Methods for treating and diagnosing multiple myeloma

Abstract

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

Description

[Technical Field]

[0001] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML format and is incorporated herein by reference in its entirety. The XML copy, created on October 4, 2023, is named 50474-309WO2_Sequence_Listing_10_4_23 and is 41,573 bytes in size.

[0002] The present invention relates to the treatment of cancer, such as B cell proliferative disorders, and methods for monitoring and evaluating such treatment. More specifically, the present invention relates to the treatment of cancer, such as B cell proliferative disorders, by increasing levels of T cell proliferation markers (e.g., a marker of proliferation Ki-67 (MKI67)) and / or increasing numbers of MKI67 + This article relates to the treatment, monitoring, and evaluation of patients with multiple myeloma (MM) who have T cells. Treatment can be performed using an anti-fragment crystallizable receptor-like 5 (FcRH5) / anti-cluster of differentiation 3 (CD3) bispecific antibody. [Background technology]

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

[0004] Hematologic cancers, in particular, are the second leading cause of cancer-related deaths. These include multiple myeloma (MM), a neoplasm characterized by the proliferation and accumulation of malignant plasma cells. Approximately 110,000 people worldwide are diagnosed with MM each year. MM remains incurable despite advances in treatment, with an estimated median survival of 8–10 years for standard-risk myeloma and 2–3 years for high-risk disease, despite autologous stem cell transplantation. Despite significant improvements in patient survival over the past 20 years, only 10–15% of patients achieve or exceed expected survival rates compared with the matched general population. Increased survival has been achieved with the introduction of proteasome inhibitors, immunomodulatory drugs (IMiDs), and monoclonal antibodies. Nevertheless, outcomes for MM patients are very poor, with survival times of less than one year for most (if not all) patients, who eventually relapse, become refractory, or are no longer able to receive proteasome inhibitors or IMiDs. Therefore, relapsed or refractory (R / R) MM in particular still constitutes a significant unmet medical need, and new therapeutic agents are needed. For such patients, alternative or secondary treatments such as bispecific antibody-based immunotherapy may be particularly effective. There is an unmet need in the field for the development of effective methods of administering therapeutic bispecific antibodies (e.g., bispecific anti-FcRH5 / anti-CD3 antibodies) for the treatment of cancer (e.g., MM, e.g., R / R) that achieve a more favorable benefit-risk profile. Summary of the Invention

[0005] Provided herein, inter alia, are methods of treating a subject having cancer (e.g., MM), methods of evaluating a treatment for cancer (e.g., MM) in a subject, and methods of monitoring a subject's response to a treatment for cancer (e.g., MM) in a subject.

[0006] In one aspect, the invention features a method of treating a subject having multiple myeloma (MM) with a bispecific antibody that binds Fc receptor homolog 5 (FcRH5) and cluster of differentiation 3 (CD3), the method including: (a) determining the level of a T cell proliferation marker in a biological sample obtained from the subject at a time after administration of the bispecific antibody; (b) comparing the level of the T cell proliferation marker in the biological sample to a reference level, wherein an increased level of the T cell proliferation marker in the biological sample compared to the reference level identifies the subject as one that is responsive to the bispecific antibody; and (c) continuing to administer the bispecific antibody to the subject if the level of the T cell proliferation marker is increased compared to the reference level.

[0007] In another aspect, the invention provides a method of treating a subject with MM with a bispecific antibody that binds FcRH5 and CD3, comprising: (a) detecting proliferation Ki-67 positivity (MK167) in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; + (b) determining the number of T cell markers; (c) determining the number of MKI67 in the biological sample; + comparing the number of T cells to a reference number, and determining whether MKI67 in the biological sample is higher than the reference number; + (c) comparing an increased number of T cells to identify the subject as responding to the bispecific antibody; and (d) detecting MKI67 in the subject's biological sample. + If the number of T cells is increased compared to the reference number, continuing to administer the bispecific antibody to the subject.

[0008] In another aspect, the invention features a method of monitoring the response of a subject with MM to treatment with a bispecific antibody that binds FcRH5 and CD3, comprising: (a) determining the level of a T cell proliferation marker in a biological sample obtained from the subject at a time after administration of the bispecific antibody; and (b) comparing the level of the T cell proliferation marker in the biological sample to a reference level, wherein an increased level of the T cell proliferation marker in the biological sample compared to the reference level identifies the subject as one that is responding to the bispecific antibody, thereby monitoring the subject's response to treatment with the bispecific antibody.

[0009] In another aspect, the invention provides a method for monitoring the response of a subject with MM to treatment with a bispecific antibody that binds FcRH5 and CD3, comprising: (a) detecting MKI67 in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; + (b) determining the number of T cells; and (b) MKI67 in the biological sample. + comparing the number of T cells to a reference number, and determining whether MKI67 in the biological sample is higher than the reference number; + and comparing an increased number of T cells to identify the subject as a subject responding to the bispecific antibody, thereby featuring a method for monitoring the subject's response to treatment with the bispecific antibody.

[0010] In another aspect, the invention features a method for assessing the treatment response of a subject with MM to treatment with a bispecific antibody that binds FcRH5 and CD3, the method comprising: (a) determining the level of a T cell proliferation marker in a biological sample obtained from the subject at a time after administration of the bispecific antibody; and (b) maintaining, adjusting, or stopping the subject's treatment based on a comparison of the level of the T cell proliferation marker in the biological sample to a reference level, wherein a change in the level of the T cell proliferation marker in the biological sample compared to the reference level indicates a response to treatment with the bispecific antibody.

[0011] In another aspect, the invention provides a method for assessing the treatment response of a subject with MM to treatment with a bispecific antibody that binds FcRH5 and CD3, comprising: (a) detecting MKI67 in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; + (b) determining the number of T cells; and (b) MKI67 in the biological sample. + maintaining, adjusting, or stopping the subject's treatment based on a comparison of the number of T cells to a reference number; + The method is featured, wherein a change in the number of T cells indicates a response to treatment with the bispecific antibody.

[0012] In another aspect, the invention features a bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, the treatment comprising: (a) determining the level of a T cell proliferation marker in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; (b) comparing the level of the T cell proliferation marker in the biological sample with a reference level, wherein an increased level of the T cell proliferation marker in the biological sample compared to the reference level identifies the subject as one that is responsive to the bispecific antibody; and (c) continuing to administer the bispecific antibody to the subject if the level of the T cell proliferation marker is increased compared to the reference level.

[0013] In another aspect, the invention provides a bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, wherein the treatment comprises (a) detecting proliferation Ki-67 positivity (MK167) in a biological sample obtained from the subject at a time point after administration of the bispecific antibody. + (b) determining the number of T cell markers; (c) determining the number of MKI67 in the biological sample; + comparing the number of T cells to a reference number, and determining whether MKI67 in the biological sample is higher than the reference number; + (c) comparing an increased number of T cells to identify the subject as responding to the bispecific antibody; and (d) detecting MKI67 in the subject's biological sample. +If the number of T cells is increased compared to the reference number, continuing to administer the bispecific antibody to the subject.

[0014] In another aspect, the invention features a bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, the treatment comprising monitoring the subject's response to the treatment, the monitoring comprising: (a) determining the level of a T cell proliferation marker in a biological sample obtained from the subject at a time after administration of the bispecific antibody; and (b) comparing the level of the T cell proliferation marker in the biological sample with a reference level, wherein an increased level of the T cell proliferation marker in the biological sample compared to the reference level identifies the subject as one that is responding to the bispecific antibody, thereby monitoring the subject's response to treatment with the bispecific antibody.

[0015] In another aspect, the invention provides a bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, the treatment comprising monitoring the subject's response to the treatment, the monitoring comprising: (a) detecting MKI67 in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; + (b) determining the number of T cells; and (b) MKI67 in the biological sample. + comparing the number of T cells to a reference number, and determining whether MKI67 in the biological sample is higher than the reference number; + and comparing an increased number of T cells to identify the subject as a subject responding to the bispecific antibody, thereby monitoring the subject's response to treatment with the bispecific antibody.

[0016] In another aspect, the invention provides a bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, the treatment comprising assessing the subject's response to the treatment, the assessment comprising: (a) determining the level of a T cell proliferation marker in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; and (b) maintaining, adjusting, or stopping the subject's treatment based on a comparison of the level of the T cell proliferation marker in the biological sample to a reference level, wherein a change in the level of the T cell proliferation marker in the biological sample compared to the reference level indicates a response to treatment with the bispecific antibody.

[0017] In another aspect, the invention provides a bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, the treatment comprising assessing the subject's response to the treatment, the assessment comprising: (a) detecting MKI67 in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; + (b) determining the number of T cells; and (b) MKI67 in the biological sample. + maintaining, adjusting, or stopping the subject's treatment based on a comparison of the number of T cells to a reference number; + A change in the number of T cells characterizes the bispecific antibody, indicating a response to treatment with the bispecific antibody.

[0018] In some embodiments, (a) if the level of the T cell proliferation marker in the biological sample increases compared to the reference level, the subject is responding to the treatment, and treatment is maintained; or (b) if the level of the T cell proliferation marker in the biological sample remains the same or decreases compared to the reference level, the subject is not responding to the treatment, and treatment is adjusted or stopped.

[0019] In some embodiments, (a) MKI67 in a biological sample + If the number of cells is increased compared to the reference number, the subject is responding to the treatment and the treatment is maintained; or (b) detecting MKI67 in the biological sample. +If the number of cells remains the same or decreases compared to the reference number, the subject is not responding to treatment and treatment is adjusted or stopped.

[0020] In some aspects, the method further comprises administering the bispecific antibody to a subject.

[0021] In some embodiments, the bispecific antibody is administered in a dosing regimen comprising: (a) a first dosing cycle comprising at least a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody; and (b) a second dosing cycle comprising a single dose (C2D1) of the bispecific antibody.

[0022] In some embodiments, the time point after administration of the bispecific antibody is before C2D1.

[0023] In some embodiments, (a) C1D1 is from about 0.5 mg to about 19.9 mg; (b) C1D2 is from about 20 mg to about 600 mg; and (c) C2D1 is from about 20 mg to about 600 mg.

[0024] In some embodiments, (a) C1D1 is from about 1.2 mg to about 10.8 mg; (b) C1D2 is from about 80 mg to about 300 mg; and (c) C2D1 is from about 80 mg to about 300 mg.

[0025] In some embodiments, (a) C1D1 is about 3.6 mg; (b) C1D2 is about 198 mg; and (c) C2D1 is about 198 mg.

[0026] In some embodiments, the first and second dosing cycles are 21 days in length.

[0027] In some embodiments, the dosing regimen comprises administering C1D1 and C1D2 to the subject on or about day 1 and on or about day 8 of a first dosing cycle, respectively, and administering C2D1 on or about day 1 of a second dosing cycle.

[0028] In some embodiments, the dosing regimen includes one or more additional dosing cycles.

[0029] In some embodiments, the dosing regimen comprises administering the bispecific antibody to the subject on or about day 1 of each additional dosing cycle.

[0030] In some embodiments, the one or more additional dosing cycles comprise: (a) a third dosing cycle comprising a single dose of the bispecific antibody (C3D1); and / or (b) a fourth dosing cycle comprising a single dose of the bispecific antibody (C4D1).

[0031] In some embodiments, the time point after administration of the bispecific antibody is before C3D1 and / or C4D1.

[0032] In some embodiments, the bispecific antibody is administered in a dosing regimen comprising: (a) a first dosing cycle comprising at least a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody; and (b) a second dosing cycle comprising a single dose of the bispecific antibody (C2D1).

[0033] In some embodiments, the time point after administration of the bispecific antibody is before C2D1.

[0034] In some embodiments, (a) C1D1 is from about 0.01 mg to about 2.9 mg; (b) C1D2 is from about 3 mg to about 19.9 mg; (c) C1D3 is from about 20 mg to about 600 mg; and (d) C2D1 is from about 20 mg to about 600 mg.

[0035] In some embodiments, (a) C1D1 is from about 0.2 mg to about 0.4 mg; (b) C1D2 is from about 3.2 mg to about 10 mg; (c) C1D3 is from about 80 mg to about 300 mg; and (d) C2D1 is from about 80 mg to about 300 mg.

[0036] In some embodiments, (a) C1D1 is about 0.3 mg; (b) C1D2 is about 3.6 mg; (c) C1D3 is about 160 mg; and (d) C2D1 is about 160 mg.

[0037] In some embodiments, the first and second dosing cycles are 21 days in length.

[0038] In some embodiments, the dosing regimen comprises administering C1D1, C1D2, and C1D3 on or about days 1, 8, and 15 of a first dosing cycle, and administering C2D1 on or about day 1 of a second dosing cycle.

[0039] In some embodiments, the dosing regimen includes one or more additional dosing cycles.

[0040] In some embodiments, the dosing regimen comprises administering the bispecific antibody to the subject on or about day 1 of each additional dosing cycle.

[0041] In some embodiments, the one or more additional dosing cycles comprise: (a) a third dosing cycle comprising a single dose of the bispecific antibody (C3D1); and / or (b) a fourth dosing cycle comprising a single dose of the bispecific antibody (C4D1).

[0042] In some embodiments, the time point after administration of the bispecific antibody is before C3D1 and / or C4D1.

[0043] In some embodiments, the T cell proliferation marker is marker of proliferation Ki-67 (MKI67).

[0044] In some embodiments, the level of the T cell proliferation marker is at the protein level.

[0045] In some embodiments, protein levels are detected by flow cytometry (FC), Western blot, enzyme-linked immunosorbent assay (ELISA), mass spectrometry (MS), immunofluorescence (IF), or immunohistochemistry (IHC).

[0046] In some embodiments, protein levels are detected with an MKI67 antibody.

[0047] In some embodiments, the MKI67 antibody is a monoclonal Ki-67 or MIB-1 antibody.

[0048] In some embodiments, the level of the T cell proliferation marker is the mRNA level of MKI67.

[0049] In some embodiments, mRNA levels are detected by polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), quantitative PCR (qPCR), microarray analysis, Northern blot, or RNA sequencing.

[0050] In some embodiments, the T cell proliferation marker is detected in T cells.

[0051] In some embodiments, the T cells are MKI67 + is.

[0052] In some embodiments, the reference level is the level of the T cell proliferation marker determined in a biological sample obtained from the subject prior to administration of the bispecific antibody to the subject.

[0053] In some embodiments, the reference level is the level of MKI67 determined in a biological sample obtained from the subject prior to administration of the bispecific antibody to the subject.

[0054] In some embodiments, MKI67 + T cells are detected by FC, Western blot, ELISA, MS, IF or IHC.

[0055] In some embodiments, MKI67 + T cells are detected with the MKI67 antibody.

[0056] In some embodiments, the MKI67 antibody is a monoclonal Ki-67 or MIB-1 antibody.

[0057] In some embodiments, the reference number is an MKI67 determined in a biological sample obtained from a subject prior to administering the bispecific antibody to the subject. + The number of T cells.

[0058] In some embodiments, the T cells are cluster of differentiation 8 (CD8) positive (CD8 + )

[0059] In some embodiments, the T cells are granzyme B (Gzb) positive (Gzb+).

[0060] In some embodiments, the biological sample is blood, serum, or plasma.

[0061] In some embodiments, the bispecific antibody comprises an anti-FcRH5 arm comprising a first binding domain comprising the following six hypervariable regions (HVRs): (a) HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) HVR-H3 comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO: 3); (d) HVR-L1 comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (f) HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6).

[0062] In some embodiments, the bispecific antibody comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8; or (c) an anti-FcRH5 arm comprising a first binding domain comprising the VH domain described in (a) and the VL domain described in (b).

[0063] 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.

[0064] In some embodiments, the bispecific antibody comprises an anti-CD3 arm comprising a second binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

[0065] In some embodiments, the bispecific antibody comprises an anti-CD3 arm comprising: (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16; or (c) a second binding domain comprising the VH domain of (a) and the VL domain of (b).

[0066] 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.

[0067] 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.

[0068] In some aspects, the bispecific antibody is cebostamab.

[0069] In some aspects, the bispecific antibody comprises an aglycosylation site mutation.

[0070] In some aspects, the aglycosylation site mutation reduces the effector function of the bispecific antibody.

[0071] In some aspects, the aglycosylation site mutation is a substitution mutation.

[0072] In some embodiments, the bispecific antibody comprises substitution mutations in the Fc region that reduce effector function.

[0073] In some embodiments, the bispecific antibody is a monoclonal antibody.

[0074] In some aspects, the bispecific antibody is a humanized antibody.

[0075] In some aspects, the bispecific antibody is a chimeric antibody.

[0076] In some embodiments, the bispecific antibody is an antibody fragment that binds FcRH5 and CD3.

[0077] In some embodiments, the antibody fragment is selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments.

[0078] In some aspects, the bispecific antibody is a full-length antibody.

[0079] In some embodiments, the bispecific antibody is an IgG antibody.

[0080] In some embodiments, the IgG antibody is an IgG1 antibody.

[0081] In some embodiments, the bispecific antibody comprises one or more heavy chain constant domains 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.

[0082] In some embodiments, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

[0083] In some embodiments, the CH31 domain and the CH32 domain each comprise a protrusion or a cavity, and the protrusion or cavity of the CH31 domain can be positioned in the cavity or protrusion of the CH32 domain, respectively.

[0084] In some embodiments, the CH31 and CH32 domains associate at the interface between the protrusion and the cavity.

[0085] 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 positioned in the cavity or protrusion of the CH22 domain, respectively.

[0086] In other embodiments, the CH21 and CH22 domains associate at the interface between the protrusion and the cavity.

[0087] In some embodiments, the anti-FcRH5 arm comprises a protrusion and the anti-CD3 arm comprises a cavity.

[0088] In some embodiments, the CH3 domain of the anti-FcRH5 arm comprises a protrusion comprising a T366W amino acid substitution mutation (EU numbering), and the CH3 domain of the anti-CD3 arm comprises a cavity comprising T366S, L368A, and Y407V amino acid substitution mutations (EU numbering).

[0089] In some embodiments, the bispecific antibody is administered to a subject as a monotherapy.

[0090] In some embodiments, the bispecific antibody is administered to a subject as a combination therapy.

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

[0092] In some embodiments, the bispecific antibody is administered to the subject prior to the administration of one or more additional therapeutic agents.

[0093] In some embodiments, the bispecific antibody is administered to the subject after administration of one or more additional therapeutic agents.

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

[0095] In some embodiments, tocilizumab is administered to the subject by intravenous infusion.

[0096] In some embodiments, (a) the subject weighs 100 kg or more and tocilizumab is administered to the subject at a dose of 800 mg; (b) the subject weighs 30 kg or more but less than 100 kg and tocilizumab is administered to the subject at a dose of 8 mg / kg; or (c) the subject weighs less than 30 kg and tocilizumab is administered to the subject at a dose of 12 mg / kg.

[0097] In some embodiments, tocilizumab is administered to the subject 2 hours prior to administration of the bispecific antibody.

[0098] In some embodiments, the one or more additional therapeutic agents comprise an effective amount of an immunomodulatory drug (IMiD), daratumumab, or a B-cell maturation antigen (BCMA)-directed therapy.

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

[0100] In some embodiments, the bispecific antibody is administered subcutaneously to the subject.

[0101] In some embodiments, the subject has a cytokine release syndrome (CRS) event and the method further comprises treating the symptoms of the CRS event while withholding treatment with the bispecific antibody.

[0102] In some embodiments, the method further comprises administering to the subject an effective amount of tocilizumab to treat the CRS event.

[0103] In some embodiments, tocilizumab is administered to the subject intravenously as a single dose of about 8 mg / kg.

[0104] In some embodiments, the CRS event does not resolve or worsens within 24 hours of treating the symptoms of the CRS event, and the method further comprises administering one or more additional doses of tocilizumab to the subject to manage the CRS event.

[0105] In some embodiments, the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 8 mg / kg.

[0106] In some embodiments, the one or more additional therapeutic agents comprises an effective amount of a corticosteroid.

[0107] In some embodiments, the corticosteroid is administered to the subject intravenously.

[0108] In some embodiments, the corticosteroid is methylprednisolone.

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

[0110] In some embodiments, the corticosteroid is dexamethasone.

[0111] In some embodiments, the dexamethasone is administered at a dose of about 20 mg.

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

[0113] In some embodiments, the acetaminophen or paracetamol is administered in a dose of about 500 mg to about 1000 mg.

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

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

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

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

[0118] In some embodiments, the MM is relapsed or refractory (R / R) MM.

[0119] In some embodiments, the individual has received at least three prior lines of treatment for MM.

[0120] In some embodiments, the individual has received at least four prior lines of treatment for MM.

[0121] In some embodiments, the individual has been exposed to a prior treatment including a proteasome inhibitor, an IMiD and / or an anti-CD38 therapeutic agent.

[0122] In some embodiments, the proteasome inhibitor is bortezomib, carfilzomib, or ixazomib.

[0123] In some embodiments, the IMiD is thalidomide, lenalidomide, or pomalidomide.

[0124] In some embodiments, the anti-CD38 therapeutic agent is an anti-CD38 antibody.

[0125] In some embodiments, the anti-CD38 antibody is daratumumab, MOR202, or isatuximab.

[0126] In some embodiments, the anti-CD38 antibody is daratumumab.

[0127] In some embodiments, the individual has been exposed to a prior treatment including an anti-SLAMF7 therapeutic agent, a nuclear export inhibitor, a histone deacetylase (HDAC) inhibitor, autologous stem cell transplant (ASCT), a bispecific antibody, an antibody-drug conjugate (ADC), a CAR-T cell therapy, or a BCMA-directed therapy.

[0128] In some embodiments, the anti-SLAMF7 therapeutic agent is an anti-SLAMF7 antibody.

[0129] In some embodiments, the anti-SLAMF7 antibody is elotuzumab.

[0130] In some embodiments, the nuclear export inhibitor is selinexor.

[0131] In some embodiments, the HDAC inhibitor is panobinostat.

[0132] In some embodiments, the BCMA-directed therapy is an antibody-drug conjugate that targets BCMA. [Brief explanation of the drawings]

[0133] [Figure 1] FIG. 1 is a schematic diagram showing the dose escalation schedule for Arm A (single dose escalation arm) and Arm B (multiple dose escalation arm) of the GO39775 Phase I dose escalation study. C: cycle; D: day; Q: all. [Figure 2A] 1 is a schematic structure of cebostamab. [Figure 2B] 1 is a schematic showing the mechanism of action of cebostamab. [Figure 2C] A typical timeline for a one-step dosing regimen and whole blood sample collection is shown. [Figure 3A] 1 is a schematic of the framework used for unbiased clustering of flow cytometry data. [Figure 3B] 1 is a representative delta area plot used in determining cluster number (k). This plot allows the user to determine the relative increase in consensus and determine the k where there is no apparent increase in the area under the cumulative distribution function (CDF) curve. [Figure 3C] 1 is a representative heatmap used to visualize marker distribution in clusters. [Figure 3D] The representative uniform manifold approximation and projection (UMAP) of the cluster. [Figure 3E] Representative volcano plot to visualize statistical significance (p-value) versus magnitude of change (fold change) obtained from differential abundance and expression analysis. [Figure 4A] Box plot showing marker of proliferation Ki-67 (MKI67) expression in granzyme B-positive (Gzb+) cluster of differentiation 8 (CD8) T cell clusters using FlowSOM. [Figure 4B] This is a box plot showing the abundance of MKI67-positive (MKI67+) CD8-positive (CD8+) T cells by conventional manual gating. [Figure 4C] Shown are UMAP (top) and box plots (bottom) from Cellular Indexing of Transcriptome and Epitopes by Sequencing (CITE-seq) analysis confirming increased expression of MKI67 after 21 days of treatment. [Figure 5A] Heatmap from FlowSOM clustering showing three cluster of differentiation 4-positive (CD4+) T cell clusters with varying cluster of differentiation 25 (CD25) expression. [Figure 5B] Figure 1 shows CD25 protein expression in CD4+ T cells in CITE-seq data. [Figure 5C] UMAP reclustering of CITE-seq Tregs is shown. [Figure 5D] 10 is a set of graphs showing that reclustering of CITE-seq Tregs produces similar CD25 patterns. [Figure 6A] Heatmap from FlowSOM clustering (top) and corresponding UMAP (bottom) showing two human leukocyte antigen-DR positive (HLA-DR+) cluster of differentiation 19 positive (CD19+) B cell clusters. [Figure 6B] UMAP demonstrating that circulating tumor cells can be distinguished from B cells in CITE-seq data. [Figure 6C] 1 is a set of graphs showing that tumor cells have lower CD19 expression (top) but higher FcRH5 expression (bottom). DETAILED DESCRIPTION OF THE INVENTION

[0134] I. Definition The term "about," as used herein, refers to a normal error range for each value, which would be readily understood by one of ordinary skill in the art. Reference to "about" with respect to a value or parameter herein includes (and describes) aspects directed to the value or parameter itself.

[0135] It will be understood that embodiments of the invention described herein include "comprising," "consisting," and "consisting essentially of" embodiments.

[0136] As used herein, the term "FcRH5" or "fragment crystalline 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 encompasses "full-length," unprocessed FcRH5, as well as any form of FcRH5 resulting from processing within a cell. The term also encompasses naturally occurring variants of FcRH5, including, for example, splice variants or allelic variants. FcRH5 includes, for example, the human FcRH5 protein (UniProtKB / Swiss-Prot ID: Q96RD9.3), which is 977 amino acids in length.

[0137] 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 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, e.g. 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.

[0138] The term "cluster of differentiation 3" or "CD3," as used herein, unless otherwise indicated, refers to any native CD3 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), including, for example, the CD3ε, CD3γ, CD3α, and CD3β chains. The term encompasses "full-length" unprocessed CD3 (e.g., unprocessed or unmodified CD3ε or CD3γ) as well as any form of CD3 resulting from intracellular processing. The term also encompasses naturally occurring variants of CD3, including, for example, splice variants or allelic variants. CD3 includes, for example, the human CD3ε protein, 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).

