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

Abstract

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

Description

Technical Field

[0001] Sequence Listing This application includes a Sequence Listing submitted electronically in XML format, which is hereby incorporated by reference in its entirety. The XML copy created on July 17, 2023, is named 50474-302WO3_Sequence_Listing_7_17_23_.XML and is 41,595 bytes in size.

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

Background Art

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

[0004] Blood cancers are, in particular, the second leading cause of cancer-related deaths. Blood cancers include multiple myeloma (MM), a neoplasm characterized by the proliferation and accumulation of malignant plasma cells. Worldwide, approximately 110,000 people are diagnosed with MM each year. MM remains incurable despite advances in treatment and has a median estimated survival of 8 - 10 years for standard-risk myeloma and 2 - 3 years for high-risk disease, even after autologous stem cell transplant (ASCT). Despite significant improvements in patient survival over the past 20 years, only 10 - 15% of patients achieve or exceed the expected survival rate compared to the general population.

[0005] Therefore, improved treatment regimens for MM and other blood cancers are needed.

Summary of the Invention

[0006] This specification provides, inter alia, methods of treating a subject having cancer (e.g., MM), compositions for use, and related articles of manufacture.

[0007] In one aspect, a method of treating a subject having multiple myeloma (MM) with high-risk cytogenetic features, the method comprising administering to the subject (i) a bispecific antibody that binds to fragment crystallizable receptor-like 5 (FcRH5) and cluster of differentiation 3 (CD3), and (ii) lenalidomide, is provided herein.

[0008] In another aspect, a bispecific antibody that binds to FcRH5 and CD3 for use in treating a subject having MM with high-risk cytogenetic features, wherein the treatment comprises administering the bispecific antibody and lenalidomide to the subject, is provided herein.

[0009] In some aspects, the subject has experienced a partial response (PR) or better after induction therapy.

[0010] In some aspects, the subject has received autologous stem cell transplantation (ASCT) within 100 days of the start of the method or treatment and / or does not have progressive disease.

[0011] In some aspects, the bispecific antibody and lenalidomide are administered to the patient as post-transplant maintenance therapy.

[0012] In some aspects, the high-risk cytogenetic features include one or more of the translocation events t(4;14) or t(14;16), del(17p), or 1q gain.

[0013] In some aspects, the subject had high-risk cytogenetic features at the time of diagnosis of MM.

[0014] In some embodiments, the bispecific antibody and lenalidomide are administered to a subject in a dosing regimen that includes: (i) a first phase comprising one or more dosing cycles, wherein the bispecific antibody is administered to the subject every two weeks (Q2W); and (ii) a second phase comprising one or more dosing cycles, wherein the bispecific antibody is administered to the subject every four weeks (Q4W).

[0015] In some embodiments, each dosing cycle of the first phase and / or the second phase is a 28-day dosing cycle.

[0016] In some embodiments, the method or treatment further comprises a pre-phase comprising one or more dosing cycles before the first phase, wherein the bispecific antibody is administered to the subject weekly (QW).

[0017] In some embodiments, each dosing cycle of the pre-phase is a 28-day dosing cycle.

[0018] In some embodiments, the pre-phase comprises one dosing cycle (C1).

[0019] In some embodiments, the pre-phase comprises administering the bispecific antibody to the subject on days 1, 8, and 15 of C1.

[0020] In some embodiments, the target dose of the bispecific antibody is administered to the subject for each administration in the pre-phase.

[0021] In some embodiments, the pre-phase comprises administering a first escalating dose of the bispecific antibody to the subject.

[0022] In some embodiments, the first escalating dose is administered to the subject on day 1 of C1.

[0023] In some embodiments, the target dose is administered to the subject on days 8 and 15 of C1.

[0024] In some embodiments, the pre-phase comprises administering a bispecific antibody at a first step-up dose and a second step-up dose.

[0025] 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.

[0026] In some embodiments, the target dose is administered to the subject on day 15 of C1.

[0027] In some embodiments, the first step-up dose is 3.6 mg.

[0028] In some embodiments, the first step-up dose is 0.3 mg and the second step-up dose is 3.6 mg.

[0029] In some embodiments, the first phase comprises at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, or at least five dosing cycles.

[0030] In some embodiments, the first 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).

[0031] In some embodiments, the first phase comprises administering the bispecific antibody to the subject on days 1 and 15 of C1, C2, C3, C4, and / or C5.

[0032] In some embodiments, the bispecific antibody at the target dose is administered to the subject for each administration during the first phase.

[0033] In some embodiments, the second phase includes at least 2 dosing cycles, at least 3 dosing cycles, at least 4 dosing cycles, at least 5 dosing cycles, at least 6 dosing cycles, or at least 7 dosing cycles.

[0034] 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), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7).

[0035] In some embodiments, the second phase includes administering the bispecific antibody to the subject on day 1 of C1, C2, C3, C4, C5, C6, and / or C7.

[0036] In some embodiments, the target dose of the bispecific antibody is administered to the subject for each administration during the second phase.

[0037] In some embodiments, the target dose is 90 mg to 198 mg, including the endpoints.

[0038] In some embodiments, the target dose is 90 mg.

[0039] In some embodiments, the target dose is 132 mg.

[0040] In some embodiments, the target dose is 160 mg.

[0041] In some embodiments, the bispecific antibody is administered intravenously to the subject.

[0042] In some embodiments, lenalidomide is administered to the subject on days 1 to 21 of each dosing cycle in the first phase and / or the second phase.

[0043] In some embodiments, lenalidomide is administered to a subject on days 1 to 21 of each dosing cycle in the pre-phase.

[0044] In some embodiments, lenalidomide is administered to a subject at a dosage of about 10 mg to about 20 mg.

[0045] In some embodiments, lenalidomide is administered to a subject at a dosage of about 10 mg.

[0046] In some embodiments, lenalidomide is administered to a subject at a dosage of about 15 mg.

[0047] In some embodiments, lenalidomide is orally administered to a subject.

[0048] In some embodiments, the method or treatment further comprises administering a corticosteroid to a subject.

[0049] In some embodiments, the method or treatment further comprises administering a corticosteroid to a subject during the first phase and / or the second phase.

[0050] In some embodiments, the corticosteroid is administered to a subject on days 1 and 15 of C1 of the first phase during the first phase.

[0051] In some embodiments, if a subject has experienced a cytokine release syndrome (CRS) event at a previous dose, the corticosteroid is administered to the subject at C2, C3, C4 and / or C5 of the first phase.

[0052] In some embodiments, if a subject has experienced a CRS event at a previous dose, the corticosteroid is administered to the subject at C1, C2, C3, C4, C5, C6 and / or C7 of the second phase.

[0053] In some embodiments, the method or treatment further comprises administering a corticosteroid to a subject during the pre-phase.

[0054] In some embodiments, the corticosteroid is administered to the subject on days 1, 8, and 15 of C1 during the pre-phase.

[0055] In some embodiments, the corticosteroid is administered to the subject intravenously or orally.

[0056] In some embodiments, the corticosteroid is administered to the subject intravenously.

[0057] In some embodiments, the corticosteroid is administered to the subject intravenously prior to the administration of the bispecific antibody.

[0058] In some embodiments, the corticosteroid is administered to the subject intravenously approximately 1 hour prior to the administration of the bispecific antibody.

[0059] In some embodiments, the corticosteroid is dexamethasone or methylprednisolone.

[0060] In some embodiments, the corticosteroid is dexamethasone.

[0061] In some embodiments, dexamethasone is administered to the subject at a dosage of about 20 mg.

[0062] In some embodiments, methylprednisolone is administered to the subject at a dosage of about 80 mg.

[0063] In some embodiments, the bispecific antibody comprises an anti-FcRH5 arm having a first binding domain comprising the following six hypervariable regions (HVRs): (a) HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) HVR-H3 comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO: 3); (d) HVR-L1 comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); (f) HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6).

[0064] In some embodiments, the bispecific antibody comprises an anti-FcRH5 arm comprising: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8; or (c) a first binding domain comprising the VH domain of (a) and the VL domain of (b).

[0065] 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.

[0066] In some embodiments, the bispecific antibody comprises an anti-CD3 arm having a second binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); (f) HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

[0067] In some embodiments, the bispecific antibody comprises an anti-CD3 arm comprising a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15, 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).

[0068] 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.

[0069] 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 (a) H1 comprises the amino acid sequence of SEQ ID NO: 35, (b) L1 comprises the amino acid sequence of SEQ ID NO: 36, (c) H2 comprises the amino acid sequence of SEQ ID NO: 37, and (d) L2 comprises the amino acid sequence of SEQ ID NO: 38.

[0070] In some embodiments, the bispecific antibody comprises an aglycosylation site mutation.

[0071] In some embodiments, the aglycosylation site mutation reduces the effector function of the bispecific antibody.

[0072] In some embodiments, the aglycosylation site mutation is a substitution mutation.

[0073] In some embodiments, the bispecific antibody comprises a substitution mutation in the Fc region that reduces effector function.

[0074] In some embodiments, the bispecific antibody is a monoclonal antibody.

[0075] In some embodiments, the bispecific antibody is a humanized antibody.

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

[0077] In some embodiments, the bispecific antibody is an antibody fragment that binds to FcRH5 and CD3.

[0078] In some embodiments, the antibody fragment is selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments.

[0079] In some embodiments, the bispecific antibody is a full-length antibody.

[0080] In some embodiments, the bispecific antibody is an IgG antibody.

[0081] In some embodiments, the IgG antibody is an IgG1 antibody.

[0082] In some embodiments, the bispecific antibody comprises one or more heavy chain constant domains, and the one or more heavy chain constant domains are selected from a first CH1 (CH11) domain, a first CH2 (CH21) domain, a first CH3 (CH31) domain, a second CH1 (CH12) domain, a second CH2 (CH22) domain, and a second CH3 (CH32) domain.

[0083] In some embodiments, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

[0084] In some embodiments, the CH31 and CH32 domains each form a protrusion or a cavity, and the protrusion or cavity in the CH31 domain can be respectively disposed in the cavity or protrusion in the CH32 domain.

[0085] In some embodiments, the CH31 domain and the CH32 domain associate at the interface between the protrusion and the cavity.

[0086] In some embodiments, the CH21 domain and the CH22 domain each comprise a protrusion or a cavity, and the protrusion or cavity of the CH21 domain can be respectively disposed in the cavity or protrusion of the CH22 domain.

[0087] In some embodiments, the CH21 domain and the CH22 domain associate at the interface between the protrusion and the cavity.

[0088] In some embodiments, the anti-FcRH5 arm comprises a protrusion and the anti-CD3 arm comprises a cavity.

[0089] In some embodiments, 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).

[0090] In some embodiments, the bispecific antibody is cevostamab.

[0091] In some embodiments, the bispecific antibody and lenalidomide are administered to a subject simultaneously with one or more additional therapeutic agents.

[0092] In some embodiments, the bispecific antibody and / or lenalidomide are administered to a subject prior to the administration of one or more additional therapeutic agents.

[0093] In some embodiments, the bispecific antibody and / or lenalidomide are administered to a subject after the administration of one or more additional therapeutic agents.

[0094] In some embodiments, the one or more additional therapeutic agents comprise an effective amount of tocilizumab.

[0095] In some embodiments, the subject has a CRS event and the method further comprises treating the symptoms of the CRS event while withholding treatment with the bispecific antibody.

[0096] In some embodiments, the method or treatment further comprises administering an effective amount of tocilizumab to a subject to treat a CRS event.

[0097] In some embodiments, the CRS event does not resolve or worsens within 24 hours after treating the symptoms of the CRS event, and the method further comprises administering one or more additional doses of tocilizumab to the subject to manage the CRS event.

[0098] In some embodiments, tocilizumab is administered to the subject by intravenous infusion.

[0099] In some embodiments, (a) the subject weighs 30 kg or more and tocilizumab is administered to the subject at a dose of 8 mg / kg, or (b) the subject weighs less than 30 kg and tocilizumab is administered to the subject at a dose of 12 mg / kg.

[0100] In some embodiments, tocilizumab is administered to the subject 2 hours before administration of the bispecific antibody.

[0101] In some embodiments, the one or more additional therapeutic agents include an effective amount of B cell maturation antigen (BCMA)-directed therapy, an additional immunomodulatory drug (IMiD), CD38-directed therapy, or any combination of the foregoing.

[0102] In some embodiments, the one or more additional therapeutic agents include an effective amount of acetaminophen or paracetamol.

[0103] In some embodiments, acetaminophen or paracetamol is administered to the subject at a dose of about 500 mg to about 1000 mg.

[0104] In some embodiments, acetaminophen or paracetamol is administered to the subject orally.

[0105] In some embodiments, the one or more additional therapeutic agents include an effective amount of diphenhydramine.

[0106] In some embodiments, diphenhydramine is administered to a subject at a dose of about 25 mg to about 50 mg.

[0107] In some embodiments, diphenhydramine is administered orally to a subject.

[0108] In some embodiments, provided herein is a method of treating a subject having MM with high-risk cytogenetic features, the method comprising administering cevostamab and lenalidomide to the subject, wherein (i) the subject has experienced PR or better after induction therapy, (ii) the subject has received ASCT within 100 days from the start of the method and / or does not have progressive disease, (iii) cevostamab and lenalidomide are administered to the patient as post-transplant maintenance therapy, and (iv) the high-risk cytogenetic features include one or more of the translocation events t(4;14) or t(14;16), del(17p) or 1q gain.

[0109] In some embodiments, provided herein is cevostamab for use in treating a subject having MM with high-risk cytogenetic features, wherein the treatment comprises administering cevostamab and lenalidomide to the subject, wherein (i) the subject has experienced PR or better after induction therapy, (ii) the subject has received ASCT within 100 days from the start of the method and / or does not have progressive disease, (iii) cevostamab and lenalidomide are administered to the patient as post-transplant maintenance therapy, and (iv) the high-risk cytogenetic features include one or more of the translocation events t(4;14) or t(14;16), del(17p) or 1q gain.

[0110] In another aspect, provided herein is a method of treating a subject having MM with high-risk cytogenetic features, the method comprising administering to the subject, in a dosing regimen comprising: (i) a pre-phase comprising a 28-day dosing cycle (C1); (ii) a first phase following the pre-phase, the first phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5), each dosing cycle of the first phase being a 28-day dosing cycle; and (iii) a second phase following the first phase, the second phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7), each dosing cycle of the second phase being a 28-day dosing cycle, wherein sevosetamab is administered to the subject (i) on day 1 of C1 at a first step-up dose during the pre-phase and on day 8 of C1 as a second step-up dose during the pre-phase; (ii) at a target dose on day 15 of C1 during the pre-phase; (iii) at a target dose on days 1 and 15 of C1, C2, C3, C4, and C5 during the first phase; and (iv) at a target dose on day 1 of C1, C2, C3, C4, C5, C6, and C7 during the second phase, and lenalidomide is administered to the subject (i) on days 1-21 of C1 during the pre-phase; (ii) on days 1-21 of C1, C2, C3, C4, and C5 during the first phase; and (iii) on days 1-21 of C1, C2, C3, C4, C5, C6, and C7 during the second phase.

[0111] In another aspect, it is a selinexor for use in treating a subject having MM with high-risk cytogenetic features, the treatment comprising administering to the subject selinexor and lenalidomide in a dosing regimen comprising: (i) a pre-phase comprising a 28-day dosing cycle (C1); (ii) a first phase following the pre-phase, the first phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5), each dosing cycle of the first phase being a 28-day dosing cycle; and (iii) a second phase following the first phase, the second phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7), each dosing cycle of the second phase being a 28-day dosing cycle, wherein selinexor is administered (i) at a first step-up dose on day 1 of C1 during the pre-phase and at a second step-up dose on day 8 of C1 during the pre-phase; (ii) at a target dose on day 15 of C1 during the pre-phase; (iii) at a target dose on days 1 and 15 of C1, C2, C3, C4, and C5 during the first phase; and (iv) at a target dose on day 1 of C1, C2, C3, C4, C5, C6, and C7 during the second phase, and lenalidomide is administered (i) on days 1 to 21 of C1 during the pre-phase; (ii) on days 1 to 21 of C1, C2, C3, C4, and C5 during the first phase; and (iii) on days 1 to 21 of C1, C2, C3, C4, C5, C6, and C7 during the second phase to the subject.

[0112] In some embodiments, (i) the subject has experienced PR or better after induction therapy, (ii) the subject has received ASCT within 100 days from the start of the method and / or does not have progressive disease, (iii) cevostamab and lenalidomide are administered to the patient as post-transplant maintenance therapy, and (iv) high-risk cytogenetic features include one or more of the translocation events t(4;14) or t(14;16), del(17p), or 1q gain.

[0113] In some embodiments, (i) the first step-up dose of cevostamab is 0.3 mg, (ii) the second step-up dose of cevostamab is 3.6 mg, (iii) the target dose of cevostamab is 90 mg to 198 mg, inclusive of both endpoints, and (iv) lenalidomide is administered at a dose of 10 mg or 15 mg.

[0114] In some embodiments, the target dose is 90 mg.

[0115] In some embodiments, the target dose is 132 mg.

[0116] In some embodiments, the target dose is 160 mg. BRIEF DESCRIPTION OF THE DRAWINGS

[0117]

Figure 1

[0118] I. Definitions As used herein, the term "about" refers to the normal error range of each value that would be readily understood by one of ordinary skill in the art. References to "about" with respect to a value or parameter herein include (and describe) aspects directed to that value or parameter itself.

[0119] It will be understood that the embodiments of the invention described herein include "comprising," "consisting of," and "consisting essentially of" embodiments.

[0120] As used herein, the term "FcRH5" or "fragment crystallizable receptor-like 5" 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.

[0121] 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, as measured, for example, 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.

[0122] As used herein, the term "cluster of differentiation 3" or "CD3" refers to any native CD3 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated, including, for example, CD3ε, CD3γ, CD3α, and CD3β chains. The term encompasses "full-length" unprocessed CD3 (e.g., unprocessed or unmodified CD3ε or CD3γ), as well as any form of CD3 resulting from processing within a cell. The term also encompasses naturally occurring variants of CD3, including, for example, splice variants or allelic variants. CD3 includes, for example, the human CD3ε protein, which is 207 amino acids long (NCBI Reference SEQ ID NO: NP_000724), and the human CD3γ protein, which is 182 amino acids long (NCBI Reference SEQ ID NO: NP_000064).

[0123] 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 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.

[0124] For the purposes of this specification, "sevastamab" (also known as BFCR4350A or RO7187797) is an Fc-engineered humanized full-length non-glycosylated IgG1κ T cell-dependent bispecific antibody (TDB) that binds to FcRH5 and CD3 and comprises an anti-FcRH5 arm containing the heavy chain polypeptide sequence of SEQ ID NO: 35 and the light chain polypeptide sequence of SEQ ID NO: 36, and an anti-CD3 arm containing the heavy chain polypeptide sequence of SEQ ID NO: 37 and the light chain polypeptide sequence of SEQ ID NO: 38. Sevastamab contains an amino acid substitution from threonine to tryptophan (T366W) at position 366 on the heavy chain of the anti-FcRH5 arm using the EU numbering of Fc region amino acid residues, and three (tyrosine to valine at position 407, threonine to serine at position 366, and leucine to alanine at position 368) amino acid substitutions (Y407V, T366S, L368A) on the heavy chain of the anti-CD3 arm using the EU numbering of Fc region amino acid residues, which drive the heterodimerization of the two arms (half-antibodies). Sevastamab also contains an amino acid substitution (from asparagine to glycine) at position 297 on each heavy chain (N297G) using the EU numbering of Fc region amino acid residues, resulting in a non-glycosylated antibody with minimal binding to Fc (Fcγ) receptors and thus interfering with Fc effector functions. Sevastamab is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Recommended INN: List 84, Vol. 34, No. 3 (issued in 2020) (see page 701).

[0125] The term "antibody" is used herein in the broadest sense and includes, without limitation, various antibody structures, including monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments (e.g., bis-Fab), so long as they exhibit the desired antigen-binding activity.

[0126] "Affinity" refers to the total strength of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects the 1:1 interaction between the members of a binding pair (e.g., an antibody and an antigen). The affinity of molecule X for its partner Y can generally be represented by the dissociation constant (K D ). Affinity can be measured by methods common in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

[0127] An "affinity matured" antibody refers to an antibody that has one or more modifications in one or more hypervariable regions (HVRs) compared to the parental antibody without such modifications, and such modifications improve the affinity of the antibody for the antigen.

[0128] The terms "full-length antibody", "intact antibody", and "whole antibody" are used interchangeably herein to refer to an antibody having a structure substantially the same as the native antibody structure or having a heavy chain that contains an Fc region as defined herein.

[0129] "Antibody fragment" refers to a molecule other than an intact antibody that includes a portion of an intact antibody that binds an antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, bis-Fab; Fv; Fab; Fab, Fab'-SH; F(ab')2; diabody; linear antibody; single-chain antibody molecule (e.g., scFv, ScFab); and multispecific antibodies formed from antibody fragments.

[0130] "Single domain antibody" refers to an antibody fragment that includes all or a portion of the heavy chain variable domain of an antibody, or all or a portion of the light chain variable domain. In certain embodiments, the single domain antibody is a human single domain antibody (see, e.g., U.S. Patent No. 6,248,516 B1). Examples of single domain antibodies include, but are not limited to, VHH.

[0131] The "Fab" fragment is an antigen-binding fragment produced by papain digestion of an antibody and consists of the entire L chain and the variable region domain (VH) of the H chain and the first constant domain (CH1) of one heavy chain. Papain digestion of an antibody generates two identical Fab fragments. Pepsin treatment of an antibody yields a single large F(ab')2 fragment, which corresponds approximately to two disulfide-linked Fab fragments with bivalent antigen-binding activity and can still cross-link antigens. The Fab' fragment differs from the Fab fragment in having several additional residues at the carboxy terminus of the CH1 domain that contain one or more cysteines from the antibody hinge region. Fab'-SH is the nomenclature herein for Fab' in which the cysteine residue(s) of the constant domain have free thiol groups. The F(ab')2 antibody fragment was originally produced as a pair of Fab' fragments with hinge cysteines in between. Other chemical couplings of antibody fragments are also known.

[0132] "Fv" consists of a dimer in which one heavy chain and one light chain variable region domain form a strong non-covalent bond. Folding of these two domains gives rise to six hypervariable loops (three loops each from the H chain and the L chain) that provide amino acid residues for antigen binding and confer antigen-binding specificity on the antibody. However, even a single variable domain (or half of the Fv containing only the three CDRs specific for the antigen), although often having a lower affinity than the entire binding site, has the ability to recognize and bind the antigen.

[0133] As used herein, the term "Fc region" is used to define the C-terminal region of an immunoglobulin heavy chain, including the native sequence Fc region and variant Fc regions. The boundaries of the Fc region of an immunoglobulin heavy chain can vary, but the human IgG heavy chain Fc region is generally defined as extending from the amino acid residue at position Cys226 or Pro230 to its carboxyl terminus. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region can be removed, for example, during antibody production or purification, or by recombinant manipulation of the nucleic acid encoding the antibody heavy chain. Thus, a composition of intact antibodies can include a population of antibodies in which all Lys447 residues have been removed, a population of antibodies in which the Lys447 residues have not been removed, and a population of antibodies that is a mixture of antibodies having and not having the Lys447 residue.

[0134] A "functional Fc region" has the "effector functions" of the native sequence Fc region. Exemplary "effector functions" include C1q binding: CDC; Fc receptor binding; ADCC; phagocytosis; downregulation of cell surface receptors (e.g., B cell receptor; BCR), etc. Such effector functions generally require the Fc region to bind to a binding domain (e.g., an antibody variable domain) and can be evaluated using various assays, as disclosed, for example, in the definitions herein.

[0135] A "native sequence Fc region" includes an amino acid sequence that is identical to the amino acid sequence of the Fc region found in nature. Native sequence human Fc regions include the native sequence human IgG1 Fc region (non-A and A allotypes); the native sequence human IgG2 Fc region; the native sequence human IgG3 Fc region; and the native sequence human IgG4 Fc region, as well as their naturally occurring variants.

[0136] A "variant Fc region" comprises an amino acid sequence that is different from that of the native sequence Fc region by at least one amino acid modification, preferably one or more amino acid substitutions (plural possible). Preferably, the variant Fc region has at least one amino acid substitution compared to the Fc region of the native sequence or the Fc region of the parent polypeptide, for example, about 1 to about 10 amino acid substitutions, preferably about 1 to about 5 amino acid substitutions in the Fc region of the native sequence or the Fc region of the parent polypeptide. The variant Fc regions herein will preferably have at least about 80% homology, preferably at least about 90% homology, or more preferably at least about 95% homology with the Fc region of the native sequence and / or the Fc region of the parent polypeptide.

[0137] As used herein, "Fc complex" refers to the CH3 domains of two Fc regions that interact with each other to form a dimer, or in certain embodiments, two Fc regions interact to form a dimer, and the cysteine residues and / or CH3 domains of the hinge region interact via bonds and / or forces (e.g., van der Waals, hydrophobic forces, hydrogen bonds, electrostatic forces, or disulfide bonds).

[0138] As used herein, "Fc moiety" refers to the hinge region, CH2 domain, or CH3 domain of the Fc region.

[0139] 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).

[0140] The "lower hinge region" of the Fc region is typically defined as an extension of the residues immediately C-terminal to the hinge region, i.e., residues 233 - 239 (EU numbering) of the Fc region.

[0141] A "variant Fc region" includes an amino acid sequence that is different from that of the native sequence Fc region by at least one amino acid modification, preferably one or more amino acid substitutions (multiple possible). Preferably, the variant Fc region has at least one amino acid substitution compared to the Fc region of the native sequence or the Fc region of the parent polypeptide, for example, about 1 to about 10 amino acid substitutions, preferably about 1 to about 5 amino acid substitutions, in the Fc region of the native sequence or the Fc region of the parent polypeptide. The variant Fc region herein preferably has at least about 80% homology, and most preferably at least about 90% homology, more preferably at least about 95% homology with the native sequence Fc region and / or the Fc region of the parent polypeptide.

[0142] "Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. Preferred FcRs are native sequence human FcRs. Further preferred FcRs are those that bind to IgG antibodies (gamma receptors), including receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternative splicing forms of these receptors. Examples of FcγRII receptors include FcγRIIA ("activating receptor") and FcγRIIB ("inhibitory receptor"), which have similar amino acid sequences that differ mainly in their cytoplasmic domains. The activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. The inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain (see review by M. in Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term "FcR" herein. This term also includes the neonatal receptor FcRn, which is involved in the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)).

[0143] As used herein, the term "knob-into-hole" or "KnH" technology refers to a technique that directs the pairing of two polypeptides in vitro or in vivo by introducing a protrusion (knob) into one polypeptide and a cavity (hole) into the other polypeptide at the interface where they interact. For example, KnH has been introduced at the Fc:Fc interaction interface, the CL:CH1 interface, or the VH / VL interface of an antibody (e.g., US Patent Application Publication No. 2007 / 0178552, International Publication No. 96 / 027011, International Publication No. 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.

