 mg, between about 0.2 mg and about 1 mg, or between about 0.2 mg and about 0.4 mg, between about 0.1 mg and about 9.5 mg, between about 0.2 mg and about 10 mg). about 9 mg, about 0.3 mg to about 8.5 mg, about 0.4 mg to about 8 mg, about 0.5 mg to about 7.5 mg, about 0.6 mg to about 7 mg, about 0.7 mg to about 6.5 mg, about 0.8 mg to about 6 mg, about 0.9 mg to about 5.5 mg, about 1 mg to about 5 mg, about 1.1 mg to about 4.5 mg, about 1.2 mg to about 4 mg, about 1.3 mg to about 3.5 mg, about 1.4 mg to about 3 mg, about 1.5 mg to about 2.5 mg, about 1 mg to about 3 mg, about 0.1 mg to about 1 mg, about 0.2 mg to about 1.5 mg, about 0.3 mg to about g to about 2 mg, about 0.4 mg to about 2.5 mg, about 0.5 mg to about 3 mg, about 0.6 mg to about 3.5 mg, about 0.7 mg to about 4 mg, about 0.8 mg to about 4.5 mg, about 0.9 mg to about 5 mg, about 1 mg to about 6 mg, about 1.5 mg to about 6.5 mg, about 2 mg to about 7 mg, about 2.5 mg to about 7.5 mg, about 3 mg to about 8 mg, about 3.5 mg to about 8.5 mg, about 4 mg to about 9 mg, about 4.5 mg to about 9.5 mg, or about 5 mg to about 10 mg); and C1D2 is between about 1 mg to about 50 mg (e.g. , between about 3 mg to about 18 mg, between about 3.1 mg to about 15 mg, between about 3.2 mg to about 10 mg, between about 3.3 mg to about 6 mg, between about 3.4 mg to about 4 mg, between about 0.2 mg to about 35 mg, between about 0.3 mg to about 30 mg, between about 0.4 mg to about 29 mg, between about 0.5 mg to about 28 mg, between about 1 mg to about 27 mg, between about 1.5 mg to about 26 mg, between about 2 mg to about 25 mg, between about 2.5 mg to about 24 mg, between about 3 mg to about 23 mg, between about 3.5 mg to about 22 mg, between about 4 mg to about 21 mg, between about 4.5 mg to about 20 mg,about 5 mg to about 19 mg, about 5.5 mg to about 18 mg, about 6 mg to about 17 mg, about 6.5 mg to about 16 mg, about 7 mg to about 15 mg, about 7.5 mg to about 14 mg, about 8 mg to about 13 mg, about 8 mg to about 12 mg, about 8.5 mg to about 12 mg, about 9 mg to about 11 mg, about 1 mg to about 6 mg, about 1.5 mg to about 6.5 mg, about 2 mg to about 7 mg, about 2.5 mg to about 7.5 mg, about 3 mg to about 8 mg, about 3.5 mg to about 8.5 mg, about 4 mg to about 9 mg, about 4.5 mg to about 9.5 mg about 5 mg to about 10 mg, about 5.5 mg to about 10.5 mg, about 6 mg to about 11 mg, about 6.5 mg to about 11.5 mg, about 7 mg to about 12 mg, about 7.5 mg to about 12.5 mg, about 8 mg to about 13 mg, about 8.5 mg to about 13.5 mg, about 9 mg to about 14 mg, about 9.5 mg to about 14.5 mg, about 10 mg to about 15 mg, about 11 mg to about 16 mg, about 12 mg to about 17 mg, about 13 mg to about 18 mg, about 14 mg to about 19 mg, about 15 mg to about 20 mg, about 16 mg to about 21 mg g, between about 17 mg and about 22 mg, between about 18 mg and about 23 mg, between about 19 mg and about 24 mg, between about 20 mg and about 25 mg, between about 21 mg and about 26 mg, between about 22 mg and about 27 mg, between about 23 mg and about 28 mg, between about 24 mg and about 29 mg, between about 25 mg and about 30 mg, between about 26 mg and about 31 mg, between about 27 mg and about 32 mg, between about 28 mg and about 33 mg, between about 29 mg and about 34 mg, between about 30 mg and about 35 mg, between about 31 mg and about 36 mg, between about 32 mg and about 37 mg, between about 33 mg and about 38 mg, between about 34 mg about 39 mg to about 39 mg, about 35 mg to about 40 mg, about 36 mg to about 41 mg, about 37 mg to about 42 mg, about 38 mg to about 43 mg, about 39 mg to about 44 mg, about 40 mg to about 45 mg, about 41 mg to about 46 mg, about 42 mg to about 47 mg, about 43 mg to about 48 mg, about 44 mg to about 49 mg, or about 45 mg to about 50 mg); and C1D3 is between about 10 mg to about 1000 mg (e.g., between about 10 mg to about 70 mg, about 15 mg to about 65 mg, about 20 mg to about 60 mg, about 25 mg to about 55 mg,about 30 mg to about 50 mg, about 35 mg to about 45 mg, about 15 mg to about 225 mg, about 20 mg to about 220 mg, about 25 mg to about 215 mg, about 30 mg to about 210 mg, about 35 mg to about 205 mg, about 40 mg to about 200 mg, about 45 mg to about 195 mg, about 50 mg to about 190 mg, about 55 mg to about 185 mg, about 60 mg to about 180 mg, about 65 mg to about 175 mg, about 70 mg to about 170 mg, about 75 mg to about 165 mg, about 80 mg to about 160 mg, about 85 mg g to about 155 mg, about 90 mg to about 150 mg, about 95 mg to about 145 mg, about 100 mg to about 140 mg, about 105 mg to about 135 mg, about 110 mg to about 130 mg, about 115 mg to about 125 mg, about 10 mg to about 50 mg, about 25 mg to about 75 mg, about 50 mg to about 100 mg, about 75 mg to about 125 mg, about 100 mg to about 150 mg, about 125 mg to about 175 mg, about 150 mg to about 200 mg, about 175 mg to about 225 mg, about 200 mg to about 250 mg , between about 225 mg and about 275 mg, between about 250 mg and about 300 mg, between about 275 mg and about 325 mg, between about 300 mg and about 350 mg, between about 325 mg and about 375 mg, between about 350 mg and about 400 mg, between about 375 mg and about 425 mg, between about 400 mg and about 450 mg, between about 425 mg and about 475 mg, between about 450 mg and about 500 mg, between about 475 mg and about 525 mg, between about 500 mg and about 550 mg, between about 525 mg and about 575 mg, between about 550 mg and about 600 mg, between about 575 mg and about 625 mg, between about In some aspects, C1D2 is greater than C1D1 and C1D3 is greater than C1D2.

[0277] In some aspects, C1D3 is between about 10 mg and about 200 mg (e.g., between 10 mg and about 170 mg, between about 11 mg and about 165 mg, between about 12 mg and about 160 mg, between about 13 mg and about 155 mg, between about 14 mg and about 150 mg, between about 15 mg and about 145 mg, between about 16 mg and about 140 mg, between about 17 mg and about 135 mg, between about 18 mg and about 130 mg, between about 19 mg and about 125 mg, between about 20 mg and about 120 mg, between about 21 mg and about 115 mg, between about 22 mg and about 110 mg, between about 23 mg and about 105 mg). g, about 24 mg to about 100 mg, about 25 mg to about 95 mg, about 26 mg to about 90 mg, about 27 mg to about 85 mg, about 28 mg to about 80 mg, about 29 mg to about 75 mg, about 30 mg to about 70 mg, about 31 mg to about 65 mg, about 32 mg to about 60 mg, about 33 mg to about 55 mg, about 34 mg to about 50 mg, about 35 mg to about 45 mg, about 40 mg to about 200 mg, about 45 mg to about 195 mg, about 50 mg to about 190 mg, about 55 mg to about 185 mg, about 6 0 mg to about 180 mg, about 65 mg to about 175 mg, about 70 mg to about 170 mg, about 75 mg to about 165 mg, about 80 mg to about 160 mg, about 85 mg to about 155 mg, about 90 mg to about 150 mg, about 95 mg to about 145 mg, about 100 mg to about 140 mg, about 105 mg to about 135 mg, about 110 mg to about 130 mg, about 115 mg to about 125 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about 50 mg or about 190 mg to about 200 mg).

[0278] In some aspects, C1D1 is between 0.1 mg and 10 mg (e.g., between 0.2 mg and 0.4 mg, between 0.1 mg and 9.5 mg, between 0.2 mg and 9 mg, between 0.3 mg and 8.5 mg, between 0.4 mg and 8 mg, between 0.5 mg and 7.5 mg, between 0.6 mg and 7 mg, between 0.7 mg and 6.5 mg, between 0.8 mg and 6 mg, between 0.9 mg and 5.5 mg, between 1 mg and 5 mg, between 1.1 mg and 4.5 mg, between 1.2 mg and 4 mg, between 1.3 mg and 3.5 mg, between 1.4 mg and 3 mg, between 1.5 mg and 2.5 mg). , between 1 mg and 3 mg, between 0.1 mg and 1 mg, between 0.2 mg and 1.5 mg, between 0.3 mg and 2 mg, between 0.4 mg and 2.5 mg, between 0.5 mg and 3 mg, between 0.6 mg and 3.5 mg, between 0.7 mg and 4 mg, between 0.8 mg and 4.5 mg, between 0.9 mg and 5 mg, between 1 mg and 6 mg, between 1.5 mg and 6.5 mg, between 2 mg and 7 mg, between 2.5 mg and 7.5 mg, between 3 mg and 8 mg, between 3.5 mg and 8.5 mg, between 4 mg and 9 mg, between 4.5 mg and 9.5 mg, or between 5 mg and 10 mg).

[0279] In some aspects, C1D2 is between 1 mg and 50 mg (e.g., between 3 mg and 18 mg, between 3.1 mg and 15 mg, between 3.2 mg and 10 mg, between 3.3 mg and 6 mg, between 3.4 mg and 4 mg, between 0.2 mg and 35 mg, between 0.3 mg and 30 mg, between 0.4 mg and 29 mg, between 0.5 mg and 28 mg, between 1 mg and 27 mg, between 1.5 mg and 26 mg, between 2 mg and 25 mg, between 2.5 mg and 24 mg, between 3 mg and 23 mg, between 3.5 mg and 22 mg, between 4 mg and 21 mg, between 4.5 mg and 20 mg, between 5 mg and 19 mg, between 5.5 mg and 18 mg, between 6 mg and 17 mg, between 6.5 mg and 16 mg, between 7 mg and 18 mg, between 8 mg and 19 mg, between 9 mg and 20 mg, between 10 mg and 11 mg, between 12 mg and 13 mg, between 14 mg and 15 mg, between 16 mg and 17 mg, between 18 mg and 19 mg, between 20 mg and 21 mg, between 21 mg and 20 mg, between 22 mg and 23 mg, between 24 mg and 25 mg, between 26 mg and 27 mg, between 28 mg and 28 mg, between 10 mg and 11 mg, between 22 mg and 25 mg, between 25 ... Between 15mg and 70mg, between 7.5mg and 14mg, between 8mg and 13mg, between 8mg and 12mg, between 8.5mg and 12mg, between 9mg and 11mg, between 1mg and 6mg, between 1.5mg and 6.5mg, between 2mg and 7mg, between 2.5mg and 7.5mg, between 3mg and 8mg, between 3.5mg and 8.5mg, between 4mg and 9mg, between 4.5mg and 9.5mg, between 5mg and 10mg, between 5.5mg and 10.5mg, between 6mg and 11mg, between 6.5mg and 11.5mg, between 7mg and 12mg, between 7.5mg and 12.5mg, between 8mg and 13mg, between 8.5mg and 13.5mg, between 9mg and 14mg, between 9.5mg and 14.Between 5mg, between 10mg and 15mg, between 11mg and 16mg, between 12mg and 17mg, between 13mg and 18mg, between 14mg and 19mg, between 15mg and 20mg, between 16mg and 21mg, between 17mg and 22mg, between 18mg and 23mg, between 19mg and 24mg, between 20mg and 25mg, between 21mg and 26mg, between 22mg and 27mg, between 23mg and 28mg, between 24mg and 29mg, between 25mg and 30mg, between 26mg and 31mg, between 27mg and 32mg between 28mg and 33mg, between 29mg and 34mg, between 30mg and 35mg, between 31mg and 36mg, between 32mg and 37mg, between 33mg and 38mg, between 34mg and 39mg, between 35mg and 40mg, between 36mg and 41mg, between 37mg and 42mg, between 38mg and 43mg, between 39mg and 44mg, between 40mg and 45mg, between 41mg and 46mg, between 42mg and 47mg, between 43mg and 48mg, between 44mg and 49mg, or between 45mg and 50mg).

[0280] In some aspects, C1D3 is between 10 mg and 1000 mg (e.g., between 10 mg and 70 mg, between 15 mg and 65 mg, between 20 mg and 60 mg, between 25 mg and 55 mg, between 30 mg and 50 mg, between 35 mg and 45 mg, between 15 mg and 225 mg, between 20 mg and 220 mg, between 25 mg and 215 mg, between 30 mg and 210 mg, between 35 mg and 205 mg, between 40 mg and 200 mg, between 45 mg and 195 mg, between 50 mg and 190 mg, between 55 mg and 185 mg, between 60 mg and 180 mg). , between 65mg and 175mg, between 70mg and 170mg, between 75mg and 165mg, between 80mg and 160mg, between 85mg and 155mg, between 90mg and 150mg, between 95mg and 145mg, between 100mg and 140mg, between 105mg and 135mg, between 110mg and 130mg, between 115mg and 125mg, between 10mg and 50mg, between 25mg and 75mg, between 50mg and 100mg, between 75mg and 125mg, between 100mg and 150mg, between 125mg and 175mg, 150mg Between 175mg and 225mg, between 200mg and 250mg, between 225mg and 275mg, between 250mg and 300mg, between 275mg and 325mg, between 300mg and 350mg, between 325mg and 375mg, between 350mg and 400mg, between 375mg and 425mg, between 400mg and 450mg, between 425mg and 475mg, between 450mg and 500mg, between 475mg and 525mg, between 500mg and 550mg, between 525mg and 575mg, between 550mg and 600mg g, 575 mg to 625 mg, 600 mg to 650 mg, 625 mg to 675 mg, 650 mg to 700 mg, 675 mg to 725 mg, 700 mg to 750 mg, 725 mg to 775 mg, 750 mg to 800 mg, 775 mg to 825 mg, 800 mg to 850 mg, 825 mg to 875 mg, 850 mg to 900 mg, 875 mg to 925 mg, 900 mg to 950 mg, 925 mg to 975 mg, or 950 mg to 1000 mg).

[0281] In some aspects, C1D3 is between 10 mg and 200 mg (e.g., between 10 mg and 170 mg, between 11 mg and 165 mg, between 12 mg and 160 mg, between 13 mg and 155 mg, between 14 mg and 150 mg, between 15 mg and 145 mg, between 16 mg and 140 mg, between 17 mg and 135 mg, between 18 mg and 130 mg, between 19 mg and 125 mg, between 20 mg and 120 mg, between 21 mg and 115 mg, between 22 mg and 110 mg, between 23 mg and 10 Between 5mg, 24mg and 100mg, 25mg and 95mg, 26mg and 90mg, 27mg and 85mg, 28mg and 80mg, 29mg and 75mg, 30mg and 70mg, 31mg and 65mg, 32mg and 60mg, 33mg and 55mg, 34mg and 50mg, 35mg and 45mg, 40mg and 200mg, 45mg and 195mg, 50mg and 190mg, 55mg and 185mg, 60 Between mg and 180mg, between 65mg and 175mg, between 70mg and 170mg, between 75mg and 165mg, between 80mg and 160mg, between 85mg and 155mg, between 90mg and 150mg, between 95mg and 145mg, between 100mg and 140mg, between 105mg and 135mg, between 110mg and 130mg, between 115mg and 125mg, between 10mg and 20mg, between 20mg and 30mg, between 30mg and 40mg, between 40mg and 50mg between 150mg and 160mg, between 160mg and 170mg, between 170mg and 180mg, between 180mg and 190mg, or between 190mg and 200mg).