[0139] 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, e.g. 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.

[0140] For purposes herein, "cebostamab" (also referred to as BFCR4350A or RO7187797) is an Fc-engineered humanized full-length aglycosylated IgG1κ T-cell-dependent bispecific antibody (TDB) that binds FcRH5 and CD3 and comprises an anti-FcRH5 arm comprising a heavy chain polypeptide sequence of SEQ ID NO: 35 and a light chain polypeptide sequence of SEQ ID NO: 36, and an anti-CD3 arm comprising a heavy chain polypeptide sequence of SEQ ID NO: 37 and a light chain polypeptide sequence of SEQ ID NO: 38. Sebostamab contains a threonine-to-tryptophan amino acid substitution (T366W) at position 366 in the heavy chain of the anti-FcRH5 arm (using EU numbering of amino acid residues), and three amino acid substitutions (Y407V, T366S, L368A) in the heavy chain of the anti-CD3 arm (tyrosine to valine at position 407, threonine to serine at position 366, and leucine to alanine at position 368) (using EU numbering of amino acid residues) to drive heterodimerization of the two arms (half antibodies). Sebostamab also contains an asparagine-to-glycine amino acid substitution (N297G) at position 297 in each heavy chain (using EU numbering of amino acid residues) in the Fc region, resulting in an aglycosylated antibody with minimal binding to Fc (Fcγ) receptors and consequently preventing Fc effector function. Sebostamab is also listed in the WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Recommended INN:List 84, Vol. 34, No. 3, published in 2020 (see page 701).

[0141] The term "antibody" is used herein in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments (e.g., bis-Fab), so long as they exhibit the desired antigen-binding activity.

[0142] "Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y is generally determined by the dissociation constant (K D ) Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

[0143] An "affinity matured" antibody refers to an antibody that has one or more alterations in one or more hypervariable regions (HVRs) compared to a parent antibody that does not possess such alterations, which alterations improve the affinity of the antibody for antigen.

[0144] The terms "full length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody having a heavy chain that has a structure substantially similar to a native antibody structure or that contains an Fc region as defined herein.

[0145] "Antibody fragment" refers to a molecule other than an intact antibody that contains a portion of the intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, bis-Fab; Fv; Fab; Fab, Fab'-SH; F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv, ScFab); and multispecific antibodies formed from antibody fragments.

[0146] A "single domain antibody" refers to an antibody fragment that contains all or part of the heavy chain variable domain or all or part of the light chain variable domain of an antibody. In certain embodiments, a single domain antibody is a human single domain antibody (see, e.g., U.S. Pat. No. 6,248,516 B1). Examples of single domain antibodies include, but are not limited to, VHHs.

[0147] A "Fab" fragment is an antigen-binding fragment produced by papain digestion of an antibody and consists of an entire light chain, the variable region domain (VH) of the heavy chain, and the first constant domain (CH1) of one heavy chain. Papain digestion of an antibody produces two identical Fab fragments. Pepsin treatment of an antibody produces a single large F(ab')2 fragment, which roughly corresponds to two disulfide-linked Fab fragments with bivalent antigen-binding activity and is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments in that they contain additional residues at the carboxy terminus of the CH1 domain, including one or more cysteines from the antibody hinge region. Fab'-SH is the designation used herein for Fab' in which the cysteine ​​residues in the constant domains bear free thiol groups. F(ab')2 antibody fragments were originally produced as pairs of Fab' fragments with hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0148] An "Fv" consists of a dimer of one heavy chain and one light chain variable region domain in tight, non-covalent association. The folding of these two domains results in six hypervariable loops (three loops from each H chain and L chain) that provide amino acid residues for antigen binding and confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three antigen-specific CDRs) has the ability to recognize and bind to an antigen, although often with lower affinity than the entire binding site.

[0149] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain, including native-sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain can vary, the human IgG heavy chain Fc region is usually defined to stretch from the amino acid residue at position Cys226 or from Pro230 to its carboxyl terminus. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) can be removed, for example, during antibody production or purification or by recombinantly engineering the nucleic acid encoding the antibody heavy chain. Thus, an intact antibody composition can include antibody populations in which all Lys447 residues have been removed, antibody populations in which the Lys447 residue has not been removed, and antibody populations having a mixture of antibodies with and without the Lys447 residue.

[0150] A "functional Fc region" possesses an "effector function" of a native sequence Fc region. Exemplary "effector functions" include C1q binding; CDC; Fc receptor binding; ADCC; phagocytosis; down-regulation of cell surface receptors (e.g., B cell receptors; BCRs); and the like. Such effector functions generally require association of the Fc region with a binding domain (e.g., an antibody variable domain) and can be assessed using various assays, e.g., as disclosed in the definitions herein.

[0151] A "native sequence Fc region" comprises an amino acid sequence identical to that of an Fc region found in nature. Native sequence human Fc regions include native sequence human IgG1 Fc regions (non-A and A allotypes); native sequence human IgG2 Fc regions; native sequence human IgG3 Fc regions; and native sequence human IgG4 Fc regions, as well as naturally occurring variants thereof.

[0152] A "variant Fc region" comprises an amino acid sequence that differs from that of a native-sequence Fc region by virtue of at least one amino acid modification, preferably one or more amino acid substitution(s). Preferably, the variant Fc region has at least one amino acid substitution, e.g., about one to about ten amino acid substitutions, and more preferably about one to about five amino acid substitutions, compared to the native-sequence Fc region or the Fc region of the parent polypeptide. The variant Fc region herein will preferably have at least about 80% homology, preferably at least about 90% homology, or more preferably at least about 95% homology, with the native-sequence Fc region and / or the Fc region of the parent polypeptide.

[0153] As used herein, "Fc complex" refers to the CH3 domains of two Fc regions interacting together to form a dimer, or in certain embodiments, two Fc regions interacting to form a dimer, wherein cysteine ​​residues in the hinge regions and / or CH3 domains interact via bonds and / or forces (e.g., van der Waals, hydrophobic, hydrogen bonding, electrostatic, or disulfide bonds).

[0154] As used herein, "Fc component" refers to the hinge region, CH2 domain, or CH3 domain of the Fc region.

[0155] The "hinge region" is generally defined as extending from about residue 216 to about 230 of IgG (EU numbering), from about residue 226 to about 243 of IgG (Kabat numbering), or from about residue 1 to about 15 of IgG (IMGT unique numbering).

[0156] The "lower hinge region" of an Fc region is usually defined as the stretch of residues immediately C-terminal to the hinge region, ie, residues 233 to 239 (EU numbering) of the Fc region.

[0157] A "variant Fc region" comprises an amino acid sequence that differs from that of a native-sequence Fc region by virtue of at least one amino acid modification, preferably one or more amino acid substitution(s). Preferably, the variant Fc region has at least one amino acid substitution compared to a native-sequence Fc region or the Fc region of a parent polypeptide, e.g., about one to about ten amino acid substitutions, preferably about one to about five amino acid substitutions, in the native-sequence Fc region or the Fc region of a parent polypeptide. The variant Fc region herein preferably retains at least about 80% homology with the native-sequence Fc region and / or the Fc region of the parent polypeptide, and most preferably at least about 90% homology therewith, and more preferably at least about 95% homology therewith.

[0158] "Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. A preferred FcR is a native-sequence human FcR. Additionally, a preferred FcR is one that binds IgG antibodies (gamma receptors), including receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. FcγRII receptors include FcγRIIA (an "activating receptor") and FcγRIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (see review M. in Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those yet to be identified, are encompassed herein by the term "FcR." 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)).

[0159] The term "knobs-into-holes" or "KnH" technology, as used herein, refers to a technique that directs 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 their interacting interface. For example, KnH has been introduced into the Fc:Fc interaction interface, CL:CH1 interface, or VH / VL interface of an antibody (e.g., US 2007 / 0178552, WO 96 / 027011, WO 98 / 050431, and Zhu et al. (1997) Protein Science 6:781-788). This is particularly useful for driving pairing of two different heavy chains together during the production of multispecific antibodies. For example, a multispecific antibody with KnH in the Fc region may further comprise a single variable domain linked to each Fc region, or may further comprise different heavy chain variable domains paired with identical, similar, or different light chain variable domains. KnH technology can also be used to pair two different receptor extracellular domains together, or any other polypeptide sequence comprising different target recognition sequences.

[0160] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Thus, the HVR and FR sequences generally appear in VH (or VL) in the following order: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0161] The "CH1 region" or "CH1 domain" comprises a stretch of residues from about residue 118 to residue 215 of IgG (EU numbering), from about residue 114 to residue 223 of IgG (Kabat numbering), or from about residue 1.4 to residue 121 of IgG (IMGT specific numbering) (Lefranc MP, Giudicelli V, Duroux P, Jabado-Michaloud J, Folch G, Aouinti S, Carillon E, Duvergey H, Houles A, Paysan-Lafosse T, Hadi-Saljoqi S, Sasorith S, Lefranc G, Kossida S. IMGT®, the international ImMunoGeneTics information system® 25 years on. Nucleic Acids Res. 2015 Jan;43(Database issue):D413-22).

[0162] The "CH2 domain" of the human IgG Fc region typically spans from about residue 244 to about residue 360 ​​of IgG (Kabat numbering), from about residue 231 to about residue 340 of IgG (EU numbering), or from about residue 1.6 to about residue 125 of IgG (IGMT unique numbering). The CH2 domain is unique in that it is not tightly paired with other domains. Rather, two N-linked branched carbohydrate chains are interposed between the two CH2 domains in an intact native IgG molecule. It has been speculated that the carbohydrates may provide an alternative for domain-domain pairing and help stabilize the CH2 domains. Burton, Molec. Immunol. 22:161-206 (1985).

[0163] The "CH3 domain" comprises the extension from the C-terminal residue of the Fc region to the CH2 domain (i.e., from about amino acid residues 361 to about 478 of IgG (Kabat numbering), from about amino acid residues 341 to about 447 of IgG (EU numbering), or from about amino acid residues 1.4 to about 130 of IgG (IGMT-specific numbering)).

[0164] The "CL domain" or "constant light domain" comprises the stretch of residues C-terminal to the light chain variable domain (VL). The light chain of an antibody may be a kappa (κ) ("CK") or lambda (λ) ("Cλ") light chain region. The CK region generally extends from about residues 108 to about 214 in IgG (Kabat or EU numbering) or from about residues 1.4 to about 126 in IgG (IMGT specific numbering). The Cλ residues generally extend from about residue 107a to about residue 215 (Kabat numbering) or from about residue 1.5 to about residue 127 (IMGT specific numbering) (Lefranc MP, Giudicelli V, Douroux P, Jabado-Michaloud J, Folch G, Aouinti S, Carillon E, Duvergey H, Houles A, Paysan-Lafosse T, Hadi-Saljoqi S, Sasorith S, Lefranc G, Kossida S. IMGT®, the international ImMunoGeneTics information system® 25 years on. Nucleic Acids Res. 2015 Jan;43(Database issue):D413-22).

[0165] 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 sequence of their constant domains. Immunoglobulins can be assigned to different classes or isotypes depending on the amino acid sequence of the constant domains (CHs) of their heavy chains. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, each with a heavy chain called α, δ, γ, ε, and μ. The γ and α classes are further divided into subclasses based on relatively minor differences in CH sequence and function; for example, humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0166] The term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0167] The "class" of an antibody refers to the type of constant domain or constant region carried by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0168] A "human antibody" is an antibody having an amino acid sequence corresponding to an antibody produced by a human or human cell, or an antibody of non-human origin using human antibody-encoding sequences, such as the human antibody repertoire. This definition of a human antibody specifically excludes humanized antibodies, which contain non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage display libraries. Methods described in Hoogenboom and Winter, J. Mol. Biol. 227:381, 1991; Marks et al., J. Mol. Biol. 222:581, 1991; Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(1):86-95, 1991, can also be used to prepare human monoclonal antibodies. See also van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74, 2001. Human antibodies can be prepared by administering antigen to immunized transgenic animals, such as XenoMouse, that have been engineered to produce such antibodies in response to antigen challenge, but whose endogenous gene loci have been disabled (see, for example, U.S. Patent Nos. 6,075,181 and 6,150,584, relating to XENOMOUSE™ technology). See also, for example, Li et al. Proc. Natl. Acad. Sci. USA 103:3557-3562, 2006, relating to human antibodies produced by human B cell hybridoma technology.

[0169] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda, MD (1991), vols. 1-3. In one embodiment, for VL, the subgroup is subgroup kappa I, as described in Kabat et al., supra. In one embodiment, for VH, the subgroup is subgroup kappa III, as described in Kabat et al., supra.

[0170] A "humanized" antibody refers to a chimeric antibody comprising amino acid residues derived from non-human HVRs and human FRs. In certain embodiments, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, with all or substantially all HVRs (e.g., CDRs) corresponding to those of a non-human antibody and all or substantially all FRs corresponding to those of a human antibody. In certain embodiments in which all or substantially all FRs of a humanized antibody correspond to those of a human antibody, any of the FRs of the humanized antibody may contain one or more amino acid residues from the non-human FR(s) (e.g., one or more Vernier position residues of the FR). A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0171] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to an antigen. The variable domains of the heavy and light chains of native antibodies (VH and VL, respectively) generally have similar structures, with each domain containing four conserved framework regions (FR) and three hypervariable regions (HVR). (See, e.g., Kindt et al., Kuby Immunology, 6th ed. W.H. Freeman and Co., p. 91 (2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind to a specific antigen can be isolated using the VH or VL domain of an antibody that binds to that antigen, and a library of complementary VL or VH domains, respectively, can be screened. See, e.g., Portolano et al. J. Immunol. 150:880-887, 1993; Clarkson et al. Nature 352:624-628, 1991.

[0172] As used herein, the term "hypervariable region" or "HVR" refers to each region of an antibody variable domain that is hypervariable in sequence ("complementarity determining region" or "CDR"). Generally, antibodies contain six CDRs, three in the VH (CDR-H1, CDR-H2, CDR-H3) and three in the VL (CDR-L1, CDR-L2, CDR-L3). Exemplary CDRs herein include: (a) CDRs located at amino acid residues 26–32 (L1), 50–52 (L2), 91–96 (L3), 26–32 (H1), 53–55 (H2), and 96–101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901–917, 1987); (b) CDRs located at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991)); and (c) Antigen contacts occurring at amino acid residues 27c–36 (L1), 46–55 (L2), 89–96 (L3), 30–35b (H1), 47–58 (H2), and 93–101 (H3) (MacCallum et al. J. Mol. Biol. 262:732–745, 1996).

[0173] Unless otherwise indicated, HVR residues and other residues of the variable domain (e.g., FR residues) are numbered herein according to Kabat et al., supra.

[0174] A "single-chain Fv," also abbreviated as "sFv" or "scFv," is an antibody fragment comprising VH and VL antibody domains connected in a single polypeptide chain. Preferably, the scFv polypeptide further comprises a polypeptide linker between the VH and VL domains, which enables the scFv to form the desired structure for antigen binding. For a general review of scFvs, see Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994); Malmborg et al., J. Immunol. Methods 183:7-13, 1995.

[0175] "Targeting domain" refers to a portion of a compound or molecule that specifically binds to a target epitope, antigen, ligand, or receptor. Targeting domains include, but are not limited to, antibodies (e.g., monoclonal antibodies, polyclonal antibodies, recombinant antibodies, humanized antibodies, and chimeric antibodies), antibody fragments or portions thereof (e.g., bis-Fab fragments, Fab fragments, F(ab')2, scFab, scFv antibodies, SMIPs, single-domain antibodies, diabodies, minibodies, scFv-Fc, affibodies, nanobodies, and the VH and / or VL domains of antibodies), receptors, ligands, aptamers, peptide targeting domains (e.g., cysteine ​​knot proteins (CKPs)), and other molecules with identified binding partners. A targeting domain can target, block, agonize, or antagonize the antigen to which it binds.

[0176] 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 variant antibodies that contain, for example, naturally occurring mutations or that may arise during production of the monoclonal antibody preparation, in which such variants are generally present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention may be produced by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci; such methods and other exemplary methods for producing monoclonal antibodies are described herein.

[0177] The term "multispecific antibody" is used in the broadest sense and particularly encompasses antibodies with polyepitopic specificity. In one embodiment, a multispecific antibody binds to two different targets (e.g., bispecific antibodies). Such multispecific antibodies include, but are not limited to, antibodies comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH / VL unit has multiepitopic specificity; antibodies having two or more VL and VH domains, each VH / VL unit binding a different epitope; antibodies having two or more single variable domains, each of which binds a different epitope; full-length antibodies; antibody fragments such as Fab, Fv, dsFv, scFv, diabodies, bispecific diabodies, and triabodies; and covalently or non-covalently linked antibody fragments. "Polyepitopic specificity" refers to the ability to specifically bind to two or more different epitopes on the same or different target(s). "Monospecificity" refers to the ability to bind to only one antigen. In one embodiment, a monospecific biepitope antibody binds two different epitopes on the same target / antigen. In one embodiment, a monospecific polyepitope antibody binds to multiple different epitopes on the same target / antigen. According to one embodiment, the multispecific antibody is an IgG antibody that binds to each epitope with an affinity of 5 μM to 0.001 pM, 3 μM to 0.001 pM, 1 μM to 0.001 pM, 0.5 μM to 0.001 pM, or 0.1 μM to 0.001 pM.

[0178] A "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel. The naked antibody may be present in a pharmaceutical formulation.

[0179] "Native antibodies" refer to naturally occurring immunoglobulin molecules with various structures. For example, native IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons, composed of two identical disulfide-bonded light chains and two identical heavy chains. From the N-terminus to the C-terminus, each heavy chain contains a variable region (VH), also called a variable heavy domain or heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain contains a variable region (VL), also called a variable light domain or light chain variable domain, followed by a constant light (CL) domain. Based on the amino acid sequence of its constant domain, the light chain of an antibody can be assigned to one of two types, called kappa (κ) or lambda (λ).

[0180] As used herein, the term "immunoadhesin" refers to a molecule that combines the binding specificity of a heterologous protein ("adhesin") with the effector functions of an immunoglobulin constant domain. Structurally, immunoadhesins comprise an amino acid sequence with the desired binding specificity that is an amino acid sequence other than the antigen recognition and binding site of an antibody (i.e., "heterologous" compared to the constant region of an antibody) fused to an immunoglobulin constant domain sequence (e.g., the CH2 and / or CH3 sequences of an IgG). The adhesin and immunoglobulin constant domains may optionally be separated by an amino acid spacer. Exemplary adhesin sequences include contiguous amino acid sequences comprising a portion of a receptor or ligand that binds to a protein of interest. Adhesin sequences can also be sequences that bind to a protein of interest but are not receptor or ligand sequences (e.g., adhesin sequences in peptibodies). Such polypeptide sequences can be selected or identified by a variety of methods, including phage display techniques and high-throughput selection methods. The immunoglobulin constant domain sequences in the immunoadhesin can be obtained from any immunoglobulin, such as IgG1, IgG2, IgG3, or IgG4 subtypes, IgA (including IgA1 and IgA2), IgE, IgD, or IgM.

[0181] A "chemotherapeutic agent" includes chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech / OSI Pharm), bortezomib (VELCADE®, Millennium), and erythropoietin (ERT). Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), Radicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer / Sugen)), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasteride (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, GlaxoSmithKline), Kline), lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Alkylating agents such as cyclophosphamide (IRESSA®, AstraZeneca), AG1478, thiotepa, and CYTOXAN®; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carbocuron, metoledopa, and uredopa; ethylenimines and methylmelamines such as altretamine, triethylenemelamine, triethylenephosphamide, triethylenethiophosphamide, and trimethylmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (topotecan and irinotecan); bryostatin; karystatin; 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-reductase inhibitors, including finasteride and dutasteride; vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat; dolastatins; aldesleukin, talc; duocarmycins (including synthetic analogs, KW-2189 and CB1-TM1); eletarobin; pancratistatin; sarcodictin; spongistatin, chlorambucil, chromafadine, chlorophosphamide, estramustine, ifosfamide , nitrogen mustards such as mechlorestamine, mechlorestamine oxide hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as endene antibiotics (e.g., calicheamicins, particularly calicheamicin γ1I and calicheamicin ω1I (Angew Chem. Intl. Ed. Engl. 1994) 33:183-186); dynemicins, including dynemicin A; bisphosphonates such as clodronate; espermycin; as well as neocarzinostatin chromophores and related enediyne antibiotic chromophores (enediyne antibiotic chromophores), aclacinomycins, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, Adriamycin (doxorubicin), morpholinodoxorubicin, cyano ... Mitomycins such as rubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, and mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, chelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; metabolic antagonists such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate;Purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifuridine, enocitabine, and floxuridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiosteine, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilosteine; folic acid supplements such as furoic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; etanercept Niruracil; Amsacrine; Bestravcil; Bisantrene; Edatraxate; Defofamine; Demecolcine; Diaziquion; Elfomitin; Elliptinium acetate; Epothilone; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidynin; Maytansinoids such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidanol; Nitraerin; Pentostatin; Fenameth; Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK® Polysaccharide Complex (JHS) Natural Products, Eugene, Oreg.); razoxane; rhizoxin; schizofuran; spirogermanium; tenuazonic acid; triaziquione; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veraculin 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, NJ), ABRAXANE® (cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® (paclitaxel; Sanofi-Aventis): chlorambucil, GEMZAR® (gemcitabine), 6-thioguanine, mercaptopurine; methotrexate;Platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); nobandrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid, and pharmaceutically acceptable salts, acids, and derivatives of any of the above;

[0182] Chemotherapeutic agents also include: (i) antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), e.g., tamoxifen (including NOLVADEX®, tamoxifen citrate), raloxifene, droxifene, iodoxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) adrenal gland estrogen inhibitors. Aromatase inhibitors, which inhibit the enzyme aromatase, which regulates strogen production, such as 4(5)-imidazole, aminoglutethimide, MEGASE® (megstrol acetate), AROMASIN® (exemestane; Pfizer), formestany, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) flutamide, nilutamide, bicalutamide (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly agents that inhibit the expression of genes involved in signal transduction pathways involved in abnormal cell growth, e.g., PKC-alpha, Ral, f and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®), HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, e.g., ALLOVECTIN®, LEUVECTIN®, VAXID®; PROLEUKIN®, rIL-2; topoisomerase 1 inhibitors such as LURTOTECAN®; ABARELIX® rmRH; and (ix) pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0183] Chemotherapeutic agents also include antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Imclone), panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody-drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, celizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, nat ... tuzumab, nimotuzumab, norobizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pexelizumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, reslizumab, reslivizumab, rovelizumab, lupizumab, sibrotuzumab, siplizumab, sontuzumab, tacatatuzumab tetraxetan, tadoxizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoreukin, tuxituuzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and interleukin-12 and anti-interleukin-12 (ABT-874 / J695, Wyeth Research and Abbott Laboratories), a human-sequence only, full-length IgG1λ antibody genetically engineered to recognize the p40 protein.

[0184] Chemotherapeutic agents also include "EGFR inhibitors," which refer to compounds that bind to or otherwise directly interact with EGFR and inhibit or reduce its signaling activity, alternatively referred to as "EGFR antagonists." Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies that bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see U.S. Pat. No. 4,943,533, Mendelsohn et al.), and variants thereof, such as chimerized 225 (C225 or cetuximab; ERBUTIX®) and reshaped human 225 (H225) (see WO 96 / 40210, Imclone Systems, Inc.). Inc.); the fully human EGFR-targeting antibody IMC-11F8 (Imclone); antibodies that bind type II mutant EGFR (U.S. Pat. No. 5,212,290); humanized and chimeric antibodies that bind EGFR, such as those described in U.S. Pat. No. 5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab (WO 98 / 50433, Abgenix / Amgen); EMD 55900 (Stragliotto et al., Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab), a humanized EGFR antibody against EGFR that competes with both EGF and TGF-α for EGFR binding (EMD / Merck); the human EGFR antibody, HuMax-EGFR (GenMab); the fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3 and described in U.S. 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)).Anti-EGFR antibodies can be conjugated to cytotoxic agents to generate immunoconjugates (see, for example, European Patent Application Publication No. 659,439A2, Merck Patent GmbH). EGFR antagonists include those disclosed 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, 5,866,573, 5,866,574, 5,866,575, 5,866,576, 5,866,577, 5,866,578, 5,866,579 ... and 5,747,498, and the following PCT publications: WO 98 / 14451, WO 98 / 50038, WO 99 / 09016, and WO 99 / 24037.Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA®, Genentech / OSI Pharmaceuticals), PD183805 (CI1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.), ZD1839, gefitinib (IRESSA®) 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca), ZM105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca), BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim), Ingelheim), PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol), (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine), CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide), EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7 -ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butynamide) (Wyeth), AG1478 (Pfizer), AG1571 (SU5271, Pfizer), and dual EGFR / HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).