[0144] "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: an FR1 domain, an FR2 domain, an FR3 domain, and an FR4 domain. Thus, HVR and FR sequences generally appear in the following sequence in VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0145] 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).

[0146] The "CH2 domain" of the human IgG Fc region generally 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 other domains. Rather, two N-linked branched carbohydrate chains intervene between the two CH2 domains of an intact native IgG molecule. It is speculated that the carbohydrate provides an alternative to domain-domain pairing and may help to stabilize the CH2 domain. Burton, Molec. Immunol. 22:161-206 (1985).

[0147] The "CH3 domain" includes the extension from the C-terminal residue of the Fc region to the CH2 domain (i.e., from approximately amino acid residue 361 to approximately 478 of IgG (Kabat numbering), from approximately amino acid residue 341 to approximately 447 of IgG (EU numbering), or from approximately amino acid residue 1.4 to approximately 130 of IgG (IGMT unique numbering)).

[0148] The "CL domain" or "constant light domain" includes a stretch of residues on the C-terminal side of the variable light domain (VL) of the light chain. The light chain of an antibody may be the 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., IMGT®, the international ImMunoGeneTics information system® 25 years on. Nucleic Acids Res. 2015 Jan;43 (Database issue):D413-22).

[0149] Light chains (LCs) from all vertebrate species can be assigned to one of two distinct types called kappa and lambda based on the amino acid sequences of their constant domains. Immunoglobulins can be assigned to different classes or isotypes according to the amino acid sequence of the constant domain (CH) of their heavy chains. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, which have heavy chains designated α, δ, γ, ε, and μ, respectively. The γ and α classes are further divided into subclasses based on relatively minor differences in the sequence and function of the CH. For example, humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0150] 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.

[0151] 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, namely IgA, IgD, IgE, IgG, and IgM, and some of these can be further divided into subclasses (isotypes), for example, IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0152] 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 using 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 various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol. 227:381, 1991; Marks et al., J. Mol. Biol. 222:581, 1991. Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(1):86 - 95, 1991. The methods described therein are also available for the preparation of human monoclonal antibodies. See also van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368 - 74, 2001. Human antibodies can be prepared by administering an antigen to a transgenic animal that has been modified to produce such antibodies in response to antigen administration but whose endogenous locus is disabled, for example, an immunized xenomouse (see, for example, U.S. Patent Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE™ technology). See also Li et al., Proc. Natl. Acad. Sci. USA. 103:3557 - 3562, 2006 regarding human antibodies generated by human B cell hybridoma techniques.

[0153] The "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in the selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup such as those in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3. In one embodiment, in the case of VL, the subgroup is subgroup kappa I as described in the aforementioned Kabat et al. In one embodiment, in the case of VH, the subgroup is subgroup kappa III as in the aforementioned Kabat et al.

[0154] A "humanized" antibody refers to a chimeric antibody that contains amino acid residues derived from non-human HVRs and amino acid residues derived from human FRs. In certain 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. The "humanized form" of an antibody, e.g., a non-human antibody, refers to the antibody that has been humanized.

[0155] The term "variable region" or "variable domain" refers to the domain of an antibody heavy chain or antibody light chain that is involved in the binding of an antibody to an antigen. The variable domains of the heavy and light chains of a native antibody (VH and VL, respectively) generally have a similar structure, and each domain contains four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, e.g., Kindt et al., Kuby Immunology, 6 th th ed. W.H. Freeman and Co., page 91 (2007).) A single VH domain or VL domain may be sufficient to confer antigen-binding specificity. Further, an antibody that binds a particular antigen can be isolated using the VH domain or VL domain of an antibody that binds that antigen, and libraries of complementary VL domains or VH domains, respectively, can be screened. See, for example, Portolano et al. J. Immunol. 150:880-887, 1993; Clarkson et al. Nature 352:624-628, 1991.

[0156] As used herein, the term "hypervariable region" or "HVR" refers to the region within each region of an antibody variable domain where the sequence is hypervariable ("complementary determining region" or "CDR"). Generally, an antibody contains six CDRs, three in VH (CDR-H1, CDR-H2, CDR-H3) and three in VL (CDR-L1, CDR-L2, CDR-L3). Exemplary CDRs herein include 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).

[0157] Unless otherwise indicated, HVR residues and other residues of the variable domains (e.g., FR residues) are numbered herein according to Kabat et al. supra.

[0158] A "single-chain Fv", also abbreviated as "sFv" or "scFv", is an antibody fragment that contains VH and VL antibody domains connected in a single polypeptide chain. Preferably, the scFv polypeptide further 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.

[0159] The "targeting domain" refers to a compound or a part of a molecule that specifically binds to a target epitope, antigen, ligand, or receptor. Examples of 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 (CKPs), etc.), and other molecules with identified binding partners, but are not limited thereto. The targeting domain can target, block, activate, or antagonize the antigen to which it binds.

[0160] 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 generally occur in trace amounts. In contrast to polyclonal antibody preparations, which typically contain various antibodies against various determinants (epitopes), each monoclonal antibody in a monoclonal antibody preparation is 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 the production of an antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention may be produced 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. Such methods and other exemplary methods for producing monoclonal antibodies are described herein.

[0161] The term "multispecific antibody" is used in the broadest sense and encompasses antibodies having polyepitope specificity in particular. In one aspect, a multispecific antibody binds to two different targets (e.g., bispecific antibody). Such multispecific antibodies include 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, diabody, bispecific diabody, and triabody, etc., antibody fragments; and antibody fragments linked by covalent or non-covalent bonds, but are not limited thereto. "Polyepitope specificity" refers to the ability to specifically bind to two or more different epitopes on the same or different target(s). "Monospecificity" refers to the ability to bind to only one antigen. In one aspect, a monospecific bivalent antibody binds to two different epitopes on the same target / antigen. In one aspect, a monospecific polyepitope antibody binds to multiple different epitopes of the same target / antigen. According to one aspect, the multispecific antibody is an IgG antibody that binds to each epitope having an affinity of 5 μM to 0.001 pM, 3 μM to 0.001 pM, 1 μM to 0.001 pM, 0.5 μM to 0.001 pM, or 0.1 μM to 0.001 pM.

[0162] "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.

[0163] The term "native antibody" refers to immunoglobulin molecules that exist natively with various structures. For example, a native IgG antibody is a heterotetrameric glycoprotein of approximately 150,000 daltons composed of two identical light chains and two identical heavy chains linked by disulfide bonds. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also called the variable heavy domain or heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also called the variable light domain or light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody can be assigned to one of two types called kappa (κ) and lambda (λ) based on the amino acid sequence of its constant domain.

[0164] As used herein, the term "immunoadhesin" refers to a molecule that combines the binding specificity of a heterologous protein ("adhesin") with the effector function of an immunoglobulin constant domain. Structurally, an immunoadhesin comprises an amino acid sequence having the desired binding specificity that is an amino acid sequence other than the antigen recognition binding site of an antibody (i.e., "heterologous" compared to the constant region of an antibody) and an immunoglobulin constant domain sequence (e.g., the CH2 and / or CH3 sequences of IgG), which are fused together. The adhesin and the immunoglobulin constant domain can optionally be separated by an amino acid spacer. Exemplary adhesin sequences include continuous amino acid sequences containing a portion of a receptor or ligand that binds to the protein of interest. The adhesin sequence can also be a sequence that binds to the protein of interest but is not a receptor or ligand sequence (e.g., the adhesin sequence in a peptibody). Such polypeptide sequences can be selected or identified by various methods including phage display techniques and high-throughput screening methods. The immunoglobulin constant domain sequence in an immunoadhesin can be obtained from any immunoglobulin such as IgG1, IgG2, IgG3, or IgG4 subtypes, IgA (including IgA1 and IgA2), IgE, IgD, or IgM.

[0165] "Chemotherapeutic agents" include chemical compounds useful for the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech / OSI Pharm), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitinib (SUTENT®, Pfizer / Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasanate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), lonafarnib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, thiotepa and alkylating agents such as CYTOXAN® cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carbochromen, meturedopa and uredopa; ethyleneimines and methylmelamines such as altretamine, triethylenemelamine, triethylenephosphamide, triethylenethiophosphamide and trimethylmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (topotecan and irinotecan); bryostatin; calicheamicin; CC-1065 (including its synthetic analogs adozelesin, carzelesin and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); corticosteroids (including prednisone and prednisolone); cyproterone acetate;5α-reductases including finasteride and dutasteride; vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat, fostriecin; aldoxorubicin, talarozole, duocarmycin (synthetic analogs including KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; chlorambucil, chromomycin, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobenbine, phenesterine, prednimustine, trofosfamide, uracil mustard, etc. nitrogen mustards; carmustine, chloroazotocin, fotemustine, lomustine, nimustine, and ranimustine, etc. nitrosoureas; antibiotics such as enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin γ1I and calicheamicin ω1I (Angew Chem.Intl.Ed.Engl. 1994 33:183-186); dynemicin including dynemicin A; bisphosphonates such as clodronate; esperamicin; similarly, neocarzinostatin chromophore and related chromophore enediyne antibiotic chromophores), aclacinomycins, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, cardinophilin, chromomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, adriamycin (registered trademark) (doxorubicin), morpholino doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, keramycin, rhodomycin, streptozocin, streptonigrin, tubercidin, ubenimex, dinostatin, zorubicin; metabolic antagonists such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimethoprim, etc.Purine analogs such as fludarabine, 6-mercaptopurine, thiampurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, drostanolone propionate, epithiostanol, mepithiostane, testolactone; antiadrenal 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; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK (registered trademark) polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2”-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verrucarin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids 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; 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 RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid, and pharmaceutically acceptable salts, acids and derivatives of any of the above.;

[0166] In addition, as chemotherapeutic agents, (i) antihormonal agents that act to regulate or inhibit the hormonal action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), for example, tamoxifen (including NOLVADEX (registered trademark), tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON (registered trademark) (toremifene citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase that regulates estrogen production in the adrenal glands, for example, 4(5)-imidazole, aminoglutethimide, MEGASE (registered trademark) (megestrol acetate), AROMASIN (registered trademark) (exemestane; Pfizer), formestane, fadrozole, RIVISOR (registered trademark) (vorozole), FEMARA (registered trademark) (letrozole; Novartis), and ARIMIDEX (registered trademark) (anastrozole; AstraZeneca); (iii) antiandrogen agents such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all-trans retinoic acid, fenretinide, and troxacitabine (1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly agents that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, for example, PKC-alpha, Ralf, and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME (registered trademark)), HER2 expression inhibitors, etc.; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN (registered trademark), LEUVECTIN (registered trademark), VAXID (registered trademark); topoisomerase 1 inhibitors such as PROLEUKIN (registered trademark), rIL-2; LURTOTECAN (registered trademark), etc.; ABARELIX (registered trademark) rmRH; and (ix) pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0167] 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, pecfostuxizumab, pecilizumab, pecilizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, reslizumab, rovelizumab, rupizumab, sibrotuzumab, siplizumab, sonotuzumab, takatuzumab tetraxetan, tadoxizumab, talizumab, tefibazumab, tocilizumab, tralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, ultuxizumab, ustekinumab, visilizumab, and anti-interleukin-12 (ABT-874 / J695, Wyeth Research and Abbott Laboratories), a full-length IgG1λ antibody of only human sequence genetically engineered to recognize interleukin-12 p40 protein.

[0168] 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 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, Mendelsohn et al.) 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); an 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-alpha for EGFR binding; 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 A2, Merck Patent GmbH). Examples of EGFR antagonists include the compounds 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 small molecules such as those described in the following PCT publications: International Publication Nos. 98 / 14451, 98 / 50038, 99 / 09016, and 99 / 24037.Examples of specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA (registered trademark), Genentech / OSI Pharmaceuticals), PD183805 (CI1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.), ZD1839, gefitinib (IRESSA (registered trademark)) 4-(3’-chloro-4’-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca), ZM105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca), BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim), PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol), (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine), CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide), EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-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).

[0169] Chemotherapeutic agents also include "tyrosine kinase inhibitors" (including the EGFR-targeted drugs described in the previous paragraph), small molecule HER2 tyrosine kinase inhibitors (such as TAK165 available from Takeda), CP-724,714 (Pfizer and OSI), an oral selective inhibitor of ErbB2 receptor tyrosine kinase, dual HER inhibitors (such as EKB-569 (available from Wyeth) that preferentially binds to EGFR but inhibits both HER2- and EGFR-overexpressing cells), lapatinib (GSK572016, available from Glaxo-SmithKline), oral HER2 and EGFR tyrosine kinase inhibitors, PKI-166 (available from Novartis), pan-HER inhibitors (such as canertinib (CI-1033, Pharmacia)), Raf-1 inhibitors (such as the antisense agent ISIS-5132 available from ISIS Pharmaceuticals that inhibits Raf-1 signaling), non-HER-targeted TK inhibitors (such as imatinib mesylate (GLEEVEC®, available from Glaxo SmithKline)), multi-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 (PD153035, 4-(3-chloroanilino)quinazoline, etc.), pyridopyrimidines, pyrimidopyrimidines, pyrrolopyrimidines (such as CGP59326, CGP60261, and CGP62706, etc.), 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), trioxsalen (U.S. Patent No. 5,804,396, ZD6474 (Astra Zeneca), PTK-787 (Novartis / Schering AG), pan-HER inhibitors (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).

[0170] 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, nol fetomomab, oprelvekin, paricalcitol, 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.

[0171] Chemotherapeutic agents include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivoxate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fludrocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, acrometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasone-17-propionate, fludrocortolone caproate, fludrocortolone pivoxate, and fluprednidene acetate; immunoselective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-form (feG) (IMULAN BioTherapeutics, LLC); antirheumatic drugs such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, minocycline, sulfasalazine; tumor necrosis factor alpha (TNFα) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi); interleukin 1 (IL-1) blockers such as anakinra (Kineret); T-cell costimulation blockers such as abatacept (Orencia); interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMRA (registered trademark)); interleukin 13 (IL-13) blockers such as lebrikizumab; interferon alpha (IFN) blockers such as lonafarnib; beta7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as anti-M1 prime; secreted homotrimeric LTa3 and membrane-bound heterotrimeric LTa1 / β2 blockers such as anti-lymphotoxin alpha (LTa); radioisotopes (e.g., At 211 、I 131 、I 125 、Y 90 、Re 186 、Re 188 、Sm 153 、Bi 212 、P32 , Pb 212, and radioisotopes of Lu); various investigational drugs such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3, or farnesyltransferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavin, flavanol, procyanidin, betulinic acid and its derivatives; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL (registered trademark)); beta-lapachone; lapachol; colchicine; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin); podophyllotoxin; tegafur (UFTORAL (registered trademark)); bexarotene (TARGRETIN (registered trademark)); bisphosphonates such as clodronate (e.g., BONEFOS (registered trademark) or OSTAC (registered trademark)), etidronate (DIDROCAL (registered trademark)), NE-58095, zoledronic acid / zoledronate (ZOMETA (registered trademark)), alendronate (FOSAMAX (registered trademark)), pamidronate (AREDIA (registered trademark)), tiludronate (SKELID (registered trademark)), or risedronate (ACTONEL (registered trademark)); and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE (registered trademark) vaccine; perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteasome inhibitors (e.g., PS341); CCI-779; tipifarnib (R11577); obatoclax, 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).

[0172] Also included as chemotherapeutic agents are non-steroidal anti-inflammatory drugs having an analgesic effect, an antipyretic effect, and an anti-inflammatory effect. Examples of 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, etc., tenoxicam, droxicam, lornoxicam, isoxicam, 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. NSAIDs can be indicated for the relief of symptoms of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathy, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headache, and migraine, postoperative pain, mild to moderate pain, fever, intestinal obstruction, and renal colic caused by inflammation and tissue injury.

[0173] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cell function and / or causes cell death or destruction. Examples of cytotoxic agents include 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, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, 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, but not limited thereto.

[0174] "Disorder" includes those pathological conditions that predispose a mammal to the disorder in question, including, but not limited to, chronic and acute disorders or diseases, and any condition that would benefit from treatment. In one aspect, the disorder is cancer, such as multiple myeloma (MM).

[0175] 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.

[0176] As used herein, "tumor" refers to the growth and proliferation of all neoplastic cells, whether malignant or benign, and all preneoplastic and neoplastic cells and tissues. The terms "cancer", "cancerous", "cell proliferative disorder", "proliferative disorder", and "tumor" are not mutually exclusive when referred to herein.

[0177] 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 multiple myeloma (MM) (which may 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 may be newly diagnosed MM (NDMM).

[0178] MM can have one or more cytogenetic features. In some examples, the cytogenetic features are "high-risk cytogenetic features", such as t(4;14), t(11;14), t(14;16) and / or del(17p) (provided in Table 1 in Sonneveld et al., Blood, 127(24):2955-2962, 2016 and described in the International Myeloma Working Group (IMWG) criteria, which are hereby incorporated by reference in their entirety) and / or 1q21 (described in Chang et al., Bone Marrow Transplantation, 45:117-121, 2010, which is hereby incorporated by reference in its entirety). In some examples, the high-risk cytogenetic features include one or more of the following: (i) translocation events: t(4;14), t(14;16) (IMWG criteria); deletion (del)(17p) (IMWG criteria); or gain in chromosome 1q. The cytogenetic features can be detected, for example, using fluorescence in situ hybridization (FISH).

Table 1

[0179] 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, disorders such as lymphoma, leukemia, myeloma, and myelodysplastic syndromes. In one embodiment, the B-cell proliferative disorder is a lymphoma such as non-Hodgkin lymphoma (NHL), including, for example, diffuse large B-cell lymphoma (DLBCL) (e.g., relapsed or refractory DLBCL). In another embodiment, the B-cell proliferative disorder is a leukemia such as chronic lymphocytic leukemia (CLL). Other specific examples of cancer include germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL), activated B-cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenström macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt lymphoma (BL), B-cell prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma / leukemia, unclassifiable, diffuse red pulp small B-cell lymphoma, hairy cell leukemia variant, heavy chain disease, alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasmacytic myeloma, solitary bone plasmacytoma, extraosseous plasmacytoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), nodal marginal zone lymphoma, pediatric nodal marginal zone lymphoma, pediatric follicular lymphoma, primary cutaneous follicle center lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, primary CNS DLBCL, primary cutaneous DLBCL, lower extremity type, EBV-positive DLBCL in the elderly, chronic inflammation-related DLBCL, lymphomatoid granulomatosis, mediastinal (thymic) primary B-cell large cell lymphoma, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma due to HHV8-related 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.Further examples of cancer include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and lymphoid malignancies including leukemia or B-cell lymphoma. Even more specific examples of such cancers include low-grade / follicular NHL; small lymphocytic (SL) NHL; intermediate-grade / follicular NHL; intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphocytic NHL; high-grade small non-cleaved cell NHL; large tumor lesion NHL; AIDS-related lymphoma; and acute lymphocytic leukemia (ALL); chronic myelogenous leukemia; and post-transplant lymphoproliferative disorder (PTLD). Examples of solid tumors include squamous cell carcinomas (e.g., epithelial squamous cell carcinomas), small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and lung cancers including squamous carcinoma of the lung, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, and gastric cancer (gastric cancer) or stomach cancer including gastrointestinal stromal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urological cancers, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial carcinoma or uterine carcinoma, salivary gland carcinoma, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer species, anal carcinoma, penile carcinoma, melanoma, superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanoma, nodular melanoma, as well as phakomatosis, edema (such as those associated with brain tumors), Meigs syndrome, the brain, and head and neck cancers, and abnormal blood vessel proliferation associated with related metastases. In certain embodiments, cancers suitable for treatment with the antibodies disclosed herein include breast cancer, colorectal cancer, rectal cancer, non-small cell lung cancer, glioblastoma, non-Hodgkin lymphoma (NHL), renal cell cancer, prostate cancer, liver cancer, pancreatic cancer, soft tissue sarcoma, Kaposi sarcoma, carcinoid carcinoma, head and neck cancer, ovarian cancer, and mesothelioma.

[0180] The term "FcRH5-positive cancer" refers to a cancer that includes 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, in methods such as immunohistochemistry, FACS, etc. In some embodiments, FcRH5 is one or more of FcRH5a, FcRH5b, FcRH5c, UniProt identifier Q96RD9-2, and / or FcRH5d. In some embodiments, FcRH5 is FcRH5c. For example, an FcRH5-positive cancer can be FcRH5-positive MM.

[0181] "Effector function" refers to a biological activity resulting from the Fc region of an antibody that varies depending on the isotype of the antibody. Examples of antibody effector functions include: C1q binding and complement-dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, downregulation of cell surface receptors (e.g., B cell receptor), and B cell activation.

[0182] "Complement-dependent cytotoxicity" or "CDC" refers to the lysis of target cells in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to an antibody (of the appropriate subclass). To evaluate complement activation, an assay such as that described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996) can be performed, for example.

[0183] "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 required for such killing. While NK cells, which are primary cells mediating ADCC, express only FcγRIII, monocytes express FcγRI, FcγRII, and FcγRIII. The expression of FcRs in hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet. Annu. Rev. Immunol. 9:457-92, 1991. To evaluate the ADCC activity of a molecule of interest, an in vitro ADCC assay 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 in addition, 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.

[0184] As used herein, "complex" or "complex form" refers to the association of two or more molecules that interact with each other through bonds and / or forces that are not peptide bonds (e.g., van der Waals forces, hydrophobic forces, hydrophilic forces). In one aspect, the complex is a heteromultimer. As used herein, the terms "protein complex" or "polypeptide complex" 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).

[0185] As used herein, "delaying the progression" of a disorder or disease means deferring, preventing, decelerating, retarding, stabilizing, and / or delaying the development of a disease or disorder (e.g., a cell proliferative disorder, e.g., cancer). This delay can be for varying lengths of time depending on the medical history and / or the individual being treated. As will be apparent to those skilled in the art, a sufficient or significant delay can, in effect, encompass prevention in the sense that the individual does not develop the disease. For example, it is possible to delay advanced cancer such as the occurrence of metastasis.

[0186] An "effective amount" of a compound, e.g., an anti-FcRH5 / anti-CD3 T cell-dependent bispecific antibody (TDB) disclosed herein, lenalidomide, or a composition thereof (e.g., a pharmaceutical composition) (e.g., a pharmaceutical composition comprising an anti-FcRH5 / anti-CD3 TDB and / or lenalidomide disclosed herein) is at least the minimum amount necessary to achieve a desired therapeutic or prophylactic result such as a measurable improvement or prevention of a particular disorder (e.g., a cell proliferative disorder, e.g., cancer, e.g., MM, e.g., MM with high-risk cytogenetic features). The effective amount herein can vary depending on factors such as the patient's disease state, age, gender, and weight, as well as the ability of the antibody to induce a desired response in the individual. An effective amount is also one in which the therapeutically beneficial effects outweigh any toxic or detrimental effects of the treatment. Beneficial or desired results for prophylactic use include removal or reduction of risk, reduction of severity, or delay in the onset of the disease, including the biochemical, histological, and / or kinetic symptoms of the disease, its complications, and intermediate pathological phenotypes that appear during the onset of the disease. For therapeutic use, beneficial or desired results include a decrease in one or more symptoms resulting from the disease, an improvement in the quality of life of the person suffering from the disease, a decrease in the dosage of other drugs required for treatment of the disease, enhancement of the effect of another drug (e.g., by targeting), delay in the progression of the disease, and / or extension of the survival period, and other clinical outcomes. In the case of cancer or a tumor, an effective amount of the drug can reduce the number of cancer cells, reduce the tumor size, inhibit (i.e., delay to some extent or preferably stop) the invasion of cancer cells into peripheral organs, inhibit (i.e., delay to some extent or preferably stop) tumor metastasis, inhibit tumor growth to some extent, and / or reduce to some extent one or more of the symptoms associated with the disorder. The effective amount can be administered in one or more administrations. For the purposes of the present invention, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve a prophylactic treatment or a therapeutic treatment. As understood in the clinical art, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition.Accordingly, an "effective amount" can be considered in the context of administration of one or more therapeutic agents, and a single agent, in combination with one or more other agents, can be considered to be administered in an effective amount if a desired result can be achieved or, if achieved, is achieved.

[0187] As used herein, "overall survival" or "OS" refers to the percentage of individuals within a group likely to survive after a specified period.

[0188] As used herein, "objective response rate" (ORR) refers to the sum of the stringent complete remission (sCR) rate, complete remission (CR) rate, very good partial remission (VGPR) rate, and partial remission (PR) rate determined using the International Myeloma Working Group response criteria (Table 8).

[0189] 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.

[0190] 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 and M phase 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 ara-C, also affect S phase arrest. Further information can be found in Mendelsohn and Israel, eds., The Molecular Basis of Cancer, Chapter 1, entitled “Cell cycle regulation, oncogenes, and antineoplastic drugs” by Murakami et al. (W.B. Saunders, Philadelphia, 1995), e.g., p. 13. Taxanes (paclitaxel and docetaxel) are both anticancer drugs derived from yew. Docetaxel (TAXOTERE®, Rhone-Poulenc Rorer), derived from the European yew, is a semi-synthetic analogue 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.

[0191] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules (plural), including but not limited to, a cytotoxic agent.

[0192] The term "immunomodulatory agent" or "IMiD" refers to a class of molecules that modify the response or function of the immune system. Immunomodulatory agents include, but are not limited to, PD-1 axis-binding antagonists, thalidomide (α-N-phthalimide-glutarimide) and its analogs, OTEZLA® (apremilast), REVLIMID® (lenalidomide) and POMALYST® (pomalidomide), and pharmaceutically acceptable salts or acids thereof.

[0193] "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, e.g., monkeys), rabbits and rodents (e.g., mice and rats). In certain embodiments, the subject or individual is a human. In certain embodiments, the subject or individual is a patient, e.g., a human patient.

[0194] An "isolated" protein or peptide is separated from the components of its natural environment. In some embodiments, the protein or peptide is purified to a purity of 95% or greater, or 99% or greater, as determined, for example, by electrophoresis (e.g., SDS-PAGE, isoelectric focusing electrophoresis (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC).

[0195] An "isolated" nucleic acid is a nucleic acid molecule that has been separated from the components of its natural environment. Isolated nucleic acids typically contain the nucleic acid molecule(s) present in the cells that contain the nucleic acid molecule(s), but the nucleic acid molecule(s) are present extrachromosomally or at a chromosomal location different from their natural chromosomal location.

[0196] 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.