[0282] In some aspects, C1D1 is about 0.1 mg. In some aspects, C1D1 is about 0.2 mg. In some aspects, C1D1 is about 0.3 mg. In some aspects, C1D1 is about 0.4 mg. In some aspects, C1D1 is about 0.5 mg. In some aspects, C1D1 is about 0.6 mg. In some aspects, C1D1 is about 0.7 mg. In some aspects, C1D1 is about 0.8 mg. In some aspects, C1D1 is about 0.9 mg. In some aspects, C1D1 is about 1 mg. In some aspects, C1D1 is about 2 mg. In some aspects, C1D1 is about 3 mg. In some aspects, C1D1 is about 4 mg. In some aspects, C1D1 is about 5 mg. In some aspects, C1D1 is about 6 mg. In some aspects, C1D1 is about 7 mg. In some aspects, C1D1 is about 8 mg. In some aspects, C1D1 is about 9 mg. In some aspects, C1D1 is about 10 mg.

[0283] In some aspects, C1D2 is about 1 mg. In some aspects, C1D2 is about 2 mg. In some aspects, C1D2 is about 3 mg. In some aspects, C1D2 is about 4 mg. In some aspects, C1D2 is about 5 mg. In some aspects, C1D2 is about 6 mg. In some aspects, C1D2 is about 7 mg. In some aspects, C1D2 is about 8 mg. In some aspects, C1D2 is about 9 mg. In some aspects, C1D2 is about 10 mg. In some aspects, C1D2 is about 11 mg. In some aspects, C1D2 is about 12 mg. In some aspects, C1D2 is about 13 mg. In some aspects, C1D2 is about 14 mg. In some aspects, C1D2 is about 15 mg. In some aspects, C1D2 is about 16 mg. In some aspects, C1D2 is about 17 mg. In some aspects, C1D2 is about 18 mg. In some aspects, C1D2 is about 19 mg. In some aspects, C1D2 is about 20 mg. In some aspects, C1D2 is about 21 mg. In some aspects, C1D2 is about 22 mg. In some aspects, C1D2 is about 23 mg. In some aspects, C1D2 is about 24 mg. In some aspects, C1D2 is about 25 mg. In some aspects, C1D2 is about 26 mg. In some aspects, C1D2 is about 27 mg. In some aspects, C1D2 is about 28 mg. In some aspects, C1D2 is about 29 mg. In some aspects, C1D2 is about 30 mg. In some aspects, C1D2 is about 31 mg. In some aspects, C1D2 is about 32 mg. In some aspects, C1D2 is about 33 mg. In some aspects, C1D2 is about 34 mg. In some aspects, C1D2 is about 35 mg. In some aspects, C1D2 is about 36 mg. In some aspects, C1D2 is about 37 mg. In some aspects, C1D2 is about 38 mg. In some aspects, C1D2 is about 39 mg. In some aspects, C1D2 is about 40 mg. In some aspects, C1D2 is about 41 mg. In some aspects, C1D2 is about 42 mg. In some aspects, C1D2 is about 43 mg. In some aspects, C1D2 is about 44 mg. In some aspects, C1D2 is about 45 mg. In some aspects, C1D2 is about 46 mg. In some aspects, C1D2 is about 47 mg. In some aspects, C1D2 is about 48 mg. In some aspects, C1D2 is about 49 mg. In some aspects, C1D2 is about 50 mg.

[0284] In some aspects, C1D3 is about 10 mg. In some aspects, C1D3 is about 15 mg. In some aspects, C1D3 is about 20 mg. In some aspects, C1D3 is about 25 mg. In some aspects, C1D3 is about 30 mg. In some aspects, C1D3 is about 35 mg. In some aspects, C1D3 is about 40 mg. In some aspects, C1D3 is about 45 mg. In some aspects, C1D3 is about 50 mg. In some aspects, C1D3 is about 55 mg. In some aspects, C1D3 is about 60 mg. In some aspects, C1D3 is about 65 mg. In some aspects, C1D3 is about 70 mg. In some aspects, C1D3 is about 75 mg. In some aspects, C1D3 is about 80 mg. In some aspects, C1D3 is about 85 mg. In some aspects, C1D3 is about 90 mg. In some aspects, C1D3 is about 95 mg. In some aspects, C1D3 is about 100 mg. In some aspects, C1D3 is about 105 mg. In some aspects, C1D3 is about 110 mg. In some aspects, C1D3 is about 115 mg. In some aspects, C1D3 is about 120 mg. In some aspects, C1D3 is about 125 mg. In some aspects, C1D3 is about 130 mg. In some aspects, C1D3 is about 135 mg. In some aspects, C1D3 is about 140 mg. In some aspects, C1D3 is about 145 mg. In some aspects, C1D3 is about 150 mg. In some aspects, C1D3 is about 155 mg. In some aspects, C1D3 is about 160 mg. In some aspects, C1D3 is about 165 mg. In some aspects, C1D3 is about 170 mg. In some aspects, C1D3 is about 175 mg. In some aspects, C1D3 is about 180 mg. In some aspects, C1D3 is about 185 mg. In some aspects, C1D3 is about 190 mg. In some aspects, C1D3 is about 195 mg. In some aspects, C1D3 is about 200 mg. In some aspects, C1D3 is about 205 mg. In some aspects, C1D3 is about 210 mg. In some aspects, C1D3 is about 215 mg. In some aspects, C1D3 is about 220 mg. In some aspects, C1D3 is about 225 mg. In some aspects, C1D3 is about 230 mg. In some aspects, C1D3 is about 235 mg. In some aspects, C1D3 is about 240 mg. In some aspects, C1D3 is about 245 mg. In some aspects, C1D3 is about 250 mg. In some aspects, C1D3 is about 255 mg. In some aspects, C1D3 is about 260 mg. In some aspects, C1D3 is about 265 mg. In some aspects, C1D3 is about 270 mg. In some aspects, C1D3 is about 275 mg. In some aspects, C1D3 is about 280 mg. In some aspects, C1D3 is about 285 mg.In some aspects, C1D3 is about 290 mg. In some aspects, C1D3 is about 295 mg. In some aspects, C1D3 is about 300 mg. In some aspects, C1D3 is about 305 mg. In some aspects, C1D3 is about 310 mg. In some aspects, C1D3 is about 315 mg. In some aspects, C1D3 is about 320 mg. In some aspects, C1D3 is about 325 mg. In some aspects, C1D3 is about 330 mg. In some aspects, C1D3 is about 335 mg. In some aspects, C1D3 is about 340 mg. In some aspects, C1D3 is about 345 mg. In some aspects, C1D3 is about 350 mg. In some aspects, C1D3 is about 355 mg. In some aspects, C1D3 is about 360 mg. In some aspects, C1D3 is about 365 mg. In some aspects, C1D3 is about 370 mg. In some aspects, C1D3 is about 375 mg. In some aspects, C1D3 is about 380 mg. In some aspects, C1D3 is about 385 mg. In some aspects, C1D3 is about 390 mg. In some aspects, C1D3 is about 395 mg. In some aspects, C1D3 is about 400 mg. In some aspects, C1D3 is about 405 mg. In some aspects, C1D3 is about 410 mg. In some aspects, C1D3 is about 415 mg. In some aspects, C1D3 is about 420 mg. In some aspects, C1D3 is about 425 mg. In some aspects, C1D3 is about 430 mg. In some aspects, C1D3 is about 435 mg. In some aspects, C1D3 is about 440 mg. In some aspects, C1D3 is about 445 mg. In some aspects, C1D3 is about 450 mg. In some aspects, C1D3 is about 455 mg. In some aspects, C1D3 is about 460 mg. In some aspects, C1D3 is about 465 mg. In some aspects, C1D3 is about 470 mg. In some aspects, C1D3 is about 475 mg. In some aspects, C1D3 is about 480 mg. In some aspects, C1D3 is about 485 mg. In some aspects, C1D3 is about 490 mg. In some aspects, C1D3 is about 495 mg. In some aspects, C1D3 is about 500 mg. In some aspects, C1D3 is about 505 mg. In some aspects, C1D3 is about 510 mg. In some aspects, C1D3 is about 515 mg. In some aspects, C1D3 is about 520 mg. In some aspects, C1D3 is about 525 mg. In some aspects, C1D3 is about 530 mg. In some aspects, C1D3 is about 535 mg. In some aspects, C1D3 is about 540 mg. In some aspects, C1D3 is about 545 mg. In some aspects, C1D3 is about 550 mg. In some aspects, C1D3 is about 555 mg. In some aspects, C1D3 is about 560 mg.In some aspects, C1D3 is about 565 mg. In some aspects, C1D3 is about 570 mg. In some aspects, C1D3 is about 575 mg. In some aspects, C1D3 is about 580 mg. In some aspects, C1D3 is about 585 mg. In some aspects, C1D3 is about 590 mg. In some aspects, C1D3 is about 595 mg. In some aspects, C1D3 is about 600 mg. In some aspects, C1D3 is about 605 mg. In some aspects, C1D3 is about 610 mg. In some aspects, C1D3 is about 615 mg. In some aspects, C1D3 is about 620 mg. In some aspects, C1D3 is about 625 mg. In some aspects, C1D3 is about 630 mg. In some aspects, C1D3 is about 635 mg. In some aspects, C1D3 is about 640 mg. In some aspects, C1D3 is about 645 mg. In some aspects, C1D3 is about 650 mg. In some aspects, C1D3 is about 655 mg. In some aspects, C1D3 is about 660 mg. In some aspects, C1D3 is about 665 mg. In some aspects, C1D3 is about 670 mg. In some aspects, C1D3 is about 675 mg. In some aspects, C1D3 is about 680 mg. In some aspects, C1D3 is about 685 mg. In some aspects, C1D3 is about 690 mg. In some aspects, C1D3 is about 695 mg. In some aspects, C1D3 is about 700 mg. In some aspects, C1D3 is about 705 mg. In some aspects, C1D3 is about 710 mg. In some aspects, C1D3 is about 715 mg. In some aspects, C1D3 is about 720 mg. In some aspects, C1D3 is about 725 mg. In some aspects, C1D3 is about 730 mg. In some aspects, C1D3 is about 735 mg. In some aspects, C1D3 is about 740 mg. In some aspects, C1D3 is about 745 mg. In some aspects, C1D3 is about 750 mg. In some aspects, C1D3 is about 755 mg. In some aspects, C1D3 is about 760 mg. In some aspects, C1D3 is about 765 mg. In some aspects, C1D3 is about 770 mg. In some aspects, C1D3 is about 775 mg. In some aspects, C1D3 is about 780 mg. In some aspects, C1D3 is about 785 mg. In some aspects, C1D3 is about 790 mg. In some aspects, C1D3 is about 795 mg. In some aspects, C1D3 is about 800 mg. In some aspects, C1D3 is about 805 mg. In some aspects, C1D3 is about 810 mg. In some aspects, C1D3 is about 815 mg. In some aspects, C1D3 is about 820 mg. In some aspects, C1D3 is about 825 mg. In some aspects, C1D3 is about 830 mg. In some aspects, C1D3 is about 835 mg.In some aspects, C1D3 is about 840 mg. In some aspects, C1D3 is about 845 mg. In some aspects, C1D3 is about 850 mg. In some aspects, C1D3 is about 855 mg. In some aspects, C1D3 is about 860 mg. In some aspects, C1D3 is about 865 mg. In some aspects, C1D3 is about 870 mg. In some aspects, C1D3 is about 875 mg. In some aspects, C1D3 is about 880 mg. In some aspects, C1D3 is about 885 mg. In some aspects, C1D3 is about 890 mg. In some aspects, C1D3 is about 895 mg. In some aspects, C1D3 is about 900 mg. In some aspects, C1D3 is about 905 mg. In some aspects, C1D3 is about 910 mg. In some aspects, C1D3 is about 915 mg. In some aspects, C1D3 is about 920 mg. In some aspects, C1D3 is about 925 mg. In some aspects, C1D3 is about 930 mg. In some aspects, C1D3 is about 935 mg. In some aspects, C1D3 is about 940 mg. In some aspects, C1D3 is about 945 mg. In some aspects, C1D3 is about 950 mg. In some aspects, C1D3 is about 955 mg. In some aspects, C1D3 is about 960 mg. In some aspects, C1D3 is about 965 mg. In some aspects, C1D3 is about 970 mg. In some aspects, C1D3 is about 975 mg. In some aspects, C1D3 is about 980 mg. In some aspects, C1D3 is about 985 mg. In some aspects, C1D3 is about 990 mg. In some aspects, C1D3 is about 995 mg. In some aspects, C1D3 is about 1000 mg.

[0285] In some aspects, C1D1 is 0.1 mg. In some aspects, C1D1 is 0.2 mg. In some aspects, C1D1 is 0.3 mg. In some aspects, C1D1 is 0.4 mg. In some aspects, C1D1 is 0.5 mg. In some aspects, C1D1 is 0.6 mg. In some aspects, C1D1 is 0.7 mg. In some aspects, C1D1 is 0.8 mg. In some aspects, C1D1 is 0.9 mg. In some aspects, C1D1 is 1 mg. In some aspects, C1D1 is 2 mg. In some aspects, C1D1 is 3 mg. In some aspects, C1D1 is 4 mg. In some aspects, C1D1 is 5 mg. In some aspects, C1D1 is 6 mg. In some aspects, C1D1 is 7 mg. In some aspects, C1D1 is 8 mg. In some aspects, C1D1 is 9 mg. In some aspects, C1D1 is 10 mg.

[0286] In some aspects, C1D2 is 1 mg. In some aspects, C1D2 is 2 mg. In some aspects, C1D2 is 3 mg. In some aspects, C1D2 is 4 mg. In some aspects, C1D2 is 5 mg. In some aspects, C1D2 is 6 mg. In some aspects, C1D2 is 7 mg. In some aspects, C1D2 is 8 mg. In some aspects, C1D2 is 9 mg. In some aspects, C1D2 is 10 mg. In some aspects, C1D2 is 11 mg. In some aspects, C1D2 is 12 mg. In some aspects, C1D2 is 13 mg. In some aspects, C1D2 is 14 mg. In some aspects, C1D2 is 15 mg. In some aspects, C1D2 is 16 mg. In some aspects, C1D2 is 17 mg. In some aspects, C1D2 is 18 mg. In some aspects, C1D2 is 19 mg. In some aspects, C1D2 is 20 mg. In some aspects, C1D2 is 21 mg. In some aspects, C1D2 is 22 mg. In some aspects, C1D2 is 23 mg. In some aspects, C1D2 is 24 mg. In some aspects, C1D2 is 25 mg. In some aspects, C1D2 is 26 mg. In some aspects, C1D2 is 27 mg. In some aspects, C1D2 is 28 mg. In some aspects, C1D2 is 29 mg. In some aspects, C1D2 is 30 mg. In some aspects, C1D2 is 31 mg. In some aspects, C1D2 is 32 mg. In some aspects, C1D2 is 33 mg. In some aspects, C1D2 is 34 mg. In some aspects, C1D2 is 35 mg. In some aspects, C1D2 is 36 mg. In some aspects, C1D2 is 37 mg. In some aspects, C1D2 is 38 mg. In some aspects, C1D2 is 39 mg. In some aspects, C1D2 is 40 mg. In some aspects, C1D2 is 41 mg. In some aspects, C1D2 is 42 mg. In some aspects, C1D2 is 43 mg. In some aspects, C1D2 is 44 mg. In some aspects, C1D2 is 45 mg. In some aspects, C1D2 is 46 mg. In some aspects, C1D2 is 47 mg. In some aspects, C1D2 is 48 mg. In some aspects, C1D2 is 49 mg. In some aspects, C1D2 is 50 mg.

