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

Abstract

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

Description

Technical Field

[0001] Sequence Listing This application includes a Sequence Listing submitted electronically in ASCII format, the entire content of which is incorporated herein by reference. The name of the above ASCII copy created on May 9, 2022 is 50474-278WO1_Sequence_Listing_5_9_22_ST25, and the size is 33,561 bytes.

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

Background Art

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

[0004] Blood cancer is, in particular, the second leading cause of cancer-related death. Blood cancers include multiple myeloma (MM), a neoplasm characterized by the proliferation and accumulation of malignant plasma cells. Approximately 160,000 people are diagnosed with MM worldwide each year. MM remains incurable despite advances in treatment and has a median estimated survival of 8 - 10 years in standard-risk myeloma and 2 - 3 years in high-risk disease, even after autologous stem cell transplantation. Despite a significant improvement in patient survival over the past 20 years, only 10 - 15% of patients achieve or exceed the expected survival compared to the general population. The introduction of proteasome inhibitors, immunomodulatory drugs (IMiDs), and monoclonal antibodies has achieved an increase in survival. Nevertheless, most patients (if not all) ultimately relapse and become refractory, and the outcome of MM patients after relapse or after they can no longer receive proteasome inhibitors or IMiDs is very poor, with a survival of less than 1 year.

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

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

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

[0008] In some aspects, each dosing cycle is a 28-day dosing cycle.

[0009] In some aspects, the first phase comprises a first dosing cycle (C1).

[0010] In some aspects, the first phase consists of C1.

[0011] In some aspects, the first phase comprises administration of the bispecific antibody to the subject on days 1, 8, and 15 of C1.

[0012] In some aspects, the target dose of the bispecific antibody is administered to the subject for each administration during the first phase.

[0013] In some aspects, the first phase comprises administration of a first step-up dose of the bispecific antibody to the subject.

[0014] In some aspects, the first step-up dose is administered to the subject on day 1 of C1.

[0015] In some aspects, the target dose is administered to the subject on days 8 and 15 of C1.

[0016] In some embodiments, the first step-up dose is about 1% to 30% of the target dose.

[0017] In some embodiments, the first step-up dose is about 5% to 25% of the target dose.

[0018] In some embodiments, the first step-up dose is 5% of the target dose.

[0019] In some embodiments, the first step-up dose is 25% of the target dose.

[0020] In some embodiments, the first step-up dose is 2 mg.

[0021] In some embodiments, the first step-up dose is 10 mg.

[0022] In some embodiments, the first phase includes administration of the bispecific antibody of the first step-up dose and the second step-up dose to the subject.

[0023] In some embodiments, the first step-up dose is administered to the subject on day 1 of C1, and the second step-up dose is administered to the subject on day 8 of C1.

[0024] In some embodiments, the target dose is administered to the subject on day 15 of C1.

[0025] In some embodiments, (i) the first step-up dose is 1% to 10% of the target dose, and (ii) the second step-up dose is 15% to 45% of the target dose.

[0026] In some embodiments, (i) the first step-up dose is 5% of the target dose, and (ii) the second step-up dose is 25% of the target dose.

[0027] In some embodiments, the first step-up dose is 2 mg and the second step-up dose is 10 mg.

[0028] In some embodiments, the bispecific antibody is not administered to the subject on day 22 of C1.

[0029] In some embodiments, the bispecific antibody is administered to the subject a total of 3 times during C1.

[0030] In some embodiments, the bispecific antibody is administered to the subject on day 22 of C1.

[0031] In some embodiments, the second phase includes at least 2 dosing cycles, at least 3 dosing cycles, at least 4 dosing cycles, or at least 5 dosing cycles.

[0032] In some embodiments, 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).

[0033] In some embodiments, the second phase consists of C1, C2, C3, C4, and C5.

[0034] In some embodiments, the second phase includes administration of the bispecific antibody to the subject on days 1 and 15 of C1, C2, C3, C4 and / or C5.

[0035] In some embodiments, the target dose of the bispecific antibody is administered to the subject for each administration during the second phase.

[0036] In some embodiments, the third phase includes at least 2 dosing cycles, at least 3 dosing cycles, at least 4 dosing cycles, at least 5 dosing cycles, at least 6 dosing cycles, or at least 7 dosing cycles.

[0037] In some embodiments, 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).

[0038] In some embodiments, the third phase consists of C1, C2, C3, C4, C5, C6, and C7.

[0039] In some embodiments, the third phase includes administration of the bispecific antibody to the subject on day 1 of C1, C2, C3, C4, C5, C6, and / or C7.

[0040] In some embodiments, the target dose of the bispecific antibody is administered to the subject for each administration during the third phase.

[0041] In some embodiments, the dosing regimen further includes a fourth phase that includes one or more dosing cycles.

[0042] In some embodiments, the fourth phase includes subcutaneous administration of the bispecific antibody to the subject weekly (QW), every two weeks (Q2W), every three weeks (Q3W), or every four weeks (Q4W).

[0043] In some embodiments, the target dose of the bispecific antibody is administered to the subject for each administration during the fourth phase.

[0044] In some embodiments, the fourth phase includes administering the bispecific antibody to the subject until the disease progresses.

[0045] In some embodiments, the target dose is 40 mg.

[0046] In some embodiments, the target dose is 120 mg.

[0047] In some embodiments, the bispecific antibody is administered to a subject as a single agent therapy.

[0048] In another aspect, the present 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 in an administration regimen comprising: (i) a first dose of 0.1 mg to 10 mg of the bispecific antibody; (ii) a second dose of 1 mg to 50 mg of the bispecific antibody; and (iii) a third dose of 10 mg to 200 mg of the bispecific antibody.

[0049] In some embodiments, (i) the first dose of the bispecific antibody is 1 mg to 3 mg; (ii) the second dose of the bispecific antibody is 8 mg to 12 mg; and (iii) the third dose of the bispecific antibody is 35 mg to 45 mg.

[0050] In some embodiments, (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.

[0051] In some embodiments, (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.

[0052] In some embodiments, the bispecific antibody is administered to the subcutaneous tissue of the abdomen.

[0053] In some embodiments, the subject's abdomen comprises four quadrants and the bispecific antibody is administered to one of the four quadrants.

[0054] In some embodiments, each successive dose of the bispecific antibody is administered to a different portion of the four quadrants on a rotation basis.

[0055] In some embodiments, the bispecific antibody is administered to the thigh of the subject.

[0056] In some embodiments, the bispecific antibody is administered subcutaneously by injection or infusion.

[0057] In some embodiments, the bispecific antibody is administered subcutaneously by injection.

[0058] In some embodiments, the bispecific antibody is administered at an injection rate of from about 0.25 mL / min to about 4 mL / min.

[0059] In some embodiments, the bispecific antibody is administered at an injection rate of about 1 mL / min.

[0060] In some embodiments, the bispecific antibody is administered by syringe.

[0061] In some embodiments, the syringe is a prefilled syringe.

[0062] In some embodiments, the bispecific antibody is administered by pump.

[0063] In some embodiments, the pump includes a patch pump, a syringe pump, or an infusion pump.

[0064] In some embodiments, the pump is a wearable pump.

[0065] In some embodiments, 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).

[0066] In some embodiments, the bispecific antibody comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8; or (c) an anti-FcRH5 arm comprising a first binding domain comprising the VH domain described in (a) and the VL domain described in (b).

[0067] In some embodiments, the first binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO:7 and a VL domain comprising the amino acid sequence of SEQ ID NO:8.

[0068] In some embodiments, the bispecific antibody comprises an anti-CD3 arm having a second binding domain comprising the following six HVRs: (i) HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (ii) HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (iii) HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11); (iv) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (v) HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (vi) HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

[0069] In some embodiments, the bispecific antibody comprises an anti-CD3 arm comprising: (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16; or (c) a second binding domain comprising the VH domain described in (a) and the VL domain described in (b).

[0070] In some embodiments, the second binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO:15 and a VL domain comprising the amino acid sequence of SEQ ID NO:16.

[0071] In some embodiments, the bispecific antibody comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1) and a light chain polypeptide (L1), and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), wherein (i) H1 comprises the amino acid sequence of SEQ ID NO: 35, (ii) L1 comprises the amino acid sequence of SEQ ID NO: 36, (iii) H2 comprises the amino acid sequence of SEQ ID NO: 37, and (iv) L2 comprises the amino acid sequence of SEQ ID NO: 38.

[0072] In some aspects, the bispecific antibody comprises an aglycosylation site mutation.

[0073] In some aspects, the aglycosylation site mutation reduces the effector function of the bispecific antibody.

[0074] In some embodiments, the aglycosylation site mutation is a substitution mutation.

[0075] In some embodiments, the bispecific antibody comprises substitution mutations in the Fc region that reduce effector function.

[0076] In some embodiments, the bispecific antibody is a monoclonal antibody.

[0077] In some embodiments, the bispecific antibody is a humanized antibody.

[0078] In some embodiments, the bispecific antibody is a chimeric antibody.

[0079] In some embodiments, the bispecific antibody is an antibody fragment that binds FcRH5 and CD3.

[0080] In some embodiments, antibody fragments include Fab, Fab'-SH, Fv, scFv, and (Fab') 2 The fragment is selected from the group consisting of:

[0081] In some embodiments, the bispecific antibody is a full-length antibody.

[0082] In some embodiments, the bispecific antibody is an IgG antibody.

[0083] In some embodiments, the IgG antibody is 1 It is an antibody.

[0084] In some embodiments, the bispecific antibody comprises one or more heavy chain constant domains, the one or more heavy chain constant domains comprising a first CH1 (CH1 1 ) domain, the first CH2 (CH2 1 ) domain, the first CH3 (CH3 1 ) domain, the second CH1 (CH1 2 ) domain, the second CH2 (CH2 2 ) domain, and the second CH3 (CH3 2 ) domain.

[0085] In some embodiments, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

[0086] In some embodiments, CH3 1 Domain and CH3 2 Each domain contains a protuberance or a cavity, and a CH3 1 The domain projection or cavity is CH3 2 They can be located in cavities or protrusions of the domain, respectively.

[0087] In some embodiments, CH3 1 Domain and CH3 2 The domains meet at the interface between the projections and the cavities.

[0088] In some embodiments, CH2 1 Domain and CH2 2 Each domain contains a protuberance or a cavity, and a CH2 1 The protrusion or cavity of the domain is CH2 2They can be located in cavities or protrusions of the domain, respectively.

[0089] In other embodiments, CH2 1 Domain and CH2 2 The domains meet at the interface between the projections and the cavities.

[0090] In some embodiments, the anti-FcRH5 arm comprises a protrusion and the anti-CD3 arm comprises a cavity.

[0091] In some embodiments, the CH3 domain of the anti-FcRH5 arm comprises a protrusion comprising a T366W amino acid substitution mutation (EU numbering) and the CH3 domain of the anti-CD3 arm comprises a cavity comprising T366S, L368A, and Y407V amino acid substitution mutations (EU numbering).

[0092] In some embodiments, the bispecific antibody is cebostamab.

[0093] In some embodiments, the bispecific antibody is administered to a subject simultaneously with one or more additional therapeutic agents.

[0094] In some embodiments, the bispecific antibody is administered to a subject prior to the administration of one or more additional therapeutic agents.

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

[0096] In some embodiments, the one or more additional therapeutic agents comprises an effective amount of tocilizumab.

[0097] In some embodiments, the subject has a cytokine release syndrome (CRS) event and the method further comprises treating a symptom of the CRS event while pending treatment with the bispecific antibody.

[0098] In some embodiments, the methods further include administering to the subject an effective amount of tocilizumab to treat the CRS event.

[0099] In some embodiments, tocilizumab is administered to the subject by intravenous infusion.

[0100] In some embodiments, (i) the subject weighs 30 kg or more and tocilizumab is administered to the subject at a dose of 8 mg / kg, (ii) the subject weighs less than 30 kg and tocilizumab is administered to the subject at a dose of 12 mg / kg, or (iii) the final dose administered does not exceed 800 mg.

[0101] In some embodiments, if the CRS event does not resolve or worsen within 8 hours of treating the symptoms of the CRS event, the method further includes administering one or more additional doses of tocilizumab to the subject to manage the CRS event.

[0102] In some embodiments, the one or more additional therapeutic agents comprises an effective amount of a corticosteroid.

[0103] In some embodiments, the corticosteroid is administered to the subject intravenously.

[0104] In some embodiments, the corticosteroid is methylprednisolone.

[0105] In some embodiments, methylprednisolone is administered at a dose of 80 mg.

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

[0107] In some embodiments, dexamethasone is administered in a dose of 20 mg.

[0108] In some embodiments, the corticosteroid is administered to the subject 45 to 75 minutes prior to administration of the bispecific antibody.

[0109] In some embodiments, the corticosteroid is administered to the subject 60 minutes prior to administering the bispecific antibody to the subject.

[0110] In some embodiments, if the bispecific antibody was previously administered to the subject and the subject experienced CRS, a corticosteroid is administered to the subject prior to administration of the bispecific antibody.

[0111] In some embodiments, the one or more additional therapeutic agents comprises an effective amount of acetaminophen or paracetamol.

[0112] In some embodiments, acetaminophen or paracetamol is administered in a dose of 500 mg to 1000 mg.

[0113] In some embodiments, acetaminophen or paracetamol is orally administered to the subject.

[0114] In some embodiments, acetaminophen or paracetamol is administered to the subject prior to administration of the bispecific antibody to the subject.

[0115] In some embodiments, the one or more additional therapeutic agents comprises an effective amount of diphenhydramine.

[0116] In some embodiments, diphenhydramine is administered in a dose of 25 mg to 50 mg.

[0117] In some embodiments, the diphenhydramine is administered orally to the subject.

[0118] In some embodiments, diphenhydramine is administered to the subject prior to administration of the bispecific antibody to the subject.

[0119] In some embodiments, the one or more additional therapeutic agents comprise an effective amount of an immunomodulatory agent (IMiD), cluster of differentiation 38 (CD38)-directed therapy, or B-cell maturation antigen (BCMA)-directed therapy.

[0120] In some embodiments, the IMiD is pomalidomide.

[0121] In some embodiments, the CD38 directed therapy is an anti-CD38 antibody.

[0122] In some embodiments, the anti-CD38 antibody is daratumumab, MOR202, or isatuximab.

[0123] In some embodiments, the anti-CD38 antibody is daratumumab.

[0124] In some embodiments, the BCMA directed therapy is an antibody-drug conjugate that targets BCMA.

[0125] In some embodiments, the MM is relapsed or refractory (R / R) MM.

[0126] In some embodiments, the subject has a diagnosis of R / R MM where established therapies for MM are not appropriate and are not available, or intolerance to established therapies.

[0127] In some embodiments, the subject has measurable disease defined as at least one of the following: (i) serum M protein > 0.5 g / dL; (ii) urinary M protein > 200 mg / 24 hr; or (iii) serum free light chain (SFLC) assay: SFLC > 10 mg / dL and involving an abnormal SFLC ratio (< 0.26 or > 1.65).

[0128] In another aspect, the present invention features a method of treating a subject having R / R MM, the method comprising administering cevostamab to the subject in a dosing regimen comprising: (i) a first phase comprising a first dosing cycle (C1), wherein C1 is a 28-day dosing cycle, and the first phase comprises administering cevostamab to the subject as a first step-up dose on day 1 of C1, as a second step-up dose on day 8 of C1, and at a target dose on day 15 of C1, wherein the first step-up dose is 2 mg, the second step-up dose is 10 mg, and the target dose is 40 mg; (ii) a second phase comprising the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), and the fifth dosing cycle (C5), wherein each dosing cycle of the second phase is a 28-day dosing cycle, and the second phase comprises administering cevostamab to the subject at the target dose of 40 mg on days 1 and 15 of C1, C2, C3, C4, and C5; and (iii) a third phase comprising 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), wherein each dosing cycle of the third phase is a 28-day dosing cycle, and the third phase comprises administering cevostamab at the target dose of 40 mg on day 1 of C1, C2, C3, C4, C5, C6, and C7, by subcutaneous administration.

[0129] In another aspect, the present invention features a subcutaneous administration device comprising a bispecific antibody that binds to FcRH5 and CD3, the subcutaneous administration device comprising: (i) a first dose of the bispecific antibody from 0.5 mg to 8 mg; (ii) a second dose of the bispecific antibody from 2 mg to 40 mg; and / or (iii) a third dose of the bispecific antibody from 10 mg to 160 mg.

[0130] In some embodiments, (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.

[0131] In some embodiments, (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.

[0132] In some embodiments, (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.

[0133] In some embodiments, the subcutaneous administration device is a syringe.

[0134] In some embodiments, the subcutaneous administration device is a pre-filled syringe.

[0135] In some embodiments, the subcutaneous administration device is a pump.

[0136] In some embodiments, the pump comprises a patch pump, a syringe pump, or an infusion pump.

[0137] In some aspects, the pump is a wearable pump.

[0138] In some embodiments, the subcutaneous administration device is for use in the treatment of MM.

[0139] In some embodiments, the MM is R / R MM.

[0140] In another aspect, the invention features a bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, the treatment comprising subcutaneously administering the bispecific antibody to the subject in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, the first phase comprising administering the bispecific antibody to the subject every week (QW); (ii) a second phase comprising one or more dosing cycles, the second phase comprising administering the bispecific antibody to the subject every two weeks (Q2W); and (iii) a third phase comprising one or more dosing cycles, the third phase comprising administering the bispecific antibody to the subject every four weeks (Q4W).

[0141] In another aspect, the invention features a bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, the treatment comprising subcutaneously administering the bispecific antibody to the subject in a dosing regimen including: (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.

[0142] In another aspect, the invention features cebostamab for use in treating a subject with R / R MM, the treatment comprising administering cebostamab to the subject in (i) a first phase including a first administration cycle (C1), where C1 is a 28 day administration cycle, the first phase including administering cebostamab to the subject as a first step-up dose on day 1 of C1, as a second step-up dose on day 8 of C1, and at a target dose on day 15 of C1, where the first step-up dose is 2 mg, the second step-up dose is 10 mg, and the target dose is 40 mg; (ii) a second phase including a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), and a fifth administration cycle (C5), where the second phase (iii) a third phase, comprising a first administration cycle (C1), a second administration cycle (C2), a third administration cycle (C3), a fourth administration cycle (C4), a fifth administration cycle (C5), a sixth administration cycle (C6), and a seventh administration cycle (C7), wherein each administration cycle of the third phase is a 28 day administration cycle, and the third phase comprises administering cebostamab to the subject on days 1 and 15 of C1, C2, C3, C4, C5, C6, and C7 at a target dose of 40 mg. [Brief description of the drawings]

[0143]

Figure 1

Figure 2

[0144] I. Definition The term "about" as used herein refers to the normal error range for the respective value, which is readily understood by one of ordinary skill in the art. Reference to "about" with respect to a value or parameter herein includes (and describes) aspects directed to the value or parameter itself.

[0145] It will be understood that the embodiments of the invention described herein include "comprising," "consisting of," and "consisting essentially of" embodiments.

[0146] The term "FcRH5" or "fragment crystallographic receptor-like 5" as used herein refers to any native FcRH5 from any vertebrate, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated, and includes "full-length" and unprocessed FcRH5, as well as any form of FcRH5 resulting from processing within a cell. This term also includes naturally occurring variants of FcRH5, including, for example, splice variants or allelic variants. FcRH5 includes, for example, the human FcRH5 protein (UniProtKB / Swiss-Prot ID: Q96RD9.3), which is 977 amino acids long.

[0147] The terms "anti-FcRH5 antibody" and "antibody that binds FcRH5" refer to an antibody that can bind FcRH5 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent targeting FcRH5. In one embodiment, the degree of binding of an anti-FcRH5 antibody to an unrelated, non-FcRH5 protein is less than about 10% of the binding of the antibody to FcRH5, e.g., as measured by radioimmunoassay (RIA). In certain embodiments, an antibody that binds FcRH5 has an affinity of ≦1 μM, ≦250 nM, ≦100 nM, ≦15 nM, ≦10 nM, ≦6 nM, ≦4 nM, ≦2 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., 10 -8 M or less, e.g. 10 -8 M~10 -13 M, for example 10 -9 M~10 -13 Dissociation constant (K D In certain embodiments, the anti-FcRH5 antibody binds to an epitope of FcRH5 that is conserved among FcRH5 from different species.

[0148] The term "cluster of differentiation 3" or "CD3", as used herein, unless otherwise indicated, refers to any native CD3 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), including, for example, CD3ε, CD3γ, CD3α, and CD3β chains. The term encompasses "full-length" unprocessed CD3 (e.g., unprocessed or unmodified CD3ε or CD3γ), as well as any form of CD3 resulting from intracellular processing. The term also encompasses naturally occurring variants of CD3, including, for example, splice variants or allelic variants. CD3 includes, for example, the human CD3ε protein (NCBI Reference SEQ ID NO: NP_000724), which is 207 amino acids long, and the human CD3γ protein (NCBI Reference SEQ ID NO: NP_000064), which is 182 amino acids long.

[0149] The terms "anti-CD3 antibody" and "antibody that binds to CD3" refer to an antibody that can bind to CD3 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent targeting CD3. In one embodiment, the degree of binding of an anti-CD3 antibody to an unrelated non-CD3 protein is less than about 10% of the binding of the antibody to CD3, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds to CD3 has an affinity of ≦1 μM, ≦250 nM, ≦100 nM, ≦15 nM, ≦10 nM, ≦5 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., 10 -8 M or less, e.g. 10 -8 M~10 -13 M, for example 10 -9 M~10 -13 Dissociation constant (K D In certain embodiments, the anti-CD3 antibody binds to an epitope of CD3 that is conserved among CD3 from different species.

[0150] For purposes herein, "cebostamab" (also referred to as BFCR4350A or RO7187797) is an Fc-engineered humanized full-length aglycosylated IgG1κ T-cell-dependent bispecific antibody (TDB) that binds FcRH5 and CD3 and comprises an anti-FcRH5 arm comprising a heavy chain polypeptide sequence of SEQ ID NO: 35 and a light chain polypeptide sequence of SEQ ID NO: 36, and an anti-CD3 arm comprising a heavy chain polypeptide sequence of SEQ ID NO: 37 and a light chain polypeptide sequence of SEQ ID NO: 38. Sebostamab contains an amino acid substitution (T366W) from threonine to tryptophan at position 366 on the heavy chain of the anti-FcRH5 arm using EU numbering of Fc region amino acid residues, and three amino acid substitutions (Y407V, T366S, L368A) on the heavy chain of the anti-CD3 arm using EU numbering of Fc region amino acid residues (tyrosine to valine at position 407, threonine to serine at position 366, and leucine to alanine at position 368) to drive heterodimerization of the two arms (half antibodies). Sebostamab also contains an amino acid substitution (N297G) at position 297 (asparagine to glycine) on each heavy chain using EU numbering of Fc region amino acid residues, resulting in an aglycosylated antibody with minimal binding to Fc (Fcγ) receptors and consequently preventing Fc effector function. Sebostamab is also listed in the WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Recommended INN:List 84, Vol. 34, No. 3 (published in 2020) (see page 701).

[0151] The term "antibody" is used herein in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments (e.g., bis-Fab), so long as they exhibit the desired antigen-binding activity.

[0152] "Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between the members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y is generally determined by the dissociation constant (K D Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

[0153] An "affinity matured" antibody refers to an antibody that has one or more modifications in one or more hypervariable regions (HVRs), compared to a parent antibody that does not possess such modifications, which improve the affinity of the antibody for antigen.

[0154] The terms "full length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody having a heavy chain having a structure substantially similar to a native antibody structure or containing an Fc region as defined herein.

[0155] "Antibody fragment" refers to a molecule other than an intact antibody that contains a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, bis-Fab; Fv; Fab; Fab'-SH; F(ab') 2 including diabodies, linear antibodies, single chain antibody molecules (eg, scFv, ScFab), and multispecific antibodies formed from antibody fragments.

[0156] "Single domain antibody" refers to an antibody fragment that contains all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain embodiments, a single domain antibody is a human single domain antibody (see, e.g., U.S. Pat. No. 6,248,516 B1). Examples of single domain antibodies include, but are not limited to, VHHs.

[0157] A "Fab" fragment is an antigen-binding fragment produced by papain digestion of an antibody, consisting of the entire L chain, the variable region domain of the H chain (VH), and the first constant domain of one heavy chain (CH1). Papain digestion of an antibody produces two identical Fab fragments. Pepsin treatment of an antibody produces a single large F(ab') fragment. 2 The resulting fragment corresponds roughly to two disulfide-linked Fab fragments with divalent antigen-binding activity and is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments in that they have additional residues at the carboxy terminus of the CH1 domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine ​​residues of the constant domains bear a free thiol group. F(ab') 2 Antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0158] "Fv" consists of a dimer of one heavy chain and one light chain variable region domain in tight non-covalent association. The folding of these two domains results in six hypervariable loops (three loops each from the H chain and L chain) that provide amino acid residues for antigen binding and confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although often with lower affinity than the entire binding site.

[0159] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain, including native sequence Fc regions and variant Fc regions. Although the boundaries of an immunoglobulin heavy chain Fc region can vary, the human IgG heavy chain Fc region is usually defined as extending from the amino acid residue at position Cys226 or from Pro230 to its carboxyl terminus. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) can be removed, for example, during antibody production or purification, or by recombinantly engineering the nucleic acid encoding the antibody heavy chain. Thus, a composition of intact antibodies can include an antibody population with all Lys447 residues removed, an antibody population with no Lys447 residues removed, and an antibody population with a mixture of antibodies with and without the Lys447 residue.

[0160] A "functional Fc region" has an "effector function" of a native sequence Fc region. Exemplary "effector functions" include C1q binding, complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptor, BCR); B cell activation, and the like. Such effector functions generally require that the Fc region be combined with a binding domain (e.g., an antibody variable domain) and can be assessed using various assays, e.g., as disclosed in the definitions herein.

[0161] A "native sequence Fc region" comprises an amino acid sequence identical to that of an Fc region found in nature. Native sequence human Fc regions include native sequence human IgG1 Fc regions (non-A and A allotypes), native sequence human IgG2 Fc regions, native sequence human IgG3 Fc regions, and native sequence human IgG4 Fc regions, as well as naturally occurring variants thereof.

[0162] A "variant Fc region" comprises an amino acid sequence that differs from that of a native sequence Fc region by at least one amino acid modification, preferably one or more amino acid substitutions. Preferably, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or the Fc region of a parent polypeptide, e.g., about 1 to about 10 amino acid substitutions, preferably about 1 to about 5 amino acid substitutions in the native sequence Fc region or the Fc region of a parent polypeptide. The variant Fc region herein will preferably have at least about 80% homology, preferably at least about 90% homology, or more preferably at least about 95% homology with the native sequence Fc region and / or the Fc region of the parent polypeptide.

[0163] As used herein, "Fc complex" refers to the CH3 domains of two Fc regions that interact together to form a dimer, or in certain embodiments, two Fc regions that interact to form a dimer, where cysteine ​​residues in the hinge region and / or the CH3 domains interact via bonds and / or forces (e.g., van der Waals, hydrophobic forces, hydrogen bonds, electrostatic forces, or disulfide bonds).

[0164] The term "FcRH5 positive cancer" refers to a cancer that contains cells expressing FcRH5 on the surface. For the purpose of determining whether a cell expresses FcRH5 on the surface, FcRH5 mRNA expression is considered to correlate 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 using an antibody against FcRH5, for example, by immunohistochemistry, FACS, or other methods. 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.

[0165] The "hinge region" is generally defined as extending between about residues 216 to about 230 of IgG (EU numbering), about residues 226 to about 243 of IgG (Kabat numbering), or about residues 1 to about 15 of IgG (IMGT unique numbering).

[0166] The "lower hinge region" of an Fc region is usually defined as the stretch of residues immediately C-terminal to the hinge region, ie, residues 233 to 239 (EU numbering) of the Fc region.

[0167] "Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. A preferred FcR is a native sequence human FcR. Additionally, a preferred FcR is one that binds IgG antibodies (gamma receptors), including receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. FcγRII receptors include FcγRIIA ("activating receptor") and FcγRIIB ("inhibiting receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain (see review M. in Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those yet to be identified, are encompassed herein by the term "FcR". The term also includes the neonatal receptor FcRn, which is 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)).

[0168] The term "knob-into-hole" or "KnH" technology as referred to herein refers to a technique that instructs the pairing of two polypeptides in vitro or in vivo by introducing a protrusion (knob) into one polypeptide and a cavity (hole) into the other polypeptide at the interface where they interact. For example, KnH has been introduced at the Fc:Fc interaction interface, 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 the pairing of two different heavy chains together during the production of multispecific antibodies. For example, a multispecific antibody having KnH in the Fc region may further comprise a single variable domain linked to each Fc region, or different heavy chain variable domains paired with the same, similar, or different light chain variable domains. The KnH technology can also be used to pair two different receptor extracellular domains together, or any other polypeptide sequences that constitute different target recognition sequences.

[0169] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3 and FR4. Thus, HVR and FR sequences generally appear in the following sequences in VH (or VL). FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0170] The "CH1 region" or "CH1 domain" includes the stretch of residues from approximately residue 118 to residue 215 of IgG (EU numbering), from approximately residue 114 to residue 223 of IgG (Kabat numbering), or from approximately residue 1.4 to residue 121 of IgG (IMGT unique numbering) (Lefranc et al., IMGT®, the international ImMunoGeneTics information system® 25 years on. Nucleic Acids Res. 2015 Jan;43(Database issue):D413-22).

[0171] The "CH2 domain" of the human IgG Fc region typically extends from approximately residue 244 to approximately 360 of IgG (Kabat numbering), from approximately residue 231 to approximately 340 of IgG (EU numbering), or from approximately 1.6 to approximately 125 of IgG (IGMT unique numbering). The CH2 domain is unique in that it is not closely paired with another domain. Rather, two N-linked branched carbohydrate chains intervene between the two CH2 domains of an intact native IgG molecule. It is speculated that the carbohydrate provides an alternative to domain-domain pairing and may help to stabilize the CH2 domain. Burton, Molec. Immunol. 22:161-206 (1985).

[0172] The "CH3 domain" includes the extension from the C-terminal residues of the Fc region to the CH2 domain (i.e., from approximately amino acid residue 361 to approximately 478 of IgG (Kabat numbering), from approximately amino acid residue 341 to approximately 447 of IgG (EU numbering), or from approximately amino acid residue 1.4 to approximately 130 of IgG (IGMT unique numbering)).

[0173] The "CL domain" or "constant light domain" includes a stretch of residues on the C-terminal side of the light chain variable domain (VL). The light chain (LC) of an antibody can be a kappa (κ) ("Cκ") or lambda (λ) ("Cλ") light chain region. The Cκ region generally extends from about residue 108 to about residue 214 of IgG (Kabat or EU numbering), or from about residue 1.4 to about residue 126 of IgG (IMGT unique numbering). The Cλ residues generally span from about residue 107a to residue 215 (Kabat numbering) or from about residue 1.5 to residue 127 (IMGT unique numbering) (Lefranc et al., supra).

[0174] The term "chimeric" antibody refers to an antibody in which part of the heavy and / or light chain is derived from a particular source or species and the remaining part of the heavy and / or light chain is derived from a different source or species.

[0175] The "class" of an antibody refers to the type of constant domain or constant region carried by its heavy chain. There are five main classes of antibodies: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), e.g., IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 , and IgA 2 . The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0176] A "human antibody" is an antibody having an amino acid sequence corresponding to an antibody produced by a human or human cell, or a non-human-derived antibody utilizing a sequence encoding a human antibody such as a human antibody repertoire. This definition of a human antibody specifically excludes humanized antibodies containing non-human antigen-binding residues. Human antibodies can be generated using a variety of techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol. 227:381, 1991; Marks et al., J. Mol. Biol. 222:581, 1991. The methods 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 are also available for the preparation of human monoclonal antibodies. See also Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74, 2001. Human antibodies can be prepared by administering an antigen to a transgenic animal whose endogenous locus has been inactivated but has been modified to produce such antibodies in response to antigen exposure, e.g., an immunized xenomouse (see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE™ technology). See, e.g., Li et al., Proc. Natl. Acad. Sci. USA. 103:3557-3562, 2006 regarding human antibodies generated via human B cell hybridoma technology.