[0197] 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 a specific embodiment, the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 and / or B7-1. In some cases, the PD-L1 binding antagonist includes an anti-PD-L1 antibody, its antigen-binding fragment, 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 example, the PD-L1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes via signal transduction through PD-L1 so as to prevent dysfunctional T cells from becoming dysfunctional (e.g., enhancing the effector response to antigen recognition). In some cases, the PD-L1 binding antagonist binds to PD-L1. In some cases, the PD-L1 binding antagonist is an anti-PD-L1 antibody (e.g., an anti-PD-L1 antagonist antibody). Exemplary anti-PD-L1 antagonist antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001, enoblituzumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosibelimab, rodaplimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636.In some embodiments, the anti-PD-L1 antibody is atezolizumab, MDX-1105, MEDI4736 (durvalumab), or MSB0010718C (avelumab). In a particular embodiment, the PD-L1 binding antagonist is MDX-1105. In another specific embodiment, the PD-L1 binding antagonist is MEDI4736 (durvalumab). In another specific embodiment, the PD-L1 binding antagonist is MSB0010718C (semiplimab). 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 particular embodiment, the PD-L1 binding antagonist is atezolizumab.

[0198] The term "PD-1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses, or interferes with the signaling resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and / or PD-L2. PD-1 (programmed death 1) is also referred to in the art as "programmed cell death 1", "PDCD1", "CD279", and "SLEB2". Exemplary human PD-1 is shown in UniProtKB / Swiss-Prot accession number Q15116. In some cases, a PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In a specific aspect, a PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and / or PD-L2. For example, a PD-1 binding antagonist includes an anti-PD-1 antibody, its antigen-binding fragment, an immunoadhesin, a fusion protein, an oligopeptide, and other molecules that reduce, block, inhibit, suppress, or interfere with the signaling resulting from the interaction of PD-1 with PD-L1 and / or PD-L2. In one example, a PD-1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes via signaling through PD-1 such that dysfunctional T cells are prevented from becoming dysfunctional (e.g., enhancing 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, prolegozumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanelimab, pemprilimab, CS1003, HLX10, SCT-I10A, zinberelimab, balsilimab, genolimzumab, BI 754091, cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, and hAb21. In a specific embodiment, the PD-1 binding antagonist is MDX-1106 (nivolumab). In another specific embodiment, the PD-1 binding antagonist is MK-3475 (pembrolizumab). In another specific embodiment, the PD-1 binding antagonist is a PD-L2 Fc fusion protein, such as AMP-224. In another specific embodiment, the PD-1 binding antagonist is MED1-0680. In another specific embodiment, the PD-1 binding antagonist is PDR001 (spartalizumab). In another specific embodiment, the PD-1 binding antagonist is REGN2810 (semiplimab). In another specific embodiment, the PD-1 binding antagonist is BGB-108. In another specific embodiment, the PD-1 binding antagonist is prolegozumab. In another specific embodiment, the PD-1 binding antagonist is camrelizumab. In another specific embodiment, the PD-1 binding antagonist is sintilimab. In another specific embodiment, the PD-1 binding antagonist is tislelizumab. In another specific embodiment, the PD-1 binding antagonist is toripalimab. Other further exemplary PD-1 binding antagonists include BION-004, CB201, AUNP-012, ADG104, and LBL-006.

[0199] The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses, or interferes with the signaling resulting from the interaction of PD-L2 with any one or more of its binding partners, such as the 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". An exemplary human PD-L2 is shown in UniProtKB / Swiss-Prot Accession No. Q9BQ51. In some cases, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In a specific embodiment, the PD-L2 binding antagonist inhibits the binding of PD-L2 to PD-1. Exemplary PD-L2 antagonists include anti-PD-L2 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, suppress, or interfere with the signaling resulting from the interaction of PD-L2 with any 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 that mediate signaling via PD-L2 so as not to further incapacitate dysfunctional T cells (e.g., to enhance 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.

[0200] 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 the "full-length", untreated protein and the protein resulting from processing within the cell. This term also encompasses naturally occurring variants of the protein, such as splice variants or allelic variants.

[0201] 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 alignment. Alignments for determining percent amino acid sequence identity can be achieved using a variety of methods within the skill in the art, such as publicly available computer software like 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 aligning the sequences, including any algorithms necessary to achieve maximum alignment over the full 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 United States Copyright Office (Washington D.C., 20559), registered under United States Copyright Registration No. TXU510087, and described in International Publication No. WO 2001 / 007611.

[0202] However, for the purposes of this specification, the percent amino acid sequence identity value is generated using the ggsearch program of the FASTA package version 36.3.8c or, thereafter, using the BLOSUM50 comparison matrix. The FASTA program package is accredited 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, using the ggsearch (global protein:protein) program and default options (BLOSUM50; open: -10; ext: -2; Ktup = 2), sequences can be compared using the public server accessible at fasta.bioch.virginia.edu / fasta_www2 / index.cgi to ensure a global rather than a local alignment is performed. The percent amino acid identity is indicated in the output alignment header.

[0203] 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 constituents that are unacceptably toxic to the subject to which the preparation is administered.

[0204] “Pharmaceutically acceptable carrier” refers to a component in a pharmaceutical preparation other than the active ingredient that is non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers or preservatives.

[0205] "Radiation therapy" means using directed gamma or beta rays to inflict sufficient damage to cells to limit their ability to function normally or to completely destroy them. It will be understood that there are many methods known in the art for determining dosage and treatment duration. A typical treatment is given as a single dose, and typical dosages range from 10 to 200 units (gray) per day.

[0206] As used herein, "treatment" (and its grammatical variants, e.g., "treat" or "treating") refers to a clinical intervention in an attempt to alter the natural course of the individual being treated and can be done for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing the onset or recurrence of a disease, alleviating symptoms, attenuating the direct or indirect pathological consequences of a disease, preventing metastasis, reducing the rate of disease progression, improving or alleviating the condition, and achieving remission or improving the prognosis. In some embodiments, the antibodies disclosed herein (e.g., the anti-FcRH5 / anti-CD3 TDB disclosed herein) and / or lenalidomide are used to delay the onset of a disease or to slow the progression of a disease.

[0207] "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 complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cell phagocytosis (ADCP).

[0208] According to the present invention, the term "vaccine" relates to a pharmaceutical preparation (pharmaceutical composition) or product that induces an immune response, particularly a cellular immune response, upon administration and recognizes and attacks disease cells such as pathogens or cancer cells. A vaccine can 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 the immune response of a subject against cancer. A cancer vaccine typically consists of a source of a cancer-related substance or cell (antigen), which can be autologous (derived from the subject itself) or allogeneic (derived from another) 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 producing killer T cells that attack cancer cells bearing those antigens.

[0209] As used herein, "administration" means a method of giving a subject a dosage of a compound (e.g., the anti-FcRH5 / anti-CD3 TDB (e.g., cevostamab) or lenalidomide of the present invention). 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, topically, intratumorally, peritoneally, subcutaneously, subconjunctivally, intravesicularly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, directly by a local perfusion bath target cell, by catheter, by perfusion, in a cream, or in a lipid composition. The method of administration can vary depending on various factors (e.g., the compound or composition being administered and the severity of the condition, disease, or disorder being treated).

[0210] As used herein, "CD38" refers to the CD38 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 expressed at a higher level and more uniformly on myeloma cells compared to normal lymphoid and myeloid cells. The term encompasses "full-length", unprocessed CD38, and any form of CD38 resulting from intracellular processing. The term also encompasses naturally occurring variants of CD38, such as splice variants or allelic variants. CD38 is also known in the art as cluster of differentiation 38, ADP-ribosyl cyclase 1, cADPr hydrolase 1, and cyclic ADP-ribose hydrolase 1. CD38 is encoded by the CD38 gene. An exemplary human CD38 nucleic acid sequence is shown in NCBI reference sequence NM_001775.4 or SEQ ID NO: 33. The amino acid sequence of an exemplary human CD38 protein encoded by CD38 is shown in UniProt accession number P28907 or SEQ ID NO: 34.

[0211] The term "anti-CD38 antibody" encompasses all antibodies that bind to CD38 with sufficient affinity such that they are useful as therapeutic agents when targeting cells that express the antigen and do not 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 via complement-dependent cytotoxicity, ADCC, antibody-dependent cell phagocytosis (ADCP), and activation of apoptosis mediated by Fc bridging, resulting in depletion of malignant cells and reduction of overall cancer burden. Anti-CD38 antibodies can also modulate CD38 enzyme activity via 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 -8 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, such as 10 -13 M to 10 -9 M, such as 10 -13 M to 10- D 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 also encompasses 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).

[0212] II. Therapeutic Methods and Compositions for Use The present invention is based, in part, on a method of treating a subject having cancer (e.g., multiple myeloma (MM) (e.g., MM with high-risk cytogenetic features)) with an anti-fragment crystallizable receptor-like 5 (FcRH5) / anti-cluster of differentiation 3 (CD3) bispecific antibody and lenalidomide, for example, using a fractionated dose escalation dosing regimen as disclosed herein.

[0213] Currently, there is no curative treatment for MM and almost all patients will ultimately relapse. Lenalidomide is currently the only drug approved as maintenance treatment after autologous stem cell transplantation (ASCT), delaying relapse and prolonging survival. To date, maintenance treatment has typically been performed as monotherapy, and patients with cytogenetically low-risk features derive a survival benefit. However, patients with cytogenetically high-risk features have unmet medical needs that remain high, with very low survival benefit from single-agent maintenance and a hazard ratio of death 6 - 15 times higher than that of patients in the low-risk category. In the high-risk population, dual-agent maintenance as described herein using sevosumab and lenalidomide is expected to improve and deepen responses, thereby increasing survival while maintaining quality of life.

[0214] A. Dosing Regimen i. Dosing Regimen for the Treatment of Cancer Having High-Risk Cytogenetic Features The present disclosure provides methods and compositions for treating cancer having high-risk cytogenetic features (e.g., blood cancers (e.g., B-cell proliferative disorders (e.g., MM))).

[0215] For example, provided herein is a method of treating a subject having cancer (e.g., blood cancer (e.g., B-cell proliferative disorder (e.g., MM))) having high-risk cytogenetic features, the method comprising administering to the subject (i) a bispecific antibody that binds to fragment crystallizable receptor-like 5 (FcRH5) and cluster of differentiation 3 (CD3), and (ii) lenalidomide.

[0216] In another example, a bispecific antibody that binds to FcRH5 and CD3 for use in treating a subject having a cancer with high-risk cytogenetic features (e.g., a blood cancer (e.g., a B-cell proliferative disorder (e.g., MM))), wherein the treatment comprises administration of the bispecific antibody and lenalidomide to the subject, is provided herein.

[0217] In some examples, the subject has experienced a partial response (PR) or better after induction therapy.

[0218] In some examples, the subject has received autologous stem cell transplantation (ASCT) within 100 days (e.g., within 100 days, within 95 days, within 90 days, within 85 days, within 80 days, within 75 days, within 70 days, within 65 days, within 60 days, within 55 days, within 50 days, within 45 days, within 40 days, within 35 days, within 30 days, within 25 days, within 20 days, within 15 days, within 10 days, within 5 days, within 4 days, within 3 days, within 2 days, or within 1 day) from the start of the method or treatment (e.g., the first administration of the bispecific antibody) and / or has no progressive disease.

[0219] In some examples, the bispecific antibody and lenalidomide are administered to the patient as maintenance therapy after transplantation.

[0220] The patient may have any suitable high-risk cytogenetic feature or combination thereof. In some examples, the high-risk cytogenetic features include one or more of the translocation events t(4;14) or t(14;16), del(17p), or 1q gain.

[0221] In some examples, the subject had high-risk cytogenetic features at the time of diagnosis of the cancer (e.g., a blood cancer (e.g., MM)).

[0222] In some examples, the bispecific antibody and lenalidomide are administered to a subject in a dosing regimen that includes: (i) a first phase comprising one or more dosing cycles, wherein the bispecific antibody is administered to the subject once a week (Q1W), every two weeks (Q2W), every three weeks (Q3W), or every four weeks (Q4W); and (ii) a second phase comprising one or more dosing cycles, wherein the bispecific antibody is administered to the subject once a week (Q1W), every two weeks (Q2W), every three weeks (Q3W), or every four weeks (Q4W).

[0223] In one specific example, the bispecific antibody and lenalidomide are administered to a subject in a dosing regimen that includes: (i) a first phase comprising one or more dosing cycles, wherein the bispecific antibody is administered to the subject every two weeks (Q2W); and (ii) a second phase comprising one or more dosing cycles, wherein the bispecific antibody is administered to the subject every four weeks (Q4W).

[0224] Each dosing cycle of the first phase and / or the second phase can have any suitable length. In some examples, each dosing cycle of the first phase and / or the second phase is a 28-day dosing cycle. However, in other examples, each dosing cycle of the first phase and / or the second phase can be a 7-day dosing cycle, a 14-day dosing cycle, or a 21-day dosing cycle. It should be understood that the dosing cycles do not have to all be of the same length.

[0225] In some examples, the method or treatment further includes a pre-phase comprising one or more dosing cycles before the first phase, wherein the bispecific antibody is administered to the subject once a week (QW), every two weeks (Q2W), every three weeks (Q3W), or every four weeks (Q4W).

[0226] In particular, the method or treatment further includes a pre-phase that includes one or more dosing cycles prior to the first phase, and the pre-phase includes administering the bispecific antibody to the subject once weekly (QW).

[0227] Each dosing cycle of the pre-phase can have any suitable length. In some examples, each dosing cycle of the pre-phase is a 28-day dosing cycle. However, in other examples, each dosing cycle of the pre-phase can be a 7-day dosing cycle, a 14-day dosing cycle, or a 21-day dosing cycle. It should be understood that the dosing cycles do not all have to be the same length.

[0228] The pre-phase can include any suitable number of dosing cycles, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more dosing cycles.

[0229] In a specific example, the pre-phase includes one dosing cycle (C1).

[0230] The pre-phase can include administering the bispecific antibody to the subject on any suitable day(s) of the dosing cycle (e.g., C1), for example, 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 and / or day 28 of the dosing cycle.

[0231] In one specific example, the pre-phase includes administering the bispecific antibody to the subject on days 1, 8 and 15 of C1. In another example, the pre-phase includes administering the bispecific antibody to the subject on days 1, 2 and 15 of C1.

[0232] In some examples, the target dose of the bispecific antibody is administered to the subject for each administration in the pre-phase. In other words, the pre-phase does not have to utilize escalated dosing.

[0233] In other examples, the pre-phase involves administering a bispecific antibody at a first escalating dose. In some examples, the pre-phase involves a single escalating dose of the bispecific antibody. Any of the single escalating dosing regimens described in Subsection II below may be used.

[0234] The first escalating dose can be administered to the subject on any suitable day(s) of a dosing cycle (e.g., C1), such as 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, and / or day 28 of the dosing cycle.

[0235] In one particular example, the first escalating dose is administered to the subject on day 1 of C1.

[0236] In a single-step escalating dosing regimen, the target dose can be administered on any suitable day after the first escalating dose, such as 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, and / or day 28 of a dosing cycle (e.g., C1). In one particular example, the target dose is administered to the subject on days 8 and 15 of C1.

[0237] In some examples, the pre-phase involves administering a bispecific antibody at a first escalating dose and a second escalating dose. Any of the two-step escalating dosing regimens described in Subsection III below may be used.

[0238] The first step-up dose and / or the second step-up dose can be administered to a subject on any suitable day of the dosing cycle (e.g., C1), such as the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, and / or 28th day of the dosing cycle.

[0239] In one particular example, the first step-up dose is administered to the subject on the 1st day of C1, and the second step-up dose is administered to the subject on the 8th day of C1.

[0240] In a two-step up dosing regimen, the target dose can be administered to a subject on any suitable day after the second step-up dose, such as the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, and / or 28th day of the dosing cycle. In one particular example, the target dose is administered to the subject on the 15th day of C1.

[0241] For the first step-up dose, any suitable dose can be used that includes any of the doses described in Subsections II and III below. In some examples, the first step-up dose is 3.6 mg.

[0242] For the first step-up dose, any suitable dose can be used that includes any of the doses described in Subsection III below. In some examples, the first step-up dose is 0.3 mg and the second step-up dose is 3.6 mg. In other examples, the first step-up dose is 0.3 mg and the second step-up dose is 3.3 mg.

[0243] The first phase may include any suitable number of dosing cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more dosing cycles). In some examples, the first phase includes at least 2 dosing cycles, at least 3 dosing cycles, at least 4 dosing cycles, or at least 5 dosing cycles. In some examples, the first phase consists of 5 dosing cycles.

[0244] In some examples, the first 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).

[0245] In some examples, the first phase includes administering the bispecific antibody to the subject on days 1 and 15 of C1, C2, C3, C4, and / or C5.

[0246] In some examples, the target dose of the bispecific antibody is administered to the subject for each administration during the first phase. Any suitable target dose can be used, including any of the doses described in Subsections II and / or III. In some examples, the target dose is 20 mg to 600 mg (e.g., 30 mg to 500 mg, 40 mg to 400 mg, 60 mg to 350 mg, 80 mg to 300 mg, 100 mg to 200 mg, or 140 mg to 180 mg, e.g., 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some embodiments, C1D3 is 80 mg to 300 mg. In some embodiments, the target dose is about 90 mg. In some embodiments, the target dose is about 132 mg. In some target doses, C1D3 is about 160 mg. In some target doses, C1D3 is about 198 mg.

[0247] The second phase may include any suitable number of dosing cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more dosing cycles). In some examples, the second phase includes at least 2 dosing cycles, at least 3 dosing cycles, at least 4 dosing cycles, at least 5 dosing cycles, at least 6 dosing cycles, or at least 7 dosing cycles. In some examples, the second phase consists of 7 dosing cycles.

[0248] In some examples, the second 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).

[0249] In some examples, the second phase includes administering the bispecific antibody to the subject on day 1 of C1, C2, C3, C4, C5, C6, and / or C7.

[0250] In some examples, the bispecific antibody at the target dose is administered to the subject for each administration during the second phase. Any suitable target dose can be used, including any of the doses described in Subsections II and / or III. In some examples, the target dose is 20 mg to 600 mg (e.g., 30 mg to 500 mg, 40 mg to 400 mg, 60 mg to 350 mg, 80 mg to 300 mg, 100 mg to 200 mg, or 140 mg to 180 mg, e.g., 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some embodiments, C1D3 is 80 mg to 300 mg. In some embodiments, the target dose is about 90 mg. In some embodiments, the target dose is about 132 mg. In some target doses, C1D3 is about 160 mg. In some target doses, C1D3 is about 198 mg.

[0251] In some examples, the target dose is 90 mg to 198 mg, including the end values. In some examples, the target dose is 90 mg. In some examples, the target dose is 132 mg. In some examples, the target dose is 160 mg.

[0252] The bispecific antibody can be administered by any suitable route of administration. In some examples, the bispecific antibody is administered intravenously to the subject. In other examples, the bispecific antibody is administered subcutaneously to the subject.

[0253] Lenalidomide can be administered on any suitable day of the dosing cycle, for example, on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, and / or 28th day of the dosing cycle. In certain examples, lenalidomide is administered to the subject on days 1 to 21 of each dosing cycle in the first phase and / or the second phase. In some examples, lenalidomide is administered to the subject on days 1 to 21 of each dosing cycle in the pre-phase.

[0254] Any suitable dose of lenalidomide can be used (e.g., 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, or about 30 mg). In some examples, lenalidomide is administered to the subject at a dose of about 10 mg to about 20 mg. In some examples, lenalidomide is administered to the subject at a dose of 10 mg to 20 mg.

[0255] In some examples, lenalidomide is administered to the subject at a dose of about 10 mg. In some examples, lenalidomide is administered to the subject at a dose of 10 mg. In other examples, lenalidomide is administered to the subject at a dose of about 15 mg. In other examples, lenalidomide is administered to the subject at a dose of 15 mg. For example, lenalidomide can be administered at a dose of 15 mg after 3 cycles (e.g., the first 3 cycles can include administering lenalidomide at a dose of 10 mg, and then, for example, at the discretion of the clinician, the dose can be increased to 15 mg).

[0256] Lenalidomide can be administered by any suitable route of administration. In some examples, lenalidomide is administered orally to the subject.

[0257] In some examples, the method or treatment further comprises administering a corticosteroid to the subject. Any suitable corticosteroid, such as dexamethasone or methylprednisolone, may be used.

[0258] In some examples, the method or treatment further comprises administering a corticosteroid to the subject during the first phase and / or the second phase.

[0259] The corticosteroid may be administered on any suitable day during the dosing cycle in the first phase and / or the second phase, such as, for example, on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and / or 28 of the dosing cycle. The corticosteroid may be administered on the same day as the bispecific antibody, or on a different day (e.g., one or more days before or one day after the administration of the bispecific antibody). In some examples, the corticosteroid is administered to the subject on days 1 and 15 of C1 of the first phase during the first phase.

[0260] In some examples, if the subject has experienced cytokine release syndrome (CRS) at a previous dose, a corticosteroid is administered to the subject. In some examples, if the subject has experienced a CRS event at a previous dose, the corticosteroid is administered to the subject in C2, C3, C4, and / or C5 of the first phase.

[0261] In some examples, if the subject has experienced a CRS event at a previous dose, the corticosteroid is administered to the subject in C1, C2, C3, C4, C5, C6, and / or C7 of the second phase.

[0262] In some examples, the method or treatment further comprises administering a corticosteroid during the pre-phase.

[0263] The corticosteroid can be administered on any suitable day during the dosing cycle in the pre-phase, for example, on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th and / or 28th day of the dosing cycle. In some examples, the corticosteroid is administered to the subject on the 1st, 8th, and 15th days of C1 during the pre-phase.

[0264] The corticosteroid can be administered by any suitable route of administration. In some examples, the corticosteroid is administered intravenously or orally to the subject. In some examples, the corticosteroid is administered intravenously to the subject.

[0265] In some examples, the corticosteroid is administered intravenously to the subject prior to administration of the bispecific antibody.

[0266] The corticosteroid can be administered at any suitable time prior to administration of the bispecific antibody, for example, about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours before administration of the bispecific antibody. In some examples, the corticosteroid is administered intravenously to the subject about 1 hour before administration of the bispecific antibody.

[0267] In some examples, the corticosteroid is dexamethasone or methylprednisolone.

[0268] In some examples, the corticosteroid is dexamethasone.

[0269] Dexamethasone can be administered at any suitable dosage, such as 1 mg to 100 mg. In some examples, dexamethasone is administered to the subject at a dosage of about 20 mg.

[0270] Methylprednisolone can be administered at any suitable dosage, such as 1 mg to 400 mg. In some examples, methylprednisolone is administered to the subject at a dosage of about 80 mg.

[0271] Any suitable bispecific antibody can be used, such as any bispecific antibody disclosed herein (e.g., Section H below).

[0272] In some examples, the bispecific antibody is cevostamab.

[0273] In some examples, the bispecific antibody and lenalidomide are administered to the subject simultaneously with one or more additional therapeutic agents. Any suitable additional therapeutic agent(s), including any disclosed herein, can be used.

[0274] In some examples, the bispecific antibody and / or lenalidomide are administered to the subject prior to the administration of one or more additional therapeutic agents.

[0275] In some examples, the bispecific antibody and / or lenalidomide are administered to the subject after the administration of one or more additional therapeutic agents.

[0276] In some examples, one or more additional therapeutic agents include an effective amount of tocilizumab.

[0277] In some examples, the subject has a CRS event, and the method further includes treating the symptoms of the CRS event while withholding treatment with the bispecific antibody.

[0278] In some examples, the method or treatment further comprises administering to the subject an effective amount of tocilizumab to treat a CRS event.

[0279] In some examples, the CRS event does not resolve or worsens within 24 hours after treating the symptoms of the CRS event, and the method further comprises administering to the subject one or more additional doses of tocilizumab to manage the CRS event.

[0280] In some examples, tocilizumab is administered to the subject by intravenous infusion.

[0281] In some examples, (a) the subject weighs 30 kg or more and tocilizumab is administered to the subject at a dose of 8 mg / kg, or (b) the subject weighs less than 30 kg and tocilizumab is administered to the subject at a dose of 12 mg / kg.

[0282] In some examples, tocilizumab is administered to the subject 2 hours prior to administration of the bispecific antibody.

[0283] In some examples, the one or more additional therapeutic agents include an effective amount of B cell maturation antigen (BCMA)-directed therapy, an additional immunomodulatory drug (IMiD), CD38-directed therapy, or any combination of the foregoing.

[0284] In some examples, the one or more additional therapeutic agents include an effective amount of acetaminophen or paracetamol.

[0285] Any suitable dose of acetaminophen or paracetamol may be used. In some examples, acetaminophen or paracetamol is administered to the subject at a dose of about 500 mg to about 1000 mg.

[0286] Acetaminophen or paracetamol may be administered by any suitable route of administration including any route of administration disclosed herein. In some examples, acetaminophen or paracetamol is administered orally to the subject.

[0287] In some examples, one or more additional therapeutic agents include an effective amount of diphenhydramine.

[0288] Any suitable dosage of diphenhydramine can be used. In some examples, diphenhydramine is administered to the subject at a dosage of about 25 mg to about 50 mg.

[0289] Diphenhydramine can be administered by any suitable route of administration, including any route of administration disclosed herein. In some examples, diphenhydramine is administered orally to the subject.

[0290] In another example, a method of treating a subject having a cancer with high-risk cytogenetic features (e.g., a blood cancer (e.g., a B-cell proliferative disorder (e.g., MM))), comprising administering to the subject sevosumab and lenalidomide, wherein (i) the subject has experienced PR or better after induction therapy, (ii) the subject has received ASCT within 100 days from the start of the method and / or does not have progressive disease, (iii) sevosumab and lenalidomide are administered to the patient as post-transplant maintenance therapy, and (iv) the high-risk cytogenetic features include one or more of the translocation events t(4;14) or t(14;16), del(17p) or 1q gain, sevosumab is provided herein.

[0291] Sevostamab for use in treating a subject having cancer (e.g., a blood cancer (e.g., a B cell proliferative disorder (e.g., MM))) having high-risk cytogenetic features, wherein the treatment comprises administering to the subject sevostamab and lenalidomide, (i) the subject has experienced PR or above after induction therapy, (ii) the subject has received ASCT within 100 days from the start of the method and / or does not have progressive disease, (iii) sevostamab and lenalidomide are administered to the patient as post-transplant maintenance therapy, and (iv) the high-risk cytogenetic features include one or more of the translocation events t(4;14) or t(14;16), del(17p) or 1q gain, are provided herein.