[0287] In some aspects, C1D3 is 10 mg. In some aspects, C1D3 is 15 mg. In some aspects, C1D3 is 20 mg. In some aspects, C1D3 is 25 mg. In some aspects, C1D3 is 30 mg. In some aspects, C1D3 is 35 mg. In some aspects, C1D3 is 40 mg. In some aspects, C1D3 is 45 mg. In some aspects, C1D3 is 50 mg. In some aspects, C1D3 is 55 mg. In some aspects, C1D3 is 60 mg. In some aspects, C1D3 is 65 mg. In some aspects, C1D3 is 70 mg. In some aspects, C1D3 is 75 mg. In some aspects, C1D3 is 80 mg. In some aspects, C1D3 is 85 mg. In some aspects, C1D3 is 90 mg. In some aspects, C1D3 is 95 mg. In some aspects, C1D3 is 100 mg. In some aspects, C1D3 is 105 mg. In some aspects, C1D3 is 110 mg. In some aspects, C1D3 is 115 mg. In some aspects, C1D3 is 120 mg. In some aspects, C1D3 is 125 mg. In some aspects, C1D3 is 130 mg. In some aspects, C1D3 is 135 mg. In some aspects, C1D3 is 140 mg. In some aspects, C1D3 is 145 mg. In some aspects, C1D3 is 150 mg. In some aspects, C1D3 is 155 mg. In some aspects, C1D3 is 160 mg. In some aspects, C1D3 is 165 mg. In some aspects, C1D3 is 170 mg. In some aspects, C1D3 is 175 mg. In some aspects, C1D3 is 180 mg. In some aspects, C1D3 is 185 mg. In some aspects, C1D3 is 190 mg. In some aspects, C1D3 is 195 mg. In some aspects, C1D3 is 200 mg. In some aspects, C1D3 is 205 mg. In some aspects, C1D3 is 210 mg. In some aspects, C1D3 is 215 mg. In some aspects, C1D3 is 220 mg. In some aspects, C1D3 is 225 mg. In some aspects, C1D3 is 230 mg. In some aspects, C1D3 is 235 mg. In some aspects, C1D3 is 240 mg. In some aspects, C1D3 is 245 mg. In some aspects, C1D3 is 250 mg. In some aspects, C1D3 is 255 mg. In some aspects, C1D3 is 260 mg. In some aspects, C1D3 is 265 mg. In some aspects, C1D3 is 270 mg. In some aspects, C1D3 is 275 mg. In some aspects, C1D3 is 280 mg. In some aspects, C1D3 is 285 mg. In some aspects, C1D3 is 290 mg. In some aspects, C1D3 is 295 mg. In some aspects, C1D3 is 300 mg.In some aspects, C1D3 is 305 mg. In some aspects, C1D3 is 310 mg. In some aspects, C1D3 is 315 mg. In some aspects, C1D3 is 320 mg. In some aspects, C1D3 is 325 mg. In some aspects, C1D3 is 330 mg. In some aspects, C1D3 is 335 mg. In some aspects, C1D3 is 340 mg. In some aspects, C1D3 is 345 mg. In some aspects, C1D3 is 350 mg. In some aspects, C1D3 is 355 mg. In some aspects, C1D3 is 360 mg. In some aspects, C1D3 is 365 mg. In some aspects, C1D3 is 370 mg. In some aspects, C1D3 is 375 mg. In some aspects, C1D3 is 380 mg. In some aspects, C1D3 is 385 mg. In some aspects, C1D3 is 390 mg. In some aspects, C1D3 is 395 mg. In some aspects, C1D3 is 400 mg. In some aspects, C1D3 is 405 mg. In some aspects, C1D3 is 410 mg. In some aspects, C1D3 is 415 mg. In some aspects, C1D3 is 420 mg. In some aspects, C1D3 is 425 mg. In some aspects, C1D3 is 430 mg. In some aspects, C1D3 is 435 mg. In some aspects, C1D3 is 440 mg. In some aspects, C1D3 is 445 mg. In some aspects, C1D3 is 450 mg. In some aspects, C1D3 is 455 mg. In some aspects, C1D3 is 460 mg. In some aspects, C1D3 is 465 mg. In some aspects, C1D3 is 470 mg. In some aspects, C1D3 is 475 mg. In some aspects, C1D3 is 480 mg. In some aspects, C1D3 is 485 mg. In some aspects, C1D3 is 490 mg. In some aspects, C1D3 is 495 mg. In some aspects, C1D3 is 500 mg. In some aspects, C1D3 is 505 mg. In some aspects, C1D3 is 510 mg. In some aspects, C1D3 is 515 mg. In some aspects, C1D3 is 520 mg. In some aspects, C1D3 is 525 mg. In some aspects, C1D3 is 530 mg. In some aspects, C1D3 is 535 mg. In some aspects, C1D3 is 540 mg. In some aspects, C1D3 is 545 mg. In some aspects, C1D3 is 550 mg. In some aspects, C1D3 is 555 mg. In some aspects, C1D3 is 560 mg. In some aspects, C1D3 is 565 mg. In some aspects, C1D3 is 570 mg. In some aspects, C1D3 is 575 mg. In some aspects, C1D3 is 580 mg. In some aspects, C1D3 is 585 mg. In some aspects, C1D3 is 590 mg.In some aspects, C1D3 is 595 mg. In some aspects, C1D3 is 600 mg. In some aspects, C1D3 is 605 mg. In some aspects, C1D3 is 610 mg. In some aspects, C1D3 is 615 mg. In some aspects, C1D3 is 620 mg. In some aspects, C1D3 is 625 mg. In some aspects, C1D3 is 630 mg. In some aspects, C1D3 is 635 mg. In some aspects, C1D3 is 640 mg. In some aspects, C1D3 is 645 mg. In some aspects, C1D3 is 650 mg. In some aspects, C1D3 is 655 mg. In some aspects, C1D3 is 660 mg. In some aspects, C1D3 is 665 mg. In some aspects, C1D3 is 670 mg. In some aspects, C1D3 is 675 mg. In some aspects, C1D3 is 680 mg. In some aspects, C1D3 is 685 mg. In some aspects, C1D3 is 690 mg. In some aspects, C1D3 is 695 mg. In some aspects, C1D3 is 700 mg. In some aspects, C1D3 is 705 mg. In some aspects, C1D3 is 710 mg. In some aspects, C1D3 is 715 mg. In some aspects, C1D3 is 720 mg. In some aspects, C1D3 is 725 mg. In some aspects, C1D3 is 730 mg. In some aspects, C1D3 is 735 mg. In some aspects, C1D3 is 740 mg. In some aspects, C1D3 is 745 mg. In some aspects, C1D3 is 750 mg. In some aspects, C1D3 is 755 mg. In some aspects, C1D3 is 760 mg. In some aspects, C1D3 is 765 mg. In some aspects, C1D3 is 770 mg. In some aspects, C1D3 is 775 mg. In some aspects, C1D3 is 780 mg. In some aspects, C1D3 is 785 mg. In some aspects, C1D3 is 790 mg. In some aspects, C1D3 is 795 mg. In some aspects, C1D3 is 800 mg. In some aspects, C1D3 is 805 mg. In some aspects, C1D3 is 810 mg. In some aspects, C1D3 is 815 mg. In some aspects, C1D3 is 820 mg. In some aspects, C1D3 is 825 mg. In some aspects, C1D3 is 830 mg. In some aspects, C1D3 is 835 mg. In some aspects, C1D3 is 840 mg. In some aspects, C1D3 is 845 mg. In some aspects, C1D3 is 850 mg. In some aspects, C1D3 is 855 mg. In some aspects, C1D3 is 860 mg. In some aspects, C1D3 is 865 mg. In some aspects, C1D3 is 870 mg. In some aspects, C1D3 is 875 mg. In some aspects, C1D3 is 880 mg.In some aspects, C1D3 is 885 mg. In some aspects, C1D3 is 890 mg. In some aspects, C1D3 is 895 mg. In some aspects, C1D3 is 900 mg. In some aspects, C1D3 is 905 mg. In some aspects, C1D3 is 910 mg. In some aspects, C1D3 is 915 mg. In some aspects, C1D3 is 920 mg. In some aspects, C1D3 is 925 mg. In some aspects, C1D3 is 930 mg. In some aspects, C1D3 is 935 mg. In some aspects, C1D3 is 940 mg. In some aspects, C1D3 is 945 mg. In some aspects, C1D3 is 950 mg. In some aspects, C1D3 is 955 mg. In some aspects, C1D3 is 960 mg. In some aspects, C1D3 is 965 mg. In some aspects, C1D3 is 970 mg. In some aspects, C1D3 is 975 mg. In some aspects, C1D3 is 980 mg. In some aspects, C1D3 is 985 mg. In some aspects, C1D3 is 990 mg. In some aspects, C1D3 is 995 mg. In some aspects, C1D3 is 1000 mg.

[0288] In some cases, the above methods may include a first dosing cycle of four weeks or 28 days. In some cases, the methods may include administering C1D1 and C1D2 to the subject on or around day 1 and day 8 of the first dosing cycle, respectively. In some cases, the methods may include administering C1D1, C1D2, and C1D3 to the subject on or around day 1, day 8, and day 15 of the first dosing cycle, respectively.

[0289] In some aspects, the method comprises only a single dosing cycle of the bispecific antibody (eg, a dosing cycle comprising C1D1, C1D2, and C1D3).

[0290] iv. Additional dosing cycles

[0291] Any of the methods described herein may include additional dosing cycles. For example, in some cases, the above methods may include a second dosing cycle of four weeks or 28 days. In some cases, the method may include administering C2D1 to a subject on or around day 1 and day 15 of the second dosing cycle.

[0292] In some cases where the method includes at least the second dosing cycle, the method may include one or more additional dosing cycles. In some cases, the dosing regimen includes 1 to 17 additional dosing cycles (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17 additional dosing cycles, for example, 1 to 3 additional dosing cycles, 1 to 5 additional dosing cycles, 3 to 8 additional dosing cycles, 5 to 10 additional dosing cycles, 8 to 12 additional dosing cycles, 10 to 15 additional dosing cycles, 12 to 17 additional dosing cycles or 15 to 17 additional dosing cycles, that is, the dosing regimen includes one or more additional dosing cycles C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18 and C19.

[0293] In some embodiments, the length of each of the one or more additional dosing cycles is 7 days, 14 days, 21 days, or 28 days. In some embodiments, the length of each of the one or more additional dosing cycles is between 5 days and 30 days, for example, between 5 days and 9 days, between 7 days and 11 days, between 9 days and 13 days, between 11 days and 15 days, between 13 days and 17 days, between 15 days and 19 days, between 17 days and 21 days, between 19 days and 23 days, between 21 days and 25 days, between 23 days and 27 days, or between 25 days and 30 days. In some cases, the length of each of the one or more additional dosing cycles is three weeks or 21 days. In some cases, the length of each of the one or more additional dosing cycles is four weeks or 28 days.

[0294] In some cases, each of the one or more additional dosing cycles comprises a single dose of the bispecific antibody. In some aspects, the dose of the bispecific antibody in the one or more additional dosing cycles is equal to C1D3, for example, between about 10 mg to about 1000 mg (e.g., between about 10 mg to about 70 mg, between about 15 mg to about 65 mg, between about 20 mg to about 60 mg, between about 25 mg to about 55 mg, between about 30 mg to about 50 mg, between about 35 mg to about 45 mg, between about 15 mg to about 225 mg, between about 20 mg to about 220 mg, between about 25 mg to about 215 mg, between about 30 mg to about 210 mg, between about 35 mg to about 205 mg, between about 40 mg to about 200 mg, between about 45 mg to about 500 mg). g to about 195 mg, about 50 mg to about 190 mg, about 55 mg to about 185 mg, about 60 mg to about 180 mg, about 65 mg to about 175 mg, about 70 mg to about 170 mg, about 75 mg to about 165 mg, about 80 mg to about 160 mg, about 85 mg to about 155 mg, about 90 mg to about 150 mg, about 95 mg to about 145 mg, about 100 mg to about 140 mg, about 105 mg to about 135 mg, about 110 mg to about 130 mg, about 115 mg to about 125 mg, about 10 mg to about 50 mg , between about 25 mg and about 75 mg, between about 50 mg and about 100 mg, between about 75 mg and about 125 mg, between about 100 mg and about 150 mg, between about 125 mg and about 175 mg, between about 150 mg and about 200 mg, between about 175 mg and about 225 mg, between about 200 mg and about 250 mg, between about 225 mg and about 275 mg, between about 250 mg and about 300 mg, between about 275 mg and about 325 mg, between about 300 mg and about 350 mg, between about 325 mg and about 375 mg, between about 350 mg and about 400 mg, between about 375 mg and about 425 mg, between about between about 400 mg and about 450 mg, between about 425 mg and about 475 mg, between about 450 mg and about 500 mg, between about 475 mg and about 525 mg, between about 500 mg and about 550 mg, between about 525 mg and about 575 mg, between about 550 mg and about 600 mg, between about 575 mg and about 625 mg, between about 600 mg and about 650 mg, between about 625 mg and about 675 mg, between about 650 mg and about 700 mg, between about 675 mg and about 725 mg, between about 700 mg and about 750 mg, between about 725 mg and about 775 mg, between about 750 mg and about 800 mg,In some aspects, C1D2 is greater than C1D1 and C1D3 is greater than C1D2.

[0295] In some aspects, the dose of the bispecific antibody in the one or more additional dosing cycles is between about 10 mg and about 200 mg (e.g., between about 10 mg and about 170 mg, between about 11 mg and about 165 mg, between about 12 mg and about 160 mg, between about 13 mg and about 155 mg, between about 14 mg and about 150 mg, between about 15 mg and about 145 mg, between about 16 mg and about 140 mg, between about 17 mg and about 135 mg, between about 18 mg and about 130 mg, between about 19 mg and about 125 mg, between about 20 mg and about 120 mg, between about 21 mg and about 115 mg, between about 22 mg and about 110 mg). g, about 23 mg to about 105 mg, about 24 mg to about 100 mg, about 25 mg to about 95 mg, about 26 mg to about 90 mg, about 27 mg to about 85 mg, about 28 mg to about 80 mg, about 29 mg to about 75 mg, about 30 mg to about 70 mg, about 31 mg to about 65 mg, about 32 mg to about 60 mg, about 33 mg to about 55 mg, about 34 mg to about 50 mg, about 35 mg to about 45 mg, about 40 mg to about 200 mg, about 45 mg to about 195 mg, about 50 mg to about 190 mg, about 55 mg to about about 185 mg, about 60 mg to about 180 mg, about 65 mg to about 175 mg, about 70 mg to about 170 mg, about 75 mg to about 165 mg, about 80 mg to about 160 mg, about 85 mg to about 155 mg, about 90 mg to about 150 mg, about 95 mg to about 145 mg, about 100 mg to about 140 mg, about 105 mg to about 135 mg, about 110 mg to about 130 mg, about 115 mg to about 125 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about or about 190 mg to about 200 mg).