[0177] The "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in the selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup such as those in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, NIH Publication 91-3242, Bethesda MD (1991), Volumes 1-3. In one embodiment, for VL, the subgroup is subgroup kappa I as in the above Kabat et al. In one embodiment, for VH, the subgroup is subgroup III as in the above Kabat et al.

[0178] A "humanized" antibody refers to a chimeric antibody that includes amino acid residues derived from non-human HVRs and amino acid residues derived from human FRs. In certain embodiments, a humanized antibody includes substantially at least one, typically two, variable domains in their entirety, and all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to the FRs of a human antibody. In certain embodiments where all or substantially all of the FRs of the humanized antibody correspond to the FRs of a human antibody, any of the FRs of the humanized antibody may include one or more amino acid residues (e.g., one or more Vernier position residues of the FR) from a non-human FR(s). A humanized antibody may optionally include at least a portion of an antibody constant region derived from a human antibody. An "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has been humanized.

[0179] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding of the antibody to an antigen. The variable domains of the heavy and light chains of a native antibody (VH and VL, respectively) generally have similar structures, and each domain includes four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, e.g., Kindt et al., Kuby Immunology, 6 th ed. W.H. Freeman and Co., page 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. Further, an antibody that binds a particular antigen may be isolated by screening a library of complementary VL or VH domains using the VH or VL domain of the antibody that binds the antigen. See, e.g., Portolano et al., J. Immunol. 150:880-887, 1993; Clarkson et al. Nature 352:624-628, 1991.

[0180] As used herein, the term "hypervariable region" or "HVR" refers to a region of each of the antibody variable domains in which the sequence is hypervariable ("complementary determining region" or "CDR"). Generally, an antibody includes six CDRs, three of which are in VH (CDR-H1, CDR-H2, CDR-H3) and three of which are in VL (CDR-L1, CDR-L2, CDR-L3). Exemplary CDRs herein include the following. (a) CDRs present at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917, 1987); (b) CDRs present in amino acid residues 24 - 34 (L1), 50 - 56 (L2), 89 - 97 (L3), 31 - 35b (H1), 50 - 65 (H2), and 95 - 102 (H3) (Kabat et al. Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)), and, (c) Antigen contacts occurring at amino acid residues 27c - 36 (L1), 46 - 55 (L2), 89 - 96 (L3), 30 - 35b (H1), 47 - 58 (H2) and 93 - 101 (H3) (MacCallum et al. J. Mol. Biol. 262:732 - 745, 1996).

[0181] Unless otherwise indicated, HVR residues and other residues within the variable domain (e.g., FR residues) are numbered herein according to Kabat et al. as described above.

[0182] "Single-chain Fv", also abbreviated as "sFv" or "scFv", is an antibody fragment that contains VH and VL antibody domains connected in a single polypeptide chain. Preferably, the scFv polypeptide further contains a polypeptide linker between the VH domain and the VL domain, which enables the scFv to form the desired structure for antigen binding. For an overview of scFv, see Pluckthun, The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenberg and Moore eds., Springer-Verlag, New York, pp. 269 - 315 (1994); Malmborg et al., J. Immunol. Methods 183:7 - 13, 1995.

[0183] The "targeting domain" refers to a compound or a part of a molecule that specifically binds to a target epitope, antigen, ligand, or receptor. Targeting domains include antibodies (e.g., monoclonal antibodies, polyclonal antibodies, recombinant antibodies, humanized antibodies, and chimeric antibodies), antibody fragments or parts thereof (e.g., bis-Fab fragments, Fab fragments, F(ab’) 2 , scFab, scFv antibodies, SMIP, single-domain antibodies, diabodies, minibodies, scFv-Fc, affibodies, nanobodies, and VH and / or VL domains of antibodies), receptors, ligands, aptamers, peptide targeting domains (e.g., cysteine knot proteins (CKP), etc.), and other molecules having identified binding partners, but are not limited thereto. The targeting domain can target, block, activate, or antagonize the antigen to which it binds.

[0184] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies comprising the population are identical and / or bind to the same epitope, except for variants such as naturally occurring mutations or variant antibodies that may occur during the production of the monoclonal antibody preparation, which variants generally occur in minor amounts. In contrast to polyclonal antibody preparations, which typically contain different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the characteristic of an antibody obtained from a substantially homogeneous collection of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention can be made by a variety of techniques including, but not limited to, the hybridoma method, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin locus, and such methods and other exemplary methods for making monoclonal antibodies are described herein.

[0185] The term "multispecific antibody" is used in the broadest sense and encompasses antibodies having polyepitope specificity in particular. In one aspect, a multispecific antibody binds to two different targets (e.g., a bispecific antibody). Examples of such multispecific antibodies include, but are not limited to, antibodies comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), where the VH / VL unit has multi-epitope specificity; antibodies having two or more VL and VH domains, where each VH / VL unit binds to a different epitope; antibodies having two or more single variable domains, where each single variable domain binds to a different epitope; full-length antibodies, Fab, Fv, dsFv, scFv, diabodies, bispecific diabodies, and triabodies, such as antibody fragments; antibody fragments linked by covalent or non-covalent bonds. "Polyepitope specificity" refers to the ability to specifically bind to two or more different epitopes on the same or different target(s). "Monospecificity" refers to the ability to bind to only one antigen. In one aspect, a monospecific bivalent antibody binds to two different epitopes on the same target / antigen. In one aspect, a monospecific polyepitope antibody binds to multiple different epitopes on the same target / antigen. According to one aspect, the multispecific antibody is an IgG antibody that binds to each epitope having an affinity of 5 μM to 0.001 pM, 3 μM to 0.001 pM, 1 μM to 0.001 pM, 0.5 μM to 0.001 pM, or 0.1 μM to 0.001 pM.

[0186] A "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or a radiolabel. A naked antibody may be present in a pharmaceutical formulation.

[0187] "Native antibody" refers to naturally occurring immunoglobulin molecules having various structures. For example, native IgG antibodies are approximately 150,000 Dalton heterotetrameric glycoproteins composed of two identical light chains and two identical heavy chains linked by disulfide bonds. Each heavy chain, from the N-terminus to the C-terminus, has a variable region (VH), also called the variable heavy domain or heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, each light chain, from the N-terminus to the C-terminus, has a variable region (VL), also called the variable light chain domain or light chain variable domain, followed by a constant light chain (CL) domain. The light chains of an antibody may be assigned to one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequence of their constant domains.

[0188] As used herein, the term "immunoadhesin" refers to a molecule that combines the binding specificity of a heterologous protein ("adhesin") with the effector functions of an immunoglobulin constant domain. Structurally, an immunoadhesin comprises an amino acid sequence having a desired binding specificity that is an amino acid sequence other than the antigen recognition binding site of an antibody (i.e., "heterologous" compared to the constant region of an antibody) and an immunoglobulin constant domain sequence (e.g., the CH2 and / or CH3 sequence of IgG), which are fused together. The adhesin and the immunoglobulin constant domain may optionally be separated by an amino acid spacer. Exemplary adhesin sequences include contiguous amino acid sequences that include a portion of a receptor or ligand that binds to a target protein. The adhesin sequence may also be a sequence that binds to a target protein but is not a receptor or ligand sequence (e.g., the adhesin sequence in a peptibody). Such polypeptide sequences can be selected or identified by various methods including phage display techniques and high-throughput screening methods. The immunoglobulin constant domain sequence in an immunoadhesin can be obtained from any immunoglobulin, such as IgG1, IgG2, IgG3, or IgG4 subtypes, IgA (including IgA1 and IgA2), IgE, IgD, or IgM.

[0189] "Chemotherapeutic agents" include chemical compounds useful for the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech / OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitinib (SUTENT®, Pfizer / Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasanutate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), lonafarnib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN®, cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, piposulfan; aziridine compounds such as benzodopa, carbocone, metopopa, uredopa; ethyleneimines and methylamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylmelamine; acetogenin (especially, bullatacin and bullatacinone); camptothecin (including topotecan and irinotecan); bryostatin; calistatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycin (especially cryptophycin 1 and cryptophycin 8); corticosteroids (such as prednisone and prednisolone); cyproterone acetate;5α-reductase inhibitors including finasteride and dutasteride; vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat, dristatin; aldosterone, talactomycin (including synthetic analogs, KW-2189, CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chromafazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobenbitin, fenestrolone, prednimustine, trophosphamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γ1I and calicheamicin ω1I (Angew Chem.Intl.Ed.Engl. 1994 33:183-186), etc.), dynemicin including dynemicin A; bisphosphonates such as clodronate; esperamicin; and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN (registered trademark) (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolinodoxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin C and other mitomycins, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, promycin, keramycin, rhodomycin, streptozocin, streptozotocin, tubercidin, ubenimex, dinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimethoprim;Purine analogs such as fludarabine, 6-mercaptopurine, thiampurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, drostanolone propionate, epithiostanol, mepitiostane, testolactone; anti-adrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; dexamethasone; diaziquone; elfomithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK (registered trademark) polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; risoxacin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2”-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verrucarin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids such as taxol (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE (registered trademark) (without cremophor), albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE (registered trademark) (paclitaxel, docetaxel; Sanofi-Aventis); chlorambucil, GEMZAR (registered trademark) (gemcitabine), 6-thioguanine, mercaptopurine;Methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE (registered trademark) (vinorelbine); nobandron; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA (registered trademark)); ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid, and pharmaceutically acceptable salts, acids and derivatives of any of the above are included.;

[0190] In addition, examples of the chemotherapeutic agent include the following.(i) Anti-hormonal agents that act to modulate or inhibit the hormonal action on tumors, such as anti-estrogens and selective estrogen receptor modulators (SERMs), for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifene citrate); (ii) Aromatase inhibitors that inhibit the enzyme aromatase which regulates estrogen production in the adrenal glands, for example, 4(5)-imidazole, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestane, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), ARIMIDEX® (anastrozole; AstraZeneca), and other anti-androgen agents; (iii) Anti-androgen agents such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; buserelin, triptorelin, medroxyprogesterone acetate, diethylstilbestrol, Premarin, fluoxymesterone, all-trans retinoic acid, fenretinide along with troxacitabine (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 involved in abnormal cell proliferation, such as PKC-α, Ralf, and H-Ras;; (vii) Ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) Gene therapy vaccines, for example, vaccines such as ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN®, rIL-2; topoisomerase 1 inhibitors such as LURTOTECAN®; ABARELIX® rmRH; and (ix) Pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0191] Chemotherapeutic agents include antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Imclone), panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and antibody-drug conjugates such as gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies having therapeutic potential as agents in combination with the compounds of the present invention include apolizumab, aselizumab, atorizumab, bapineuzumab, bevacizumab mertansine, canertinib mertansine, cedelizumab, certolizumab pegol, cidfostuxizumab, cidotuzumab, daclizumab, eclizumab, efalizumab, epratuzumab, elotuzumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labelizumab, lintuzumab, matuzumab, mapolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, norovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecificumumab, pexelizumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, reslizumab, rovelizumab, rupizumab, sibrotuzumab, siprilizumab, sonotuzumab, takatuzumab tetraxetan, tadoxizumab, talizumab, tefibazumab, tocilizumab, tralizumab, tucotuzumab celmoleukin, tucusituzumab, umabizumab, ultuxizumab, ustekinumab, visilizumab, and anti-interleukin-12 (ABT-874 / J695, Wyeth Research and Abbott Laboratories), a full-length IgG1λ antibody of only human sequence that is genetically engineered to recognize interleukin-12 p40 protein.

[0192] The chemotherapeutic agent also includes an "EGFR inhibitor", which refers to a compound that binds to or otherwise directly interacts with EGFR and inhibits or reduces the signaling activity of EGFR, and is alternatively referred to as an "EGFR antagonist". Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies that bind to EGFR include the following: MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see U.S. Patent No. 4,943,533) and variants thereof, such as chimerized 225 (C225 or cetuximab; ERBUTIX®) and reshaped human 225 (H225) (see International Publication No. 96 / 40210, Imclone Systems Inc.); fully human EGFR-targeted antibody IMC-11F8 (Imclone); antibody that binds to type II mutant EGFR (U.S. Patent No. 5,212,290); humanized and chimeric antibodies that bind to EGFR as described in U.S. Patent No. 5,891,996; and human antibodies that bind to EGFR such as ABX-EGF or Panitumumab (see International Publication No. 98 / 50433, Abgenix / Amgen); EMD 55900 (Stragliotto et al., Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab), a humanized EGFR antibody that competes with both EGF and TGF-α for EGFR binding (EMD / Merck); human EGFR antibody, HuMax-EGFR (GenMab); fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3 and described in U.S. Patent No. 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)).An anti-EGFR antibody can be conjugated to a cytotoxic agent, thereby generating an immunoconjugate (see, e.g., European Patent Application Publication No. 659,439, Merck Patent GmbH). EGFR antagonists include small molecules such as those described in U.S. Patent Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, as well as the following PCT publications: International Publication Nos. 98 / 14451, 98 / 50038, 99 / 09016, and 99 / 24037, and the like.Examples of specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA (registered trademark), Genentech / OSI Pharmaceuticals), PD183805 (CI1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.), ZD1839, gefitinib (IRESSA (registered trademark)) 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca), ZM105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca), BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim), PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol), (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine), CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide), EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolynyl]-4-(dimethylamino)-2-butynamide) (Wyeth), AG1478 (Pfizer), AG1571 (SU5271, Pfizer), and dual EGFR / HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB (registered trademark), GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolineamine).

[0193] As chemotherapeutic agents, there are also "tyrosine kinase inhibitors" (including the EGFR-targeted drugs described in the previous paragraph), small molecule HER2 tyrosine kinase inhibitors (such as TAK165 available from Takeda), CP-724,714 (Pfizer and OSI), an oral selective inhibitor of ErbB2 receptor tyrosine kinase, dual HER inhibitors (such as EKB-569 (available from Wyeth) that preferentially binds to EGFR but inhibits both HER2- and EGFR-overexpressing cells), lapatinib (GSK572016, available from Glaxo-SmithKline), 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 the antisense agent ISIS-5132 available from ISIS Pharmaceuticals that inhibits Raf-1 signaling), non-HER target TK inhibitors (such as imatinib mesylate (GLEEVEC®, available from Glaxo SmithKline)), multi-target tyrosine kinase inhibitors (such as sunitinib (SUTENT®, available from Pfizer)), VEGF receptor tyrosine kinase inhibitors (such as batatinib (PTK787 / ZK222584, available from Novartis / Schering AG)), MAPK extracellular regulatory kinase I inhibitor CI-1040 (available from Pharmacia), quinazolines (such as PD153035, 4-(3-chloroanilino)quinazoline), pyridopyrimidines, pyrimidopyrimidines, pyrrolopyrimidines (such as CGP59326, CGP60261, and CGP62706), pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine, curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide), tilorone containing a nitrothiophene moiety, PD-0183805 (Warner-Lambert), antisense molecules (e.g., those that bind to HER-encoding nucleic acids), quinoxalines (U.S. Patent No. 5,804,396), trioxolane (U.S. Patent No. 5,804,396, ZD6474 (Astra Zeneca), PTK-787 (Novartis / Schering AG), pan-HER inhibitor (such as CI-1033 (Pfizer)), Affinitac (ISIS3521, Isis / Lilly), imatinib mesylate (GLEEVEC (registered trademark)), PKI166 (Novartis), GW2016 (Glaxo SmithKline), CI-1033 (Pfizer), EKB-569 (Wyeth), semaxinib (Pfizer), ZD6474 (AstraZeneca), PTK-787 (Novartis / Schering AG), INC-1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE (registered trademark)), or those described in any of the following patent publications: U.S. Patent No. 5,804,396, International Publication No. WO 99 / 09016 (American Cyanamid), WO 98 / 43960 (American Cyanamid), WO 97 / 38983 (Warner Lambert), WO 99 / 06378 (Warner Lambert), WO 99 / 06396 (Warner Lambert), WO 96 / 30347 (Pfizer, Inc), WO 96 / 33978 (Zeneca), WO 96 / 3397 (Zeneca), and WO 96 / 33980 (Zeneca).

[0194] Chemotherapeutic agents also include dexamethasone, interferon, colchicine, methotrexate, 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, ibritumomab, interferon alpha-2a, interferon alpha-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nolfetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegasparaginase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, tamoxifen, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, as well as their pharmaceutically acceptable salts.

[0195] As chemotherapeutic agents, there are hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivolate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fludrocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, acrometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasone-17-propionate, fludrocortolone caproate, fludrocortolone pivolate and fluprednidene acetate; immune-selective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-form (feG) (IMULAN BioTherapeutics, LLC); antirheumatic drugs such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide minocycline, sulfasalazine, tumor necrosis factor alpha (TNFα) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), interleukin 1 (IL-1) blockers such as anakinra (Kineret), T-cell costimulation blockers such as abatacept (Orencia), interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMRA (registered trademark)); interleukin 13 (IL-13) blockers such as lebrikizumab; interferon alpha (IFN) blockers such as lonafarnib; beta7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as anti-M1 prime; secretory homotrimeric LTa3 and membrane-bound heterotrimeric LTa1 / β2 blockers such as anti-lymphotoxin alpha (LTa); radioisotopes (e.g., At 211 、I 131 、I 125 、Y 90 、Re 186 、Re 188 、Sm 153 、Bi212 , P 32 , Pb 212and radioactive isotopes of Lu); various investigational drugs such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3, or farnesyltransferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavin, flavanol, procyanidin, betulinic acid and its derivatives; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL (registered trademark)); beta-lapachone; lapachol; cortisone; betulinic acid; acetylcamptothecin, scoplectin, and 9-aminocamptothecin); podophyllotoxin; tegafur (UFTORAL (registered trademark)); bexarotene (TARGRETIN (registered trademark)); bisphosphonates such as clodronate (e.g., BONEFOS (registered trademark) or OSTAC (registered trademark)), etidronate (DIDROCAL (registered trademark)), NE-58095, zoledronic acid / zoledronate (ZOMETA (registered trademark)), alendronate (FOSAMAX (registered trademark)), pamidronate (AREDIA (registered trademark)), tiludronate (SKELID (registered trademark)), or risedronate (ACTONEL (registered trademark)); and epidermal growth factor receptor (EGF-R); vaccines such as the THERATOPE (registered trademark) vaccine; perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteasome inhibitors (e.g., PS341); CCI-779; tipifarnib (R11577); olaphenib, ABT510; Bcl-2 inhibitors such as oblimersen sodium (GENASENSE (registered trademark)); pixantrone; farnesyltransferase inhibitors such as lonafarnib (SCH6636, SARASAR (trademark)); and pharmaceutically acceptable salts, acids, or derivatives of any of the above; and combinations of two or more of CHOP, an abbreviation for a combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone, and FOLFOX, an abbreviation for a treatment regimen using oxaliplatin (ELOXATIN (trademark)) in combination with 5-FU and leucovorin).

[0196] As chemotherapeutic agents, non-steroidal anti-inflammatory drugs having an analgesic effect, antipyretic effect, and anti-inflammatory effect may also be mentioned. NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase. Specific examples of non-steroidal anti-inflammatory drugs include propionic acid derivatives such as aspirin, ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, naproxen, etc., acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, etc., enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, etc., fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, etc., and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, etc. The indications of NSAIDs can be the symptomatic relief of symptoms such as rheumatoid arthritis, osteoarthritis, inflammatory joint diseases, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headache and migraine, postoperative pain, mild to moderate pain caused by inflammation and tissue damage, fever, intestinal obstruction, and renal colic, etc.

[0197] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cell function and / or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212and radioisotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, doxorubicin (ADRIAMYCIN®), vinca alkaloids (vincristine, vinblastine, etoposide), melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitors; enzymes and fragments thereof, such as nucleolytic enzymes; antibiotics; toxins such as low molecular weight toxins or enzymatically active toxins derived from bacteria, fungi, plants or animals (including fragments and / or variants thereof); and various antitumor or anticancer agents disclosed below are included.

[0198] "Disorder" includes, but is not limited to, chronic and acute disorders or diseases that include those pathological conditions that predispose a mammal to the disorder in question, and any symptom that would benefit from treatment. In one aspect, the disorder is cancer, such as a B cell proliferative disorder such as MM, such as relapsed or refractory MM.

[0199] The terms "cell proliferative disorder" and "proliferative disorder" refer to disorders associated with some degree of abnormal cell proliferation. In one aspect, the cell proliferative disorder is cancer. In one aspect, the cell proliferative disorder is a tumor.

[0200] "Tumor", as used herein, refers to the growth and proliferation of all neoplastic cells, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms "cancer", "cancerous", "cell proliferative disorder", "proliferative disorder", and "tumor" are not mutually exclusive as referred to herein.

[0201] The terms "cancer" and "cancerous" refer to or describe physiological conditions in mammals that are typically characterized by uncontrolled cell growth / proliferation. Aspects of cancer include solid tumor cancers and non-solid tumor cancers. Examples of cancer include, but are not limited to, B cell proliferative disorders such as MM which can be relapsed or refractory MM. MM can be, for example, typical MM (e.g., immunoglobulin G (IgG) MM, IgA MM, IgD MM, IgE MM, or IgM MM), light chain MM (LCMM) (e.g., lambda light chain MM or kappa light chain MM), or non-secretory MM. MM can have one or more cytogenetic features (e.g., high-risk cytogenetic features), for example, t(4;14), t(11;14), t(14;16), and / or del(17p) (described in the International Myeloma Working Group (IMWG) criteria provided in Table 1 and Sonneveld et al., Blood, 127(24):2955-2962, 2016) and / or 1q21 (described in Chang et al., Bone Marrow Transplantation, 45:117-121, 2010). Cytogenetic features can be detected, for example, using fluorescence in situ hybridization (FISH). Examples of solid tumors include squamous cell cancer (e.g., epithelial squamous cell cancer), small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and lung cancer including squamous cell carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, and gastric cancer (gastric cancer) or stomach cancer including gastrointestinal stromal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urinary system cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial carcinoma or uterine carcinoma, salivary gland carcinoma, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer species, anal carcinoma, penile carcinoma, melanoma, superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanoma, nodular melanoma, as well as neurofibromatosis, edema (such as those associated with brain tumors), Meigs syndrome, brain, and head and neck cancer, and abnormal blood vessel growth associated with related metastases.In certain embodiments, cancers suitable for treatment with the antibodies of the invention include breast cancer, colorectal cancer, rectal cancer, non-small cell lung cancer, glioblastoma, non-Hodgkin lymphoma (NHL), renal cell cancer, prostate cancer, liver cancer, pancreatic cancer, soft tissue sarcoma, Kaposi's sarcoma, carcinoid tumor, head and neck cancer, ovarian cancer, and mesothelioma.

Table 1

[0202] The terms "B cell proliferative disorder" or "B cell malignancy" refer to disorders associated with abnormal B cell proliferation to some extent, including, for example, lymphomas, leukemias, myelomas, and myelodysplastic syndromes. In one embodiment, the B cell proliferative disorder is a lymphoma such as non-Hodgkin lymphoma (NHL), including, for example, diffuse large B cell lymphoma (DLBCL) (e.g., relapsed or refractory DLBCL). In other embodiments, the B cell proliferative disorder is a leukemia such as chronic lymphocytic leukemia (CLL). Other specific examples of cancer include germinal center B cell-like (GCB) diffuse large B cell lymphoma (DLBCL), activated B cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenström macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt lymphoma (BL), B cell prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma / leukemia, unclassifiable, diffuse red spleen small B cell lymphoma, hairy cell leukemia variant, heavy chain disease, alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasmacytic myeloma, solitary bone plasmacytoma, extramedullary plasmacytoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), nodal marginal zone lymphoma, pediatric nodal marginal zone lymphoma, pediatric follicular lymphoma, primary cutaneous follicle center lymphoma, T cell / histiocyte-rich large B cell lymphoma, primary CNS DLBCL, primary cutaneous DLBCL, lower extremity type, EBV-positive DLBCL in the elderly, chronic inflammation-related DLBCL, lymphomatoid granulomatosis, mediastinal (thymic) primary B cell large cell lymphoma, intravascular large B cell lymphoma, ALK-positive large B cell lymphoma, plasmablastic lymphoma, large B cell lymphoma resulting from HHV8-associated multicentric Castleman disease, primary effusion lymphoma: unclassifiable B cell lymphoma with intermediate characteristics between DLBCL and Burkitt lymphoma, and unclassifiable B cell lymphoma with intermediate characteristics between DLBCL and classical Hodgkin lymphoma, and the like.Furthermore, examples of cancers include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and lymphoid malignancies including leukemia or B-cell lymphoma. More specific examples of such cancers include, but are not limited to, low grade / follicular NHL; small lymphocytic (SL) NHL; intermediate grade / follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; large tumor lesion NHL; AIDS-related lymphoma; and acute lymphoblastic leukemia (ALL); chronic myelogenous leukemia; and post-transplant lymphoproliferative disorder (PTLD).

[0203] "Complement-dependent cytotoxicity" or "CDC" refers to the lysis of target cells in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to an antibody (of the appropriate subclass). To assess complement activation, for example, an assay such as that described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996) can be performed.

[0204] "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a form of cytotoxicity in which secreted Ig bound to Fc receptors (FcRs) present on certain cytotoxic cells (e.g., natural killer (NK) cells, neutrophils, macrophages) enables these cytotoxic effector cells to specifically bind to target cells containing an antigen and then kill the target cells with cytotoxic agents. These antibodies "arm" the cytotoxic cells and are absolutely necessary for such killing. While NK cells, which are primary cells mediating ADCC, express only FcγRIII, monocytes express FcγRI, FcγRII, and FcγRIII. The expression of FcRs in hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet. Annu. Rev. Immunol. 9:457-92, 1991. To evaluate the ADCC activity of a molecule of interest, an in vitro ADCC assay as described in U.S. Patent No. 5,500,362 or 5,821,337 can be performed. Effector cells useful in such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. Alternatively or additionally, the ADCC activity of a molecule of interest can be evaluated in vivo, for example, in an animal model such as those disclosed in Clynes et al., Proc. Natl. Acad. Sci. USA. 95:652-656, 1998.

[0205] As used herein, "complex" or "complex form" refers to the association of two or more molecules that interact with each other via bonds and / or forces that are not peptide bonds (e.g., van der Waals, hydrophobic, hydrophilic forces). In one aspect, the complex is a heteromultimer. The terms "protein complex" or "polypeptide complex" as used herein are understood to include complexes having a non-protein entity conjugated to a protein in the protein complex (e.g., including, but not limited to, chemical molecules such as toxins or detection agents).

[0206] As used herein, "delaying the progression" of a disorder or disease means deferring, preventing, slowing, retarding, stabilizing, and / or arresting the development of a disease or disorder (e.g., a cell proliferative disorder, e.g., cancer (e.g., MM)). This delay can be for various periods depending on the medical history and / or the individual being treated. As will be apparent to those skilled in the art, a sufficient or significant delay can in effect encompass prevention in the sense that the individual does not develop the disease. For example, it can delay advanced cancers such as the occurrence of metastasis.

[0207] An "effective amount" of a compound, e.g., an anti-FcRH5 / anti-CD3 T cell-dependent bispecific antibody (TDB) or a composition thereof (e.g., a pharmaceutical composition) disclosed herein, is at least the minimal amount necessary to achieve a desired therapeutic or prophylactic result such as a measurable improvement or prevention of a particular disorder (e.g., a cell proliferative disorder, e.g., cancer). The effective amount herein may vary depending on factors such as the patient's disease state, age, gender, and weight, as well as the ability of the antibody to elicit a desired response in an individual. The effective amount is also one in which the therapeutically beneficial effects exceed any toxic or detrimental effects of the treatment. Beneficial or desired results for prophylactic use include removal or reduction of risk, reduction in severity, or delay in the onset of disease, including biochemical, histological, and / or kinetic symptoms of the disease, its complications, and intermediate pathological phenotypes that appear during the development of the disease. In the case of therapeutic use, beneficial or desired results include reduction of one or more symptoms attributable to the disease, improvement in the quality of life of an individual suffering from the disease, reduction in the dosage of other agents required for treatment of the disease, enhancement of the effect of another agent (e.g., target-directed), delay in the progression of the disease, and / or extension of survival time, among other clinical outcomes. In the case of cancer or a tumor, an effective amount of a drug reduces the number of cancer cells, reduces tumor size, inhibits the invasion of cancer cells into peripheral organs (i.e., delays to some extent or preferably halts), inhibits tumor metastasis (i.e., delays to some extent or preferably halts), inhibits tumor growth to some extent, and / or reduces to some extent one or more of the symptoms associated with the disorder. The effective amount may be administered in a single dose or in multiple doses. In the present invention, the effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve a prophylactic or therapeutic treatment. As understood in the clinical art, the effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" can be considered in the context of administration of one or more therapeutic agents, and a single agent can be considered to be administered in an effective amount if, alone or in combination with one or more other agents, a desired result can be achieved or is achieved.

[0208] As used herein, "overall survival" or "OS" refers to the percentage of individuals within a group likely to survive after a specified period of time.

[0209] As used herein, "objective response rate" (ORR) refers to the sum of the stringent complete response (sCR) rate, complete response (CR) rate, very good partial response (VGPR) rate, and partial response (PR) rate determined using the International Myeloma Working Group response criteria (see, e.g., Tables 8A and 8B of Example 1).

[0210] The term "epitope" refers to a specific site on an antigen molecule to which an antibody binds. In some embodiments, the specific site on the antigen molecule to which the antibody binds is determined by a hydroxyl radical footprint. In some embodiments, the specific site on the antigen molecule to which the antibody binds is determined crystallographically.

[0211] As used herein, "growth inhibitor" refers to a compound or composition that inhibits cell growth in vitro or in vivo. In one aspect, the growth inhibitor is a growth inhibitory antibody that inhibits or reduces the growth of cells expressing an antigen to which the antibody binds. In another aspect, the growth inhibitor may significantly reduce the proportion of cells in the S phase. Examples of growth inhibitors include agents that block the progression of the cell cycle (at locations other than the S phase), such as agents that induce G1 arrest or M arrest. Classical M phase blockers include vinca (vincristine and vinblastine), taxanes, and topoisomerase II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. Agents that arrest G1, such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and DNA alkylating agents such as araC, also affect S phase arrest. Further information can be found in Mendelsohn and Israel, eds., The Molecular Basis of Cancer, Chapter 1, entitled "Cell cycle regulation, oncogenes, and antineoplastic drugs" (Murakami et al. (W.B. Saunders, Philadelphia, 1995)), for example, on page 13. Taxanes (paclitaxel and docetaxel) are both anticancer drugs derived from yew. Docetaxel (TAXOTERE®, Rhone-Poulenc Rorer), derived from the European yew, is a semisynthetic analog of paclitaxel (TAXOL®, Bristol-Myers Squibb). Paclitaxel and docetaxel stabilize microtubules by promoting the assembly of microtubules from tubulin dimers and preventing depolymerization, thereby inhibiting mitosis in cells.

[0212] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including but not limited to a cytotoxic agent.

[0213] The term "immunomodulator" or "IMiD" refers to a class of molecules that modify the response or function of the immune system. Immunomodulators include, but are not limited to, POMALYST® (pomalidomide), thalidomide (α-N-phthalimidoglutarimide) and its analogs, OTEZLA® (apremilast), REVLIMID® (lenalidomide), and PD-1 axis-binding antagonists, as well as their pharmaceutically acceptable salts or acids.

[0214] A "subject" or "individual" is a mammal. Mammals include, but are not limited to, domestic animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the subject or individual is a human. The subject may be a patient.

[0215] An "isolated" protein or peptide is separated from the components of its natural environment. In some embodiments, the protein or peptide is purified to a purity of greater than 95% or 99%, as determined by, for example, electrophoresis (e.g., sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), isoelectric focusing electrophoresis (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC).

[0216] An "isolated" nucleic acid refers to a nucleic acid molecule that has been separated from the components of its natural environment. Isolated nucleic acids include nucleic acid molecules that are normally contained within a cell that contains 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.