[0292] In another example, a method of treating a subject having a cancer with high-risk cytogenetic features (e.g., a blood cancer (e.g., a B-cell proliferative disorder (e.g., MM))), the method comprising administering to the subject a dosing regimen comprising sevosumab and lenalidomide in: (i) a pre-phase comprising a 28-day dosing cycle (C1); (ii) a first phase following the pre-phase, the first phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5), each dosing cycle of the first phase being a 28-day dosing cycle; and (iii) a second phase following the first phase, the second phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7), each dosing cycle of the second phase being a 28-day dosing cycle, wherein sevosumab is administered (i) on day 1 of C1 at a first step-up dose during the pre-phase and on day 8 of C1 as a second step-up dose during the pre-phase; (ii) at a target dose on day 15 of C1 during the pre-phase; (iii) at a target dose on days 1 and 15 of C1, C2, C3, C4, and C5 during the first phase; and (iv) at a target dose on day 1 of C1, C2, C3, C4, C5, C6, and C7 during the second phase, and lenalidomide is administered (i) on days 1 to 21 of C1 during the pre-phase; (ii) on days 1 to 21 of C1, C2, C3, C4, and C5 during the first phase; and (iii) on days 1 to 21 of C1, C2, C3, C4, C5, C6, and C7 during the second phase. A method is provided herein.

[0293] In another example, provided herein is sevosetamab for use in treating a subject having a cancer with high-risk cytogenetic features (e.g., a blood cancer (e.g., a B-cell proliferative disorder (e.g., MM))), the treatment comprising administering to the subject sevosetamab and lenalidomide in a dosing regimen comprising: (i) a pre-phase comprising a 28-day dosing cycle (C1); (ii) a first phase following the pre-phase, the first phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), and a fifth dosing cycle (C5), each dosing cycle of the first phase being a 28-day dosing cycle; and (iii) a second phase following the first phase, the second phase comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7), each dosing cycle of the second phase being a 28-day dosing cycle, wherein sevosetamab is administered (i) on day 1 of C1 at a first step-up dose during the pre-phase and on day 8 of C1 as a second step-up dose during the pre-phase; (ii) at a target dose on day 15 of C1 during the pre-phase; (iii) at a target dose on days 1 and 15 of C1, C2, C3, C4, and C5 during the first phase; and (iv) at a target dose on day 1 of C1, C2, C3, C4, C5, C6, and C7 during the second phase, and lenalidomide is administered (i) on days 1 to 21 of C1 during the pre-phase; (ii) on days 1 to 21 of C1, C2, C3, C4, and C5 during the first phase; and (iii) on days 1 to 21 of C1, C2, C3, C4, C5, C6, and C7 of the second phase to the subject, and sevosetamab is provided herein.

[0294] In some examples, (i) the subject has experienced PR or better after induction therapy, (ii) the subject has received ASCT within 100 days from the start of the method and / or does not have progressive disease, (iii) sevosumab and lenalidomide are administered to the patient as post-transplant maintenance therapy, and (iv) high-risk cytogenetic features include one or more of the translocation events t(4;14) or t(14;16), del(17p) or 1q gain.

[0295] In some examples, (i) the first step-up dose of sevosumab is 0.3 mg, (ii) the second step-up dose of sevosumab is 3.6 mg, (iii) the target dose of sevosumab is 90 mg to 198 mg including both end values, and (iv) lenalidomide is administered at a dose of 10 mg or 15 mg.

[0296] In some examples, the target dose is 90 mg.

[0297] In some examples, the target dose is 132 mg.

[0298] In some examples, the target dose is 160 mg.

[0299] ii. Single-step escalation dosing regimen In some aspects, the present invention provides a method of treating a subject having cancer (e.g., blood cancer (e.g., B cell proliferative disorder (e.g., MM (e.g., MM with high-risk cytogenetic features)))), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 and lenalidomide in a single-step escalation dosing regimen.

[0300] In some embodiments, the invention is a method of treating a subject having MM (e.g., MM with high-risk cytogenetic features), comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 and lenalidomide in a dosing regimen that includes at least a first dosing cycle, the first dosing cycle including a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, C1D1 being from about 0.05 mg to about 180 mg (e.g., from about 0.1 mg to about 160 mg, from about 0.5 mg to about 140 mg, from about 1 mg to about 120 mg, from about 1.5 mg to about 100 mg, from about 2.0 mg to about 80 mg, from about 2.5 mg to about 50 mg, from about 3.0 mg to about 25 mg, from about 3.0 mg to about 15 mg, from about 3.0 mg to about 10 mg, or from about 3.0 mg to about 5 mg), and C1D2 being from about 0.15 mg to about 1000 mg (e.g., from about 0.5 mg to about 800 mg, from about 1 mg to about 700 mg, from about 5 mg to about 500 mg, from about 10 mg to about 400 mg, from about 25 mg to about 300 mg, from about 40 mg to about 200 mg, from about 50 mg to about 100 mg, from about 75 mg to about 100 mg, or from about 85 mg to about 100 mg), and C1D2 being from about 0.15 mg to about 1000 mg (e.g., from about 0.5 mg to about 800 mg, from about 1 mg to about 700 mg, from about 5 mg to about 500 mg, from about 10 mg to about 400 mg, from about 25 mg to about 300 mg, from about 50 mg to about 250 mg, from about 100 mg to about 225 mg, or from about 150 mg to about 200 mg).

[0301] In some aspects, the present invention is a method of treating a subject having cancer (e.g., a blood cancer (e.g., a B cell proliferative disorder (e.g., MM (e.g., MM with high-risk cytogenetic features)))), comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 and lenalidomide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein (a) the first dosing cycle comprises a first dose (C1D1; cycle 1, dose 1) and a second dose of the bispecific antibody (C1D2; cycle 1, dose 2), C1D1 is less than C1D2, C1D1 is from about 0.05 mg to about 180 mg (e.g., from about 0.1 mg to about 160 mg, from about 0.5 mg to about 140 mg, from about 1 mg to about 120 mg, from about 1.5 mg to about 100 mg, from about 2.0 mg to about 80 mg, from about 2.5 mg to about 50 mg, from about 3.0 mg to about 25 mg, from about 3.0 mg to about 15 mg, from about 3.0 mg to about 10 mg, or from about 3.0 mg to about 5 mg), and C1D2 is from about 0.15 mg to about 1000 mg (e.g., from about 0.5 mg to about 800 mg, from about 1 mg to about 700 mg, from about 5 mg to about 500 mg, from about 10 mg to about 400 mg, from about 25 mg to about 300 mg, from about 40 mg to about 200 mg, from about 50 mg to about 100 mg, from about 75 mg to about 100 mg, or from about 85 mg to about 100 mg), and (b) the second dosing cycle comprises a single dose of the bispecific antibody (C2D1; cycle 2, dose 1), C2D1 is greater than or equal to C1D2, and is from about 0.15 mg to about 1000 mg (e.g., from about 0.5 mg to about 800 mg, from about 1 mg to about 700 mg, from about 5 mg to about 500 mg, from about 10 mg to about 400 mg, from about 25 mg to about 300 mg, from about 40 mg to about 200 mg, from about 50 mg to about 100 mg, from about 75 mg to about 100 mg, or from about 85 mg to about 100 mg).

[0302] In some embodiments, (a) C1D1 is from about 0.5 mg to about 19.9 mg (e.g., from about 1 mg to about 18 mg, from about 2 mg to about 15 mg, from about 3 mg to about 10 mg, from about 3.3 mg to about 6 mg, or from about 3.4 mg to about 4 mg, e.g., about 3 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.6 mg, 3.8 mg, 4 mg, 4.2 mg, 4.4 mg, 4.6 mg, 4.8 mg, 5 mg, 5.2 mg, 5.6 mg, 5.8 mg, 6 mg, 6.2 mg, 6.4 mg, 6.6 mg, 6.8 mg, 7 mg, 7.2 mg, 7.4 mg, 7.6 mg, 7.8 mg, 8 mg, 8.2 mg, 8.4 mg, 8.6 mg, 8.8 mg, 9 mg, 9.2 mg, 9.4 mg, 9.6 mg, 9.8 mg, 10 mg, 10.2 mg, 10.4 mg, 10.6 mg, 10.8 mg, 11 mg, 11.2 mg, 11.4 mg, 11.6 mg, 11.8 mg, 12 mg, 12.2 mg, 12.4 mg, 12.6 mg, 12.8 mg, 13 mg, 13.2 mg, 13.4 mg, 13.6 mg, 13.8 mg, 14 mg, 14.2 mg, 14.4 mg, 14.6 mg, 14.8 mg, 15 mg, 15.2 mg, 15.4 mg, 15.6 mg, 15.8 mg, 16 mg, 16.2 mg, 16.4 mg, 16.6 mg, 16.8 mg, 17 mg, 18.2 mg, 18.4 mg, 18.6 mg, 18.8 mg, 19 mg, 19.2 mg, 19.4 mg, 19.6 mg, or 19.8 mg), and (b) C1D2 is from about 20 mg to about 600 mg (e.g., from about 30 mg to 500 mg, from 40 mg to 400 mg, from 60 mg to 350 mg, from 80 mg to 300 mg, from 100 mg to 200 mg, or from 140 mg to 180 mg, e.g., about 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg).

[0303] In some embodiments, C1D1 is from about 1.2 mg to about 10.8 mg, and C1D2 is from about 80 mg to about 300 mg. In some embodiments, C1D1 is about 3.6 mg and C1D2 is about 198 mg. In some embodiments, C1D1 is 1.2 mg to 10.8 mg and C1D2 is 80 mg to 300 mg. In some embodiments, C1D1 is 3.6 mg and C1D2 is 90 mg. In some embodiments, C1D1 is 3.6 mg and C1D2 is 132 mg. In some embodiments, C1D1 is 3.6 mg and C1D2 is 160 mg. In some embodiments, C1D1 is 3.6 mg and C1D2 is 198 mg.

[0304] In other embodiments, C1D1 is 3.3 mg. In some embodiments, C1D1 is 3.3 mg and C1D2 is from 90 mg to 198 mg, such as 90 mg, 132 mg, 160 mg, or 198 mg.

[0305] In some cases, these methods described above may include a first dosing cycle of 3 weeks or 21 days. In some cases, the method may include administering C1D1 and C1D2 to a subject on the first and eighth days, respectively, of the first dosing cycle, or on or about those days.

[0306] iii. Two-step escalating dosing regimen In other embodiments, the present invention provides a method of treating a subject having cancer (e.g., a blood cancer (e.g., a B cell proliferative disorder (e.g., MM (e.g., MM with high-risk cytogenetic features)))), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 in a two-step escalating dosing regimen.

[0307] In some embodiments, the present disclosure is a method of treating a subject having cancer (e.g., MM (e.g., MM with high-risk cytogenetic features)), comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 and lenalidomide in a dosing regimen comprising at least a first dosing cycle, the first dosing cycle comprising a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, wherein C1D1 is from about 0.2 mg to about 0.4 mg (e.g., about 0.20 mg, 0.21 mg, 0.22 mg, 0.23 mg, 0.24 mg, 0.25 mg, 0.26 mg, 0.27 mg, 0.28 mg, 0.29 mg, 0.30 mg, 0.31 mg, 0.32 mg, 0.33 mg, 0.34 mg, 0.35 mg, 0.36 mg, 0.37 mg, 0.38 mg, 0.39 mg, or 0.40 mg), C1D2 is greater than C1D1, and C1D3 is greater than C1D2. In some embodiments, C1D1 is about 0.3 mg.

[0308] In some embodiments, C1D1 is from 0.2 mg to 0.4 mg (e.g., 0.20 mg, 0.21 mg, 0.22 mg, 0.23 mg, 0.24 mg, 0.25 mg, 0.26 mg, 0.27 mg, 0.28 mg, 0.29 mg, 0.30 mg, 0.31 mg, 0.32 mg, 0.33 mg, 0.34 mg, 0.35 mg, 0.36 mg, 0.37 mg, 0.38 mg, 0.39 mg, or 0.40 mg). In some embodiments, C1D1 is 0.3 mg.

[0309] In some aspects, the present disclosure provides a method of treating a subject having cancer (e.g., a blood cancer (e.g., a B-cell proliferative disorder (e.g., MM (e.g., MM with high-risk cytogenetic features)))), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 and lenalidomide in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, C1D1 is from about 0.01 mg to about 2.9 mg, C1D2 is from about 3 mg to about 19.9 mg, and C1D3 is from about 20 mg to about 600 mg.

[0310] In some aspects, the present invention provides a method of treating a subject having cancer (e.g., a blood cancer (e.g., a B-cell proliferative disorder (e.g., MM (e.g., MM with high-risk cytogenetic features)))), the method comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 and lenalidomide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, C1D1 and C1D2 are each less than C1D3, C1D1 is from about 0.01 mg to about 2.9 mg, C1D2 is from about 3 mg to about 19.9 mg, and C1D3 is from about 20 mg to about 600 mg; and (b) the second dosing cycle comprises a single dose (C2D1) of the bispecific antibody, C2D1 is greater than or equal to C1D3, and C2D1 is from about 20 mg to about 600 mg.

[0311] In some embodiments, C1D1 is from about 0.05 mg to about 2.5 mg, from about 0.1 mg to about 2 mg, from about 0.2 mg to about 1 mg, or from about 0.2 mg to about 0.4 mg (e.g., about 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, or 2.9 mg). In some embodiments, C1D1 is about 0.3 mg.

[0312] In some embodiments, C1D1 is 0.05 mg - 2.5 mg, 0.1 mg - 2 mg, 0.2 mg - 1 mg, or 0.2 mg - 0.4 mg (e.g., 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, or 2.9 mg). In some embodiments, C1D1 is 0.3 mg.

[0313] In some embodiments, C1D2 is from about 3 mg to about 19.9 mg (e.g., from about 3 mg to about 18 mg, from about 3.1 mg to about 15 mg, from about 3.2 mg to about 10 mg, from about 3.3 mg to about 6 mg, or from about 3.4 mg to about 4 mg, e.g., about 3 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.6 mg, 3.8 mg, 4 mg, 4.2 mg, 4.4 mg, 4.6 mg, 4.8 mg, 5 mg, 5.2 mg, 5.6 mg, 5.8 mg, 6 mg, 6.2 mg, 6.4 mg, 6.6 mg, 6.8 mg, 7 mg, 7.2 mg, 7.4 mg, 7.6 mg, 7.8 mg, 8 mg, 8.2 mg, 8.4 mg, 8.6 mg, 8.8 mg, 9 mg, 9.2 mg, 9.4 mg, 9.6 mg, 9.8 mg, 10 mg, 10.2 mg, 10.4 mg, 10.6 mg, 10.8 mg, 11 mg, 11.2 mg, 11.4 mg, 11.6 mg, 11.8 mg, 12 mg, 12.2 mg, 12.4 mg, 12.6 mg, 12.8 mg, 13 mg, 13.2 mg, 13.4 mg, 13.6 mg, 13.8 mg, 14 mg, 14.2 mg, 14.4 mg, 14.6 mg, 14.8 mg, 15 mg, 15.2 mg, 15.4 mg, 15.6 mg, 15.8 mg, 16 mg, 16.2 mg, 16.4 mg, 16.6 mg, 16.8 mg, 17 mg, 18.2 mg, 18.4 mg, 18.6 mg, 18.8 mg, 19 mg, 19.2 mg, 19.4 mg, 19.6 mg, or 19.8 mg). In some embodiments, C1D2 is from about 3.2 mg to about 10 mg. In some embodiments, C1D2 is about 3.6 mg. In other embodiments, C1D2 is about 3.3 mg.

[0314] In some embodiments, C1D2 is from 3 mg to 19.9 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, or from 3.4 mg to 4 mg, e.g., 3 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.6 mg, 3.8 mg, 4 mg, 4.2 mg, 4.4 mg, 4.6 mg, 4.8 mg, 5 mg, 5.2 mg, 5.6 mg, 5.8 mg, 6 mg, 6.2 mg, 6.4 mg, 6.6 mg, 6.8 mg, 7 mg, 7.2 mg, 7.4 mg, 7.6 mg, 7.8 mg, 8 mg, 8.2 mg, 8.4 mg, 8.6 mg, 8.8 mg, 9 mg, 9.2 mg, 9.4 mg, 9.6 mg, 9.8 mg, 10 mg, 10.2 mg, 10.4 mg, 10.6 mg, 10.8 mg, 11 mg, 11.2 mg, 11.4 mg, 11.6 mg, 11.8 mg, 12 mg, 12.2 mg, 12.4 mg, 12.6 mg, 12.8 mg, 13 mg, 13.2 mg, 13.4 mg, 13.6 mg, 13.8 mg, 14 mg, 14.2 mg, 14.4 mg, 14.6 mg, 14.8 mg, 15 mg, 15.2 mg, 15.4 mg, 15.6 mg, 15.8 mg, 16 mg, 16.2 mg, 16.4 mg, 16.6 mg, 16.8 mg, 17 mg, 18.2 mg, 18.4 mg, 18.6 mg, 18.8 mg, 19 mg, 19.2 mg, 19.4 mg, 19.6 mg, or 19.8 mg). In some embodiments, C1D2 is from 3.2 mg to 10 mg. In some embodiments, C1D2 is 3.6 mg. In other embodiments, C1D2 is 3.3 mg.

[0315] In some embodiments, C1D3 is from about 20 mg to about 600 mg (e.g., from about 30 mg to about 500 mg, from about 40 mg to about 400 mg, from about 60 mg to about 350 mg, from about 80 mg to about 300 mg, from about 100 mg to about 200 mg, or from about 140 mg to about 180 mg, e.g., about 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some embodiments, C1D3 is from about 80 mg to about 300 mg. In some embodiments, C1D3 is about 90 mg. In some embodiments, C1D3 is about 132 mg. In some embodiments, C1D3 is about 160 mg. In some embodiments, C1D3 is about 198 mg.

[0316] In some embodiments, C1D3 is 20 mg to 600 mg (e.g., 30 mg to 500 mg, 40 mg to 400 mg, 60 mg to 350 mg, 80 mg to 300 mg, 100 mg to 200 mg, or 140 mg to 180 mg, e.g., 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some embodiments, C1D3 is 80 mg to 300 mg. In some embodiments, C1D3 is about 90 mg. In some embodiments, C1D3 is about 132 mg. In some embodiments, C1D3 is about 160 mg. In some embodiments, C1D3 is about 198 mg.

[0317] In some embodiments, the method comprises only a single dosing cycle (e.g., a dosing cycle including C1D1, C1D2, and C1D3). In other embodiments, the dosing regimen further comprises a second dosing cycle comprising at least a single dose (C2D1) of the bispecific antibody. In some embodiments, C2D1 is greater than or equal to C1D3 and is from about 20 mg to about 600 mg (e.g., from about 30 mg to about 500 mg, from about 40 mg to about 400 mg, from about 60 mg to about 350 mg, from about 80 mg to about 300 mg, from about 100 mg to about 200 mg, or from about 140 mg to about 180 mg, e.g., about 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some embodiments, C2D1 is from about 80 mg to about 300 mg. In some embodiments, C2D1 is about 90 mg. In some embodiments, C2D1 is about 132 mg. In some embodiments, C2D1 is about 160 mg. In some embodiments, C2D1 is about 198 mg.

[0318] In some embodiments, C2D1 is from 20 mg to 600 mg (e.g., from 30 mg to 500 mg, from 40 mg to 400 mg, from 60 mg to 350 mg, from 80 mg to 300 mg, from 100 mg to 200 mg, or from 140 mg to 180 mg, e.g., 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some embodiments, C2D1 is from 80 mg to 300 mg. In some embodiments, C2D1 is 160 mg. In some embodiments, C2D1 is 159 mg.

[0319] Alternatively, in any of the above embodiments, C1D1 may be from about 0.01 mg to about 60 mg (e.g., from about 0.05 mg to about 50 mg, from about 0.01 mg to about 40 mg, from about 0.1 mg to about 20 mg, from about 0.1 mg to about 10 mg, from about 0.1 mg to about 5 mg, from about 0.1 mg to about 2 mg, from about 0.1 mg to about 1.5 mg, from about 0.1 mg to about 1.2 mg, from about 0.1 mg to about 0.5 mg, or from about 0.2 mg to about 0.4 mg, e.g., about 0.3 mg, e.g., 0.3 mg), C1D2 may be from about 0.05 mg to about 180 mg (e.g., from about 0.1 mg to about 160 mg, from about 0.5 mg to about 140 mg, from about 1 mg to about 120 mg, from about 1.5 mg to about 100 mg, from about 2.0 mg to about 80 mg, from about 2.5 mg to about 50 mg, from about 3.0 mg to about 25 mg, from about 3.0 mg to about 15 mg, from about 3.0 mg to about 10 mg, from about 3.0 mg to about 5 mg, or from about 3.0 mg to about 4.0 mg, e.g., about 3.6 mg, e.g., 3.6 mg), C1D3 may be from about 0.15 mg to about 1000 mg (e.g., from about 0.5 mg to about 800 mg, from about 1 mg to about 700 mg, from about 5 mg to about 500 mg, from about 10 mg to about 400 mg, from about 25 mg to about 300 mg, from about 40 mg to about 200 mg, from about 50 mg to about 190 mg, from about 140 mg to about 180 mg, or from about 150 mg to about 170 mg, e.g., about 160 mg, e.g., 160 mg), and in embodiments including a second dosing cycle, C2D1 may be from about 0.15 mg to about 1000 mg (e.g., from about 0.5 mg to about 800 mg, from about 1 mg to about 700 mg, from about 5 mg to about 500 mg, from about 10 mg to about 400 mg, from about 25 mg to about 300 mg, from about 40 mg to about 200 mg, from about 50 mg to about 190 mg, from about 140 mg to about 180 mg, or from about 150 mg to about 170 mg, e.g., about 160 mg, e.g., 160 mg).

[0320] In some cases, the length of the first dosing cycle is 4 weeks or 28 days. In other cases, the length of the first dosing cycle is 3 weeks or 21 days. In some cases, the method may include administering C1D1, C1D2, and C1D3 to the subject on the 1st, 8th, and 15th days, or on about those days, of the first dosing cycle respectively.

[0321] iv. Further dosing cycles In some cases, these methods described above may include a second dosing cycle of 4 weeks or 28 days. In other cases, the length of the first dosing cycle is 1 week or 7 days, 2 weeks or 14 days, or 3 weeks or 21 days. In some cases, the method may include administering C2D1 to the subject on day 1 of the second dosing cycle, or approximately that day.

[0322] 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 C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, and C19. 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 5 days to 30 days, e.g., 5 to 9 days, 7 to 11 days, 9 to 13 days, 11 to 15 days, 13 to 17 days, 15 to 19 days, 17 to 21 days, 19 to 23 days, 21 to 25 days, 23 to 27 days, or 25 to 30 days. In some cases, the length of each of the one or more additional dosing cycles is 3 weeks or 21 days. In some cases, each of the one or more additional dosing cycles includes a single dose of the bispecific antibody. In some aspects, the dose of the bispecific antibody in the one or more additional dosing cycles is equal to C2D1, e.g., about 20 mg to about 600 mg (e.g., about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 60 mg to about 350 mg, about 80 mg to about 300 mg, about 100 mg to about 200 mg, or about 140 mg to about 180 mg, e.g., about 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg).In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is about 90 mg. In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is about 132 mg. In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is about 160 mg. In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is about 198 mg. In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is equal to C2D1, for example, 20 mg to 600 mg (e.g., 30 mg to 500 mg, 40 mg to 400 mg, 60 mg to 350 mg, 80 mg to 300 mg, 100 mg to 200 mg, or 140 mg to 180 mg, e.g., 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is 90 mg. In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is 132 mg. In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is 160 mg. In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is 198 mg. In some cases, the method includes administering a single dose of the bispecific antibody to the subject on the first day or approximately the first day of one or more additional dosing cycles.

[0323] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject as a monotherapy.

[0324] B. Combination Therapy with Additional Therapeutic Agents In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide are administered to the subject together with one or more additional therapeutic agents, including any additional therapeutic agents disclosed herein.

[0325] i. Anti-CD38 antibody In some cases, bispecific anti-FcRH5 / anti-CD3 antibodies and lenalidomide are administered to a subject in combination with an anti-CD38 antibody. The anti-CD38 antibody can be administered to the subject by any suitable route of administration, such as intravenously (IV) or subcutaneously (SC). In some embodiments, the anti-CD38 antibody is daratumumab (e.g., daratumumab / rHuPH20). Daratumumab can be administered to the subject at a dose of about 900 mg to about 3600 mg (e.g., about 900 mg, about 950 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg). Daratumumab can be administered to the subject at a dose of about 1800 mg. In some embodiments, daratumumab is administered by intravenous infusion (e.g., an infusion over 3-5 hours) at a dose of 16 mg / kg once a week, once every two weeks, or once every four weeks. In some embodiments, daratumumab is administered by intravenous infusion (e.g., an infusion over 3-5 hours) at a dose of 16 mg / kg. In some embodiments, daratumumab is administered subcutaneously. In other embodiments, the anti-CD38 antibody is isatuximab. In some embodiments, the anti-CD38 antibody (e.g., daratumumab or isatuximab) is administered to the subject prior to the administration of the bispecific anti-FcRH5 / anti-CD3 antibody, e.g., one day prior to the administration of the bispecific anti-FcRH5 / anti-CD3 antibody. In some embodiments, the anti-CD38 antibody (e.g., daratumumab or isatuximab) is administered to the subject simultaneously with the administration of the bispecific anti-FcRH5 / anti-CD3 antibody.

[0326] ii. Corticosteroid In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide are administered to a subject in combination with a corticosteroid. The corticosteroid can be administered orally to the subject. The corticosteroid can be administered to the subject by any suitable route of administration, such as intravenously or subcutaneously. Any suitable corticosteroid, such as dexamethasone, methylprednisolone, prednisone, prednisolone, betamethasone, hydrocortisone, etc. can be used. In some embodiments, the corticosteroid is methylprednisolone. Methylprednisolone can be administered to the subject at a dose of about 80 mg. In other embodiments, the corticosteroid is dexamethasone. Dexamethasone can be administered to the subject at a dose of about 20 mg. In some embodiments, the corticosteroid (e.g., methylprednisolone or dexamethasone) is administered to the subject prior to the administration of the bispecific anti-FcRH5 / anti-CD3 antibody and / or lenalidomide, for example, 1 hour before the administration of the bispecific anti-FcRH5 / anti-CD3 antibody and / or lenalidomide. In some embodiments, the corticosteroid (e.g., methylprednisolone or dexamethasone) is administered to the subject about 1 day before the administration of the bispecific anti-FcRH5 / anti-CD3 antibody and / or lenalidomide. In some embodiments, the corticosteroid (e.g., methylprednisolone or dexamethasone) is administered to the subject simultaneously with the administration of the bispecific anti-FcRH5 / anti-CD3 antibody and / or lenalidomide.

[0327] iii. Immunomodulatory drug (IMiD) In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide are administered to a subject in combination with an additional immunomodulatory drug (IMiD). The IMiD can be administered to the subject by any suitable route of administration, for example, orally. The IMiD can be administered to the subject intravenously. The IMiD can be administered to the subject subcutaneously. In some embodiments, the IMiD is pomalidomide. Pomalidomide can be administered to the subject at a dose of about 4 mg. In some embodiments, the IMiD (e.g., pomalidomide) is administered to the subject prior to the administration of the bispecific anti-FcRH5 / anti-CD3 antibody and / or lenalidomide, for example, 1 hour prior to the administration of the bispecific anti-FcRH5 / anti-CD3 antibody and / or lenalidomide. In some embodiments, the IMiD (e.g., pomalidomide) is administered to the subject simultaneously with the administration of the bispecific anti-FcRH5 / anti-CD3 antibody and / or lenalidomide. In some embodiments, the IMiD (e.g., pomalidomide) is administered daily between doses of the bispecific anti-FcRH5 / anti-CD3 antibody and / or lenalidomide.