[0296] In some aspects, the dose of the bispecific antibody in the one or more additional dosing cycles is about 40 mg. In some aspects, the dose of the bispecific antibody in the one or more additional dosing cycles is about 120 mg.In some aspects, the dose of the bispecific antibody in the one or more additional dosing cycles is equal to C1D3, for example, between 10 mg 10 mg and 1000 mg (e.g., between 10 mg and 70 mg, between 15 mg and 65 mg, between 20 mg and 60 mg, between 25 mg and 55 mg, between 30 mg and 50 mg, between 35 mg and 45 mg, between 15 mg and 225 mg, between 20 mg and 220 mg, between 25 mg and 215 mg, between 30 mg and 210 mg, between 35 mg and 205 mg, between 40 mg and 200 mg, between 45 mg and 195 mg, between 50 mg and 190 mg, between 55 mg and 185 mg, between 60 mg and 180 mg, between 65 mg and 175 mg). Between 5mg, between 70mg and 170mg, between 75mg and 165mg, between 80mg and 160mg, between 85mg and 155mg, between 90mg and 150mg, between 95mg and 145mg, between 100mg and 140mg, between 105mg and 135mg, between 110mg and 130mg, between 115mg and 125mg, between 10mg and 50mg, between 25mg and 75mg, between 50mg and 100mg, between 75mg and 125mg, between 100mg and 150mg, between 125mg and 175mg, between 150mg and 200mg g, between 175mg and 225mg, between 200mg and 250mg, between 225mg and 275mg, between 250mg and 300mg, between 275mg and 325mg, between 300mg and 350mg, between 325mg and 375mg, between 350mg and 400mg, between 375mg and 425mg, between 400mg and 450mg, between 425mg and 475mg, between 450mg and 500mg, between 475mg and 525mg, between 500mg and 550mg, between 525mg and 575mg, between 550mg and 600mg , 575 mg to 625 mg, 600 mg to 650 mg, 625 mg to 675 mg, 650 mg to 700 mg, 675 mg to 725 mg, 700 mg to 750 mg, 725 mg to 775 mg, 750 mg to 800 mg, 775 mg to 825 mg, 800 mg to 850 mg, 825 mg to 875 mg, 850 mg to 900 mg, 875 mg to 925 mg, 900 mg to 950 mg, 925 mg to 975 mg, or 950 mg to 1000 mg). In some aspects, C1D2 is greater than C1D1 and C1D3 is greater than C1D2.

[0297] In some aspects, C1D3 is between 10 mg and 200 mg (e.g., between 10 mg and 170 mg, between 11 mg and 165 mg, between 12 mg and 160 mg, between 13 mg and 155 mg, between 14 mg and 150 mg, between 15 mg and 145 mg, between 16 mg and 140 mg, between 17 mg and 135 mg, between 18 mg and 130 mg, between 19 mg and 125 mg, between 20 mg and 120 mg, between 21 mg and 115 mg, between 22 mg and 110 mg, between 23 mg and 10 Between 5mg, 24mg and 100mg, 25mg and 95mg, 26mg and 90mg, 27mg and 85mg, 28mg and 80mg, 29mg and 75mg, 30mg and 70mg, 31mg and 65mg, 32mg and 60mg, 33mg and 55mg, 34mg and 50mg, 35mg and 45mg, 40mg and 200mg, 45mg and 195mg, 50mg and 190mg, 55mg and 185mg, 60 Between mg and 180mg, between 65mg and 175mg, between 70mg and 170mg, between 75mg and 165mg, between 80mg and 160mg, between 85mg and 155mg, between 90mg and 150mg, between 95mg and 145mg, between 100mg and 140mg, between 105mg and 135mg, between 110mg and 130mg, between 115mg and 125mg, between 10mg and 20mg, between 20mg and 30mg, between 30mg and 40mg, between 40mg and 50mg In some aspects, the dosage of the bispecific antibody in the one or more additional dosing cycles is 40 mg. In some aspects, the dosage of the bispecific antibody in the one or more additional dosing cycles is about 120 mg.

[0298] In some cases, the method comprises administering a single dose of the bispecific antibody to the subject subcutaneously on or around day 1 and day 15 of the one or more additional dosing cycles. In some cases, the method comprises administering a single dose of the bispecific antibody to the subject on or around day 1 of the one or more additional dosing cycles. In some cases, the method comprises administering a single dose of the bispecific antibody to the subject on or around day 1, day 8, day 15, and / or day 22 of the one or more additional dosing cycles.

[0299] In some aspects, bispecific antibodies are administered subcutaneously to subjects every 7 days (QW) until disease progression is observed, for up to 18 cycles, or until minimal residual disease (MRD) is observed. In some aspects, bispecific antibodies are administered to subjects every 14 days (Q2W) until disease progression is observed, for up to 18 cycles, or until minimal residual disease (MRD) is observed. In some aspects, bispecific antibodies are administered to subjects every 21 days (Q3W) until disease progression is observed, for up to 18 cycles, or until minimal residual disease (MRD) is observed. In some aspects, bispecific antibodies are administered to subjects every 28 days (Q4W) until disease progression is observed, for up to 18 cycles, or until minimal residual disease (MRD) is observed.

[0300] In some aspects, the bispecific antibody is administered subcutaneously to the subject QW until disease progression is observed. In some aspects, the bispecific antibody is administered subcutaneously to the subject Q2W until disease progression is observed. In some aspects, the bispecific antibody is administered subcutaneously to the subject Q3W until disease progression is observed. In some aspects, the bispecific antibody is administered subcutaneously to the subject Q4W until disease progression is observed. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject as a monotherapy. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject in combination with another therapeutic agent. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject in combination with an anti-CD38 antibody. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject in combination with a corticosteroid. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject in combination with an immunomodulatory drug (IMiD). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject in combination with an anti-CD38 antibody and a corticosteroid. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to a subject in combination with an IMiD and a corticosteroid. Exemplary anti-CD38 antibodies to be used in combination therapy include daratumumab and isatuximab. Exemplary corticosteroids to be used in combination therapy include dexamethasone and methylprednisolone. Exemplary IMiDs to be used in combination therapy include pomalidomide and lenalidomide.

[0301] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is sivosetumab. In some cases, sivosetumab is administered to a subject as a monotherapy. In some cases, sivosetumab is administered to a subject in combination with pomalidomide (P). In some cases, sivosetumab is administered to a subject in combination with dexamethasone (d). In some cases, sivosetumab is administered to a subject in combination with pomalidomide and dexamethasone (Pd). In some cases, sivosetumab is administered to a subject in combination with daratumumab (D). In some cases, sivosetumab is administered to a subject in combination with daratumumab and dexamethasone (Dd).

[0302] B. Dosing regimen: frequency and duration of administration

[0303] The present disclosure describes a method for treating a subject with cancer (e.g., multiple myeloma (MM)), the method comprising subcutaneously administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen described herein. In some examples, the dosing regimen includes: a first phase, which includes one or more dosing cycles; a second phase, which includes one or more dosing cycles; and a third phase, which includes one or more dosing cycles. In some examples, each dosing cycle is a 28-day dosing cycle. The first phase may include administering the bispecific antibody to the subject every week (QW), the second phase may include administering the bispecific antibody to the subject every two weeks (Q2W), and / or the third phase may include administering the bispecific antibody to the subject every four weeks (Q4W).

[0304] For example, provided herein is a method for treating a subject with cancer (e.g., MM), the method comprising subcutaneously administering to the subject a bispecific antibody that binds to FcRH5 and CD3 with a dosing regimen that includes: (i) a first phase, which includes one or more dosing cycles, wherein the first phase includes administering the bispecific antibody to the subject every week (QW); (ii) a second phase, which includes one or more dosing cycles, wherein the second phase includes administering the bispecific antibody to the subject every two weeks (Q2W); and / or (iii) a third phase, which includes one or more dosing cycles, wherein the third phase includes administering the bispecific antibody to the subject every four weeks (Q4W). In some instances, the dosing regimen includes the first phase. In some instances, the dosing regimen includes the second phase. In some instances, the dosing regimen includes the third phase. In some instances, the dosing regimen includes the first phase and the second phase. In some instances, the dosing regimen includes the first phase and the third phase. In some instances, the dosing regimen includes the second phase and the third phase. In some instances, the dosing regimen includes the first phase, the second phase, and the third phase.

[0305] In another example, provided herein is a bispecific antibody that binds to FcRH5 and CD3, the bispecific antibody being used in the treatment of a subject with cancer (e.g., MM), the treatment comprising administering the bispecific antibody subcutaneously to the subject in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the subject weekly (QW); (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the subject every two weeks (Q2W); and / or (iii) a third phase comprising one or more dosing cycles, wherein the third phase comprises administering the bispecific antibody to the subject every four weeks (Q4W). In some examples, the dosing regimen comprises the first phase. In some examples, the dosing regimen comprises the second phase. In some examples, the dosing regimen comprises the third phase. In some examples, the dosing regimen comprises the first phase and the second phase. In some examples, the dosing regimen comprises the first phase and the third phase. In some examples, the dosing regimen comprises the second phase and the third phase. In some examples, the dosing regimen includes a first phase, a second phase, and a third phase.

[0306] In another example, provided herein is a use of a bispecific antibody that binds to FcRH5 and CD3 in the manufacture of a medicament for treating a subject with cancer (e.g., MM), the treatment comprising administering the bispecific antibody subcutaneously to the subject in a dosing regimen that includes: (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the subject weekly (QW); (ii) a second phase comprising one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the subject every two weeks (Q2W); and / or (iii) a third phase comprising one or more dosing cycles, wherein the third phase comprises administering the bispecific antibody to the subject every four weeks (Q4W). In some examples, the dosing regimen includes the first phase. In some examples, the dosing regimen includes the second phase. In some examples, the dosing regimen includes the third phase. In some examples, the dosing regimen includes the first phase and the second phase. In some examples, the dosing regimen includes the first phase and the third phase. In some examples, the dosing regimen includes the second phase and the third phase. In some examples, the dosing regimen includes a first phase, a second phase, and a third phase.

[0307] The first phase may include any suitable number of dosing cycles. For example, in some instances, the first phase may include at least one dosing cycle, at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, at least five dosing cycles, at least six dosing cycles, at least seven dosing cycles, at least eight dosing cycles, at least nine dosing cycles, at least ten dosing cycles, at least eleven dosing cycles, at least twelve dosing cycles, or at least thirteen dosing cycles, or more.

[0308] In some examples, the first phase includes a first dosing cycle (C1); a first dosing cycle and a second dosing cycle (C2); a first dosing cycle, a second dosing cycle (C2), and a third dosing cycle (C3); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), and a fourth dosing cycle (C4); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5). 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) and the eighth dosing cycle (C8); Dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6), seventh dosing cycle (C7), eighth dosing cycle (C8) and ninth dosing cycle (C9); first dosing cycle (C1), second dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6), seventh dosing cycle (C7), eighth dosing cycle (C8), ninth dosing cycle (C9) and tenth dosing cycle (C10); first dosing cycle (C1), second dosing cycle (C2), third dosing cycle (C3), 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). ;

[0309] The bispecific antibody can be administered on any suitable day of a given dosing cycle. For example, for a 28-day dosing 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, for a 21 day dosing cycle, the bispecific antibody may 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, for a 14 day dosing cycle, the bispecific antibody may 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, for a 7 day dosing cycle, the bispecific antibody may be administered on day 1, day 2, day 3, day 4, day 5, day 6, or day 7.

[0310] In some examples, the first phase includes administering the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C1. In other examples, the first phase includes administering the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C2. In other examples, the first phase includes administering the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C3. In other examples, the first phase includes administering the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C4. In other examples, the first phase includes administering the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C5. In other examples, the first phase includes administering the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C6. In other examples, the first phase includes administering the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C7. In other examples, the first phase includes administering the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C8. In other examples, the first phase includes administering the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C9. In other examples, the first phase includes administering the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C10. In other examples, the first phase includes administering the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C11. In other examples, the first phase includes administering the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C12. In other examples, the first phase includes administering the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C13.

[0311] In some examples, a target dose of the bispecific antibody is administered to the subject for each administration during the first stage.

[0312] In some examples, the first phase includes administering a target dose of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C1. In other examples, the first phase includes administering a target dose of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C2. In other examples, the first phase includes administering a target dose of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C3. In other examples, the first phase includes administering a target dose of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C4. In other examples, the first phase includes administering a target dose of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C5. In other examples, the first phase includes administering a target dose of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C6. In other examples, the first phase includes administering a target dose of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C7. In other examples, the first phase includes administering a target dose of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C8. In other examples, the first phase includes administering a target dose of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C9. In other examples, the first phase includes administering a target dose of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C10. In other examples, the first phase includes administering a target dose of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C11. In other examples, the first phase includes administering a target dose of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C12. In other examples, the first phase includes administering a target dose of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C13.

[0313] In some examples, the first stage includes applying the first step-up dose and target dose of the bispecific antibody to the subject. The first step-up dose may be applied to the subject on the 1st day of C1, on the 2nd day of C1, on the 3rd day of C1, on the 4th day of C1, on the 5th day of C1, on the 6th day of C1, or on the 7th day of C1 during the first stage. The target dose may be applied to the subject on the 8th day and / or the 15th day of C1 during the first stage. In other examples, the target dose may be applied to the subject on the 1st day, the 8th day and / or the 15th day of C2 during the first stage. In other examples, the target dose may be applied to the subject on the 1st day, the 8th day and / or the 15th day of C3 during the first stage. In other examples, the target dose may be applied to the subject on the 1st day, the 8th day and / or the 15th day of C4 during the first stage. In other examples, the target dose may be applied to the subject on the 1st day, the 8th day and / or the 15th day of C5 during the first stage. In another example, the target dose may be administered to the subject at day 1, day 8, and / or day 15 of C6 during the first stage. In another example, the target dose may be administered to the subject at day 1, day 8, and / or day 15 of C7 during the first stage. In another example, the target dose may be administered to the subject at day 1, day 8, and / or day 15 of C8 during the first stage. In another example, the target dose may be administered to the subject at day 1, day 8, and / or day 15 of C9 during the first stage. In another example, the target dose may be administered to the subject at day 1, day 8, and / or day 15 of C10 during the first stage. In another example, the target dose may be administered to the subject at day 1, day 8, and / or day 15 of C11 during the first stage. In another example, the target dose may be administered to the subject at day 1, day 8, and / or day 15 of C12 during the first stage. In further examples, a target dose can be administered to a subject on day 1, day 8, and / or day 15 of C13 during the first phase.

[0314] In some instances, the first step-up dose is between about 15% and about 45% of the target dose. In some instances, the first step-up dose is about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, or about 45% of the target dose. In some instances, the first step-up dose is about 25% of the target dose.