[0217] The term "PD-1 axis-binding antagonist" refers to a molecule that inhibits the interaction between a PD-1 axis-binding partner and one or more of its binding partners in order to remove T cell dysfunction resulting from signaling on the PD-1 signaling axis, and as a result, restore or enhance T cell function (e.g., proliferation, cytokine production, and / or target cell killing). As used herein, PD-1 axis-binding antagonists include PD-L1-binding antagonists, PD-1-binding antagonists, and PD-L2-binding antagonists. In some cases, PD-1 axis-binding antagonists include PD-L1-binding antagonists or PD-1-binding antagonists. In a preferred embodiment, the PD-1 axis-binding antagonist is a PD-L1-binding antagonist.

[0218] The term "PD-L1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses, or interferes with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and / or B7-1. In some cases, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partner. In certain embodiments, the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 and / or B7-1. In some cases, a PD-L1 binding antagonist includes an anti-PD-L1 antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, and other molecules that reduce, block, inhibit, suppress, or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and / or B7-1. In one case, a PD-L1 binding antagonist reduces a negative co-stimulatory signal mediated by or through a cell surface protein expressed on T lymphocytes via signal transduction through PD-L1 such that dysfunctional T cells are not rendered dysfunctional (e.g., enhancing the effector response to antigen recognition). In some cases, a PD-L1 binding antagonist binds to PD-L1. In some cases, a PD-L1 binding antagonist is an anti-PD-L1 antibody (e.g., an anti-PD-L1 antagonist antibody). Exemplary anti-PD-L1 antagonist antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001, enoblituzumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosibelimab, rodaplimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636.In some embodiments, the anti-PD-L1 antibody is atezolizumab, MDX-1105, MEDI4736 (durvalumab), or MSB0010718C (avelumab). In one particular embodiment, the PD-L1 binding antagonist is MDX-1105. In another particular embodiment, the PD-L1 binding antagonist is MEDI4736 (durvalumab). In another particular embodiment, the PD-L1 binding antagonist is MSB0010718C (avelumab). In other embodiments, the PD-L1 binding antagonist can be a small molecule, such as GS-4224, INCB086550, MAX-10181, INCB090244, CA-170 or ABSK041, and in some cases can be administered orally. Other exemplary PD-L1 binding antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003 and JS-003. In a preferred embodiment, the PD-L1 binding antagonist is atezolizumab. Atezolizumab is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances (proposed INN)) List 112, Vol. 28, No. 4, 2014, p. 488.

[0219] The term "PD-1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses, or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and / or PD-L2. PD-1 (programmed death 1) is also referred to in the art as "programmed cell death 1", "PDCD1", "CD279", and "SLEB2". An exemplary human PD-1 is shown by the UniProtKB / Swiss-Prot accession number Q15116. In some cases, a PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In certain embodiments, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and / or PD-L2. For example, a PD-1 binding antagonist includes an anti-PD-1 antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, and other molecules that reduce, block, inhibit, suppress, or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and / or PD-L2. In one case, a PD-1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes via signal transduction through PD-1 such that dysfunctional T cells are prevented from becoming dysfunctional (e.g., enhancing the effector response to antigen recognition). In some cases, a PD-1 binding antagonist binds to PD-1. In some cases, a PD-1 binding antagonist is an anti-PD-1 antibody (e.g., an anti-PD-1 antagonist antibody).Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (semiplimab), BGB-108, prorolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanalimab, pemprilimab, CS1003, HLX10, SCT-I10A, zinberelimab, balsilimab, genolimzumab, BI 754091, cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, and hAb21. In certain embodiments, the PD-1 binding antagonist is MDX-1106 (nivolumab). In another particular embodiment, the PD-1 binding antagonist is MK-3475 (pembrolizumab). In another particular embodiment, the PD-1 binding antagonist is a PD-L2 Fc fusion protein, such as AMP-224. In another particular embodiment, the PD-1 binding antagonist is MED1-0680. In another particular embodiment, the PD-1 binding antagonist is PDR001 (spartalizumab). In another particular embodiment, the PD-1 binding antagonist is REGN2810 (semiplimab). In another particular embodiment, the PD-1 binding antagonist is BGB-108. In another particular embodiment, the PD-1 binding antagonist is prorolimab. In another particular embodiment, the PD-1 binding antagonist is camrelizumab. In another particular embodiment, the PD-1 binding antagonist is sintilimab. In another particular embodiment, the PD-1 binding antagonist is tislelizumab. In another particular embodiment, the PD-1 binding antagonist is toripalimab. Other additional exemplary PD-1 binding antagonists include BION-004, CB201, AUNP-012, ADG104, and LBL-006.

[0220] The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses, or interferes with signal transduction resulting from the interaction of PD-L2 with one or more of its binding partners, e.g., interaction with PD-1. PD-L2 (programmed death ligand 2) is also referred to in the art as "programmed cell death 1 ligand 2", "PDCD1LG2", "CD273", "B7-DC", "Btdc", and "PDL2". Exemplary human PD-L2 is shown under UniProtKB / Swiss-Prot accession number Q9BQ51. In some cases, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In certain embodiments, the PD-L2 binding antagonist inhibits the binding of PD-L2 to PD-1. Exemplary PD-L2 antagonists include anti-PD-L2 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, suppress, or interfere with signal transduction resulting from the interaction of PD-L2 with one or more of its binding partners such as PD-1. In one embodiment, the PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes via signal transduction through PD-L2 such that dysfunctional T cells are not rendered dysfunctional (e.g., enhancing the effector response to antigen recognition). In some embodiments, the PD-L2 binding antagonist binds to PD-L2. In some embodiments, the PD-L2 binding antagonist is an immunoadhesin. In other embodiments, the PD-L2 binding antagonist is an anti-PD-L2 antagonist antibody.

[0221] Unless otherwise indicated, as used herein, the term "protein" refers to any native protein from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice, rats), unless otherwise specified. This term includes any form of "full-length", untreated protein and protein resulting from intracellular processing. This term also encompasses naturally occurring variants of the protein, such as splice variants or allelic variants.

[0222] The "percent amino acid sequence identity (%)" to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps if necessary to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity for the purpose of alignment. Alignments for determining the percent amino acid sequence identity can be achieved in a variety of ways within the skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, Clustal W, Megalign (DNASTAR) software or the FASTA program package. One of ordinary skill in the art can determine appropriate parameters for the alignment of sequences, including any algorithm necessary to achieve the maximum alignment over the entire length of the sequences being compared. Alternatively, the value of the identity rate can be generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., the source code of which is filed in the user documentation of the U.S. Copyright Office (Washington D.C., 20559), registered under U.S. Copyright Registration No. TXU510087, and described in International Publication No. WO 2001 / 007611.

[0223] Unless otherwise indicated, for the purposes of this specification, the value of the percent amino acid sequence identity is generated using the ggsearch program of the FASTA package version 36.3.8c, or the subsequent BLOSUM50 comparison matrix. The FASTA program package is described by W.R. Pearson and D.J. Lipman (1988), "Improved Tools for Biological Sequence Analysis" PNAS 85:2444-2448; W.R. Pearson (1996) "Effective protein sequence comparison" Meth. Enzymol. 266:227-258; and Pearson et.al. (1997) Genomics 46:24-36, and is publicly available from www.fasta.bioch.virginia.edu / fasta_www2 / fasta_down.shtml or www.ebi.ac.uk / Tools / sss / fasta. Alternatively, the ggsearch (global protein:protein) program and default options (BLOSUM50; open: -10; ext: -2; Ktup = 2) can be used to compare sequences using a public server accessible at fasta.bioch.virginia.edu / fasta_www2 / index.cgi, ensuring a global rather than a local alignment is performed. The percent amino acid identity is shown in the output alignment header.

[0224] The term "pharmaceutical preparation" refers to a preparation that is in a form such that the biological activity of the active ingredient contained therein is effective and that does not contain additional components that are unacceptably toxic to the subject to which the preparation is administered.

[0225] "Pharmaceutically acceptable carrier" refers to components in a pharmaceutical preparation other than the active ingredient that are non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0226] "Radiation therapy" means using directed gamma or beta rays to cause sufficient damage to cells to limit their ability to function normally or to destroy the cells completely. It will be understood that there are many methods known in the art for determining dosage and treatment duration. A typical treatment is given as a single dose, and a typical dosage ranges from 10 to 200 units (gray) per day.

[0227] As used herein, "treatment" (and its grammatical variants, e.g., "treat" or "treating") refers to a clinical intervention in an attempt to alter the natural course of the individual being treated, which can be done for prophylaxis or during the course of clinical pathology. Desired effects of treatment include preventing the onset or recurrence of disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the disease progression rate, remission or palliation of the condition, and recovery or improved prognosis. In some embodiments, the antibodies disclosed herein (e.g., the anti-FcRH5 / anti-CD3 TDB disclosed herein) are used to delay the onset of disease or to slow the progression of the disease.

[0228] "Reduce" or "inhibit" means, for example, the ability to cause an overall decrease of 20% or more, 50% or more, or 75%, 85%, 90%, 95%, or more. In certain embodiments, reduction or inhibition can refer to the effector function of an antibody mediated by the Fc region of the antibody, and such effector functions specifically include CDC, ADCC, and ADCP.

[0229] According to the present invention, the term "vaccine" relates to a pharmaceutical preparation (pharmaceutical composition) or product that, upon administration, induces an immune response, particularly a cellular immune response, and recognizes and attacks disease cells such as pathogens or cancer cells. Vaccines may be used for the prevention or treatment of diseases. The vaccine may be a cancer vaccine. As used herein, a "cancer vaccine" is a composition that stimulates an immune response in a subject against cancer. A cancer vaccine typically consists of a source of a substance or cell (antigen) related to cancer, which is autologous (self-derived) or allogeneic (derived from others) to the subject, and is administered to the subject together with other components (e.g., adjuvants) to further stimulate and enhance the immune response against the antigen. A cancer vaccine can result in stimulating the subject's immune system to produce antibodies against one or more specific antigens and / or produce killer T cells that attack cancer cells bearing those antigens.

[0230] As used herein, "administration" refers to a method of giving a dosage of a compound (e.g., an anti-FcRH5 / anti-CD3 TDB such as sevastamab) to a subject. In some embodiments, the compositions utilized in the methods herein are administered intravenously. The compositions utilized in the methods described herein can be administered, for example, intramuscularly, intravenously, intradermally, transdermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, rectally, locally, intratumorally, peritoneally, subcutaneously, subconjunctivally, intravesicularly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, regionally, by inhalation, by injection, by infusion, by continuous infusion, directly by a local perfusion bath target cell, by catheter, by perfusion, in a cream, or in a lipid composition. The method of administration can vary depending on various factors (e.g., the compound or composition being administered and the severity of the condition, disease, or disorder being treated).

[0231] As used herein, "CD38" refers to a glycoprotein found on the surface of many immune cells, including CD4+, CD8+, B lymphocytes, and natural killer (NK) cells, and includes any native CD38 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. CD38 is typically expressed at a higher level and more uniformly on myeloma cells compared to normal lymphoid and myeloid cells. The term encompasses "full-length", unprocessed CD38, and any form of CD38 resulting from intracellular processing. The term also encompasses naturally occurring variants of CD38, such as splice variants or allelic variants. CD38 is also known in the art as cluster of differentiation 38, ADP-ribosyl cyclase 1, cADPr hydrolase 1, and cyclic ADP-ribose hydrolase 1. CD38 is encoded by the CD38 gene. An exemplary nucleic acid sequence of human CD38 is shown in NCBI reference sequence NM_001775.4 or SEQ ID NO: 33. The amino acid sequence of an exemplary human CD38 protein encoded by CD38 is shown in UniProt accession number P28907 or SEQ ID NO: 34.

[0232] The term "anti-CD38 antibody" includes all antibodies that are useful as therapeutic agents when targeting cells expressing the antigen and that bind to CD38 with sufficient affinity so as not to significantly cross-react with other proteins such as negative control proteins in the assays described below. For example, anti-CD38 antibodies bind to CD38 on the surface of MM cells and mediate cell lysis through complement-dependent cytotoxicity, ADCC, antibody-dependent cell phagocytosis (ADCP), and activation of apoptosis mediated by Fc cross-linking, resulting in depletion of malignant cells and reduction of the overall cancer burden. Anti-CD38 antibodies can also regulate CD38 enzyme activity through inhibition of ribosyl cyclase enzyme activity and stimulation of the cyclic adenosine diphosphate ribose (cADPR) hydrolase activity of CD38. In certain embodiments, the anti-CD38 antibody that binds to CD38 has a dissociation constant (K D ) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 -8 M or less, e.g., 10 -8 M to 10 -13 M, e.g., 10 -9 M to 10- -13 M). In certain embodiments, the anti-CD38 antibody can bind to both human CD38 and chimpanzee CD38. Anti-CD38 antibodies include anti-CD38 antagonist antibodies. Bispecific antibodies in which one arm of the antibody binds to CD38 are also contemplated. This definition of anti-CD38 antibody includes functional fragments of the aforementioned antibodies. Examples of antibodies that bind to CD38 include daratumumab (DARZALEX®) (U.S. Patent No. 7,829,673 and U.S. Patent Publication No.: 20160067205A1); "MOR202" (U.S. Patent No. 8,263,746); and isatuximab (SAR-650984).

[0233] "Subcutaneous administration device" refers to a device adapted or designed to administer a drug, such as a therapeutic antibody (e.g., an anti-FcRH5 / anti-CD3 bispecific antibody (e.g., cevostamab)) or a pharmaceutical formulation, via the subcutaneous route. Exemplary subcutaneous administration devices include, but are not limited to, syringes including prefilled syringes, injection devices, infusion pumps, pen injectors, needleless devices, and patch delivery systems. A subcutaneous administration device can administer a specific volume of a pharmaceutical 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.

[0234] II. Treatment Methods The present invention is based, in part, on a method of treating a subject having cancer (e.g., multiple myeloma (MM)) using a dosing regimen that includes a fractional dose escalation dosing regimen using an anti-fragment crystallizable receptor-like 5 (FcRH5) / anti-cluster of differentiation 3 (CD3) bispecific antibody. The present invention provides a dosing regimen for a cevostamab monotherapy, in which cevostamab is administered subcutaneously to a subject. Exemplary dosing regimens described herein are those of cevostamab as a single agent in a subcutaneous dosing regimen, in which cevostamab is administered in 28-day cycles, cevostamab is administered subcutaneously Q1W in the first cycle (C1), subcutaneously Q2W in cycles 2-6, and subcutaneously Q4W in cycles 7-13. The methods disclosed herein can, for example, facilitate alignment with the dosing schedule of a combination therapy partner. Without wishing to be bound by theory, subcutaneous administration can, for example, reduce C max and / or can reduce C max to time (t max) can be delayed. This method is expected to reduce or inhibit unwanted treatment effects, including cytokine-driven toxicity (e.g., cytokine release syndrome (CRS)), infusion-related reactions (IRR), macrophage activation syndrome (MAS), neurotoxicity, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, and / or elevated liver enzymes. Thus, these methods are useful for treating a subject while achieving a more favorable benefit-risk profile.

[0235] The present invention provides a method useful for treating a subject having cancer (e.g., multiple myeloma), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (i.e., an anti-FcRH5 / anti-CD3 antibody) as a single agent therapy, 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 combinations thereof), in a split-dose escalating dosing regimen, for example, by subcutaneous administration.

[0236] A. Dosing with no escalation, one-step escalation, and two-step escalation in the dosing regimen i. Dosing regimen with no escalation In some embodiments, the present 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 without any step-up doses.

[0237] In some embodiments, the present invention provides a method of treating a subject having MM, comprising subcutaneously administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, the first dosing cycle comprising a first dose (C1D1) of the bispecific antibody, and C1D1 is from about 10 mg to about 1000 mg (e.g., from about 10 mg to about 70 mg, from about 15 mg to about 65 mg, from about 20 mg to about 60 mg, from about 25 mg to about 55 mg, from about 30 mg to about 50 mg, from about 35 mg to about 45 mg, from about 15 mg to about 225 mg, from about 20 mg to about 220 mg, 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 135 mg, from about 110 mg to about 130 mg, from about 115 mg to about 125 mg, from about 10 mg to about 50 mg, from about 25 mg to about 75 mg, from about 50 mg to about 100 mg, from about 75 mg to about 125 mg, from about 100 mg to about 150 mg, from about 125 mg to about 175 mg, from about 150 mg to about 200 mg, from about 175 mg to about 225 mg, from about 200 mg to about 250 mg, from about 225 mg to about 275 mg, from about 250 mg to about 300 mg, from about 275 mg to about 325 mg, from about 300 mg to about 350 mg, from about 325 mg to about 375 mg, from about 350 mg to about 400 mg, from about 375 mg to about 425 mg, from about 400 mg to about 450 mg, from about 425 mg to about 475 mg, from about 450 mg to 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 725 mg to about 775 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,is 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).

[0238] In some embodiments, C1D1 is from about 10 mg to about 200 mg (e.g., from about 10 mg to about 170 mg, from about 11 mg to about 165 mg, from about 12 mg to about 160 mg, from about 13 mg to about 155 mg, from about 14 mg to about 150 mg, from about 15 mg to about 145 mg, from about 16 mg to about 140 mg, from about 17 mg to about 135 mg, from about 18 mg to about 130 mg, from about 19 mg to about 125 mg, from about 20 mg to about 120 mg, from about 21 mg to about 115 mg, from about 22 mg to about 110 mg, from about 23 mg to about 105 mg, from about 24 mg to about 100 mg, from about 25 mg to about 95 mg, from about 26 mg to about 90 mg, from about 27 mg to about 85 mg, from about 28 mg to about 80 mg, from about 29 mg to about 75 mg, from about 30 mg to about 70 mg, from about 31 mg to about 65 mg, from about 32 mg to about 60 mg, from about 33 mg to about 55 mg, from about 34 mg to about 50 mg, from about 35 mg to about 45 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 135 mg, from about 110 mg to about 130 mg, from about 115 mg to about 125 mg, from about 10 mg to about 20 mg, from about 20 mg to about 30 mg, from about 30 mg to about 40 mg, from about 40 mg to about 50 mg, from about 50 mg to about 60 mg, from about 60 mg to about 70 mg, from about 70 mg to about 80 mg, from about 80 mg to about 90 mg, from about 90 mg to about 100 mg, from about 100 mg to about 110 mg, from about 110 mg to about 120 mg, from about 120 mg to about 130 mg, from about 130 mg to about 140 mg, from about 140 mg to about 150 mg, from about 150 mg to about 160 mg, from about 160 mg to about 170 mg, from about 170 mg to about 180 mg, from about 180 mg to about 190 mg, or from about 190 mg to about 200 mg).

[0239] In some embodiments, C1D1 is from 10 mg to 1000 mg (e.g., 10 mg to 70 mg, 15 mg to 65 mg, 20 mg to 60 mg, 25 mg to 55 mg, 30 mg to 50 mg, 35 mg to 45 mg, 15 mg to 225 mg, 20 mg to 220 mg, 25 mg to 215 mg, 30 mg to 210 mg, 35 mg to 205 mg, 40 mg to 200 mg, 45 mg to 195 mg, 50 mg to 190 mg, 55 mg to 185 mg, 60 mg to 180 mg, 65 mg to 175 mg, 70 mg to 170 mg, 75 mg to 165 mg, 80 mg to 160 mg, 85 mg to 155 mg, 90 mg to 150 mg, 95 mg to 145 mg, 100 mg to 140 mg, 105 mg to 135 mg, 110 mg to 130 mg, 115 mg to 125 mg, 10 mg to 50 mg, 25 mg to 75 mg, 50 mg to 100 mg, 75 mg to 125 mg, 100 mg to 150 mg, 125 mg to 175 mg, 150 mg to 200 mg, 175 mg to 225 mg, 200 mg to 250 mg, 225 mg to 275 mg, 250 mg to 300 mg, 275 mg to 325 mg, 300 mg to 350 mg, 325 mg to 375 mg, 350 mg to 400 mg, 375 mg to 425 mg, 400 mg to 450 mg, 425 mg to 475 mg, 450 mg to 500 mg, 475 mg to 525 mg, 500 mg to 550 mg, 525 mg to 575 mg, 550 mg to 600 mg, 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).

[0240] In some embodiments, C1D1 is from 10 mg to 200 mg (e.g., from 10 mg to 170 mg, from 11 mg to 165 mg, from 12 mg to 160 mg, from 13 mg to 155 mg, from 14 mg to 150 mg, from 15 mg to 145 mg, from 16 mg to 140 mg, from 17 mg to 135 mg, from 18 mg to 130 mg, from 19 mg to 125 mg, from 20 mg to 120 mg, from 21 mg to 115 mg, from 22 mg to 110 mg, from 23 mg to 105 mg, from 24 mg to 100 mg, from 25 mg to 95 mg, from 26 mg to 90 mg, from 27 mg to 85 mg, from 28 mg to 80 mg, from 29 mg to 75 mg, from 30 mg to 70 mg, from 31 mg to 65 mg, from 32 mg to 60 mg, from 33 mg to 55 mg, from 34 mg to 50 mg, from 35 mg to 45 mg, from 40 mg to 200 mg, from 45 mg to 195 mg, from 50 mg to 190 mg, from 55 mg to 185 mg, from 60 mg to 180 mg, from 65 mg to 175 mg, from 70 mg to 170 mg, from 75 mg to 165 mg, from 80 mg to 160 mg, from 85 mg to 155 mg, from 90 mg to 150 mg, from 95 mg to 145 mg, from 100 mg to 140 mg, from 105 mg to 135 mg, from 110 mg to 130 mg, from 115 mg to 125 mg, from 10 mg to 20 mg, from 20 mg to 30 mg, from 30 mg to 40 mg, from 40 mg to 50 mg, from 50 mg to 60 mg, from 60 mg to 70 mg, from 70 mg to 80 mg, from 80 mg to 90 mg, from 90 mg to 100 mg, from 100 mg to 110 mg, from 110 mg to 120 mg, from 120 mg to 130 mg, from 130 mg to 140 mg, from 140 mg to 150 mg, from 150 mg to 160 mg, from 160 mg to 170 mg, from 170 mg to 180 mg, or from 190 mg to 200 mg).

[0241] In some embodiments, the present invention provides a method of treating a subject having cancer (e.g., MM), comprising subcutaneously administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle is from about 10 mg to about 1000 mg (e.g., from about 10 mg to about 70 mg, from about 15 mg to about 65 mg, from about 20 mg to about 60 mg, from about 25 mg to about 55 mg, from about 30 mg to about 50 mg, from about 35 mg to about 45 mg, from about 15 mg to about 225 mg, from about 20 mg to about 220 mg, 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 135 mg, from about 110 mg to about 130 mg, from about 115 mg to about 125 mg, from about 10 mg to about 50 mg, from about 25 mg to about 75 mg, from about 50 mg to about 100 mg, from about 75 mg to about 125 mg, from about 100 mg to about 150 mg, from about 125 mg to about 175 mg, from about 150 mg to about 200 mg, from about 175 mg to about 225 mg, from about 200 mg to about 250 mg, from about 225 mg to about 275 mg, from about 250 mg to about 300 mg, from about 275 mg to about 325 mg, from about 300 mg to about 350 mg, from about 325 mg to about 375 mg, from about 350 mg to about 400 mg, from about 375 mg to about 425 mg, from about 400 mg to about 450 mg, from about 425 mg to about 475 mg, from about 450 mg to 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 725 mg to about 775 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,It includes a first dose (C1D1) of the bispecific antibody of about 925 mg to about 975 mg, or about 950 mg to about 1000 mg).

[0242] In some embodiments, C1D1 is about 10 mg to about 200 mg (e.g., about 10 mg to about 200 mg (e.g., about 10 mg to about 170 mg, about 11 mg to about 165 mg, about 12 mg to about 160 mg, about 13 mg to about 155 mg, about 14 mg to about 150 mg, about 15 mg to about 145 mg, about 16 mg to about 140 mg, about 17 mg to about 135 mg, about 18 mg to about 130 mg, about 19 mg to about 125 mg, about 20 mg to about 120 mg, about 21 mg to about 115 mg, about 22 mg to about 110 mg, 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 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 50 mg, about 50 mg to about 60 mg, about 60 mg to about 70 mg, about 70 mg to about 80 mg, about 80 mg to about 90 mg, about 90 mg to about 100 mg, about 100 mg to about 110 mg, about 110 mg to about 120 mg, about 120 mg to about 130 mg, about 130 mg to about 140 mg, about 140 mg to about 150 mg, about 150 mg to about 160 mg, about 160 mg to about 170 mg, about 170 mg to about 180 mg, about 180 mg to about 190 mg, or about 190 mg to about 200 mg).

[0243] In some embodiments, C1D1 is from 10 mg to 1000 mg (e.g., 10 mg to 70 mg, 15 mg to 65 mg, 20 mg to 60 mg, 25 mg to 55 mg, 30 mg to 50 mg, 35 mg to 45 mg, 15 mg to 225 mg, 20 mg to 220 mg, 25 mg to 215 mg, 30 mg to 210 mg, 35 mg to 205 mg, 40 mg to 200 mg, 45 mg to 195 mg, 50 mg to 190 mg, 55 mg to 185 mg, 60 mg to 180 mg, 65 mg to 175 mg, 70 mg to 170 mg, 75 mg to 165 mg, 80 mg to 160 mg, 85 mg to 155 mg, 90 mg to 150 mg, 95 mg to 145 mg, 100 mg to 140 mg, 105 mg to 135 mg, 110 mg to 130 mg, 115 mg to 125 mg, 10 mg to 50 mg, 25 mg to 75 mg, 50 mg to 100 mg, 75 mg to 125 mg, 100 mg to 150 mg, 125 mg to 175 mg, 150 mg to 200 mg, 175 mg to 225 mg, 200 mg to 250 mg, 225 mg to 275 mg, 250 mg to 300 mg, 275 mg to 325 mg, 300 mg to 350 mg, 325 mg to 375 mg, 350 mg to 400 mg, 375 mg to 425 mg, 400 mg to 450 mg, 425 mg to 475 mg, 450 mg to 500 mg, 475 mg to 525 mg, 500 mg to 550 mg, 525 mg to 575 mg, 550 mg to 600 mg, 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).

[0244] In some embodiments, C1D1 is from 10 mg to 200 mg (e.g., from 10 mg to 170 mg, from 11 mg to 165 mg, from 12 mg to 160 mg, from 13 mg to 155 mg, from 14 mg to 150 mg, from 15 mg to 145 mg, from 16 mg to 140 mg, from 17 mg to 135 mg, from 18 mg to 130 mg, from 19 mg to 125 mg, from 20 mg to 120 mg, from 21 mg to 115 mg, from 22 mg to 110 mg, from 23 mg to 105 mg, from 24 mg to 100 mg, from 25 mg to 95 mg, from 26 mg to 90 mg, from 27 mg to 85 mg, from 28 mg to 80 mg, from 29 mg to 75 mg, from 30 mg to 70 mg, from 31 mg to 65 mg, from 32 mg to 60 mg, from 33 mg to 55 mg, from 34 mg to 50 mg, from 35 mg to 45 mg, from 40 mg to 200 mg, from 45 mg to 195 mg, from 50 mg to 190 mg, from 55 mg to 185 mg, from 60 mg to 180 mg, from 65 mg to 175 mg, from 70 mg to 170 mg, from 75 mg to 165 mg, from 80 mg to 160 mg, from 85 mg to 155 mg, from 90 mg to 150 mg, from 95 mg to 145 mg, from 100 mg to 140 mg, from 105 mg to 135 mg, from 110 mg to 130 mg, from 115 mg to 125 mg, from 10 mg to 20 mg, from 20 mg to 30 mg, from 30 mg to 40 mg, from 40 mg to 50 mg, from 50 mg to 60 mg, from 60 mg to 70 mg, from 70 mg to 80 mg, from 80 mg to 90 mg, from 90 mg to 100 mg, from 100 mg to 110 mg, from 110 mg to 120 mg, from 120 mg to 130 mg, from 130 mg to 140 mg, from 140 mg to 150 mg, from 150 mg to 160 mg, from 160 mg to 170 mg, from 170 mg to 180 mg, or from 180 mg to 200 mg).