[0328] iv. Tocilizumab and Treatment of CRS In one case, the additional therapeutic agent is an effective amount of tocilizumab (ACTEMRA®). In some cases, the subject has a cytokine release syndrome (CRS) event (e.g., has a CRS event after treatment with the bispecific antibody, e.g., has a CRS event after C1D1, C1D2, C1D3, C2D1 of the bispecific antibody, or after an additional dose), and the method further includes treating the symptoms of the CRS event while withholding treatment with the bispecific antibody (e.g., treating the CRS event by administering an effective amount of tocilizumab to the subject). In some embodiments, tocilizumab is administered intravenously to the subject as a single dose of about 8 mg / kg. In some embodiments, the CRS event does not resolve or worsens within 24 hours after treating the symptoms of the CRS event, and the method further includes administering to the subject one or more additional doses of tocilizumab to manage the CRS event, for example, administering one or more additional doses of tocilizumab intravenously to the subject at a dose of about 8 mg / kg.

[0329] In some embodiments, treating the symptoms of a CRS event further comprises treatment with a high dose pressor agent (e.g., norepinephrine, dopamine, phenylephrine, epinephrine, or vasopressin and norepinephrine), such as described in Tables 2A and 2B.

[0330] In other cases, tocilizumab is administered as a premedication, e.g., to a subject prior to administration of a bispecific anti-FcRH5 / anti-CD3 antibody. In some cases, tocilizumab is administered as a premedication in Cycle 1, e.g., prior to the first dose of the bispecific antibody (C1D1), the second dose of the bispecific antibody (C1D2), and / or the third dose of the bispecific anti-FcRH5 / anti-CD3 antibody (C1D3). In some embodiments, tocilizumab is administered intravenously to a subject as a single dose of about 8 mg / kg.

[0331] v. Symptoms and Grading of CRS CRS can be graded according to the Modified Cytokine Release Syndrome Grading System established by Lee et al., Blood, 124:188-195, 2014 or Lee et al., Biol Blood Marrow Transplant, 25(4):625-638, 2019, as described in Table 2A. In addition to the diagnostic criteria, recommendations for the management of CRS based on its severity, including early intervention with corticosteroids and / or anti-cytokine therapy, are provided and are referenced in Tables 2A and 2B. [Table 2A] Lee 2014 Criteria: Lee et al., Blood, 124:188-195, 2014. ASTCT Consensus Grading: Lee et al., Biol Blood Marrow Transplant, 25(4):625-638, 2019. aLow-dose vasopressor: A single-dose vasopressor at a dose less than that shown in Table 2B. b High-dose vasopressor: As defined in Table 2B. * Fever is defined as a temperature of 38°C or higher not attributable to other causes. Subsequently, patients with CRS receive antipyretic or anti-cytokine therapy such as tocilizumab or steroids, but fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and / or hypoxia. † CRS grade is determined by more severe events: hypotension or hypoxia not attributable to other causes. For example, a patient with a body temperature of 39.5°C, hypotension requiring one vasopressor, and hypoxia requiring a low-flow nasal cannula is classified as having grade 3 CRS. ‡ A low-flow nasal cannula is defined as oxygen delivered at ≤6 L / min. Low flow also includes blow-by oxygen delivery sometimes used in pediatrics. A high-flow nasal cannula is defined as oxygen delivered at >6 L / min.

Table 2B

[0332] Mild to moderate symptoms of CRS and / or infusion-related reactions (IRR) can include symptoms such as fever, headache, and myalgia, and can be treated symptomatically with analgesics, antipyretics, and antihistamines as indicated. Severe or life-threatening symptoms of CRS and / or IRR, such as hypotension, tachycardia, dyspnea, or chest discomfort, should be actively treated with supportive and resuscitative therapies as indicated, including the use of high-dose corticosteroids, IV fluids, admission to the intensive care unit, and other supportive therapies. Severe CRS can be associated with other clinical sequelae such as disseminated intravascular coagulation syndrome, capillary leak syndrome, or macrophage activation syndrome (MAS). The standard treatment for severe or life-threatening CRS resulting from immune-based therapies has not been established; case reports and recommendations using anti-cytokine therapies such as tocilizumab have been published (Teachey et al., Blood, 121:5154-5157, 2013; Lee et al., Blood, 124:188-195, 2014; Maude et al., New Engl J Med, 371:1507-1517, 2014).

[0333] As shown in Table 2A, even moderate symptoms of CRS in subjects with extensive comorbidities should be closely monitored with consideration for admission to the intensive care unit and tocilizumab administration.

[0334] vi. Administration of tocilizumab as premedication In some embodiments, an effective amount of an interleukin-6 receptor (IL-6R) antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) is administered as a pre-medication (prophylaxis), e.g., administered to a subject prior to administration of a bispecific antibody (e.g., administered about 2 hours prior to administration of the bispecific antibody). Administration of tocilizumab as a pre-medication can reduce the frequency or severity of CRS. In some embodiments, tocilizumab is administered as a pre-medication in cycle 1, e.g., prior to the first dose (C1D1; cycle 1, dose 1), second dose (C1D2; cycle 1, dose 2), and / or third dose (C1D3; cycle 1, dose 3) of the bispecific antibody. In some embodiments, tocilizumab is administered intravenously to a subject as a single dose of about 1 mg / kg to about 15 mg / kg, e.g., about 4 mg / kg to about 10 mg / kg, e.g., about 6 mg / kg to about 10 mg / kg, e.g., about 8 mg / kg. In some embodiments, tocilizumab is administered intravenously to a subject as a single dose of about 8 mg / kg. In some embodiments, tocilizumab is administered intravenously to a subject as a single dose of about 8 mg / kg (maximum 800 mg) for patients weighing 30 kg or more, and as a dose of about 12 mg / kg for patients weighing less than 30 kg. Other anti-IL-6R antibodies that can be used in combination with tocilizumab include sarilumab, baliliximab (ALX-0061), SA-237, and variants thereof.

[0335] For example, in one embodiment, the bispecific antibody is co-administered with tocilizumab (ACTEMRA® / ROACTEMRA®), and the subject is first administered tocilizumab (ACTEMRA® / ROACTEMRA®) and then the bispecific antibody is administered separately (e.g., the subject is pre-treated with tocilizumab (ACTEMRA® / ROACTEMRA®)).

[0336] In some embodiments, the incidence of CRS (e.g., grade 1 CRS, grade 2 CRS, and / or grade 3+ CRS) is reduced in patients treated with tocilizumab as a premedication compared to patients not treated with tocilizumab as a premedication. In some embodiments, compared to patients not treated with tocilizumab as a premedication, patients treated with tocilizumab as a premedication require fewer interventions to treat CRS (e.g., less need for additional tocilizumab, IV fluids, steroids, or O2). In some embodiments, the CRS symptoms are less severe in patients treated with tocilizumab as a premedication compared to patients not treated with tocilizumab as a premedication (e.g., limited to fever and rigors).

[0337] vii. Tocilizumab administered to treat CRS In some embodiments, the subject experiences a CRS event during treatment with a therapeutic bispecific antibody, and an effective amount of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) is administered to manage the CRS event.

[0338] In some embodiments, the subject has a CRS event (e.g., has a CRS event after treatment with a bispecific antibody, e.g., has a CRS event after the first dose or a subsequent dose of a bispecific antibody), and the method further comprises treating the symptoms of the CRS event while withholding treatment with the bispecific antibody.

[0339] In some embodiments, the subject experiences a CRS event, and the method further comprises administering to the subject an effective amount of an interleukin-6 receptor (IL-6R) antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to manage the CRS event while withholding treatment with the bispecific antibody. In some embodiments, the IL-6R antagonist (e.g., tocilizumab) is administered intravenously to the subject as a single dose of about 1 mg / kg to about 15 mg / kg, e.g., about 4 mg / kg to about 10 mg / kg, e.g., about 6 mg / kg to about 10 mg / kg, e.g., about 8 mg / kg. In some embodiments, tocilizumab is administered intravenously to the subject as a single dose of about 8 mg / kg. Other anti-IL-6R antibodies that can be used in combination with tocilizumab include sarilumab, bobaliizumab (ALX-0061), SA-237, and variants thereof.

[0340] In some embodiments, the CRS event does not resolve or worsens within 24 hours after treating the symptoms of the CRS event, and the method further comprises administering to the subject one or more additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab) to manage the CRS event, e.g., administering one or more additional doses of tocilizumab intravenously to the subject at a dose of about 1 mg / kg to about 15 mg / kg, e.g., about 4 mg / kg to about 10 mg / kg, e.g., about 6 mg / kg to about 10 mg / kg, e.g., about 8 mg / kg. In some embodiments, one or more additional doses of tocilizumab are administered intravenously to the subject as a single dose of about 8 mg / kg.

[0341] In some embodiments, the method further comprises administering to the subject an effective amount of a corticosteroid. The corticosteroid can be administered intravenously to the subject. In other examples, the corticosteroid can be administered subcutaneously to the subject. In some embodiments, the corticosteroid is methylprednisolone. In some cases, methylprednisolone is administered in a single dose of about 1 mg / kg per day to about 5 mg / kg per day, for example, about 2 mg / kg per day. In some cases, the corticosteroid is dexamethasone. In some cases, dexamethasone is administered in a dose of about 10 mg (e.g., a single intravenous dose of about 10 mg) or a dose of about 0.5 mg / kg / day.

[0342] If the CRS event is not managed by the administration of an IL-6R antagonist (e.g., tocilizumab) alone, a corticosteroid, such as methylprednisolone or dexamethasone, may be administered to the subject. In some embodiments, treating the symptoms of the CRS event further comprises treating with a high-dose vasopressor (e.g., norepinephrine, dopamine, phenylephrine, epinephrine, or vasopressin and norepinephrine), as described, for example, in Tables 2A and 2B. Tables 3A and 3B further provide details regarding the tocilizumab treatment of severe or life-threatening CRS.

[0343] viii. Management of CRS events by grade The management of CRS events can be tailored based on the grade of CRS (Tables 2A and 3A) and the presence of coexisting diseases. Table 3A provides recommendations for the management of CRS syndrome by grade. Table 3B provides recommendations for the management of IRR syndrome by grade.

Table 3A

Table 3B

[0344] ix. Management of Grade 2 CRS events If the subject has a Grade 2 CRS event (e.g., a Grade 2 CRS event in the absence or minimal presence of comorbidities) after administration of the therapeutic bispecific antibody, the method may further comprise treating the symptoms of the Grade 2 CRS event while withholding treatment with the bispecific antibody. If the Grade 2 CRS event resolves to a Grade ≤ 1 CRS event for at least 3 consecutive days, the method may further comprise restarting treatment with the bispecific antibody without changing the dose. On the other hand, if the Grade 2 CRS event does not resolve within 24 hours after treating the symptoms of the Grade 2 CRS event or does not deteriorate to a Grade ≥ 3 event, the method may further comprise administering to the subject an effective amount of an interleukin-6 receptor (IL-6R) antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to manage the Grade 2 or Grade ≥ 3 CRS event. In some cases, tocilizumab is administered intravenously to the subject as a single dose of about 8 mg / kg. Other anti-IL-6R antibodies that may be used in combination with tocilizumab include sarilumab, balilixizumab (ALX-0061), SA-237, and variants thereof.

[0345] If the subject has a Grade 2 CRS event in the presence of a wide range of complications after administration of a therapeutic bispecific antibody, the method may further comprise administering a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to the subject and managing the Grade 2 CRS event while withholding treatment with the bispecific antibody. In some cases, the first dose of tocilizumab is administered intravenously to the subject at a dose of about 8 mg / kg. Other anti-IL-6R antibodies that can be used in combination with tocilizumab include sarilumab, bobaliizumab (ALX-0061), SA-237, and variants thereof. In some cases, if the Grade 2 CRS event resolves to a Grade ≤1 CRS event within two weeks, the method further comprises restarting treatment with the bispecific antibody at a reduced dose. In some cases, if the event occurs during or within 24 hours of the infusion, the reduced dose is 50% of the initial infusion rate of the previous cycle. On the other hand, if the Grade 2 CRS event does not resolve within 24 hours of treating the symptoms of the Grade 2 CRS event or does not deteriorate to a Grade ≥3 CRS event, the method may further comprise administering one or more (e.g., 1, 2, 3, 4, or 5 or more) additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab) to the subject to manage the Grade 2, or Grade ≥3 CRS event. In some specific cases, since the Grade 2 CRS event does not resolve within 24 hours of treating the symptoms of the Grade 2 CRS event or does not deteriorate to a Grade ≥3 CRS event, the method may further comprise administering one or more additional doses of tocilizumab to the subject to manage the Grade 2, or Grade ≥3 CRS event. In some cases, one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 1 mg / kg to about 15 mg / kg, such as about 4 mg / kg to about 10 mg / kg, such as about 6 mg / kg to about 10 mg / kg, such as about 8 mg / kg. In some cases, the method further comprises administering an effective amount of corticosteroid to the subject.Corticosteroids can be administered before, after, or simultaneously with one or more additional doses of tocilizumab or another anti-IL-6R antibody. In some cases, corticosteroids are administered intravenously to the subject. In some cases, the corticosteroid is methylprednisolone. In some cases, methylprednisolone is administered as a single dose of from about 1 mg / kg per day to about 5 mg / kg per day, for example, about 2 mg / kg per day. In some cases, the corticosteroid is dexamethasone. In some cases, dexamethasone is administered at a dose of about 10 mg (e.g., a single intravenous dose of about 10 mg) or at a dose of about 0.5 mg / kg / day.

[0346] x. Management of Grade 3 CRS Events If a subject has a grade 3 CRS event after administration of a therapeutic bispecific antibody, the method may further comprise administering a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to the subject and managing the grade 3 CRS event while withholding treatment with the bispecific antibody. In some cases, the first dose of tocilizumab is administered intravenously to the subject at a dose of about 8 mg / kg. Other anti-IL-6R antibodies that can be used in combination with tocilizumab include sarilumab, bavalirizumab (ALX-0061), SA-237, and variants thereof. In some cases, the subject recovers within 8 hours after treatment with the bispecific antibody (e.g., no fever, no pressor agents), and the method further comprises restarting treatment with the bispecific antibody at a reduced dose. In some cases, if the event occurs during or within 24 hours of the infusion, the reduced dose is 50% of the initial infusion rate of the previous cycle. In other cases, if the grade 3 CRS event does not resolve within 24 hours after treating the symptoms of the grade 3 CRS event or does not deteriorate into a grade 4 CRS event, the method may further comprise administering one or more (e.g., 1, 2, 3, 4, or 5 or more) additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab) to the subject to manage the grade 3 or grade 4 CRS event. In some specific cases, since the grade 3 CRS event does not resolve within 24 hours after treating the symptoms of the grade 3 CRS event or does not deteriorate into a grade 4 CRS event, the method further comprises administering one or more additional doses of tocilizumab to the subject to manage the grade 3 or grade 4 CRS event. In some cases, one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 1 mg / kg to about 15 mg / kg, such as about 4 mg / kg to about 10 mg / kg, such as about 6 mg / kg to about 10 mg / kg, such as about 8 mg / kg. In some cases, the method further comprises administering an effective amount of corticosteroid to the subject.Corticosteroids can be administered before, after, or simultaneously with one or more additional doses of tocilizumab or another anti-IL-6R antibody. In some cases, corticosteroids are administered intravenously to the subject. In some cases, the corticosteroid is methylprednisolone. In some cases, methylprednisolone is administered as a single dose of about 1 mg / kg per day to about 5 mg / kg per day, for example, about 2 mg / kg per day. In some cases, the corticosteroid is dexamethasone. In some cases, dexamethasone is administered at a dose of about 10 mg (e.g., a single intravenous dose of about 10 mg) or at a dose of about 0.5 mg / kg / day.

[0347] xi. Management of Grade 4 CRS events If a subject has a Grade 4 CRS event after administration of a therapeutic bispecific antibody, the method may further comprise administering a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to the subject, managing the Grade 4 CRS event, and continuously interrupting treatment with the bispecific antibody. In some cases, the first dose of tocilizumab is administered intravenously to the subject at a dose of about 8 mg / kg. Other anti-IL-6R antibodies that can be used in combination with tocilizumab include sarilumab, balilimumab (ALX-0061), SA-237, and variants thereof. In some cases, the Grade 4 CRS event may resolve within 24 hours after treating the symptoms of the Grade 4 CRS event. If the Grade 4 CRS event does not resolve within 24 hours after treating the symptoms of this Grade 4 CRS event, the method may further comprise administering one or more additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to the subject to manage the Grade 4 CRS event. In some specific cases, the Grade 4 CRS event does not resolve within 24 hours after treating the symptoms of the Grade 4 CRS event, and the method further comprises administering one or more (e.g., 1, 2, 3, 4, or 5 or more) additional doses of tocilizumab to the subject to manage the Grade 4 CRS event. In some cases, one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 1 mg / kg to about 15 mg / kg, such as about 4 mg / kg to about 10 mg / kg, such as about 6 mg / kg to about 10 mg / kg, such as about 8 mg / kg. In some cases, the method further comprises administering an effective amount of a corticosteroid to the subject. The corticosteroid can be administered before, after, or simultaneously with one or more additional doses of tocilizumab or another anti-IL-6R antibody. In some cases, the corticosteroid is administered intravenously to the subject. In some cases, the corticosteroid is methylprednisolone.In some cases, methylprednisolone is administered as a single dose of from about 1 mg / kg per day to about 5 mg / kg per day, for example, about 2 mg / kg per day. In some cases, the corticosteroid is dexamethasone. In some cases, dexamethasone is administered at a dose of about 10 mg (for example, a single intravenous dose of about 10 mg) or at a dose of about 0.5 mg / kg / day.

[0348] xii. Acetaminophen or paracetamol In another case, the additional therapeutic agent is an effective amount of acetaminophen or paracetamol. Acetaminophen or paracetamol may be administered orally to the subject, for example, at a dose of about 500 mg to about 1000 mg. In some embodiments, acetaminophen or paracetamol is administered to the subject as a premedication, for example, prior to administration of the bispecific anti-FcRH5 / anti-CD3 antibody.

[0349] xiii. Diphenhydramine In another case, the additional therapeutic agent is an effective amount of diphenhydramine. Diphenhydramine may be administered orally to the subject, for example, at a dose of about 25 mg to about 50 mg. In some embodiments, diphenhydramine is administered to the subject as a premedication, for example, prior to administration of the bispecific anti-FcRH5 / anti-CD3 antibody.

[0350] xiv. Anti-myeloma agent In another case, the additional therapeutic agent is an effective amount of an anti-myeloma agent, for example, an anti-myeloma agent that enhances and / or complements T cell-mediated killing of myeloma cells. The anti-myeloma agent can be, for example, pomalidomide, daratumumab, and / or B cell maturation antigen (BCMA)-directed therapy (for example, an antibody-drug conjugate (BCMA-ADC) targeting BCMA). In some embodiments, the anti-myeloma agent is administered in 4-week cycles.

[0351] xv. Other combination therapies In some embodiments, the one or more additional therapeutic agents include a PD-1 axis-binding antagonist, an immunomodulatory agent, an anti-tumor agent, a chemotherapeutic agent, a growth inhibitor, an anti-angiogenic agent, radiation therapy, a cytotoxic agent, a cell-based therapy, or a combination thereof.

[0352] xvi. PD-1 axis-binding antagonist In some embodiments, the one or more additional therapeutic agents include a PD-1 axis-binding antagonist. The PD-1 axis-binding antagonist can include a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist. Any suitable PD-1 axis-binding antagonist can be used.

[0353] In some cases, the PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners. In other cases, the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1. In still other cases, the PD-L1 binding antagonist inhibits the binding of PD-L1 to B7-1. In some cases, the PD-L1 binding antagonist inhibits the binding of PD-L1 to both PD-1 and B7-1. The PD-L1 binding antagonist can be, but is not limited to, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule. In some cases, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 (e.g., GS-4224, INCB 086550, MAX-10181, INCB 090244, CA-170, or ABSK 041). In some cases, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and VISTA. In some cases, the PD-L1 binding antagonist is CA-170 (also known as AUPM-170). In some cases, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and TIM3. In some cases, the small molecule is a compound described in International Publication No. WO 2015 / 033301 and / or WO 2015 / 033299.

[0354] In some cases, the PD-L1 binding antagonist is an anti-PD-L1 antibody. A variety of anti-PD-L1 antibodies are contemplated and described herein. In any of the examples herein, the isolated anti-PD-L1 antibody can bind to human PD-L1, such as human PD-L1 as shown by UniProtKB / Swiss-Prot accession number Q9NZQ7-1, or a variant thereof. In some cases, the anti-PD-L1 antibody can inhibit the binding between PD-L1 and PD-1 and / or between PD-L1 and B7-1. In some cases, the anti-PD-L1 antibody is a monoclonal antibody. In some cases, the anti-PD-L1 antibody is an antibody fragment selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some cases, the anti-PD-L1 antibody is a humanized antibody. In some cases, the anti-PD-L1 antibody is a human antibody. Exemplary anti-PD-L1 antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001, enoblituzumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosibelimab, 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 cases, the anti-PD-L1 antibody is atezolizumab. Examples of anti-PD-L1 antibodies useful in the methods of the present invention and methods of making them are described in International Patent Application Publication No. 2010 / 077634 and U.S. Patent No. 8,217,149, each of which is incorporated herein by reference in its entirety.

[0355] In some cases, the anti-PD-L1 antibody is avelumab (CAS Registry Number: 1537032-82-8). Avelumab, also known as MSB0010718C, is a human monoclonal IgG1 anti-PD-L1 antibody (Merck KGaA, Pfizer).

[0356] In some cases, the anti-PD-L1 antibody is durvalumab (CAS Registry Number: 1428935-60-7). Durvalumab, also known as MEDI4736, is an Fc-optimized human monoclonal IgG1 kappa anti-PD-L1 antibody (MedImmune, AstraZeneca) described in International Publication No. WO 2011 / 066389 and U.S. Patent Application Publication No. US 2013 / 034559.

[0357] In some cases, the anti-PD-L1 antibody is MDX-1105 (Bristol Myers Squibb). MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in International Publication No. WO 2007 / 005874.

[0358] In some cases, the anti-PD-L1 antibody is LY3300054 (Eli Lilly).

[0359] In some cases, the anti-PD-L1 antibody is STI-A1014 (Sorrento). STI-A1014 is a human anti-PD-L1 antibody.

[0360] In some cases, the anti-PD-L1 antibody is KN035 (Suzhou Alphamab). KN035 is a single domain antibody (dAB) generated from a camelid phage display library.

[0361] In some cases, the anti-PD-L1 antibody is composed of a cleavable site or linker that, when cleaved (e.g., by proteases in the tumor microenvironment), activates the antibody antigen-binding domain to enable binding to its antigen, e.g., by removing a non-binding steric site. In some cases, the anti-PD-L1 antibody is CX-072 (CytomX Therapeutics).

[0362] In some cases, the anti-PD-L1 antibody comprises six HVR sequences (e.g., three heavy chain HVRs and three light chain HVRs), and / or a heavy chain variable domain and a light chain variable domain from an anti-PD-L1 antibody described in US Patent Application Publication No. 20160108123, International Publication No. 2016 / 000619, International Publication No. 2012 / 145493, US Patent No. International Publication No. 9,205,148, International Publication No. 2013 / 181634, or International Publication No. 2016 / 061142.

[0363] In some cases, the PD-1 axis-binding antagonist is a PD-1-binding antagonist. For example, in some cases, the PD-1-binding antagonist inhibits binding to one or more of its ligand-binding partners of PD-1. In some cases, the PD-1-binding antagonist inhibits the binding of PD-1 to PD-L1. In other cases, the PD-1-binding antagonist inhibits the binding of PD-1 to PD-L2. In still other cases, the PD-1-binding antagonist inhibits the binding of PD-1 to both PD-L1 and PD-L2. The PD-1-binding antagonist can be, but is not limited to, an antibody, its antigen-binding fragment, an immunoadhesin, a fusion protein, an oligopeptide or a small molecule. In some cases, the PD-1-binding antagonist is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1-binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., the Fc region of an immunoglobulin sequence)). For example, in some cases, the PD-1-binding antagonist is an Fc fusion protein. In some cases, the PD-1-binding antagonist is AMP-224. AMP-224, also known as B7-DCIg, is a PD-L2-Fc fusion soluble receptor described in WO 2010 / 027827 and WO 2011 / 066342. In some cases, the PD-1-binding antagonist is a peptide or a small molecule compound. In some cases, the PD-1-binding antagonist is AUNP-12 (Pierre Fabre / Aurigene). See, for example, WO 2012 / 168944, WO 2015 / 036927, WO 2015 / 044900, WO 2015 / 033303, WO 2013 / 144704, WO 2013 / 132317 and WO 2011 / 161699. In some cases, the PD-1-binding antagonist is a small molecule that inhibits PD-1.

[0364] In some cases, the PD-1 binding antagonist is an anti-PD-1 antibody. A variety of anti-PD-1 antibodies can be utilized in the methods and uses disclosed herein. In any of the examples herein, the PD-1 antibody can bind to human PD-1 or a variant thereof. In some cases, the anti-PD-1 antibody is a monoclonal antibody. In some cases, the anti-PD-1 antibody is an antibody fragment selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some cases, the anti-PD-1 antibody is a humanized antibody. In other cases, the anti-PD-1 antibody is a human antibody. Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (semiplimab), BGB-108, prolegozumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanelimab, pemprilimab, CS1003, HLX10, SCT-I10A, zinberelimab, balsilimab, genolimzumab, BI 754091, cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, and hAb21.

[0365] In some cases, the anti-PD-1 antibody is nivolumab (CAS Registry Number: 946414-94-4). Nivolumab (Bristol-Myers Squibb / Ono), also known as MDX-1106-04, MDX-1106, ONO-4538, BMS-936558, and OPDIVO® is an anti-PD-1 antibody described in WO 2006 / 121168.

[0366] In some cases, the anti-PD-1 antibody is pembrolizumab (CAS Registry Number: 1374853-91-4). Pembrolizumab (Merck) is also known as MK-3475, Merck 3475, lambrolizumab, KEYTRUDA®, and SCH-900475, and is the anti-PD-1 antibody described in International Publication No. WO 2009 / 114335.

[0367] In some cases, the anti-PD-1 antibody is MEDI-0680 (AMP-514; AstraZeneca). MEDI-0680 is a humanized IgG4 anti-PD-1 antibody.