[0185] 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) which preferentially binds to EGFR but inhibits both HER2 and EGFR overexpressing cells), lapatinib (GSK572016, available from Glaxo-SmithKline), oral HER2 and EGFR tyrosine kinase inhibitor, PKI-166 (available from Novartis), pan-HER inhibitors (such as canertinib (CI-1033, Pharmacia)), Raf-1 inhibitors (such as ISIS inhibitors which inhibit Raf-1 signaling) antisense drug ISIS-5132 available from Novartis / Schering Pharmaceuticals), non-HER-targeted TK inhibitors (such as imatinib mesylate (GLEEVEC®, available from GlaxoSmithKline)), multi-targeted tyrosine kinase inhibitors (such as sunitinib (SUTENT®, available from Pfizer)), VEGF receptor tyrosine kinase inhibitors (vatalanib (PTK787 / ZK222584, Novartis / Schering)), available from AG), MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia), quinazolines (such as PD153035, 4-(3-chloroanilino)quinazoline), pyridopyrimidines, pyrimidopyrimidines, pyrrolopyrimidines (such as CGP59326, CGP60261, and CGP62706), pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine, curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide), tyrphostins containing a nitrothiophene moiety, PD-0183805 (Warner-Lambert), antisense molecules (e.g., those that bind to HER-encoding nucleic acids), quinoxalines (U.S. Pat. No. 5,804,396), tryphostins (U.S. Pat. No. 5,804,No. 396), ZD6474 (AstraZeneca), PTK-787 (Novartis / Schering AG), pan-HER inhibitors (such as CI-1033 (Pfizer)), Affinitac (ISIS3521, Isis / Lilly), imatinib mesylate (GLEEVEC®), PKI166 (Novartis), GW2016 (GlaxoSmithKline), CI-1033 (Pfizer), EKB-569 (Wyeth), semaxinib (Pfizer), ZD6474 (AstraZeneca), PTK-787 (Novartis / Schering AG), INC-1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE®), or those described in any of the following patent publications: U.S. Pat. No. 5,804,396, WO 1999 / 09016 (American Cyanamid), WO 1998 / 43960 (American Cyanamid), WO 1997 / 38983 (Warner Lambert), WO 1999 / 06378 (Warner Lambert), WO 1999 / 06396 (Warner Lambert), WO 1996 / 30347 (Pfizer, Inc), WO 1996 / 33978 (Zeneca), WO 1996 / 3397 (Zeneca), and WO 1996 / 33980 (Zeneca).

[0186] Chemotherapeutic agents also include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, live BCG, bevacizumab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, erotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa- 2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof.

[0187] Chemotherapeutic agents include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, and hydrocortisone-17- butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasone-17-propionate, fluocortolone caproate, fluocortolone pivalate, and fluprednidene acetate; phenylalanine-glutamine-glycine (FEG) and its D-form (feG) (IMULAN) Immunoselective anti-inflammatory peptides (ImSAIDs) such as BioTherapeutics, LLC; antirheumatic drugs such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, minocycline, and sulfasalazine; etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), cetolithumab pegol (Cimzia), and golimumab (Simpson) tumor necrosis factor alpha (TNFα) blockers such as anakinra (Kineret), interleukin 1 (IL-1) blockers such as anakinra (Kineret), T-cell costimulation blockers such as abatacept (Orencia), interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMRA®); interleukin 13 (IL-13) blockers such as lebrikizumab; interferon alpha (IFN) blockers such as rontalizumab; beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as anti-M1 prime; secreted homotrimeric LTa3 and membrane-bound heterotrimeric LTa1 / β2 blockers such as anti-lymphotoxin alpha (LTa); radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi212 、P 32 、Pb 212, and radioactive isotopes of Lu); various investigational drugs such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3, or farnesyltransferase inhibitors (L-739749, L-744832); polyphenols, such as quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavins, flavanols, procyanidins, betulinic acid and its derivatives; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); tarapachone; lapachol; colchicine; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin; podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); clodronate (e.g., BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid / zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate bisphosphonates such as thiazolinone (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R); vaccines such as the THERATOPE® vaccine; perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteosome inhibitors (e.g., PS341); CCI-779; tipifarnib (R11577); orafenib, ABT510; oblimersen sodium (GENASENSE®); pixantrone; farnesyltransferase inhibitors such as lonafarnib (SCH6636, SARASAR™); and pharmaceutically acceptable salts, acids, or derivatives of any of the above; and combinations of two or more of CHOP, which is an abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone, and FOLFOX, which is an abbreviation for a treatment regimen with oxaliplatin in combination with 5-FU and leucovorin (ELOXATIN™).

[0188] Chemotherapeutic agents may also include nonsteroidal anti-inflammatory drugs (NSAIDs) with analgesic, antipyretic, and anti-inflammatory effects. NSAIDs include nonselective inhibitors of the enzyme cyclooxygenase. Specific examples of nonsteroidal anti-inflammatory drugs include propionic acid derivatives such as aspirin, ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, and naproxen; acetic acid derivatives such as indomethacin, sulindac, etodolac, and diclofenac; enolic acid derivatives such as piroxicam and meloxicam; fenamic acid derivatives such as tenoxicam, droxicam, lonoxicam, isoxicam, mefenamic acid, meclofenamic acid, flufenamic acid, and tolfenamic acid; and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, and valdecoxib. NSAIDs may be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathy, ankylosing spondylosis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headache and migraine, postoperative pain, mild to moderate pain due to inflammation and tissue injury, fever, intestinal obstruction, and renal colic.

[0189] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cellular function and / or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212, and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof, e.g., nucleases; antibiotics; toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof; and various anti-tumor or anti-cancer agents disclosed below.

[0190] A "disorder" is any condition that would benefit from treatment, including chronic and acute disorders or diseases, including, but not limited to, those pathological conditions that predispose a mammal to the disorder in question. In one embodiment, the disorder is cancer, e.g., multiple myeloma (MM).

[0191] The terms "cell proliferative disorder" and "proliferative disorder" refer to disorders involving 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.

[0192] "Tumor," as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms "cancer," "cancerous," "cell proliferative disorder," "proliferative disorder," and "tumor" are not mutually exclusive when referred to herein.

[0193] The terms "cancer" and "cancerous" refer to or describe a physiological condition in a mammal that is typically characterized by uncontrolled cell growth / proliferation. Cancer aspects include solid tumor cancers and non-solid tumor cancers. Examples of cancer include, but are not limited to, B-cell proliferative disorders, such as multiple myeloma (MM), which may be relapsed or refractory. MM may be, for example, a typical MM (e.g., immunoglobulin G (IgG) MM, IgA MM, IgD MM, IgE MM, or IgM MM), a light chain MM (LCMM) (e.g., lambda light chain MM or kappa light chain MM), or a non-secretory MM. MM may have one or more cytogenetic features (e.g., high-risk cytogenetic features), such as t(4;14), t(11;14), t(14;16), and / or del(17p) (as described in Table 1 and the International Myeloma Working Group (IMWG) criteria provided in Sonneveld et al., Blood, 127(24):2955-2962, 2016) and / or 1q21 (as described in Chang et al., Bone Marrow Transplantation, 45:117-121, 2010). Cytogenetic features can be detected, for example, using fluorescence in situ hybridization (FISH). [Table 1]

[0194] The terms "B-cell proliferative disorder" or "B-cell malignancy" refer to disorders that are associated with some degree of abnormal B-cell proliferation and include, for example, lymphoma, leukemia, myeloma, and myelodysplastic syndrome. In one embodiment, the B-cell proliferative disorder is a lymphoma, such as, for example, non-Hodgkin's lymphoma (NHL), including, for example, diffuse large B-cell lymphoma (DLBCL) (e.g., relapsed or refractory DLBCL). In another embodiment, the B-cell proliferative disorder is a leukemia, such as chronic lymphocytic leukemia (CLL). Other specific examples of cancers include germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL), activated B-cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenstrom's hypergammaglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt's lymphoma (BL), B-cell lymphoma Follicular prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma / leukemia, unclassifiable, diffuse red pulp small B-cell lymphoma, hairy cell leukemia variant, heavy chain disease, alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasma cell myeloma, isolated bone plasmacytoma, extraskeletal 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 of the elderly, chronic inflammation-associated DLBCL, lymphomatoid granulomatosis, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma due to HHV8-associated multicentric Castleman disease, primary effusion lymphoma; unclassifiable B-cell lymphoma with features intermediate between DLBCL and Burkitt lymphoma; and unclassifiable B-cell lymphoma with features intermediate between DLBCL and classical Hodgkin lymphoma.Further examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and lymphoid malignancies, including leukemia or B-cell lymphoma.More specific examples of such cancer include, but are not limited to, low-grade / follicular NHL; small lymphocytic (SL) NHL; intermediate-grade / follicular NHL; intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphocytic NHL; high-grade small non-dividing cell NHL; bulky mass disease NHL; AIDS-related lymphoma; and acute lymphocytic leukemia (ALL); chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD). Examples of solid tumors include lung cancer, including squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous cell carcinoma of the lung; cancer of the peritoneum, hepatocellular carcinoma, gastric cancer, including gastrointestinal cancer, and gastrointestinal stromal cancer; cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, cancer of the urinary system, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma, anal carcinoma, penile carcinoma, melanoma, superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanoma, nodular melanoma, and abnormal blood vessel growth associated with nevus, edema (such as that associated with brain tumors), Meigs syndrome, brain, and head and neck cancer, and related metastases. In certain embodiments, cancers suitable for treatment with the antibodies of the invention include breast cancer, colorectal cancer, rectal cancer, non-small cell lung cancer, glioblastoma, non-Hodgkin's lymphoma (NHL), renal cell carcinoma, prostate cancer, liver cancer, pancreatic cancer, soft tissue sarcoma, Kaposi's sarcoma, carcinoid carcinoma, head and neck cancer, ovarian cancer, and mesothelioma.

[0195] "Effector function" refers to the biological activities attributable to the Fc region of an antibody, which vary depending on the antibody isotype. 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 receptors); and B cell activation.

[0196] "Complement-dependent cytotoxicity" or "CDC" refers to the lysis of target cells in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to antibodies (of the appropriate subclass) that are bound to their cognate antigen. Complement activation can be assessed, for example, by assays such as those described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996).

[0197] "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 antigen-bearing target cells and subsequently kill them with cytotoxic agents. These antibodies "arm" the cytotoxic cells and are absolutely necessary for such killing. NK cells, the primary cells for mediating ADCC, express only FcγRIII, whereas monocytes express FcγRI, FcγRII, and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet. Annu. Rev. Immunol. 9:457-92, 1991. To assess the ADCC activity of a molecule of interest, an in vitro ADCC assay such as that described in U.S. Patent No. 5,500,362 or 5,821,337 can be performed. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. Alternatively or additionally, the ADCC activity of a molecule of interest can be assessed in vivo in an animal model, such as that disclosed in Clynes et al. Proc. Natl. Acad. Sci. USA 95:652-656, 1998.

[0198] As used herein, "complex" or "complex-type" refers to an association of two or more molecules that interact with each other through bonds and / or forces (e.g., van der Waals, hydrophobic, hydrophilic) that are not peptide bonds. In one embodiment, the complex is a heteromultimer. As used herein, the term "protein complex" or "polypeptide complex" should be understood to include complexes having non-protein entities conjugated to proteins in the protein complex (e.g., including, but not limited to, chemical molecules such as toxins or detection agents).

[0199] As used herein, "delaying the progression" of a disorder or disease means postponing, preventing, slowing down, 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 of various lengths of time, depending on the disease being treated and / or the individual's medical history. As will be apparent to those skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, late-stage cancer, such as the development of metastasis, can be delayed.

[0200] An "effective amount" of a compound, e.g., an anti-FcRH5 / anti-CD3 T cell-dependent bispecific antibody (TDB) of the present invention or a composition thereof (e.g., a pharmaceutical composition), is at least the minimum amount necessary to achieve a desired therapeutic or prophylactic result, such as a measurable improvement or prevention of a particular disorder (e.g., a cell proliferative disorder, e.g., cancer). An effective amount herein may vary depending on factors such as the patient's disease state, age, sex, and weight, as well as the ability of the antibody to elicit a desired response in the individual. An effective amount is also one in which any toxic or adverse effects of the treatment are outweighed by the therapeutically beneficial effects. Beneficial or desired results for prophylactic use include results such as elimination or reduction of risk, reduction in severity, or delay in the onset of disease, including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes manifesting during the development of the disease. In the case of therapeutic use, beneficial or desired results include clinical results such as a reduction in one or more symptoms caused by the disease, an improvement in the quality of life of those suffering from the disease, a reduction in the dose of other drugs required to treat the disease, an enhancement of the effect of another drug (e.g., by targeting), a delay in disease progression, and / or an increase in survival time. In the case of cancer or tumors, an effective amount of a drug may have the effect of reducing the number of cancer cells, reducing tumor size, inhibiting (i.e., slowing or desirably stopping) the infiltration of cancer cells into peripheral organs, inhibiting (i.e., slowing or desirably stopping) tumor metastasis, inhibiting tumor growth to some extent, and / or alleviating to some extent one or more symptoms associated with the disorder. An effective amount can be administered in one or more administrations. In the present invention, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve prophylactic or therapeutic treatment. As understood in the clinical field, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" may be considered in relation to the administration of one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desired result can be or is achieved.

[0201] As used herein, "overall survival" or "OS" refers to the percentage of individuals in a group who are likely to be alive after a particular period of time.

[0202] As used herein, "objective response rate" (ORR) refers to the sum of the stringent complete response (sCR) rate, the complete response (CR) rate, the very good partial response (VGPR) rate, and the partial response (PR) rate, as determined using the International Myeloma Working Group response criteria (Table 4).

[0203] The term "epitope" refers to a specific site on an antigen molecule to which an antibody binds. In some embodiments, the specific site on an antigen molecule to which an antibody binds is determined by hydroxyl radical footprinting. In some embodiments, the specific site on an antigen molecule to which an antibody binds is determined crystallographically.

[0204] As used herein, a "growth inhibitory agent" refers to a compound or composition that inhibits cell proliferation in vitro or in vivo. In one embodiment, the growth inhibitory agent is a growth inhibitory antibody that inhibits or reduces the proliferation of cells expressing the antigen to which the antibody binds. In another embodiment, the growth inhibitory agent may significantly reduce the proportion of cells in S phase. Embodiments of growth inhibitory agents include agents that block cell cycle progression (at a location other than S phase), such as agents that induce G1 arrest or M-phase arrest. Classical M-phase blockers include vincas (vincristine and vinblastine), taxanes, and topoisomerase II inhibitors, such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. Agents that arrest G1, such as DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and araC, also induce S-phase arrest. Further information can be found in Mendelsohn and Israel, eds., The Molecular Basis of Cancer, Chapter 1, entitled "Cell cycle regulation, oncogenes, and antitineoplastic drugs" (Murakami et al. (WB Saunders, Philadelphia, 1995)), e.g., page 13. Taxanes (paclitaxel and docetaxel) are anticancer drugs, both derived from the yew tree. Docetaxel (TAXOTERE®, Rhone-Poulenc Rorer), derived from the European yew, is a semisynthetic analog of paclitaxel (TAXOL®, Bristol-Myers Squibb). Paclitaxel and docetaxel promote the assembly of microtubules derived from tubulin dimers, stabilize microtubules by preventing depolymerization, and inhibit mitosis in cells.

[0205] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including, but not limited to, cytotoxic agents.

[0206] The term "immunomodulatory agent" refers to a class of molecules that modify immune system responses or immune system function. Immunomodulatory agents include, but are not limited to, PD-1 axis binding antagonists, thalidomide (α-N-phthalimido-glutarimide) and its analogs, OTEZLA® (apremilast), REVLIMID® (lenalidomide), and POMALYST® (pomalidomide), and pharmaceutically acceptable salts or acids thereof.

[0207] A "subject" or "individual" is a mammal. Mammals include, but are not limited to, domestic animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the subject or individual is human.

[0208] An "isolated" protein or peptide is one that is separated from a component of its natural environment. In some embodiments, the protein or peptide is purified to greater than 95% or 99% purity, as determined, for example, by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse-phase HPLC).

[0209] An "isolated" nucleic acid refers to a nucleic acid molecule that is separated from components of its natural environment. Isolated nucleic acid includes a nucleic acid molecule that is contained in cells that ordinarily contain the nucleic acid molecule, but where the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0210] The term "PD-1 axis-binding antagonist" refers to a molecule that inhibits the interaction of a PD-1 axis-binding partner with one or more of its binding partners in order to eliminate T cell dysfunction resulting from signaling on the PD-1 signaling axis, thereby restoring or enhancing T cell function (e.g., proliferation, cytokine production, and / or target cell killing). As used herein, PD-1 axis-binding antagonists include PD-L1-binding antagonists, PD-1-binding antagonists, and PD-L2-binding antagonists. In some cases, the PD-1 axis-binding antagonist includes a PD-L1-binding antagonist or a PD-1-binding antagonist. In a preferred embodiment, the PD-1 axis-binding antagonist is a PD-L1-binding antagonist.

[0211] The term "PD-L1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or prevents signaling resulting from the interaction of PD-L1 with any one or more of its binding partners, e.g., PD-1 and / or B7-1. In some cases, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In specific embodiments, PD-L1 binding antagonists inhibit the binding of PD-L1 to PD-1 and / or B7-1. In some cases, PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or prevent signaling resulting from the interaction of PD-L1 with one or more of its binding partners, e.g., PD-1 and / or B7-1. In one case, the PD-L1 binding antagonist reduces the negative costimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes via signaling 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, embafolimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636.In some embodiments, the anti-PD-L1 antibody is atezolizumab, MDX-1105, MEDI4736 (durvalumab), or MSB0010718C (avelumab). In one specific 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 (avelumab). In other embodiments, the PD-L1 binding antagonist may be a small molecule, such as GS-4224, INCB086550, MAX-10181, INCB090244, CA-170, or ABSK041, and in some cases may be administered orally. Other exemplary PD-L1 binding antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003, and JS- 003. In a preferred embodiment, the PD-L1 binding antagonist is atezolizumab.

[0212] For purposes of this specification, "atezolizumab" refers to an Fc-engineered humanized, aglycosylated IgG1 kappa immunoglobulin that binds to PD-L1. Atezolizumab contains a single amino acid substitution (asparagine to alanine) (N297A) at position 297 on the heavy chain using the EU numbering of Fc region amino acid residues, resulting in an aglycosylated antibody with minimal binding to Fc receptors. Atezolizumab is also listed in the WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances (proposed INN)) List 112, Vol. 28, No. 4, 2014, p. 488.

[0213] The term "PD-1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or prevents signaling resulting from the interaction of PD-1 with one or more of its binding partners, e.g., PD-L1 and / or PD-L2. PD-1 (programmed death 1) is also referred to in the art as "programmed cell death 1," "PDCD1," "CD279," and "SLEB2." An exemplary human PD-1 is set forth in UniProtKB / Swiss-Prot Accession No. Q15116. In some cases, a PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In a specific embodiment, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and / or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or interfere with signaling resulting from the interaction of PD-1 with PD-L1 and / or PD-L2. In one case, the PD-1 binding antagonist reduces negative costimulatory signals mediated by or through cell surface proteins expressed on T lymphocytes via signaling through PD-1, so as to prevent dysfunctional T cells from becoming dysfunctional (e.g., enhancing effector responses to antigen recognition). In some cases, the PD-1 binding antagonist binds to PD-1. In some cases, the PD-1 binding antagonist is an anti-PD-1 antibody (e.g., an anti-PD-1 antagonist antibody).Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (cemiplimab), BGB-108, prorugolimab, canrelizumab, sintilimab, tislelizumab, toripalimab, dostarimab, retifanlimab, sasanlimab, penprimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimuzumab, BI Examples of PD-1 binding antagonists include 754091, cetrelimab, YBL-006, BAT1306, HX008, budicalimab, AMG404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, and hAb21. In a 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 (cemiplimab). In another specific embodiment, the PD-1 binding antagonist is BGB-108. In another specific embodiment, the PD-1 binding antagonist is progolimab. In another specific embodiment, the PD-1 binding antagonist is canrelizumab. In another specific embodiment, the PD-1 binding antagonist is sintilimab. In another specific embodiment, the PD-1 binding antagonist is ticerelizumab. In another specific embodiment, the PD-1 binding antagonist is toripalimab. Other additional exemplary PD-1 binding antagonists include BION-004, CB201, AUNP-012, ADG104, and LBL-006.

[0214] The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or prevents signaling resulting from the interaction of PD-L2 with any one or more of its binding partners, e.g., PD-1. PD-L2 (programmed death ligand 2) is also referred to in the art as "programmed cell death 1 ligand 2," "PDCD1LG2," "CD273," "B7-DC," "Btdc," and "PDL2." An exemplary human PD-L2 is set forth in UniProtKB / Swiss-Prot Accession No. Q9BQ51. In some cases, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In 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, abrogate, or interfere with signaling resulting from the interaction of PD-L2 with any one or more of its binding partners, such as PD-1. In one embodiment, the PD-L2 binding antagonist reduces the negative costimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes via signaling through PD-L2, such that dysfunctional T cells are rendered non-dysfunctional (e.g., enhance effector responses to antigen recognition). In some embodiments, the PD-L2 binding antagonist binds to PD-L2. In some embodiments, the PD-L2 binding antagonist is an immunoadhesin. In other embodiments, the PD-L2 binding antagonist is an anti-PD-L2 antagonist antibody.

[0215] 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. The term also includes "full-length," unprocessed proteins and any forms of proteins resulting from processing within a cell. The term also encompasses naturally occurring variants of the protein, such as splice variants or allelic variants.

[0216] "Percent identity (%) of amino acid sequence" 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, without considering any conservative substitutions as part of sequence identity, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent identity for the purpose of alignment.Alignment for determining percent identity of amino acid sequence can be achieved in various ways within the skill of the art, for example, using publicly available computer software, such as BLAST, BLAST-2, Clustal W, Megalign (DNASTAR) software or FASTA program package.Those skilled in the art can determine the appropriate parameters for sequence alignment, including any algorithms required to achieve maximum alignment over the entire length of the sequences being compared.Alternatively, percent identity values ​​can be generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was written by Genentech, Inc., and the source code is on file in the user documentation at the U.S. Copyright Office, Washington, DC, 20559, registered under U.S. Copyright Registration No. TXU510087, and described in WO 2001 / 007611.

[0217] Unless otherwise indicated, for purposes herein, percent amino acid sequence identity values ​​are generated using the ggsearch program in the FASTA package version 36.3.8c, or the subsequent BLOSUM50 comparison matrix. The FASTA program package is described by W.R. Pearson and D.J. Lipman (1988), "Improved Tools for Biological Sequence Analysis," PNAS 85:2444-2448; W.R. Pearson (1996), "Effective protein sequence comparison," Meth. Enzymol. 266:227-258; and Pearson et al. (1997) Genomics 46:24-36, and is publicly available at www.fasta.bioch.virginia.edu / fasta_www2 / fasta_down.shtml or www.ebi.ac.uk / Tools / sss / fasta. Alternatively, sequences can be compared using the public server accessible at fasta.bioch.virginia.edu / fasta_www2 / index.cgi using the ggsearch(globalprotein:protein) program and default options (BLOSUM50; open: -10; ext: -2; Ktup=2), ensuring a global rather than local alignment. The percent amino acid identity is shown in the output alignment header.

[0218] The term "pharmaceutical formulation" refers to a preparation in which the biological activity of the active ingredients contained in the preparation is in a form such that it is effective, and which does not contain additional components that are unacceptably toxic to the subject to which the formulation is administered.

[0219] A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0220] "Radiation therapy" refers to the use of directed gamma or beta radiation to inflict sufficient damage on cells to limit their ability to function normally or to destroy them entirely. It will be appreciated that there are many methods known in the art for determining dosage and duration of treatment. A typical treatment is given as a single administration, with typical dosages ranging from 10 to 200 units (Gy) per day.

[0221] As used herein, "treatment" (and grammatical variants thereof, e.g., "treat" or "treating") refers to clinical intervention in an attempt to alter the natural course of the individual being treated and can be performed prophylactically or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing the onset or recurrence of disease, alleviating symptoms, reducing the direct or indirect pathological consequences of disease, preventing metastasis, reducing the rate of disease progression, ameliorating or palliating disease symptoms, and achieving remission or improved prognosis. In some embodiments, the antibodies of the present invention (e.g., the anti-FcRH5 / anti-CD3 TDBs of the present invention) are used to delay the onset of disease or slow the progression of disease.

[0222] "Reducing" or "inhibiting" refers to the ability to cause an overall decrease, for example, of 20% or more, 50% or more, or 75%, 85%, 90%, 95%, or more. In certain embodiments, reducing or inhibiting can refer to antibody effector functions mediated by the antibody Fc region, such effector functions specifically including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP).

[0223] According to the present invention, the term "vaccine" refers to a pharmaceutical preparation (pharmaceutical composition) or product that, upon administration, induces an immune response, particularly a cellular immune response, to recognize and attack pathogens or diseased cells, such as cancer cells. Vaccines 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 a subject's immune response against cancer. Cancer vaccines typically consist of a source of cancer-related material or cells (antigens), which can be autologous (self-derived) or allogeneic (derived from another person), to the subject, along with other components (e.g., adjuvants) to further stimulate and boost the immune response against the antigens. Cancer vaccines can stimulate the subject's immune system to produce antibodies against one or more specific antigens and / or killer T cells to attack cancer cells bearing those antigens.

[0224] As used herein, "administration" refers to a method of providing a subject with a dosage of a compound (e.g., an anti-FcRH5 / anti-CD3 TDB of the present disclosure). 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, intrarectally, topically, intratumorally, subcutaneously, subconjunctivally, intravesicularly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, by a local perfusion bath target cell directly, 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 symptom, disease, or disorder being treated).

[0225] 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 higher levels and more uniformly on myeloma cells compared to normal lymphoid and myeloid cells. The term encompasses "full-length," unprocessed CD38 and any form of CD38 resulting from 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. The nucleic acid sequence of an exemplary human CD38 is set forth 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 set forth in UniProt Accession No. P28907 or SEQ ID NO: 34.

[0226] The term "anti-CD38 antibody" encompasses all antibodies that bind to CD38 with sufficient affinity so that the antibody is useful as a therapeutic agent in targeting cells expressing the antigen and does not significantly cross-react with other proteins, such as negative control proteins, in the assays described below. For example, an anti-CD38 antibody can bind to CD38 on the surface of MM cells and mediate cell lysis through activation of complement-dependent cytotoxicity, ADCC, antibody-dependent cellular phagocytosis (ADCP), and Fc cross-linking-mediated apoptosis, resulting in depletion of malignant cells and a reduction in overall cancer burden. An anti-CD38 antibody can also modulate CD38 enzyme activity through inhibition of ribosyl cyclase enzyme activity and stimulation of cyclic adenosine diphosphate ribose (cADPR) hydrolase activity of CD38. In certain embodiments, an anti-CD38 antibody that binds to CD38 has a binding affinity of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., ≦10 -8 M or less, e.g. 10 -8 M~10 -13 M, e.g. 10 -9 M~10- -13 Dissociation constant (K D ). In certain embodiments, the anti-CD38 antibody can bind to both human CD38 and chimpanzee CD38. Anti-CD38 antibodies also include anti-CD38 antagonist antibodies. Bispecific antibodies in which one arm of the antibody binds to CD38 are also contemplated. This definition of anti-CD38 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).