[0315] In some instances, the first step-up dose is between 15% and 45% of the target dose. In some instances, the first step-up dose is 15%, 16%, 17%, 18%, 19%, 20%, 21%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, or 45% of the target dose. In some instances, the first step-up dose is 25% of the target dose.

[0316] In some examples, the first step-up dose is between 0.1 mg and about 50 mg (e.g., between about 0.1 mg and about 9.5 mg, between about 0.2 mg and about 9 mg, between about 0.3 mg and about 8.5 mg, between about 0.4 mg and about 8 mg, between about 0.5 mg and about 7.5 mg, between about 0.6 mg and about 7 mg, between about 0.7 mg and about 6.5 mg, between about 0.8 mg and about 6 mg, between about 0.9 mg and about 5.5 mg, between about 1 mg and about 5 mg, between about 1.1 mg and about 4.5 mg, between about 1.2 mg and about 4 mg, between about 1.3 mg and about 3.5 mg, between about 1.4 mg and about 3 mg, about 1.5 mg to about 2.5 mg, about 1 mg to about 3 mg, about 0.2 mg to about 35 mg, about 0.3 mg to about 30 mg, about 0.4 mg to about 29 mg, about 0.5 mg to about 28 mg, about 1 mg to about 27 mg, about 1.5 mg to about 26 mg, about 2 mg to about 25 mg, about 2.5 mg to about 24 mg, about 3 mg to about 23 mg, about 3.5 mg to about 22 mg, about 4 mg to about 21 mg, about 4.5 mg to about 20 mg, about 5 mg to about 19 mg, about 5.5 mg to about 18 mg, about 6 mg to about 17 mg, about 6 .5 mg to about 16 mg, about 7 mg to about 15 mg, about 7.5 mg to about 14 mg, about 8 mg to about 13 mg, about 8 mg to about 12 mg, about 8.5 mg to about 12 mg, about 9 mg to about 11 mg, about 0.1 mg to about 1 mg, about 0.2 mg to about 1.5 mg, about 0.3 mg to about 2 mg, about 0.4 mg to about 2.5 mg, about 0.5 mg to about 3 mg, about 0.6 mg to about 3.5 mg, about 0.7 mg to about 4 mg, about 0.8 mg to about 4.5 mg, about 0.9 mg to about 5 mg, about 1 mg to about 6 mg, about Between 1.5 mg and about 6.5 mg, between about 2 mg and about 7 mg, between about 2.5 mg and about 7.5 mg, between about 3 mg and about 8 mg, between about 3.5 mg and about 8.5 mg, between about 4 mg and about 9 mg, between about 4.5 mg and about 9.5 mg, between about 5 mg and about 10 mg, between about 5.5 mg and about 10.5 mg, between about 6 mg and about 11 mg, between about 6.5 mg and about 11.5 mg, between about 7 mg and about 12 mg, between about 7.5 mg and about 12.5 mg, between about 8 mg and about 13 mg, between about 8.5 mg and about 13.5 mg, between about 9 mg and about 14 mg, between about 9.5 mg and about 14.about 15 mg, about 16 mg to about 17 mg, about 13 mg to about 18 mg, about 14 mg to about 19 mg, about 15 mg to about 20 mg, about 16 mg to about 21 mg, about 17 mg to about 22 mg, about 18 mg to about 23 mg, about 19 mg to about 24 mg, about 20 mg to about 25 mg, about 21 mg to about 26 mg, about 22 mg to about 27 mg, about 23 mg to about 28 mg, about 24 mg to about 29 mg, about 25 mg to about 30 mg, about 26 mg to about 31 mg, about 27 mg to about 32 mg about 28 mg to about 33 mg, about 29 mg to about 34 mg, about 30 mg to about 35 mg, about 31 mg to about 36 mg, about 32 mg to about 37 mg, about 33 mg to about 38 mg, about 34 mg to about 39 mg, about 35 mg to about 40 mg, about 36 mg to about 41 mg, about 37 mg to about 42 mg, about 38 mg to about 43 mg, about 39 mg to about 44 mg, about 40 mg to about 45 mg, about 41 mg to about 46 mg, about 42 mg to about 47 mg, about 43 mg to about 48 mg, about 44 mg to about 49 mg, about 45 mg to about 50 mg).

[0317] In some examples, the first step-up dose is between 0.1 mg and 50 mg (e.g., between 0.1 mg and 9.5 mg, between 0.2 mg and 9 mg, between 0.3 mg and 8.5 mg, between 0.4 mg and 8 mg, between 0.5 mg and 7.5 mg, between 0.6 mg and 7 mg, between 0.7 mg and 6.5 mg, between 0.8 mg and 6 mg, between 0.9 mg and 5.5 mg, between 1 mg and 5 mg, between 1.1 mg and 4.5 mg, between 1.2 mg and 4 mg, between 1.3 mg and 3.5 mg, between 1.4 mg and 3 mg). g, 1.5mg to 2.5mg, 1mg to 3mg, 0.2mg to 35mg, 0.3mg to 30mg, 0.4mg to 29mg, 0.5mg to 28mg, 1mg to 27mg, 1.5mg to 26mg, 2mg to 25mg, 2.5mg to 24mg, 3mg to 23mg, 3.5mg to 22mg, 4mg to 21mg, 4.5mg to 20mg, 5mg to 19mg, 5.5mg to 18mg, 6mg to 17mg , between 6.5mg and 16mg, between 7mg and 15mg, between 7.5mg and 14mg, between 8mg and 13mg, between 8mg and 12mg, between 8.5mg and 12mg, between 9mg and 11mg, between 0.1mg and 1mg, between 0.2mg and 1.5mg, between 0.3mg and 2mg, between 0.4mg and 2.5mg, between 0.5mg and 3mg, between 0.6mg and 3.5mg, between 0.7mg and 4mg, between 0.8mg and 4.5mg, between 0.9mg and 5mg, between 1mg and 6mg, Between 1.5mg and 6.5mg, between 2mg and 7mg, between 2.5mg and 7.5mg, between 3mg and 8mg, between 3.5mg and 8.5mg, between 4mg and 9mg, between 4.5mg and 9.5mg, between 5mg and 10mg, between 5.5mg and 10.5mg, between 6mg and 11mg, between 6.5mg and 11.5mg, between 7mg and 12mg, between 7.5mg and 12.5mg, between 8mg and 13mg, between 8.5mg and 13.5mg, between 9mg and 14mg, between 9.5mg and 14.5mg, 10mg to 15mg, 11mg to 16mg, 12mg to 17mg, 13mg to 18mg, 14mg to 19mg, 15mg to 20mg, 16mg to 21mg, 17mg to 22mg, 18mg to 23mg, 19mg to 24mg, 20mg to 25mg, 21mg to 26mg, 22mg to 27mg, 23mg to 28mg, 24mg to 29mg, 25mg to 30mg, 26mg to 31mg, 27mg to 32mg between 28mg and 33mg, between 29mg and 34mg, between 30mg and 35mg, between 31mg and 36mg, between 32mg and 37mg, between 33mg and 38mg, between 34mg and 39mg, between 35mg and 40mg, between 36mg and 41mg, between 37mg and 42mg, between 38mg and 43mg, between 39mg and 44mg, between 40mg and 45mg, between 41mg and 46mg, between 42mg and 47mg, between 43mg and 48mg, between 44mg and 49mg, between 45mg and 50mg).

[0318] In some examples, the first step-up dose is about 0.1 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 4mg, about 25mg, about 26mg, about 27mg, about 28mg, about 29mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, or about 50mg.

[0319] In some examples, the first step-up dose is 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg or 50 mg.

[0320] In some examples, the first phase includes administering a first step-up dose and a second step-up dose of the bispecific antibody to the subject. In some examples, the first step-up dose is administered to the subject on day 1 of C1 during the first phase, and the second step-up dose is administered on day 8 of C1. In some examples, the first step-up dose is administered to the subject on day 2 of C1 during the first phase, and the second step-up dose is administered on day 9 of C1. In some examples, the first step-up dose is administered to the subject on day 3 of C1 during the first phase, and the second step-up dose is administered on day 10 of C1. In some examples, the first step-up dose is administered to the subject on day 4 of C1 during the first phase, and the second step-up dose is administered on day 11 of C1. In some examples, the first step-up dose is administered to the subject on day 5 of C1 during the first phase, and the second step-up dose is administered on day 12 of C1. In some examples, a first step-up dose is administered to a subject on day 6 of C1 during the first phase, and a second step-up dose is administered on day 13 of C1. In some examples, a first step-up dose is administered to a subject on day 7 of C1 during the first phase, and a second step-up dose is administered on day 14 of C1. In some examples, a first step-up dose is administered to a subject on day 8 of C1 during the first phase, and a second step-up dose is administered on day 15 of C1. In some examples, a first step-up dose is administered to a subject on day 9 of C1 during the first phase, and a second step-up dose is administered on day 16 of C1. In some examples, a first step-up dose is administered to a subject on day 10 of C1 during the first phase, and a second step-up dose is administered on day 17 of C1. In some examples, a first step-up dose is administered to a subject on day 11 of C1 during the first phase, and a second step-up dose is administered on day 18 of C1. In some examples, a first step-escalating dose is administered to a subject on day 12 of C1 during the first phase, and a second step-escalating dose is administered on day 19 of C1. In some examples, a first step-escalating dose is administered to a subject on day 13 of C1 during the first phase, and a second step-escalating dose is administered on day 20 of C1. In some examples, a first step-escalating dose is administered to a subject on day 14 of C1 during the first phase, and a second step-escalating dose is administered on day 21 of C1.

[0321] In other examples, the target dose is administered to the subject after the second step-up dose is administered during the first stage. In some examples, the target dose is administered to the subject on the 15th and / or 22nd day of C1. In some examples, the target dose is administered to the subject on the 16th and / or 23rd day of C1. In some examples, the target dose is administered to the subject on the 17th and / or 24th day of C1. In some examples, the target dose is administered to the subject on the 18th and / or 25th day of C1. In some examples, the target dose is administered to the subject on the 19th and / or 26th day of C1. In some examples, the target dose is administered to the subject on the 20th and / or 27th day of C1. In some examples, the target dose is administered to the subject on the 21st and / or 28th day of C1.

[0322] In another example, the target dose is further administered to the subject at the 1st day, the 8th day, and / or the 15th day of C2 during the first stage. In another example, the target dose is administered to the subject at the 1st day, the 8th day, and / or the 15th day of C3 during the first stage. In another example, the target dose is administered to the subject at the 1st day, the 8th day, and / or the 15th day of C4 during the first stage. In another example, the target dose is administered to the subject at the 1st day, the 8th day, and / or the 15th day of C5 during the first stage. In another example, the target dose is administered to the subject at the 1st day, the 8th day, and / or the 15th day of C6 during the first stage. In another example, the target dose is administered to the subject at the 1st day, the 8th day, the 15th day, and the 22nd day of C7 during the first stage. In another example, the target dose is administered to the subject at the 1st day, the 8th day, and / or the 15th day of C8 during the first stage. In further examples, the target dose is administered to the subject on day 1, day 8, and / or day 15 of C9 during the first phase. In further examples, the target dose is administered to the subject on day 1, day 8, and / or day 15 of C10 during the first phase. In further examples, the target dose is administered to the subject on day 1, day 8, and / or day 15 of C11 during the first phase. In further examples, the target dose is administered to the subject on day 1, day 8, and / or day 15 of C12 during the first phase. In further examples, the target dose is administered to the subject on day 1, day 8, and / or day 15 of C13 during the first phase.

[0323] In some examples, the first stepped dose is about 1% to about 10% of the target dose, and the second stepped dose is about 15% to about 45% of the target dose. In some examples, the first step-up dose is about 1%, about 1.5%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% of the target dose and the second step-up dose is about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, or about 45% of the target dose. In some examples, the first stepped dose is about 5% of the target dose and the second stepped dose is about 25% of the target dose.

[0324] In some instances, the first step-up dose is 1% to 10% of the target dose, and the second step-up dose is 15% to 45% of the target dose. In some instances, the first step-up dose is 1%, 1.5%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of the target dose, and the second step-up dose is 15%, 16%, 17%, 18%, 19%, 20%, 21%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, or 45% of the target dose. In some examples, the first stepped dose is 5% of the target dose and the second stepped dose is 25% of the target dose.

[0325] In some examples, the first step-up dose is between about 0.1 mg and about 10 mg (e.g., between about 0.1 mg and about 2 mg, between about 0.2 mg and about 1 mg, or between about 0.2 mg and about 0.4 mg, between about 0.1 mg and about 9.5 mg, between about 0.2 mg and about 9 mg, between about 0.3 mg and about 8.5 mg, between about 0.4 mg and about 8 mg, between about 0.5 mg and about 7.5 mg, between about 0.6 mg and about 7 mg, between about 0.7 mg and about 6.5 mg, between about 0.8 mg and about 6 mg, between about 0.9 mg and about 5.5 mg, between about 1 mg and about 5 mg, between about 1.1 mg and about 4.5 mg). between about 1.2 mg and about 4 mg, between about 1.3 mg and about 3.5 mg, between about 1.4 mg and about 3 mg, between about 1.5 mg and about 2.5 mg, between about 1 mg and about 3 mg, between about 0.1 mg and about 1 mg, between about 0.2 mg and about 1.5 mg, between about 0.3 mg and about 2 mg, between about 0.4 mg and about 2.5 mg, between about 0.5 mg and about 3 mg, between about 0.6 mg and about 3.5 mg, between about 0.7 mg and about 4 mg, between about 0.8 mg and about 4.5 mg, between about 0.9 mg and about 5 mg, between about 1 mg and about 6 mg, between about 1.5 mg and about 6.5 mg, about 2 mg and a second stepped increasing dose of between about 1 mg to about 50 mg (e.g., between about 3 mg to about 18 mg, between about 3.1 mg to about 15 mg, between about 3.2 mg to about 10 mg, between about 3.3 mg to about 6 mg, between about 3.4 mg to about 4 mg, between about 0.2 mg to about 35 mg, between about 0.3 mg to about 30 mg, between about 0.4 mg to about 29 mg). about 0.5 mg to about 28 mg, about 1 mg to about 27 mg, about 1.5 mg to about 26 mg, about 2 mg to about 25 mg, about 2.5 mg to about 24 mg, about 3 mg to about 23 mg, about 3.5 mg to about 22 mg, about 4 mg to about 21 mg, about 4.5 mg to about 20 mg, about 5 mg to about 19 mg, about 5.5 mg to about 18 mg, about 6 mg to about 17 mg, about 6.5 mg to about 16 mg, about 7 mg to about 15 mg, about 7.5 mg to about 14 mg, about 8 mg to about 13 mg, about 8 mg to about 12 mg, about 8.5mg to about 12mg, about 9mg to about 11mg, about 1mg to about 6mg, about 1.5mg to about 6.5mg, about 2mg to about 7mg, about 2.5mg to about 7.5mg, about 3mg to about 8mg, about 3.5mg to about 8.5mg, about 4mg to about 9mg, about 4.5mg to about 9.5mg, about 5mg to about 10mg, about 5.5mg to about 10.5mg, about 6mg to about 11mg, about 6.5mg to about 11.5mg, about 7mg to about 12mg, about 7.5mg to about 12.5mg, about 8mg to about 13mg, about 8.5mg to about 13.5mg, about 9mg to about 14mg, about 9.5mg to about 14.5mg, about 10mg to about 15mg, about 11mg to about 16mg, about 12mg to about 17mg, about 13mg to about 18mg, about 14mg to about 19mg, about 15mg to about 20mg, about 16mg to about 21mg, about 17mg to about 22mg between about 18 mg and about 23 mg, between about 19 mg and about 24 mg, between about 20 mg and about 25 mg, between about 21 mg and about 26 mg, between about 22 mg and about 27 mg, between about 23 mg and about 28 mg, between about 24 mg and about 29 mg, between about 25 mg and about 30 mg, between about 26 mg and about 31 mg, between about 27 mg and about 32 mg, between about 28 mg and about 33 mg, between about 29 mg and about 34 mg, between about 30 mg and about 35 mg, between about 31 mg and about 36 mg , about 32 mg to about 37 mg, about 33 mg to about 38 mg, about 34 mg to about 39 mg, about 35 mg to about 40 mg, about 36 mg to about 41 mg, about 37 mg to about 42 mg, about 38 mg to about 43 mg, about 39 mg to about 44 mg, about 40 mg to about 45 mg, about 41 mg to about 46 mg, about 42 mg to about 47 mg, about 43 mg to about 48 mg, about 44 mg to about 49 mg, or about 45 mg to about 50 mg).