[0245] In some embodiments, C1D1 is about 10 mg. In some embodiments, C1D1 is about 15 mg. In some embodiments, C1D1 is about 20 mg. In some embodiments, C1D1 is about 25 mg. In some embodiments, C1D1 is about 30 mg. In some embodiments, C1D1 is about 35 mg. In some embodiments, C1D1 is about 40 mg. In some embodiments, C1D1 is about 45 mg. In some embodiments, C1D1 is about 50 mg. In some embodiments, C1D1 is about 55 mg. In some embodiments, C1D1 is about 60 mg. In some embodiments, C1D1 is about 65 mg. In some embodiments, C1D1 is about 70 mg. In some embodiments, C1D1 is about 75 mg. In some embodiments, C1D1 is about 80 mg. In some embodiments, C1D1 is about 85 mg. In some embodiments, C1D1 is about 90 mg. In some embodiments, C1D1 is about 95 mg. In some embodiments, C1D1 is about 100 mg. In some embodiments, C1D1 is about 105 mg. In some embodiments, C1D1 is about 110 mg. In some embodiments, C1D1 is about 115 mg. In some embodiments, C1D1 is about 120 mg. In some embodiments, C1D1 is about 125 mg. In some embodiments, C1D1 is about 130 mg. In some embodiments, C1D1 is about 135 mg. In some embodiments, C1D1 is about 140 mg. In some embodiments, C1D1 is about 145 mg. In some embodiments, C1D1 is about 150 mg. In some embodiments, C1D1 is about 155 mg. In some embodiments, C1D1 is about 160 mg. In some embodiments, C1D1 is about 165 mg. In some embodiments, C1D1 is about 170 mg. In some embodiments, C1D1 is about 175 mg. In some embodiments, C1D1 is about 180 mg. In some embodiments, C1D1 is about 185 mg. In some embodiments, C1D1 is about 190 mg. In some embodiments, C1D1 is about 195 mg. In some embodiments, C1D1 is about 200 mg. In some embodiments, C1D1 is about 205 mg.In some embodiments, C1D1 is about 210 mg. In some embodiments, C1D1 is about 215 mg. In some embodiments, C1D1 is about 220 mg. In some embodiments, C1D1 is about 225 mg. In some embodiments, C1D1 is about 230 mg. In some embodiments, C1D1 is about 235 mg. In some embodiments, C1D1 is about 240 mg. In some embodiments, C1D1 is about 245 mg. In some embodiments, C1D1 is about 250 mg. In some embodiments, C1D1 is about 255 mg. In some embodiments, C1D1 is about 260 mg. In some embodiments, C1D1 is about 265 mg. In some embodiments, C1D1 is about 270 mg. In some embodiments, C1D1 is about 275 mg. In some embodiments, C1D1 is about 280 mg. In some embodiments, C1D1 is about 285 mg. In some embodiments, C1D1 is about 290 mg. In some embodiments, C1D1 is about 295 mg. In some embodiments, C1D1 is about 300 mg. In some embodiments, C1D1 is about 305 mg. In some embodiments, C1D1 is about 310 mg. In some embodiments, C1D1 is about 315 mg. In some embodiments, C1D1 is about 320 mg. In some embodiments, C1D1 is about 325 mg. In some embodiments, C1D1 is about 330 mg. In some embodiments, C1D1 is about 335 mg. In some embodiments, C1D1 is about 340 mg. In some embodiments, C1D1 is about 345 mg. In some embodiments, C1D1 is about 350 mg. In some embodiments, C1D1 is about 355 mg. In some embodiments, C1D1 is about 360 mg. In some embodiments, C1D1 is about 365 mg. In some embodiments, C1D1 is about 370 mg. In some embodiments, C1D1 is about 375 mg. In some embodiments, C1D1 is about 380 mg. In some embodiments, C1D1 is about 385 mg. In some embodiments, C1D1 is about 390 mg. In some embodiments, C1D1 is about 395 mg. In some embodiments, C1D1 is about 400 mg. In some embodiments, C1D1 is about 405 mg.In some embodiments, C1D1 is about 410 mg. In some embodiments, C1D1 is about 415 mg. In some embodiments, C1D1 is about 420 mg. In some embodiments, C1D1 is about 425 mg. In some embodiments, C1D1 is about 430 mg. In some embodiments, C1D1 is about 435 mg. In some embodiments, C1D1 is about 440 mg. In some embodiments, C1D1 is about 445 mg. In some embodiments, C1D1 is about 450 mg. In some embodiments, C1D1 is about 455 mg. In some embodiments, C1D1 is about 460 mg. In some embodiments, C1D1 is about 465 mg. In some embodiments, C1D1 is about 470 mg. In some embodiments, C1D1 is about 475 mg. In some embodiments, C1D1 is about 480 mg. In some embodiments, C1D1 is about 485 mg. In some embodiments, C1D1 is about 490 mg. In some embodiments, C1D1 is about 495 mg. In some embodiments, C1D1 is about 500 mg. In some embodiments, C1D1 is about 505 mg. In some embodiments, C1D1 is about 510 mg. In some embodiments, C1D1 is about 515 mg. In some embodiments, C1D1 is about 520 mg. In some embodiments, C1D1 is about 525 mg. In some embodiments, C1D1 is about 530 mg. In some embodiments, C1D1 is about 535 mg. In some embodiments, C1D1 is about 540 mg. In some embodiments, C1D1 is about 545 mg. In some embodiments, C1D1 is about 550 mg. In some embodiments, C1D1 is about 555 mg. In some embodiments, C1D1 is about 560 mg. In some embodiments, C1D1 is about 565 mg. In some embodiments, C1D1 is about 570 mg. In some embodiments, C1D1 is about 575 mg. In some embodiments, C1D1 is about 580 mg. In some embodiments, C1D1 is about 585 mg. In some embodiments, C1D1 is about 590 mg. In some embodiments, C1D1 is about 595 mg. In some embodiments, C1D1 is about 600 mg. In some embodiments, C1D1 is about 605 mg.In some embodiments, C1D1 is about 610 mg. In some embodiments, C1D1 is about 615 mg. In some embodiments, C1D1 is about 620 mg. In some embodiments, C1D1 is about 625 mg. In some embodiments, C1D1 is about 630 mg. In some embodiments, C1D1 is about 635 mg. In some embodiments, C1D1 is about 640 mg. In some embodiments, C1D1 is about 645 mg. In some embodiments, C1D1 is about 650 mg. In some embodiments, C1D1 is about 655 mg. In some embodiments, C1D1 is about 660 mg. In some embodiments, C1D1 is about 665 mg. In some embodiments, C1D1 is about 670 mg. In some embodiments, C1D1 is about 675 mg. In some embodiments, C1D1 is about 680 mg. In some embodiments, C1D1 is about 685 mg. In some embodiments, C1D1 is about 690 mg. In some embodiments, C1D1 is about 695 mg. In some embodiments, C1D1 is about 700 mg. In some embodiments, C1D1 is about 705 mg. In some embodiments, C1D1 is about 710 mg. In some embodiments, C1D1 is about 715 mg. In some embodiments, C1D1 is about 720 mg. In some embodiments, C1D1 is about 725 mg. In some embodiments, C1D1 is about 730 mg. In some embodiments, C1D1 is about 735 mg. In some embodiments, C1D1 is about 740 mg. In some embodiments, C1D1 is about 745 mg. In some embodiments, C1D1 is about 750 mg. In some embodiments, C1D1 is about 755 mg. In some embodiments, C1D1 is about 760 mg. In some embodiments, C1D1 is about 765 mg. In some embodiments, C1D1 is about 770 mg. In some embodiments, C1D1 is about 775 mg. In some embodiments, C1D1 is about 780 mg. In some embodiments, C1D1 is about 785 mg. In some embodiments, C1D1 is about 790 mg. In some embodiments, C1D1 is about 795 mg. In some embodiments, C1D1 is about 800 mg. In some embodiments, C1D1 is about 805 mg.In some embodiments, C1D1 is about 810 mg. In some embodiments, C1D1 is about 815 mg. In some embodiments, C1D1 is about 820 mg. In some embodiments, C1D1 is about 825 mg. In some embodiments, C1D1 is about 830 mg. In some embodiments, C1D1 is about 835 mg. In some embodiments, C1D1 is about 840 mg. In some embodiments, C1D1 is about 845 mg. In some embodiments, C1D1 is about 850 mg. In some embodiments, C1D1 is about 855 mg. In some embodiments, C1D1 is about 860 mg. In some embodiments, C1D1 is about 865 mg. In some embodiments, C1D1 is about 870 mg. In some embodiments, C1D1 is about 875 mg. In some embodiments, C1D1 is about 880 mg. In some embodiments, C1D1 is about 885 mg. In some embodiments, C1D1 is about 890 mg. In some embodiments, C1D1 is about 895 mg. In some embodiments, C1D1 is about 900 mg. In some embodiments, C1D1 is about 905 mg. In some embodiments, C1D1 is about 910 mg. In some embodiments, C1D1 is about 915 mg. In some embodiments, C1D1 is about 920 mg. In some embodiments, C1D1 is about 925 mg. In some embodiments, C1D1 is about 930 mg. In some embodiments, C1D1 is about 935 mg. In some embodiments, C1D1 is about 940 mg. In some embodiments, C1D1 is about 945 mg. In some embodiments, C1D1 is about 950 mg. In some embodiments, C1D1 is about 955 mg. In some embodiments, C1D1 is about 960 mg. In some embodiments, C1D1 is about 965 mg. In some embodiments, C1D1 is about 970 mg. In some embodiments, C1D1 is about 975 mg. In some embodiments, C1D1 is about 980 mg. In some embodiments, C1D1 is about 985 mg. In some embodiments, C1D1 is about 990 mg. In some embodiments, C1D1 is about 995 mg. In some embodiments, C1D1 is about 1000 mg.

[0246] In some embodiments, C1D1 is 10 mg. In some embodiments, C1D1 is 15 mg. In some embodiments, C1D1 is 20 mg. In some embodiments, C1D1 is 25 mg. In some embodiments, C1D1 is 30 mg. In some embodiments, C1D1 is 35 mg. In some embodiments, C1D1 is 40 mg. In some embodiments, C1D1 is 45 mg. In some embodiments, C1D1 is 50 mg. In some embodiments, C1D1 is 55 mg. In some embodiments, C1D1 is 60 mg. In some embodiments, C1D1 is 65 mg. In some embodiments, C1D1 is 70 mg. In some embodiments, C1D1 is 75 mg. In some embodiments, C1D1 is 80 mg. In some embodiments, C1D1 is 85 mg. In some embodiments, C1D1 is 90 mg. In some embodiments, C1D1 is 95 mg. In some embodiments, C1D1 is 100 mg. In some embodiments, C1D1 is 105 mg. In some embodiments, C1D1 is 110 mg. In some embodiments, C1D1 is 115 mg. In some embodiments, C1D1 is 120 mg. In some embodiments, C1D1 is 125 mg. In some embodiments, C1D1 is 130 mg. In some embodiments, C1D1 is 135 mg. In some embodiments, C1D1 is 140 mg. In some embodiments, C1D1 is 145 mg. In some embodiments, C1D1 is 150 mg. In some embodiments, C1D1 is 155 mg. In some embodiments, C1D1 is 160 mg. In some embodiments, C1D1 is 165 mg. In some embodiments, C1D1 is 170 mg. In some embodiments, C1D1 is 175 mg. In some embodiments, C1D1 is 180 mg. In some embodiments, C1D1 is 185 mg. In some embodiments, C1D1 is 190 mg. In some embodiments, C1D1 is 195 mg. In some embodiments, C1D1 is 200 mg. In some embodiments, C1D1 is 205 mg. In some embodiments, C1D1 is 210 mg. In some embodiments, C1D1 is 215 mg.In some embodiments, C1D1 is 220 mg. In some embodiments, C1D1 is 225 mg. In some embodiments, C1D1 is 230 mg. In some embodiments, C1D1 is 235 mg. In some embodiments, C1D1 is 240 mg. In some embodiments, C1D1 is 245 mg. In some embodiments, C1D1 is 250 mg. In some embodiments, C1D1 is 255 mg. In some embodiments, C1D1 is 260 mg. In some embodiments, C1D1 is 265 mg. In some embodiments, C1D1 is 270 mg. In some embodiments, C1D1 is 275 mg. In some embodiments, C1D1 is 280 mg. In some embodiments, C1D1 is 285 mg. In some embodiments, C1D1 is 290 mg. In some embodiments, C1D1 is 295 mg. In some embodiments, C1D1 is 300 mg. In some embodiments, C1D1 is 305 mg. In some embodiments, C1D1 is 310 mg. In some embodiments, C1D1 is 315 mg. In some embodiments, C1D1 is 320 mg. In some embodiments, C1D1 is 325 mg. In some embodiments, C1D1 is 330 mg. In some embodiments, C1D1 is 335 mg. In some embodiments, C1D1 is 340 mg. In some embodiments, C1D1 is 345 mg. In some embodiments, C1D1 is 350 mg. In some embodiments, C1D1 is 355 mg. In some embodiments, C1D1 is 360 mg. In some embodiments, C1D1 is 365 mg. In some embodiments, C1D1 is 370 mg. In some embodiments, C1D1 is 375 mg. In some embodiments, C1D1 is 380 mg. In some embodiments, C1D1 is 385 mg. In some embodiments, C1D1 is 390 mg. In some embodiments, C1D1 is 395 mg. In some embodiments, C1D1 is 400 mg. In some embodiments, C1D1 is 405 mg. In some embodiments, C1D1 is 410 mg. In some embodiments, C1D1 is 415 mg. In some embodiments, C1D1 is 420 mg.In some embodiments, C1D1 is 425 mg. In some embodiments, C1D1 is 430 mg. In some embodiments, C1D1 is 435 mg. In some embodiments, C1D1 is 440 mg. In some embodiments, C1D1 is 445 mg. In some embodiments, C1D1 is 450 mg. In some embodiments, C1D1 is 455 mg. In some embodiments, C1D1 is 460 mg. In some embodiments, C1D1 is 465 mg. In some embodiments, C1D1 is 470 mg. In some embodiments, C1D1 is 475 mg. In some embodiments, C1D1 is 480 mg. In some embodiments, C1D1 is 485 mg. In some embodiments, C1D1 is 490 mg. In some embodiments, C1D1 is 495 mg. In some embodiments, C1D1 is 500 mg. In some embodiments, C1D1 is 505 mg. In some embodiments, C1D1 is 510 mg. In some embodiments, C1D1 is 515 mg. In some embodiments, C1D1 is 520 mg. In some embodiments, C1D1 is 525 mg. In some embodiments, C1D1 is 530 mg. In some embodiments, C1D1 is 535 mg. In some embodiments, C1D1 is 540 mg. In some embodiments, C1D1 is 545 mg. In some embodiments, C1D1 is 550 mg. In some embodiments, C1D1 is 555 mg. In some embodiments, C1D1 is 560 mg. In some embodiments, C1D1 is 565 mg. In some embodiments, C1D1 is 570 mg. In some embodiments, C1D1 is 575 mg. In some embodiments, C1D1 is 580 mg. In some embodiments, C1D1 is 585 mg. In some embodiments, C1D1 is 590 mg. In some embodiments, C1D1 is 595 mg. In some embodiments, C1D1 is 600 mg. In some embodiments, C1D1 is 605 mg. In some embodiments, C1D1 is 610 mg. In some embodiments, C1D1 is 615 mg. In some embodiments, C1D1 is 620 mg. In some embodiments, C1D1 is 625 mg.In some embodiments, C1D1 is 630 mg. In some embodiments, C1D1 is 635 mg. In some embodiments, C1D1 is 640 mg. In some embodiments, C1D1 is 645 mg. In some embodiments, C1D1 is 650 mg. In some embodiments, C1D1 is 655 mg. In some embodiments, C1D1 is 660 mg. In some embodiments, C1D1 is 665 mg. In some embodiments, C1D1 is 670 mg. In some embodiments, C1D1 is 675 mg. In some embodiments, C1D1 is 680 mg. In some embodiments, C1D1 is 685 mg. In some embodiments, C1D1 is 690 mg. In some embodiments, C1D1 is 695 mg. In some embodiments, C1D1 is 700 mg. In some embodiments, C1D1 is 705 mg. In some embodiments, C1D1 is 710 mg. In some embodiments, C1D1 is 715 mg. In some embodiments, C1D1 is 720 mg. In some embodiments, C1D1 is 725 mg. In some embodiments, C1D1 is 730 mg. In some embodiments, C1D1 is 735 mg. In some embodiments, C1D1 is 740 mg. In some embodiments, C1D1 is 745 mg. In some embodiments, C1D1 is 750 mg. In some embodiments, C1D1 is 755 mg. In some embodiments, C1D1 is 760 mg. In some embodiments, C1D1 is 765 mg. In some embodiments, C1D1 is 770 mg. In some embodiments, C1D1 is 775 mg. In some embodiments, C1D1 is 780 mg. In some embodiments, C1D1 is 785 mg. In some embodiments, C1D1 is 790 mg. In some embodiments, C1D1 is 795 mg. In some embodiments, C1D1 is 800 mg. In some embodiments, C1D1 is 805 mg. In some embodiments, C1D1 is 810 mg. In some embodiments, C1D1 is 815 mg. In some embodiments, C1D1 is 820 mg. In some embodiments, C1D1 is 825 mg. In some embodiments, C1D1 is 830 mg.In some embodiments, C1D1 is 835 mg. In some embodiments, C1D1 is 840 mg. In some embodiments, C1D1 is 845 mg. In some embodiments, C1D1 is 850 mg. In some embodiments, C1D1 is 855 mg. In some embodiments, C1D1 is 860 mg. In some embodiments, C1D1 is 865 mg. In some embodiments, C1D1 is 870 mg. In some embodiments, C1D1 is 875 mg. In some embodiments, C1D1 is 880 mg. In some embodiments, C1D1 is 885 mg. In some embodiments, C1D1 is 890 mg. In some embodiments, C1D1 is 895 mg. In some embodiments, C1D1 is 900 mg. In some embodiments, C1D1 is 905 mg. In some embodiments, C1D1 is 910 mg. In some embodiments, C1D1 is 915 mg. In some embodiments, C1D1 is 920 mg. In some embodiments, C1D1 is 925 mg. In some embodiments, C1D1 is 930 mg. In some embodiments, C1D1 is 935 mg. In some embodiments, C1D1 is 940 mg. In some embodiments, C1D1 is 945 mg. In some embodiments, C1D1 is 950 mg. In some embodiments, C1D1 is 955 mg. In some embodiments, C1D1 is 960 mg. In some embodiments, C1D1 is 965 mg. In some embodiments, C1D1 is 970 mg. In some embodiments, C1D1 is 975 mg. In some embodiments, C1D1 is 980 mg. In some embodiments, C1D1 is 985 mg. In some embodiments, C1D1 is 990 mg. In some embodiments, C1D1 is 995 mg. In some embodiments, C1D1 is 1000 mg.

[0247] ii. One-step escalating dosing regimen In some embodiments, 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 one-step escalating dosing regimen.

[0248] In some embodiments, the present invention provides a method of treating a subject having MM, comprising subcutaneously administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a first dose of the bispecific antibody (C1D1) and a second dose of the bispecific antibody (C1D2), and C1D1 is from about 0.1 mg to about 50 mg (e.g., from about 0.1 mg to about 9.5 mg, from about 0.2 mg to about 9 mg, from about 0.3 mg to about 8.5 mg, from about 0.4 mg to about 8 mg, from about 0.5 mg to about 7.5 mg, from about 0.6 mg to about 7 mg, from about 0.7 mg to about 6.5 mg, from about 0.8 mg to about 6 mg, from about 0.9 mg to about 5.5 mg, from about 1 mg to about 5 mg, from about 1.1 mg to about 4.5 mg, from about 1.2 mg to about 4 mg, from about 1.3 mg to about 3.5 mg, from about 1.4 mg to about 3 mg, from about 1.5 mg to about 2.5 mg, from about 1 mg to about 3 mg, from about 0.2 mg to about 35 mg, from about 0.3 mg to about 30 mg, from about 0.4 mg to about 29 mg, from about 0.5 mg to about 28 mg, from about 1 mg to about 27 mg, from about 1.5 mg to about 26 mg, from about 2 mg to about 25 mg, from about 2.5 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, from about 0.4 mg to about 2.5 mg, from about 0.5 mg to about 3 mg, from about 0.6 mg to about 3.5 mg, from about 0.7 mg to about 4 mg, from about 0.8 mg to about 4.5 mg, from about 0.9 mg to about 5 mg, from about 1 mg to about 6 mg, from about 1.5 mg to about 6.5 mg, from about 2 mg to about 7 mg, from about 2.5 mg to about 7.5 mg, from about 3 mg to about 8 mg, from about 3.5 mg to about 8.5 mg, from about 4 mg to about 9 mg, from about 4.5 mg to about 9.5 mg, from about 5 mg to about 10 mg, from about 5.5 mg to about 10.5 mg, from about 6 mg to about 11 mg, from about 6.5 mg to about 11.5 mg, from about 7 mg to about 12 mg, from about 7.5 mg to about 12.5 mg, from about 8 mg to about 13 mg, from about 8.5 mg to about 13.5 mg, from about 9 mg to about 14 mg, from about 9.5 mg to about 14.5 mg,from 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 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), and C1D2 is from about 10 mg to about 1000 mg (for example, 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 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, 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 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),

[0249] In some embodiments, C1D2 is from about 10 mg to 200 mg (e.g., 10 mg to about 170 mg, about 11 mg to about 165 mg, about 12 mg to about 160 mg, about 13 mg to about 155 mg, about 14 mg to about 150 mg, about 15 mg to about 145 mg, about 16 mg to about 140 mg, about 17 mg to about 135 mg, about 18 mg to about 130 mg, about 19 mg to about 125 mg, about 20 mg to about 120 mg, about 21 mg to about 115 mg, about 22 mg to about 110 mg, 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 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 50 mg, about 50 mg to about 60 mg, about 60 mg to about 70 mg, about 70 mg to about 80 mg, about 80 mg to about 90 mg, about 90 mg to about 100 mg, about 100 mg to about 110 mg, about 110 mg to about 120 mg, about 120 mg to about 130 mg, about 130 mg to about 140 mg, about 140 mg to about 150 mg, about 150 mg to about 160 mg, about 160 mg to about 170 mg, about 170 mg to about 180 mg, or about 180 mg to about 200 mg).

[0250] In some embodiments, C1D1 is from 0.1 mg to 50 mg (for example, from 0.1 mg to 9.5 mg, from 0.2 mg to 9 mg, from 0.3 mg to 8.5 mg, from 0.4 mg to 8 mg, from 0.5 mg to 7.5 mg, from 0.6 mg to 7 mg, from 0.7 mg to 6.5 mg, from 0.8 mg to 6 mg, from 0.9 mg to 5.5 mg, from 1 mg to 5 mg, from 1.1 mg to 4.5 mg, from 1.2 mg to 4 mg, from 1.3 mg to 3.5 mg, from 1.4 mg to 3 mg, from 1.5 mg to 2.5 mg, from 1 mg to 3 mg, from 0.2 mg to 35 mg, from 0.3 mg to 30 mg, from 0.4 mg to 29 mg, from 0.5 mg to 28 mg, from 1 mg to 27 mg, from 1.5 mg to 26 mg, from 2 mg to 25 mg, from 2.5 mg to 24 mg, from 3 mg to 23 mg, from 3.5 mg to 22 mg, from 4 mg to 21 mg, from 4.5 mg to 20 mg, from 5 mg to 19 mg, from 5.5 mg to 18 mg, from 6 mg to 17 mg, from 6.5 mg to 16 mg, from 7 mg to 15 mg, from 7.5 mg to 14 mg, from 8 mg to 13 mg, from 8 mg to 12 mg, from 8.5 mg to 12 mg, from 9 mg to 11 mg, from 0.1 mg to 1 mg, from 0.2 mg to 1.5 mg, from 0.3 mg to 2 mg, from 0.4 mg to 2.5 mg, from 0.5 mg to 3 mg, from 0.6 mg to 3.5 mg, from 0.7 mg to 4 mg, from 0.8 mg to 4.5 mg, from 0.9 mg to 5 mg, from 1 mg to 6 mg, from 1.5 mg to 6.5 mg, from 2 mg to 7 mg, from 2.5 mg to 7.5 mg, from 3 mg to 8 mg, from 3.5 mg to 8.5 mg, from 4 mg to 9 mg, from 4.5 mg to 9.5 mg, from 5 mg to 10 mg, from 5.5 mg to 10.5 mg, from 6 mg to 11 mg, from 6.5 mg to 11.5 mg, from 7 mg to 12 mg, from 7.5 mg to 12.5 mg, from 8 mg to 13 mg, from 8.5 mg to 13.5 mg, from 9 mg to 14 mg, from 9.5 mg to 14.5 mg, from 10 mg to 15 mg, from 11 mg to 16 mg, from 12 mg to 17 mg, from 13 mg to 18 mg, from 14 mg to 19 mg, from 15 mg to 20 mg, from 16 mg to 21 mg, from 17 mg to 22 mg, from 18 mg to 23 mg, from 19 mg to 24 mg, from 20 mg to 25 mg, from 21 mg to 26 mg, from 22 mg to 27 mg, from 23 mg to 28 mg, from 24 mg to 29 mg, from 25 mg to 30 mg, from 26 mg to 31 mg, from 27 mg to 32 mg, from 28 mg to 33 mg, from 29 mg to 34 mg, from 30 mg to 35 mg, from 31 mg to 36 mg, from 32 mg to 37 mg, from 33 mg to 38 mg, from 34 mg to 39 mg, from 35 mg to 40 mg, from 36 mg to 41 mg, from 37 mg to 42 mg,38 mg to 43 mg, 39 mg to 44 mg, 40 mg to 45 mg, 41 mg to 46 mg, 42 mg to 47 mg, 43 mg to 48 mg, 44 mg to 49 mg, 45 mg to 50 mg), and C1D2 is 10 mg to 1000 mg (for example, 10 mg to 70 mg, 15 mg to 65 mg, 20 mg to 60 mg, 25 mg to 55 mg, 30 mg to 50 mg, 35 mg to 45 mg, 15 mg to 225 mg, 20 mg to 220 mg, 25 mg to 215 mg, 30 mg to 210 mg, 35 mg to 205 mg, 40 mg to 200 mg, 45 mg to 195 mg, 50 mg to 190 mg, 55 mg to 185 mg, 60 mg to 180 mg, 65 mg to 175 mg, 70 mg to 170 mg, 75 mg to 165 mg, 80 mg to 160 mg, 85 mg to 155 mg, 90 mg to 150 mg, 95 mg to 145 mg, 100 mg to 140 mg, 105 mg to 135 mg, 110 mg to 130 mg, 115 mg to 125 mg, 10 mg to 50 mg, 25 mg to 75 mg, 50 mg to 100 mg, 75 mg to 125 mg, 100 mg to 150 mg, 125 mg to 175 mg, 150 mg to 200 mg, 175 mg to 225 mg, 200 mg to 250 mg, 225 mg to 275 mg, 250 mg to 300 mg, 275 mg to 325 mg, 300 mg to 350 mg, 325 mg to 375 mg, 350 mg to 400 mg, 375 mg to 425 mg, 400 mg to 450 mg, 425 mg to 475 mg, 450 mg to 500 mg, 475 mg to 525 mg, 500 mg to 550 mg, 525 mg to 575 mg, 550 mg to 600 mg, 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).

[0251] In some embodiments, C1D2 is from 10 mg to 200 mg (e.g., from 10 mg to 170 mg, from 11 mg to 165 mg, from 12 mg to 160 mg, from 13 mg to 155 mg, from 14 mg to 150 mg, from 15 mg to 145 mg, from 16 mg to 140 mg, from 17 mg to 135 mg, from 18 mg to 130 mg, from 19 mg to 125 mg, from 20 mg to 120 mg, from 21 mg to 115 mg, from 22 mg to 110 mg, from 23 mg to 105 mg, from 24 mg to 100 mg, from 25 mg to 95 mg, from 26 mg to 90 mg, from 27 mg to 85 mg, from 28 mg to 80 mg, from 29 mg to 75 mg, from 30 mg to 70 mg, from 31 mg to 65 mg, from 32 mg to 60 mg, from 33 mg to 55 mg, from 34 mg to 50 mg, from 35 mg to 45 mg, from 40 mg to 200 mg, from 45 mg to 195 mg, from 50 mg to 190 mg, from 55 mg to 185 mg, from 60 mg to 180 mg, from 65 mg to 175 mg, from 70 mg to 170 mg, from 75 mg to 165 mg, from 80 mg to 160 mg, from 85 mg to 155 mg, from 90 mg to 150 mg, from 95 mg to 145 mg, from 100 mg to 140 mg, from 105 mg to 135 mg, from 110 mg to 130 mg, from 115 mg to 125 mg, from 10 mg to 20 mg, from 20 mg to 30 mg, from 30 mg to 40 mg, from 40 mg to 50 mg, from 50 mg to 60 mg, from 60 mg to 70 mg, from 70 mg to 80 mg, from 80 mg to 90 mg, from 90 mg to 100 mg, from 100 mg to 110 mg, from 110 mg to 120 mg, from 120 mg to 130 mg, from 130 mg to 140 mg, from 140 mg to 150 mg, from 150 mg to 160 mg, from 160 mg to 170 mg, from 170 mg to 180 mg, or from 180 mg to 200 mg).

[0252] In some embodiments, the present invention provides a method of treating a subject having cancer (e.g., MM), comprising subcutaneously administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein 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 (C1D1; cycle 1, dose 2), C1D1 is less than C1D1, and C1D1 is from about 0.1 mg to about 50 mg (e.g., from about 0.1 mg to about 9.5 mg, from about 0.2 mg to about 9 mg, from about 0.3 mg to about 8.5 mg, from about 0.4 mg to about 8 mg, from about 0.5 mg to about 7.5 mg, from about 0.6 mg to about 7 mg, from about 0.7 mg to about 6.5 mg, from about 0.8 mg to about 6 mg, from about 0.9 mg to about 5.5 mg, from about 1 mg to about 5 mg, from about 1.1 mg to about 4.5 mg, from about 1.2 mg to about 4 mg, from about 1.3 mg to about 3.5 mg, from about 1.4 mg to about 3 mg, from about 1.5 mg to about 2.5 mg, from about 1 mg to about 3 mg, from about 0.2 mg to about 35 mg, from about 0.3 mg to about 30 mg, from about 0.4 mg to about 29 mg, from about 0.5 mg to about 28 mg, from about 1 mg to about 27 mg, from about 1.5 mg to about 26 mg, from about 2 mg to about 25 mg, from about 2.5 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, from about 0.4 mg to about 2.5 mg, from about 0.5 mg to about 3 mg, from about 0.6 mg to about 3.5 mg, from about 0.7 mg to about 4 mg, from about 0.8 mg to about 4.5 mg, from about 0.9 mg to about 5 mg, from about 1 mg to about 6 mg, from about 1.5 mg to about 6.5 mg, from about 2 mg to about 7 mg, from about 2.5 mg to about 7.5 mg, from about 3 mg to about 8 mg, from about 3.5 mg to about 8.5 mg, from about 4 mg to about 9 mg, from about 4.5 mg to about 9.5 mg, from about 5 mg to about 10 mg, from about 5.5 mg to about 10.5 mg, from about 6 mg to about 11 mg, from about 6.5 mg to about 11.5 mg, from about 7 mg to about 12 mg, from about 7.5 mg to about 12.5 mg,from about 8 mg to about 13 mg, from about 8.5 mg to about 13.5 mg, from about 9 mg to about 14 mg, from about 9.5 mg to about 14.5 mg, from about 10 mg to about 15 mg, from about 11 mg to about 16 mg, from about 12 mg to about 17 mg, from about 13 mg to about 18 mg, from about 14 mg to about 19 mg, from about 15 mg to about 20 mg, from about 16 mg to about 21 mg, from about 17 mg to about 22 mg, from about 18 mg to about 23 mg, from about 19 mg to about 24 mg, from about 20 mg to about 25 mg, from about 21 mg to about 26 mg, from about 22 mg to about 27 mg, from about 23 mg to about 28 mg, from about 24 mg to about 29 mg, from about 25 mg to about 30 mg, from about 26 mg to about 31 mg, from about 27 mg to about 32 mg, from about 28 mg to about 33 mg, from about 29 mg to about 34 mg, from about 30 mg to about 35 mg, from about 31 mg to about 36 mg, from about 32 mg to about 37 mg, from about 33 mg to about 38 mg, from about 34 mg to about 39 mg, from about 35 mg to about 40 mg, from about 36 mg to about 41 mg, from about 37 mg to about 42 mg, from about 38 mg to about 43 mg, from about 39 mg to about 44 mg, from about 40 mg to about 45 mg, from about 41 mg to about 46 mg, from about 42 mg to about 47 mg, from about 43 mg to about 48 mg, from about 44 mg to about 49 mg, from about 45 mg to about 50 mg), and C1D2 is from about 10 mg to about 1000 mg (for example, from about 10 mg to about 70 mg, from about 15 mg to about 65 mg, from about 20 mg to about 60 mg, from about 25 mg to about 55 mg, from about 30 mg to about 50 mg, from about 35 mg to about 45 mg, from about 15 mg to about 225 mg, from about 20 mg to about 220 mg, 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 135 mg, from about 110 mg to about 130 mg, from about 115 mg to about 125 mg, from about 10 mg to about 50 mg, from about 25 mg to about 75 mg, from about 50 mg to about 100 mg, from about 75 mg to about 125 mg, from about 100 mg to about 150 mg, from about 125 mg to about 175 mg, from about 150 mg to about 200 mg, from about 175 mg to about 225 mg, from about 200 mg to about 250 mg, from 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 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).

[0253] In some embodiments, C1D2 is from about 10 mg to 200 mg (e.g., 10 mg to about 170 mg, about 11 mg to about 165 mg, about 12 mg to about 160 mg, about 13 mg to about 155 mg, about 14 mg to about 150 mg, about 15 mg to about 145 mg, about 16 mg to about 140 mg, about 17 mg to about 135 mg, about 18 mg to about 130 mg, about 19 mg to about 125 mg, about 20 mg to about 120 mg, about 21 mg to about 115 mg, about 22 mg to about 110 mg, 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 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 50 mg, about 50 mg to about 60 mg, about 60 mg to about 70 mg, about 70 mg to about 80 mg, about 80 mg to about 90 mg, about 90 mg to about 100 mg, about 100 mg to about 110 mg, about 110 mg to about 120 mg, about 120 mg to about 130 mg, about 130 mg to about 140 mg, about 140 mg to about 150 mg, about 150 mg to about 160 mg, about 160 mg to about 170 mg, about 170 mg to about 180 mg, or about 180 mg to about 200 mg).