[0227] The terms "marker of proliferation Ki-67," "Ki-67," and "MKI67" are used interchangeably and can refer to the MKI67 gene, transcript, or protein. MKI67 is a marker of cell proliferation (e.g., a T cell proliferation marker).

[0228] The term "T cell proliferation marker" refers to any marker of cell proliferation that can be detected in T cells. Exemplary T cell proliferation markers include, but are not limited to, MKI67, proliferating cell nuclear antigen (PCNA), minichromosome maintenance 2 (MCM2), bromodeoxyuridine (BrdU) incorporation, and other markers known in the art. In some examples, T cell proliferation markers are associated with cell division or DNA replication across multiple cell types. In other examples, T cell proliferation markers are specifically expressed in T cells but not in other cell types.

[0229] The terms "level" (when used in the context of "level of a T cell proliferation marker," "level of a cell proliferation marker," "reference level," "level of MKI67," "protein level," or "mRNA level"), "level of expression," and "expression level" are used interchangeably and generally refer to the amount of a polynucleotide (e.g., mRNA) or amino acid product or protein in a biological sample. "Expression" generally refers to the process of converting genetic coding information into structures present and operating within a cell. Thus, according to the present invention, "expression" of a gene may refer to transcription into a polynucleotide, translation into a protein, or even post-translational modification of a protein. Fragments of a transcribed polynucleotide, a translated protein, or a post-translationally modified protein should also be considered expressed, regardless of whether they are derived from transcripts generated by alternative splicing, degraded transcripts, or post-translational processing of a protein, for example, by proteolysis. "Expressed genes" include those that are transcribed into polynucleotides as mRNA and then translated into polypeptides, as well as those that are transcribed into RNA but not translated into polypeptides (e.g., transfer and ribosomal RNAs).

[0230] As used herein, the term "marker" or "biomarker" refers to an indicator that can be detected in a sample, e.g., pharmacodynamic, predictive, diagnostic, and / or prognostic, such as T cell proliferation markers (e.g., MKI67, PCNA, MCM2, and molecules incorporating exogenous BrdU). Biomarkers can serve as indicators of specific subtypes of diseases or disorders (e.g., cancer) characterized by specific molecular, pathological, histological, and / or clinical features. Biomarkers can serve as indicators of response, e.g., to treatments including bispecific anti-FcRH5 / anti-CD3 antibodies (e.g., cevostamab) as disclosed herein. In some embodiments, the biomarker is a gene. Biomarkers include, but are not limited to, molecular markers based on polynucleotides (e.g., DNA and / or RNA), alterations in polynucleotide copy number (e.g., DNA copy number), polypeptides, polypeptide and polynucleotide modifications (e.g., post-translational modifications), carbohydrates, and / or glycolipids.

[0231] The term "sample" as used herein refers to a composition obtained from or derived from a subject and / or individual of interest, containing cells and / or other molecular entities to be characterized and / or identified, for example, based on physical, biochemical, chemical, and / or physiological properties. Samples include, but are not limited to, tissue samples, primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous fluid, lymphatic fluid, synovial fluid, follicular fluid, semen, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebrospinal fluid, saliva, sputum, tears, sweat, mucus, tumor lysates, and tissue culture media, tissue extracts such as homogenized tissues, tumor tissues, cell extracts, and combinations thereof.

[0232] As used herein, the term "reference level" refers to a level used for comparison purposes. In some embodiments, the reference level is a level of MKI67 (e.g., mRNA or protein level) determined in a biological sample obtained from a subject before administering the bispecific antibody to the subject. In some embodiments, the reference level is obtained from a healthy and / or non-diseased part of the body (e.g., tissue or cell) of the same subject. For example, healthy and / or non-diseased cells or tissue adjacent to diseased cells or tissue (e.g., cells or tissue adjacent to a tumor). In another embodiment, the reference level is obtained from untreated tissue and / or cells of the body of the same subject. In yet another embodiment, the reference level is obtained from a healthy and / or non-diseased part of the body (e.g., tissue or cell) of a subject who is not the subject. In yet another embodiment, the reference level is obtained from untreated tissue and / or cells of the body of an individual who is not the subject. In some embodiments, the reference level is the median protein level of a T cell proliferation marker determined in a population of individuals with MM. In some embodiments, the reference level is the median mRNA level of a T cell proliferation marker determined in a population of individuals with MM.

[0233] As used herein, the term "reference number" refers to the number of cells used for comparison purposes. In some embodiments, the reference number is the MKI67 number determined in a biological sample obtained from a subject prior to administering the bispecific antibody to the subject. +The reference number is the number of cells. In some embodiments, the reference number is obtained from a healthy and / or non-diseased part of the body (e.g., tissue or cells) of the same subject. For example, healthy and / or non-diseased cells adjacent to diseased cells or tissues (e.g., cells or tissues adjacent to a tumor). In another embodiment, the reference number is obtained from untreated tissues and / or cells of the body of the same subject. In yet another embodiment, the reference number is obtained from a healthy and / or non-diseased part of the body (e.g., tissue or cells) of a subject who is not the subject. In yet another embodiment, the reference number is obtained from untreated tissues and / or cells of the body of an individual who is not the subject. In some embodiments, the reference number is the median number of cells expressing the T cell proliferation marker determined in a population of individuals with MM.

[0234] II. Therapeutic and Diagnostic Methods The present invention relates to the treatment of T-cell proliferation markers and / or elevated levels of MKI67 + This method is based, in part, on the discovery that T cells are maintained in cancer (e.g., multiple myeloma (MM)) subjects receiving a fractionated-dose escalation regimen using a bispecific anti-fragment crystallizable receptor-like 5 (FcRH5) / anti-cluster of differentiation 3 (CD3) antibody. For example, as demonstrated herein, levels of a marker of proliferation, Ki-67 (MKI67), are elevated and maintained in responders (R) to a regimen using a bispecific anti-FcRH5 / anti-CD3 antibody compared to non-responders (NR). The methods described herein enable patient monitoring and evaluation and can be used to inform treatment decisions, such as whether to continue treatment including a bispecific anti-FcRH5 / anti-CD3 antibody, or whether to select and / or administer treatments other than or in addition to a bispecific anti-FcRH5 / anti-CD3 antibody. Thus, these methods are useful for treating subjects while achieving a more favorable benefit-risk profile.

[0235] The present invention provides methods for treating T cell proliferation markers (e.g., MKI67) by increasing levels of MKI67 and / or increasing numbers of MKI67. +Provided are methods useful for treating a subject with a T-cell-containing cancer (e.g., MM), comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (i.e., a bispecific anti-FcRH5 / anti-CD3 antibody), e.g., in a fractionated-dose escalation dosing regimen. Furthermore, the methods described herein are useful for monitoring and assessing the response of a subject undergoing the treatments described herein.

[0236] A. Monitoring method The present invention provides methods for monitoring the response of a subject with cancer (e.g., MM) to treatment with a bispecific antibody. The subject may have elevated levels of a T cell proliferation marker (e.g., MKI67) and / or elevated numbers of MKI67. + The treatment may include administering to the subject a bispecific antibody (e.g., a bispecific anti-FcRH5 / anti-CD3 antibody) in a dosing regimen (e.g., a one-step escalation or two-step escalation dosing regimen) described herein.

[0237] In some embodiments, the method includes determining the level of a T cell proliferation marker (e.g., MKI67) in a biological sample (e.g., blood, serum, or plasma) from the subject. The biological sample can be obtained from a cancer (e.g., MM) subject (e.g., a human) being treated with a bispecific antibody (e.g., a bispecific anti-FcRH5 / anti-CD3 antibody described herein). Additionally, the biological sample can be obtained from the subject at a time point after administration of the bispecific antibody. Exemplary time points after administration of the bispecific antibody are one or more days (e.g., 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, or more) after administration of the bispecific antibody.

[0238] In some embodiments, the methods comprise comparing the level of a T cell proliferation marker (e.g., MKI67) in a cell (e.g., a T cell) to a reference level, wherein an increased level of the T cell proliferation marker in the biological sample compared to the reference level identifies the subject as one that is responsive to the bispecific antibody, thereby monitoring the subject's response to treatment with the bispecific antibody.

[0239] In some aspects, provided herein are methods for monitoring the response of a subject having cancer (e.g., MM) to treatment with a bispecific antibody that binds FcRH5 and CD3, comprising: (a) determining the level of a T cell proliferation marker in a biological sample obtained from the subject at a time after administration of the bispecific antibody; and (b) comparing the level of the T cell proliferation marker in the biological sample with a reference level, wherein an increased level of the T cell proliferation marker in the biological sample compared to the reference level identifies the subject as one that is responding to the bispecific antibody, thereby monitoring the subject's response to treatment with the bispecific antibody.

[0240] In some embodiments, provided herein is a bispecific antibody that binds to FcRH5 and CD3 for use in treating a subject with MM, wherein the treatment comprises monitoring the subject's response to the treatment, the monitoring comprising: (a) determining the level of a T cell proliferation marker in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; and (b) comparing the level of the T cell proliferation marker in the biological sample with a reference level, wherein an increased level of the T cell proliferation marker in the biological sample compared to the reference level identifies the subject as responding to the bispecific antibody, thereby monitoring the subject's response to treatment with the bispecific antibody. Any suitable reference level (e.g., baseline level) may be used. In some embodiments, the reference level is the level (e.g., mRNA or protein level) of a T cell proliferation marker (e.g., MKI67) determined in a biological sample obtained from the subject before administering the bispecific antibody to the subject. In some embodiments, the biological sample is obtained from the subject at least 30 seconds (e.g., at least 1 minute, at least 2 minutes, at least 3 minutes, at least 4 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 5 hours, at least 10 hours, at least 15 hours, at least 20 hours, or at least 24 hours) before administering the bispecific antibody to the subject. In some embodiments, the biological sample is obtained from the subject at least 1 day (e.g., at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, or more) prior to administering the bispecific antibody to the subject.In some embodiments, the biological sample is obtained from the subject at least 1 week (e.g., at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or more) prior to administering the bispecific antibody to the subject.

[0241] In some embodiments, the reference level is the median protein expression level of MKI67 determined in a population of individuals with MM. In some embodiments, the reference level is the median mRNA expression level of MKI67 determined in a population of individuals with MM.

[0242] In some embodiments, a reference level is less than 100% (e.g., 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%, 78%, 77%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 69%, 68%, 67%, 66%, 65%, 64%, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 59 ... 6%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less). In some embodiments, the reference level is about 50% to about 99% (e.g., about 55% to about 75%, about 60% to about 80%, about 65% to about 85%, about 75% to about 85%, about 85% to about 95%, or about 90% to about 99%) of the level of a T cell proliferation marker (e.g., MKI67) determined in a biological sample obtained from a subject prior to administration of the bispecific antibody. In some embodiments, the reference level is about 1% to about 50% (e.g., about 1% to about 20%, about 5% to about 25%, about 10% to about 30%, about 20% to about 40%, about 25% to about 45%, or about 45% to about 50%) of the level of a T cell proliferation marker (e.g., MKI67) determined in a biological sample obtained from a subject prior to administration of the bispecific antibody. In some embodiments, the reference level is about 0.01% to about 1% (e.g., about 0.05% to about 0.01%, about 0.01% to about 0.5%, or about 5% to about 1%) of the level of a T cell proliferation marker (e.g., MKI67) determined in a biological sample obtained from the subject prior to administration of the bispecific antibody.

[0243] In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is greater than 100% of the reference level (e.g., 101%, 105%, 110%, 120%, 150%, 200%, 250%, 300%, or greater). In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is about 101% to about 1000% of the reference level (e.g., about 101% to about 500%, about 200% to about 400%, about 300% to about 600%, about 400% to about 700%, about 500% to about 800%, about 600% to about 900%, or about 700% to about 1000%). In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is about 101% to about 500% (e.g., about 101% to about 500%, about 101% to about 400%, about 101% to about 300%, or about 101% to about 200%) of the reference level.

[0244] In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is more than 1-fold higher (e.g., 1.1-fold higher, 1.2-fold higher, 1.3-fold higher, 1.4-fold higher, 1.5-fold higher, 1.6-fold higher, 1.7-fold higher, 1.8-fold higher, 1.9-fold higher, 2-fold higher, 2.5-fold higher, 3-fold higher, 3.5-fold higher, 4-fold higher, 4.5-fold higher, 5-fold higher, 5.5-fold higher, 6-fold higher, 6.5-fold higher, 7-fold higher, 7.5-fold higher, 8-fold higher, 8.5-fold higher, 9-fold higher, 9.5-fold higher, 10-fold higher, or more) compared to a reference level. In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is about 1.1-fold to about 5-fold higher (e.g., about 1.2-fold to about 2-fold higher, about 1.5-fold to about 3-fold higher, about 2.5-fold to about 4-fold higher, or about 4-fold to about 5-fold higher) compared to a reference level. In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is about 2-fold to about 10-fold higher (e.g., about 2-fold to about 4-fold higher, about 3-fold to about 5-fold higher, about 5-fold to about 7-fold higher, about 6-fold to about 8-fold, or about 7-fold to about 10-fold higher) compared to a reference level. In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is about 5-fold to about 10-fold higher (e.g., about 5-fold to about 6-fold higher, about 6-fold to about 7-fold higher, about 7-fold to about 8-fold higher, about 8-fold to about 9-fold, or about 9-fold to about 10-fold higher) compared to a reference level.

[0245] In some embodiments, the method may further comprise administering to the subject a bispecific antibody (e.g., a bispecific anti-FcRH5 / anti-CD3 antibody described herein). In some examples, the bispecific antibody is cebostamab.

[0246] In some embodiments, the T cell proliferation marker (e.g., MKI67) is at the protein level. Any suitable laboratory technique for determining protein levels in a sample can be used, including, but not limited to, flow cytometry (FC), fluorescence-activated cell sorting (FACS), Western blot, enzyme-linked immunosorbent assay (ELISA), mass spectrometry (MS), immunofluorescence (IF), immunoprecipitation (IP), radioimmunoassay, dot blotting, high-performance liquid chromatography (HPLC), surface plasmon resonance, optical spectroscopy, and immunohistochemistry (IHC). Any immune-based technique can include the use of an MKI67 antibody, such as a monoclonal Ki-67 antibody or MIB-1 antibody.

[0247] In some embodiments, the T cell proliferation marker (e.g., MKI67) is at the mRNA level. Any suitable laboratory technique for determining protein expression levels in a sample can be used, including, but not limited to, polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), quantitative PCR (qPCR), RT-qPCR, microarray analysis, Northern blot, MassArray® technology, serial analysis of gene expression (SAGE), and RNA sequencing.

[0248] In some embodiments, a T cell proliferation marker (e.g., MKI67) is detected in T cells in the biological sample. + T cell and / or granzyme B (Gzb) positivity (Gzb + ) T cells.

[0249] In some embodiments, the present invention provides methods for monitoring the response of a subject with cancer (e.g., MM) to treatment with a bispecific antibody. + Cells (e.g., MKI67 + The treatment may include administering to the subject a bispecific antibody (e.g., a bispecific anti-FcRH5 / anti-CD3 antibody) in a dosing regimen (e.g., a one-step escalation or two-step escalation dosing regimen) described herein.

[0250] In some embodiments, the method includes detecting MKI67-positive (MKI67 + ) cells (e.g., MKI67 + The method includes determining the number of T cells (e.g., T cells). A biological sample can be obtained from a cancer (e.g., MM) subject (e.g., a human) being treated with a bispecific antibody (e.g., the bispecific anti-FcRH5 / anti-CD3 antibody described herein). Additionally, a biological sample can be obtained from the subject at a time point after administration of the bispecific antibody. Exemplary time points after administration of the bispecific antibody are one or more days (e.g., 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, or more) after administration of the bispecific antibody.

[0251] In some embodiments, the method further comprises: + Number of cells (e.g., MKI67 + T cells) to a reference number, + An increased number of cells (eg, T cells) identifies the subject as one that is responding to the bispecific antibody, thereby monitoring the subject's response to treatment with the bispecific antibody.

[0252]

[0013] In some aspects, provided herein are methods for monitoring the response of a subject with cancer (e.g., MM) to treatment with a bispecific antibody that binds FcRH5 and CD3, comprising: (a) detecting MKI67 in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; + (b) determining the number of T cells; and (b) MKI67 in the biological sample. + comparing the number of T cells to a reference number, and determining whether MKI67 in the biological sample is higher than the reference number; + and comparing an increased number of T cells identifies the subject as one that is responding to the bispecific antibody, thereby providing a method for monitoring a subject's response to treatment with the bispecific antibody.

[0253]

[0010] In some aspects, provided herein is a bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, wherein the treatment comprises monitoring the subject's response to the treatment, the monitoring comprising: (a) detecting MKI67 in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; + (b) determining the number of T cells; and (b) MKI67 in the biological sample. + comparing the number of T cells to a reference number, and determining whether MKI67 in the biological sample is higher than the reference number; + and comparing an increased number of T cells to identify the subject as a subject responding to the bispecific antibody, thereby monitoring the subject's response to treatment with the bispecific antibody.

[0254] Any suitable reference number (e.g., baseline level) may be used. In some embodiments, the reference number is the MKI67 level determined in a biological sample obtained from a subject prior to administering the bispecific antibody to the subject. + Cells (e.g., MKI67 +In some embodiments, the biological sample is obtained from the subject at least 30 seconds (e.g., at least 1 minute, at least 2 minutes, at least 3 minutes, at least 4 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 5 hours, at least 10 hours, at least 15 hours, at least 20 hours, or at least 24 hours) prior to administering the bispecific antibody to the subject. In some embodiments, the biological sample is obtained from the subject at least 1 day (e.g., at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, or more) before administering the bispecific antibody to the subject. In some embodiments, the biological sample is obtained from the subject at least 1 week (e.g., at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or more) before administering the bispecific antibody to the subject.

[0255] In some embodiments, the reference number is a MKI67 determined in a population of individuals with MM. + Cells (e.g., MKI67 + In some embodiments, the reference number is the median number of MKI67 T cells (MKI67 T cells) determined in a biological sample obtained from the subject prior to administration of the bispecific antibody. + Cells (e.g., MKI67 +T cells) are less than 100% of the number (e.g., 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%, 78%, 77%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 69%, 68%, 67%, 66%, 65%, 64%, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52% %, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less). In some embodiments, the reference number is the MKI67 determined in a biological sample obtained from the subject prior to administration of the bispecific antibody. + Cells (e.g., MKI67 + In some embodiments, the reference number is about 50% to about 99% (e.g., about 55% to about 75%, about 60% to about 80%, about 65% to about 85%, about 75% to about 85%, about 85% to about 95%, or about 90% to about 99%) of the number of MKI67 T cells (MKI67 T cells) determined in a biological sample obtained from the subject prior to administration of the bispecific antibody. + Cells (e.g., MKI67 + In some embodiments, the reference number is about 1% to about 50% (e.g., about 1% to about 20%, about 5% to about 25%, about 10% to about 30%, about 20% to about 40%, about 25% to about 45%, or about 45% to about 50%) of the number of MKI67 T cells (MKI67 T cells) determined in a biological sample obtained from the subject prior to administration of the bispecific antibody. + Cells (e.g., MKI67 + T cells) (for example, about 0.01% to about 1% (for example, about 0.05% to about 0.01%, about 0.01% to about 0.5%, or about 5% to about 1%).

[0256] In some embodiments, MKI67 +Cells (e.g., MKI67 + In some embodiments, the number of MKI67 T cells is greater than 100% of the reference number (e.g., 101%, 105%, 110%, 120%, 150%, 200%, 250%, 300% or more). + Cells (e.g., MKI67 + The number of MKI67 T cells is about 101% to about 1000% (e.g., about 101% to about 500%, about 200% to about 400%, about 300% to about 600%, about 400% to about 700%, about 500% to about 800%, about 600% to about 900%, or about 700% to about 1000%) of the reference number. + Cells (e.g., MKI67 + T cells) is about 101% to about 500% (e.g., about 101% to about 500%, about 101% to about 400%, about 101% to about 300%, or about 101% to about 200%) of the reference number.

[0257] In some embodiments, MKI67 + Cells (e.g., MKI67 + T cells) is more than 1-fold higher (e.g., 1.1-fold higher, 1.2-fold higher, 1.3-fold higher, 1.4-fold higher, 1.5-fold higher, 1.6-fold higher, 1.7-fold higher, 1.8-fold higher, 1.9-fold higher, 2-fold higher, 2.5-fold higher, 3-fold higher, 3.5-fold higher, 4-fold higher, 4.5-fold higher, 5-fold higher, 5.5-fold higher, 6-fold higher, 6.5-fold higher, 7-fold higher, 7.5-fold higher, 8-fold higher, 8.5-fold higher, 9-fold higher, 9.5-fold higher, 10-fold higher, or more) compared to a reference number. + Cells (e.g., MKI67 + T cells) is about 1.1-fold to about 5-fold higher (e.g., about 1.2-fold to about 2-fold higher, about 1.5-fold to about 3-fold higher, about 2.5-fold to about 4-fold higher, or about 4-fold to about 5-fold higher) compared to a reference number. + Cells (e.g., MKI67 + T cells) is about 2-fold to about 10-fold higher (e.g., about 2-fold to about 4-fold higher, about 3-fold to about 5-fold higher, about 5-fold to about 7-fold higher, about 6-fold to about 8-fold, or about 7-fold to about 10-fold higher) compared to a reference number.+ Cells (e.g., MKI67 + T cells) is about 5-fold to about 10-fold higher (e.g., about 5-fold to about 6-fold higher, about 6-fold to about 7-fold higher, about 7-fold to about 8-fold higher, about 8-fold to about 9-fold, or about 9-fold to about 10-fold higher) compared to a reference number.

[0258] In some embodiments, MKI67 in the sample + Cells (e.g., MKI67 + The number of T cells can be detected by, for example, FC, FACS, Western blot, ELISA, MS, IF, IP, radioimmunoassay, dot blotting, HPLC, surface plasmon resonance, optical spectroscopy, or IHC. Any immune-based technique can include the use of an MKI67 antibody, such as a monoclonal Ki-67 antibody or MIB-1 antibody.

[0259] In some embodiments, MKI67 + The cells were MKI67 + T cells and / or Gzb + T cells.

[0260] In some embodiments, the method may further comprise administering to the subject a bispecific antibody (e.g., a bispecific anti-FcRH5 / anti-CD3 antibody described herein). In some examples, the bispecific antibody is cebostamab.

[0261] B. Evaluation Method The present invention provides a method for assessing the response of a subject with cancer (e.g., MM) to treatment with a bispecific antibody. The subject may have elevated levels of a T cell proliferation marker (e.g., MKI67). The treatment may include administering a bispecific antibody (e.g., a bispecific anti-FcRH5 / anti-CD3 antibody) to the subject in a dosing regimen (e.g., a one-step escalation or two-step escalation dosing regimen) described herein.

[0262] In some embodiments, the method includes determining the level of a T cell proliferation marker (e.g., MKI67) in a biological sample (e.g., blood, serum, or plasma) from the subject. The biological sample can be obtained from a cancer (e.g., MM) subject (e.g., a human) being treated with a bispecific antibody (e.g., a bispecific anti-FcRH5 / anti-CD3 antibody described herein). Additionally, the biological sample can be obtained from the subject at a time point after administration of the bispecific antibody. Exemplary time points after administration of the bispecific antibody are one or more days (e.g., 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, or more) after administration of the bispecific antibody.

[0263] In some embodiments, the methods further comprise maintaining, adjusting, or ceasing treatment of the subject based on a comparison of the level of a T cell proliferation marker (e.g., MKI67) in the biological sample to a reference level, wherein a change in the level of the T cell proliferation marker in the biological sample compared to the reference level indicates a response to treatment with the bispecific antibody.

[0264] In some aspects, provided herein are methods for assessing the treatment response of a subject having cancer (e.g., MM) to treatment with a bispecific antibody that binds FcRH5 and CD3, the methods comprising: (a) determining the level of a T-cell proliferation marker in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; and (b) maintaining, adjusting, or stopping the subject's treatment based on a comparison of the level of the T-cell proliferation marker in the biological sample to a reference level, wherein a change in the level of the T-cell proliferation marker in the biological sample compared to the reference level indicates a response to treatment with the bispecific antibody.

[0265] In some embodiments, the method may further comprise administering to the subject a bispecific antibody (e.g., a bispecific anti-FcRH5 / anti-CD3 antibody described herein). In some examples, the bispecific antibody is cebostamab.

[0266] In some embodiments, if the level of a T cell proliferation marker (e.g., MKI67) in the biological sample increases compared to the reference level, the subject is responding to the treatment and the treatment is maintained. In other embodiments, if the level of a T cell proliferation marker (e.g., MKI67) in the biological sample remains the same or decreases compared to the reference level, the subject is not responding to the treatment and the treatment is adjusted or stopped.

[0267] In some aspects, provided herein is a bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, the treatment comprising assessing the subject's response to the treatment, the assessment comprising: (a) determining the level of a T cell proliferation marker in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; and (b) maintaining, adjusting, or ceasing the subject's treatment based on a comparison of the level of the T cell proliferation marker in the biological sample to a reference level, wherein a change in the level of the T cell proliferation marker in the biological sample compared to the reference level indicates a response to treatment with the bispecific antibody.