[0368] In some cases, the anti-PD-1 antibody is PDR001 (CAS Registry Number 1859072-53-9; Novartis). PDR001 is a humanized IgG4 anti-PD-1 antibody that blocks the binding of PD-L1 and PD-L2 to PD-1.

[0369] In some cases, the anti-PD-1 antibody is REGN2810 (Regeneron). REGN2810 is a human anti-PD-1 antibody.

[0370] In some cases, the anti-PD-1 antibody is BGB-108 (BeiGene).

[0371] In some cases, the anti-PD-1 antibody is BGB-A317 (BeiGene).

[0372] In some cases, the anti-PD-1 antibody is JS-001 (Shanghai Junshi). JS-001 is a humanized anti-PD-1 antibody.

[0373] In some cases, the anti-PD-1 antibody is STI-A1110 (Sorrento). STI-A1110 is a human anti-PD-1 antibody.

[0374] In some cases, the anti-PD-1 antibody is INCSHR-1210 (Incyte). INCSHR-1210 is a human IgG4 anti-PD-1 antibody.

[0375] In some cases, the anti-PD-1 antibody is PF-06801591 (Pfizer). In some cases, the anti-PD-1 antibody is TSR-042 (also known as ANB 011; Tesaro / AnaptysBio).

[0376] In some cases, the anti-PD-1 antibody is AM 0001 (ARMO Biosciences).

[0377] In some cases, the anti-PD-1 antibody is ENUM 244C8 (Enumeral Biomedical Holdings). ENUM244C8 is an anti-PD-1 antibody that inhibits PD-1 function without blocking the binding of PD-L1 to PD-1.

[0378] In some cases, the anti-PD-1 antibody is ENUM388D4 (Enumeral Biomedical Holdings). ENUM388D4 is an anti-PD-1 antibody that competitively inhibits the binding of PD-L1 to PD-1.

[0379] In some cases, the anti-PD-1 antibody comprises six HVR sequences (e.g., three heavy chain HVRs and three light chain HVRs) and / or the heavy chain variable domain and the light chain variable domain derived from an anti-PD-1 antibody described in WO 2015 / 112800, WO 2015 / 112805, WO 2015 / 112900, US 20150210769, WO 2016 / 089873, WO 2015 / 035606, WO 2015 / 085847, WO 2014 / 206107, WO 2012 / 145493, US 9,205,148, WO 2015 / 119930, WO 2015 / 119923, WO 2016 / 032927, WO 2014 / 179664, WO 2016 / 106160, and WO 2014 / 194302.

[0380] In some cases, the PD-1 axis binding antagonist is a PD-L2 binding antagonist. In some cases, the PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its ligand binding partner. In one specific aspect, the PD-L2 binding ligand partner is PD-1. The PD-L2 binding antagonist can be, but is not limited to, an antibody, its antigen-binding fragment, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule.

[0381] In some cases, the PD-L2 binding antagonist is an anti-PD-L2 antibody. In any of the examples herein, the anti-PD-L2 antibody can bind to human PD-L2 or a variant thereof. In some cases, the anti-PD-L2 antibody is a monoclonal antibody. In some cases, the anti-PD-L2 antibody is an antibody fragment selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some cases, the anti-PD-L2 antibody is a humanized antibody. In other cases, the anti-PD-L2 antibody is a human antibody. In still further specific embodiments, the anti-PD-L2 antibody has reduced or minimal effector function. In still further specific embodiments, the minimal effector function is due to an "effector-less Fc mutation" or an aglycosylation mutation. In still further cases, the effector-less Fc mutation is an N297A or D265A / N297A substitution within the constant region. In some cases, the isolated anti-PD-L2 antibody is glycosylated.

[0382] xvii. Growth inhibitor In some embodiments, the one or more additional therapeutic agents include a growth inhibitor. Exemplary growth inhibitors include agents that inhibit the progression of the cell cycle outside of the S phase, such as agents that induce G1 arrest (e.g., DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, or araC), or M phase arrest agents (e.g., vincristine, vinblastine, taxanes (e.g., paclitaxel and docetaxel), doxorubicin, epirubicin, daunorubicin, etoposide, or bleomycin).

[0383] xviii. Radiation therapy In some embodiments, one or more additional therapeutic agents include radiation therapy. Radiation therapy may involve using directed gamma or beta rays to induce sufficient damage to cells to limit their ability to function normally or to completely destroy them. A typical treatment is given as a single dose, and typical dosages range from 10 to 200 units (gray) per day.

[0384] xix. Cytotoxic agents In some embodiments, the additional therapeutic agent is a cytotoxic agent, e.g., a substance that inhibits or prevents cell function and / or causes cell death or cell destruction. Cytotoxic agents include radioisotopes (e.g., radioisotopes of At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 , and radioisotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitors; enzymes and their fragments, e.g., nucleolytic enzymes; antibiotics; toxins such as low molecular weight toxins or enzymatically active toxins derived from bacteria, fungi, plants or animals (including fragments and / or variants thereof); and anti-tumor or anti-cancer agents, but are not limited thereto.

[0385] xx. Additional anti-cancer therapies In some cases, the method further comprises administering to the patient an effective amount of an additional therapeutic agent. In some cases, the additional therapeutic agent is selected from the group consisting of an anti-neoplastic agent, a chemotherapeutic agent, a growth inhibitor, an anti-angiogenic agent, radiation therapy, a cytotoxic agent, and combinations thereof. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with chemotherapy or a chemotherapeutic agent. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with a radiation therapy agent. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with a targeted therapy or a targeted therapeutic agent. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with immunotherapy or an immunotherapeutic agent, such as a monoclonal antibody. In some cases, the additional therapeutic agent is an agonist directed against a co-stimulatory molecule. In some cases, the additional therapeutic agent is an antagonist directed against a co-inhibitory molecule.

[0386] Although not wishing to be bound by theory, it is thought that enhancing T cell stimulation, by promoting co-stimulatory molecules or inhibiting co-inhibitory molecules, may promote tumor cell death and thereby treat or delay cancer progression. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an agonist directed against a co-stimulatory molecule. In some cases, the co-stimulatory molecules that are activated may include CD40, CD226, CD28, OX40, GITR, CD137, CD27, HVEM, or CD127. In some cases, the agonist for a co-stimulatory molecule is an agonist antibody that binds to CD40, CD226, CD28, OX40, GITR, CD137, CD27, HVEM, or CD127. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an antagonist directed against a co-inhibitory molecule. In some cases, the co-inhibitory molecules may include CTLA-4 (also known as CD152), TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO, TIGIT, MICA / B, or arginase. In some cases, the antagonist for a co-inhibitory molecule is an antagonist antibody that binds to CTLA-4, TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO, TIGIT, MICA / B, or arginase.

[0387] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an antagonist to CTLA-4 (also known as CD152), such as a blocking antibody. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with ipilimumab (also known as MDX-010, MDX-101, or YERVOY®). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with tremelimumab (also known as ticilimumab or CP-675,206). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an antagonist directed to B7-H3 (also known as CD276), such as a blocking antibody. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with MGA271. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an antagonist directed to TGF-beta, such as metelimumab (also known as CAT-192), fresolimumab (also known as GC1008), or LY2157299.

[0388] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with a treatment that includes adoptive transfer of T cells expressing a chimeric antigen receptor (CAR), such as cytotoxic T cells or CTLs. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with a treatment that includes adoptive transfer of T cells that include a dominant negative TGF beta receptor, such as a dominant negative TGF beta type II receptor. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with a treatment that includes the HERCREEM protocol (see, for example, ClinicalTrials.gov Identifier NCT00889954).

[0389] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an agonist directed against CD137 (also known as TNFRSF9, 4-1BB, or ILA), such as an activating antibody. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with urelumab (also known as BMS-663513). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an agonist directed against CD40, such as an activating antibody. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with CP-870893. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an agonist directed against OX40 (also known as CD134), such as an activating antibody. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an anti-OX40 antibody (e.g., AgonOX). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an agonist directed against CD27, such as an activating antibody. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with CDX-1127. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an antagonist against indoleamine-2,3-dioxygenase (IDO). In some cases, the IDO antagonist is 1-methyl-D-tryptophan (also known as 1-D-MT).

[0390] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an antibody-drug conjugate. In some cases, the antibody-drug conjugate comprises mertansine or monomethyl auristatin E (MMAE). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an anti-NaPi2b antibody-MMAE conjugate (also known as DNIB0600A or RG7599). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with trastuzumab emtansine (T-DM1, ado-trastuzumab emtansine, or KADCYLA®, also known as Genentech). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with DMUC5754A. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an antibody-drug conjugate that targets the endothelin B receptor (EDNBR), for example, an antibody directed against EDNBR conjugated to MMAE.

[0391] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an anti-angiogenic agent. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an antibody against VEGF, such as VEGF-A. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with bevacizumab (AVASTIN®, also known as Genentech). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an antibody against angiopoietin 2 (also known as Ang2). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with MEDI3617.

[0392] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an anti-neoplastic agent. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an agent that targets CSF-1R (also known as M-CSFR or CD115). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with anti-CSF-1R (also known as IMC-CS4). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with interferon, such as interferon alpha or interferon gamma. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with Roferon-A (also known as recombinant interferon alpha-2a). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with GM-CSF (also known as recombinant human granulocyte macrophage colony stimulating factor, rhu GM-CSF, sargramostim, or LEUKINE®). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with IL-2 (also known as aldesleukin or PROLEUKIN®). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with IL-12. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an antibody that targets CD20. In some cases, the antibody that targets CD20 is obinutuzumab (also known as GA101 or GAZYVA®) or rituximab. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an antibody that targets GITR. In some cases, the antibody that targets GITR is TRX518.

[0393] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with a cancer vaccine. In some cases, the cancer vaccine is a peptide cancer vaccine, and in some cases, an individualized peptide vaccine. In some cases, the peptide cancer vaccine is a multivalent long peptide vaccine, a multipeptide vaccine, a peptide cocktail vaccine, a hybrid peptide vaccine, or a peptide-pulsed dendritic cell vaccine (see, e.g., Yamada et al., Cancer Sci. 104:14-21, 2013). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an adjuvant. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with a treatment comprising a TLR agonist, such as Poly-ICLC (also known as HILTONOL®), LPS, MPL, or CpG ODN. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with tumor necrosis factor (TNF) alpha. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with IL-1. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with HMGB1. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an IL-10 antagonist. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an IL-4 antagonist. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an IL-13 antagonist. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an HVEM antagonist. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an ICOS agonist, for example, by administration of ICOS-L, or in combination with an agonist antibody directed against ICOS.In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with a treatment targeting CX3CL1. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with a treatment targeting CXCL9. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with a treatment targeting CXCL10. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with a treatment targeting CCL5. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an LFA-1 or ICAM1 agonist. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with a selectin agonist.

[0394] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with a targeted therapy. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an inhibitor of B-Raf. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with vemurafenib (also known as ZELBORAF®). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with dabrafenib (also known as TAFINLAR®). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with erlotinib (also known as TARCEVA®). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an inhibitor of MEK, such as MEK1 (also known as MAP2K1) or MEK2 (also known as MAP2K2). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with cobimetinib (also known as GDC-0973 or XL-518). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with trametinib (also known as MEKINIST®). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an inhibitor of K-Ras. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an inhibitor of c-Met. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with onartuzumab (also known as MetMAb). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an inhibitor of Alk. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with AF802 (also known as CH5424802 or alectinib).In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an inhibitor of phosphatidylinositol 3-kinase (PI3K). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with BKM120. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with idelalisib (also known as GS-1101 or CAL-101). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with perifosine (also known as KRX-0401). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an inhibitor of Akt. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with MK2206. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with GSK690693. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with GDC-0941. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with an inhibitor of mTOR. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with sirolimus (also known as rapamycin). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with temsirolimus (also known as CCI-779 or TORISEL®). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with everolimus (also known as RAD001). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with ridafolimus (also known as AP-23573, MK-8669, or deforolimus). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with OSI-027.In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with AZD8055. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with INK128. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with a dual PI3K / mTOR inhibitor. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with XL765. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with GDC-0980. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with BEZ235 (also known as NVP-BEZ235). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with BGT226. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with GSK2126458. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with PF-04691502. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with PF-05212384 (also known as PKI-587).

[0395] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide may be administered in combination with a chemotherapeutic agent. A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer. Exemplary chemotherapeutic agents include erlotinib (TARCEVA®, Genentech / OSI Pharm.), antihormonal agents that act to modulate or inhibit the hormonal action on tumors such as antiestrogens and selective estrogen receptor modulators (SERMs), for example alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), or trastuzumab (HERCEPTIN®, Genentech) and other antibodies; EGFR inhibitors (EGFR antagonists), tyrosine kinase inhibitors, but are not limited thereto, and chemotherapeutic agents also include non-steroidal anti-inflammatory drugs (NSAIDs) having analgesic, antipyretic and anti-inflammatory effects.

[0396] When the methods described herein involve combination therapies such as the above-described specific combination therapy, etc., the combination therapy includes co-administration of the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide with one or more additional therapeutic agents, and such co-administration may be co-administration (two or more therapeutic agents are included in the same formulation, or separate formulations), or separate administrations, and in this case, administration of the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide can occur before, simultaneously with, and / or after administration of the additional therapeutic agent(s). In one embodiment, administration of the bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide, and administration of the additional therapeutic agent, or exposure to radiation therapy, can occur within about one month of each other, or within about one, two, three, four, five or six days of each other, or within about one week, two weeks or three weeks of each other.

[0397] In some embodiments, the subject does not have an increased risk of CRS (e.g., has not experienced grade 3+ CRS during treatment with a bispecific antibody or CAR-T therapy; does not have detectable circulating plasma cells; and / or does not have extensive extramedullary disease).

[0398] C. Cancer Any of the methods of the invention described herein may be useful for treating cancer (e.g., blood cancer (e.g., B cell proliferative disorder (e.g., MM (e.g., MM with high-risk cytogenetic features)))). In some embodiments, the subject's cancer has one or more high-risk cytogenetic features. In some examples, the high-risk cytogenetic features include one or more of the translocation events t(4;14) or t(14;16), del(17p), or 1q gain.

[0399] Other examples of B cell proliferative disorders / malignancies that may be amenable to treatment with bispecific anti-FcRH5 / anti-CD3 antibodies according to the methods described herein include non-Hodgkin lymphomas (NHL) such as diffuse large B cell lymphoma (DLBCL), which can be recurrent or refractory, and other cancers, including but not limited to these other cancers are germinal center B cell-like (GCB) diffuse large B cell lymphoma (DLBCL), activated B cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), small lymphocyte leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenström macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt lymphoma (BL), B cell prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma / leukemia, unclassifiable, diffuse red pulp small B cell lymphoma, hairy cell leukemia variant, Waldenström macroglobulinemia, heavy chain disease, alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasmacytic myeloma, solitary plasmacytoma of bone, extramedullary plasmacytoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), nodal marginal zone lymphoma, pediatric nodal marginal zone lymphoma, pediatric follicular lymphoma, primary cutaneous follicle center lymphoma, T cell / histiocyte-rich large B cell lymphoma, primary CNS DLBCL, primary cutaneous DLBCL, lower extremity type, elderly EBV-positive DLBCL, chronic inflammation-related DLBCL, lymphomatoid granulomatosis, mediastinal (thymic) primary B cell large cell lymphoma, intravascular large B cell lymphoma, ALK-positive large B cell lymphoma, plasmablastic lymphoma, large B cell lymphoma due to HHV8-related multicentric Castleman disease, primary effusion lymphoma: unclassifiable B cell lymphoma with intermediate features between DLBCL and Burkitt lymphoma, and unclassifiable B cell lymphoma with intermediate features between DLBCL and classical Hodgkin lymphoma.Further examples of B cell proliferative disorders include, but are not limited to, multiple myeloma (MM); low grade / follicular NHL; small lymphocytic (SL) NHL; intermediate grade / follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphocytic NHL; high grade small non-cleaved cell NHL; large tumor lesion NHL; AIDS-related lymphoma; and acute lymphoblastic leukemia (ALL); chronic myelogenous leukemia; and post-transplant lymphoproliferative disorder (PTLD). Further examples of cancers include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and lymphoid malignancies including leukemia or B cell lymphoma. More specific examples of such cancers include, but are not limited to, low grade / follicular NHL; small lymphocytic (SL) NHL; intermediate grade / follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphocytic NHL; high grade small non-cleaved cell NHL; large tumor lesion NHL; AIDS-related lymphoma; and acute lymphoblastic leukemia (ALL); chronic myelogenous leukemia; and post-transplant lymphoproliferative disorder (PTLD). Solid tumors that may be amenable to treatment with a bispecific anti-FcRH5 / anti-CD3 antibody according to the methods described herein include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and lung cancer including squamous cell carcinoma of the lung, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, and gastric cancer (including gastric cancer or stomach cancer) including gastrointestinal stromal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urological cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial carcinoma or uterine carcinoma, salivary gland carcinoma, kidney cancer or renal carcinoma, prostate cancer, vulvar cancer, thyroid cancer, liver cancer species, anal carcinoma, penile carcinoma, melanoma, superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanoma, nodular melanoma, as well as nevus syndrome, edema (such as those associated with brain tumors), Meigs syndrome, brain, as well as head and neck cancer, and abnormal blood vessel proliferation associated with related metastases.In certain embodiments, cancers suitable for treatment with the antibodies disclosed herein 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.

[0400] D. Prior anticancer therapy In some embodiments, the subject has been previously treated for cancer (e.g., blood cancer (e.g., B cell proliferative disorder (e.g., MM (e.g., MM with high-risk cytogenetic features)))).

[0401] In some embodiments, the subject has received an induction therapy. Any suitable induction therapy can be used. Exemplary induction therapies for MM include CyBorD regimen (cyclophosphamide, bortezomib, and dexamethasone); VRD regimen (bortezomib, lenalidomide, and dexamethasone); VRD light (reduced doses and schedules of bortezomib, lenalidomide, and dexamethasone); thalidomide and dexamethasone; lenalidomide and low-dose dexamethasone; bortezomib and dexamethasone; Vd regimen (bortezomib and dexamethasone); VTD regimen (bortezomib, thalidomide, and dexamethasone); bortezomib, cyclophosphamide, and prednisone; bortezomib, doxorubicin, and dexamethasone; DARZALEX FASPRO® (daratumumab and hyaluronidase), bortezomib, ALKERAN® (melphalan), and prednisone; DARZALEX FASPRO® (daratumumab and hyaluronidase), lenalidomide, and dexamethasone; DARZALEX FASPRO® (daratumumab and hyaluronidase), bortezomib, thalidomide, and dexamethasone; and liposomal doxorubicin, vincristine, and dexamethasone, but are not limited thereto.

[0402] In some embodiments, the subject has undergone autologous stem cell transplantation (ASCT). For example, in some embodiments, the subject has undergone ASCT within about 100 days (e.g., within 100 days, within 90 days, within 80 days, within 70 days, within 60 days, within 50 days, within 40 days, within 30 days, within 20 days, within 10 days, within 5 days, or within 1 day) from the start of the method (e.g., first administration of a bispecific antibody and / or lenalidomide). In some examples, the subject does not have a progressive disease.

[0403] In some examples, the bispecific antibody and lenalidomide are administered to the patient as maintenance therapy after transplantation.

[0404] In some embodiments, the subject has received at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more than 15 lines of treatment for a B cell proliferative disorder, e.g., 2L+, 3L+, 4L+, 5L+, 6L+, 7L+, 8L+, 9L+, 10L+, 11L+, 12L+, 13L+, 14L+ or 15L+.

[0405] In some embodiments, the subject has received at least 3 prior lines of treatment for cancer (e.g., a blood cancer (e.g., a B cell proliferative disorder (e.g., MM (e.g., MM with high-risk cytogenetic features)))), e.g., 4L+, e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more than 15 lines of treatment. In some embodiments, the subject has relapsed or refractory (R / R) multiple myeloma (MM), e.g., has 4L+R / R MM.

[0406] In some embodiments, the prior treatment line comprises one or more proteasome inhibitors (PIs) (e.g., bortezomib, carfilzomib or ixazomib); immunomodulatory drugs (IMiDs), such as thalidomide, lenalidomide or pomalidomide; autologous stem cell transplantation (ASCT); anti-CD38 agents, such as daratumumab (DARZALEX®) (U.S. Patent No. 7,829,673 and U.S. Patent Publication No.: 20160067205A1), "MOR202" (U.S. Patent No. 8,263,746), isatuximab (SAR-650984); CAR-T therapy; treatment comprising a bispecific antibody; anti-SLAMF7 therapeutic agent (e.g., an anti-SLAMF7 antibody, such as elotuzumab); an inhibitor of nuclear export (e.g., selinexor); and a histone deacetylase (HDAC) inhibitor (e.g., panobinostat). In some embodiments, the prior treatment line comprises an antibody-drug conjugate (ADC). In some embodiments, the prior treatment line comprises a B cell maturation antigen (BCMA)-directed therapy, such as an antibody-drug conjugate targeting BCMA (BCMA-ADC).

[0407] In some embodiments, the prior treatment line comprises all three of a proteasome inhibitor (PI), an IMiD, and an anti-CD38 agent (e.g., daratumumab).

[0408] In some embodiments, the cancer (e.g., a blood cancer (e.g., a B cell proliferative disorder (e.g., MM (e.g., MM with high-risk cytogenetic features)))) is refractory to the treatment line, e.g., refractory to one or more of daratumumab, PI, IMiD, ASCT, anti-CD38 agent, CAR-T therapy, treatment comprising a bispecific antibody, anti-SLAMF7 therapeutic agent, inhibitor of nuclear export, HDAC inhibitor, ADC or BCMA-directed therapy. In some embodiments, the B cell proliferative disorder (e.g., MM) is refractory to daratumumab.

[0409] E. Risk-Benefit Profile The methods described herein can provide an improved benefit-risk profile for patients having cancer (e.g., blood cancers (e.g., B cell proliferative disorders (e.g., MM (e.g., MM with high-risk cytogenetic features)))). In some cases, a treatment using the methods described herein that results in administration of a bispecific anti-FcRH5 / anti-CD3 antibody and lenalidomide in a fractionated dose escalation regimen, as compared to treatment with a bispecific anti-FcRH5 / anti-CD3 antibody using an unfractionated dosing regimen, can result in a reduction (by 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more) or complete inhibition (100% reduction) of undesirable events such as cytokine-driven toxicities (e.g., cytokine release syndrome (CRS)), infusion-related reactions (IRR), macrophage activation syndrome (MAS), neurotoxicity, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, elevated liver enzymes, and / or central nervous system (CNS) toxicity after treatment with a bispecific anti-FcRH5 / anti-CD3 antibody using the fractionated dose escalation regimen of the invention.

[0410] F. Safety and Efficacy i. Safety In some embodiments, less than 15% (e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%) of patients treated using the methods described herein experience grade 3 or grade 4 cytokine release syndrome (CRS). In some embodiments, less than 5% of patients treated using the methods described herein experience grade 3 or grade 4 CRS.

[0411] In some embodiments, less than 10% (e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%) of the patients treated using the methods described herein experience grade 4+ CRS. In some embodiments, less than 3% of the patients treated using the methods described herein experience grade 4+ CRS. In some embodiments, no patients experience grade 4+ CRS.

[0412] In some embodiments, less than 10% (e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%) of the patients treated using the methods described herein experience grade 3 CRS. In some embodiments, less than 5% of the patients treated using the methods described herein experience grade 3 CRS. In some embodiments, no patients experience grade 3 CRS.

[0413] In some embodiments, grade 2+ CRS events occur only in the first treatment cycle. In some embodiments, grade 2 CRS events occur only in the first treatment cycle. In some embodiments, no grade 2 CRS events occur.

[0414] In some embodiments, less than 3% of the patients treated using the methods described herein experience grade 4+ CRS, less than 5% of the patients treated using the methods described herein experience grade 3 CRS, and grade 2+ CRS events occur only in the first treatment cycle.

[0415] In some embodiments, no grade 3+ CRS events occur and grade 2 CRS events occur only in the first treatment cycle.

[0416] In some embodiments, the symptoms of immune effector cell-associated neurotoxicity syndrome (ICANS) are limited to confusion, disorientation, and expressive aphasia and resolve with steroids.

[0417] In some embodiments, less than 10% (e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%) of the patients treated using the methods described herein experience seizures or other grade 3+ neurological adverse events. In some embodiments, less than 5% of the patients experience seizures or other grade 3+ neurological adverse events. In some embodiments, no patients experience seizures or other grade 3+ neurological adverse events.

[0418] In some embodiments, all neurological symptoms are self-limiting or resolved with steroid and / or tocilizumab therapy.

[0419] ii. Efficacy In some embodiments, the overall response rate (ORR) for patients treated using the methods described herein is at least 25%, for example, at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100%. In some embodiments, the ORR is at least 40%. In some embodiments, the ORR is at least 45% (for example, at least 45%, 45.5%, 46%, 46.5%, 47%, 47.5%, 48%, 48.5%, 49%, 49.5%, or 50%), at least 55%, or at least 65%. In some embodiments, the ORR is at least 47.2%. In some embodiments, the ORR is about 47.2%. In some embodiments, the ORR is 75% or more. In some embodiments, at least 1% of the patients (for example, at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the patients) have a complete response (CR) or a very good partial response (VGPR). In some embodiments, the ORR is 40% - 50% and 10% - 20% of the patients have a CR or VGPR. In some embodiments, the ORR is at least 40% and at least 20% of the patients have a CR or VGPR.

[0420] In some embodiments, the mean duration of response (DoR) for patients treated using the methods described herein is at least 2 months, e.g., at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 1 year, or more than 1 year. In some embodiments, the mean DoR is at least 4 months. In some embodiments, the mean DoR is at least 5 months. In some embodiments, the mean DoR is at least 7 months.

[0421] In some embodiments, the 6-month progression-free survival (PFS) rate for patients treated using the methods described herein is at least 10%, e.g., at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100%. In some embodiments, the 6-month PFS rate is at least 25%. In some embodiments, the 6-month PFS rate is at least 40%. In some embodiments, the 6-month PFS rate is at least 55%.

[0422] G. Administration Method The methods and treatments may include administering the bispecific anti-FcRH5 / anti-CD3 antibody, lenalidomide, and / or any additional therapeutic agent by any suitable means including parenteral administration, intralung administration and intranasal administration, and intralesional administration if desired for local treatment. Parenteral injection includes intravenous, subcutaneous, intramuscular, intraarterial, and intraperitoneal administration routes. In some embodiments, the bispecific anti-FcRH5 / anti-CD3 antibody is administered by intravenous injection. In other cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered subcutaneously.

[0423] In some cases, a bispecific anti-FcRH5 / anti-CD3 antibody administered by intravenous injection exhibits a lower toxicity response (i.e., fewer unwanted effects) in patients than the same bispecific anti-FcRH5 / anti-CD3 antibody administered by subcutaneous injection, or vice versa.