[0326] In some examples, the first step-up dose is between 0.1 mg and 10 mg (e.g., between 0.1 mg and 2 mg, between 0.2 mg and 1 mg, or between 0.2 mg and 0.4 mg, between 0.1 mg and 9.5 mg, between 0.2 mg and 9 mg, between 0.3 mg and 8.5 mg, between 0.4 mg and 8 mg, between 0.5 mg and 7.5 mg, between 0.6 mg and 7 mg, between 0.7 mg and 6.5 mg, between 0.8 mg and 6 mg, between 0.9 mg and 5.5 mg, between 1 mg and 5 mg, between 1.1 mg and 4.5 mg, between 1.2 mg and 4 mg, between 1.3 mg and 3.5 mg, between 1.4 mg and 3 mg). between 1.5mg and 2.5mg, between 1mg and 3mg, between 0.1mg and 1mg, between 0.2mg and 1.5mg, between 0.3mg and 2mg, between 0.4mg and 2.5mg, between 0.5mg and 3mg, between 0.6mg and 3.5mg, between 0.7mg and 4mg, between 0.8mg and 4.5mg, between 0.9mg and 5mg, between 1mg and 6mg, between 1.5mg and 6.5mg, between 2mg and 7mg, between 2.5mg and 7.5mg, between 3mg and 8mg, between 3.5mg and 8.5mg, between 4mg and 9mg, between 4.5mg and 9.5mg, or between 5mg and 10mg) and the second step-up dose is between 1 mg and 50 mg (e.g., between 3 mg and 18 mg, between 3.1 mg and 15 mg, between 3.2 mg and 10 mg, between 3.3 mg and 6 mg, between 3.4 mg and 4 mg, between 0.2 mg and 35 mg, between 0.3 mg and 30 mg, between 0.4 mg and 29 mg, between 0.5 mg and 28 mg, between 1 mg and 27 mg, between 1.5 mg and 26 mg, between 2 mg and 25 mg, between 2.5 mg and 24 mg, between 3 mg and 23 mg, between 3.5 mg and 22 mg, between 4 mg and 21 mg, between 4.5 mg and 20 mg, between 5 mg and 19 mg) , between 5.5mg and 18mg, between 6mg and 17mg, between 6.5mg and 16mg, between 7mg and 15mg, between 7.5mg and 14mg, between 8mg and 13mg, between 8mg and 12mg, between 8.5mg and 12mg, between 9mg and 11mg, between 1mg and 6mg, between 1.5mg and 6.5mg, between 2mg and 7mg, between 2.5mg and 7.5mg, between 3mg and 8mg, between 3.5mg and 8.5mg, between 4mg and 9mg, between 4.5mg and 9.5mg, between 5mg and 10mg, between 5.5mg and 10.5mg, between 6mg and 11mg, between 6.5mg and 11.Between 5mg, between 7mg and 12mg, between 7.5mg and 12.5mg, between 8mg and 13mg, between 8.5mg and 13.5mg, between 9mg and 14mg, between 9.5mg and 14.5mg, between 10mg and 15mg, between 11mg and 16mg, between 12mg and 17mg, between 13mg and 18mg, between 14mg and 19mg, between 15mg and 20mg, between 16mg and 21mg, between 17mg and 22mg, between 18mg and 23mg, between 19mg and 24mg, between 20mg and 25mg, between 21mg and 26mg, between 22mg and 27mg, between 23mg and 28mg, between 24mg and 29mg between 25mg and 30mg, between 26mg and 31mg, between 27mg and 32mg, between 28mg and 33mg, between 29mg and 34mg, between 30mg and 35mg, between 31mg and 36mg, between 32mg and 37mg, between 33mg and 38mg, between 34mg and 39mg, between 35mg and 40mg, between 36mg and 41mg, between 37mg and 42mg, between 38mg and 43mg, between 39mg and 44mg, between 40mg and 45mg, between 41mg and 46mg, between 42mg and 47mg, between 43mg and 48mg, between 44mg and 49mg, or between 45mg and 50mg).

[0327] In some examples, the first step-up dose is about 2 mg and the second step-up dose is about 10 mg. In some examples, the first step-up dose is about 0.1 mg, about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. At the same time, the second step-up dose is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg , about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, or about 50 mg.

[0328] In some examples, the first step-up dose is 2 mg and the second step-up dose is 10 mg. In some examples, the first step-up dose is 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg or 10 mg, while the second step-up dose is 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg , 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg , 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg or 50mg.

[0329] In any of the foregoing examples, the second phase may include at least one dosing cycle, at least two dosing cycles, at least three dosing cycles, or at least four dosing cycles, at least five dosing cycles, at least six dosing cycles, at least seven, at least eight dosing cycles, at least nine dosing cycles, at least ten dosing cycles, at least eleven dosing cycles, at least twelve dosing cycles, or at least thirteen dosing cycles, or more.

[0330] The second phase may include any suitable number of dosing cycles. For example, in some instances, the second phase may include a first dosing cycle (C1); a first dosing cycle and a second dosing cycle (C2); a first dosing cycle, a second dosing cycle (C2), and a third dosing cycle (C3); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), and a fourth dosing cycle (C4); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5). 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) and the tenth dosing cycle (C10). ), 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). ;

[0331] In some examples, the target dose of the bispecific antibody may be administered to the subject on day 1 and / or day 15 of C1 during the second stage. In other examples, the target dose of the bispecific antibody may be administered to the subject on day 1 and / or day 15 of C2 during the second stage. In other examples, the target dose of the bispecific antibody may be administered to the subject on day 1 and / or day 15 of C3 during the second stage. In other examples, the target dose of the bispecific antibody may be administered to the subject on day 1 and / or day 15 of C4 during the second stage. In other examples, the target dose of the bispecific antibody may be administered to the subject on day 1 and / or day 15 of C5 during the second stage. In other examples, the target dose of the bispecific antibody may be administered to the subject on day 1 and / or day 15 of C6 during the second stage. In other examples, the target dose of the bispecific antibody may be administered to the subject on day 1 and / or day 15 of C7 during the second stage. In other examples, the target dose of the bispecific antibody may be administered to the subject at day 1 and / or day 15 of C8 during the second stage. In other examples, the target dose of the bispecific antibody may be administered to the subject at day 1 and / or day 15 of C9 during the second stage. In other examples, the target dose of the bispecific antibody may be administered to the subject at day 1 and / or day 15 of C10 during the second stage. In other examples, the target dose of the bispecific antibody may be administered to the subject at day 1 and / or day 15 of C11 during the second stage. In other examples, the target dose of the bispecific antibody may be administered to the subject at day 1 and / or day 15 of C12 during the second stage. In other examples, the target dose of the bispecific antibody may be administered to the subject at day 1 and / or day 15 of C13 during the second stage.

[0332] In some examples, a target dose of the bispecific antibody is administered to the subject for each administration during the second stage.

[0333] The third phase may include any suitable number of dosing cycles. For example, in any of the foregoing examples, the third phase may include at least one dosing cycle, at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, at least five dosing cycles, at least six dosing cycles, at least seven dosing cycles, at least eight dosing cycles, at least nine dosing cycles, at least ten dosing cycles, at least eleven dosing cycles, at least twelve dosing cycles, or at least thirteen dosing cycles, or more.

[0334] In some examples, the third phase includes a first dosing cycle (C1); a first dosing cycle and a second dosing cycle (C2); a first dosing cycle, a second dosing cycle (C2), and a third dosing cycle (C3); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), and a fourth dosing cycle (C4); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5); a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5). 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) and the eighth dosing cycle (C8); Dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6), seventh dosing cycle (C7), eighth dosing cycle (C8) and ninth dosing cycle (C9); first dosing cycle (C1), second dosing cycle (C2), third dosing cycle (C3), fourth dosing cycle (C4), fifth dosing cycle (C5), sixth dosing cycle (C6), seventh dosing cycle (C7), eighth dosing cycle (C8), ninth dosing cycle (C9) and tenth dosing cycle (C10); first dosing cycle (C1), second dosing cycle (C2), third dosing cycle (C3), 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). ;

[0335] In some examples, the third phase includes administering the bispecific antibody to the subject on day 1 of C1. In other examples, the third phase includes administering the bispecific antibody to the subject on day 1 of C2. In other examples, the third phase includes administering the bispecific antibody to the subject on day 1 of C3. In other examples, the third phase includes administering the bispecific antibody to the subject on day 1 of C4. In other examples, the third phase includes administering the bispecific antibody to the subject on day 1 of C5. In other examples, the third phase includes administering the bispecific antibody to the subject on day 1 of C6. In other examples, the third phase includes administering the bispecific antibody to the subject on day 1 of C7. In other examples, the third phase includes administering the bispecific antibody to the subject on day 1 of C8. In other examples, the third phase includes administering the bispecific antibody to the subject on day 1 of C9. In other examples, the third phase includes administering the bispecific antibody to the subject on day 1 of C10. In other examples, the third phase includes administering the bispecific antibody to the subject on day 1 of C11. In further examples, the third phase comprises administering the bispecific antibody to the subject on day 1 of C12. In further examples, the third phase comprises administering the bispecific antibody to the subject on day 1 of C13.

[0336] In some examples, a target dose of the bispecific antibody is administered to the subject for each administration during the third stage.

[0337] In any of the foregoing examples, the target dose can be between about 10 mg and about 1000 mg (e.g., between about 10 mg and about 70 mg, between about 15 mg and about 65 mg, between about 20 mg and about 60 mg, between about 25 mg and about 55 mg, between about 30 mg and about 50 mg, between about 35 mg and about 45 mg, between about 15 mg and about 225 mg, between about 20 mg and about 220 mg, between about 25 mg and about 215 mg, between about 30 mg and about 210 mg, between about 35 mg and about 205 mg, between about 40 mg and about 200 mg, between about 45 mg and about 195 mg, between about 50 mg and about 190 mg, between about 55 mg and about 190 mg). about 185 mg, about 60 mg to about 180 mg, about 65 mg to about 175 mg, about 70 mg to about 170 mg, about 75 mg to about 165 mg, about 80 mg to about 160 mg, about 85 mg to about 155 mg, about 90 mg to about 150 mg, about 95 mg to about 145 mg, about 100 mg to about 140 mg, about 105 mg to about 135 mg, about 110 mg to about 130 mg, about 115 mg to about 125 mg, about 10 mg to about 50 mg, about 25 mg to about 75 mg, about 50 mg to about 100 mg, about 75 mg to about 125 mg between about 100 mg and about 150 mg, between about 125 mg and about 175 mg, between about 150 mg and about 200 mg, between about 175 mg and about 225 mg, between about 200 mg and about 250 mg, between about 225 mg and about 275 mg, between about 250 mg and about 300 mg, between about 275 mg and about 325 mg, between about 300 mg and about 350 mg, between about 325 mg and about 375 mg, between about 350 mg and about 400 mg, between about 375 mg and about 425 mg, between about 400 mg and about 450 mg, between about 425 mg and about 475 mg, between about 450 mg and about 500 mg, about 475 mg about 525 mg, about 500 mg to about 550 mg, about 525 mg to about 575 mg, about 550 mg to about 600 mg, about 575 mg to about 625 mg, about 600 mg to about 650 mg, about 625 mg to about 675 mg, about 650 mg to about 700 mg, about 675 mg to about 725 mg, about 700 mg to about 750 mg, about 725 mg to about 775 mg, about 750 mg to about 800 mg, about 775 mg to about 825 mg, about 800 mg to about 850 mg, about 825 mg to about 875 mg, about 850 mg to about 900 mg,In some aspects, C1D2 is greater than C1D1 and C1D3 is greater than C1D2.

[0338] In some aspects, the target dose is between about 10 mg and about 200 mg (e.g., between 10 mg and about 170 mg, between about 11 mg and about 165 mg, between about 12 mg and about 160 mg, between about 13 mg and about 155 mg, between about 14 mg and about 150 mg, between about 15 mg and about 145 mg, between about 16 mg and about 140 mg, between about 17 mg and about 135 mg, between about 18 mg and about 130 mg, between about 19 mg and about 125 mg, between about 20 mg and about 120 mg, between about 21 mg and about 115 mg, between about 22 mg and about 110 mg, between about 23 mg and about 105 mg). g, about 24 mg to about 100 mg, about 25 mg to about 95 mg, about 26 mg to about 90 mg, about 27 mg to about 85 mg, about 28 mg to about 80 mg, about 29 mg to about 75 mg, about 30 mg to about 70 mg, about 31 mg to about 65 mg, about 32 mg to about 60 mg, about 33 mg to about 55 mg, about 34 mg to about 50 mg, about 35 mg to about 45 mg, about 40 mg to about 200 mg, about 45 mg to about 195 mg, about 50 mg to about 190 mg, about 55 mg to about 185 mg, about 6 0 mg to about 180 mg, about 65 mg to about 175 mg, about 70 mg to about 170 mg, about 75 mg to about 165 mg, about 80 mg to about 160 mg, about 85 mg to about 155 mg, about 90 mg to about 150 mg, about 95 mg to about 145 mg, about 100 mg to about 140 mg, about 105 mg to about 135 mg, about 110 mg to about 130 mg, about 115 mg to about 125 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about 50 mg or about 190 mg to about 200 mg).