[0268] Any suitable reference level (e.g., baseline level) may be used. In some embodiments, the reference level is the level (e.g., mRNA or protein level) of a T cell proliferation marker (e.g., MKI67) determined in a biological sample obtained from a subject before administering the bispecific antibody to the subject. In some embodiments, the biological sample is obtained from the subject at least 30 seconds (e.g., at least 1 minute, at least 2 minutes, at least 3 minutes, at least 4 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 5 hours, at least 10 hours, at least 15 hours, at least 20 hours, or at least 24 hours) before administering the bispecific antibody to the subject. In some embodiments, the biological sample is obtained from the subject at least 1 day (e.g., at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, or more) before administering the bispecific antibody to the subject. In some embodiments, the biological sample is obtained from the subject at least 1 week (e.g., at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or more) before administering the bispecific antibody to the subject.

[0269] In some embodiments, the reference level is the median protein expression level of MKI67 determined in a population of individuals with MM. In some embodiments, the reference level is the median mRNA expression level of MKI67 determined in a population of individuals with MM. In some embodiments, a reference level is less than 100% (e.g., 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%, 78%, 77%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 69%, 68%, 67%, 66%, 65%, 64%, 63%, 62%, 64% or less) of the level of a T cell proliferation marker measured in a subject being treated with a bispecific antibody and / or a subject being evaluated or monitored after that treatment. %, 61%, 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less). In some embodiments, the reference level is about 50% to about 99% (e.g., about 55% to about 75%, about 60% to about 80%, about 65% to about 85%, about 75% to about 85%, about 85% to about 95%, or about 90% to about 99%) of the level of a T cell proliferation marker (e.g., MKI67) determined in a biological sample obtained from a subject prior to administration of the bispecific antibody. In some embodiments, the reference level is about 1% to about 50% (e.g., about 1% to about 20%, about 5% to about 25%, about 10% to about 30%, about 20% to about 40%, about 25% to about 45%, or about 45% to about 50%) of the level of a T cell proliferation marker (e.g., MKI67) determined in a biological sample obtained from a subject prior to administration of the bispecific antibody.In some embodiments, the reference level is about 0.01% to about 1% (e.g., about 0.05% to about 0.01%, about 0.01% to about 0.5%, or about 5% to about 1%) of the level of a T cell proliferation marker (e.g., MKI67) determined in a biological sample obtained from the subject prior to administration of the bispecific antibody.

[0270] In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is greater than 100% of the reference level (e.g., 101%, 105%, 110%, 120%, 150%, 200%, 250%, 300%, or greater). In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is about 101% to about 1000% of the reference level (e.g., about 101% to about 500%, about 200% to about 400%, about 300% to about 600%, about 400% to about 700%, about 500% to about 800%, about 600% to about 900%, or about 700% to about 1000%). In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is about 101% to about 500% (e.g., about 101% to about 500%, about 101% to about 400%, about 101% to about 300%, or about 101% to about 200%) of the reference level.

[0271] In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is more than 1-fold higher (e.g., 1.1-fold higher, 1.2-fold higher, 1.3-fold higher, 1.4-fold higher, 1.5-fold higher, 1.6-fold higher, 1.7-fold higher, 1.8-fold higher, 1.9-fold higher, 2-fold higher, 2.5-fold higher, 3-fold higher, 3.5-fold higher, 4-fold higher, 4.5-fold higher, 5-fold higher, 5.5-fold higher, 6-fold higher, 6.5-fold higher, 7-fold higher, 7.5-fold higher, 8-fold higher, 8.5-fold higher, 9-fold higher, 9.5-fold higher, 10-fold higher, or more) compared to a reference level. In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is about 1.1-fold to about 5-fold higher (e.g., about 1.2-fold to about 2-fold higher, about 1.5-fold to about 3-fold higher, about 2.5-fold to about 4-fold higher, or about 4-fold to about 5-fold higher) compared to a reference level. In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is about 2-fold to about 10-fold higher (e.g., about 2-fold to about 4-fold higher, about 3-fold to about 5-fold higher, about 5-fold to about 7-fold higher, about 6-fold to about 8-fold, or about 7-fold to about 10-fold higher) compared to a reference level. In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is about 5-fold to about 10-fold higher (e.g., about 5-fold to about 6-fold higher, about 6-fold to about 7-fold higher, about 7-fold to about 8-fold higher, about 8-fold to about 9-fold, or about 9-fold to about 10-fold higher) compared to a reference level.

[0272] In some embodiments, the method may further comprise administering to the subject a bispecific antibody (e.g., a bispecific anti-FcRH5 / anti-CD3 antibody described herein). In some examples, the bispecific antibody is cebostamab.

[0273] In some embodiments, the T cell proliferation marker (e.g., MKI67) is at the protein level. Any suitable laboratory technique for determining protein levels in a sample can be used, including but not limited to, FC, FACS, Western blot, ELISA, MS, IF, IP, radioimmunoassay, dot blotting, HPLC, surface plasmon resonance, optical spectroscopy, and IHC. Any immune-based technique can include the use of an MKI67 antibody, such as a monoclonal Ki-67 antibody or MIB-1 antibody.

[0274] In some embodiments, the T cell proliferation marker (e.g., MKI67) is at the mRNA level. Any suitable laboratory technique for determining protein expression levels in a sample can be used, including, but not limited to, PCR, RT-PCR, qPCR, RT-qPCR, microarray analysis, Northern blot, MassArray® technology, SAGE, and RNA sequencing.

[0275] In some embodiments, a T cell proliferation marker (e.g., MKI67) is detected in T cells in the biological sample. + T cell and / or granzyme B (Gzb) positivity (Gzb + ) T cells.

[0276] In some embodiments, a T cell proliferation marker (e.g., MKI67) is detected in T cells in the biological sample. + T cells and / or Gzb + It may be a T cell.

[0277] In some embodiments, the present invention provides methods for assessing the response of a subject with cancer (e.g., MM) to treatment with a bispecific antibody. + Cells (e.g., MKI67 +The treatment may include administering to the subject a bispecific antibody (e.g., a bispecific anti-FcRH5 / anti-CD3 antibody) in a dosing regimen (e.g., a one-step escalation or two-step escalation dosing regimen) described herein.

[0278] In some embodiments, the methods involve detecting MKI67 in a biological sample (e.g., blood, serum, or plasma) from a subject. + Cells (e.g., MKI67 + The method includes determining the number of T cells (e.g., T cells). A biological sample can be obtained from a cancer (e.g., MM) subject (e.g., a human) being treated with a bispecific antibody (e.g., the bispecific anti-FcRH5 / anti-CD3 antibody described herein). Additionally, a biological sample can be obtained from the subject at a time point after administration of the bispecific antibody. Exemplary time points after administration of the bispecific antibody are one or more days (e.g., 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, or more) after administration of the bispecific antibody.

[0279] In some embodiments, the method comprises detecting MKI67 in a biological sample. + Cells (e.g., MKI67 + and maintaining, adjusting, or ceasing treatment of the subject based on a comparison of the number of MKI67 in the biological sample (T cells) to a reference number, + Cells (e.g., MKI67 + Changes in the number of T cells indicate a response to treatment with the bispecific antibody.

[0280]

[0013] In some aspects, provided herein are methods for assessing the treatment response of a subject having cancer (e.g., MM) to treatment with a bispecific antibody that binds FcRH5 and CD3, the methods comprising: (a) detecting MKI67 in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; +(b) determining the number of T cells; and (b) MKI67 in the biological sample. + maintaining, adjusting, or stopping the subject's treatment based on a comparison of the number of T cells to a reference number; + Methods are provided wherein a change in the number of T cells indicates a response to treatment with the bispecific antibody.

[0281]

[0010] In some aspects, provided herein is a bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, wherein the treatment comprises assessing the subject's response to the treatment, the assessment comprising: (a) detecting MKI67 in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; + (b) determining the number of T cells; and (b) MKI67 in the biological sample. + maintaining, adjusting, or stopping the subject's treatment based on a comparison of the number of T cells to a reference number; + Bispecific antibodies are provided in which a change in the number of T cells indicates a response to treatment with the bispecific antibody.

[0282] Any suitable reference number (e.g., baseline level) may be used. In some embodiments, the reference number is the MKI67 level determined in a biological sample obtained from a subject prior to administering the bispecific antibody to the subject. + Cells (e.g., MKI67 +In some embodiments, the biological sample is obtained from the subject at least 30 seconds (e.g., at least 1 minute, at least 2 minutes, at least 3 minutes, at least 4 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 5 hours, at least 10 hours, at least 15 hours, at least 20 hours, or at least 24 hours) prior to administering the bispecific antibody to the subject. In some embodiments, the biological sample is obtained from the subject at least 1 day (e.g., at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, or more) before administering the bispecific antibody to the subject. In some embodiments, the biological sample is obtained from the subject at least 1 week (e.g., at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or more) before administering the bispecific antibody to the subject.

[0283] In some embodiments, the reference number is a MKI67 determined in a population of individuals with MM. + Cells (e.g., MKI67 + In some embodiments, the reference number is the median number of MKI67 T cells measured in subjects being treated with the bispecific antibody and / or being evaluated or monitored after that treatment. +Less than 100% of the T cell count (e.g., 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%, 78%, 77%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 69%, 68%, 67%, 66%, 65%, 64%, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52%) , 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less). In some embodiments, the reference number is the MKI67 determined in a biological sample obtained from the subject prior to administration of the bispecific antibody. + Cells (e.g., MKI67 + In some embodiments, the reference number is about 50% to about 99% (e.g., about 55% to about 75%, about 60% to about 80%, about 65% to about 85%, about 75% to about 85%, about 85% to about 95%, or about 90% to about 99%) of the number of MKI67 T cells (MKI67 T cells) determined in a biological sample obtained from the subject prior to administration of the bispecific antibody. + Cells (e.g., MKI67 + In some embodiments, the reference number is about 1% to about 50% (e.g., about 1% to about 20%, about 5% to about 25%, about 10% to about 30%, about 20% to about 40%, about 25% to about 45%, or about 45% to about 50%) of the number of MKI67 T cells (MKI67 T cells) determined in a biological sample obtained from the subject prior to administration of the bispecific antibody. + Cells (e.g., MKI67 + T cells) (for example, about 0.01% to about 1% (for example, about 0.05% to about 0.01%, about 0.01% to about 0.5%, or about 5% to about 1%).

[0284] In some embodiments, MKI67 +Cells (e.g., MKI67 + In some embodiments, the number of MKI67 T cells is greater than 100% of the reference number (e.g., 101%, 105%, 110%, 120%, 150%, 200%, 250%, 300% or more). + Cells (e.g., MKI67 + The number of MKI67 T cells is about 101% to about 1000% (e.g., about 101% to about 500%, about 200% to about 400%, about 300% to about 600%, about 400% to about 700%, about 500% to about 800%, about 600% to about 900%, or about 700% to about 1000%) of the reference number. + Cells (e.g., MKI67 + T cells) is about 101% to about 500% (e.g., about 101% to about 500%, about 101% to about 400%, about 101% to about 300%, or about 101% to about 200%) of the reference number.

[0285] In some embodiments, MKI67 + Cells (e.g., MKI67 + T cells) is more than 1-fold higher (e.g., 1.1-fold higher, 1.2-fold higher, 1.3-fold higher, 1.4-fold higher, 1.5-fold higher, 1.6-fold higher, 1.7-fold higher, 1.8-fold higher, 1.9-fold higher, 2-fold higher, 2.5-fold higher, 3-fold higher, 3.5-fold higher, 4-fold higher, 4.5-fold higher, 5-fold higher, 5.5-fold higher, 6-fold higher, 6.5-fold higher, 7-fold higher, 7.5-fold higher, 8-fold higher, 8.5-fold higher, 9-fold higher, 9.5-fold higher, 10-fold higher, or more) compared to a reference number. + Cells (e.g., MKI67 + T cells) is about 1.1-fold to about 5-fold higher (e.g., about 1.2-fold to about 2-fold higher, about 1.5-fold to about 3-fold higher, about 2.5-fold to about 4-fold higher, or about 4-fold to about 5-fold higher) compared to a reference number. + Cells (e.g., MKI67 + T cells) is about 2-fold to about 10-fold higher (e.g., about 2-fold to about 4-fold higher, about 3-fold to about 5-fold higher, about 5-fold to about 7-fold higher, about 6-fold to about 8-fold, or about 7-fold to about 10-fold higher) compared to a reference number.+ Cells (e.g., MKI67 + T cells) is about 5-fold to about 10-fold higher (e.g., about 5-fold to about 6-fold higher, about 6-fold to about 7-fold higher, about 7-fold to about 8-fold higher, about 8-fold to about 9-fold, or about 9-fold to about 10-fold higher) compared to a reference number.

[0286] In some embodiments, MKI67 in the sample + Cells (e.g., MKI67 + The number of T cells can be detected by, for example, FC, FACS, Western blot, ELISA, MS, IF, IP, radioimmunoassay, dot blotting, HPLC, surface plasmon resonance, optical spectroscopy, or IHC. Any immune-based technique can include the use of an MKI67 antibody, such as a monoclonal Ki-67 antibody or MIB-1 antibody.

[0287] In some embodiments, MKI67 + The cells were MKI67 + T cells and / or Gzb + T cells.

[0288] In some embodiments, the method may further comprise administering to the subject a bispecific antibody (e.g., a bispecific anti-FcRH5 / anti-CD3 antibody described herein). In some examples, the bispecific antibody is cebostamab.

[0289] In some embodiments, MKI67 in a biological sample + Cells (e.g., MKI67 + If the number of MKI67 T cells in the biological sample is increased compared to the reference number, the subject has responded to the treatment and the treatment is maintained. + Cells (e.g., MKI67 + If the number of MKI67 T cells (as measured by the MM marker) is the same or decreased compared to the reference number, the subject is not responding to treatment and treatment is adjusted or stopped. In some embodiments, the reference number is the number of MKI67 T cells (as measured by the MM marker) determined in a population of individuals with MM. + Cells (e.g., MKI67 + The median number of T cells.

[0290] C. Treatment Method The present invention provides a method of treating a subject with cancer (e.g., MM) with a bispecific antibody. The subject may have elevated levels of a T cell proliferation marker (e.g., MKI67). Treatment may include administering a bispecific antibody (e.g., a bispecific anti-FcRH5 / anti-CD3 antibody) to the subject in a dosing regimen (e.g., a one-step escalation or two-step escalation dosing regimen) described herein.

[0291] In some embodiments, the method includes determining the level of a T cell proliferation marker (e.g., MKI67) in a biological sample (e.g., blood, serum, or plasma) from the subject. The biological sample can be obtained from a cancer (e.g., MM) subject (e.g., a human) being treated with a bispecific antibody (e.g., a bispecific anti-FcRH5 / anti-CD3 antibody described herein). Additionally, the biological sample can be obtained from the subject at a time point after administration of the bispecific antibody. Exemplary time points after administration of the bispecific antibody are one or more days (e.g., 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, or more) after administration of the bispecific antibody.

[0292] In some embodiments, the method further comprises comparing the level of a T cell proliferation marker (e.g., MKI67) in the cell (e.g., T cell) to a reference level, wherein an increased level of the T cell proliferation marker in the biological sample compared to the reference level identifies the subject as one that is responsive to the bispecific anti-FcRH5 / anti-CD3 antibody.

[0293] In some embodiments, provided herein are methods of treating a subject having cancer (e.g., MM) with a bispecific antibody that binds FcRH5 and CD3, the method comprising administering the bispecific antibody to the subject, wherein the subject has previously been monitored according to any of the monitoring methods disclosed herein.

[0294] In some embodiments, provided herein are methods of treating a subject having cancer (e.g., MM) with a bispecific antibody that binds FcRH5 and CD3, the methods comprising administering the bispecific antibody to a subject, wherein the subject has previously been evaluated according to any of the methods of evaluating disclosed herein.

[0295] In some aspects, provided herein are methods of treating a subject having cancer (e.g., MM) with a bispecific antibody that binds FcRH5 and CD3, the method comprising: (a) determining the level of a T cell proliferation marker in a biological sample obtained from the subject at a time after administration of the bispecific antibody; (b) comparing the level of the T cell proliferation marker in the biological sample with a reference level, wherein an increased level of the T cell proliferation marker in the biological sample compared to the reference level identifies the subject as one that is responsive to the bispecific antibody; and (c) continuing to administer the bispecific antibody to the subject if the level of the T cell proliferation marker is increased compared to the reference level.

[0296] In some embodiments, provided herein is a bispecific antibody that binds to FcRH5 and CD3 for use in treating a subject with MM, wherein the treatment comprises: (a) determining the level of a T cell proliferation marker in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; (b) comparing the level of the T cell proliferation marker in the biological sample with a reference level, wherein an increased level of the T cell proliferation marker in the biological sample compared to the reference level identifies the subject as a subject that is responding to the bispecific antibody; and (c) continuing to administer the bispecific antibody to the subject if the level of the T cell proliferation marker is increased compared to the reference level. Any suitable reference level (e.g., baseline level) may be used. In some embodiments, the reference level is the level (e.g., mRNA or protein level) of a T cell proliferation marker (e.g., MKI67) determined in a biological sample obtained from the subject before administering the bispecific antibody to the subject. In some embodiments, the biological sample is obtained from the subject at least 30 seconds (e.g., at least 1 minute, at least 2 minutes, at least 3 minutes, at least 4 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 5 hours, at least 10 hours, at least 15 hours, at least 20 hours, or at least 24 hours) before administering the bispecific antibody to the subject. In some embodiments, the biological sample is obtained from the subject at least 1 day (e.g., at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, or more) prior to administering the bispecific antibody to the subject.In some embodiments, the biological sample is obtained from the subject at least 1 week (e.g., at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or more) prior to administering the bispecific antibody to the subject.

[0297] In some aspects, the reference level is the median protein level of MKI67 determined in a population of individuals with MM. In some aspects, the reference level is the median mRNA level of MKI67 determined in a population of individuals with MM. In some embodiments, the reference level is less than 100% (e.g., 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%, 78%, 77%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 69%, 68%, 67%, 66%, 65%, 64%, 63%, 65%, 66%, 67%, 68%, 69 ... 2%, 61%, 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less). In some embodiments, the reference level is about 50% to about 99% (e.g., about 55% to about 75%, about 60% to about 80%, about 65% to about 85%, about 75% to about 85%, about 85% to about 95%, or about 90% to about 99%) of the level of a T cell proliferation marker (e.g., MKI67) determined in a biological sample obtained from a subject prior to administration of the bispecific antibody. In some embodiments, the reference level is about 1% to about 50% (e.g., about 1% to about 20%, about 5% to about 25%, about 10% to about 30%, about 20% to about 40%, about 25% to about 45%, or about 45% to about 50%) of the level of a T cell proliferation marker (e.g., MKI67) determined in a biological sample obtained from a subject prior to administration of the bispecific antibody.In some embodiments, the reference level is about 0.01% to about 1% (e.g., about 0.05% to about 0.01%, about 0.01% to about 0.5%, or about 5% to about 1%) of the level of a T cell proliferation marker (e.g., MKI67) determined in a biological sample obtained from the subject prior to administration of the bispecific antibody.

[0298] In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is greater than 100% of the reference level (e.g., 101%, 105%, 110%, 120%, 150%, 200%, 250%, 300%, or greater). In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is about 101% to about 1000% of the reference level (e.g., about 101% to about 500%, about 200% to about 400%, about 300% to about 600%, about 400% to about 700%, about 500% to about 800%, about 600% to about 900%, or about 700% to about 1000%). In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is about 101% to about 500% (e.g., about 101% to about 500%, about 101% to about 400%, about 101% to about 300%, or about 101% to about 200%) of the reference level.

[0299] In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is more than 1-fold higher (e.g., 1.1-fold higher, 1.2-fold higher, 1.3-fold higher, 1.4-fold higher, 1.5-fold higher, 1.6-fold higher, 1.7-fold higher, 1.8-fold higher, 1.9-fold higher, 2-fold higher, 2.5-fold higher, 3-fold higher, 3.5-fold higher, 4-fold higher, 4.5-fold higher, 5-fold higher, 5.5-fold higher, 6-fold higher, 6.5-fold higher, 7-fold higher, 7.5-fold higher, 8-fold higher, 8.5-fold higher, 9-fold higher, 9.5-fold higher, 10-fold higher, or more) compared to a reference level. In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is about 1.1-fold to about 5-fold higher (e.g., about 1.2-fold to about 2-fold higher, about 1.5-fold to about 3-fold higher, about 2.5-fold to about 4-fold higher, or about 4-fold to about 5-fold higher) compared to a reference level. In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is about 2-fold to about 10-fold higher (e.g., about 2-fold to about 4-fold higher, about 3-fold to about 5-fold higher, about 5-fold to about 7-fold higher, about 6-fold to about 8-fold, or about 7-fold to about 10-fold higher) compared to a reference level. In some embodiments, the level of a T cell proliferation marker (e.g., MKI67) is about 5-fold to about 10-fold higher (e.g., about 5-fold to about 6-fold higher, about 6-fold to about 7-fold higher, about 7-fold to about 8-fold higher, about 8-fold to about 9-fold, or about 9-fold to about 10-fold higher) compared to a reference level.

[0300] In some embodiments, the method may further comprise administering to the subject a bispecific antibody (e.g., a bispecific anti-FcRH5 / anti-CD3 antibody described herein). In some examples, the bispecific antibody is cebostamab.

[0301] In some embodiments, the T cell proliferation marker (e.g., MKI67) is at the protein level. Any suitable laboratory technique for determining protein levels in a sample can be used, including but not limited to, FC, FACS, Western blot, ELISA, MS, IF, IP, radioimmunoassay, dot blotting, HPLC, surface plasmon resonance, optical spectroscopy, and IHC. Any immune-based technique can include the use of an MKI67 antibody, such as a monoclonal Ki-67 antibody or MIB-1 antibody.

[0302] In some embodiments, the T cell proliferation marker (e.g., MKI67) is at the mRNA level. Any suitable laboratory technique for determining protein expression levels in a sample can be used, including, but not limited to, PCR, RT-PCR, qPCR, RT-qPCR, microarray analysis, Northern blot, MassArray® technology, SAGE, and RNA sequencing.

[0303] In some embodiments, a T cell proliferation marker (e.g., MKI67) is detected in T cells in the biological sample. + T cell and / or granzyme B (Gzb) positivity (Gzb + ) T cells.

[0304] In some embodiments, the present invention provides methods of treating a subject with cancer (e.g., MM) with a bispecific antibody. + Cells (e.g., MKI67 + The treatment may include administering to the subject a bispecific antibody (e.g., a bispecific anti-FcRH5 / anti-CD3 antibody) in a dosing regimen (e.g., a one-step escalation or two-step escalation dosing regimen) described herein.

[0305] In some embodiments, the methods involve detecting MKI67 in a biological sample (e.g., blood, serum, or plasma) from a subject. + Cells (e.g., MKI67+ The method includes determining the number of T cells (e.g., T cells). A biological sample can be obtained from a cancer (e.g., MM) subject (e.g., a human) being treated with a bispecific antibody (e.g., the bispecific anti-FcRH5 / anti-CD3 antibody described herein). Additionally, a biological sample can be obtained from the subject at a time point after administration of the bispecific antibody. Exemplary time points after administration of the bispecific antibody are one or more days (e.g., 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, or more) after administration of the bispecific antibody.

[0306] In some embodiments, the method further comprises: + Number of cells (e.g., MKI67 + T cells) to a reference number, + An increased number of cells (eg, T cells) identifies the subject as one that is responding to the bispecific antibody.

[0307] In some embodiments, provided herein are methods of treating a subject having cancer (e.g., MM) with a bispecific antibody that binds FcRH5 and CD3, comprising: (a) detecting proliferation, Ki-67 positivity (MKI67) in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; + (b) determining the number of T cell markers; (c) determining the number of MKI67 in the biological sample; + comparing the number of T cells to a reference number, and determining whether MKI67 in the biological sample is higher than the reference number; + (c) comparing an increased number of T cells to identify the subject as responding to the bispecific antibody; and (d) detecting MKI67 in the subject's biological sample. + If the number of T cells is increased compared to the reference number, continuing to administer the bispecific antibody to the subject is provided.

[0308] In some aspects, provided herein is a bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, wherein the treatment comprises (a) increasing proliferation Ki-67 positivity (KI67 positivity) in a biological sample obtained from the subject at a time point after administration of the bispecific antibody. + (b) determining the number of T cell markers; (c) determining the number of MKI67 in the biological sample; + comparing the number of T cells to a reference number, and determining whether MKI67 in the biological sample is higher than the reference number; + (c) comparing an increased number of T cells to identify the subject as responding to the bispecific antibody; and (d) detecting MKI67 in the subject's biological sample. + if the number of T cells is increased compared to the reference number, continuing to administer the bispecific antibody to the subject.

[0309] Any suitable reference number (e.g., baseline level) may be used. In some embodiments, the reference number is the MKI67 level determined in a biological sample obtained from a subject prior to administering the bispecific antibody to the subject. + Cells (e.g., MKI67 +In some embodiments, the biological sample is obtained from the subject at least 30 seconds (e.g., at least 1 minute, at least 2 minutes, at least 3 minutes, at least 4 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 5 hours, at least 10 hours, at least 15 hours, at least 20 hours, or at least 24 hours) prior to administering the bispecific antibody to the subject. In some embodiments, the biological sample is obtained from the subject at least 1 day (e.g., at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, or more) before administering the bispecific antibody to the subject. In some embodiments, the biological sample is obtained from the subject at least 1 week (e.g., at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, or more) before administering the bispecific antibody to the subject.