[0254] In some embodiments, C1D1 is 0.1 mg to 50 mg (e.g., 0.1 mg to 9.5 mg, 0.2 mg to 9 mg, 0.3 mg to 8.5 mg, 0.4 mg to 8 mg, 0.5 mg to 7.5 mg, 0.6 mg to 7 mg, 0.7 mg to 6.5 mg, 0.8 mg to 6 mg, 0.9 mg to 5.5 mg, 1 mg to 5 mg, 1.1 mg to 4.5 mg, 1.2 mg to 4 mg, 1.3 mg to 3.5 mg, 1.4 mg to 3 mg, 1.5 mg to 2.5 mg, 1 mg to 3 mg, 0.2 mg to 35 mg, 0.3 mg 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, 0.2 mg to 1.5 mg, 0.3 mg to 2 mg, 0.4 mg to 2.5 mg, 0.5 mg to 3 mg, 0.6 mg to 3.5 mg, 0.7 mg to 4 mg, 0.8 mg to 4.5 mg, 0.9 mg to 5 mg, 1 mg to 6 mg, 1.5 mg to 6.5 mg, 2 mg to 7 mg, 2.5 mg to 7.5 mg, 3 mg to 8 mg, 3.5 mg to 8.5 mg, 4 mg to 9 mg, 4.5 mg to 9.5 mg, 5 mg to 10 mg, 5.5 mg to 10.5 mg, 6 mg to 11 mg, 6.5 mg to 11.5 mg, 7 mg to 12 mg, 7.5 mg to 12.5 mg, 8 mg to 13 mg, 8 mg to 12 mg, 8.5 mg to 13.5 mg, 9 mg to 14 mg, 9.5 mg to 14.5 mg, 10 mg to 15 mg, 11 mg to 16 mg, 12 mg to 17 mg, 13 mg to 18 mg, 14 mg to 19 mg, 15 mg to 20 mg, 16 mg to 21 mg, 17 mg to 22 mg, 18 mg to 23 mg, 19 mg to 24 mg, 20 mg to 25 mg, 21 mg to 26 mg, 22 mg to 27 mg, 23 mg to 28 mg, 24 mg to 29 mg, 25 mg to 30 mg, 26 mg to 31 mg, 27 mg to 32 mg, 28 mg to 33 mg, 29 mg to 34 mg, 30 mg to 35 mg, 31 mg to 36 mg, 32 mg to 37 mg, 33 mg to 38 mg, 34 mg to 39 mg, 35 mg to 40 mg, 36 mg to 41 mg, 37 mg to 42 mg,38 mg to 43 mg, 39 mg to 44 mg, 40 mg to 45 mg, 41 mg to 46 mg, 42 mg to 47 mg, 43 mg to 48 mg, 44 mg to 49 mg, 45 mg to 50 mg), and C1D2 is 10 mg to 1000 mg (for example, 10 mg to 70 mg, 15 mg to 65 mg, 20 mg to 60 mg, 25 mg to 55 mg, 30 mg to 50 mg, 35 mg to 45 mg, 15 mg to 225 mg, 20 mg to 220 mg, 25 mg to 215 mg, 30 mg to 210 mg, 35 mg to 205 mg, 40 mg to 200 mg, 45 mg to 195 mg, 50 mg to 190 mg, 55 mg to 185 mg, 60 mg to 180 mg, 65 mg to 175 mg, 70 mg to 170 mg, 75 mg to 165 mg, 80 mg to 160 mg, 85 mg to 155 mg, 90 mg to 150 mg, 95 mg to 145 mg, 100 mg to 140 mg, 105 mg to 135 mg, 110 mg to 130 mg, 115 mg to 125 mg, 10 mg to 50 mg, 25 mg to 75 mg, 50 mg to 100 mg, 75 mg to 125 mg, 100 mg to 150 mg, 125 mg to 175 mg, 150 mg to 200 mg, 175 mg to 225 mg, 200 mg to 250 mg, 225 mg to 275 mg, 250 mg to 300 mg, 275 mg to 325 mg, 300 mg to 350 mg, 325 mg to 375 mg, 350 mg to 400 mg, 375 mg to 425 mg, 400 mg to 450 mg, 425 mg to 475 mg, 450 mg to 500 mg, 475 mg to 525 mg, 500 mg to 550 mg, 525 mg to 575 mg, 550 mg to 600 mg, 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).

[0255] In some embodiments, C1D2 is from 10 mg to 200 mg (e.g., from 10 mg to 170 mg, from 11 mg to 165 mg, from 12 mg to 160 mg, from 13 mg to 155 mg, from 14 mg to 150 mg, from 15 mg to 145 mg, from 16 mg to 140 mg, from 17 mg to 135 mg, from 18 mg to 130 mg, from 19 mg to 125 mg, from 20 mg to 120 mg, from 21 mg to 115 mg, from 22 mg to 110 mg, from 23 mg to 105 mg, from 24 mg to 100 mg, from 25 mg to 95 mg, from 26 mg to 90 mg, from 27 mg to 85 mg, from 28 mg to 80 mg, from 29 mg to 75 mg, from 30 mg to 70 mg, from 31 mg to 65 mg, from 32 mg to 60 mg, from 33 mg to 55 mg, from 34 mg to 50 mg, from 35 mg to 45 mg, from 40 mg to 200 mg, from 45 mg to 195 mg, from 50 mg to 190 mg, from 55 mg to 185 mg, from 60 mg to 180 mg, from 65 mg to 175 mg, from 70 mg to 170 mg, from 75 mg to 165 mg, from 80 mg to 160 mg, from 85 mg to 155 mg, from 90 mg to 150 mg, from 95 mg to 145 mg, from 100 mg to 140 mg, from 105 mg to 135 mg, from 110 mg to 130 mg, from 115 mg to 125 mg, from 10 mg to 20 mg, from 20 mg to 30 mg, from 30 mg to 40 mg, from 40 mg to 50 mg, from 50 mg to 60 mg, from 60 mg to 70 mg, from 70 mg to 80 mg, from 80 mg to 90 mg, from 90 mg to 100 mg, from 100 mg to 110 mg, from 110 mg to 120 mg, from 120 mg to 130 mg, from 130 mg to 140 mg, from 140 mg to 150 mg, from 150 mg to 160 mg, from 160 mg to 170 mg, from 170 mg to 180 mg, or from 190 mg to 200 mg).

[0256] In some embodiments, C1D1 is about 1 mg. In some embodiments, C1D1 is about 2 mg. In some embodiments, C1D1 is about 3 mg. In some embodiments, C1D1 is about 4 mg. In some embodiments, C1D1 is about 5 mg. In some embodiments, C1D1 is about 6 mg. In some embodiments, C1D1 is about 7 mg. In some embodiments, C1D1 is about 8 mg. In some embodiments, C1D1 is about 9 mg. In some embodiments, C1D1 is about 10 mg. In some embodiments, C1D1 is about 11 mg. In some embodiments, C1D1 is about 12 mg. In some embodiments, C1D1 is about 13 mg. In some embodiments, C1D1 is about 14 mg. In some embodiments, C1D1 is about 15 mg. In some embodiments, C1D1 is about 16 mg. In some embodiments, C1D1 is about 17 mg. In some embodiments, C1D1 is about 18 mg. In some embodiments, C1D1 is about 19 mg. In some embodiments, C1D1 is about 20 mg. In some embodiments, C1D1 is about 21 mg. In some embodiments, C1D1 is about 22 mg. In some embodiments, C1D1 is about 23 mg. In some embodiments, C1D1 is about 24 mg. In some embodiments, C1D1 is about 25 mg. In some embodiments, C1D1 is about 26 mg. In some embodiments, C1D1 is about 27 mg. In some embodiments, C1D1 is about 28 mg. In some embodiments, C1D1 is about 29 mg. In some embodiments, C1D1 is about 30 mg. In some embodiments, C1D1 is about 31 mg. In some embodiments, C1D1 is about 32 mg. In some embodiments, C1D1 is about 33 mg. In some embodiments, C1D1 is about 34 mg. In some embodiments, C1D1 is about 35 mg. In some embodiments, C1D1 is about 36 mg. In some embodiments, C1D1 is about 37 mg. In some embodiments, C1D1 is about 38 mg. In some embodiments, C1D1 is about 39 mg. In some embodiments, C1D1 is about 40 mg. In some embodiments, C1D1 is about 41 mg. In some embodiments, C1D1 is about 42 mg.In some embodiments, C1D1 is about 43 mg. In some embodiments, C1D1 is about 44 mg. In some embodiments, C1D1 is about 45 mg. In some embodiments, C1D1 is about 46 mg. In some embodiments, C1D1 is about 47 mg. In some embodiments, C1D1 is about 48 mg. In some embodiments, C1D1 is about 49 mg. In some embodiments, C1D1 is about 50 mg.

[0257] In some embodiments, C1D2 is about 10 mg. In some embodiments, C1D2 is about 15 mg. In some embodiments, C1D2 is about 20 mg. In some embodiments, C1D2 is about 25 mg. In some embodiments, C1D2 is about 30 mg. In some embodiments, C1D2 is about 35 mg. In some embodiments, C1D2 is about 40 mg. In some embodiments, C1D2 is about 45 mg. In some embodiments, C1D2 is about 50 mg. In some embodiments, C1D2 is about 55 mg. In some embodiments, C1D2 is about 60 mg. In some embodiments, C1D2 is about 65 mg. In some embodiments, C1D2 is about 70 mg. In some embodiments, C1D2 is about 75 mg. In some embodiments, C1D2 is about 80 mg. In some embodiments, C1D2 is about 85 mg. In some embodiments, C1D2 is about 90 mg. In some embodiments, C1D2 is about 95 mg. In some embodiments, C1D2 is about 100 mg. In some embodiments, C1D2 is about 105 mg. In some embodiments, C1D2 is about 110 mg. In some embodiments, C1D2 is about 115 mg. In some embodiments, C1D2 is about 120 mg. In some embodiments, C1D2 is about 125 mg. In some embodiments, C1D2 is about 130 mg. In some embodiments, C1D2 is about 135 mg. In some embodiments, C1D2 is about 140 mg. In some embodiments, C1D2 is about 145 mg. In some embodiments, C1D2 is about 150 mg. In some embodiments, C1D2 is about 155 mg. In some embodiments, C1D2 is about 160 mg. In some embodiments, C1D2 is about 165 mg. In some embodiments, C1D2 is about 170 mg. In some embodiments, C1D2 is about 175 mg. In some embodiments, C1D2 is about 180 mg. In some embodiments, C1D2 is about 185 mg. In some embodiments, C1D2 is about 190 mg. In some embodiments, C1D2 is about 195 mg. In some embodiments, C1D2 is about 200 mg. In some embodiments, C1D2 is about 205 mg.In some embodiments, C1D2 is about 210 mg. In some embodiments, C1D2 is about 215 mg. In some embodiments, C1D2 is about 220 mg. In some embodiments, C1D2 is about 225 mg. In some embodiments, C1D2 is about 230 mg. In some embodiments, C1D2 is about 235 mg. In some embodiments, C1D2 is about 240 mg. In some embodiments, C1D2 is about 245 mg. In some embodiments, C1D2 is about 250 mg. In some embodiments, C1D2 is about 255 mg. In some embodiments, C1D2 is about 260 mg. In some embodiments, C1D2 is about 265 mg. In some embodiments, C1D2 is about 270 mg. In some embodiments, C1D2 is about 275 mg. In some embodiments, C1D2 is about 280 mg. In some embodiments, C1D2 is about 285 mg. In some embodiments, C1D2 is about 290 mg. In some embodiments, C1D2 is about 295 mg. In some embodiments, C1D2 is about 300 mg. In some embodiments, C1D2 is about 305 mg. In some embodiments, C1D2 is about 310 mg. In some embodiments, C1D2 is about 315 mg. In some embodiments, C1D2 is about 320 mg. In some embodiments, C1D2 is about 325 mg. In some embodiments, C1D2 is about 330 mg. In some embodiments, C1D2 is about 335 mg. In some embodiments, C1D2 is about 340 mg. In some embodiments, C1D2 is about 345 mg. In some embodiments, C1D2 is about 350 mg. In some embodiments, C1D2 is about 355 mg. In some embodiments, C1D2 is about 360 mg. In some embodiments, C1D2 is about 365 mg. In some embodiments, C1D2 is about 370 mg. In some embodiments, C1D2 is about 375 mg. In some embodiments, C1D2 is about 380 mg. In some embodiments, C1D2 is about 385 mg. In some embodiments, C1D2 is about 390 mg. In some embodiments, C1D2 is about 395 mg. In some embodiments, C1D2 is about 400 mg. In some embodiments, C1D2 is about 405 mg.In some embodiments, C1D2 is about 410 mg. In some embodiments, C1D2 is about 415 mg. In some embodiments, C1D2 is about 420 mg. In some embodiments, C1D2 is about 425 mg. In some embodiments, C1D2 is about 430 mg. In some embodiments, C1D2 is about 435 mg. In some embodiments, C1D2 is about 440 mg. In some embodiments, C1D2 is about 445 mg. In some embodiments, C1D2 is about 450 mg. In some embodiments, C1D2 is about 455 mg. In some embodiments, C1D2 is about 460 mg. In some embodiments, C1D2 is about 465 mg. In some embodiments, C1D2 is about 470 mg. In some embodiments, C1D2 is about 475 mg. In some embodiments, C1D2 is about 480 mg. In some embodiments, C1D2 is about 485 mg. In some embodiments, C1D2 is about 490 mg. In some embodiments, C1D2 is about 495 mg. In some embodiments, C1D2 is about 500 mg. In some embodiments, C1D2 is about 505 mg. In some embodiments, C1D2 is about 510 mg. In some embodiments, C1D2 is about 515 mg. In some embodiments, C1D2 is about 520 mg. In some embodiments, C1D2 is about 525 mg. In some embodiments, C1D2 is about 530 mg. In some embodiments, C1D2 is about 535 mg. In some embodiments, C1D2 is about 540 mg. In some embodiments, C1D2 is about 545 mg. In some embodiments, C1D2 is about 550 mg. In some embodiments, C1D2 is about 555 mg. In some embodiments, C1D2 is about 560 mg. In some embodiments, C1D2 is about 565 mg. In some embodiments, C1D2 is about 570 mg. In some embodiments, C1D2 is about 575 mg. In some embodiments, C1D2 is about 580 mg. In some embodiments, C1D2 is about 585 mg. In some embodiments, C1D2 is about 590 mg. In some embodiments, C1D2 is about 595 mg. In some embodiments, C1D2 is about 600 mg. In some embodiments, C1D2 is about 605 mg.In some embodiments, C1D2 is about 610 mg. In some embodiments, C1D2 is about 615 mg. In some embodiments, C1D2 is about 620 mg. In some embodiments, C1D2 is about 625 mg. In some embodiments, C1D2 is about 630 mg. In some embodiments, C1D2 is about 635 mg. In some embodiments, C1D2 is about 640 mg. In some embodiments, C1D2 is about 645 mg. In some embodiments, C1D2 is about 650 mg. In some embodiments, C1D2 is about 655 mg. In some embodiments, C1D2 is about 660 mg. In some embodiments, C1D2 is about 665 mg. In some embodiments, C1D2 is about 670 mg. In some embodiments, C1D2 is about 675 mg. In some embodiments, C1D2 is about 680 mg. In some embodiments, C1D2 is about 685 mg. In some embodiments, C1D2 is about 690 mg. In some embodiments, C1D2 is about 695 mg. In some embodiments, C1D2 is about 700 mg. In some embodiments, C1D2 is about 705 mg. In some embodiments, C1D2 is about 710 mg. In some embodiments, C1D2 is about 715 mg. In some embodiments, C1D2 is about 720 mg. In some embodiments, C1D2 is about 725 mg. In some embodiments, C1D2 is about 730 mg. In some embodiments, C1D2 is about 735 mg. In some embodiments, C1D2 is about 740 mg. In some embodiments, C1D2 is about 745 mg. In some embodiments, C1D2 is about 750 mg. In some embodiments, C1D2 is about 755 mg. In some embodiments, C1D2 is about 760 mg. In some embodiments, C1D2 is about 765 mg. In some embodiments, C1D2 is about 770 mg. In some embodiments, C1D2 is about 775 mg. In some embodiments, C1D2 is about 780 mg. In some embodiments, C1D2 is about 785 mg. In some embodiments, C1D2 is about 790 mg. In some embodiments, C1D2 is about 795 mg. In some embodiments, C1D2 is about 800 mg. In some embodiments, C1D2 is about 805 mg.In some embodiments, C1D2 is about 810 mg. In some embodiments, C1D2 is about 815 mg. In some embodiments, C1D2 is about 820 mg. In some embodiments, C1D2 is about 825 mg. In some embodiments, C1D2 is about 830 mg. In some embodiments, C1D2 is about 835 mg. In some embodiments, C1D2 is about 840 mg. In some embodiments, C1D2 is about 845 mg. In some embodiments, C1D2 is about 850 mg. In some embodiments, C1D2 is about 855 mg. In some embodiments, C1D2 is about 860 mg. In some embodiments, C1D2 is about 865 mg. In some embodiments, C1D2 is about 870 mg. In some embodiments, C1D2 is about 875 mg. In some embodiments, C1D2 is about 880 mg. In some embodiments, C1D2 is about 885 mg. In some embodiments, C1D2 is about 890 mg. In some embodiments, C1D2 is about 895 mg. In some embodiments, C1D2 is about 900 mg. In some embodiments, C1D2 is about 905 mg. In some embodiments, C1D2 is about 910 mg. In some embodiments, C1D2 is about 915 mg. In some embodiments, C1D2 is about 920 mg. In some embodiments, C1D2 is about 925 mg. In some embodiments, C1D2 is about 930 mg. In some embodiments, C1D2 is about 935 mg. In some embodiments, C1D2 is about 940 mg. In some embodiments, C1D2 is about 945 mg. In some embodiments, C1D2 is about 950 mg. In some embodiments, C1D2 is about 955 mg. In some embodiments, C1D2 is about 960 mg. In some embodiments, C1D2 is about 965 mg. In some embodiments, C1D2 is about 970 mg. In some embodiments, C1D2 is about 975 mg. In some embodiments, C1D2 is about 980 mg. In some embodiments, C1D2 is about 985 mg. In some embodiments, C1D2 is about 990 mg. In some embodiments, C1D2 is about 995 mg. In some embodiments, C1D2 is about 1000 mg.

[0258] In some embodiments, C1D1 is 1 mg. In some embodiments, C1D1 is 2 mg. In some embodiments, C1D1 is 3 mg. In some embodiments, C1D1 is 4 mg. In some embodiments, C1D1 is 5 mg. In some embodiments, C1D1 is 6 mg. In some embodiments, C1D1 is 7 mg. In some embodiments, C1D1 is 8 mg. In some embodiments, C1D1 is 9 mg. In some embodiments, C1D1 is 10 mg. In some embodiments, C1D1 is 11 mg. In some embodiments, C1D1 is 12 mg. In some embodiments, C1D1 is 13 mg. In some embodiments, C1D1 is 14 mg. In some embodiments, C1D1 is 15 mg. In some embodiments, C1D1 is 16 mg. In some embodiments, C1D1 is 17 mg. In some embodiments, C1D1 is 18 mg. In some embodiments, C1D1 is 19 mg. In some embodiments, C1D1 is 20 mg. In some embodiments, C1D1 is 21 mg. In some embodiments, C1D1 is 22 mg. In some embodiments, C1D1 is 23 mg. In some embodiments, C1D1 is 24 mg. In some embodiments, C1D1 is 25 mg. In some embodiments, C1D1 is 26 mg. In some embodiments, C1D1 is 27 mg. In some embodiments, C1D1 is 28 mg. In some embodiments, C1D1 is 29 mg. In some embodiments, C1D1 is 30 mg. In some embodiments, C1D1 is 31 mg. In some embodiments, C1D1 is 32 mg. In some embodiments, C1D1 is 33 mg. In some embodiments, C1D1 is 34 mg. In some embodiments, C1D1 is 35 mg. In some embodiments, C1D1 is 36 mg. In some embodiments, C1D1 is 37 mg. In some embodiments, C1D1 is 38 mg. In some embodiments, C1D1 is 39 mg. In some embodiments, C1D1 is 40 mg. In some embodiments, C1D1 is 41 mg. In some embodiments, C1D1 is 42 mg. In some embodiments, C1D1 is 43 mg.In some embodiments, C1D1 is 44 mg. In some embodiments, C1D1 is 45 mg. In some embodiments, C1D1 is 46 mg. In some embodiments, C1D1 is 47 mg. In some embodiments, C1D1 is 48 mg. In some embodiments, C1D1 is 49 mg. In some embodiments, C1D1 is 50 mg.

[0259] In some embodiments, C1D2 is 10 mg. In some embodiments, C1D2 is 15 mg. In some embodiments, C1D2 is 20 mg. In some embodiments, C1D2 is 25 mg. In some embodiments, C1D2 is 30 mg. In some embodiments, C1D2 is 35 mg. In some embodiments, C1D2 is 40 mg. In some embodiments, C1D2 is 45 mg. In some embodiments, C1D2 is 50 mg. In some embodiments, C1D2 is 55 mg. In some embodiments, C1D2 is 60 mg. In some embodiments, C1D2 is 65 mg. In some embodiments, C1D2 is 70 mg. In some embodiments, C1D2 is 75 mg. In some embodiments, C1D2 is 80 mg. In some embodiments, C1D2 is 85 mg. In some embodiments, C1D2 is 90 mg. In some embodiments, C1D2 is 95 mg. In some embodiments, C1D2 is 100 mg. In some embodiments, C1D2 is 105 mg. In some embodiments, C1D2 is 110 mg. In some embodiments, C1D2 is 115 mg. In some embodiments, C1D2 is 120 mg. In some embodiments, C1D2 is 125 mg. In some embodiments, C1D2 is 130 mg. In some embodiments, C1D2 is 135 mg. In some embodiments, C1D2 is 140 mg. In some embodiments, C1D2 is 145 mg. In some embodiments, C1D2 is 150 mg. In some embodiments, C1D2 is 155 mg. In some embodiments, C1D2 is 160 mg. In some embodiments, C1D2 is 165 mg. In some embodiments, C1D2 is 170 mg. In some embodiments, C1D2 is 175 mg. In some embodiments, C1D2 is 180 mg. In some embodiments, C1D2 is 185 mg. In some embodiments, C1D2 is 190 mg. In some embodiments, C1D2 is 195 mg. In some embodiments, C1D2 is 200 mg. In some embodiments, C1D2 is 205 mg. In some embodiments, C1D2 is 210 mg. In some embodiments, C1D2 is 215 mg.In some embodiments, C1D2 is 220 mg. In some embodiments, C1D2 is 225 mg. In some embodiments, C1D2 is 230 mg. In some embodiments, C1D2 is 235 mg. In some embodiments, C1D2 is 240 mg. In some embodiments, C1D2 is 245 mg. In some embodiments, C1D2 is 250 mg. In some embodiments, C1D2 is 255 mg. In some embodiments, C1D2 is 260 mg. In some embodiments, C1D2 is 265 mg. In some embodiments, C1D2 is 270 mg. In some embodiments, C1D2 is 275 mg. In some embodiments, C1D2 is 280 mg. In some embodiments, C1D2 is 285 mg. In some embodiments, C1D2 is 290 mg. In some embodiments, C1D2 is 295 mg. In some embodiments, C1D2 is 300 mg. In some embodiments, C1D2 is 305 mg. In some embodiments, C1D2 is 310 mg. In some embodiments, C1D2 is 315 mg. In some embodiments, C1D2 is 320 mg. In some embodiments, C1D2 is 325 mg. In some embodiments, C1D2 is 330 mg. In some embodiments, C1D2 is 335 mg. In some embodiments, C1D2 is 340 mg. In some embodiments, C1D2 is 345 mg. In some embodiments, C1D2 is 350 mg. In some embodiments, C1D2 is 355 mg. In some embodiments, C1D2 is 360 mg. In some embodiments, C1D2 is 365 mg. In some embodiments, C1D2 is 370 mg. In some embodiments, C1D2 is 375 mg. In some embodiments, C1D2 is 380 mg. In some embodiments, C1D2 is 385 mg. In some embodiments, C1D2 is 390 mg. In some embodiments, C1D2 is 395 mg. In some embodiments, C1D2 is 400 mg. In some embodiments, C1D2 is 405 mg. In some embodiments, C1D2 is 410 mg. In some embodiments, C1D2 is 415 mg. In some embodiments, C1D2 is 420 mg.In some embodiments, C1D2 is 425 mg. In some embodiments, C1D2 is 430 mg. In some embodiments, C1D2 is 435 mg. In some embodiments, C1D2 is 440 mg. In some embodiments, C1D2 is 445 mg. In some embodiments, C1D2 is 450 mg. In some embodiments, C1D2 is 455 mg. In some embodiments, C1D2 is 460 mg. In some embodiments, C1D2 is 465 mg. In some embodiments, C1D2 is 470 mg. In some embodiments, C1D2 is 475 mg. In some embodiments, C1D2 is 480 mg. In some embodiments, C1D2 is 485 mg. In some embodiments, C1D2 is 490 mg. In some embodiments, C1D2 is 495 mg. In some embodiments, C1D2 is 500 mg. In some embodiments, C1D2 is 505 mg. In some embodiments, C1D2 is 510 mg. In some embodiments, C1D2 is 515 mg. In some embodiments, C1D2 is 520 mg. In some embodiments, C1D2 is 525 mg. In some embodiments, C1D2 is 530 mg. In some embodiments, C1D2 is 535 mg. In some embodiments, C1D2 is 540 mg. In some embodiments, C1D2 is 545 mg. In some embodiments, C1D2 is 550 mg. In some embodiments, C1D2 is 555 mg. In some embodiments, C1D2 is 560 mg. In some embodiments, C1D2 is 565 mg. In some embodiments, C1D2 is 570 mg. In some embodiments, C1D2 is 575 mg. In some embodiments, C1D2 is 580 mg. In some embodiments, C1D2 is 585 mg. In some embodiments, C1D2 is 590 mg. In some embodiments, C1D2 is 595 mg. In some embodiments, C1D2 is 600 mg. In some embodiments, C1D2 is 605 mg. In some embodiments, C1D2 is 610 mg. In some embodiments, C1D2 is 615 mg. In some embodiments, C1D2 is 620 mg. In some embodiments, C1D2 is 625 mg.In some embodiments, C1D2 is 630 mg. In some embodiments, C1D2 is 635 mg. In some embodiments, C1D2 is 640 mg. In some embodiments, C1D2 is 645 mg. In some embodiments, C1D2 is 650 mg. In some embodiments, C1D2 is 655 mg. In some embodiments, C1D2 is 660 mg. In some embodiments, C1D2 is 665 mg. In some embodiments, C1D2 is 670 mg. In some embodiments, C1D2 is 675 mg. In some embodiments, C1D2 is 680 mg. In some embodiments, C1D2 is 685 mg. In some embodiments, C1D2 is 690 mg. In some embodiments, C1D2 is 695 mg. In some embodiments, C1D2 is 700 mg. In some embodiments, C1D2 is 705 mg. In some embodiments, C1D2 is 710 mg. In some embodiments, C1D2 is 715 mg. In some embodiments, C1D2 is 720 mg. In some embodiments, C1D2 is 725 mg. In some embodiments, C1D2 is 730 mg. In some embodiments, C1D2 is 735 mg. In some embodiments, C1D2 is 740 mg. In some embodiments, C1D2 is 745 mg. In some embodiments, C1D2 is 750 mg. In some embodiments, C1D2 is 755 mg. In some embodiments, C1D2 is 760 mg. In some embodiments, C1D2 is 765 mg. In some embodiments, C1D2 is 770 mg. In some embodiments, C1D2 is 775 mg. In some embodiments, C1D2 is 780 mg. In some embodiments, C1D2 is 785 mg. In some embodiments, C1D2 is 790 mg. In some embodiments, C1D2 is 795 mg. In some embodiments, C1D2 is 800 mg. In some embodiments, C1D2 is 805 mg. In some embodiments, C1D2 is 810 mg. In some embodiments, C1D2 is 815 mg. In some embodiments, C1D2 is 820 mg. In some embodiments, C1D2 is 825 mg. In some embodiments, C1D2 is 830 mg.In some embodiments, C1D2 is 835 mg. In some embodiments, C1D2 is 840 mg. In some embodiments, C1D2 is 845 mg. In some embodiments, C1D2 is 850 mg. In some embodiments, C1D2 is 855 mg. In some embodiments, C1D2 is 860 mg. In some embodiments, C1D2 is 865 mg. In some embodiments, C1D2 is 870 mg. In some embodiments, C1D2 is 875 mg. In some embodiments, C1D2 is 880 mg. In some embodiments, C1D2 is 885 mg. In some embodiments, C1D2 is 890 mg. In some embodiments, C1D2 is 895 mg. In some embodiments, C1D2 is 900 mg. In some embodiments, C1D2 is 905 mg. In some embodiments, C1D2 is 910 mg. In some embodiments, C1D2 is 915 mg. In some embodiments, C1D2 is 920 mg. In some embodiments, C1D2 is 925 mg. In some embodiments, C1D2 is 930 mg. In some embodiments, C1D2 is 935 mg. In some embodiments, C1D2 is 940 mg. In some embodiments, C1D2 is 945 mg. In some embodiments, C1D2 is 950 mg. In some embodiments, C1D2 is 955 mg. In some embodiments, C1D2 is 960 mg. In some embodiments, C1D2 is 965 mg. In some embodiments, C1D2 is 970 mg. In some embodiments, C1D2 is 975 mg. In some embodiments, C1D2 is 980 mg. In some embodiments, C1D2 is 985 mg. In some embodiments, C1D2 is 990 mg. In some embodiments, C1D2 is 995 mg. In some embodiments, C1D2 is 1000 mg.

[0260] In some cases, these methods described above may include a first dosing cycle of 4 weeks or 28 days. In some cases, the method may include administering C1D1 and C1D2 to the subject on the first and eighth days, respectively, of the first dosing cycle, or on or about that day.

[0261] iii. Two-step escalating dosing regimen In another aspect, the invention provides a method of treating a subject having cancer (e.g., MM), the method comprising subcutaneously administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a two-step escalating dosing regimen.

[0262] In some aspects, the present disclosure features a method of treating a subject having cancer (e.g., MM), 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 from about 0.1 mg to about 10 mg (e.g., from about 0.1 mg to about 2 mg, from about 0.2 mg to about 1 mg, or from about 0.2 mg to about 0.4 mg, from about 0.1 mg to about 9.5 mg, from about 0.2 mg to about 9 mg, from about 0.3 mg to about 8.5 mg, from about 0.4 mg to about 8 mg, from about 0.5 mg to about 7.5 mg, from about 0.6 mg to about 7 mg, from about 0.7 mg to about 6.5 mg, from about 0.8 mg to about 6 mg, from about 0.9 mg to about 5.5 mg, from about 1 mg to about 5 mg, from about 1.1 mg to about 4.5 mg, from about 1.2 mg to about 4 mg, from about 1.3 mg to about 3.5 mg, from about 1.4 mg to about 3 mg, from about 1.5 mg to about 2.5 mg, from about 1 mg to about 3 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, from about 0.4 mg to about 2.5 mg, from about 0.5 mg to about 3 mg, from about 0.6 mg to about 3.5 mg, from about 0.7 mg to about 4 mg, from about 0.8 mg to about 4.5 mg, from about 0.9 mg to about 5 mg, from about 1 mg to about 6 mg, from about 1.5 mg to about 6.5 mg, from about 2 mg to about 7 mg, from about 2.5 mg to about 7.5 mg, from about 3 mg to about 8 mg, from about 3.5 mg to about 8.5 mg, from about 4 mg to about 9 mg, from about 4.5 mg to about 9.5 mg, or from about 5 mg to about 10 mg); C1D2 is from about 1 mg to about 50 mg (e.g., from about 3 mg to about 18 mg, from about 3.1 mg to about 15 mg, from about 3.2 mg to about 10 mg, from about 3.3 mg to about 6 mg, from about 3.4 mg to about 4 mg, from about 0.2 mg to about 35 mg, from about 0.3 mg to about 30 mg, from about 0.4 mg to about 29 mg, from about 0.5 mg to about 28 mg, from about 1 mg to about 27 mg, from about 1.5 mg to about 26 mg, from about 2 mg to about 25 mg, from about 2.5 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 1 mg to about 6 mg, from about 1.5 mg to about 6.5 mg, from about 2 mg to about 7 mg, from about 2.5 mg to about 7.5 mg, from about 3 mg to about 8 mg, from about 3.5 mg to about 8.5 mg, from about 4 mg to about 9 mg, from about 4.5 mg to about 9.5 mg, from about 5 mg to about 10 mg, from about 5.5 mg to about 10.5 mg, from about 6 mg to about 11 mg, from about 6.5 mg to about 11.5 mg, from about 7 mg to about 12 mg, from about 7.5 mg to about 12.5 mg, from about 8 mg to about 13 mg, from about 8.5 mg to about 13.5 mg, from about 9 mg to about 14 mg, from about 9.5 mg to about 14.5 mg, from about 10 mg to about 15 mg, from about 11 mg to about 16 mg, from about 12 mg to about 17 mg, from about 13 mg to about 18 mg, from about 14 mg to about 19 mg, from about 15 mg to about 20 mg, from about 16 mg to about 21 mg, from about 17 mg to about 22 mg, from about 18 mg to about 23 mg, from about 19 mg to about 24 mg, from about 20 mg to about 25 mg, from about 21 mg to about 26 mg, from about 22 mg to about 27 mg, from about 23 mg to about 28 mg, from about 24 mg to about 29 mg, from about 25 mg to about 30 mg, from about 26 mg to about 31 mg, from about 27 mg to about 32 mg, from about 28 mg to about 33 mg, from about 29 mg to about 34 mg, from about 30 mg to about 35 mg, from about 31 mg to about 36 mg, from about 32 mg to about 37 mg, from about 33 mg to about 38 mg, from about 34 mg to about 39 mg, from about 35 mg to about 40 mg, from about 36 mg to about 41 mg, from about 37 mg to about 42 mg, from about 38 mg to about 43 mg, from about 39 mg to about 44 mg, from about 40 mg to about 45 mg, from about 41 mg to about 46 mg, from about 42 mg to about 47 mg, from about 43 mg to about 48 mg, from about 44 mg to about 49 mg, or from about 45 mg to about 50 mg); C1D3 is from about 10 mg to about 1000 mg (for example, from about 10 mg to about 70 mg, from about 15 mg to about 65 mg, from about 20 mg to about 60 mg, from about 25 mg to about 55 mg, from about 30 mg to about 50 mg, from about 35 mg to about 45 mg, from about 15 mg to about 225 mg, from about 20 mg to about 220 mg, 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,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, 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 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). In some embodiments, C1D2 is greater than C1D1 and C1D3 is greater than C1D2.,

[0263] In some embodiments, C1D3 is from about 10 mg to 200 mg (e.g., 10 mg to about 170 mg, about 11 mg to about 165 mg, about 12 mg to about 160 mg, about 13 mg to about 155 mg, about 14 mg to about 150 mg, about 15 mg to about 145 mg, about 16 mg to about 140 mg, about 17 mg to about 135 mg, about 18 mg to about 130 mg, about 19 mg to about 125 mg, about 20 mg to about 120 mg, about 21 mg to about 115 mg, about 22 mg to about 110 mg, 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 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 50 mg, about 50 mg to about 60 mg, about 60 mg to about 70 mg, about 70 mg to about 80 mg, about 80 mg to about 90 mg, about 90 mg to about 100 mg, about 100 mg to about 110 mg, about 110 mg to about 120 mg, about 120 mg to about 130 mg, about 130 mg to about 140 mg, about 140 mg to about 150 mg, about 150 mg to about 160 mg, about 160 mg to about 170 mg, about 170 mg to about 180 mg, or about 190 mg to about 200 mg).