[0339] In some instances, the target dose is about 10 mg. In some instances, the target dose is about 15 mg. In some instances, the target dose is about 20 mg. In some instances, the target dose is about 25 mg. In some instances, the target dose is about 30 mg. In some instances, the target dose is about 35 mg. In some instances, the target dose is about 40 mg. In some instances, the target dose is about 45 mg. In some instances, the target dose is about 50 mg. In some instances, the target dose is about 55 mg. In some instances, the target dose is about 60 mg. In some instances, the target dose is about 65 mg. In some instances, the target dose is about 70 mg. In some instances, the target dose is about 75 mg. In some instances, the target dose is about 80 mg. In some instances, the target dose is about 85 mg. In some instances, the target dose is about 90 mg. In some instances, the target dose is about 95 mg. In some instances, the target dose is about 100 mg. In some instances, the target dose is about 105 mg. In some instances, the target dose is about 110 mg. In some instances, the target dose is about 115 mg. In some instances, the target dose is about 120 mg. In some instances, the target dose is about 125 mg. In some instances, the target dose is about 130 mg. In some instances, the target dose is about 132 mg. In some instances, the target dose is about 135 mg. In some instances, the target dose is about 140 mg. In some instances, the target dose is about 145 mg. In some instances, the target dose is about 150 mg. In some instances, the target dose is about 155 mg. In some instances, the target dose is about 160 mg. In some instances, the target dose is about 165 mg. In some instances, the target dose is about 170 mg. In some instances, the target dose is about 175 mg. In some instances, the target dose is about 180 mg. In some instances, the target dose is about 185 mg. In some instances, the target dose is about 190 mg. In some instances, the target dose is about 195 mg. In some instances, the target dose is about 200 mg. In some aspects, C1D1 is about 210 mg. In some aspects, C1D1 is about 220 mg. In some aspects, C1D1 is about 230 mg. In some aspects, C1D1 is about 240 mg. In some aspects, C1D1 is about 250 mg. In some aspects, C1D1 is about 260 mg. In some aspects, C1D1 is about 270 mg. In some aspects, C1D1 is about 280 mg. In some aspects, C1D1 is about 290 mg. In some aspects, C1D1 is about 300 mg. In some aspects, C1D1 is about 310 mg. In some aspects, C1D1 is about 320 mg. In some aspects, C1D1 is about 330 mg. In some aspects, C1D1 is about 340 mg.In some aspects, C1D1 is about 350 mg. In some aspects, C1D1 is about 360 mg. In some aspects, C1D1 is about 370 mg. In some aspects, C1D1 is about 380 mg. In some aspects, C1D1 is about 390 mg. In some aspects, C1D1 is about 400 mg. In some aspects, C1D1 is about 410 mg. In some aspects, C1D1 is about 420 mg. In some aspects, C1D1 is about 430 mg. In some aspects, C1D1 is about 440 mg. In some aspects, C1D1 is about 450 mg. In some aspects, C1D1 is about 460 mg. In some aspects, C1D1 is about 470 mg. In some aspects, C1D1 is about 480 mg. In some aspects, C1D1 is about 490 mg. In some aspects, C1D1 is about 500 mg. In some aspects, C1D1 is about 510 mg. In some aspects, C1D1 is about 520 mg. In some aspects, C1D1 is about 530 mg. In some aspects, C1D1 is about 540 mg. In some aspects, C1D1 is about 550 mg. In some aspects, C1D1 is about 560 mg. In some aspects, C1D1 is about 570 mg. In some aspects, C1D1 is about 580 mg. In some aspects, C1D1 is about 590 mg. In some aspects, C1D1 is about 600 mg. In some aspects, C1D1 is about 610 mg. In some aspects, C1D1 is about 620 mg. In some aspects, C1D1 is about 630 mg. In some aspects, C1D1 is about 640 mg. In some aspects, C1D1 is about 650 mg. In some aspects, C1D1 is about 660 mg. In some aspects, C1D1 is about 670 mg. In some aspects, C1D1 is about 680 mg. In some aspects, C1D1 is about 690 mg. In some aspects, C1D1 is about 700 mg. In some aspects, C1D1 is about 710 mg. In some aspects, C1D1 is about 720 mg. In some aspects, C1D1 is about 730 mg. In some aspects, C1D1 is about 740 mg. In some aspects, C1D1 is about 750 mg. In some aspects, C1D1 is about 760 mg. In some aspects, C1D1 is about 770 mg. In some aspects, C1D1 is about 780 mg. In some aspects, C1D1 is about 790 mg. In some aspects, C1D1 is about 800 mg. In some aspects, C1D1 is about 810 mg. In some aspects, C1D1 is about 820 mg. In some aspects, C1D1 is about 830 mg. In some aspects, C1D1 is about 840 mg. In some aspects, C1D1 is about 850 mg. In some aspects, C1D1 is about 860 mg. In some aspects, C1D1 is about 870 mg. In some aspects, C1D1 is about 880 mg. In some aspects, C1D1 is about 890 mg.In some aspects, C1D1 is about 900 mg. In some aspects, C1D1 is about 910 mg. In some aspects, C1D1 is about 920 mg. In some aspects, C1D1 is about 930 mg. In some aspects, C1D1 is about 940 mg. In some aspects, C1D1 is about 950 mg. In some aspects, C1D1 is about 960 mg. In some aspects, C1D1 is about 970 mg. In some aspects, C1D1 is about 980 mg. In some aspects, C1D1 is about 990 mg. In some aspects, C1D1 is about 1000 mg.

[0340] In some instances, the target dose is 10 mg. In some instances, the target dose is 15 mg. In some instances, the target dose is 20 mg. In some instances, the target dose is 25 mg. In some instances, the target dose is 30 mg. In some instances, the target dose is 35 mg. In some instances, the target dose is 40 mg. In some instances, the target dose is 45 mg. In some instances, the target dose is 50 mg. In some instances, the target dose is 55 mg. In some instances, the target dose is 60 mg. In some instances, the target dose is 65 mg. In some instances, the target dose is 70 mg. In some instances, the target dose is 75 mg. In some instances, the target dose is 80 mg. In some instances, the target dose is 85 mg. In some instances, the target dose is 90 mg. In some instances, the target dose is 95 mg. In some instances, the target dose is 100 mg. In some instances, the target dose is 105 mg. In some instances, the target dose is 110 mg. In some instances, the target dose is 115 mg. In some instances, the target dose is 120 mg. In some instances, the target dose is 125 mg. In some instances, the target dose is 130 mg. In some instances, the target dose is 132 mg. In some instances, the target dose is 135 mg. In some instances, the target dose is 140 mg. In some instances, the target dose is 145 mg. In some instances, the target dose is 150 mg. In some instances, the target dose is 155 mg. In some instances, the target dose is 160 mg. In some instances, the target dose is 165 mg. In some instances, the target dose is 170 mg. In some instances, the target dose is 175 mg. In some instances, the target dose is 180 mg. In some instances, the target dose is 185 mg. In some instances, the target dose is 190 mg. In some instances, the target dose is 195 mg. In some instances, the target dose is 200 mg. In some aspects, C1D1 is 210 mg. In some aspects, C1D1 is 220 mg. In some aspects, C1D1 is 230 mg. In some aspects, C1D1 is 240 mg. In some aspects, C1D1 is 250 mg. In some aspects, C1D1 is 260 mg. In some aspects, C1D1 is 270 mg. In some aspects, C1D1 is 280 mg. In some aspects, C1D1 is 290 mg. In some aspects, C1D1 is 300 mg. In some aspects, C1D1 is 310 mg. In some aspects, C1D1 is 320 mg. In some aspects, C1D1 is 330 mg. In some aspects, C1D1 is 340 mg. In some aspects, C1D1 is 350 mg. In some aspects, C1D1 is 360 mg. In some aspects, C1D1 is 370 mg.In some aspects, C1D1 is 380 mg. In some aspects, C1D1 is 390 mg. In some aspects, C1D1 is 400 mg. In some aspects, C1D1 is 410 mg. In some aspects, C1D1 is 420 mg. In some aspects, C1D1 is 430 mg. In some aspects, C1D1 is 440 mg. In some aspects, C1D1 is 450 mg. In some aspects, C1D1 is 460 mg. In some aspects, C1D1 is 470 mg. In some aspects, C1D1 is 480 mg. In some aspects, C1D1 is 490 mg. In some aspects, C1D1 is 500 mg. In some aspects, C1D1 is 510 mg. In some aspects, C1D1 is 520 mg. In some aspects, C1D1 is 530 mg. In some aspects, C1D1 is 540 mg. In some aspects, C1D1 is 550 mg. In some aspects, C1D1 is 560 mg. In some aspects, C1D1 is 570 mg. In some aspects, C1D1 is 580 mg. In some aspects, C1D1 is 590 mg. In some aspects, C1D1 is 600 mg. In some aspects, C1D1 is 610 mg. In some aspects, C1D1 is 620 mg. In some aspects, C1D1 is 630 mg. In some aspects, C1D1 is 640 mg. In some aspects, C1D1 is 650 mg. In some aspects, C1D1 is 660 mg. In some aspects, C1D1 is 670 mg. In some aspects, C1D1 is 680 mg. In some aspects, C1D1 is 690 mg. In some aspects, C1D1 is 700 mg. In some aspects, C1D1 is 710 mg. In some aspects, C1D1 is 720 mg. In some aspects, C1D1 is 730 mg. In some aspects, C1D1 is 740 mg. In some aspects, C1D1 is 750 mg. In some aspects, C1D1 is 760 mg. In some aspects, C1D1 is 770 mg. In some aspects, C1D1 is 780 mg. In some aspects, C1D1 is 790 mg. In some aspects, C1D1 is 800 mg. In some aspects, C1D1 is 810 mg. In some aspects, C1D1 is 820 mg. In some aspects, C1D1 is 830 mg. In some aspects, C1D1 is 840 mg. In some aspects, C1D1 is 850 mg. In some aspects, C1D1 is 860 mg. In some aspects, C1D1 is 870 mg. In some aspects, C1D1 is 880 mg. In some aspects, C1D1 is 890 mg. In some aspects, C1D1 is 900 mg. In some aspects, C1D1 is 910 mg. In some aspects, C1D1 is 920 mg. In some aspects, C1D1 is 930 mg. In some aspects, C1D1 is 940 mg. In some aspects, C1D1 is 950 mg.In some aspects, C1D1 is 960 mg. In some aspects, C1D1 is 970 mg. In some aspects, C1D1 is 980 mg. In some aspects, C1D1 is 990 mg. In some aspects, C1D1 is 1000 mg. In any of the foregoing examples, each dose of the bispecific anti-FcRH5 / anti-CD3 antibody can be administered subcutaneously. However, it is also contemplated that a subset of doses can be administered using alternative routes of administration (e.g., intravenous).

[0341] C. Combination therapy

[0342] 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 co-administered with one or more additional therapeutic agents described herein.

[0343] i. Anti-CD38 Antibody

[0344] In some cases, a 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 a subject by any suitable route of administration (e.g., intravenous (IV) or subcutaneous (SC)). In some aspects, the anti-CD38 antibody is daratumumab (e.g., daratumumab / rHuPH20). The bispecific anti-FcRH5 / anti-CD3 antibody can be administered to a subject in an amount 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,...

Claims

1. A method for treating a subject with multiple myeloma (MM), the method comprising subcutaneously 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, which comprises one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the subject weekly (QW); (ii) a second phase, which comprises one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the subject every two weeks (Q2W); and (iii) a third phase, which comprises one or more dosing cycles, wherein the third phase comprises administering the bispecific antibody to the subject every four weeks (Q4W).

2. The method according to claim 1, wherein each dosing cycle is a 28-day dosing cycle.

3. The method according to claim 2, wherein the first phase comprises a first administration cycle (C1).

4. The method of claim 2, wherein the first stage consists of C1. 5 . The method according to claim 3 , wherein the first phase comprises administering the bispecific antibody to the subject on day 1 , day 8 and day 15 of the C1.

6. The method according to any one of claims 1 to 5, wherein a target dose of the bispecific antibody is administered to the subject for each administration during the first stage.

7. The method according to any one of claims 1 to 5, wherein the first phase comprises administering to the subject a first step-escalating dose of the bispecific antibody.

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

9. The method of claim 8, wherein the target dose is administered to the subject on Day 8 and Day 15 of the C1.

10. The method of claim 9, wherein the first step-escalation dose is 1% to 30% of the target dose. The method of claim 10 , wherein the first step-escalation dose is 5% to 25% of the target dose. 12 . The method of claim 11 , wherein the first step-escalation dose is 5% of the target dose or 25% of the target dose.

13. The method according to any one of claims 7 to 12, wherein the first stepped increasing dose is 2 mg or 10 mg.

14. The method according to any one of claims 1 to 5, wherein the first phase comprises administering to the subject a first step-escalating dose and a second step-escalating dose of the bispecific antibody. 15 . The method of claim 14 , wherein the first step-escalating dose is administered to the subject on day 1 of the C1 and the second step-escalating dose is administered to the subject on day 8 of the C1.

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

17. A method according to any one of claims 14 to 16, wherein: (a) the first step-increase dose is 1% to 10% of the target dose; and (b) the second step-escalating dose is 15% to 45% of the target dose.

18. A method according to any one of claims 14 to 17, wherein: (a) the first step-increase dose is 5% of the target dose; and (b) the second step-escalating dose is 25% of the target dose.

19. The method of any one of claims 14 to 18, wherein the first stepped increasing dose is 2 mg and the second stepped increasing dose is 10 mg.

20. The method of any one of claims 3 to 19, wherein the bispecific antibody is not administered to the subject on day 22 of C1.

21. The method of claim 20, wherein the bispecific antibody is administered to the subject a total of three times during the C1 period.

22. The method of any one of claims 3 to 19, wherein the bispecific antibody is administered to the subject on day 22 of C1.

23. The method of any one of claims 2 to 22, wherein the second phase comprises at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, or at least five dosing cycles.

24. The method according to claim 23, wherein the second phase comprises a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4) and a fifth dosing cycle (C5).

25. The method of claim 23, wherein the second stage consists of C1, C2, C3, C4 and C5.

26. The method of claim 24 or 25, wherein the second phase comprises administering the bispecific antibody to the subject on day 1 and day 15 of C1, C2, C3, C4 and / or C5.

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

28. The method of any one of claims 2 to 27, wherein the third phase comprises at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, at least five dosing cycles, at least six dosing cycles, or at least seven dosing cycles.

29. The method of claim 28, wherein the third phase comprises a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6) and a seventh dosing cycle (C7).

30. The method of claim 28, wherein the third stage consists of C1, C2, C3, C4, C5, C6 and C7.

31. The method of claim 29 or 30, wherein the third phase comprises administering the bispecific antibody to the subject on day 1 of C1, C2, C3, C4, C5, C6 and / or C7.

32. The method according to any one of claims 29 to 31, wherein a target dose of the bispecific antibody is administered to the subject for each administration during the third phase.

33. The method according to any one of claims 1 to 32, further comprising a fourth phase comprising one or more dosing cycles.

34. The method of claim 33, wherein the fourth phase comprises subcutaneously administering the bispecific antibody to the subject every week (QW), every two weeks (Q2W), every three weeks (Q3W), or every four weeks (Q4W).

35. The method of claim 33 or 34, wherein a target dose of the bispecific antibody is administered to the subject for each administration during the fourth stage.

36. The method according to any one of claims 33 to 35, wherein the fourth stage comprises administering the bispecific antibody to the subject until disease progression.

37. The method of any one of claims 6, 9 to 13, 16 to 22, 27, 32, 35, and 36, wherein the target dose is 40 mg.

38. The method of any one of claims 1 to 37, wherein the bispecific antibody is administered to the subject as a monotherapy.

39. A method of treating a subject having MM, the method comprising subcutaneously administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising: (i) a first dose of the bispecific antibody between 0.1 mg and 10 mg; (ii) a second dose of the bispecific antibody between 1 mg and 50 mg; as well as (iii) a third dose of the bispecific antibody between 10 mg and 200 mg.

40. The method of claim 39, wherein: (i) the first dose of the bispecific antibody is between 1 mg and 3 mg; (ii) the second dose of the bispecific antibody is between 8 mg and 12 mg; and (iii) the third dose of the bispecific antibody is between 35 mg and 45 mg.

41. The method of claim 39 or 40, wherein: (i) the first dose of the bispecific antibody is 2 mg; (ii) the second dose of the bispecific antibody is 10 mg; and (iii) the third dose of the bispecific antibody is 40 mg.