[0310] In some embodiments, the reference number is a MKI67 determined in a population of individuals with MM. + Cells (e.g., MKI67 + In some embodiments, the reference number is the median number of MKI67 cells (e.g., MKI67 T cells) measured in subjects being treated with the bispecific antibody and / or being evaluated or monitored after that treatment. +T cells) are less than 100% of the number (e.g., 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%, 78%, 77%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 69%, 68%, 67%, 66%, 65%, 64%, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52% %, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less). In some embodiments, the reference number is the MKI67 determined in a biological sample obtained from the subject prior to administration of the bispecific antibody. + Cells (e.g., MKI67 + In some embodiments, the reference number is about 50% to about 99% (e.g., about 55% to about 75%, about 60% to about 80%, about 65% to about 85%, about 75% to about 85%, about 85% to about 95%, or about 90% to about 99%) of the number of MKI67 T cells (MKI67 T cells) determined in a biological sample obtained from the subject prior to administration of the bispecific antibody. + Cells (e.g., MKI67 + In some embodiments, the reference number is about 1% to about 50% (e.g., about 1% to about 20%, about 5% to about 25%, about 10% to about 30%, about 20% to about 40%, about 25% to about 45%, or about 45% to about 50%) of the number of MKI67 T cells (MKI67 T cells) determined in a biological sample obtained from the subject prior to administration of the bispecific antibody. + Cells (e.g., MKI67 + T cells) (for example, about 0.01% to about 1% (for example, about 0.05% to about 0.01%, about 0.01% to about 0.5%, or about 5% to about 1%).

[0311] In some embodiments, MKI67 +Cells (e.g., MKI67 + In some embodiments, the number of MKI67 T cells is greater than 100% of the reference number (e.g., 101%, 105%, 110%, 120%, 150%, 200%, 250%, 300% or more). + Cells (e.g., MKI67 + The number of MKI67 T cells is about 101% to about 1000% (e.g., about 101% to about 500%, about 200% to about 400%, about 300% to about 600%, about 400% to about 700%, about 500% to about 800%, about 600% to about 900%, or about 700% to about 1000%) of the reference number. + Cells (e.g., MKI67 + T cells) is about 101% to about 500% (e.g., about 101% to about 500%, about 101% to about 400%, about 101% to about 300%, or about 101% to about 200%) of the reference number.

[0312] In some embodiments, MKI67 + Cells (e.g., MKI67 + T cells) is more than 1-fold higher (e.g., 1.1-fold higher, 1.2-fold higher, 1.3-fold higher, 1.4-fold higher, 1.5-fold higher, 1.6-fold higher, 1.7-fold higher, 1.8-fold higher, 1.9-fold higher, 2-fold higher, 2.5-fold higher, 3-fold higher, 3.5-fold higher, 4-fold higher, 4.5-fold higher, 5-fold higher, 5.5-fold higher, 6-fold higher, 6.5-fold higher, 7-fold higher, 7.5-fold higher, 8-fold higher, 8.5-fold higher, 9-fold higher, 9.5-fold higher, 10-fold higher, or more) compared to a reference number. + Cells (e.g., MKI67 + T cells) is about 1.1-fold to about 5-fold higher (e.g., about 1.2-fold to about 2-fold higher, about 1.5-fold to about 3-fold higher, about 2.5-fold to about 4-fold higher, or about 4-fold to about 5-fold higher) compared to a reference number. + Cells (e.g., MKI67 + T cells) is about 2-fold to about 10-fold higher (e.g., about 2-fold to about 4-fold higher, about 3-fold to about 5-fold higher, about 5-fold to about 7-fold higher, about 6-fold to about 8-fold, or about 7-fold to about 10-fold higher) compared to a reference number.+ Cells (e.g., MKI67 + T cells) is about 5-fold to about 10-fold higher (e.g., about 5-fold to about 6-fold higher, about 6-fold to about 7-fold higher, about 7-fold to about 8-fold higher, about 8-fold to about 9-fold, or about 9-fold to about 10-fold higher) compared to a reference number.

[0313] In some embodiments, the method may further comprise administering to the subject a bispecific antibody (e.g., a bispecific anti-FcRH5 / anti-CD3 antibody described herein). In some examples, the bispecific antibody is cebostamab.

[0314] In some embodiments, the number of MKI67+ cells (e.g., MKI67+ T cells) in a sample is detected by, for example, FC, FACS, Western blot, ELISA, MS, IF, IP, radioimmunoassay, dot blotting, HPLC, surface plasmon resonance, optical spectroscopy, or IHC. Any immune-based technique may include the use of an MKI67 antibody, such as a monoclonal Ki-67 antibody or MIB-1 antibody.

[0315] In some embodiments, a T cell proliferation marker (e.g., MKI67) is detected in T cells in the biological sample. + T cells and / or Gzb + It may be a T cell.

[0316] D. Medication Regimen In some embodiments, the present invention provides an antibody against an increased level of a T cell proliferation marker (e.g., MKI67) and / or an increased number of MKI67 +The present invention provides a method for treating a subject with cancer (e.g., MM) having cells with a dosing regimen. Any suitable dosing regimen may be used. In some examples, the dosing regimen is a dosing regimen described in International Patent Application No. PCT / US2022 / 023161 or PCT / US2022 / 028770, each of which is incorporated herein by reference in its entirety. In some examples, the dosing regimen is a dosing regimen described in U.S. Patent Application No. 63 / 368,352 or 63 / 368,811, each of which is incorporated herein by reference in its entirety. In some embodiments, the present invention provides a method for treating a subject with cancer (e.g., MM) having cells with a dosing regimen. In some examples, the dosing regimen is a dosing regimen described in U.S. Patent Application No. 63 / 368,352 or 63 / 368,811, each of which is incorporated herein by reference in its entirety. In some embodiments, the present invention provides a method for treating a subject with cancer (e.g., MM) having cells with an elevated level of a T cell proliferation marker (e.g., MKI67) and / or an increased number of MKI67. + Methods are provided for treating a subject with a cancer (e.g., MM) having a cell-ascending tumor in a one-step escalation or two-step escalation dosing regimen as described below.

[0317] One-step escalation dosing regimen In some embodiments, the present invention provides an antibody against an increased level of a T cell proliferation marker (e.g., MKI67) and / or an increased number of MKI67 + Provided are methods of treating a subject with a cancer having cells (e.g., multiple myeloma (MM)), comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 (e.g., cebostamab) in an escalating dosing regimen.

[0318] In some embodiments, the present invention provides an antibody against an increased level of a T cell proliferation marker (e.g., MKI67) and / or an increased number of MKI67 +A method of treating a subject having a cancer (e.g., multiple myeloma (MM)) comprising administering to the subject a bispecific antibody (e.g., cebostamab) that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, the first dosing cycle comprising a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein C1D1 is between about 0.05 mg and about 180 mg (e.g., between about 0.1 mg and about 160 mg, between about 0.5 mg and about 140 mg, between about 1 mg and about 120 mg, between about 1.5 mg and about 100 mg). g, about 2.0 mg to about 80 mg, about 2.5 mg to about 50 mg, about 3.0 mg to about 25 mg, about 3.0 mg to about 15 mg, about 3.0 mg to about 10 mg, or about 3.0 mg to about 5 mg), and C1D2 is about 0.15 mg to about 1000 mg (e.g., about 0.5 mg to about 800 mg, about 1 mg to about 700 mg, about 5 mg to about 500 mg, about 10 mg to about 400 mg, about 25 mg to about 300 mg, about 40 mg to about 200 mg, about 50 mg to about 100 mg, about 75 mg to about 100 mg, or about 85 mg to about 100 mg).

[0319] In some embodiments, the present invention provides an antibody against an increased level of a T cell proliferation marker (e.g., MKI67) and / or an increased number of MKI67 +1. A method of treating a subject with a cancer (e.g., MM) having cells, comprising administering to the subject a bispecific antibody that binds FcRH5 and CD3 (e.g., cebostamab) 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 (C1D2; cycle 1, dose 2), wherein C1D1 is less than C1D2, and C1D1 is about 0.05 mg to about 180 mg (e.g., about 0.1 mg to about 160 mg, about 0.5 mg to about 140 mg, about 1 mg to about 120 mg, about 1.5 mg to about 100 mg, about 2.0 mg to about 80 mg, about 2.5 mg to about 50 mg, about 3.0 mg to about 25 mg, about 3.0 mg to about 15 mg, about 3.0 mg to about 10 mg, or about 3.0 mg to about 5 mg ), C1D2 is about 0.15 mg to about 1000 mg (e.g., about 0.5 mg to about 800 mg, about 1 mg to about 700 mg, about 5 mg to about 500 mg, about 10 mg to about 400 mg, about 25 mg to about 300 mg, about 40 mg to about 200 mg, about 50 mg to about 100 mg, about 75 mg to about 100 mg, or about 85 mg to about 100 mg), and (b) the second dosing cycle is a single dose of the bispecific antibody (C2 D1; cycle 2, dose 1), wherein C2D1 is equal to or greater than C1D2 and is about 0.15 mg to about 1000 mg (e.g., about 0.5 mg to about 800 mg, about 1 mg to about 700 mg, about 5 mg to about 500 mg, about 10 mg to about 400 mg, about 25 mg to about 300 mg, about 40 mg to about 200 mg, about 50 mg to about 100 mg, about 75 mg to about 100 mg, or about 85 mg to about 100 mg).

[0320] In some embodiments, (a) C1D1 is from about 0.5 mg to about 19.9 mg (e.g., from about 1 mg to about 18 mg, from about 2 mg to about 15 mg, from about 3 mg to about 10 mg, from about 3.3 mg to about 6 mg, or from about 3.4 mg to about 4 mg, e.g., about 3 mg, 3.2 mg, 3.4 mg, 3.6 mg, 3.8 mg, 4 mg, 4.2 mg, 4.4 mg, 4.6 mg, 4.8 mg, 5 mg, 5.2 mg, 5.6 mg, 5.8 mg, 6 mg, 6.2 mg, 6.4 mg, 6.6 mg, 6.8 mg). g, 7mg, 7.2mg, 7.4mg, 7.6mg, 7.8mg, 8mg, 8.2mg, 8.4mg, 8.6mg, 8.8mg, 9mg, 9.2mg, 9.4mg, 9.6mg, 9.8mg, 10mg, 10.2mg, 10.4m g, 10.6mg, 10.8mg, 11mg, 11.2mg, 11.4mg, 11.6mg, 11.8mg, 12mg, 12.2mg, 12.4mg, 12.6mg, 12.8mg, 13mg, 13.2mg, 13.4mg, 13 0.6 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 about 20 mg to about 600 mg ( For example, about 30 mg to 500 mg, 40 mg to 400 mg, 60 mg to 350 mg, 80 mg to 300 mg, 100 mg to 200 mg, or 140 mg to 180 mg, for example, 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).

[0321] In some embodiments, C1D1 is about 1.2 mg to about 10.8 mg, and C1D2 is about 80 mg to about 300 mg. In some embodiments, C1D1 is 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 198 mg.

[0322] In some cases, the methods described above may include a first dosing cycle of one week or seven days. In some cases, the methods may include administering only C1D1 to the subject on or about day 1 of the first dosing cycle.

[0323] In some cases, the method can include a first dosing cycle of 2 weeks or 14 days. In some cases, the method can include administering C1D1 and C1D2 to the subject on or about day 1 and on or about day 8 of the first dosing cycle, respectively.

[0324] In some cases, the method can include a first dosing cycle of 3 weeks or 21 days. In some cases, the method can include administering C1D1 and C1D2 to the subject on or about day 1 and on or about day 8 of the first dosing cycle, respectively.

[0325] In some cases, the method can include a first dosing cycle of 4 weeks or 28 days. In some cases, the method can include administering C1D1 and C1D2 to the subject on or about day 1 and on or about day 8 of the first dosing cycle, respectively.

[0326] In some embodiments, the subject has an elevated level of a T cell proliferation marker compared to a reference level. In some embodiments, the subject has an elevated number of MKI67 compared to a reference number. + Cells (e.g., MKI67 +T cells).

[0327] Two-step ascending dosing regimen In other aspects, the present invention provides antibodies against T cell proliferation markers (e.g., MKI67) and / or increased numbers of MKI67 + Provided are methods of treating a subject with a cancer (e.g., MM) having cells, comprising administering to the subject a bispecific antibody (e.g., cebostamab) that binds FcRH5 and CD3 in a two-step ascending dosing regimen.

[0328] In some embodiments, the present disclosure provides methods for detecting elevated levels of T cell proliferation markers (e.g., MKI67) and / or increased numbers of MKI67 + 1. A method of treating a subject with a cancer (e.g., MM) having cells, comprising administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cebostamab) 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 about 0.2 mg to about 0.4 mg (e.g., In some embodiments, C1D1 is about 0.3 mg, 0.20 mg, 0.21 mg, 0.22 mg, 0.23 mg, 0.24 mg, 0.25 mg, 0.26 mg, 0.27 mg, 0.28 mg, 0.29 mg, 0.30 mg, 0.31 mg, 0.32 mg, 0.33 mg, 0.34 mg, 0.35 mg, 0.36 mg, 0.37 mg, 0.38 mg, 0.39 mg, or 0.40 mg), wherein C1D2 is greater than C1D1 and C1D3 is greater than C1D2. In some embodiments, C1D1 is about 0.3 mg.

[0329] In some embodiments, C1D1 is 0.2 mg to 0.4 mg (e.g., 0.20 mg, 0.21 mg, 0.22 mg, 0.23 mg, 0.24 mg, 0.25 mg, 0.26 mg, 0.27 mg, 0.28 mg, 0.29 mg, 0.30 mg, 0.31 mg, 0.32 mg, 0.33 mg, 0.34 mg, 0.35 mg, 0.36 mg, 0.37 mg, 0.38 mg, 0.39 mg, or 0.40 mg). In some embodiments, C1D1 is 0.3 mg.

[0330] In some embodiments, the present disclosure provides methods for detecting elevated levels of T cell proliferation markers (e.g., MKI67) and / or increased numbers of MKI67 + Provided is a method of treating a subject with a cancer (e.g., MM) having cells, comprising administering to the subject a bispecific antibody (e.g., cebostamab) that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle, wherein the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, wherein C1D1 is from about 0.01 mg to about 2.9 mg, C1D2 is from about 3 mg to about 19.9 mg, and C1D3 is from about 20 mg to about 600 mg.

[0331] In some embodiments, the present invention provides an antibody against an increased level of a T cell proliferation marker (e.g., MKI67) and / or an increased number of MKI67 +Provided is a method of treating a subject with a cancer (e.g., MM) having cells, comprising administering to the subject a bispecific antibody (e.g., cebostamab) that binds to FcRH5 and CD3 in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, wherein C1D1 and C1D2 are each less than C1D3, C1D1 being from about 0.01 mg to about 2.9 mg, C1D2 being from about 3 mg to about 19.9 mg, and C1D3 being from about 20 mg to about 600 mg; and (b) the second dosing cycle comprises a single dose (C2D1) of the bispecific antibody, wherein C2D1 is equal to or greater than C1D3 and is from about 20 mg to about 600 mg.

[0332] In some embodiments, C1D1 is about 0.05 mg to about 2.5 mg, about 0.1 mg to about 2 mg, about 0.2 mg to about 1 mg, or about 0.2 mg to about 0.4 mg (e.g., about 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, or 2.9 mg). In some embodiments, C1D1 is about 0.3 mg.

[0333] In some embodiments, C1D1 is 0.05 mg to 2.5 mg, 0.1 mg to 2 mg, 0.2 mg to 1 mg, or 0.2 mg to 0.4 mg (e.g., 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, or 2.9 mg). In some embodiments, C1D1 is 0.3 mg.

[0334] In some embodiments, C1D2 is administered in an amount of about 3 mg to about 19.9 mg (e.g., about 3 mg to about 18 mg, about 3.1 mg to about 15 mg, about 3.2 mg to about 10 mg, about 3.3 mg to about 6 mg, or about 3.4 mg to about 4 mg, e.g., about 3 mg, 3.2 mg, 3.4 mg, 3.6 mg, 3.8 mg, 4 mg, 4.2 mg, 4.4 mg, 4.6 mg, 4.8 mg, 5 mg, 5.2 mg, 5.6 mg, 5.8 mg, 6 mg, 6.2 mg, 6.4 mg, 6.6 mg, 6.8 mg, 7 mg, 7.2 mg, 7.4 mg, 7.6 mg, 7.8 mg, 8 mg, 8.2 mg, 8.4 mg, 8.6 mg, 8.8 mg, 9 mg, 9.2 mg, 9.4 mg, 9.6 mg, 9.8 mg, 10 mg, 1 0.2mg, 10.4mg, 10.6mg, 10.8mg, 11mg, 11.2mg, 11.4mg, 11.6mg, 11.8mg, 12mg, 12.2mg, 12 .4mg, 12.6mg, 12.8mg, 13mg, 13.2mg, 13.4mg, 13.6mg, 13.8mg, 14mg, 14.2mg, 14.4mg, 14.6 mg, 14.8 mg, 15 mg, 15.2 mg, 15.4 mg, 15.6 mg, 15.8 mg, 16 mg, 16.2 mg, 16.4 mg, 16.6 mg, 16.8 mg, 17 mg, 18.2 mg, 18.4 mg, 18.6 mg, 18.8 mg, 19 mg, 19.2 mg, 19.4 mg, 19.6 mg, or 19.8 mg). In some embodiments, C1D2 is about 3.2 mg to about 10 mg. In some embodiments, C1D2 is about 3.6 mg.

[0335] In some embodiments, C1D2 is administered in an amount of 3 mg to 19.9 mg (e.g., 3 mg to 18 mg, 3.1 mg to 15 mg, 3.2 mg to 10 mg, 3.3 mg to 6 mg, or 3.4 mg to 4 mg, e.g., 3 mg, 3.2 mg, 3.4 mg, 3.6 mg, 3.8 mg, 4 mg, 4.2 mg, 4.4 mg, 4.6 mg, 4.8 mg, 5 mg, 5.2 mg, 5.6 mg, 5.8 mg, 6 mg, 6.2 mg, 6.4 mg, 6.6 mg, 6.8 mg, 7 mg, 7.2 mg, 7.4 mg, 7.6 mg, 7.8 mg, 8 mg, 8.2 mg, 8.4 mg, 8.6 mg, 8.8 mg, 9 mg, 9.2 mg, 9.4 mg, 9.6 mg, 9.8 mg, 10 mg, 10.2 mg, 10.4mg, 10.6mg, 10.8mg, 11mg, 11.2mg, 11.4mg, 11.6mg, 11.8mg, 12mg, 12.2mg, 12.4mg, 12.6mg, 12.8mg, 13mg, 13.2mg, 13.4mg, 13.6mg, 13.8mg, 14mg, 14.2mg, 14.4mg, 14.6mg, In some embodiments, C1D2 is 3.2 mg to 10 mg. In some embodiments, C1D2 is 3.6 mg.

[0336] In some embodiments, C1D3 is about 20 mg to about 600 mg (e.g., about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 60 mg to about 350 mg, about 80 mg to about 300 mg, about 100 mg to about 200 mg, or about 140 mg to about 180 mg, e.g., about 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some embodiments, C1D3 is about 80 mg to about 300 mg. In some embodiments, the C1D3 is about 160 mg.

[0337] 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 160 mg.

[0338] In some embodiments, the method includes only a single dosing cycle (e.g., a dosing cycle including C1D1, C1D2, and C1D3). In other embodiments, the dosing regimen further includes a second dosing cycle including at least a single dose of the bispecific antibody (C2D1). In some embodiments, C2D1 is greater than or equal to C1D3 and is about 20 mg to about 600 mg (e.g., about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 60 mg to about 350 mg, about 80 mg to about 300 mg, about 100 mg to about 200 mg, or about 140 mg to about 180 mg, e.g., about 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some embodiments, C2D1 is about 80 mg to about 300 mg. In some embodiments, the C2D1 is about 160 mg.

[0339] In some embodiments, C2D1 is 20 mg to 600 mg (e.g., 30 mg to 500 mg, 40 mg to 400 mg, 60 mg to 350 mg, 80 mg to 300 mg, 100 mg to 200 mg, or 140 mg to 180 mg, e.g., 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some embodiments, C2D1 is 80 mg to 300 mg. In some embodiments, C2D1 is 160 mg. In some embodiments, the C2D1 is 159 mg.

[0340] Alternatively, in any of the above embodiments, C1D1 is present in an amount of about 0.01 mg to about 60 mg (e.g., about 0.05 mg to about 50 mg, about 0.01 mg to about 40 mg, about 0.1 mg to about 20 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 5 mg, about 0.1 mg to about 2 mg, about 0.1 mg to about 1.5 mg, about 0.1 mg to about 1.2 mg, about 0.1 mg to about 0.5 mg, or about 0.2 mg to about 0.4 mg, for example, about 0.3 mg, C1D2 may be about 0.05 mg to about 180 mg (e.g., about 0.1 mg to about 160 mg, about 0.5 mg to about 140 mg, about 1 mg to about 120 mg, about 1.5 mg to about 100 mg, about 2.0 mg to about 80 mg, about 2.5 mg to about 50 mg, about 3.0 mg to about 25 mg, about 3.0 mg to about 15 mg, about 3.0 mg to about 10 mg, about 3.0 mg to about 5 mg, or about 3.0 mg to about 4.0 mg, for example, about 3.6 mg, for example, 3.6 mg), and C1D3 may be about 0.15 mg to about 1000 mg (for example, about 0.5 mg to about 800 mg, about 1 mg to about 700 mg, about 5 mg to about 500 mg, about 10 mg to about 400 mg, about 25 mg to about 300 mg, about 40 mg to about 200 mg, about 50 mg to about 190 mg, about 140 mg to about 180 mg, or about 150 mg to about 170 mg, for example, about 160 mg, for example, 160 mg). Preferably, in embodiments including a second dosing cycle, C2D1 may be about 0.15 mg to about 1000 mg (e.g., about 0.5 mg to about 800 mg, about 1 mg to about 700 mg, about 5 mg to about 500 mg, about 10 mg to about 400 mg, about 25 mg to about 300 mg, about 40 mg to about 200 mg, about 50 mg to about 190 mg, about 140 mg to about 180 mg, or about 150 mg to about 170 mg, e.g., about 160 mg).

[0341] In some 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 a subject on or about days 1, 8, and 15 of the first dosing cycle, respectively.

[0342] In some embodiments, the subject has an elevated level of a T cell proliferation marker compared to a reference level. In some embodiments, the subject has an elevated number of MKI67 compared to a reference number. + Cells (e.g., MKI67 + T cells).

[0343] Further medication cycles In some cases, the method may include one or more additional dosing cycles. In some cases, the dosing regimen may include 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, 13 to 18 additional dosing cycles, 14 to 18 additional dosing cycles, 15 to 16 additional dosing cycles, 16 to 18 additional dosing cycles, 17 to 18 additional dosing cycles, 18 to 19 additional dosing cycles, 19 to 20 additional dosing cycles, 20 to 21 additional dosing cycles, 21 to 22 additional dosing cycles, 22 to 23 additional dosing cycles, 23 to 24 additional dosing cycles, 24 to 25 additional dosing cycles, 25 to 26 additional dosing cycles, 26 to 27 additional dosing cycles, 27 to 28 additional dosing cycles, 28 to 29 additional dosing cycles, 29 to 30 additional dosing cycles, 30 to 31 additional dosing cycles, 31 to 32 additional dosing cycles, 32 to 33 additional dosing cycles, 33 to 34 additional dosing cycles, 34 to 35 additional In some embodiments, the dosing regimen includes 17 additional dosing cycles, or 15 to 17 additional dosing cycles, i.e., the dosing regimen includes one or more additional dosing cycle(s) C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, and C19. In some embodiments, the length of each of the one or more additional dosing cycles is 7 days, 14 days, 21 days, or 28 days. In some embodiments, the length of each of the one or more additional dosing cycles is between 5 days and 30 days, e.g., between 5 and 9 days, between 7 and 11 days, between 9 and 13 days, between 11 and 15 days, between 13 and 17 days, between 15 and 19 days, between 17 and 21 days, between 19 and 23 days, between 21 and 25 days, between 23 and 27 days, or between 25 and 30 days. In some cases, the length of each of the one or more additional dosing cycles is 1 week or 7 days. In some cases, the length of each of the one or more additional dosing cycles is 2 weeks or 14 days. In some cases, the length of each of the one or more additional dosing cycles is 3 weeks or 21 days. In some cases, the length of each of the one or more additional dosing cycles is 4 weeks or 28 days. In some cases, each of the one or more additional dosing cycles comprises a single dose of the bispecific antibody.In some embodiments, the dose of the bispecific antibody in one or more additional dosing cycles is equal to 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 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, e.g., 20 mg to 600 mg (e.g., 30 mg to 500 mg, 40 mg to 400 mg, 60 mg to 350 mg, 80 mg to 300 mg, 100 mg to 200 mg, or 140 mg to 180 mg, e.g., 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 mg). In some embodiments, the dose of the bispecific antibody in one or more additional 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 comprises administering a single dose of the bispecific antibody to the subject on or about day 1 of the one or more additional dosing cycles.

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

[0345] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to the subject as a monotherapy.

[0346] In some cases, the bispecific antibody (e.g., a bispecific anti-FcRH5 / anti-CD3 antibody) is cebostamab.

[0347] In some embodiments, the subject has an elevated level of a T cell proliferation marker compared to a reference level. In some embodiments, the subject has an elevated number of MKI67 compared to a reference number. + Cells (e.g., MKI67 + T cells).

[0348] E. Combination Therapy In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered to a subject in a combination therapy, e.g., the bispecific anti-FcRH5 / anti-CD3 antibody may be administered simultaneously with one or more additional therapeutic agents.

[0349] i. Tocilizumab and CRS Treatment In one case, the additional therapeutic agent is an effective amount of tocilizumab (ACTEMRA®). In some cases, the subject has a cytokine release syndrome (CRS) event (e.g., has a CRS event after treatment with a bispecific antibody (e.g., cebostamab), e.g., has a CRS event after C1D1, C1D2, C1D3, C2D1, or a supplemental dose of a bispecific antibody), and the method further includes treating the symptoms of the CRS event (e.g., treating the CRS event by administering an effective amount of tocilizumab to the subject) while withholding treatment with the bispecific antibody. 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 of treating the symptoms of the CRS event, and the method further includes administering one or more additional doses of tocilizumab to the subject to manage the CRS event, e.g., administering one or more additional doses of tocilizumab intravenously to the subject at a dose of about 8 mg / kg.