[0264] In some embodiments, C1D1 is from 0.1 mg to 10 mg (for example, from 0.2 mg to 0.4 mg, from 0.1 mg to 9.5 mg, from 0.2 mg to 9 mg, from 0.3 mg to 8.5 mg, from 0.4 mg to 8 mg, from 0.5 mg to 7.5 mg, from 0.6 mg to 7 mg, from 0.7 mg to 6.5 mg, from 0.8 mg to 6 mg, from 0.9 mg to 5.5 mg, from 1 mg to 5 mg, from 1.1 mg to 4.5 mg, from 1.2 mg to 4 mg, from 1.3 mg to 3.5 mg, from 1.4 mg to 3 mg, from 1.5 mg to 2.5 mg, from 1 mg to 3 mg, from 0.1 mg to 1 mg, from 0.2 mg to 1.5 mg, from 0.3 mg to 2 mg, from 0.4 mg to 2.5 mg, from 0.5 mg to 3 mg, from 0.6 mg to 3.5 mg, from 0.7 mg to 4 mg, from 0.8 mg to 4.5 mg, from 0.9 mg to 5 mg, from 1 mg to 6 mg, from 1.5 mg to 6.5 mg, from 2 mg to 7 mg, from 2.5 mg to 7.5 mg, from 3 mg to 8 mg, from 3.5 mg to 8.5 mg, from 4 mg to 9 mg, from 4.5 mg to 9.5 mg, or from 5 mg to 10 mg).

[0265] In some embodiments, C1D2 is from 1 mg to 50 mg (e.g., from 3 mg to 18 mg, from 3.1 mg to 15 mg, from 3.2 mg to 10 mg, from 3.3 mg to 6 mg, from 3.4 mg to 4 mg, from 0.2 mg to 35 mg, from 0.3 mg to 30 mg, from 0.4 mg to 29 mg, from 0.5 mg to 28 mg, from 1 mg to 27 mg, from 1.5 mg to 26 mg, from 2 mg to 25 mg, from 2.5 mg to 24 mg, from 3 mg to 23 mg, from 3.5 mg to 22 mg, from 4 mg to 21 mg, from 4.5 mg to 20 mg, from 5 mg to 19 mg, from 5.5 mg to 18 mg, from 6 mg to 17 mg, from 6.5 mg to 16 mg, from 7 mg to 15 mg, from 7.5 mg to 14 mg, from 8 mg to 13 mg, from 8 mg to 12 mg, from 8.5 mg to 12 mg, from 9 mg to 11 mg, from 1 mg to 6 mg, from 1.5 mg to 6.5 mg, from 2 mg to 7 mg, from 2.5 mg to 7.5 mg, from 3 mg to 8 mg, from 3.5 mg to 8.5 mg, from 4 mg to 9 mg, from 4.5 mg to 9.5 mg, from 5 mg to 10 mg, from 5.5 mg to 10.5 mg, from 6 mg to 11 mg, from 6.5 mg to 11.5 mg, from 7 mg to 12 mg, from 7.5 mg to 12.5 mg, from 8 mg to 13 mg, from 8.5 mg to 13.5 mg, from 9 mg to 14 mg, from 9.5 mg to 14.5 mg, from 10 mg to 15 mg, from 11 mg to 16 mg, from 12 mg to 17 mg, from 13 mg to 18 mg, from 14 mg to 19 mg, from 15 mg to 20 mg, from 16 mg to 21 mg, from 17 mg to 22 mg, from 18 mg to 23 mg, from 19 mg to 24 mg, from 20 mg to 25 mg, from 21 mg to 26 mg, from 22 mg to 27 mg, from 23 mg to 28 mg, from 24 mg to 29 mg, from 25 mg to 30 mg, from 26 mg to 31 mg, from 27 mg to 32 mg, from 28 mg to 33 mg, from 29 mg to 34 mg, from 30 mg to 35 mg, from 31 mg to 36 mg, from 32 mg to 37 mg, from 33 mg to 38 mg, from 34 mg to 39 mg, from 35 mg to 40 mg, from 36 mg to 41 mg, from 37 mg to 42 mg, from 38 mg to 43 mg, from 39 mg to 44 mg, from 40 mg to 45 mg, from 41 mg to 46 mg, from 42 mg to 47 mg, from 43 mg to 48 mg, from 44 mg to 49 mg, or from 45 mg to 50 mg).

[0266] In some embodiments, C1D3 is from 10 mg to 1000 mg (e.g., 10 mg to 70 mg, 15 mg to 65 mg, 20 mg to 60 mg, 25 mg to 55 mg, 30 mg to 50 mg, 35 mg to 45 mg, 15 mg to 225 mg, 20 mg to 220 mg, 25 mg to 215 mg, 30 mg to 210 mg, 35 mg to 205 mg, 40 mg to 200 mg, 45 mg to 195 mg, 50 mg to 190 mg, 55 mg to 185 mg, 60 mg to 180 mg, 65 mg to 175 mg, 70 mg to 170 mg, 75 mg to 165 mg, 80 mg to 160 mg, 85 mg to 155 mg, 90 mg to 150 mg, 95 mg to 145 mg, 100 mg to 140 mg, 105 mg to 135 mg, 110 mg to 130 mg, 115 mg to 125 mg, 10 mg to 50 mg, 25 mg to 75 mg, 50 mg to 100 mg, 75 mg to 125 mg, 100 mg to 150 mg, 125 mg to 175 mg, 150 mg to 200 mg, 175 mg to 225 mg, 200 mg to 250 mg, 225 mg to 275 mg, 250 mg to 300 mg, 275 mg to 325 mg, 300 mg to 350 mg, 325 mg to 375 mg, 350 mg to 400 mg, 375 mg to 425 mg, 400 mg to 450 mg, 425 mg to 475 mg, 450 mg to 500 mg, 475 mg to 525 mg, 500 mg to 550 mg, 525 mg to 575 mg, 550 mg to 600 mg, 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).

[0267] In some embodiments, C1D3 is from 10 mg to 200 mg (e.g., 10 mg to 170 mg, 11 mg to 165 mg, 12 mg to 160 mg, 13 mg to 155 mg, 14 mg to 150 mg, 15 mg to 145 mg, 16 mg to 140 mg, 17 mg to 135 mg, 18 mg to 130 mg, 19 mg to 125 mg, 20 mg to 120 mg, 21 mg to 115 mg, 22 mg to 110 mg, 23 mg to 105 mg, 24 mg to 100 mg, 25 mg to 95 mg, 26 mg to 90 mg, 27 mg to 85 mg, 28 mg to 80 mg, 29 mg to 75 mg, 30 mg to 70 mg, 31 mg to 65 mg, 32 mg to 60 mg, 33 mg to 55 mg, 34 mg to 50 mg, 35 mg to 45 mg, 40 mg to 200 mg, 45 mg to 195 mg, 50 mg to 190 mg, 55 mg to 185 mg, 60 mg to 180 mg, 65 mg to 175 mg, 70 mg to 170 mg, 75 mg to 165 mg, 80 mg to 160 mg, 85 mg to 155 mg, 90 mg to 150 mg, 95 mg to 145 mg, 100 mg to 140 mg, 105 mg to 135 mg, 110 mg to 130 mg, 115 mg to 125 mg, 10 mg to 20 mg, 20 mg to 30 mg, 30 mg to 40 mg, 40 mg to 50 mg, 50 mg to 60 mg, 60 mg to 70 mg, 70 mg to 80 mg, 80 mg to 90 mg, 90 mg to 100 mg, 100 mg to 110 mg, 110 mg to 120 mg, 120 mg to 130 mg, 130 mg to 140 mg, 140 mg to 150 mg, 150 mg to 160 mg, 160 mg to 170 mg, 170 mg to 180 mg, 180 mg to 190 mg, or 190 mg to 200 mg).

[0268] In some embodiments, C1D1 is about 0.1 mg. In some embodiments, C1D1 is about 0.2 mg. In some embodiments, C1D1 is about 0.3 mg. In some embodiments, C1D1 is about 0.4 mg. In some embodiments, C1D1 is about 0.5 mg. In some embodiments, C1D1 is about 0.6 mg. In some embodiments, C1D1 is about 0.7 mg. In some embodiments, C1D1 is about 0.8 mg. In some embodiments, C1D1 is about 0.9 mg. In some embodiments, C1D1 is about 1 mg. In some embodiments, C1D1 is about 2 mg. In some embodiments, C1D1 is about 3 mg. In some embodiments, C1D1 is about 4 mg. In some embodiments, C1D1 is about 5 mg. In some embodiments, C1D1 is about 6 mg. In some embodiments, C1D1 is about 7 mg. In some embodiments, C1D1 is about 8 mg. In some embodiments, C1D1 is about 9 mg. In some embodiments, C1D1 is about 10 mg.

[0269] In some embodiments, C1D2 is about 1 mg. In some embodiments, C1D2 is about 2 mg. In some embodiments, C1D2 is about 3 mg. In some embodiments, C1D2 is about 4 mg. In some embodiments, C1D2 is about 5 mg. In some embodiments, C1D2 is about 6 mg. In some embodiments, C1D2 is about 7 mg. In some embodiments, C1D2 is about 8 mg. In some embodiments, C1D2 is about 9 mg. In some embodiments, C1D2 is about 10 mg. In some embodiments, C1D2 is about 11 mg. In some embodiments, C1D2 is about 12 mg. In some embodiments, C1D2 is about 13 mg. In some embodiments, C1D2 is about 14 mg. In some embodiments, C1D2 is about 15 mg. In some embodiments, C1D2 is about 16 mg. In some embodiments, C1D2 is about 17 mg. In some embodiments, C1D2 is about 18 mg. In some embodiments, C1D2 is about 19 mg. In some embodiments, C1D2 is about 20 mg. In some embodiments, C1D2 is about 21 mg. In some embodiments, C1D2 is about 22 mg. In some embodiments, C1D2 is about 23 mg. In some embodiments, C1D2 is about 24 mg. In some embodiments, C1D2 is about 25 mg. In some embodiments, C1D2 is about 26 mg. In some embodiments, C1D2 is about 27 mg. In some embodiments, C1D2 is about 28 mg. In some embodiments, C1D2 is about 29 mg. In some embodiments, C1D2 is about 30 mg. In some embodiments, C1D2 is about 31 mg. In some embodiments, C1D2 is about 32 mg. In some embodiments, C1D2 is about 33 mg. In some embodiments, C1D2 is about 34 mg. In some embodiments, C1D2 is about 35 mg. In some embodiments, C1D2 is about 36 mg. In some embodiments, C1D2 is about 37 mg. In some embodiments, C1D2 is about 38 mg. In some embodiments, C1D2 is about 39 mg. In some embodiments, C1D2 is about 40 mg. In some embodiments, C1D2 is about 41 mg. In some embodiments, C1D2 is about 42 mg.In some embodiments, C1D2 is about 43 mg. In some embodiments, C1D2 is about 44 mg. In some embodiments, C1D2 is about 45 mg. In some embodiments, C1D2 is about 46 mg. In some embodiments, C1D2 is about 47 mg. In some embodiments, C1D2 is about 48 mg. In some embodiments, C1D2 is about 49 mg. In some embodiments, C1D2 is about 50 mg.

[0270] In some embodiments, C1D3 is about 10 mg. In some embodiments, C1D3 is about 15 mg. In some embodiments, C1D3 is about 20 mg. In some embodiments, C1D3 is about 25 mg. In some embodiments, C1D3 is about 30 mg. In some embodiments, C1D3 is about 35 mg. In some embodiments, C1D3 is about 40 mg. In some embodiments, C1D3 is about 45 mg. In some embodiments, C1D3 is about 50 mg. In some embodiments, C1D3 is about 55 mg. In some embodiments, C1D3 is about 60 mg. In some embodiments, C1D3 is about 65 mg. In some embodiments, C1D3 is about 70 mg. In some embodiments, C1D3 is about 75 mg. In some embodiments, C1D3 is about 80 mg. In some embodiments, C1D3 is about 85 mg. In some embodiments, C1D3 is about 90 mg. In some embodiments, C1D3 is about 95 mg. In some embodiments, C1D3 is about 100 mg. In some embodiments, C1D3 is about 105 mg. In some embodiments, C1D3 is about 110 mg. In some embodiments, C1D3 is about 115 mg. In some embodiments, C1D3 is about 120 mg. In some embodiments, C1D3 is about 125 mg. In some embodiments, C1D3 is about 130 mg. In some embodiments, C1D3 is about 135 mg. In some embodiments, C1D3 is about 140 mg. In some embodiments, C1D3 is about 145 mg. In some embodiments, C1D3 is about 150 mg. In some embodiments, C1D3 is about 155 mg. In some embodiments, C1D3 is about 160 mg. In some embodiments, C1D3 is about 165 mg. In some embodiments, C1D3 is about 170 mg. In some embodiments, C1D3 is about 175 mg. In some embodiments, C1D3 is about 180 mg. In some embodiments, C1D3 is about 185 mg. In some embodiments, C1D3 is about 190 mg. In some embodiments, C1D3 is about 195 mg. In some embodiments, C1D3 is about 200 mg. In some embodiments, C1D3 is about 205 mg.In some embodiments, C1D3 is about 210 mg. In some embodiments, C1D3 is about 215 mg. In some embodiments, C1D3 is about 220 mg. In some embodiments, C1D3 is about 225 mg. In some embodiments, C1D3 is about 230 mg. In some embodiments, C1D3 is about 235 mg. In some embodiments, C1D3 is about 240 mg. In some embodiments, C1D3 is about 245 mg. In some embodiments, C1D3 is about 250 mg. In some embodiments, C1D3 is about 255 mg. In some embodiments, C1D3 is about 260 mg. In some embodiments, C1D3 is about 265 mg. In some embodiments, C1D3 is about 270 mg. In some embodiments, C1D3 is about 275 mg. In some embodiments, C1D3 is about 280 mg. In some embodiments, C1D3 is about 285 mg. In some embodiments, C1D3 is about 290 mg. In some embodiments, C1D3 is about 295 mg. In some embodiments, C1D3 is about 300 mg. In some embodiments, C1D3 is about 305 mg. In some embodiments, C1D3 is about 310 mg. In some embodiments, C1D3 is about 315 mg. In some embodiments, C1D3 is about 320 mg. In some embodiments, C1D3 is about 325 mg. In some embodiments, C1D3 is about 330 mg. In some embodiments, C1D3 is about 335 mg. In some embodiments, C1D3 is about 340 mg. In some embodiments, C1D3 is about 345 mg. In some embodiments, C1D3 is about 350 mg. In some embodiments, C1D3 is about 355 mg. In some embodiments, C1D3 is about 360 mg. In some embodiments, C1D3 is about 365 mg. In some embodiments, C1D3 is about 370 mg. In some embodiments, C1D3 is about 375 mg. In some embodiments, C1D3 is about 380 mg. In some embodiments, C1D3 is about 385 mg. In some embodiments, C1D3 is about 390 mg. In some embodiments, C1D3 is about 395 mg. In some embodiments, C1D3 is about 400 mg. In some embodiments, C1D3 is about 405 mg.In some embodiments, C1D3 is about 410 mg. In some embodiments, C1D3 is about 415 mg. In some embodiments, C1D3 is about 420 mg. In some embodiments, C1D3 is about 425 mg. In some embodiments, C1D3 is about 430 mg. In some embodiments, C1D3 is about 435 mg. In some embodiments, C1D3 is about 440 mg. In some embodiments, C1D3 is about 445 mg. In some embodiments, C1D3 is about 450 mg. In some embodiments, C1D3 is about 455 mg. In some embodiments, C1D3 is about 460 mg. In some embodiments, C1D3 is about 465 mg. In some embodiments, C1D3 is about 470 mg. In some embodiments, C1D3 is about 475 mg. In some embodiments, C1D3 is about 480 mg. In some embodiments, C1D3 is about 485 mg. In some embodiments, C1D3 is about 490 mg. In some embodiments, C1D3 is about 495 mg. In some embodiments, C1D3 is about 500 mg. In some embodiments, C1D3 is about 505 mg. In some embodiments, C1D3 is about 510 mg. In some embodiments, C1D3 is about 515 mg. In some embodiments, C1D3 is about 520 mg. In some embodiments, C1D3 is about 525 mg. In some embodiments, C1D3 is about 530 mg. In some embodiments, C1D3 is about 535 mg. In some embodiments, C1D3 is about 540 mg. In some embodiments, C1D3 is about 545 mg. In some embodiments, C1D3 is about 550 mg. In some embodiments, C1D3 is about 555 mg. In some embodiments, C1D3 is about 560 mg. In some embodiments, C1D3 is about 565 mg. In some embodiments, C1D3 is about 570 mg. In some embodiments, C1D3 is about 575 mg. In some embodiments, C1D3 is about 580 mg. In some embodiments, C1D3 is about 585 mg. In some embodiments, C1D3 is about 590 mg. In some embodiments, C1D3 is about 595 mg. In some embodiments, C1D3 is about 600 mg. In some embodiments, C1D3 is about 605 mg.In some embodiments, C1D3 is about 610 mg. In some embodiments, C1D3 is about 615 mg. In some embodiments, C1D3 is about 620 mg. In some embodiments, C1D3 is about 625 mg. In some embodiments, C1D3 is about 630 mg. In some embodiments, C1D3 is about 635 mg. In some embodiments, C1D3 is about 640 mg. In some embodiments, C1D3 is about 645 mg. In some embodiments, C1D3 is about 650 mg. In some embodiments, C1D3 is about 655 mg. In some embodiments, C1D3 is about 660 mg. In some embodiments, C1D3 is about 665 mg. In some embodiments, C1D3 is about 670 mg. In some embodiments, C1D3 is about 675 mg. In some embodiments, C1D3 is about 680 mg. In some embodiments, C1D3 is about 685 mg. In some embodiments, C1D3 is about 690 mg. In some embodiments, C1D3 is about 695 mg. In some embodiments, C1D3 is about 700 mg. In some embodiments, C1D3 is about 705 mg. In some embodiments, C1D3 is about 710 mg. In some embodiments, C1D3 is about 715 mg. In some embodiments, C1D3 is about 720 mg. In some embodiments, C1D3 is about 725 mg. In some embodiments, C1D3 is about 730 mg. In some embodiments, C1D3 is about 735 mg. In some embodiments, C1D3 is about 740 mg. In some embodiments, C1D3 is about 745 mg. In some embodiments, C1D3 is about 750 mg. In some embodiments, C1D3 is about 755 mg. In some embodiments, C1D3 is about 760 mg. In some embodiments, C1D3 is about 765 mg. In some embodiments, C1D3 is about 770 mg. In some embodiments, C1D3 is about 775 mg. In some embodiments, C1D3 is about 780 mg. In some embodiments, C1D3 is about 785 mg. In some embodiments, C1D3 is about 790 mg. In some embodiments, C1D3 is about 795 mg. In some embodiments, C1D3 is about 800 mg. In some embodiments, C1D3 is about 805 mg.In some embodiments, C1D3 is about 810 mg. In some embodiments, C1D3 is about 815 mg. In some embodiments, C1D3 is about 820 mg. In some embodiments, C1D3 is about 825 mg. In some embodiments, C1D3 is about 830 mg. In some embodiments, C1D3 is about 835 mg. In some embodiments, C1D3 is about 840 mg. In some embodiments, C1D3 is about 845 mg. In some embodiments, C1D3 is about 850 mg. In some embodiments, C1D3 is about 855 mg. In some embodiments, C1D3 is about 860 mg. In some embodiments, C1D3 is about 865 mg. In some embodiments, C1D3 is about 870 mg. In some embodiments, C1D3 is about 875 mg. In some embodiments, C1D3 is about 880 mg. In some embodiments, C1D3 is about 885 mg. In some embodiments, C1D3 is about 890 mg. In some embodiments, C1D3 is about 895 mg. In some embodiments, C1D3 is about 900 mg. In some embodiments, C1D3 is about 905 mg. In some embodiments, C1D3 is about 910 mg. In some embodiments, C1D3 is about 915 mg. In some embodiments, C1D3 is about 920 mg. In some embodiments, C1D3 is about 925 mg. In some embodiments, C1D3 is about 930 mg. In some embodiments, C1D3 is about 935 mg. In some embodiments, C1D3 is about 940 mg. In some embodiments, C1D3 is about 945 mg. In some embodiments, C1D3 is about 950 mg. In some embodiments, C1D3 is about 955 mg. In some embodiments, C1D3 is about 960 mg. In some embodiments, C1D3 is about 965 mg. In some embodiments, C1D3 is about 970 mg. In some embodiments, C1D3 is about 975 mg. In some embodiments, C1D3 is about 980 mg. In some embodiments, C1D3 is about 985 mg. In some embodiments, C1D3 is about 990 mg. In some embodiments, C1D3 is about 995 mg. In some embodiments, C1D3 is about 1000 mg.

[0271] In some embodiments, C1D1 is 0.1 mg. In some embodiments, C1D1 is 0.2 mg. In some embodiments, C1D1 is 0.3 mg. In some embodiments, C1D1 is 0.4 mg. In some embodiments, C1D1 is 0.5 mg. In some embodiments, C1D1 is 0.6 mg. In some embodiments, C1D1 is 0.7 mg. In some embodiments, C1D1 is 0.8 mg. In some embodiments, C1D1 is 0.9 mg. In some embodiments, C1D1 is 1 mg. In some embodiments, C1D1 is 2 mg. In some embodiments, C1D1 is 3 mg. In some embodiments, C1D1 is 4 mg. In some embodiments, C1D1 is 5 mg. In some embodiments, C1D1 is 6 mg. In some embodiments, C1D1 is 7 mg. In some embodiments, C1D1 is 8 mg. In some embodiments, C1D1 is 9 mg. In some embodiments, C1D1 is 10 mg.

[0272] In some embodiments, C1D2 is 1 mg. In some embodiments, C1D2 is 2 mg. In some embodiments, C1D2 is 3 mg. In some embodiments, C1D2 is 4 mg. In some embodiments, C1D2 is 5 mg. In some embodiments, C1D2 is 6 mg. In some embodiments, C1D2 is 7 mg. In some embodiments, C1D2 is 8 mg. In some embodiments, C1D2 is 9 mg. In some embodiments, C1D2 is 10 mg. In some embodiments, C1D2 is 11 mg. In some embodiments, C1D2 is 12 mg. In some embodiments, C1D2 is 13 mg. In some embodiments, C1D2 is 14 mg. In some embodiments, C1D2 is 15 mg. In some embodiments, C1D2 is 16 mg. In some embodiments, C1D2 is 17 mg. In some embodiments, C1D2 is 18 mg. In some embodiments, C1D2 is 19 mg. In some embodiments, C1D2 is 20 mg. In some embodiments, C1D2 is 21 mg. In some embodiments, C1D2 is 22 mg. In some embodiments, C1D2 is 23 mg. In some embodiments, C1D2 is 24 mg. In some embodiments, C1D2 is 25 mg. In some embodiments, C1D2 is 26 mg. In some embodiments, C1D2 is 27 mg. In some embodiments, C1D2 is 28 mg. In some embodiments, C1D2 is 29 mg. In some embodiments, C1D2 is 30 mg. In some embodiments, C1D2 is 31 mg. In some embodiments, C1D2 is 32 mg. In some embodiments, C1D2 is 33 mg. In some embodiments, C1D2 is 34 mg. In some embodiments, C1D2 is 35 mg. In some embodiments, C1D2 is 36 mg. In some embodiments, C1D2 is 37 mg. In some embodiments, C1D2 is 38 mg. In some embodiments, C1D2 is 39 mg. In some embodiments, C1D2 is 40 mg. In some embodiments, C1D2 is 41 mg. In some embodiments, C1D2 is 42 mg. In some embodiments, C1D2 is 43 mg.In some embodiments, C1D2 is 44 mg. In some embodiments, C1D2 is 45 mg. In some embodiments, C1D2 is 46 mg. In some embodiments, C1D2 is 47 mg. In some embodiments, C1D2 is 48 mg. In some embodiments, C1D2 is 49 mg. In some embodiments, C1D2 is 50 mg.

[0273] In some embodiments, C1D3 is 10 mg. In some embodiments, C1D3 is 15 mg. In some embodiments, C1D3 is 20 mg. In some embodiments, C1D3 is 25 mg. In some embodiments, C1D3 is 30 mg. In some embodiments, C1D3 is 35 mg. In some embodiments, C1D3 is 40 mg. In some embodiments, C1D3 is 45 mg. In some embodiments, C1D3 is 50 mg. In some embodiments, C1D3 is 55 mg. In some embodiments, C1D3 is 60 mg. In some embodiments, C1D3 is 65 mg. In some embodiments, C1D3 is 70 mg. In some embodiments, C1D3 is 75 mg. In some embodiments, C1D3 is 80 mg. In some embodiments, C1D3 is 85 mg. In some embodiments, C1D3 is 90 mg. In some embodiments, C1D3 is 95 mg. In some embodiments, C1D3 is 100 mg. In some embodiments, C1D3 is 105 mg. In some embodiments, C1D3 is 110 mg. In some embodiments, C1D3 is 115 mg. In some embodiments, C1D3 is 120 mg. In some embodiments, C1D3 is 125 mg. In some embodiments, C1D3 is 130 mg. In some embodiments, C1D3 is 135 mg. In some embodiments, C1D3 is 140 mg. In some embodiments, C1D3 is 145 mg. In some embodiments, C1D3 is 150 mg. In some embodiments, C1D3 is 155 mg. In some embodiments, C1D3 is 160 mg. In some embodiments, C1D3 is 165 mg. In some embodiments, C1D3 is 170 mg. In some embodiments, C1D3 is 175 mg. In some embodiments, C1D3 is 180 mg. In some embodiments, C1D3 is 185 mg. In some embodiments, C1D3 is 190 mg. In some embodiments, C1D3 is 195 mg. In some embodiments, C1D3 is 200 mg. In some embodiments, C1D3 is 205 mg. In some embodiments, C1D3 is 210 mg. In some embodiments, C1D3 is 215 mg.In some embodiments, C1D3 is 220 mg. In some embodiments, C1D3 is 225 mg. In some embodiments, C1D3 is 230 mg. In some embodiments, C1D3 is 235 mg. In some embodiments, C1D3 is 240 mg. In some embodiments, C1D3 is 245 mg. In some embodiments, C1D3 is 250 mg. In some embodiments, C1D3 is 255 mg. In some embodiments, C1D3 is 260 mg. In some embodiments, C1D3 is 265 mg. In some embodiments, C1D3 is 270 mg. In some embodiments, C1D3 is 275 mg. In some embodiments, C1D3 is 280 mg. In some embodiments, C1D3 is 285 mg. In some embodiments, C1D3 is 290 mg. In some embodiments, C1D3 is 295 mg. In some embodiments, C1D3 is 300 mg. In some embodiments, C1D3 is 305 mg. In some embodiments, C1D3 is 310 mg. In some embodiments, C1D3 is 315 mg. In some embodiments, C1D3 is 320 mg. In some embodiments, C1D3 is 325 mg. In some embodiments, C1D3 is 330 mg. In some embodiments, C1D3 is 335 mg. In some embodiments, C1D3 is 340 mg. In some embodiments, C1D3 is 345 mg. In some embodiments, C1D3 is 350 mg. In some embodiments, C1D3 is 355 mg. In some embodiments, C1D3 is 360 mg. In some embodiments, C1D3 is 365 mg. In some embodiments, C1D3 is 370 mg. In some embodiments, C1D3 is 375 mg. In some embodiments, C1D3 is 380 mg. In some embodiments, C1D3 is 385 mg. In some embodiments, C1D3 is 390 mg. In some embodiments, C1D3 is 395 mg. In some embodiments, C1D3 is 400 mg. In some embodiments, C1D3 is 405 mg. In some embodiments, C1D3 is 410 mg. In some embodiments, C1D3 is 415 mg. In some embodiments, C1D3 is 420 mg.In some embodiments, C1D3 is 425 mg. In some embodiments, C1D3 is 430 mg. In some embodiments, C1D3 is 435 mg. In some embodiments, C1D3 is 440 mg. In some embodiments, C1D3 is 445 mg. In some embodiments, C1D3 is 450 mg. In some embodiments, C1D3 is 455 mg. In some embodiments, C1D3 is 460 mg. In some embodiments, C1D3 is 465 mg. In some embodiments, C1D3 is 470 mg. In some embodiments, C1D3 is 475 mg. In some embodiments, C1D3 is 480 mg. In some embodiments, C1D3 is 485 mg. In some embodiments, C1D3 is 490 mg. In some embodiments, C1D3 is 495 mg. In some embodiments, C1D3 is 500 mg. In some embodiments, C1D3 is 505 mg. In some embodiments, C1D3 is 510 mg. In some embodiments, C1D3 is 515 mg. In some embodiments, C1D3 is 520 mg. In some embodiments, C1D3 is 525 mg. In some embodiments, C1D3 is 530 mg. In some embodiments, C1D3 is 535 mg. In some embodiments, C1D3 is 540 mg. In some embodiments, C1D3 is 545 mg. In some embodiments, C1D3 is 550 mg. In some embodiments, C1D3 is 555 mg. In some embodiments, C1D3 is 560 mg. In some embodiments, C1D3 is 565 mg. In some embodiments, C1D3 is 570 mg. In some embodiments, C1D3 is 575 mg. In some embodiments, C1D3 is 580 mg. In some embodiments, C1D3 is 585 mg. In some embodiments, C1D3 is 590 mg. In some embodiments, C1D3 is 595 mg. In some embodiments, C1D3 is 600 mg. In some embodiments, C1D3 is 605 mg. In some embodiments, C1D3 is 610 mg. In some embodiments, C1D3 is 615 mg. In some embodiments, C1D3 is 620 mg. In some embodiments, C1D3 is 625 mg.In some embodiments, C1D3 is 630 mg. In some embodiments, C1D3 is 635 mg. In some embodiments, C1D3 is 640 mg. In some embodiments, C1D3 is 645 mg. In some embodiments, C1D3 is 650 mg. In some embodiments, C1D3 is 655 mg. In some embodiments, C1D3 is 660 mg. In some embodiments, C1D3 is 665 mg. In some embodiments, C1D3 is 670 mg. In some embodiments, C1D3 is 675 mg. In some embodiments, C1D3 is 680 mg. In some embodiments, C1D3 is 685 mg. In some embodiments, C1D3 is 690 mg. In some embodiments, C1D3 is 695 mg. In some embodiments, C1D3 is 700 mg. In some embodiments, C1D3 is 705 mg. In some embodiments, C1D3 is 710 mg. In some embodiments, C1D3 is 715 mg. In some embodiments, C1D3 is 720 mg. In some embodiments, C1D3 is 725 mg. In some embodiments, C1D3 is 730 mg. In some embodiments, C1D3 is 735 mg. In some embodiments, C1D3 is 740 mg. In some embodiments, C1D3 is 745 mg. In some embodiments, C1D3 is 750 mg. In some embodiments, C1D3 is 755 mg. In some embodiments, C1D3 is 760 mg. In some embodiments, C1D3 is 765 mg. In some embodiments, C1D3 is 770 mg. In some embodiments, C1D3 is 775 mg. In some embodiments, C1D3 is 780 mg. In some embodiments, C1D3 is 785 mg. In some embodiments, C1D3 is 790 mg. In some embodiments, C1D3 is 795 mg. In some embodiments, C1D3 is 800 mg. In some embodiments, C1D3 is 805 mg. In some embodiments, C1D3 is 810 mg. In some embodiments, C1D3 is 815 mg. In some embodiments, C1D3 is 820 mg. In some embodiments, C1D3 is 825 mg. In some embodiments, C1D3 is 830 mg.In some embodiments, C1D3 is 835 mg. In some embodiments, C1D3 is 840 mg. In some embodiments, C1D3 is 845 mg. In some embodiments, C1D3 is 850 mg. In some embodiments, C1D3 is 855 mg. In some embodiments, C1D3 is 860 mg. In some embodiments, C1D3 is 865 mg. In some embodiments, C1D3 is 870 mg. In some embodiments, C1D3 is 875 mg. In some embodiments, C1D3 is 880 mg. In some embodiments, C1D3 is 885 mg. In some embodiments, C1D3 is 890 mg. In some embodiments, C1D3 is 895 mg. In some embodiments, C1D3 is 900 mg. In some embodiments, C1D3 is 905 mg. In some embodiments, C1D3 is 910 mg. In some embodiments, C1D3 is 915 mg. In some embodiments, C1D3 is 920 mg. In some embodiments, C1D3 is 925 mg. In some embodiments, C1D3 is 930 mg. In some embodiments, C1D3 is 935 mg. In some embodiments, C1D3 is 940 mg. In some embodiments, C1D3 is 945 mg. In some embodiments, C1D3 is 950 mg. In some embodiments, C1D3 is 955 mg. In some embodiments, C1D3 is 960 mg. In some embodiments, C1D3 is 965 mg. In some embodiments, C1D3 is 970 mg. In some embodiments, C1D3 is 975 mg. In some embodiments, C1D3 is 980 mg. In some embodiments, C1D3 is 985 mg. In some embodiments, C1D3 is 990 mg. In some embodiments, C1D3 is 995 mg. In some embodiments, C1D3 is 1000 mg.