42. The method of claim 39, wherein: (i) the first dose of the bispecific antibody is 2 mg; (ii) the second dose of the bispecific antibody is 10 mg; and (iii) the third dose of the bispecific antibody is 120 mg.

43. The method of any one of claims 1 to 42, wherein the bispecific antibody is administered to subcutaneous tissue of the abdomen.

44. The method of claim 43, wherein the abdomen of the subject comprises four quadrants and the bispecific antibody is administered to one of the four quadrants.

45. The method of claim 44, wherein each sequential dose of the bispecific antibody is administered to a different member of the four quadrants in a rotating manner.

46. ​​The method of any one of claims 1 to 42, wherein the bispecific antibody is administered to the thigh of the subject.

47. The method of any one of claims 1 to 46, wherein the bispecific antibody is administered subcutaneously by injection or by infusion.

48. The method of claim 47, wherein the bispecific antibody is administered subcutaneously by injection.

49. The method of claim 48, wherein the bispecific antibody is administered at an injection rate of about 0.25 mL / min to about 4 mL / min.

50. The method of claim 49, wherein the bispecific antibody is administered at an injection rate of about 1 mL / min.

51. The method of any one of claims 1 to 50, wherein the bispecific antibody is administered by syringe.

52. The method of claim 51, wherein the syringe is a prefilled syringe.

53. The method of any one of claims 1 to 50, wherein the bispecific antibody is administered by a pump.

54. The method of claim 53, wherein the pump comprises a patch pump, a syringe pump, or an infusion pump.

55. The method of claim 53 or 54, wherein the pump is a wearable pump.

56. The method of any one of claims 1 to 55, wherein the bispecific antibody comprises an anti-CD79b5 arm comprising a first binding domain comprising the following six hypervariable regions (HVRs): (a) HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) HVR-H3 comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO: 3); (d) HVR-L1 comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO:5); and (f) HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6).

57. The method of any one of claims 1 to 56, wherein the bispecific antibody comprises an anti-FcRH5 arm, the anti-FcRH5 arm comprising a first binding domain, the first binding domain comprising: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:8; or (c) a VH domain as in (a) and a VL domain as in (b).

58. The method of claim 57, 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.

59. The method of any one of claims 1 to 58, wherein the bispecific antibody comprises an anti-CD3 arm comprising a second binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

60. The method of any one of claim 59, wherein the bispecific antibody comprises an anti-CD3 arm, the anti-CD3 arm comprising a second binding domain, the second binding domain comprising: (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 16; or (c) a VH domain as in (a) and a VL domain as in (b).

61. The method of claim 60, 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.

62. The method of any one of claims 1 to 61, wherein the bispecific antibody comprises: an anti-FcRH5 arm comprising a heavy chain polypeptide (H1) and a light chain polypeptide (L1); and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2); and wherein: (a) H1 of the anti-FcRH5 arm comprises the amino acid sequence of SEQ ID NO: 35; (b) L1 of the anti-FcRH5 arm comprises the amino acid sequence of SEQ ID NO: 36; (c) H2 of the anti-CD3 arm comprises the amino acid sequence of SEQ ID NO: 37; and (d) L2 of the anti-CD3 arm comprises the amino acid sequence of SEQ ID NO:

38.

63. The method of any one of claims 1 to 62, wherein the bispecific antibody comprises an aglycosylation site mutation.

64. The method of claim 63, wherein the aglycosylation site mutation reduces the effector function of the bispecific antibody.

65. The method of claim 64, wherein the aglycosylation site mutation is a substitution mutation.

66. The method of claim 65, wherein the bispecific antibody comprises a substitution mutation in the Fc region that reduces effector function.

67. The method of any one of claims 1 to 66, wherein the bispecific antibody is a monoclonal antibody.

68. The method of any one of claims 1 to 67, wherein the bispecific antibody is a humanized antibody.

69. The method of any one of claims 1 to 67, wherein the bispecific antibody is a chimeric antibody.

70. The method of any one of claims 1 to 69, wherein the bispecific antibody is an antibody fragment that binds FcRH5 and CD3.

71. The method of claim 70, wherein the antibody fragment is selected from the group consisting of a Fab fragment, a Fab'-SH fragment, a Fv fragment, a scFv fragment, and a (Fab')2 fragment.

72. The method of any one of claims 1 to 69, wherein the bispecific antibody is a full-length antibody.

73. The method of any one of claims 1 to 69 and 72, wherein the bispecific antibody is an IgG antibody.

74. The method of claim 73, wherein the IgG antibody is an IgG1 antibody.

75. The method of any one of claims 1 to 74, wherein the bispecific antibody comprises one or more heavy chain constant domains, wherein 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.

76. The method of claim 75, wherein at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

77. The method of claim 76, wherein the CH31 domain and the CH32 domain each comprise a protrusion or a cavity, and wherein the protrusion or the cavity in the CH31 domain is positionable in the cavity or the protrusion in the CH32 domain, respectively.

78. The method of claim 77, wherein the CH31 domain and the CH32 domain meet at the interface between the protrusion and the cavity.

79. The method according to any one of claims 75 to 78, wherein the CH21 domain and the CH22 domain each comprise a protrusion or a cavity, and wherein the protrusion or the cavity in the CH21 domain is positionable in the cavity or the protrusion in the CH22 domain, respectively.

80. The method of claim 79, wherein the CH21 domain and the CH22 domain meet at an interface between the protrusion and the cavity.

81. The method of claim 80, wherein the anti-FcRH5 arm comprises the protrusion and the anti-CD3 arm comprises the cavity.

82. The method of claim 81, wherein the CH3 domain of the anti-FcRH5 arm comprises a protrusion comprising a T366W amino acid substitution mutation (EU numbering), and the CH3 domain of the anti-CD3 arm comprises a cavity comprising T366S, L368A and Y407V amino acid substitution mutations (EU numbering).

83. The method of any one of claims 1 to 68 and 72 to 82, wherein the bispecific antibody is cevostamab.

84. The method of any one of claims 1 to 83, wherein the bispecific antibody is administered to the subject simultaneously with one or more additional therapeutic agents.

85. The method of any one of claims 1 to 83, wherein the bispecific antibody is administered to the subject prior to administration of one or more additional therapeutic agents.

86. The method of any one of claims 1 to 83, wherein the bispecific antibody is administered to the subject after administration of one or more additional therapeutic agents.

87. The method of any one of claims 84 to 86, wherein the one or more additional therapeutic agents comprises an effective amount of tocilizumab.

88. The method of any one of claims 1 to 87, wherein the subject develops a cytokine release syndrome (CRS) event, and the method further comprises treating a symptom of the CRS event while suspending treatment with the bispecific antibody.

89. The method of claim 88, wherein the method further comprises administering to the subject an effective amount of tocilizumab to treat the CRS event.

90. The method of claim 89, wherein tocilizumab is administered to the subject by intravenous infusion.

91. The method of claim 89 or 90, wherein: (a) the subject weighs ≥30 kg, and tocilizumab is administered to the subject at a dose of 8 mg / kg; (b) the subject weighs <30 kg and tocilizumab is administered to the subject at a dose of 12 mg / kg; or (c) the final dose of tocilizumab administered to the subject does not exceed 800 mg.

92. The method of any one of claims 88 to 91, wherein the CRS event does not resolve or worsens within 8 hours of treating the symptoms of the CRS event, and the method further comprises administering one or more additional doses of tocilizumab to the subject to manage the CRS event.

93. The method of any one of claims 84 to 92, wherein the one or more additional therapeutic agents comprises an effective amount of a corticosteroid.

94. The method of claim 93, wherein the corticosteroid is administered intravenously to the subject.

95. The method of claim 93 or 94, wherein the corticosteroid is methylprednisolone.

96. The method of claim 95, wherein methylprednisolone is administered at a dose of 80 mg.

97. The method of claim 93 or 94, wherein the corticosteroid is dexamethasone.

98. The method of claim 97, wherein dexamethasone is administered at a dose of 20 mg.

99. The method of any one of claims 93 to 98, wherein the corticosteroid is administered to the subject 45 minutes to 75 minutes prior to administration of the bispecific antibody.

100. The method of claim 99, wherein the corticosteroid is administered to the subject 60 minutes prior to administering the bispecific antibody to the subject.

101. The method of claim 99 or 100, wherein the corticosteroid is administered to the subject prior to administering the bispecific antibody if the subject experienced CRS when the subject was previously administered the bispecific antibody.

102. The method of any one of claims 84 to 101, wherein the one or more additional therapeutic agents comprises an effective amount of acetaminophen or paracetamol.

103. The method of claim 102, wherein acetaminophen or paracetamol is administered in a dose of between 500 mg and 1000 mg.

104. The method of claim 103, wherein acetaminophen or paracetamol is orally administered to the subject.

105. The method of any one of claims 102 to 104, wherein acetaminophen or paracetamol is administered to the subject prior to administering the bispecific antibody to the subject.

106. The method of any one of claims 84 to 105, wherein the one or more additional therapeutic agents comprises an effective amount of diphenhydramine.

107. The method of claim 106, wherein diphenhydramine is administered at a dose of between 25 mg and 50 mg.

108. The method of claim 107, wherein diphenhydramine is administered orally to the subject.

109. The method of any one of claims 106 to 108, wherein diphenhydramine is administered to the subject prior to administering the bispecific antibody to the subject.

110. The method of any one of claims 84 to 109, wherein the one or more additional therapeutic agents comprises an effective amount of an immunomodulatory agent (IMiD), a cluster of differentiation 38 (CD38)-directed therapy, or a B-cell maturation antigen (BCMA)-directed therapy.

111. The method of claim 110, wherein the IMiD is pomalidomide.

112. The method of claim 110, wherein the CD38-directed therapy is an anti-CD38 antibody.

113. The method of claim 112, wherein the anti-CD38 antibody is daratumumab, MOR202, or isatuximab.

114. The method of claim 113, wherein the anti-CD38 antibody is daratumumab.

115. The method of claim 110, wherein the BCMA-directed therapy is an antibody-drug conjugate targeting BCMA.

116. The method according to any one of claims 1 to 115, wherein the MM is relapsed or refractory (R / R) MM.

117. The method of claim 116, wherein the subject: has been diagnosed with R / R MM for whom no established therapy for MM is appropriate and available; or Intolerance to established therapy.

118. The method of any one of claims 1 to 117, wherein the subject has a measurable disease defined as at least one of: (i) serum M protein ≥ 0.5 g / dL; (ii) Urine M-protein ≥ 200 mg / 24 h; or (iii) Serum free light chain (SFLC) assay: involved SFLC ≥ 10 mg / dL, and abnormal SFLC ratio (<0.26 or >1.65).

119. A method of treating a subject with R / R MM, the method comprising subcutaneously administering silvostomumab to the subject at a dosing regimen comprising: (i) a first phase, comprising a first dosing cycle (C1), wherein the C1 is a 28-day dosing cycle, wherein the first phase comprises administering the sivostomumab to the subject at a first step-escalating dose on day 1 of the C1, at a second step-escalating dose on day 8 of the C1, and at a target dose on day 15 of the C1, and wherein the first step-escalating dose is 2 mg, the second step-escalating dose is 10 mg, and the target dose is 40 mg; (ii) a second phase, which includes a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4) and a fifth dosing cycle (C5), wherein each dosing cycle of the second phase is a 28-day dosing cycle, and wherein the second phase includes administering the sivosetumab to the subject at a target dose of 40 mg on Day 1 and Day 15 of C1, C2, C3, C4 and C5; as well as (iii) a third phase, which includes a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6) and a seventh dosing cycle (C7), wherein each dosing cycle of the third phase is a 28-day dosing cycle, and wherein the third phase includes administering the sivostatin at a target dose of 40 mg on day 1 of C1, C2, C3, C4, C5, C6 and C7.

120. A subcutaneous administration device comprising a bispecific antibody that binds to FcRH5 and CD3, wherein the subcutaneous administration device comprises: (i) a first dose of the bispecific antibody between 0.5 mg and 8 mg; (ii) a second dose of the bispecific antibody between 2 mg and 40 mg; and / or (iii) a third dose of the bispecific antibody between 10 mg and 160 mg.

121. The subcutaneous administration device of claim 120, wherein: (i) the first dose of the bispecific antibody is between 1 mg and 3 mg; (ii) the second dose of the bispecific antibody is between 8 mg and 12 mg; and / or (iii) the third dose of the bispecific antibody is between 35 mg and 45 mg.

122. The subcutaneous administration device of claim 120 or 121, wherein: (i) the first dose of the bispecific antibody is 2 mg; (ii) the second dose of the bispecific antibody is 10 mg; and / or (iii) the third dose of the bispecific antibody is 40 mg.

123. The subcutaneous administration device according to any one of claims 120 to 122, which is a syringe.

124. The subcutaneous administration device of claim 123, wherein the syringe is a prefilled syringe.

125. The subcutaneous administration device of any one of claims 120 to 122, which is a pump.

126. The subcutaneous administration device of claim 125, wherein the pump comprises a patch pump, a syringe pump, or an infusion pump.

127. A subcutaneous administration device according to claim 125 or 126, wherein the pump is a wearable pump.

128. The subcutaneous administration device according to any one of claims 120 to 127, for use in the treatment of MM.

129. The subcutaneous administration device according to claim 128, wherein the MM is a R / R MM.

130. A bispecific antibody that binds to FcRH5 and CD3 for use in the treatment of a subject suffering from MM, wherein the treatment comprises subcutaneously administering the bispecific antibody to the subject in a dosing regimen comprising: (i) a first phase, which comprises one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the subject weekly (QW); (ii) a second phase, which comprises one or more dosing cycles, wherein the second phase comprises administering the bispecific antibody to the subject every two weeks (Q2W); and (iii) a third phase, which comprises one or more dosing cycles, wherein the third phase comprises administering the bispecific antibody to the subject every four weeks (Q4W).

131. A bispecific antibody that binds to FcRH5 and CD3 for use in the treatment of a subject suffering from MM, wherein the treatment comprises subcutaneously administering the bispecific antibody to the subject in a dosing regimen comprising: (i) a first dose of the bispecific antibody between 0.5 mg and 8 mg; (ii) a second dose of the bispecific antibody between 2 mg and 40 mg; as well as (iii) a third dose of the bispecific antibody between 10 mg and 160 mg.

132. Use of silvosetumab for the treatment of a subject with R / R MM, wherein the treatment comprises subcutaneously administering silvosetumab to the subject in a dosing regimen comprising: (i) a first phase, comprising a first dosing cycle (C1), wherein the C1 is a 28-day dosing cycle, wherein the first phase comprises administering the sivostomumab to the subject at a first step-escalating dose on day 1 of the C1, at a second step-escalating dose on day 8 of the C1, and at a target dose on day 15 of the C1, and wherein the first step-escalating dose is 2 mg, the second step-escalating dose is 10 mg, and the target dose is 40 mg; (ii) a second phase, which includes a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4) and a fifth dosing cycle (C5), wherein each dosing cycle of the second phase is a 28-day dosing cycle, and wherein the second phase includes administering the sivosetumab to the subject at a target dose of 40 mg on Day 1 and Day 15 of C1, C2, C3, C4 and C5; as well as (iii) a third phase, which includes a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6) and a seventh dosing cycle (C7), wherein each dosing cycle of the third phase is a 28-day dosing cycle, and wherein the third phase includes administering the sivostatin at a target dose of 40 mg on day 1 of C1, C2, C3, C4, C5, C6 and C7.

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