[0350] In some embodiments, treating the symptoms of a CRS event further includes treatment with a high-dose vasopressor (e.g., norepinephrine, dopamine, phenylephrine, epinephrine, or vasopressin and norepinephrine), e.g., as described in Tables 5A, 5B, and 6.

[0351] In other examples, tocilizumab is administered as a premedication, e.g., administered 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., administered before the first dose (C1D1), second dose (C1D2), and / or third dose (C1D3) of a bispecific anti-FcRH5 / anti-CD3 antibody. In some embodiments, tocilizumab is administered intravenously to a subject as a single dose of about 8 mg / kg.

[0352] 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 5A. In addition to diagnostic criteria, recommendations for the management of CRS based on its severity, including early intervention with corticosteroids and / or anti-cytokine therapy, are provided and referenced in Tables 5A and 5B.

[0353] Mild to moderate symptoms of CRS and / or infusion-related reactions (IRR) may 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 treated aggressively with supportive and resuscitative care as indicated, including the use of high-dose corticosteroids, IV fluids, admission to an intensive care unit, and other supportive care. Severe CRS may be associated with other clinical sequelae, such as disseminated intravascular coagulation, capillary leak syndrome, or macrophage activation syndrome (MAS). No standard of care has been established for severe or life-threatening CRS resulting from immune-based therapies; 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).

[0354] As shown in Table 5A, even moderate symptoms of CRS in subjects with extensive comorbidities should be closely monitored with consideration of intensive care unit admission and tocilizumab administration.

[0355] Administration of tocilizumab as premedication In some embodiments, an effective amount of tocilizumab is administered as a premedication (prophylaxis), e.g., administered to a subject prior to administration of a bispecific antibody (e.g., administered about 2 hours before administration of the bispecific antibody). Administration of tocilizumab as a premedication can reduce the frequency or severity of CRS. In some embodiments, tocilizumab is administered as a premedication in cycle 1, e.g., administered before 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 at 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, bovalilizumab (ALX-0061), SA-237, and variants thereof.

[0356] For example, in one embodiment, the bispecific antibody is co-administered with tocilizumab (ACTEMRA® / ROACTEMRA®), where 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®)).

[0357] In some embodiments, the incidence of CRS (e.g., grade 1 CRS, grade 2 CRS, and / or grade 3+ CRS) is reduced in patients pre-treated with tocilizumab compared to patients not pre-treated with tocilizumab. In some embodiments, patients pre-treated with tocilizumab require fewer interventions to treat CRS (e.g., less need for additional tocilizumab, IV fluids, steroids, or O2) compared to patients not pre-treated with tocilizumab. In some embodiments, CRS symptoms are reduced in severity (e.g., limited to fever and rigors) in patients pre-treated with tocilizumab compared to patients not pre-treated with tocilizumab.

[0358] Tocilizumab given to treat CRS In some embodiments, the subject experiences a CRS event during treatment with the therapeutic bispecific antibody, and an effective amount of tocilizumab is administered to manage the CRS event.

[0359] In some embodiments, the subject has a CRS event (e.g., has a CRS event after treatment with the bispecific antibody, e.g., has a CRS event after the first dose or a subsequent dose of the bispecific antibody), and the method further comprises treating the symptoms of the CRS event while discontinuing treatment with the bispecific antibody.

[0360] In some embodiments, the subject is experiencing a CRS event, and the method further includes 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 treatment with the bispecific antibody is pending. In some embodiments, the IL-6R antagonist (e.g., tocilizumab) is administered intravenously to the subject in 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 may be used in combination with tocilizumab include sarilumab, bovalilizumab (ALX-0061), SA-237, and variants thereof.

[0361] In some embodiments, the CRS event does not resolve or worsens within 24 hours of treating the symptoms of the CRS event, and the method further includes administering one 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 CRS event, e.g., intravenously administering one or more additional doses of tocilizumab 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, the one or more additional doses of tocilizumab are administered intravenously to the subject as a single dose of about 8 mg / kg.

[0362] In some embodiments, the method further includes administering an effective amount of a corticosteroid to the subject. The corticosteroid may be administered intravenously to the subject. In some embodiments, the corticosteroid is methylprednisone (methylprednisolone). In some cases, the methylprednisone is administered at a dose of about 1 mg / kg / day to about 5 mg / kg / day, e.g., about 2 mg / kg / day. In some cases, the corticosteroid is dexamethasone. In some cases, the dexamethasone is administered at a dose of about 10 mg (e.g., a single dose of about 10 mg intravenously) or at a dose of about 0.5 mg / kg / day.

[0363] If the CRS event is not managed solely by administration of an IL-6R antagonist (e.g., tocilizumab), the subject may be administered a corticosteroid, such as methylprednisolone or dexamethasone. In some embodiments, treating the symptoms of the CRS event further includes treatment with a high-dose vasopressor (e.g., norepinephrine, dopamine, phenylephrine, epinephrine, or vasopressin and norepinephrine), for example, as described in Tables 5A, 5B, and 6. Tables 2 and 5A provide details regarding tocilizumab treatment of severe or life-threatening CRS.

[0364] Management of CRS events by grade Management of CRS events can be tailored based on the grade of CRS (Table 2 and Table 5A) and the presence of comorbidities. Table 2 provides recommendations for management of CRS syndromes by grade. [Table 2] TIFF2026500084000003.tif252170TIFF2026500084000004.tif18170

[0365] Management of Grade 2 CRS Events If the subject experiences a Grade 2 CRS event after administration of the therapeutic bispecific antibody (e.g., a Grade 2 CRS event in the absence of comorbidities or minimal comorbidities), 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 three consecutive days, the method may further comprise resuming treatment with the bispecific antibody without changing the dose. On the other hand, if the Grade 2 CRS event does not resolve or worsen to a Grade ≧3 event within 24 hours of treating the symptoms of the Grade 2 CRS 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 a 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, bovalilizumab (ALX-0061), SA-237, and variants thereof.

[0366] If the subject experiences a grade 2 CRS event in the presence of extensive complications after administration of the therapeutic bispecific antibody, the method may further include administering to the subject a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to manage 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 may be used in combination with tocilizumab include sarilumab, bovalilizumab (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 includes resuming 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 or worsen to a grade ≥ 3 CRS event within 24 hours after treating the symptoms of the grade 2 CRS event, the method may further include administering one or more (e.g., 1, 2, 3, 4, or 5 or more) additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab) to the subject to manage the grade 2 or grade ≥ 3 CRS event. In some specific cases, since the grade 2 CRS event does not resolve or worsen to a grade ≥ 3 CRS event within 24 hours after treating the symptoms of the grade 2 CRS event, the method may further include administering one or more additional doses of tocilizumab to the subject to manage the grade 2 or grade ≥ 3 CRS event. In some cases, the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 1 mg / kg to about 15 mg / kg, e.g., about 4 mg / kg to about 10 mg / kg, e.g., about 6 mg / kg to about 10 mg / kg, e.g., about 8 mg / kg. In some cases, the method further includes administering an effective amount of a corticosteroid to the subject.The corticosteroid can be administered before, after, or simultaneously with one or more additional doses of tocilizumab or other anti-IL-6R antibodies. In some cases, the corticosteroid is administered intravenously to the subject. In some cases, the corticosteroid is methylprednisolone. In some cases, the methylprednisolone is administered at a 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, the dexamethasone is administered at a dose of about 10 mg (for example, a single dose of about 10 mg intravenously) or at a dose of about 0.5 mg / kg / day.

[0367] Management of Grade 3 CRS Events If the subject experiences a grade 3 CRS event after administration of the therapeutic bispecific antibody, the method may further include administering to the subject a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to manage the grade 3 CRS event while pending 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 may be used in combination with tocilizumab include sarilumab, bovalilizumab (ALX-0061), SA-237, and variants thereof. In some cases, the subject recovers (e.g., no fever, no vasopressors) within 8 hours after treatment with the bispecific antibody, and the method further includes resuming 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 or worsen to a grade 4 CRS event within 24 hours after treating the symptoms of the grade 3 CRS event, the method may further include administering one or more (e.g., 1, 2, 3, 4, or 5 or more) additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab) to the subject to manage the grade 3 or grade 4 CRS event. In some specific cases, since the grade 3 CRS event does not resolve or worsen to a grade 4 CRS event within 24 hours after treating the symptoms of the grade 3 CRS event, the method further includes administering one or more additional doses of tocilizumab to the subject to manage the grade 3 or grade 4 CRS event. In some cases, the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 1 mg / kg to about 15 mg / kg, e.g., about 4 mg / kg to about 10 mg / kg, e.g., about 6 mg / kg to about 10 mg / kg, e.g., about 8 mg / kg. In some cases, the method further includes administering an effective amount of a corticosteroid to the subject.The corticosteroid can be administered before, after, or simultaneously with one or more additional doses of tocilizumab or other anti-IL-6R antibodies. In some cases, the corticosteroid is administered intravenously to the subject. In some cases, the corticosteroid is methylprednisolone. In some cases, the methylprednisolone is administered at a 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, the dexamethasone is administered at a dose of about 10 mg (for example, a single dose of about 10 mg intravenously) or at a dose of about 0.5 mg / kg / day.

[0368] Management of Grade 4 CRS Events If the subject experiences a grade 4 CRS event after administration of the therapeutic bispecific antibody, the method may further include administering to the subject a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to manage the grade 4 CRS event and discontinue treatment with the bispecific antibody. In some cases, the first dose of tocilizumab is administered intravenously to the subject at a dose of about 8 mg / kg. Other anti-IL-6R antibodies that may be used in combination with tocilizumab include sarilumab, bovalilizumab (ALX-0061), SA-237, and variants thereof. The grade 4 CRS event may, in some cases, resolve within 24 hours after treating the symptoms of the grade 4 CRS event. If the grade 4 CRS event does not resolve within 24 hours of treating the symptoms of the grade 4 CRS event, the method may further include administering to the subject one or more additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / ROACTEMRA®)) to manage the grade 4 CRS event. In some particular cases, if the grade 4 CRS event does not resolve within 24 hours of treating the symptoms of the grade 4 CRS event, the method further includes administering to the subject one or more (e.g., 1, 2, 3, 4, or 5 or more) additional doses of tocilizumab to manage the grade 4 CRS event. In some cases, one or more additional doses of tocilizumab are intravenously administered to the subject at a dose of about 1 mg / kg to about 15 mg / kg, for example, about 4 mg / kg to about 10 mg / kg, for example, about 6 mg / kg to about 10 mg / kg, for example, about 8 mg / kg. In some cases, the method further comprises administering an effective amount of a corticosteroid to the subject. The corticosteroid may be administered before, after, or simultaneously with the one or more additional doses of tocilizumab or other anti-IL-6R antibody. In some cases, the corticosteroid is administered intravenously to the subject. In some cases, the corticosteroid is methylprednisolone.In some cases, methylprednisolone is administered at a 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 (for example, a single dose of about 10 mg intravenously) or at a dose of about 0.5 mg / kg / day.

[0369] ii. Corticosteroids In other cases, the additional therapeutic agent is an effective amount of a corticosteroid. The corticosteroid may be administered intravenously to the subject. In some embodiments, the corticosteroid is methylprednisone. The methylprednisone may be administered to the subject at a dose of about 80 mg. In other embodiments, the corticosteroid is dexamethasone. The dexamethasone may be administered to the subject at a dose of about 80 mg. In some embodiments, the corticosteroid (e.g., methylprednisone or dexamethasone) is administered to the subject prior to administration of the bispecific anti-FcRH5 / anti-CD3 antibody (e.g., cevostamab), for example, 1 hour before administration of the bispecific anti-FcRH5 / anti-CD3 antibody.

[0370] iii. Acetaminophen or paracetamol In other cases, the additional therapeutic agent is an effective amount of acetaminophen or paracetamol. The acetaminophen or paracetamol may be orally administered to the subject, e.g., at a dose of about 500 mg to about 1000 mg. In some embodiments, the acetaminophen or paracetamol is administered to the subject as a premedication, e.g., prior to administration of the bispecific anti-FcRH5 / anti-CD3 antibody (e.g., cebostamab).

[0371] iv. Diphenhydramine In other cases, the additional therapeutic agent is an effective amount of diphenhydramine. Diphenhydramine may be orally administered to the subject, e.g., at a dose of about 25 mg to about 50 mg. In some embodiments, diphenhydramine is administered to the subject as a premedication, e.g., prior to administration of the bispecific anti-FcRH5 / anti-CD3 antibody (e.g., cebostamab).

[0372] v. Antimyeloma agents In other cases, the additional therapeutic agent is an effective amount of an antimyeloma agent, e.g., an antimyeloma agent that enhances and / or complements T cell-mediated killing of myeloma cells. The antimyeloma agent can be, for example, an IMiD (e.g., pomalidomide, thalidomide, or lenalidomide), daratumumab, and / or a B-cell maturation antigen (BCMA)-directed therapy (e.g., an antibody-drug conjugate targeting BCMA (BCMA-ADC)). In some embodiments, the antimyeloma agent is administered in a 4-week cycle.

[0373] In some embodiments, the anti-myeloma agent is pomalidomide. In some embodiments, pomalidomide is administered orally at a dose of 4 mg on days 1-28 of a 28-day cycle. In some embodiments, pomalidomide is administered in combination with dexamethasone, e.g., in combination with dexamethasone administered on days 1, 8, 15, and 22 of a 28-day cycle.

[0374] In some embodiments, the anti-myeloma agent is daratumumab. In some embodiments, daratumumab is administered by intravenous infusion (e.g., infusion over 3-5 hours) at a dose of 16 mg / kg once weekly, once every two weeks, or once every four weeks. In some embodiments, daratumumab is administered by intravenous infusion (e.g., infusion over 3-5 hours) at a dose of 16 mg / kg once weekly for two cycles of 28 days, once every two weeks for three cycles of 28 days, and once every four weeks for one or more additional cycles.

[0375] vi. Other concomitant therapies In some embodiments, the one or more additional therapeutic agents comprise a PD-1 axis binding antagonist, an immunomodulatory agent, an anti-tumor agent, a chemotherapeutic agent, a growth inhibitory agent, an anti-angiogenic agent, radiation therapy, a cytotoxic agent, a cell-based therapy, or a combination thereof.

[0376] PD-1 axis binding antagonists In some embodiments, the additional therapeutic agent is a PD-1 axis binding antagonist. Exemplary PD-1 axis binding antagonists include agents that inhibit the interaction of a PD-L1 axis binding partner with one or more of its binding partners to eliminate T cell dysfunction caused by signaling on the PD-1 signaling axis, thereby restoring or enhancing T cell function (e.g., proliferation, cytokine production, target cell killing). As used herein, PD-1 axis binding antagonists include PD-1 binding antagonists, PD-L1 binding antagonists, and PD-L2 binding antagonists. Any suitable PD-1 axis binding antagonist may be used.

[0377] 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 may be, but is not limited to, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule. In some cases, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 (e.g., GS-4224, INCB086550, MAX-10181, INCB090244, CA-170, or ABSK041). In some cases, 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 WO 2015 / 033301 and / or WO 2015 / 033299.

[0378] In some cases, the PD-L1 binding antagonist is an anti-PD-L1 antibody. A variety of anti-PD-L1 antibodies are contemplated and described herein. In any of the cases herein, the isolated anti-PD-L1 antibody can bind to human PD-L1, such as human PD-L1 as set forth in UniProtKB / Swiss-Prot Accession No. 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, embafolimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636. In some cases, the anti-PD-L1 antibody is atezolizumab. Examples of anti-PD-L1 antibodies useful in the methods of the invention and methods for making them are described in International Patent Application Publication No. WO 2010 / 077634 and U.S. Patent No. 8,217,149, each of which is incorporated by reference in its entirety.

[0379] 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).

[0380] 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 WO 2011 / 066389 and U.S. Patent Application Publication No. 2013 / 034559.

[0381] In some cases, the anti-PD-L1 antibody is MDX-1105 (Bristol Myers Squibb). MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO2007 / 005874.

[0382] In some cases, the anti-PD-L1 antibody is LY3300054 (Eli Lilly).

[0383] In some cases, the anti-PD-L1 antibody is STI-A1014 (Sorrento). STI-A1014 is a human anti-PD-L1 antibody.

[0384] In some cases, the anti-PD-L1 antibody is KN035 (Suzhou Alphamab), which is a single domain antibody (dAB) generated from a camel phage display library.

[0385] In some cases, the anti-PD-L1 antibody is composed of a cleavable moiety or linker that, when cleaved (e.g., by proteases in the tumor microenvironment), activates the antibody antigen-binding domain so that it can bind its antigen, e.g., by removing a non-binding steric moiety. In some cases, the anti-PD-L1 antibody is CX-072 (CytomX Therapeutics).

[0386] 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 heavy chain and light chain variable domains from an anti-PD-L1 antibody described in U.S. Patent Application Publication No. 20160108123, WO 2016 / 000619, WO 2012 / 145493, U.S. Patent No. 9,205,148, WO 2013 / 181634, or WO 2016 / 061142.

[0387] In some cases, the PD-1 axis binding antagonist is a PD-1 binding antagonist. For example, in some cases, the PD-1 binding antagonist inhibits the binding of PD-1 to one or more of its ligand binding partners. In some cases, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1. In other cases, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L2. In still other cases, the PD-1 binding antagonist inhibits the binding of PD-1 to both PD-L1 and PD-L2. The PD-1 binding antagonist may be, but is not limited to, an antibody, an antigen-binding fragment thereof, 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 that includes an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an 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 small molecule compound. In some cases, the PD-1 binding antagonist is AUNP-12 (PierreFabre / Aurigene). See, e.g., 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.

[0388] In some cases, the PD-1 binding antagonist is an anti-PD-1 antibody. A variety of anti-PD-1 antibodies may 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 (cemiplimab), BGB-108, prorugolimab, canrelizumab, sintilimab, tislelizumab, toripalimab, dostarimab, retifanlimab, sasanlimab, penprimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimuzumab, BI 754091, cetrelimab, YBL-006, BAT1306, HX008, budicalimab, AMG404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103 and hAb21.

[0389] 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.

[0390] In some cases, the anti-PD-1 antibody is pembrolizumab (CAS Registry Number: 1374853-91-4). Pembrolizumab (Merck), also known as MK-3475, Merck 3475, lambrolizumab, KEYTRUDA®, and SCH-900475, is an anti-PD-1 antibody described in WO 2009 / 114335.

[0391] In some cases, the anti-PD-1 antibody is MEDI-0680 (AMP-514; AstraZeneca). MEDI-0680 is a humanized IgG4 anti-PD-1 antibody.

[0392] 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.

[0393] In some cases, the anti-PD-1 antibody is REGN2810 (Regeneron). REGN2810 is a human anti-PD-1 antibody.

[0394] In some cases, the anti-PD-1 antibody is BGB-108 (BeiGene).

[0395] In some cases, the anti-PD-1 antibody is BGB-A317 (BeiGene).

[0396] In some cases, the anti-PD-1 antibody is JS-001 (Shanghai Junshi). JS-001 is a humanized anti-PD-1 antibody.

[0397] In some cases, the anti-PD-1 antibody is STI-A1110 (Sorrento). STI-A1110 is a human anti-PD-1 antibody.

[0398] In some cases, the anti-PD-1 antibody is INCSHR-1210 (Incyte). INCSHR-1210 is a human IgG4 anti-PD-1 antibody.

[0399] In some cases, the anti-PD-1 antibody is PF-06801591 (Pfizer).

[0400] In some cases, the anti-PD-1 antibody is TSR-042 (also known as ANB011; Tesaro / AnaptysBio).

[0401] In some cases, the anti-PD-1 antibody is AM0001 (ARMO Biosciences).

[0402] In some cases, the anti-PD-1 antibody is ENUM244C8 (Enumeral Biomedical Holdings). ENUM 244C8 is an anti-PD-1 antibody that inhibits PD-1 function without blocking the binding of PD-L1 to PD-1.

[0403] In some cases, the anti-PD-1 antibody is ENUM 388D4 (Enumeral Biomedical Holdings). ENUM 388D4 is an anti-PD-1 antibody that competitively inhibits the binding of PD-L1 to PD-1.

[0404] In some cases, the anti-PD-1 antibody is a PD-1 antibody described in WO 2015 / 112800, WO 2015 / 112805, WO 2015 / 112900, U.S. Patent Application Publication Nos. 20150210769, WO 2016 / 089873, WO 2015 / 035606, WO 2015 / 085847, WO 2014 / 206107, WO 2012 / 145493, U.S. Patent Nos. 9, 20 and WO 2014 / 194302. The antibodies comprise six HVR sequences (e.g., three heavy chain HVRs and three light chain HVRs) and / or heavy chain and light chain variable domains from the anti-PD-1 antibodies described in WO 2015 / 119930, WO 2015 / 119923, WO 2016 / 032927, WO 2014 / 179664, WO 2016 / 106160, and WO 2014 / 194302.

[0405] 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 a specific embodiment, the PD-L2 binding ligand partner is PD-1. The PD-L2 binding antagonist may be, but is not limited to, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule.

[0406] 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 is capable of binding 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 results from 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 aglycosylated.

[0407] Growth inhibitors In some embodiments, the additional therapeutic agent is a growth inhibitor. Exemplary growth inhibitors include agents that inhibit cell cycle progression at a stage other than S phase, such as agents that induce G1 arrest (e.g., tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, or DNA alkylating agents such as araC), or agents that arrest M phase (e.g., vincristine, vinblastine, taxanes (e.g., paclitaxel and docetaxel), doxorubicin, epirubicin, daunorubicin, etoposide, or bleomycin).

[0408] Radiation therapy In some embodiments, the additional therapeutic agent is radiation therapy. Radiation therapy involves the use of directed gamma or beta radiation to induce sufficient damage to cells to limit their ability to function normally or to destroy them completely. Typical treatments are given as a single administration, with typical dosages ranging from 10 to 200 units (Gy) per day.

[0409] Cytotoxic drugs 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 destruction. Cytotoxic agents include, but are not limited to, radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 , and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof, e.g., nucleases; antibiotics; toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof; and antitumor or anticancer agents.

[0410] Anti-cancer therapy In some cases, the method includes administering to the individual an anti-cancer therapy other than or in addition to the bispecific anti-FcRH5 / anti-CD3 antibody (e.g., an anti-neoplastic agent, a chemotherapeutic agent, a growth inhibitory agent, an anti-angiogenic agent, radiation therapy, or a cytotoxic agent).

[0411] In some cases, the method further comprises administering an effective amount of an additional therapeutic agent to the patient. 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 a combination thereof. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody (e.g., cebostamab) may be administered in conjunction with chemotherapy or a chemotherapeutic agent. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in conjunction with a radiation therapy agent. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in conjunction with a targeted therapy or a targeted therapeutic agent. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in conjunction with immunotherapy or an immunotherapeutic agent, such as a monoclonal antibody. In some cases, the additional therapeutic agent is an agonist directed against a costimulatory molecule. In some cases, the additional therapeutic agent is an antagonist directed against a co-inhibitory molecule.

[0412] Without wishing to be bound by theory, it is believed that enhancing T cell stimulation by promoting costimulatory molecules or inhibiting co-inhibitory molecules can promote tumor cell death, thereby treating or delaying cancer progression. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in conjunction with an agonist directed against a costimulatory molecule. In some cases, the activating costimulatory molecule may include CD40, CD226, CD28, OX40, GITR, CD137, CD27, HVEM, or CD127. In some cases, the agonist against a costimulatory 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 conjunction with an antagonist directed against a co-inhibitory molecule. In some cases, the co-inhibitory molecule can 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 to the co-inhibitory molecule is an antagonist antibody that binds to CTLA-4, TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO, TIGIT, MICA / B, or arginase.

[0413] In some cases, bispecific anti-FcRH5 / anti-CD3 antibodies may be administered in combination with an antagonist, e.g., a blocking antibody, directed against CTLA-4 (also known as CD152). In some cases, bispecific anti-FcRH5 / anti-CD3 antibodies may be administered in combination with ipilimumab (also known as MDX-010, MDX-101, or YERVOY®). In some cases, bispecific anti-FcRH5 / anti-CD3 antibodies may be administered in combination with tremelimumab (also known as ticilimumab or CP-675,206). In some cases, bispecific anti-FcRH5 / anti-CD3 antibodies may be administered in combination with an antagonist, e.g., a blocking antibody, directed against B7-H3 (also known as CD276). In some cases, bispecific anti-FcRH5 / anti-CD3 antibodies may be administered in combination with MGA271. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an antagonist directed against TGF-beta, such as meterimumab (also known as CAT-192), fresolimumab (also known as GC1008), or LY2157299.

[0414] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in conjunction with a treatment comprising the adoptive transfer of T cells (e.g., cytotoxic T cells or CTLs) expressing a chimeric antigen receptor (CAR). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in conjunction with a treatment comprising the adoptive transfer of T cells comprising a dominant-negative TGF beta receptor, e.g., a dominant-negative TGF beta type II receptor. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in conjunction with a treatment comprising the HERCREEM protocol (see, e.g., ClinicalTrials.gov Identifier NCT00889954).

[0415] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an agonist, e.g., an activating antibody, directed against CD137 (also known as TNFRSF9, 4-1BB, or ILA). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with urelumab (also known as BMS-663513). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an agonist, e.g., an activating antibody, directed against CD40. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with CP-870893. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an agonist, e.g., an activating antibody, directed against OX40 (also known as CD134). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an anti-OX40 antibody (e.g., AgonOX). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an agonist, such as an activating antibody, directed against CD27. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with CDX-1127. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an antagonist against indoleamine-2,3-dioxygenase (IDO). In some cases, the IDO antagonist is 1-methyl-D-tryptophan (also known as 1-D-MT).