[0274] In some cases, these methods described above may include a first dosing cycle of 4 weeks or 28 days. In some cases, the method may include administering C1D1 and C1D2 to the subject on days 1 and 8, respectively, of the first dosing cycle, or on or about those days. In some cases, the method may include administering C1D1, C1D2 and C1D3 to the subject on days 1, 8 and 15, respectively, of the first dosing cycle, or on or about those days.

[0275] In some embodiments, the method includes only a single dosing cycle of the bispecific antibody (e.g., a dosing cycle including C1D1, C1D2 and C1D3).

[0276] iv. Further dosing cycles Any of the methods described herein may include further dosing cycles. For example, in some cases, these methods described above may include a second dosing cycle of 4 weeks or 28 days. In some cases, the method may include administering C2D1 to the subject on days 1 and 15 of the second dosing cycle, or on or about those days.

[0277] In some cases where the method includes at least a second dosing cycle, the method may include one or more additional dosing cycles. In some cases, the dosing regimen includes 1 to 17 additional dosing cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 additional dosing cycles, e.g., 1 to 3 additional dosing cycles, 1 to 5 additional dosing cycles, 3 to 8 additional dosing cycles, 5 to 10 additional dosing cycles, 8 to 12 additional dosing cycles, 10 to 15 additional dosing cycles, 12 to 17 additional dosing cycles, or 15 to 17 additional dosing cycles, i.e., the dosing regimen includes one or more additional dosing cycles (s) C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, and C19.

[0278] 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, such as, for example, between 5 and 9 days, between 7 and 11 days, between 9 and 13 days, between 11 and 15 days, between 13 and 17 days, between 15 and 19 days, between 17 and 21 days, between 19 and 23 days, between 21 and 25 days, between 23 and 27 days, or between 25 and 30 days. In some cases, the length of each of the one or more additional dosing cycles is 3 weeks or 21 days. In some cases, the length of each of the one or more additional dosing cycles is 4 weeks or 28 days.

[0279] In some cases, each of the one or more additional dosing cycles comprises a single dose of the bispecific antibody.In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is equal to C1D3, for example, from about 10 mg to about 1000 mg (e.g., from about 10 mg to about 70 mg, from about 15 mg to about 65 mg, from about 20 mg to about 60 mg, from about 25 mg to about 55 mg, from about 30 mg to about 50 mg, from about 35 mg to about 45 mg, from about 15 mg to about 225 mg, from about 20 mg to about 220 mg, 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 135 mg, from about 110 mg to about 130 mg, from about 115 mg to about 125 mg, from about 10 mg to about 50 mg, from about 25 mg to about 75 mg, from about 50 mg to about 100 mg, from about 75 mg to about 125 mg, from about 100 mg to about 150 mg, from about 125 mg to about 175 mg, from about 150 mg to about 200 mg, from about 175 mg to about 225 mg, from about 200 mg to about 250 mg, from about 225 mg to about 275 mg, from about 250 mg to about 300 mg, from about 275 mg to about 325 mg, from about 300 mg to about 350 mg, from about 325 mg to about 375 mg, from about 350 mg to about 400 mg, from about 375 mg to about 425 mg, from about 400 mg to about 450 mg, from about 425 mg to about 475 mg, from about 450 mg to 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 725 mg to about 775 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).In some embodiments, C1D2 is greater than C1D1 and C1D3 is greater than C1D2.

[0280] In some embodiments, the dosage of the bispecific antibody in one or more additional dosing cycles is from about 10 mg to about 200 mg (e.g., from about 10 mg to about 200 mg (e.g., from about 10 mg to about 170 mg, from about 11 mg to about 165 mg, from about 12 mg to about 160 mg, from about 13 mg to about 155 mg, from about 14 mg to about 150 mg, from about 15 mg to about 145 mg, from about 16 mg to about 140 mg, from about 17 mg to about 135 mg, from about 18 mg to about 130 mg, from about 19 mg to about 125 mg, from about 20 mg to about 120 mg, from about 21 mg to about 115 mg, from about 22 mg to about 110 mg, from about 23 mg to about 105 mg, from about 24 mg to about 100 mg, from about 25 mg to about 95 mg, from about 26 mg to about 90 mg, from about 27 mg to about 85 mg, from about 28 mg to about 80 mg, from about 29 mg to about 75 mg, from about 30 mg to about 70 mg, from about 31 mg to about 65 mg, from about 32 mg to about 60 mg, from about 33 mg to about 55 mg, from about 34 mg to about 50 mg, from about 35 mg to about 45 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 135 mg, from about 110 mg to about 130 mg, from about 115 mg to about 125 mg, from about 10 mg to about 20 mg, from about 20 mg to about 30 mg, from about 30 mg to about 40 mg, from about 40 mg to about 50 mg, from about 50 mg to about 60 mg, from about 60 mg to about 70 mg, from about 70 mg to about 80 mg, from about 80 mg to about 90 mg, from about 90 mg to about 100 mg, from about 100 mg to about 110 mg, from about 110 mg to about 120 mg, from about 120 mg to about 130 mg, from about 130 mg to about 140 mg, from about 140 mg to about 150 mg, from about 150 mg to about 160 mg, from about 160 mg to about 170 mg, from about 170 mg to about 180 mg, or from about 180 mg to about 200 mg)).

[0281] In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is about 40 mg. In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is about 120 mg. In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is equal to C1D3, for example, 10 mg to 1000 mg (e.g., 10 mg to 70 mg, 15 mg to 65 mg, 20 mg to 60 mg, 25 mg to 55 mg, 30 mg to 50 mg, 35 mg to 45 mg, 15 mg to 225 mg, 20 mg to 220 mg, 25 mg to 215 mg, 30 mg to 210 mg, 35 mg to 205 mg, 40 mg to 200 mg, 45 mg to 195 mg, 50 mg to 190 mg, 55 mg to 185 mg, 60 mg to 180 mg, 65 mg to 175 mg, 70 mg to 170 mg, 75 mg to 165 mg, 80 mg to 160 mg, 85 mg to 155 mg, 90 mg to 150 mg, 95 mg to 145 mg, 100 mg to 140 mg, 105 mg to 135 mg, 110 mg to 130 mg, 115 mg to 125 mg, 10 mg to 50 mg, 25 mg to 75 mg, 50 mg to 100 mg, 75 mg to 125 mg, 100 mg to 150 mg, 125 mg to 175 mg, 150 mg to 200 mg, 175 mg to 225 mg, 200 mg to 250 mg, 225 mg to 275 mg, 250 mg to 300 mg, 275 mg to 325 mg, 300 mg to 350 mg, 325 mg to 375 mg, 350 mg to 400 mg, 375 mg to 425 mg, 400 mg to 450 mg, 425 mg to 475 mg, 450 mg to 500 mg, 475 mg to 525 mg, 500 mg to 550 mg, 525 mg to 575 mg, 550 mg to 600 mg, 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 embodiments, C1D2 is greater than C1D1 and C1D3 is greater than C1D2.

[0282] In some embodiments, C1D3 is from 10 mg to 200 mg (e.g., 10 mg to 170 mg, 11 mg to 165 mg, 12 mg to 160 mg, 13 mg to 155 mg, 14 mg to 150 mg, 15 mg to 145 mg, 16 mg to 140 mg, 17 mg to 135 mg, 18 mg to 130 mg, 19 mg to 125 mg, 20 mg to 120 mg, 21 mg to 115 mg, 22 mg to 110 mg, 23 mg to 105 mg, 24 mg to 100 mg, 25 mg to 95 mg, 26 mg to 90 mg, 27 mg to 85 mg, 28 mg to 80 mg, 29 mg to 75 mg, 30 mg to 70 mg, 31 mg to 65 mg, 32 mg to 60 mg, 33 mg to 55 mg, 34 mg to 50 mg, 35 mg to 45 mg, 40 mg to 200 mg, 45 mg to 195 mg, 50 mg to 190 mg, 55 mg to 185 mg, 60 mg to 180 mg, 65 mg to 175 mg, 70 mg to 170 mg, 75 mg to 165 mg, 80 mg to 160 mg, 85 mg to 155 mg, 90 mg to 150 mg, 95 mg to 145 mg, 100 mg to 140 mg, 105 mg to 135 mg, 110 mg to 130 mg, 115 mg to 125 mg, 10 mg to 20 mg, 20 mg to 30 mg, 30 mg to 40 mg, 40 mg to 50 mg, 50 mg to 60 mg, 60 mg to 70 mg, 70 mg to 80 mg, 80 mg to 90 mg, 90 mg to 100 mg, 100 mg to 110 mg, 110 mg to 120 mg, 120 mg to 130 mg, 130 mg to 140 mg, 140 mg to 150 mg, 150 mg to 160 mg, 160 mg to 170 mg, 170 mg to 180 mg, or 190 mg to 200 mg). In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is 40 mg. In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is about 120 mg.

[0283] In some cases, the method comprises subcutaneously administering a single dose of the bispecific antibody to the subject on day 1 and day 15, or about those days, of one or more additional dosing cycles. In some cases, the method comprises administering a single dose of the bispecific antibody to the subject on day 1, or about that day, of one or more additional dosing cycles. In some cases, the method comprises administering a single dose of the bispecific antibody to the subject on day 1, day 8, day 15 and / or day 22, or about those days, of one or more additional dosing cycles.

[0284] In some embodiments, the bispecific antibody is administered subcutaneously to the subject every 7 days (QW) for up to 18 cycles, or until minimal residual disease (MRD) is detected, until progressive disease is detected. In some embodiments, the bispecific antibody is administered to the subject every 14 days (Q2W) for up to 18 cycles, or until minimal residual disease (MRD) is detected, until progressive disease is detected. In some embodiments, the bispecific antibody is administered to the subject every 21 days (Q3W) for up to 18 cycles, or until minimal residual disease (MRD) is detected, until progressive disease is detected. In some embodiments, the bispecific antibody is administered to the subject every 28 days (Q4W) for up to 18 cycles, or until minimal residual disease (MRD) is detected, until progressive disease is detected.

[0285] In some embodiments, the bispecific antibody is administered subcutaneously to the subject QW until disease progression is observed. In some embodiments, the bispecific antibody is administered subcutaneously to the subject Q2W until disease progression is observed. In some embodiments, the bispecific antibody is administered subcutaneously to the subject Q3W until disease progression is observed. In some embodiments, 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 monotherapy. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject in combination with another therapeutic agent. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject in combination with an anti-CD38 antibody. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject in combination with a corticosteroid. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject in combination with an immunomodulatory drug (IMiD). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject in combination with an anti-CD38 antibody and a corticosteroid. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject in combination with an IMiD and a corticosteroid. Exemplary anti-CD38 antibodies used in combination therapy include daratumumab and isatuximab. Exemplary corticosteroids used in combination therapy include dexamethasone and methylprednisolone. Exemplary IMiDs used in combination therapy include pomalidomide and lenalidomide.

[0286] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is cevostamab. In some cases, cevostamab is administered to a subject as a monotherapy. In some cases, cevostamab is administered to a subject in combination with pomalidomide (P). In some cases, cevostamab is administered to a subject in combination with dexamethasone (d). In some cases, cevostamab is administered to a subject in combination with pomalidomide and dexamethasone (Pd). In some cases, cevostamab is administered to a subject in combination with daratumumab (D). In some cases, cevostamab is administered to a subject in combination with daratumumab and dexamethasone (Dd).

[0287] B. Administration Regimen: Frequency and Administration Cycles The present disclosure describes a method of treating a subject having cancer (e.g., multiple myeloma (MM)), the method comprising subcutaneously administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in an administration regimen described herein. In some examples, the administration regimen includes a first phase comprising one or more administration cycles, a second phase comprising one or more administration cycles, and a third phase comprising one or more administration cycles. In some examples, each administration cycle is a 28-day administration cycle. The first phase may include administering the bispecific antibody to the subject once a 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).

[0288] For example, a method of treating a subject having cancer (e.g., MM), comprising subcutaneously administering to the subject a bispecific antibody that binds to FcRH5 and CD3, in a dosing regimen comprising: (i) a first phase comprising one or more dosing cycles, wherein the bispecific antibody is administered to the subject once weekly (QW); (ii) a second phase comprising one or more dosing cycles, wherein the bispecific antibody is administered to the subject every two weeks (Q2W); and / or (iii) a third phase comprising one or more dosing cycles, wherein the bispecific antibody is administered 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 and second phases. In some examples, the dosing regimen comprises the first and third phases. In some examples, the dosing regimen comprises the second and third phases. In some examples, the dosing regimen comprises the first, second, and third phases.

[0289] In another example, bispecific antibodies that bind to FcRH5 and CD3 for use in the treatment of a subject having cancer (e.g., MM) are provided herein, and the treatment comprises: (i) a first phase comprising one or more dosing cycles, the first phase comprising administering the bispecific antibody to the subject once a week (QW); (ii) a second phase comprising one or more dosing cycles, the second phase comprising administering the bispecific antibody to the subject every two weeks (Q2W); and / or (iii) a third phase comprising one or more dosing cycles, the third phase comprising administering the bispecific antibody to the subject every four weeks (Q4W), subcutaneous administration of the bispecific antibody to the subject in a dosing regimen comprising. 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 and second phases. In some examples, the dosing regimen comprises the first and third phases. In some examples, the dosing regimen comprises the second and third phases. In some examples, the dosing regimen comprises the first, second, and third phases.

[0290] In another example, the use of a bispecific antibody that binds to FcRH5 and CD3 in the manufacture of a medicament for the treatment of a subject having cancer (e.g., MM) is provided herein, the treatment comprising: (i) a first phase comprising one or more dosing cycles, the first phase comprising administering the bispecific antibody to the subject once weekly (QW); (ii) a second phase comprising one or more dosing cycles, the second phase comprising administering the bispecific antibody to the subject every two weeks (Q2W); and / or (iii) a third phase comprising one or more dosing cycles, the third phase comprising administering the bispecific antibody to the subject every four weeks (Q4W), the treatment including subcutaneous administration of the bispecific antibody to the subject in a dosing regimen that includes one or more of the foregoing phases. 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 and second phases. In some examples, the dosing regimen includes the first and third phases. In some examples, the dosing regimen includes the second and third phases. In some examples, the dosing regimen includes the first, second, and third phases.

[0291] The first phase can include any suitable number of dosing cycles. For example, in some examples, the first phase includes at least 1 dosing cycle, at least 2 dosing cycles, at least 3 dosing cycles, at least 4 dosing cycles, at least 5 dosing cycles, at least 6 dosing cycles, at least 7 dosing cycles, at least 8 dosing cycles, at least 9 dosing cycles, at least 10 dosing cycles, at least 11 dosing cycles, at least 12 dosing cycles, or at least 13 dosing cycles, or more.

[0292] In some examples, the first phase is the first dosing cycle (C1); the first and second dosing cycles (C2); the first, second (C2), and third dosing cycles (C3); the first (C1), second (C2), third (C3), and fourth dosing cycles (C4); the first (C1), second (C2), third (C3), fourth (C4), and fifth dosing cycles (C5); the first (C1), second (C2), third (C3), fourth (C4), fifth (C5), and sixth dosing cycles (C6); the first (C1), second (C2), third (C3), fourth (C4), fifth (C5), sixth (C6), and seventh dosing cycles (C7); the first (C1), second (C2), third (C3), fourth (C4), fifth (C5), sixth (C6), seventh (C7), and eighth dosing cycles (C8); the first (C1), second (C2), third (C3), fourth (C4), fifth (C5), sixth (C6), seventh (C7), eighth (C8), and ninth dosing cycles (C9); the first (C1), second (C2), third (C3), fourth (C4), fifth (C5), sixth (C6), seventh (C7), eighth (C8), ninth (C9), and tenth dosing cycles (C10); the first (C1), second (C2), third (C3), fourth (C4), fifth (C5), sixth (C6), seventh (C7), eighth (C8), ninth (C9), tenth (C10), and eleventh dosing cycles (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 are included.;

[0293] The bispecific antibody can be administered on any suitable day of a given dosing cycle. For example, in the case of 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, in the case of a 21-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, or day 21. In another example, in the case of a 14-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, or day 14. In another example, in the case of a 7-day dosing cycle, the bispecific antibody can be administered on day 1, day 2, day 3, day 4, day 5, day 6, or day 7.;

[0294] In some examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C1. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C2. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C3. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C4. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C5. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C6. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C7. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C8. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C9. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C10. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C11. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C12. In further examples, the first phase includes administration of the bispecific antibody to the subject on day 1, day 8, and / or day 15 of C13.

[0295] In some examples, the target dose of the bispecific antibody is administered to the subject for each administration during the first phase.

[0296] In some examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on day 1, day 8, and / or day 15 of C1. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on day 1, day 8, and / or day 15 of C2. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on day 1, day 8, and / or day 15 of C3. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on day 1, day 8, and / or day 15 of C4. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on day 1, day 8, and / or day 15 of C5. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on day 1, day 8, and / or day 15 of C6. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on day 1, day 8, and / or day 15 of C7. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on day 1, day 8, and / or day 15 of C8. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on day 1, day 8, and / or day 15 of C9. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on day 1, day 8, and / or day 15 of C10. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on day 1, day 8, and / or day 15 of C11. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on day 1, day 8, and / or day 15 of C12. In further examples, the first phase includes administration of a bispecific antibody at a target dose to a subject on day 1, day 8, and / or day 15 of C13.

[0297] In some examples, the first phase includes administration of a bispecific antibody at a first step-up dose and a target dose to a subject. The first step-up dose can be administered to the subject on day 1 of cycle 1, day 2 of cycle 1, day 3 of cycle 1, day 4 of cycle 1, day 5 of cycle 1, day 6 of cycle 1, or day 7 of cycle 1 during the first phase. The target dose can be administered to the subject on day 8 and / or day 15 of cycle 1 during the first phase. In further examples, the target dose can be administered to the subject on day 1, day 8, and / or day 15 of cycle 2 during the first phase. In further examples, the target dose can be administered to the subject on day 1, day 8, and / or day 15 of cycle 3 during the first phase. In further examples, the target dose can be administered to the subject on day 1, day 8, and / or day 15 of cycle 4 during the first phase. In further examples, the target dose can be administered to the subject on day 1, day 8, and / or day 15 of cycle 5 during the first phase. In further examples, the target dose can be administered to the subject on day 1, day 8, and / or day 15 of cycle 6 during the first phase. In further examples, the target dose can be administered to the subject on day 1, day 8, and / or day 15 of cycle 7 during the first phase. In further examples, the target dose can be administered to the subject on day 1, day 8, and / or day 15 of cycle 8 during the first phase. In further examples, the target dose can be administered to the subject on day 1, day 8, and / or day 15 of cycle 9 during the first phase. In further examples, the target dose can be administered to the subject on day 1, day 8, and / or day 15 of cycle 10 during the first phase. In further examples, the target dose can be administered to the subject on day 1, day 8, and / or day 15 of cycle 11 during the first phase. In further examples, the target dose can be administered to the subject on day 1, day 8, and / or day 15 of cycle 12 during the first phase. In further examples, the target dose can be administered to the subject on day 1, day 8, and / or day 15 of cycle 13 during the first phase.

[0298] In some examples, the first step-up dose is from about 15% to about 45% of the target dose. In some examples, 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 examples, the first step-up dose is about 25% of the target dose.

[0299] In some examples, the first step-up dose is 15% - 45% of the target dose. In some examples, 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 examples, the first step-up dose is 25% of the target dose.

[0300] In some examples, the initial step-up dose is from 0.1 mg to about 50 mg (e.g., from about 0.1 mg to about 9.5 mg, from about 0.2 mg to about 9 mg, from about 0.3 mg to about 8.5 mg, from about 0.4 mg to about 8 mg, from about 0.5 mg to about 7.5 mg, from about 0.6 mg to about 7 mg, from about 0.7 mg to about 6.5 mg, from about 0.8 mg to about 6 mg, from about 0.9 mg to about 5.5 mg, from about 1 mg to about 5 mg, from about 1.1 mg to about 4.5 mg, from about 1.2 mg to about 4 mg, from about 1.3 mg to about 3.5 mg, from about 1.4 mg to about 3 mg, from about 1.5 mg to about 2.5 mg, from about 1 mg to about 3 mg, from about 0.2 mg to about 35 mg, from about 0.3 mg to about 30 mg, from about 0.4 mg to about 29 mg, from about 0.5 mg to about 28 mg, from about 1 mg to about 27 mg, from about 1.5 mg to about 26 mg, from about 2 mg to about 25 mg, from about 2.5 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, from about 0.4 mg to about 2.5 mg, from about 0.5 mg to about 3 mg, from about 0.6 mg to about 3.5 mg, from about 0.7 mg to about 4 mg, from about 0.8 mg to about 4.5 mg, from about 0.9 mg to about 5 mg, from about 1 mg to about 6 mg, from about 1.5 mg to about 6.5 mg, from about 2 mg to about 7 mg, from about 2.5 mg to about 7.5 mg, from about 3 mg to about 8 mg, from about 3.5 mg to about 8.5 mg, from about 4 mg to about 9 mg, from about 4.5 mg to about 9.5 mg, from about 5 mg to about 10 mg, from about 5.5 mg to about 10.5 mg, from about 6 mg to about 11 mg, from about 6.5 mg to about 11.5 mg, from about 7 mg to about 12 mg, from about 7.5 mg to about 12.5 mg, from about 8 mg to about 13 mg, from about 8.5 mg to about 13.5 mg, from about 9 mg to about 14 mg, from 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 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).

[0301] In some examples, the first step-up dose is from 0.1 mg to 50 mg (for example, from 0.1 mg to 9.5 mg, from 0.2 mg to 9 mg, from 0.3 mg to 8.5 mg, from 0.4 mg to 8 mg, from 0.5 mg to 7.5 mg, from 0.6 mg to 7 mg, from 0.7 mg to 6.5 mg, from 0.8 mg to 6 mg, from 0.9 mg to 5.5 mg, from 1 mg to 5 mg, from 1.1 mg to 4.5 mg, from 1.2 mg to 4 mg, from 1.3 mg to 3.5 mg, from 1.4 mg to 3 mg, from 1.5 mg to 2.5 mg, from 1 mg to 3 mg, from 0.2 mg to 35 mg, from 0.3 mg to 30 mg, from 0.4 mg to 29 mg, from 0.5 mg to 28 mg, from 1 mg to 27 mg, from 1.5 mg to 26 mg, from 2 mg to 25 mg, from 2.5 mg to 24 mg, from 3 mg to 23 mg, from 3.5 mg to 22 mg, from 4 mg to 21 mg, from 4.5 mg to 20 mg, from 5 mg to 19 mg, from 5.5 mg to 18 mg, from 6 mg to 17 mg, from 6.5 mg to 16 mg, from 7 mg to 15 mg, from 7.5 mg to 14 mg, from 8 mg to 13 mg, from 8 mg to 12 mg, from 8.5 mg to 12 mg, from 9 mg to 11 mg, from 0.1 mg to 1 mg, from 0.2 mg to 1.5 mg, from 0.3 mg to 2 mg, from 0.4 mg to 2.5 mg, from 0.5 mg to 3 mg, from 0.6 mg to 3.5 mg, from 0.7 mg to 4 mg, from 0.8 mg to 4.5 mg, from 0.9 mg to 5 mg, from 1 mg to 6 mg, from 1.5 mg to 6.5 mg, from 2 mg to 7 mg, from 2.5 mg to 7.5 mg, from 3 mg to 8 mg, from 3.5 mg to 8.5 mg, from 4 mg to 9 mg, from 4.5 mg to 9.5 mg, from 5 mg to 10 mg, from 5.5 mg to 10.5 mg, from 6 mg to 11 mg, from 6.5 mg to 11.5 mg, from 7 mg to 12 mg, from 7.5 mg to 12.5 mg, from 8 mg to 13 mg, from 8.5 mg to 13.5 mg, from 9 mg to 14 mg, from 9.5 mg to 14.5 mg, 10 mg to 15 mg, 11 mg to 16 mg, 12 mg to 17 mg, 13 mg to 18 mg, 14 mg to 19 mg, 15 mg to 20 mg, 16 mg to 21 mg, 17 mg to 22 mg, 18 mg to 23 mg, 19 mg to 24 mg, 20 mg to 25 mg, 21 mg to 26 mg, 22 mg to 27 mg, 23 mg to 28 mg, 24 mg to 29 mg, 25 mg to 30 mg, 26 mg to 31 mg, 27 mg to 32 mg, 28 mg to 33 mg, 29 mg to 34 mg, 30 mg to 35 mg, 31 mg to 36 mg, 32 mg to 37 mg, 33 mg to 38 mg, 34 mg to 39 mg, 35 mg to 40 mg, 36 mg to 41 mg, 37 mg to 42 mg, 38 mg to 43 mg, 39 mg to 44 mg, 40 mg to 45 mg, 41 mg to 46 mg, 42 mg to 47 mg, 43 mg to 48 mg, 44 mg to 49 mg, 45 mg to 50 mg).

[0302] 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 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.

[0303] 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.

[0304] In some examples, the first phase includes administration of the bispecific antibody at a first step-up dose and a second step-up dose to a 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, the first step-up dose is administered to the subject on day 6 of C1 during the first phase, and the second step-up dose is administered on day 13 of C1. In some examples, the first step-up dose is administered to the subject on day 7 of C1 during the first phase, and the second step-up dose is administered on day 14 of C1. In some examples, the first step-up dose is administered to the subject on day 8 of C1 during the first phase, and the second step-up dose is administered on day 15 of C1. In some examples, the first step-up dose is administered to the subject on day 9 of C1 during the first phase, and the second step-up dose is administered on day 16 of C1. In some examples, the first step-up dose is administered to the subject on day 10 of C1 during the first phase, and the second step-up dose is administered on day 17 of C1. In some examples, the first step-up dose is administered to the subject on day 11 of C1 during the first phase, and the second step-up dose is administered on day 18 of C1. In some examples, the first step-up dose is administered to the subject on day 12 of C1 during the first phase, and the second step-up dose is administered on day 19 of C1.In some examples, the first step-up dose is administered to the subject on day 13 of C1 during the first phase, and the second step-up dose is administered on day 20 of C1. In some examples, the first step-up dose is administered to the subject on day 14 of C1 during the first phase, and the second step-up dose is administered on day 21 of C1.

[0305] In further examples, the target dose is administered to the subject during the first phase after administration of the second step-up dose. In some examples, the target dose is administered to the subject on day 15 and / or 22 of C1. In some examples, the target dose is administered to the subject on day 16 and / or 23 of C1. In some examples, the target dose is administered to the subject on day 17 and / or 24 of C1. In some examples, the target dose is administered to the subject on day 18 and / or 25 of C1. In some examples, the target dose is administered to the subject on day 19 and / or 26 of C1. In some examples, the target dose is administered to the subject on day 20 and / or 27 of C1. In some examples, the target dose is administered to the subject on day 21 and / or 28 of C1.

[0306] In further examples, the target dose is further administered to the subject on day 1, day 8, and / or day 15 of C2 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 C3 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 C4 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 C5 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 C6 during the first phase. In further examples, the target dose is administered to the subject on day 1, day 8, day 15, and day 22 of C7 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 C8 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 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.

[0307] In some examples, the first step-up dose is from about 1% to about 10% of the target dose, and the second step-up dose is from 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 step-up dose is about 5% of the target dose, and the second step-up dose is about 25% of the target dose.

[0308] In some examples, the first step-up dose is from 1% to 10% of the target dose, and the second step-up dose is from 15% to 45% of the target dose. In some examples, 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 step-up dose is 5% of the target dose, and the second step-up dose is 25% of the target dose.

[0309] In some examples, the first step-up dose is from about 0.1 mg to about 10 mg (e.g., from about 0.1 mg to about 2 mg, from about 0.2 mg to about 1 mg, or from about 0.2 mg to about 0.4 mg, from about 0.1 mg to about 9.5 mg, from about 0.2 mg to about 9 mg, from about 0.3 mg to about 8.5 mg, from about 0.4 mg to about 8 mg, from about 0.5 mg to about 7.5 mg, from about 0.6 mg to about 7 mg, from about 0.7 mg to about 6.5 mg, from about 0.8 mg to about 6 mg, from about 0.9 mg to about 5.5 mg, from about 1 mg to about 5 mg, from about 1.1 mg to about 4.5 mg, from about 1.2 mg to about 4 mg, from about 1.3 mg to about 3.5 mg, from about 1.4 mg to about 3 mg, from about 1.5 mg to about 2.5 mg, from about 1 mg to about 3 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, from about 0.4 mg to about 2.5 mg, from about 0.5 mg to about 3 mg, from about 0.6 mg to about 3.5 mg, from about 0.7 mg to about 4 mg, from about 0.8 mg to about 4.5 mg, from about 0.9 mg to about 5 mg, from about 1 mg to about 6 mg, from about 1.5 mg to about 6.5 mg, from about 2 mg to about 7 mg, from about 2.5 mg to about 7.5 mg, from about 3 mg to about 8 mg, from about 3.5 mg to about 8.5 mg, from about 4 mg to about 9 mg, from about 4.5 mg to about 9.5 mg, or from about 5 mg to about 10 mg); the second step-up dose is from about 1 mg to about 50 mg (e.g., from about 3 mg to about 18 mg, from about 3.1 mg to about 15 mg, from about 3.2 mg to about 10 mg, from about 3.3 mg to about 6 mg, from about 3.4 mg to about 4 mg, from about 0.2 mg to about 35 mg, from about 0.3 mg to about 30 mg, from about 0.4 mg to about 29 mg, from about 0.5 mg to about 28 mg, from about 1 mg to about 27 mg, from about 1.5 mg to about 26 mg, from about 2 mg to about 25 mg, from about 2.5 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 1 mg to about 6 mg, from about 1.5 mg to about 6.5 mg, from about 2 mg to about 7 mg, from about 2.5 mg to about 7.5 mg, from about 3 mg to about 8 mg, from about 3.5 mg to about 8.5 mg, from about 4 mg to about 9 mg, from about 4.5 mg to about 9.5 mg, from about 5 mg to about 10 mg, from 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, 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, or about 45 mg to about 50 mg).