[0424] In some embodiments, the bispecific anti-FcRH5 / anti-CD3 antibody is administered intravenously over 4 hours (± 15 minutes), for example, the first dose of the antibody is administered over 4 hours ± 15 minutes.

[0425] In some embodiments, the first dose and the second dose of the antibody are administered intravenously at a median infusion time of less than 4 hours (e.g., less than 3 hours, less than 2 hours, or less than 1 hour), and further doses of the antibody are administered intravenously at a median infusion time of less than 120 minutes (e.g., less than 90 minutes, less than 60 minutes, or less than 30 minutes).

[0426] In some embodiments, the first dose and the second dose of the antibody are administered intravenously at a median infusion time of less than 3 hours, and further doses of the antibody are administered intravenously at a median infusion time of less than 90 minutes.

[0427] In some embodiments, the first dose and the second dose of the antibody are administered intravenously at a median infusion time of less than 3 hours, and further doses of the antibody are administered intravenously at a median infusion time of less than 60 minutes. In some embodiments, the patient is hospitalized during the period of one or more administrations of the anti-FcRH5 / anti-CD3 antibody (e.g., hospitalization for 72 hours, 48 hours, 24 hours, or less than 24 hours), for example, hospitalization for C1D1 (cycle 1, dose 1) or C1D1 and C1D2 (cycle 1, dose 2). In some embodiments, the patient is hospitalized 72 hours after administration of C1D1 and C1D2. In some embodiments, the patient is hospitalized 24 hours after administration of C1D1 and C1D2. In some embodiments, the patient is not hospitalized after administration of any dose of the anti-FcRH5 / anti-CD3 antibody.

[0428] For all of these methods described herein, the bispecific anti-FcRH5 / anti-CD3 antibody, lenalidomide, and / or any additional therapeutic agent(s) will be formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the dosing schedule, and other factors known to the medical practitioner. The bispecific anti-FcRH5 / anti-CD3 antibody, lenalidomide, and / or any additional therapeutic agent(s) may optionally, but not necessarily, be formulated with one or more drugs currently being used to prevent or treat the disorder in question. The effective amount of such other drugs will depend on the amount of the bispecific anti-FcRH5 / anti-CD3 antibody, lenalidomide, and / or any additional therapeutic agent(s) present in the formulation, the type of disorder or treatment, and the other factors discussed above. The bispecific anti-FcRH5 / anti-CD3 antibody, lenalidomide, and / or any additional therapeutic agent(s) may be appropriately administered to a patient over a series of treatments.

[0429] H. Anti-FcRH5 / anti-CD3 Bispecific Antibody The methods described herein include administering to a subject having cancer (e.g., a blood cancer (e.g., a B cell proliferative disorder (e.g., MM (e.g., MM with high-risk cytogenetic features)))) a bispecific antibody that binds to FcRH5 and CD3 (i.e., a bispecific anti-FcRH5 / anti-CD3 antibody). Any suitable bispecific antibody that binds to FcRH5 and CD3 (i.e., a bispecific anti-FcRH5 / anti-CD3 antibody) can be used.

[0430] In some cases, any of the methods described herein may involve administering a bispecific antibody comprising an anti-FcRH5 arm having a first binding domain that includes at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (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); (f) HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody includes at least 1 (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 each comprising the sequences of SEQ ID NOs: 17-20, and / or at least 1 (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 each comprising the sequences of SEQ ID NOs: 21-24.

[0431] In some cases, any of the methods described herein may involve administering a bispecific antibody comprising an anti-FcRH5 arm having a first binding domain that includes any of the following six 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); (f) HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody comprises at least one (e.g., one, two, three, or four) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 each comprising the sequences of SEQ ID NOs: 17-20, and / or at least one (e.g., one, two, three, or four) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 each comprising the sequences of SEQ ID NOs: 21-24.

[0432] In some cases, the bispecific antibody comprises an anti-FcRH5 arm comprising a first binding domain that includes (a) a heavy chain variable (VH) domain having an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 7 or the sequence of SEQ ID NO: 7, (b) a light chain variable (VL) domain having an amino acid sequence having at least 90% sequence (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 8 or the sequence of SEQ ID NO: 8, or (c) a first binding domain including the VH domain described in (a) and the VL domain described in (b). Thus, in some cases, the first binding domain includes 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.

[0433] In some cases, any of the methods described herein may involve administering a bispecific anti-FcRH5 / anti-CD3 antibody comprising an anti-CD3 arm having a second binding domain comprising at least 1, 2, 3, 4, 5, or 6 HVRS selected from: (a) HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); (f) HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14). In some cases, the anti-FcRH5 / anti-CD3 bispecific antibody comprises at least 1 (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4, each comprising the sequence of SEQ ID NOs: 25-28, and / or at least 1 (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4, each comprising the sequence of SEQ ID NOs: 29-32.

[0434] In some cases, any of the methods described herein may involve administering a bispecific anti-FcRH5 / anti-CD3 antibody comprising an anti-CD3 arm having a second binding domain that includes any of the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); (f) HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14). In some cases, the anti-FcRH5 / anti-CD3 bispecific antibody comprises at least one (e.g., one, two, three, or four) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 each comprising the sequences of SEQ ID NOs: 25-28, and / or at least one (e.g., one, two, three, or four) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 each comprising the sequences of SEQ ID NOs: 29-32.

[0435] In some cases, the bispecific antibody comprises an anti-CD3 arm having a second binding domain that includes (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 15 or the sequence of SEQ ID NO: 15, (b) a VL domain comprising an amino acid sequence having at least 90% sequence (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 16 or the sequence of SEQ ID NO: 16, or (c) a second binding domain that includes the VH domain described in (a) and the VL domain described in (b). Thus, in some cases, the second binding domain includes 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.

[0436] In some cases, any of the methods described herein may involve administering a bispecific antibody comprising: (1) an anti-FcRH5 arm having a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 HVRS selected from: (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); (f) HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6); and (2) an anti-CD3 arm having a second binding domain comprising at least 1, 2, 3, 4, 5, or 6 HVRS selected from: (a) HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); (f) HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

[0437] In some cases, any of the methods described herein may include administering a bispecific antibody comprising: (1) an anti-FcRH5 arm having a first binding domain comprising the following six 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); (f) HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6), and (2) an anti-CD3 arm having a second binding domain comprising the following six HVRS: (a) HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); (f) HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

[0438] In some cases, the anti-FcRH5 / anti-CD3 bispecific antibody comprises (1) at least one (e.g., 1, 2, 3, 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 each containing the sequences of SEQ ID NOs: 17-20, and / or at least one (1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 each containing the sequences of SEQ ID NOs: 21-24, and (2) at least one (1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 each containing the sequences of SEQ ID NOs: 25-28, and / or at least one (e.g., 1, 2, 3 or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 each containing the sequences of SEQ ID NOs: 29-32. In some cases, the anti-FcRH5 / anti-CD3 bispecific antibody comprises (1) all four of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 each containing the sequences of SEQ ID NOs: 17-20, and / or all four of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 each containing the sequences of SEQ ID NOs: 21-24, and (2) all four of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 each containing the sequences of SEQ ID NOs: 25-28, and / or all four of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 each containing the sequences of SEQ ID NOs: 29-32 (e.g., 1, 2, 3 or 4).

[0439] In some cases, the anti-FcRH5 / anti-CD3 bispecific antibody comprises: (1) an anti-FcRH5 arm comprising a first binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 7 or an amino acid sequence having at least 90% sequence identity thereto (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity), (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 8 or an amino acid sequence having at least 90% sequence identity thereto (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity), or (c) a VH domain as described in (a) and a VL domain as described in (b); and (2) an anti-CD3 arm comprising a second binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 15 or an amino acid sequence having at least 90% sequence identity thereto (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity), (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 16 or an amino acid sequence having at least 90% sequence identity thereto (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity), or (c) a VH domain as described in (a) and a VL domain as described in (b). In some cases, the anti-FcRH5 / anti-CD3 bispecific antibody comprises: (1) a first binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 7 and a VL domain comprising the amino acid sequence of SEQ ID NO: 8; and (2) a second binding domain comprising 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.

[0440] In some cases, the anti-FcRH5 / anti-CD3 bispecific antibody comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1) and a light chain polypeptide (L1), wherein (a) H1 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) to the sequence of SEQ ID NO: 35, and / or (b) L1 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) to the sequence of SEQ ID NO: 36.

[0441] In some cases, the anti-FcRH5 / anti-CD3 bispecific antibody comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1) and a light chain polypeptide (L1), wherein (a) H1 comprises the amino acid sequence of SEQ ID NO: 35, and / or (b) L1 comprises the amino acid sequence of SEQ ID NO: 36.

[0442] In some cases, the anti-FcRH5 / anti-CD3 bispecific antibody comprises an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), wherein (a) H2 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) to the sequence of SEQ ID NO: 37, and / or (b) L2 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) to the sequence of SEQ ID NO: 38.

[0443] In some cases, the anti-FcRH5 / anti-CD3 bispecific antibody comprises an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), wherein (a) H2 comprises the amino acid sequence of SEQ ID NO: 37, and (b) L2 comprises the amino acid sequence of SEQ ID NO: 38.

[0444] In some cases, the anti-FcRH5 / anti-CD3 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 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) with the sequence of SEQ ID NO: 35; (b) L1 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) with the sequence of SEQ ID NO: 36; (c) H2 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) with the sequence of SEQ ID NO: 37; and (d) L2 comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) with the sequence of SEQ ID NO: 38.

[0445] In some cases, the anti-FcRH5 / anti-CD3 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 comprises the amino acid sequence of SEQ ID NO: 35; (b) L1 comprises the amino acid sequence of SEQ ID NO: 36; (c) H2 comprises the amino acid sequence of SEQ ID NO: 37; and (d) L2 comprises the amino acid sequence of SEQ ID NO: 38.

[0446] In some cases, the anti-FcRH5 / anti-CD3 bispecific antibody is cevostamab.

[0447] In some cases, the anti-FcRH5 / anti-CD3 bispecific antibody according to any of the above embodiments may incorporate any of the features as described in Sections 1 to 7 below, either alone or in combination.

[0448] 1. Antibody affinity In certain embodiments, the antibodies provided herein have a dissociation constant (K D ) 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 to 10 -13 M, e.g., 10 -9 M to 10 -13 )M).

[0449] In one embodiment, K D is measured by a radiolabeled antigen binding assay (RIA). In one embodiment, the RIA is performed using the Fab version of the antibody of interest and its antigen. For example, the solution binding affinity of the Fab for the antigen is determined by equilibrating the Fab with the minimum concentration of 125 I) - labeled antigen in the presence of a titration series of unlabeled antigen and then capturing the bound antigen on a plate coated with anti - Fab antibody (see, e.g., Chen et al., J. Mol. Biol. 293:865 - 881 (1999)). To establish assay conditions, a MICROTITER® multi - well plate (Thermo Scientific) is coated overnight with 5 μg / mL of capture anti - Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6) and then blocked with 2% (w / v) bovine serum albumin in PBS for 2 - 5 hours at room temperature (approx. 23°C). In non - adsorptive plates (Nunc #269620), 100 pM or 26 pM of 125Mix the [[I]]-antigen with serial dilutions of the Fab of interest (e.g., consistent with the evaluation of anti-VEGF antibody Fab-12 in Presta et al., Cancer Res. 57:4593-4599 (1997)). Then incubate the Fab of interest overnight, although the incubation can be continued for a longer period (e.g., about 65 hours) to ensure reaching equilibrium. Thereafter, transfer the mixture to a capture plate for incubation at room temperature (e.g., 1 hour). Then remove the solution and wash the plate 8 times with 0.1% polysorbate 20 (TWEEN-20®) in PBS. When the plate is dry, add 150 μL / well of scintillant (MICROSCINT-20™; Packard) and count the plate with a TOPCOUNT™ gamma counter (Packard) for 10 minutes. Select the concentration of each Fab that results in 20% or less of the maximum binding for use in a competitive binding assay.

[0450] According to another embodiment, K DIt is measured using a BIACORE (registered trademark) surface plasmon resonance assay. For example, an assay using a BIACORE (registered trademark)-2000 or BIACORE (registered trademark)-3000 (BIAcore, Inc., Piscataway, NJ) is run at 37°C with an immobilized antigen CM5 chip at approximately 10 response units (RU). In one embodiment, a carboxymethylated dextran biosensor chip (CM5, BIACORE, Inc.) is activated using N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the supplier's instructions. The antigen is diluted to 5 μg / ml (approximately 0.2 μM) with 10 mM sodium acetate at pH 4.8 and then injected at a flow rate of 5 μl / min to achieve approximately 10 response units (RU) of the coupled protein. After injection of the antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetic measurements, two-fold serial dilutions of the Fab (0.78 nM to 500 nM) are injected at 37°C at a flow rate of approximately 25 μL / min into PBS with 0.05% polysorbate 20 (TWEEN-20 (trademark)) surfactant (PBST). The association rate (k on , or k a ) and dissociation rate (k off , or k d ) are calculated by fitting the association sensorgram and dissociation sensorgram simultaneously using a simple 1:1 Langmuir binding model (BIACORE (registered trademark) evaluation software version 3.2). The equilibrium dissociation constant (K D ) is calculated as the k off / k on ratio. See, for example, Chen et al., J. Mol. Biol. 293:865-881 (1999). The on-rate is 10 6 M -1 s -1When it exceeds, this on-rate can be determined by using a fluorescence quenching technique that measures the increase or decrease in the fluorescence emission intensity (excitation = 295 nm, emission = 340 nm, 16 nm band pass) of 20 nM anti-antigen antibody (Fab type) in PBS (pH 7.2) at 37 °C in the presence of antigen at increasing concentrations, when measured in a spectrometer such as a stopped-flow equipped spectrophotometer (Aviv Instruments) with a stirred cuvette or an 8000 series SLM-AMINCO (trademark) spectrophotometer (ThermoSpectronic).

[0451] 2. Antibody fragment In certain embodiments, the antibodies provided herein (e.g., anti-FcRH5 / anti-CD3 TDB) are antibody fragments that bind to FcRH5 and CD3. Antibody fragments include, but are not limited to, Fab, Fab’, Fab’-SH, F(ab’)2, Fv, and scFv fragments, and other fragments described below. For a general review of specific antibody fragments, see Hudson et al. Nat. Med. 9:129-134 (2003). For reference to scFv fragments, see, for example, Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenberg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994); also see International Publication No. 93 / 16185; and U.S. Patent Nos. 5,571,894 and 5,587,458. For discussion of Fab and F(ab’)2 fragments that constitute salvage receptor binding epitope residues and increase in vivo half-life, see U.S. Patent No. 5,869,046.

[0452] A diabody is an antibody fragment having two antigen-binding sites that can be bivalent or bispecific. See, for example, European Patent No. 404,097, International Publication No. 1993 / 01161, Hudson et al. Nat. Med. 9:129-134 (2003); and Hollinger et al. Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993). Triabodies and tetra-bodies are also described in Hudson et al. Nat. Med. 9:129-134 (2003).

[0453] A single-domain antibody is an antibody fragment that includes all or part of the heavy-chain variable domain or all or part of the light-chain variable domain of an antibody. In certain embodiments, the single-domain antibody is a human single-domain antibody (see, e.g., U.S. Patent No. 6,248,516 B1 to Domantis, Inc., Waltham, MA).

[0454] Antibody fragments can be made by a variety of techniques including, but not limited to, proteolytic digestion of intact antibodies and production by recombinant host cells (e.g., E. coli or phage) as described herein.

[0455] 3. Chimeric and Humanized Antibodies In certain embodiments, the antibodies provided herein (e.g., anti-FcRH5 / anti-CD3 TDB) are chimeric antibodies. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567, and Morrison et al. Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)). In one example, a chimeric antibody includes a non-human variable region (e.g., a variable region derived from a non-human primate such as a mouse, rat, hamster, rabbit, or monkey) and a human constant region. In a further example, a chimeric antibody is a "class-switch" antibody in which the class or subclass has been changed from that of the parent antibody. A chimeric antibody includes its antigen-binding fragment.

[0456] In certain embodiments, the chimeric antibody is a humanized antibody. Typically, non-human antibodies are humanized to reduce their immunogenicity in humans while retaining the specificity and affinity of the parental non-human antibody. Generally, a humanized antibody includes one or more variable domains in which, for example, the HVR (or a portion thereof) is derived from a non-human antibody and the FR (or a portion thereof) is derived from a human antibody sequence. A humanized antibody optionally also includes at least a portion of a human constant region. In some embodiments, some FR residues of the humanized antibody are replaced with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived) to, for example, restore or improve antibody specificity or affinity.

[0457] Humanized antibodies and methods of making them are reviewed in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008) and are further described below. Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat’l Acad. Sci. USA 86:10029-10033 (1989); U.S. Pat. Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specific-determining region (SDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) (describing resurfacing); Dall’Acqua et al., Methods 36:43-60 (2005) (describing “FR shuffling”); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing a “guided selection approach” to FR shuffling).

[0458] Human framework regions that can be used for humanization include, but are not limited to: framework regions selected using the "best fit" method (see, e.g., Sims et al. J. Immunol. 151:2296 (1993)); framework regions derived from consensus sequences of human antibodies of specific subgroups of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151:2623 (1993)); human mature (somatic mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from screening of FR libraries (see, e.g., Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996)).

[0459] 4. Human Antibodies In certain embodiments, the antibodies provided herein (e.g., anti-FcRH5 / anti-CD3 TDB) are human antibodies. Human antibodies can be made using a variety of techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).

[0460] Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies having human variable regions in response to an antigen challenge. Such animals typically contain all or part of a human immunoglobulin locus that replaces the endogenous immunoglobulin locus, is present episomally, or is randomly integrated into the chromosomes of the animal. In such transgenic mice, the endogenous immunoglobulin locus is generally inactivated. For an overview of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, for example, U.S. Pat. Nos. 6,075,181 and 6,150,584, which describe XENOMOUSE™ technology; U.S. Pat. No. 5,770,429, which describes HuMab® technology; U.S. Pat. No. 7,041,870, which describes K-M MOUSE® technology; and U.S. Patent Application Publication No. 2007 / 0061900, which describes VELOCIMOUSE® technology. The human variable regions from intact antibodies produced by such animals may be further modified, for example, by combining them with different human constant regions.

[0461] Human antibodies can also be made by methods based on hybridomas. Human myeloma cell lines and mouse-human heteromyeloma cell lines for producing human monoclonal antibodies have been described. (See, e.g., Kozbor J. Immunol., 133:3001 (1984), Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987) and Boerner et al., J. Immunol., 147:86 (1991)). Human antibodies generated via human B cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Additional methods include, for example, U.S. Patent No. 7,189,826 (describing the production of monoclonal human IgM antibodies from hybridoma cell lines), and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (triooma technology) is also described in Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005).

[0462] Human antibodies can also be produced by isolating Fv clone variable domain sequences selected from a human-derived phage display library. Such variable domain sequences can then be combined with desired human constant domains. Techniques for selecting human antibodies from antibody libraries are described below.

[0463] 5. Multispecific Antibodies In any one of the above aspects, the anti-FcRH5 / anti-CD3 antibody provided herein is a multispecific antibody, such as a bispecific antibody. A multispecific antibody is an antibody (e.g., a monoclonal antibody) having binding specificities for at least two different sites, e.g., an antibody having binding specificities for an immune effector cell and a cell surface antigen on a target cell other than the immune effector cell (e.g., a tumor antigen, e.g., FcRH5). In some aspects, one of the binding specificities is for FcRH5 and the other is for CD3.

[0464] In some aspects, the cell surface antigen may be expressed at low copy numbers on the target cell. For example, in some aspects, the cell surface antigen is expressed or present at less than 35,000 copies per target cell. In some embodiments, the low copy number cell surface antigen is between 100 and 35,000 copies per target cell; between 100 and 30,000 copies per target cell; between 100 and 25,000 copies per target cell; between 100 and 20,000 copies per target cell; between 100 and 15,000 copies per target cell; between 100 and 10,000 copies per target cell; between 100 and 5,000 copies per target cell; between 100 and 2,000 copies per target cell; between 100 and 1,000 copies per target cell; or between 100 and 500 copies per target cell. The copy number of the cell surface antigen can be determined, for example, using a standard Scatchard plot.

[0465] In some embodiments, the bispecific antibody may be used to localize a cytotoxic agent to cells expressing a tumor antigen, such as FcRH5. The bispecific antibody can be prepared as a full-length antibody or an antibody fragment.

[0466] Techniques for making multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs having different specificities (see Milstein and Cuello, Nature 305:537 (1983)), WO 93 / 08829, and Traunecker et al., EMBO J. 10:3655 (1991)), and "knob-in-hole" engineering (see, e.g., U.S. Patent No. 5,731,168). The "knob-in-hole" engineering of multispecific antibodies may be utilized to generate a first arm comprising a knob and a second arm comprising a hole to which the knob of the first arm binds. The knob of the multispecific antibodies disclosed herein may, in one embodiment, be an anti-CD3 arm. Alternatively, the knob of the multispecific antibodies disclosed herein may, in one embodiment, be an anti-target / antigen arm. The hole of the multispecific antibodies disclosed herein may, in one embodiment, be an anti-CD3 arm. Alternatively, the hole of the multispecific antibodies disclosed herein may, in one embodiment, be an anti-target / antigen arm.

[0467] Multispecific antibodies may also be engineered using immunoglobulin crossover (also known as Fab domain exchange or CrossMab format) technology (see, e.g., WO 2009 / 080253; Schaefer et al., Proc. Natl. Acad. Sci. USA, 108:11187-11192 (2011)). Multispecific antibodies may also be engineered by manipulation of the electrostatic steering effect to create antibody Fc heterodimeric molecules (WO 2009 / 089004A1); cross-linking of two or more antibodies or fragments (see, e.g., U.S. Pat. No. 4,676,980 and Brennan et al., Science, 229:81 (1985)); use of leucine zippers to produce bispecific antibodies (see, e.g., Kostelny et al., J. Immunol., 148(5):1547-1553 (1992)); use of the "diabody" technology to produce bispecific antibody fragments (see, e.g., Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993)); and use of single-chain Fv (sFv) dimers (see, e.g., Gruber et al., J. Immunol., 152:5368 (1994)); and can also be made, for example, by the preparation of trispecific antibodies as described in Tutt et al. J. Immunol. 147:60 (1991).

[0468] Also included herein are engineered antibodies having three or more functional antigen-binding sites, including "octopus antibodies" (see, e.g., US 2006 / 0025576A1).

[0469] Antibodies or antibody fragments herein also include "dual action FAb" or "DAF" that include an antigen-binding site that binds CD3, as well as another different antigen (e.g., a second biological molecule) (see, e.g., US2008 / 0069820).

[0470] 6. Antibody Variants In some embodiments, amino acid sequence variants of the bispecific anti-FcRH5 / anti-CD3 antibodies disclosed herein are contemplated. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of the antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions from residues within the amino acid sequence of the antibody and / or insertions into residues within the amino acid sequence of the antibody and / or substitutions of residues within the amino acid sequence of the antibody. Any combination of deletions, insertions, and substitutions can be made to arrive at the final construct, provided that the final construct retains the desired characteristics, such as antigen binding.

[0471] a. Substitution, insertion, and deletion variants In certain embodiments, antibody variants having one or more amino acid substitutions are provided. Target sites for substitution mutagenesis include CDRs and FRs. Conservative substitutions are shown in Table 4 under the heading "Preferred Substitutions". More substantial changes are provided in Table 4 under the heading "Exemplary Substitutions" and are further described below with reference to amino acid side chain classes. Amino acid substitutions can be introduced into the antibody of interest, and the product can be screened for the desired activity, such as retained / improved antigen binding, reduced immunogenicity, or improved ADCC or CDC. [Table 4] Amino acids can be classified as follows according to their common side chain properties: (1) Hydrophobic: norleucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) Acidic: Asp, Glu; (4) Basic: His, Lys, Arg; (5) Residues affecting chain orientation: Gly, Pro; (6) Aromatic: Trp, Tyr, Phe

[0472] Non-conservative substitutions will involve exchanging one member of these classes for another.

[0473] Certain substitution variants involve substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Generally, the resulting variant(s) selected for further study will have a modification (e.g., improvement) of certain biological properties (e.g., increased affinity, reduced immunogenicity) compared to the parent antibody and / or will substantially retain certain biological properties of the parent antibody. Exemplary substitution variants are affinity matured antibodies and can be readily generated, for example, using phage display-based affinity maturation techniques as described herein. Briefly, one or more CDR residues are mutated and the variant antibodies displayed on phage are screened for a particular biological activity (e.g., binding affinity).

[0474] To improve antibody affinity, for example, modifications (e.g., substitutions) may be made in the CDRs. Such modifications may be made at CDR “hot spots,” i.e., residues encoded by codons that are mutated at high frequency during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and / or residues that contact the antigen, and the resulting variant VH or VL is tested for binding affinity. Affinity maturation by construction of a secondary library and reselection therefrom is described, for example, in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O’Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some embodiments of affinity maturation, diversity is introduced into the variable gene selected for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis, etc.). A secondary library is then created. This library is then screened to identify antibody variants having the desired affinity. Another method of introducing diversity involves a CDR-directed approach in which several CDR residues (e.g., 4-6 residues at a time) are randomized. CDR residues involved in antigen binding can be specifically identified, for example, using alanine-scanning mutagenesis or modeling. In particular, CDR-H3 and CDR-L3 are often targeted.

[0475] In certain embodiments, substitutions, insertions, or deletions can occur within one or more CDRs so long as such modifications do not substantially reduce the ability of the antibody to bind the antigen. For example, conservative modifications (e.g., conservative substitutions provided herein) that do not substantially reduce binding affinity may be made within the CDRs. Such modifications may be, for example, outside of the antigen contact residues in the CDRs. In certain embodiments of the variant VH and VL sequences provided above, each CDR is either unchanged or contains one, two, or three or fewer amino acid substitutions.

[0476] A useful method for identifying residues or regions of an antibody that can be targets for mutagenesis is called "alanine scanning mutagenesis" as described in Cunningham and Wells (1989) Science, 244:1081-1085. In this method, residues or groups of target residues (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) are identified and replaced with neutral or negatively charged amino acids (e.g., alanine or polyalanine) to determine whether the interaction between the antibody and antigen is affected. Further substitutions may be introduced at amino acid positions that show functional sensitivity to the initial substitution. Alternatively, or in addition, the crystal structure of the antigen-antibody complex to identify the contact points between the antibody and antigen. Such contact residues and adjacent residues may be targeted or excluded as candidates for substitution. Variants may be screened to determine whether they have the desired properties.

[0477] Amino acid sequence insertions include amino-terminal and / or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing over 100 residues, as well as insertions within the sequence of one or more amino acid residues. Examples of terminal insertions include antibodies having an N-terminal methionyl residue. Other insertion variants of the antibody molecule include fusions of the N-terminal or C-terminal of the antibody to an enzyme (e.g., for ADEPT) or polypeptide that increases the serum half-life of the antibody.