[0310] In some examples, the first step-up dose is from 0.1 mg to 10 mg (e.g., from 0.1 mg to 2 mg, from 0.2 mg to 1 mg, or from 0.2 mg to 0.4 mg, from 0.1 mg to 9.5 mg, from 0.2 mg to 9 mg, from 0.3 mg to 8.5 mg, from 0.4 mg to 8 mg, from 0.5 mg to 7.5 mg, from 0.6 mg to 7 mg, from 0.7 mg to 6.5 mg, from 0.8 mg to 6 mg, from 0.9 mg to 5.5 mg, from 1 mg to 5 mg, from 1.1 mg to 4.5 mg, from 1.2 mg to 4 mg, from 1.3 mg to 3.5 mg, from 1.4 mg to 3 mg, from 1.5 mg to 2.5 mg, from 1 mg to 3 mg, from 0.1 mg to 1 mg, from 0.2 mg to 1.5 mg, from 0.3 mg to 2 mg, from 0.4 mg to 2.5 mg, from 0.5 mg to 3 mg, from 0.6 mg to 3.5 mg, from 0.7 mg to 4 mg, from 0.8 mg to 4.5 mg, from 0.9 mg to 5 mg, from 1 mg to 6 mg, from 1.5 mg to 6.5 mg, from 2 mg to 7 mg, from 2.5 mg to 7.5 mg, from 3 mg to 8 mg, from 3.5 mg to 8.5 mg, from 4 mg to 9 mg, from 4.5 mg to 9.5 mg, or from 5 mg to 10 mg); the second step-up dose is from 1 mg to 50 mg (e.g., from 3 mg to 18 mg, from 3.1 mg to 15 mg, from 3.2 mg to 10 mg, from 3.3 mg to 6 mg, from 3.4 mg to 4 mg, from 0.2 mg to 35 mg, from 0.3 mg to 30 mg, from 0.4 mg to 29 mg, from 0.5 mg to 28 mg, from 1 mg to 27 mg, from 1.5 mg to 26 mg, from 2 mg to 25 mg, from 2.5 mg to 24 mg, from 3 mg to 23 mg, from 3.5 mg to 22 mg, from 4 mg to 21 mg, from 4.5 mg to 20 mg, from 5 mg to 19 mg, from 5.5 mg to 18 mg, from 6 mg to 17 mg, from 6.5 mg to 16 mg, from 7 mg to 15 mg, from 7.5 mg to 14 mg, from 8 mg to 13 mg, from 8 mg to 12 mg, from 8.5 mg to 12 mg, from 9 mg to 11 mg, from 1 mg to 6 mg, from 1.5 mg to 6.5 mg, from 2 mg to 7 mg, from 2.5 mg to 7.5 mg, from 3 mg to 8 mg, from 3.5 mg to 8.5 mg, from 4 mg to 9 mg, from 4.5 mg to 9.5 mg, from 5 mg to 10 mg, from 5.5 mg to 10.5 mg, from 6 mg to 11 mg, from 6.5 mg to 11.5 mg, from 7 mg to 12 mg, from 7.5 mg to 12.5 mg, from 8 mg to 13 mg, from 8.5 mg to 13.5 mg, from 9 mg to 14 mg, from 9.5 mg to 14.5 mg, 10 mg to 15 mg, 11 mg to 16 mg, 12 mg to 17 mg, 13 mg to 18 mg, 14 mg to 19 mg, 15 mg to 20 mg, 16 mg to 21 mg, 17 mg to 22 mg, 18 mg to 23 mg, 19 mg to 24 mg, 20 mg to 25 mg, 21 mg to 26 mg, 22 mg to 27 mg, 23 mg to 28 mg, 24 mg to 29 mg, 25 mg to 30 mg, 26 mg to 31 mg, 27 mg to 32 mg, 28 mg to 33 mg, 29 mg to 34 mg, 30 mg to 35 mg, 31 mg to 36 mg, 32 mg to 37 mg, 33 mg to 38 mg, 34 mg to 39 mg, 35 mg to 40 mg, 36 mg to 41 mg, 37 mg to 42 mg, 38 mg to 43 mg, 39 mg to 44 mg, 40 mg to 45 mg, 41 mg to 46 mg, 42 mg to 47 mg, 43 mg to 48 mg, 44 mg to 49 mg, or 45 mg to 50 mg).

[0311] 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. On the other hand, 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).

[0312] 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, 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.

[0313] 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 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.

[0314] The second phase may include any suitable number of dosing cycles. For example, in some instances, the second phase is the first dosing cycle (C1); the first dosing cycle and the second dosing cycle (C2); the first dosing cycle, the second dosing cycle (C2), and the third dosing cycle (C3); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), and the fourth dosing cycle (C4); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), and the fifth dosing cycle (C5); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), and the sixth dosing cycle (C6); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), and the seventh dosing cycle (C7); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), and the eighth dosing cycle (C8); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), and the ninth dosing cycle (C9); the first dosing cycle (C1), the second dosing cycle (C2), the third dosing cycle (C3), the fourth dosing cycle (C4), the fifth dosing cycle (C5), the sixth dosing cycle (C6), the seventh dosing cycle (C7), the eighth dosing cycle (C8), the ninth dosing cycle (C9), and the tenth dosing cycle (C10);The first administration cycle (C1), the second administration cycle (C2), the third administration cycle (C3), the fourth administration cycle (C4), the fifth administration cycle (C5), the sixth administration cycle (C6), the seventh administration cycle (C7), the eighth administration cycle (C8), the ninth administration cycle (C9), the tenth administration cycle (C10), and the eleventh administration cycle (C11); the first administration cycle (C1), the second administration cycle (C2), the third administration cycle (C3), the fourth administration cycle (C4), the fifth administration cycle (C5), the sixth administration cycle (C6), the seventh administration cycle (C7), the eighth administration cycle (C8), the ninth administration cycle (C9), the tenth administration cycle (C10), the eleventh administration cycle (C11), and the twelfth administration cycle (C12); or may include the first administration cycle (C1), the second administration cycle (C2), the third administration cycle (C3), the fourth administration cycle (C4), the fifth administration cycle (C5), the sixth administration cycle (C6), the seventh administration cycle (C7), the eighth administration cycle (C8), the ninth administration cycle (C9), the tenth administration cycle (C10), the eleventh administration cycle (C11), the twelfth administration cycle (C12), and the thirteenth administration cycle.;

[0315] In some examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and / or day 15 of C1 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and / or day 15 of C2 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and / or day 15 of C3 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and / or day 15 of C4 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and / or day 15 of C5 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and / or day 15 of C6 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and / or day 15 of C7 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and / or day 15 of C8 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and / or day 15 of C9 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and / or day 15 of C10 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and / or day 15 of C11 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and / or day 15 of C12 during the second phase. In further examples, the target dose of the bispecific antibody can be administered to the subject on day 1 and / or day 15 of C13 during the second phase.

[0316] In some examples, the bispecific antibody at the target dose is administered to the subject for each administration during the second phase.

[0317] The third phase may include any suitable number of dosing cycles. For example, in any of the aforementioned examples, the third phase may include at least 1 dosing cycle, at least 2 dosing cycles, at least 3 dosing cycles, at least 4 dosing cycles, at least 5 dosing cycles, at least 6 dosing cycles, at least 7 dosing cycles, at least 8 dosing cycles, at least 9 dosing cycles, at least 10 dosing cycles, at least 11 dosing cycles, at least 12 dosing cycles, or at least 13 dosing cycles, or more.

[0318] In some examples, the third phase is the first dosing cycle (C1); the first and second dosing cycles (C2); the first, second, and third dosing cycles (C3); the first, second, third, and fourth dosing cycles (C4); the first, second, third, fourth, and fifth dosing cycles (C5); the first, second, third, fourth, fifth, and sixth dosing cycles (C6); the first, second, third, fourth, fifth, sixth, and seventh dosing cycles (C7); the first, second, third, fourth, fifth, sixth, seventh, and eighth dosing cycles (C8); the first, second, third, fourth, fifth, sixth, seventh, eighth, and ninth dosing cycles (C9); the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, and tenth dosing cycles (C10); the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, and eleventh dosing cycles (C11);The first administration cycle (C1), the second administration cycle (C2), the third administration cycle (C3), the fourth administration cycle (C4), the fifth administration cycle (C5), the sixth administration cycle (C6), the seventh administration cycle (C7), the eighth administration cycle (C8), the ninth administration cycle (C9), the tenth administration cycle (C10), the eleventh administration cycle (C11), and the twelfth administration cycle (C12); or the first administration cycle (C1), the second administration cycle (C2), the third administration cycle (C3), the fourth administration cycle (C4), the fifth administration cycle (C5), the sixth administration cycle (C6), the seventh administration cycle (C7), the eighth administration cycle (C8), the ninth administration cycle (C9), the tenth administration cycle (C10), the eleventh administration cycle (C11), the twelfth administration cycle (C12), and the thirteenth administration cycle are included.;

[0319] In some examples, the third phase includes administration of the bispecific antibody to the subject on day 1 of C1. In further examples, the third phase includes administration of the bispecific antibody to the subject on day 1 of C2. In further examples, the third phase includes administration of the bispecific antibody to the subject on day 1 of C3. In further examples, the third phase includes administration of the bispecific antibody to the subject on day 1 of C4. In further examples, the third phase includes administration of the bispecific antibody to the subject on day 1 of C5. In further examples, the third phase includes administration of the bispecific antibody to the subject on day 1 of C6. In further examples, the third phase includes administration of the bispecific antibody to the subject on day 1 of C7. In further examples, the third phase includes administration of the bispecific antibody to the subject on day 1 of C8. In further examples, the third phase includes administration of the bispecific antibody to the subject on day 1 of C9. In further examples, the third phase includes administration of the bispecific antibody to the subject on day 1 of C10. In further examples, the third phase includes administration of the bispecific antibody to the subject on day 1 of C11. In further examples, the third phase includes administration of the bispecific antibody to the subject on day 1 of C12. In further examples, the third phase includes administration of the bispecific antibody to the subject on day 1 of C13.

[0320] In some examples, the bispecific antibody at the target dose is administered to the subject for each administration during the third phase.

[0321] In any of the foregoing examples, the target dosage can be from about 10 mg to about 1000 mg (e.g., from about 10 mg to about 70 mg, from about 15 mg to about 65 mg, from about 20 mg to about 60 mg, from about 25 mg to about 55 mg, from about 30 mg to about 50 mg, from about 35 mg to about 45 mg, from about 15 mg to about 225 mg, from about 20 mg to about 220 mg, 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 135 mg, from about 110 mg to about 130 mg, from about 115 mg to about 125 mg, from about 10 mg to about 50 mg, from about 25 mg to about 75 mg, from about 50 mg to about 100 mg, from about 75 mg to about 125 mg, from about 100 mg to about 150 mg, from about 125 mg to about 175 mg, from about 150 mg to about 200 mg, from about 175 mg to about 225 mg, from about 200 mg to about 250 mg, from about 225 mg to about 275 mg, from about 250 mg to about 300 mg, from about 275 mg to about 325 mg, from about 300 mg to about 350 mg, from about 325 mg to about 375 mg, from about 350 mg to about 400 mg, from about 375 mg to about 425 mg, from about 400 mg to about 450 mg, from about 425 mg to about 475 mg, from about 450 mg to 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 725 mg to about 775 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). In some embodiments, C1D2 is greater than C1D1 and C1D3 is greater than C1D2.

[0322] In some embodiments, the target dose is from about 10 mg to 200 mg (e.g., from 10 mg to about 170 mg, from about 11 mg to about 165 mg, from about 12 mg to about 160 mg, from about 13 mg to about 155 mg, from about 14 mg to about 150 mg, from about 15 mg to about 145 mg, from about 16 mg to about 140 mg, from about 17 mg to about 135 mg, from about 18 mg to about 130 mg, from about 19 mg to about 125 mg, from about 20 mg to about 120 mg, from about 21 mg to about 115 mg, from about 22 mg to about 110 mg, from about 23 mg to about 105 mg, from about 24 mg to about 100 mg, from about 25 mg to about 95 mg, from about 26 mg to about 90 mg, from about 27 mg to about 85 mg, from about 28 mg to about 80 mg, from about 29 mg to about 75 mg, from about 30 mg to about 70 mg, from about 31 mg to about 65 mg, from about 32 mg to about 60 mg, from about 33 mg to about 55 mg, from about 34 mg to about 50 mg, from about 35 mg to about 45 mg, from about 40 mg to 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 135 mg, from about 110 mg to about 130 mg, from about 115 mg to about 125 mg, from about 10 mg to about 20 mg, from about 20 mg to about 30 mg, from about 30 mg to about 40 mg, from about 40 mg to about 50 mg, from about 50 mg to about 60 mg, from about 60 mg to about 70 mg, from about 70 mg to about 80 mg, from about 80 mg to about 90 mg, from about 90 mg to about 100 mg, from about 100 mg to about 110 mg, from about 110 mg to about 120 mg, from about 120 mg to about 130 mg, from about 130 mg to about 140 mg, from about 140 mg to about 150 mg, from about 150 mg to about 160 mg, from about 160 mg to about 170 mg, from about 170 mg to about 180 mg, or from about 180 mg to about 190 mg, or from about 190 mg to about 200 mg).

[0323] In some examples, the target dose is about 10 mg. In some examples, the target dose is about 15 mg. In some examples, the target dose is about 20 mg. In some examples, the target dose is about 25 mg. In some examples, the target dose is about 30 mg. In some examples, the target dose is about 35 mg. In some examples, the target dose is about 40 mg. In some examples, the target dose is about 45 mg. In some examples, the target dose is about 50 mg. In some examples, the target dose is about 55 mg. In some examples, the target dose is about 60 mg. In some examples, the target dose is about 65 mg. In some examples, the target dose is about 70 mg. In some examples, the target dose is about 75 mg. In some examples, the target dose is about 80 mg. In some examples, the target dose is about 85 mg. In some examples, the target dose is about 90 mg. In some examples, the target dose is about 95 mg. In some examples, the target dose is about 100 mg. In some examples, the target dose is about 105 mg. In some examples, the target dose is about 110 mg. In some examples, the target dose is about 115 mg. In some examples, the target dose is about 120 mg. In some examples, the target dose is about 125 mg. In some examples, the target dose is about 130 mg. In some examples, the target dose is about 132 mg. In some examples, the target dose is about 135 mg. In some examples, the target dose is about 140 mg. In some examples, the target dose is about 145 mg. In some examples, the target dose is about 150 mg. In some examples, the target dose is about 155 mg. In some examples, the target dose is about 160 mg. In some examples, the target dose is about 165 mg. In some examples, the target dose is about 170 mg. In some examples, the target dose is about 175 mg. In some examples, the target dose is about 180 mg. In some examples, the target dose is about 185 mg. In some examples, the target dose is about 190 mg. In some examples, the target dose is about 195 mg. In some examples, the target dose is about 200 mg. In some embodiments, C1D1 is about 210 mg. In some embodiments, C1D1 is about 220 mg.In some embodiments, C1D1 is about 230 mg. In some embodiments, C1D1 is about 240 mg. In some embodiments, C1D1 is about 250 mg. In some embodiments, C1D1 is about 260 mg. In some embodiments, C1D1 is about 270 mg. In some embodiments, C1D1 is about 280 mg. In some embodiments, C1D1 is about 290 mg. In some embodiments, C1D1 is about 300 mg. In some embodiments, C1D1 is about 310 mg. In some embodiments, C1D1 is about 320 mg. In some embodiments, C1D1 is about 330 mg. In some embodiments, C1D1 is about 340 mg. In some embodiments, C1D1 is about 350 mg. In some embodiments, C1D1 is about 360 mg. In some embodiments, C1D1 is about 370 mg. In some embodiments, C1D1 is about 380 mg. In some embodiments, C1D1 is about 390 mg. In some embodiments, C1D1 is about 400 mg. In some embodiments, C1D1 is about 410 mg. In some embodiments, C1D1 is about 420 mg. In some embodiments, C1D1 is about 430 mg. In some embodiments, C1D1 is about 440 mg. In some embodiments, C1D1 is about 450 mg. In some embodiments, C1D1 is about 460 mg. In some embodiments, C1D1 is about 470 mg. In some embodiments, C1D1 is about 480 mg. In some embodiments, C1D1 is about 490 mg. In some embodiments, C1D1 is about 500 mg. In some embodiments, C1D1 is about 510 mg. In some embodiments, C1D1 is about 520 mg. In some embodiments, C1D1 is about 530 mg. In some embodiments, C1D1 is about 540 mg. In some embodiments, C1D1 is about 550 mg. In some embodiments, C1D1 is about 560 mg. In some embodiments, C1D1 is about 570 mg. In some embodiments, C1D1 is about 580 mg. In some embodiments, C1D1 is about 590 mg. In some embodiments, C1D1 is about 600 mg. In some embodiments, C1D1 is about 610 mg. In some embodiments, C1D1 is about 620 mg.In some embodiments, C1D1 is about 630 mg. In some embodiments, C1D1 is about 640 mg. In some embodiments, C1D1 is about 650 mg. In some embodiments, C1D1 is about 660 mg. In some embodiments, C1D1 is about 670 mg. In some embodiments, C1D1 is about 680 mg. In some embodiments, C1D1 is about 690 mg. In some embodiments, C1D1 is about 700 mg. In some embodiments, C1D1 is about 710 mg. In some embodiments, C1D1 is about 720 mg. In some embodiments, C1D1 is about 730 mg. In some embodiments, C1D1 is about 740 mg. In some embodiments, C1D1 is about 750 mg. In some embodiments, C1D1 is about 760 mg. In some embodiments, C1D1 is about 770 mg. In some embodiments, C1D1 is about 780 mg. In some embodiments, C1D1 is about 790 mg. In some embodiments, C1D1 is about 800 mg. In some embodiments, C1D1 is about 810 mg. In some embodiments, C1D1 is about 820 mg. In some embodiments, C1D1 is about 830 mg. In some embodiments, C1D1 is about 840 mg. In some embodiments, C1D1 is about 850 mg. In some embodiments, C1D1 is about 860 mg. In some embodiments, C1D1 is about 870 mg. In some embodiments, C1D1 is about 880 mg. In some embodiments, C1D1 is about 890 mg. In some embodiments, C1D1 is about 900 mg. In some embodiments, C1D1 is about 910 mg. In some embodiments, C1D1 is about 920 mg. In some embodiments, C1D1 is about 930 mg. In some embodiments, C1D1 is about 940 mg. In some embodiments, C1D1 is about 950 mg. In some embodiments, C1D1 is about 960 mg. In some embodiments, C1D1 is about 970 mg. In some embodiments, C1D1 is about 980 mg. In some embodiments, C1D1 is about 990 mg. In some embodiments, C1D1 is about 1000 mg.

[0324] In some examples, the target dose is 10 mg. In some examples, the target dose is 15 mg. In...

Claims

**Claim 1** A method of treating a subject having multiple myeloma (MM), the method comprising administering to the subject a bispecific antibody that binds to Fc receptor homolog 5 (FcRH5) and cluster of differentiation 3 (CD3), (i) a first phase comprising one or more dosing cycles, the first phase comprising administering the bispecific antibody to the subject once a week (QW); (ii) a second phase comprising one or more dosing cycles, the second phase comprising administering the bispecific antibody to the subject every two weeks (Q2W); and (iii) a third phase comprising one or more dosing cycles, the third phase comprising administering the bispecific antibody to the subject every four weeks (Q4W), the method comprising subcutaneous administration according to a dosing regimen comprising the phases. **Claim 2** The method according to claim 1, wherein each dosing cycle is a 28-day dosing cycle. **Claim 3** The method according to claim 2, wherein the first phase comprises a first dosing cycle (C1). **Claim 4** The method according to claim 2, wherein the first phase consists of C1. **Claim 5** The method according to claim 3 or 4, wherein the first phase comprises administering the bispecific antibody to the subject on days 1, 8, and 15 of C1. **Claim 6** The method according to any one of claims 1-5, wherein the target dose of the bispecific antibody is administered to the subject for each administration during the first phase. **Claim 7** The method according to any one of claims 1-5, wherein the first phase comprises administering to the subject a first step-up dose of the bispecific antibody. **Claim 8** The method according to claim 7, wherein the first step-up dose is administered to the subject on day 1 of C1. **Claim 9** The method according to claim 8, wherein the target dose is administered to the subject on days 8 and 15 of C1. **Claim 10** The method according to claim 9, wherein the first step-up dose is 1% to 30% of the target dose. **Claim 11** The method according to claim 10, wherein the first step-up dose is 5% to 25% of the target dose. **Claim 12** The method according to claim 11, wherein the first step-up dose is 5% of the target dose or 25% of the target dose. **Claim 13** The method according to any one of claims 7 to 12, wherein the first step-up 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 the bispecific antibody to the subject at the first step-up dose and the second step-up dose.

15. The method according to claim 14, wherein the first step-up dose is administered to the subject on day 1 of C1, and the second step-up dose is administered to the subject on day 8 of C1.

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

17. A method according to any one of claims 14 to 16, wherein (a) the first step-up dose is 1% to 10% of the target dose, and (b) the second step-up 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-up dose is 5% of the target dose, and (b) the second step-up dose is 25% of the target dose.

19. The method according to any one of claims 14 to 18, wherein the first step-up dose is 2 mg and the second step-up dose is 10 mg.

20. The method according to 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 according to claim 20, wherein the bispecific antibody is administered to the subject a total of 3 times during C1.

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

23. The method according to any one of claims 2 to 22, wherein the second phase comprises at least 2 dosing cycles, at least 3 dosing cycles, at least 4 dosing cycles, or at least 5 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 according to claim 23, wherein the second phase consists of C1, C2, C3, C4, and C5.

26. The method according to claim 24 or 25, wherein the second phase comprises administration of 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 the bispecific antibody at the target dose is administered to the subject for each administration during the second phase.

28. The method according to any one of claims 2 to 27, wherein the third phase comprises at least 2 dosing cycles, at least 3 dosing cycles, at least 4 dosing cycles, at least 5 dosing cycles, at least 6 dosing cycles, or at least 7 dosing cycles.

29. The method according to 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 according to claim 28, wherein the third phase consists of C1, C2, C3, C4, C5, C6, and C7.

31. The method according to claim 29 or 30, wherein the third phase comprises administration of 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 the bispecific antibody at the target dose 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 according to claim 33, wherein the fourth phase comprises subcutaneous administration of the bispecific antibody to the subject once a week (QW), every two weeks (Q2W), every three weeks (Q3W), or every four weeks (Q4W).

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

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

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

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

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

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

41. The method according to 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; (iii) the third dose of the bispecific antibody is 40 mg.

42. The method according to 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; (iii) the third dose of the bispecific antibody is 120 mg.

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

44. The method according to 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 according to claim 44, wherein each successive dose of the bispecific antibody is administered to a different part of the four quadrants on a rotation basis.

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

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

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

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

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

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

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

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

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

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

56. The method according to any one of claims 1 to 55, wherein the bispecific antibody comprises the following six hypervariable regions (HVRs): (a) HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) HVR-H3 comprising the amino acid sequence 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) and comprising an anti-FcRH5 arm comprising a first binding domain.

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

58. The method according to 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 according to any one of claims 1 to 58, wherein the bispecific antibody comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising the amino acid sequence of WIYPEENDNTKYNEKFKD (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 KSSQSLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising the amino acid sequence of WTSSTRKS (SEQ ID NO: 13); and (f) HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14) and comprises an anti-CD3 arm comprising a second binding domain.

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

61. The method according to 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 according to 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), 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; (d) L2 of the anti-CD3 arm comprises the amino acid sequence of SEQ ID NO:

38.

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

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

65. The method according to claim 64, wherein the aglycosylation site mutation is a substitution mutation. **Claim 66** The method according to claim 65, wherein the bispecific antibody comprises a substitution mutation in the Fc region that reduces effector function. **Claim 67** The method according to any one of claims 1 to 66, wherein the bispecific antibody is a monoclonal antibody. **Claim 68** The method according to any one of claims 1 to 67, wherein the bispecific antibody is a humanized antibody. **Claim 69** The method according to any one of claims 1 to 67, wherein the bispecific antibody is a chimeric antibody. **Claim 70** The method according to any one of claims 1 to 69, wherein the bispecific antibody is an antibody fragment that binds to FcRH5 and CD3. **Claim 71** The method according to claim 70, wherein the antibody fragment is selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab') ２ fragment. **Claim 72** The method according to any one of claims 1 to 69, wherein the bispecific antibody is a full-length antibody. **Claim 73** The method according to any one of claims 1 to 69 and 72, wherein the bispecific antibody is an IgG antibody. **Claim 74** The IgG antibody is IgG １ The method according to claim 73, which is an antibody. **Claim 75** The bispecific antibody comprises one or more heavy chain constant domains, and the one or more heavy chain constant domains are a first CH1 (CH1 １ ), a first CH2 (CH2 １ ), a first CH3 (CH3 １ ), a second CH1 (CH1 ２ ), a second CH2 (CH2 ２ ), and a second CH3 (CH3 ２ ), and the method according to any one of claims 1 to 74. **Claim 76** The method according to claim 75, wherein at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. **Claim 77** the CH3 １ domain and the CH3 ２ domains each include a protrusion or a cavity, and the １ protrusion or cavity of the CH3 domain is such that the ２ method according to claim 76, wherein the cavity or protrusion of the CH3 domain can be respectively disposed in the protrusion or cavity of the CH3 domain. **Claim 78** said CH3 １ domain and said CH3 ２ The method according to claim 77, wherein the said domain and the said CH3 domain meet at the interface between the said protrusion and the said cavity. **Claim 79** said CH2 １ domain and said CH2 ２ domains each contain a protrusion or a cavity, and the protrusion or cavity of said CH2 １ domain is respectively capable of being disposed in the cavity or protrusion of said CH2 ２ The method according to any one of claims 75 to 78, wherein the protrusion or cavity of said CH2 domain is respectively capable of being disposed in the cavity or protrusion of said CH2 domain. **Claim 80** said CH2 １ domain and said CH2 ２ The method according to claim 79, wherein the domain and the domain meet at an interface between the protrusion and the cavity. **Claim 81** The method according to claim 80, wherein the anti-FcRH5 arm comprises the protrusion and the anti-CD3 arm comprises the cavity. **Claim 82** The method according to claim 81, wherein the CH3 domain of the anti-FcRH5 arm comprises a protrusion containing the T366W amino acid substitution mutation (EU numbering), and the CH3 domain of the anti-CD3 arm comprises a cavity containing the T366S, L368A, and Y407V amino acid substitution mutations (EU numbering). **Claim 83** The method according to any one of claims 1 to 68 and 72 to 82, wherein the bispecific antibody is cevostamab. **Claim 84** The method according to any one of claims 1 to 83, wherein the bispecific antibody is administered to the subject simultaneously with one or more additional therapeutic agents. **Claim 85** The method according to any one of claims 1 to 83, wherein the bispecific antibody is administered to the subject prior to the administration of one or more additional therapeutic agents. **Claim 86** The method according to any one of claims 1 to 83, wherein the bispecific antibody is administered to the subject after the administration of one or more additional therapeutic agents. **Claim 87** The method according to any one of claims 84 to 86, wherein the one or more additional therapeutic agents comprise an effective amount of tocilizumab.

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

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

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

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

92. The method according to any one of claims 88 to 91, wherein the CRS event does not resolve or worsens within 8 hours after 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 according to any one of claims 84 to 92, wherein the one or more additional therapeutic agents comprise an effective amount of corticosteroid.

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

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

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

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

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

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

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

101. The method according to claim 99 or 100, wherein when the bispecific antibody is pre-administered to the subject and the subject experiences CRS, the corticosteroid is administered to the subject before administering the bispecific antibody.

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

103. The method according to claim 102, wherein acetaminophen or paracetamol is administered at a dose of 500 mg to 1000 mg.

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

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

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

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

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

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

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

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

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

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

114. The method according to 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. **Claim 116** The method according to any one of claims 1 to 115, wherein the MM is relapsed or refractory (R / R) MM. **Claim 117** The method of claim 116, wherein the subject has a diagnosis of R / R MM for which an established therapy for MM is not appropriate and not available or has an intolerance to an established therapy for MM. **Claim 118** The method according to any one of claims 1 to 117, wherein the subject is as follows: (i) Serum M protein ≥ 0.5 g / dL; (ii) Urinary M protein ≥ 200 mg / 24 hours; or (iii) Serum-free light chain (SFLC) assay: SFLC ≥ 10 mg / dL and abnormal SFLC ratio (<0.26 or >1.65) involved, a method having a measurable disease defined as at least one of the above. **Claim 119** A method of treating a subject having R / R MM, the method comprising administering cevostamab to the subject (i) a first phase comprising a first dosing cycle (C1), wherein C1 is a 28-day dosing cycle, and the first phase comprises administering the cevostamab to the subject as a first step-up dose on day 1 of C1, as a second step-up dose on day 8 of C1, and at a target dose on day 15 of C1, wherein the first step-up dose is 2 mg, the second step-up 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 the second phase comprises administering the cevostamab to the subject at a target dose of 40 mg on days 1 and 15 of C1, C2, C3, C4, and C5; and (iii) A third phase, including a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7), wherein each dosing cycle of the third phase is a 28-day dosing cycle, and the third phase includes administering the cevostamab at a target dose of 40 mg on the first day of C1, C2, C3, C4, C5, C6, and C7. A method comprising subcutaneous administration in a dosing regimen including.

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

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

122. The subcutaneous administration device according to claim 120 or 121, (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. A subcutaneous administration device according to any one of claims 120 to 122, which is a syringe.

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

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

126. The subcutaneous administration device according to claim 125, wherein the pump includes a patch pump, a syringe pump, or an infusion pump.

127. The 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 R / R MM.

130. A bispecific antibody that binds to FcRH5 and CD3 for use in the treatment of a subject having MM, wherein the treatment comprises administering the bispecific antibody to the subject (i) a first phase comprising one or more dosing cycles, wherein the first phase comprises administering the bispecific antibody to the subject once a 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), in a dosing regimen comprising subcutaneous administration.

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

132. Sevostamab for use in the treatment of a subject having R / R MM, wherein the treatment comprises administering sevostamab to the subject (i) a first phase comprising a first dosing cycle (C1), wherein C1 is a 28-day dosing cycle, and the first phase comprises administering sevostamab to the subject as a first step-up dose on day 1 of C1, as a second step-up dose on day 8 of C1, and at a target dose on day 15 of C1, wherein the first step-up dose is 2 mg, the second step-up 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 the second phase comprises administering the sevastamab to the subject at a target dose of 40 mg on days 1 and 15 of C1, C2, C3, C4, and C5; and (iii) A third phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7), wherein each dosing cycle of the third phase is a 28-day dosing cycle, and the third phase comprises administering the sevastamab at a target dose of 40 mg on day 1 of C1, C2, C3, C4, C5, C6, and C7 A sevastamab comprising subcutaneous administration according to a dosing regimen comprising.

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