[0478] b. Glycosylation variants In certain embodiments, the bispecific anti-FcRH5 / anti-CD3 antibodies disclosed herein can be modified to increase or decrease the degree to which the antibody is glycosylated. Addition or deletion of glycosylation sites to the anti-FcRH5 antibodies of the invention can be conveniently achieved by altering the amino acid sequence such that one or more glycosylation sites are created or removed.

[0479] When the antibody contains an Fc region, the carbohydrates attached thereto can be modified. Native antibodies produced by mammalian cells typically contain branched, biantennary oligosaccharides that are generally attached by N-linkage to Asn297 of the CH2 domain of the Fc region. See, for example, Wright et al. TIBTECH 15:26-32 (1997). The oligosaccharides can include various carbohydrates such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose attached to the GlcNAc of the "stem" of the biantennary oligosaccharide structure. In some embodiments, modification of the oligosaccharides in the antibodies of the invention may be performed to create antibody variants having certain improved properties.

[0480] In one embodiment, provided is a bispecific anti-FcRH5 / anti-CD3 antibody variant having a carbohydrate structure lacking fucose (either directly or indirectly) linked to the Fc region. For example, the amount of fucose in such an antibody can be 1% to 80%, 1% to 65%, 5% to 65% or 20% to 40%. The amount of fucose is determined, for example, as described in WO 2008 / 077546, by calculating the average amount of fucose within the sugar chain at Asn297 relative to the total of all sugar chain structures attached to Asn297 (e.g., complex structures, hybrid structures, and high-mannose structures) when measured by MALDI-TOF mass spectrometry. Asn297 refers to the asparagine residue located at approximately position 297 of the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located about ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in the antibody. Such fucosylation variants may have improved ADCC function. See, for example, US Patent Application Publication No. 2003 / 0157108 (Presta, L.); US Patent Application Publication No. 2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications related to "defucosylated" or "fucose-deficient" antibody variants include: US Patent Application Publication No. 2003 / 0157108; WO 2000 / 61739; WO 2001 / 29246; US Patent Application Publication No. 2003 / 0115614; US Patent Application Publication No. 2002 / 0164328; US Patent Application Publication No. 2004 / 0093621; US Patent Application Publication No. 2004 / 0132140; US Patent Application Publication No. 2004 / 0110704; US Patent Application Publication No. 2004 / 0110282; US Patent Application Publication No. 2004 / 0109865; WO 2003 / 085119; WO 2003 / 084570; WO 2005 / 035586; WO 2005 / 035778; WO 2005 / 053742; US Patent Application Publication No. 2002 / 031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004).Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Patent Application Publication No. 2003 / 0157108 A1, Presta, L; and International Publication No. 2004 / 056312 A1, Adams et al., particularly Example 11), and knockout cell lines, such as alpha-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and International Publication No. 2003 / 085107).

[0481] Also provided are bispecific anti-FcRH5 / anti-CD3 antibody variants having bisected oligosaccharides, e.g., the bisected oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibody variants can have reduced fucosylation and / or improved ADCC function. Examples of such antibody variants are described, e.g., in International Publication No. 2003 / 011878 (Jean-Mairet et al.); US Patent No. 6,602,684 (Umana et al.); and US Patent Application Publication No. 2005 / 0123546 (Umana et al). Also provided are antibody variants having at least one galactose residue of the oligosaccharide attached to the Fc region. Such antibody variants can have improved CDC function. Such antibody variants are described, e.g., in International Publication No. 1997 / 30087 (Patel et al.); International Publication No. 1998 / 58964 (Raju, S.); and International Publication No. 1999 / 22764 (Raju, S.).

[0482] c. Fc region variant In certain embodiments, one or more amino acid modifications can be introduced into the Fc region of the bispecific anti-FcRH5 / anti-CD3 antibody, thereby creating an Fc region variant (see, e.g., US2012 / 0251531). The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3 or IgG4 Fc region) containing an amino acid modification (e.g., substitution) at one or more amino acid positions.

[0483] In certain embodiments, the invention contemplates bispecific anti-FcRH5 / anti-CD3 antibody variants that possess some, but not all, effector functions, such that while the in vivo half-life of the antibody is important, certain effector functions (such as complement and ADCC) are unnecessary or detrimental for certain applications, making them desirable candidates. To confirm the reduction / abrogation of CDC and / or ADCC activity, in vitro and / or in vivo cytotoxicity assays can be performed. For example, an Fc receptor (FcR) binding assay can be carried out to confirm that the antibody lacks FcγR binding (and thus is likely to lack ADCC activity), but retains FcRn binding ability. NK cells, which are the major cells mediating ADCC, express only Fc(RIII, while monocytes express Fc(RI, Fc(RII, and Fc(RIII. The expression of FcRs in hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays for evaluating the ADCC activity of the molecule of interest are described in U.S. Patent No. 5,500,362 (e.g., Hellstrom, et al. Proc. Nat’l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom et al., Proc. Nat’l Acad. Sci. USA 82:1499-1502 (1985); 5,821,337 (see Bruggemann et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assay methods may be used (e.g., the ACTI™ non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc., Mountain View, CA), and the CytoTox 96® non-radioactive cytotoxicity assay (Promega, Madison, WI)).Effector cells useful for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively or in addition, the ADCC activity of the molecule of interest can be evaluated in an animal model as disclosed in, for example, Clynes et al. Proc. Nat’l Acad. Sci. USA 95:652-656 (1998). Also, a C1q binding assay may be performed to confirm that the antibody is unable to bind C1q and lacks CDC activity. See, for example, C1q and C3c binding ELISAs in International Publication Nos. WO 2006 / 029879 and WO 2005 / 100402. A CDC assay may be performed to evaluate complement activation (see, for example, Gazzano-Santoro et al. J. Immunol. Methods 202:163 (1996); Cragg et al. Blood 101:1045-1052 (2003); and Cragg et al. Blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance / half-life determination can also be carried out using methods known in the art (see, for example, Petkova et al. Int’l. Immunol. 18(12):1759-1769 (2006)).

[0484] Antibodies having reduced effector function include antibodies having one or more substitutions among Fc region residues 238, 265, 269, 270, 297, 327, and 329 (U.S. Pat. Nos. 6,737,056 and 8,219,149). Such Fc mutants include Fc mutants having substitutions at two or more of amino acid positions 265, 269, 270, 297, and 327, including the so-called “DANA” Fc mutant in which residues 265 and 297 are substituted with alanine (U.S. Pat. Nos. 7,332,581 and 8,219,149).

[0485] In certain embodiments, the proline at position 329 of the wild-type human Fc region in the antibody is replaced with an amino acid residue large enough to disrupt the proline sandwich within the Fc / Fcγ receptor interface formed between proline 329 of the Fc and the tryptophan residues Trp87 and Trp110 of FcγRIII (Sondermann et al. Nature. 406, 267 - 273, 2000), or with glycine or arginine. In certain embodiments, the antibody further comprises at least one amino acid substitution. In one embodiment, the further amino acid substitution is S228P, E233P, L234A, L235A, L235E, N297A, N297D, or P331S, and in yet another embodiment, at least one further amino acid substitution is L234A and L235A of the human IgG1 Fc region, or S228P and L235E of the human IgG4 Fc region (see, e.g., US 2012 / 0251531), and in yet another embodiment, at least one further amino acid substitution is L234A and L235A and P329G of the human IgG1 Fc region.

[0486] Certain antibody variants with improved or decreased binding to FcR are described. (See, e.g., U.S. Patent No. 6,737,056; International Publication No. 2004 / 056312, and Shields et al., J. Biol. Chem. 9(2):6591 - 6604 (2001).)

[0487] In certain embodiments, the antibody variant comprises an Fc region having one or more amino acid substitutions that improve ADCC, such as substitutions at positions 298, 333, and / or 334 (EU numbering of residues) of the Fc region.

[0488] In some embodiments, the modification is made in the Fc region to result in modified (i.e., improved or decreased) C1q binding and / or complement-dependent cytotoxicity (CDC), as described, for example, in U.S. Patent No. 6,194,551, International Publication No. 99 / 51642, Idusogie et al. J. Immunol. 164:4178-4184 (2000).

[0489] Antibodies that play a role in transferring maternal IgG to the fetus with an increased half-life and improved binding to the neonatal Fc receptor (FcRn) (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)) are described in U.S. Patent Application Publication No. 2005 / 0014934A1 (Hinton et al.). Those antibodies contain an Fc region having one or more substitutions that improve the binding between the Fc region and FcRn. Such Fc variants include substitutions at one or more of Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, for example, variants having a substitution at Fc region residue 434 (U.S. Patent No. 7,371,826).

[0490] For other examples of Fc region variants, see also Duncan & Winter, Nature 322:738-40 (1988), U.S. Patent No. 5,648,260, U.S. Patent No. 5,624,821, and International Publication No. 94 / 29351.

[0491] In some aspects, the anti-FcRH5 antibody and / or anti-CD3 antibody (e.g., bispecific anti-FcRH5 antibody) contains an Fc region that includes the N297G mutation (EU numbering). In some aspects, the anti-FcRH5 arm of the bispecific anti-FcRH5 antibody includes the N297G mutation and / or the anti-CD3 arm of the bispecific anti-FcRH5 antibody contains an Fc region that includes the N297G mutation.

[0492] In some embodiments, an anti-FcRH5 antibody comprising an N297G mutation comprises an anti-FcRH5 arm comprising a first binding domain comprising the following six HVRS: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6; and an anti-CD3 arm comprising an N297G mutation. In some embodiments, the anti-CD3 arm comprising an N297G mutation comprises the following six HVRS: (a)...

Claims

**Claim 1** A method of treating a subject having multiple myeloma (MM) with high-risk cytogenetic features, the method comprising administering to the subject (i) a bispecific antibody that binds to fragment crystallizable receptor-like 5 (FcRH5) and cluster of differentiation 3 (CD3), and (ii) lenalidomide. **Claim 2** The method according to claim 1, wherein the subject has experienced at least a partial response (PR) or better after induction therapy. **Claim 3** The method according to claim 1 or 2, wherein the subject has received autologous stem cell transplantation (ASCT) within 100 days from the start of the method and / or does not have progressive disease. **Claim 4** The method according to any one of claims 1 to 3, wherein the bispecific antibody and lenalidomide are administered to the patient as post-transplant maintenance therapy. **Claim 5** The method according to any one of claims 1 to 4, wherein the high-risk cytogenetic features include one or more of the translocation events t(4;14) or t(14;16), del(17p) or 1q gain. **Claim 6** The method according to any one of claims 1 to 5, wherein the subject had high-risk cytogenetic features at the time of diagnosis of MM. **Claim 7** The bispecific antibody and the lenalidomide are (i) a first phase comprising one or more dosing cycles, the first phase comprising administering the bispecific antibody to the subject every two weeks (Q2W), and (ii) a second phase comprising one or more dosing cycles, the second phase comprising administering the bispecific antibody to the subject every four weeks (Q4W), and are administered to the subject according to a dosing regimen comprising the first phase and the second phase. **Claim 8** The method according to claim 7, wherein each dosing cycle of the first phase and / or the second phase is a 28-day dosing cycle. **Claim 9** The method according to claim 7 or 8, further comprising a pre-phase comprising one or more dosing cycles before the first phase, the pre-phase comprising administering the bispecific antibody to the subject weekly (QW). **Claim 10** The method according to claim 9, wherein each dosing cycle of the pre-phase is a 28-day dosing cycle. **Claim 11** The method according to claim 10, wherein the pre-phase comprises one dosing cycle (C1). **Claim 12** The method according to claim 11, wherein the pre-phase comprises administering the bispecific antibody to the subject on the 1st, 8th, and 15th days of the C1.

13. The method according to any one of claims 9 to 12, wherein the target dose of the bispecific antibody is administered to the subject for each administration in the pre-phase.

14. The method according to any one of claims 9 to 12, wherein the pre-phase comprises administering to the subject a first step-up dose of the bispecific antibody.

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

16. The method according to claim 15, wherein the target dose is administered to the subject on the 8th and 15th days of the C1.

17. The method according to any one of claims 9 to 12, wherein the pre-phase comprises administering to the subject a first step-up dose and a second step-up dose of the bispecific antibody.

18. The method according to claim 17, wherein the first step-up dose is administered to the subject on the 1st day of the C1, and the second step-up dose is administered to the subject on the 8th day of the C1.

19. The method according to claim 18, wherein the target dose is administered to the subject on the 15th day of the C1.

20. The method according to any one of claims 15 to 19, wherein the first step-up dose is 3.6 mg.

21. The method according to any one of claims 17 to 19, wherein the first step-up dose is 0.3 mg and the second step-up dose is 3.6 mg.

22. The method according to any one of claims 8 to 21, wherein the first phase comprises at least two dosing cycles, at least three dosing cycles, at least four dosing cycles, or at least five dosing cycles.

23. The method according to claim 22, wherein the first 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).

24. The method according to claim 23, wherein the first phase comprises administering the bispecific antibody to the subject on the 1st and 15th days of the C1, the C2, the C3, the C4, and / or the C5.

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

26. The method according to any one of claims 8 to 25, wherein the second 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.

27. The method according to claim 26, 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), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7).

28. The method according to claim 27, wherein the second phase comprises administering the bispecific antibody to the subject on day 1 of the C1, the C2, the C3, the C4, the C5, the C6, and / or the C7.

29. The method according to claim 28, wherein the bispecific antibody at the target dose is administered to the subject for each administration during the second phase.

30. The method according to any one of claims 13, 16, 19, 25, and 29, wherein the target dose is 90 mg to 198 mg (including both end values).

31. The method according to claim 30, wherein the target dose is 90 mg.

32. The method according to claim 30, wherein the target dose is 132 mg.

33. The method according to claim 30, wherein the target dose is 160 mg.

34. The method according to any one of claims 1 to 33, wherein the bispecific antibody is administered intravenously to the subject.

35. The method according to any one of claims 8 to 34, wherein the lenalidomide is administered to the subject on days 1 to 21 of each dosing cycle in the first phase and / or the second phase.

36. The method according to any one of claims 10 to 35, wherein the lenalidomide is administered to the subject on days 1 to 21 of each dosing cycle in the pre-phase.

37. The method according to any one of claims 1 to 36, wherein the lenalidomide is administered to the subject at a dose of about 10 mg to about 20 mg.

38. The method according to claim 37, wherein the lenalidomide is administered to the subject at a dosage of about 10 mg.

39. The method according to claim 37, wherein the lenalidomide is administered to the subject at a dosage of about 15 mg.

40. The method according to any one of claims 1 to 39, wherein the lenalidomide is orally administered to the subject.

41. The method according to any one of claims 1 to 40, further comprising administering a corticosteroid to the subject.

42. The method according to any one of claims 7 to 41, further comprising administering a corticosteroid to the subject during the first phase and / or the second phase.

43. The method according to any one of claims 24 to 42, wherein the corticosteroid is administered to the subject on the 1st and 15th days of C1 of the first phase during the first phase.

44. The method according to any one of claims 24 to 43, wherein when the subject has experienced a cytokine release syndrome (CRS) event at a previous dosage, the corticosteroid is administered to the subject at C2, C3, C4 and / or C5 of the first phase.

45. The method according to any one of claims 28 to 44, wherein when the subject has experienced a CRS event at a previous dosage, the corticosteroid is administered to the subject at C1, C2, C3, C4, C5, C6 and / or C7 of the second phase.

46. The method according to any one of claims 9 to 45, further comprising administering a corticosteroid to the subject during the pre-phase.

47. The method according to any one of claims 11 to 46, wherein the corticosteroid is administered to the subject on the 1st, 8th and 15th days of C1 during the pre-phase.

48. The method according to any one of claims 41 to 47, wherein the corticosteroid is intravenously or orally administered to the subject.

49. The method according to claim 48, wherein the corticosteroid is intravenously administered to the subject.

50. The method according to any one of claims 41 to 49, wherein the corticosteroid is intravenously administered to the subject before the administration of the bispecific antibody.

51. The method according to claim 50, wherein the corticosteroid is intravenously administered to the subject about 1 hour before the administration of the bispecific antibody.

52. The method according to any one of claims 41 to 51, wherein the corticosteroid is dexamethasone or methylprednisolone.

53. The method according to claim 52, wherein the corticosteroid is dexamethasone.

54. The method according to claim 52 or 53, wherein the dexamethasone is administered to the subject at a dose of about 20 mg.

55. The method according to claim 52, wherein the methylprednisolone is administered to the subject at a dose of about 80 mg.

56. 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 HYYGS SDYALD N (SEQ ID NO: 3); (d) HVR-L1 comprising the amino acid sequence of KASQDVRNL VV (SEQ ID NO: 4); (e) HVR-L2 comprising the amino acid sequence of SGSYRY S (SEQ ID NO: 5); and (f) HVR-L3 comprising the amino acid sequence of QQHYS PPYT (SEQ ID NO: 6) The method according to any one of claims 1 to 55, comprising an anti-FcRH5 arm comprising a first binding domain.

57. 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). The method according to any one of claims 1 to 56.

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

60. The bispecific antibody is (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). The method according to any one of claims 1 to 59.

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 bispecific antibody comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1) and a light chain polypeptide (L1), and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), (a) H1 comprises the amino acid sequence of SEQ ID NO: 35, (b) L1 comprises the amino acid sequence of SEQ ID NO: 36, (c) H2 comprises the amino acid sequence of SEQ ID NO: 37, (d) L2 comprises the amino acid sequence of SEQ ID NO: 38, The method according to any one of claims 1 to 61.

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.

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

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

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

69. The method according to any one of claims 1 to 68, wherein the bispecific antibody is a chimeric antibody.

70. The method according to any one of claims 1 to 61 and 63 to 69, wherein the bispecific antibody is an antibody fragment that binds to FcRH5 and CD3.

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.

72. The method according to any one of claims 1 to 71, wherein the bispecific antibody is a full-length antibody.

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

74. The IgG antibody is IgG １ The method according to claim 73, which is an antibody.

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 ), the method according to any one of claims 1 to 74.

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.

77. the CH3 １ domain and the CH3 ２ domains each comprise a protrusion or a cavity, and the CH3 １ protrusion or cavity within the CH3 ２ The method according to claim 76, wherein the cavity or protrusion within the CH3 domain can be respectively disposed in the protrusion or cavity within the CH3 domain.

78. said CH3 １ domain and said CH3 ２ The method according to claim 77, wherein the domain and the domain meet at an interface between the protrusion and the cavity.

79. the CH2 １ domain and the CH2 ２ domains each comprise a protrusion or a cavity, and the protrusion or cavity within the CH2 １ domain is respectively disposed within the cavity or protrusion within the CH2 ２ A method according to any one of claims 75 to 78, wherein the protrusion or cavity within the CH2 domain is respectively capable of being disposed within the cavity or protrusion within the CH2 domain.

80. said CH2 １ domain and said CH2 ２ The method according to claim 79, wherein the domain and the CH2 domain meet at an interface between the protrusion and the cavity.

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

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

83. The method according to any one of claims 1 to 69 and 72 to 82, wherein the bispecific antibody is cevostamab.

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

85. The method according to claim 84, wherein the bispecific antibody and / or the lenalidomide are administered to the subject prior to the administration of one or more additional therapeutic agents.

86. The method according to claim 84, wherein the bispecific antibody and / or the lenalidomide are administered to the subject after the administration of one or more additional therapeutic agents.

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 CRS event, and the method further comprises treating the symptoms of the CRS event while withholding treatment with the bispecific antibody.

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

90. The CRS event does not resolve or worsens within 24 hours after treating the symptoms of the CRS event, and the method further comprises administering to the subject one or more additional doses of tocilizumab to manage the CRS event, the method of claim 88.

91. The method according to any one of claims 87, 89, and 90, wherein tocilizumab is administered to the subject by intravenous infusion.

92. (a) the subject weighs 30 kg or more and tocilizumab is administered to the subject at a dose of 8 mg / kg, or (b) the subject weighs less than 30 kg and tocilizumab is administered to the subject at a dose of 12 mg / kg, the method of claim 91.

93. The method according to any one of claims 87, 91, and 92, wherein tocilizumab is administered to the subject 2 hours before administration of the bispecific antibody.

94. The method according to any one of claims 84 to 93, wherein the one or more additional therapeutic agents comprise an effective amount of B cell maturation antigen (BCMA)-directed therapy, an additional immunomodulatory drug (IMiD), CD38-directed therapy, or any combination of the foregoing.

95. The method according to any one of claims 84 to 94, wherein the one or more additional therapeutic agents comprise an effective amount of acetaminophen or paracetamol.

96. The method of claim 95, wherein acetaminophen or paracetamol is administered to the subject at a dose of about 500 mg to about 1000 mg.

97. The method of claim 96, wherein acetaminophen or paracetamol is administered orally to the subject.

98. The method according to any one of claims 84 to 97, wherein the one or more additional therapeutic agents comprise an effective amount of diphenhydramine.

99. The method of claim 98, wherein diphenhydramine is administered to the subject at a dose of about 25 mg to about 50 mg.

100. The method of claim 99, wherein diphenhydramine is administered orally to the subject.

101. A method of treating a subject having MM with high-risk cytogenetic features, the method comprising administering to the subject sevosumab and lenalidomide, (i) the subject has experienced PR or better after induction therapy, (ii) the subject has received ASCT within 100 days from the start of the method and / or does not have progressive disease, (iii) the sevosizumab and lenalidomide are administered to the patient as post-transplant maintenance therapy, and (iv) the high-risk cytogenetic features include one or more of the translocation events t(4;14) or t(14;16), del(17p) or 1q gain, method.

102. A method of treating a subject having MM with high-risk cytogenetic features, the method comprising administering sevosizumab and lenalidomide to the subject (i) a pre-phase including a 28-day dosing cycle (C1), (ii) a first phase following the pre-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 first phase is a 28-day dosing cycle, the first phase; (iii) a second phase following the first phase, comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7), wherein each dosing cycle of the second phase is a 28-day dosing cycle, the second phase; including administering to the subject in a dosing regimen comprising Sevosizumab is administered to the subject (i) on day 1 of C1 at a first step-up dose during the pre-phase and on day 8 of C1 as a second step-up dose during the pre-phase, (ii) at a target dose on day 15 of C1 during the pre-phase, (iii) at a target dose on days 1 and 15 of C1, C2, C3, C4, and C5 during the first phase, (iv) at a target dose on day 1 of C1, C2, C3, C4, C5, C6, and C7 during the second phase, Lenalidomide is administered to the subject (i) during the pre-phase, on days 1 to 21 of C1, (ii) during the first phase, administered on days 1 to 21 of said C1, said C2, said C3, said C4 and said C5, (iii) during the second phase, administered on days 1 to 21 of said C1, said C2, said C3, said C4, said C5, said C6 and said C7, A method.

103. (i) the first step-up dose of sevosatamab is 0.3 mg, (ii) the second step-up dose of sevosatamab is 3.6 mg, (iii) the target dose of sevosatamab is 90 mg to 198 mg (including both end values), (iv) lenalidomide is administered at a dose of 10 mg or 15 mg, The method according to claim 102.

104. The method according to claim 103, wherein the target dose is 90 mg.

105. The method according to claim 103, wherein the target dose is 132 mg.

106. The method according to claim 103, wherein the target dose is 160 mg.

107. (i) the subject has experienced PR or better after induction therapy, (ii) the subject has received ASCT within 100 days from the start of the method and / or does not have progressive disease, (iii) the sevosatamab and lenalidomide are administered to the patient as post-transplant maintenance therapy, and (iv) the high-risk cytogenetic features include one or more of the translocation events t(4;14) or t(14);16), del(17p) or 1q gain, The method according to any one of claims 102 to 106.

108. A bispecific antibody that binds to FcRH5 and CD3 for use in treating a subject having MM with high-risk cytogenetic features, wherein the treatment comprises administering the bispecific antibody and lenalidomide to the subject.

109. Sevosatamab for use in treating a subject having MM with high-risk cytogenetic features, wherein the treatment comprises administering sevosatamab and lenalidomide to the subject, (i) the subject has experienced PR or better after induction therapy, (ii) the subject has received ASCT within 100 days from the start of the method and / or does not have progressive disease, (iii) the sevosatamab and lenalidomide are administered to the patient as post-transplant maintenance therapy, and (iv) the high-risk cytogenetic features include one or more of the translocation events t(4;14) or t(14;16), del(17p) or 1q gain Cevostamab.

110. Cevostamab for use in treating a subject having MM with high-risk cytogenetic features, wherein the treatment comprises administering cevostamab and lenalidomide to the subject (i) a pre-phase comprising a 28-day dosing cycle (C1), (ii) a first phase following the pre-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 first phase is a 28-day dosing cycle, the first phase (iii) a second phase following the first phase, comprising a first dosing cycle (C1), a second dosing cycle (C2), a third dosing cycle (C3), a fourth dosing cycle (C4), a fifth dosing cycle (C5), a sixth dosing cycle (C6), and a seventh dosing cycle (C7), wherein each dosing cycle of the second phase is a 28-day dosing cycle, the second phase in a dosing regimen comprising administering to the subject Cevostamab is administered to the subject (i) at a first step-up dose on day 1 of C1 during the pre-phase and at a second step-up dose on day 8 of C1 during the pre-phase, (ii) at a target dose on day 15 of C1 during the pre-phase, (iii) at a target dose on days 1 and 15 of C1, C2, C3, C4 and C5 during the first phase, (iv) at a target dose on day 1 of C1, C2, C3, C4, C5, C6 and C7 during the second phase, Lenalidomide is administered to the subject (i) during the pre-phase, on days 1 to 21 of C1, (ii) during the first phase, on days 1 to 21 of C1, C2, C3, C4 and C5, (iii) during the second phase, on days 1 to 21 of C1, C2, C3, C4, C5, C6 and C7, Cevostamab.

111. (i) the first step-up dose of cevostamab is 0.3 mg, (ii) the second escalating dose of sevosetamab is 3.6 mg, (iii) the target dose of sevosetamab is 90 mg to 198 mg (including both end values), (iv) lenalidomide is administered at a dose of 10 mg or 15 mg, Sevosetamab for use according to claim 110.

112. Sevosetamab for use according to claim 111, wherein the target dose is 90 mg.

113. Sevosetamab for use according to claim 111, wherein the target dose is 132 mg.

114. Sevosetamab for use according to claim 111, wherein the target dose is 160 mg.

115. (i) the subject has experienced PR or better after induction therapy, (ii) the subject has received ASCT within 100 days from the start of the method and / or does not have progressive disease, (iii) the sevosetamab and lenalidomide are administered to the patient as post-transplant maintenance therapy, and (iv) the high-risk cytogenetic features include one or more of the translocation events t(4;14) or t(14;16), del(17p) or 1q gain, Sevosetamab for use according to any one of claims 110 to 114.

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