[0416] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an antibody-drug conjugate. In some cases, the antibody-drug conjugate comprises mertansine or monomethyl auristatin E (MMAE). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an anti-NaPi2b antibody-MMAE conjugate (also known as DNIB0600A or RG7599). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with trastuzumab emtansine (also known as T-DM1, ado-trastuzumab emtansine, or KADCYLA®, Genentech). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with DMUC5754A. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in conjunction with an antibody-drug conjugate that targets endothelin B receptor (EDNBR), for example, an antibody directed against EDNBR conjugated with MMAE.

[0417] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an anti-angiogenic agent. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an antibody against VEGF, such as VEGF-A. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with bevacizumab (also known as AVASTIN®, Genentech). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an antibody against angiopoietin 2 (also known as Ang2). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with MEDI3617.

[0418] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an anti-neoplastic agent. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an agent that targets CSF-1R (also known as M-CSFR or CD115). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with anti-CSF-1R (also known as IMC-CS4). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an interferon, such as interferon alpha or interferon gamma. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with Roferon-A (also known as recombinant interferon alpha-2a). In some cases, a bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with GM-CSF (recombinant human granulocyte-macrophage colony-stimulating factor, rhu GM-CSF, also known as sargramostim, or LEUKINE®). In some cases, a bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with IL-2 (also known as aldesleukin or PROLEUKIN®). In some cases, a bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with IL-12. In some cases, a bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an antibody targeting CD20. In some cases, the antibody targeting CD20 is obinutuzumab (also known as GA101 or GAZYVA®) or rituximab. In some cases, a bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an antibody targeting GITR. In some cases, the antibody that targets GITR is TRX518.

[0419] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in conjunction with a cancer vaccine. In some cases, the cancer vaccine is a peptide cancer vaccine, and in some cases, a personalized peptide vaccine. In some cases, the peptide cancer vaccine is a multivalent long peptide, multi-peptide, peptide cocktail, hybrid peptide, or peptide-pulsed dendritic cell vaccine (see, for example, Yamada et al., Cancer Sci. 104:14-21, 2013). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in conjunction with an adjuvant. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in conjunction with a treatment including a TLR agonist, such as Poly-ICLC (also known as HILTONOL®), LPS, MPL, or CpG ODN. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in conjunction with tumor necrosis factor (TNF) alpha. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with IL-1. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with HMGB1. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an IL-10 antagonist. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an IL-4 antagonist. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an IL-13 antagonist. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an HVEM antagonist. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an ICOS agonist, for example, by administering ICOS-L, or in combination with an agonist antibody directed against ICOS. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in conjunction with a treatment that targets CX3CL1. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in conjunction with a treatment that targets CXCL9.In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in conjunction with a treatment targeting CXCL10. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in conjunction with a treatment targeting CCL5. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in conjunction with an LFA-1 or ICAM1 agonist. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in conjunction with a selectin agonist.

[0420] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with a targeted therapy. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an inhibitor of B-Raf. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with vemurafenib (also known as ZELBORAF®). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with dabrafenib (also known as TAFINLAR®). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with erlotinib (known as TARCEVA®). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an inhibitor of MEK, such as MEK1 (also known as MAP2K1) or MEK2 (also known as MAP2K2). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with cobimetinib (also known as GDC-0973 or XL-518). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with trametinib (also known as MEKINIST®). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an inhibitor of K-Ras. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an inhibitor of c-Met. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with onartuzumab (also known as MetMAb). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an inhibitor of Alk. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with AF802 (also known as CH5424802 or alectinib). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an inhibitor of phosphatidylinositol 3-kinase (PI3K). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with BKM120.In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with idelalisib (also known as GS-1101 or CAL-101). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with perifosine (also known as KRX-0401). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an inhibitor of Akt. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with MK2206. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with GSK690693. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with GDC-0941. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with an inhibitor of mTOR. In some cases, bispecific anti-FcRH5 / anti-CD3 antibodies may be administered in combination with sirolimus (also known as rapamycin). In some cases, bispecific anti-FcRH5 / anti-CD3 antibodies may be administered in combination with temsirolimus (also known as CCI-779 or TORISEL®). In some cases, bispecific anti-FcRH5 / anti-CD3 antibodies may be administered in combination with everolimus (also known as RAD001). In some cases, bispecific anti-FcRH5 / anti-CD3 antibodies may be administered in combination with ridaforolimus (also known as AP-23573, MK-8669, or deforolimus). In some cases, bispecific anti-FcRH5 / anti-CD3 antibodies may be administered in combination with OSI-027. In some cases, bispecific anti-FcRH5 / anti-CD3 antibodies may be administered in combination with AZD8055. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with INK128. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with a dual PI3K / mTOR inhibitor. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with XL765. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with GDC-0980.In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with BEZ235 (also known as NVP-BEZ235). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with BGT226. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with GSK2126458. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with PF-04691502. In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in combination with PF-05212384 (also known as PKI-587).

[0421] In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody may be administered in conjunction with a chemotherapeutic agent. A chemotherapeutic agent is a chemical compound useful in the treatment of cancer. Exemplary chemotherapeutic agents include antihormonal agents that act to regulate or inhibit hormone action on tumors, such as erlotinib (TARCEVA®, Genentech / OSI Pharm.), antiestrogens and selective estrogen receptor modulators (SERMs), e.g., alemtuzumab (Campath), bevacizumab (Avastin®, Genentech), cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen), and the like. Antibodies such as idiopathic steroids (IDEC), pertuzumab (OMNITARG®, 2C4, Genentech), or trastuzumab (HERCEPTIN®, Genentech); EGFR inhibitors (EGFR antagonists), tyrosine kinase inhibitors, and chemotherapeutic agents also include nonsteroidal anti-inflammatory drugs (NSAIDs) which have analgesic, antipyretic, and anti-inflammatory effects.

[0422] Where the methods described herein involve combination therapy, such as the specific combination therapies described above, the combination therapy includes co-administration of a bispecific anti-FcRH5 / anti-CD3 antibody with one or more additional therapeutic agents; such co-administration may be combined (the two or more therapeutic agents are in the same formulation or in separate formulations) or separate; in this case, administration of the bispecific anti-FcRH5 / anti-CD3 antibody can occur prior to, concurrently with, and / or after administration of the additional therapeutic agent(s). In one embodiment, administration of the bispecific anti-FcRH5 / anti-CD3 antibody and administration of the additional therapeutic agent or exposure to radiation therapy can occur within about one month, or within about one, two, or three weeks, or within about one, two, three, four, five, or six days of each other.

[0423] In some embodiments, the subject does not have an increased risk of CRS (e.g., does not experience Grade 3+ CRS during treatment with the bispecific antibody or CAR-T therapy; does not have detectable circulating plasma cells; and / or does not have extensive extramedullary disease).

[0424] F. Cancer Any of the methods of the present invention described herein may be useful for treating cancers such as B cell proliferative disorders, including multiple myeloma (MM), which may be relapsed or refractory (R / R) MM. In some embodiments, the patient has received at least three prior lines of treatment for the B cell proliferative disorder (e.g., MM), e.g., 4L+, e.g., three, four, five, six, or more than six prior lines of treatment. For example, the patient may have been exposed to a therapy including a proteasome inhibitor (P1), an immunomodulatory drug (IMiD), an autologous stem cell transplant (ASCT), an anti-CD38 therapy (e.g., an anti-CD38 antibody therapy, e.g., daratumumab therapy), a CAR-T therapy, or a bispecific antibody. In some cases, the patient has been exposed to all three of P1, an IMiD, and an anti-CD38 therapy.Other examples of B-cell proliferative disorders / malignancies amenable to treatment with bispecific anti-FcRH5 / anti-CD3 antibodies (e.g., cevostamab) according to the methods described herein include, but are not limited to, non-Hodgkin's lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), which may be relapsed or refractory, and other cancers, including 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 (LPL), and other cancers. LL), Waldenstrom's hypergammaglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt's 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, Waldenstrom's hypergammaglobulinemia, heavy chain disease, alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasma cell myeloma, isolated bone plasmacytoma, extraskeletal 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 of the elderly, chronic inflammation-associated DLBCL, lymphomatoid granulomatosis, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma due to HHV8-associated multicentric Castleman disease, primary effusion lymphoma; unclassifiable B-cell lymphoma with features intermediate between DLBCL and Burkitt lymphoma; and unclassifiable B-cell lymphoma with features intermediate between DLBCL and classical Hodgkin lymphoma.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-dividing cell NHL; large mass lesion NHL; AIDS-related lymphoma; and acute lymphocytic leukemia (ALL); chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD). Further examples of cancer include but are not limited to carcinoma, lymphoma, blastoma, sarcoma, and lymphoid malignancies, including leukemia or B-cell lymphoma. More specific examples of such 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-dividing cell NHL; bulky mass disease NHL; AIDS-related lymphoma; and acute lymphoblastic leukemia (ALL); chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD). Solid tumors amenable to treatment with bispecific anti-FcRH5 / anti-CD3 antibodies according to the methods described herein include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer, including small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous cell carcinoma of the lung, cancer of the peritoneum, hepatocellular carcinoma, gastric cancer, including gastrointestinal cancer, and gastrointestinal stromal cancer, or gastric cancer. cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, cancer of the urinary system, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma, anal carcinoma, penile carcinoma, melanoma, superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanoma, nodular melanoma, and abnormal blood vessel growth associated with nevus, edema (such as that associated with brain tumors), Meigs syndrome, brain, and head and neck cancer, and related metastases.In certain embodiments, cancers suitable for treatment with the antibodies of the invention include breast cancer, colorectal cancer, rectal cancer, non-small cell lung cancer, glioblastoma, non-Hodgkin's lymphoma (NHL), renal cell carcinoma, prostate cancer, liver cancer, pancreatic cancer, soft tissue sarcoma, Kaposi's sarcoma, carcinoid carcinoma, head and neck cancer, ovarian cancer, and mesothelioma.

[0425] G. Prior anticancer therapy In some embodiments, the subject with elevated levels of a T cell proliferation marker (e.g., MKI67) and / or an increased number of MKI67+ cells has previously been treated for a B cell proliferative disorder (e.g., MM). In some embodiments, the subject has received at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more than 15 lines of treatment for the B cell proliferative disorder, e.g., 2L+, 3L+, 4L+, 5L+, 6L+, 7L+, 8L+, 9L+, 10L+, 11L+, 12L+, 13L+, 14L+, or 15L+. In some embodiments, the subject has received at least three prior lines of treatment for the B cell proliferative disorder (e.g., MM), 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), for example, 4L+R / R MM.

[0426] In some embodiments, prior lines of treatment include 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; therapy involving bispecific antibodies; anti-SLAMF7 therapeutic agents (e.g., anti-SLAMF7 antibodies, e.g., elotuzumab); nuclear export inhibitors (e.g., selinexor); and histone deacetylase (HDAC) inhibitors (e.g., panobinostat). In some embodiments, the prior line of treatment includes an antibody-drug conjugate (ADC). In some embodiments, the prior line of treatment includes a B-cell maturation antigen (BCMA)-directed therapy, e.g., an antibody-drug conjugate that targets BCMA (BCMA-ADC).

[0427] In some embodiments, the prior line of treatment includes all three of a proteasome inhibitor (PI), an IMiD, and an anti-CD38 agent (e.g., daratumumab).

[0428] In some embodiments, the B cell proliferative disorder (e.g., MM) is refractory to a line of treatment, e.g., refractory to one or more of daratumumab, a PI, an IMiD, ASCT, an anti-CD38 agent, a CAR-T therapy, a therapy comprising a bispecific antibody, an anti-SLAMF7 therapeutic agent, a nuclear export inhibitor, an HDAC inhibitor, an ADC, or a BCMA-directed therapy. In some embodiments, the B cell proliferative disorder (e.g., MM) is refractory to daratumumab.

[0429] H. Risk-Benefit Profile The methods described herein may result in an improved benefit-risk profile for patients with cancer (e.g., multiple myeloma (MM), e.g., relapsed or refractory (R / R) MM), e.g., 4L+R / R MM, being treated with a bispecific anti-FcRH5 / anti-CD3 antibody (e.g., cevostamab). In some cases, treatment using the methods described herein, which result in administering a bispecific anti-FcRH5 / anti-CD3 antibody in the context of a fractionated dose-escalating dosing regimen, may result in a reduction in cytokine-driven toxicity (e.g., cytokine release syndrome (CRS)), infusion-related reactions (IRR), macrophage activation syndrome (MRSA), and / or vasoconstriction (VPR) after treatment with a bispecific anti-FcRH5 / anti-CD3 antibody using a fractionated dose-escalating dosing regimen of the invention compared to treatment with a bispecific anti-FcRH5 / anti-CD3 antibody using a non-fractionated dosing regimen. or 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 cytotoxicity (AS), neurotoxicity, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, elevated liver enzymes, and / or central nervous system (CNS) toxicity.

[0430] I. Safety and Effectiveness i. Safety In some embodiments, fewer than 15% (e.g., fewer than 14%, fewer than 13%, fewer than 12%, fewer than 11%, fewer than 10%, fewer than 9%, fewer than 8%, fewer than 7%, fewer than 6%, fewer than 5%, fewer than 4%, fewer than 3%, fewer than 2%, or fewer than 1%) of patients treated using the methods described herein experience Grade 3 or Grade 4 cytokine release syndrome (CRS). In some embodiments, fewer than 5% of patients treated using the methods described herein experience Grade 3 or Grade 4 CRS.

[0431] 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 patients treated using the methods described herein experience Grade 4+ CRS. In some embodiments, less than 3% of patients treated using the methods described herein experience Grade 4+ CRS. In some embodiments, no patients experience Grade 4+ CRS.

[0432] 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 patients treated using the methods described herein experience Grade 3 CRS. In some embodiments, less than 5% of patients treated using the methods described herein experience Grade 3 CRS. In some embodiments, no patients experience Grade 3 CRS.

[0433] 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, Grade 2 CRS events do not occur.

[0434] In some embodiments, fewer than 3% of patients treated using the methods described herein experience Grade 4+ CRS, fewer than 5% of patients treated using the methods described herein experience Grade 3 CRS, and Grade 2+ CRS events occur only in the first treatment cycle.

[0435] In some embodiments, no grade 3+ CRS events occur and grade 2 CRS events occur only in the first treatment cycle.

[0436] In some embodiments, symptoms of immune effector cell-associated neurotoxicity syndrome (ICANS) are limited to confusion, disorientation, and expressive aphasia, and resolve with steroids.

[0437] 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 patients treated using the methods described herein experience seizures or other Grade 3+ neurological adverse events. In some embodiments, less than 5% of patients experience seizures or other Grade 3+ neurological adverse events. In some embodiments, no patients experience seizures or other Grade 3+ neurological adverse events.

[0438] In some embodiments, all neurological symptoms are self-limiting or resolve with steroid and / or tocilizumab therapy.

[0439] ii.Validity In some embodiments, the overall response rate (ORR) for patients treated using the methods described herein is at least 25%, e.g., 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% (e.g., 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 greater. In some embodiments, at least 1% of patients (e.g., 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%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 12 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) have a complete response (CR) or very good partial response (VGPR). In some embodiments, the ORR is 40% to 50%, and 10% to 20% of patients have a CR or VGPR. In some embodiments, the ORR is at least 40% with at least 20% of patients having a CR or VGPR.

[0440] 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.

[0441] 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%.

[0442] J. Administration Method The methods may include administering the bispecific anti-FcRH5 / anti-CD3 antibody (e.g., cevostamab) (and / or any additional therapeutic agent) by any suitable means, including parenteral, intrapulmonary, and intranasal administration, and, if desired for localized treatment, intralesional administration. Parenteral infusion includes intravenous, subcutaneous, intramuscular, intraarterial, and intraperitoneal routes of administration. In some embodiments, the bispecific anti-FcRH5 / anti-CD3 antibody is administered by intravenous infusion. In other cases, the bispecific anti-FcRH5 / anti-CD3 antibody is administered subcutaneously.

[0443] In some cases, a bispecific anti-FcRH5 / anti-CD3 antibody administered by intravenous injection exhibits a lower toxic response (i.e., fewer unwanted effects) in a patient than the same bispecific anti-FcRH5 / anti-CD3 antibody administered by subcutaneous injection, or vice versa.

[0444] In some embodiments, the bispecific anti-FcRH5 / anti-CD3 antibody is administered intravenously over a period of 4 hours (±15 minutes), eg, the first dose of the antibody is administered over a period of 4 hours ±15 minutes.

[0445] In some embodiments, the first and second doses of the antibody are administered intravenously with 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 an additional dose of the antibody is administered intravenously with a median infusion time of less than 120 minutes (e.g., less than 90 minutes, less than 60 minutes, or less than 30 minutes).

[0446] In some embodiments, the first and second doses of the antibody are administered intravenously with a median infusion time of less than 3 hours, and an additional dose of the antibody is administered intravenously with a median infusion time of less than 90 minutes.

[0447] In some embodiments, the first and second doses of antibody are administered intravenously with a median infusion time of less than 3 hours, and additional doses of antibody are administered intravenously with a median infusion time of less than 60 minutes. In some embodiments, the patient is hospitalized during one or more administrations of anti-FcRH5 / anti-CD3 antibody (e.g., hospitalization for 72 hours, 48 ​​hours, 24 hours, or less than 24 hours), e.g., for C1D1 (Cycle 1, Dose 1) or C1D1 and C1D2 (Cycle 1, Dose 2). In some embodiments, the patient is hospitalized for 72 hours after administration of C1D1 and C1D2. In some embodiments, the patient is hospitalized for 24 hours after administration of C1D1 and C1D2. In some embodiments, the patient is not hospitalized after administration of any dose of anti-FcRH5 / anti-CD3 antibody.

[0448] For all of the methods described herein, the bispecific anti-FcRH5 / anti-CD3 antibody will be formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to medical professionals. The bispecific anti-FcRH5 / anti-CD3 antibody is optionally, but need not necessarily, formulated with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents will depend on the amount of bispecific anti-FcRH5 / anti-CD3 antibody present in the formulation, the type of disorder or treatment, and other factors discussed above. The bispecific anti-FcRH5 / anti-CD3 antibody may be appropriately administered to the patient over a course of treatment.

[0449] K. Bispecific anti-FcRH5 / anti-CD3 antibody The methods described herein include administering a bispecific antibody that binds FcRH5 and CD3 (i.e., a bispecific anti-FcRH5 / anti-CD3 antibody) to a subject with cancer (e.g., multiple myeloma, e.g., R / R multiple myeloma). In some cases, the subject has an increased level of a T cell proliferation marker (e.g., MKI67) and / or an increased number of MKI67+ cells.

[0450] In some cases, any of the methods described herein may comprise administering a bispecific antibody comprising an anti-FcRH5 arm having a first binding domain comprising at least one, two, three, four, five, or six 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); or (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 heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 17-20, respectively, and / or at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 21-24, respectively.

[0451] In some cases, any of the methods described herein may comprise administering a bispecific antibody comprising 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); and (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 heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 17-20, respectively, and / or at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 21-24, respectively.

[0452] In some cases, the bispecific antibody comprises (a) a heavy chain variable (VH) domain 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 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: 8, or the 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). Thus, in some cases, 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.

[0453] In some cases, any of the methods described herein may comprise administering a bispecific anti-FcRH5 / anti-CD3 antibody comprising an anti-CD3 arm having a second binding domain comprising at least one, two, three, four, five, or six 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); or (f) HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 25-28, respectively, and / or at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 29-32, respectively.

[0454] In some cases, any of the methods described herein may include administering a bispecific anti-FcRH5 / anti-CD3 antibody comprising an anti-CD3 arm with a second binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14). In some cases, the bispecific anti-FcRH5 / anti-CD3 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 25-28, respectively, and / or at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 29-32, respectively.

[0455] In some cases, the bispecific antibody comprises (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 identity (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) an anti-CD3 arm comprising a second binding domain comprising the VH domain described in (a) and the VL domain described in (b). Thus, in some cases, 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.

[0456] In some cases, any of the methods described herein includes: (1) an anti-FcRH5 arm having a first binding domain comprising at least one, two, three, four, five, or six HVRs selected from: (a) an HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1); (b) an HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO: 3); (d) an HVR-L1 comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) an HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); (f) an HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6); and and (2) administering a bispecific antibody comprising an anti-CD3 arm having a second binding domain comprising at least one, two, three, four, five, or six 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); or (f) HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

[0457] In...

Claims

1. 1. A method of treating a subject with multiple myeloma (MM) with a bispecific antibody that binds Fc receptor homolog 5 (FcRH5) and cluster of differentiation 3 (CD3), comprising: (a) determining the level of a T cell proliferation marker in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; (b) comparing the level of the T cell proliferation marker in the biological sample with a reference level, wherein an increased level of the T cell proliferation marker in the biological sample compared to the reference level identifies the subject as one that is responsive to the bispecific antibody; and (c) continuing to administer the bispecific antibody to the subject if the level of the T cell proliferation marker is increased compared to the reference level. A method comprising:

2. 1. A method of treating a subject with MM with a bispecific antibody that binds FcRH5 and CD3, comprising: (a) detecting proliferation Ki-67 positivity (MKI67) in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; ＋ ) determining the number of T cell markers; (b) MKI67 in the biological sample ＋ comparing the number of T cells to a reference number, and determining whether MKI67 in the biological sample is increased compared to the reference number. ＋ comparing, where an increased number of T cells identifies the subject as responding to the bispecific antibody; and (c) MKI67 in a biological sample from the subject. ＋ if the number of T cells is increased compared to the reference number, continuing to administer the bispecific antibody to the subject. A method comprising:

3. 1. A method for monitoring the response of a subject with MM to treatment with a bispecific antibody that binds FcRH5 and CD3, comprising: (a) determining the level of a T cell proliferation marker in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; and (b) comparing the level of the T cell proliferation marker in the biological sample with a reference level, wherein an increased level of the T cell proliferation marker in the biological sample compared to the reference level identifies the subject as one that is responsive to the bispecific antibody. Including, thereby monitoring the subject's response to treatment with the bispecific antibody.

4. 1. A method for monitoring the response of a subject with MM to treatment with a bispecific antibody that binds FcRH5 and CD3, comprising: (a) detecting MKI67 in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; ＋ Determining the number of T cells; and (b) MKI67 in the biological sample ＋ comparing the number of T cells to a reference number, and determining whether MKI67 in the biological sample is increased compared to the reference number. ＋ an increased number of T cells identifies the subject as responding to the bispecific antibody. Including, thereby monitoring the subject's response to treatment with the bispecific antibody.

5. 1. A method for assessing the treatment response of a subject with MM to treatment with a bispecific antibody that binds FcRH5 and CD3, comprising: (a) determining the level of a T cell proliferation marker in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; and (b) maintaining, adjusting, or stopping said treatment of said subject based on a comparison of said level of said T cell proliferation marker in said biological sample to a reference level. Including, wherein an alteration in the level of the T cell proliferation marker in the biological sample compared to the reference level indicates a response to treatment with the bispecific antibody.

6. 6. The method of claim 5, (a) if the level of the T cell proliferation marker in the biological sample is increased compared to the reference level, the subject has responded to the treatment, and the treatment is maintained; or (b) if the level of the T cell proliferation marker in the biological sample is the same or decreased compared to the reference level, the subject is not responding to the treatment and the treatment is adjusted or stopped.

7. 1. A method for assessing the treatment response of a subject with MM to treatment with a bispecific antibody that binds FcRH5 and CD3, comprising: (a) detecting MKI67 in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; ＋ Determining the number of T cells; and (b) MKI67 in the biological sample ＋ maintaining, adjusting, or stopping said treatment of said subject based on a comparison of said number of T cells to a reference number. Including, MKI67 in said biological sample compared to said reference number ＋ wherein a change in said number of T cells indicates a response to treatment with said bispecific antibody.

8. 8. The method of claim 7, (a) MKI67 in the biological sample ＋ If the number of cells is increased compared to the reference number, the subject has responded to the treatment and the treatment is maintained; or (b) MKI67 in the biological sample ＋ If the number of cells is the same or decreased compared to the reference number, the subject is not responding to the treatment and the treatment is adjusted or stopped.

9. The method of any one of claims 3 to 8, further comprising administering the bispecific antibody to the subject.

10. 10. The method of any one of claims 1 to 9, wherein said administering of said bispecific antibody comprises: (a) a first dosing cycle comprising at least a first dose (C1D1) and a second dose (C1D2) of said bispecific antibody; and (b) a second dosing cycle comprising a single dose of the bispecific antibody (C2D1). The method is carried out with a dosing regimen comprising:

11. 11. The method of claim 10, wherein the time point after administration of the bispecific antibody is before administration of the C2D1.

12. 12. The method of claim 10 or 11, (a) the C1D1 is from about 0.5 mg to about 19.9 mg; (b) the C1D2 is from about 20 mg to about 600 mg; and (c) the C2D1 is from about 20 mg to about 600 mg.

13. The method according to any one of claims 10 to 12, (a) the C1D1 is from about 1.2 mg to about 10.8 mg; (b) the C1D2 is from about 80 mg to about 300 mg; and (c) the C2D1 is about 80 mg to about 300 mg.

14. The method according to any one of claims 10 to 13, (a) the C1D1 is about 3.6 mg; (b) the C1D2 is about 198 mg; and (c) the C2D1 is about 198 mg.

15. 15. The method of any one of claims 10 to 14, wherein the first and second dosing cycles are 21 days in length.

16. The method of claim 15, wherein the dosing regimen comprises administering the C1D1 and the C1D2 to the subject on or about day 1 and on or about day 8 of the first dosing cycle, respectively, and administering the C2D1 on or about day 1 of the second dosing cycle.

17. 17. The method of any one of claims 10 to 16, wherein the dosing regimen comprises one or more additional dosing cycles.

18. 18. The method of claim 17, wherein the dosing regimen comprises administering the bispecific antibody to the subject on or about day 1 of each of the additional dosing cycles.

19. 19. The method of claim 17 or 18, wherein the one or more additional dosing cycles comprise: (a) a third dosing cycle comprising a single dose of the bispecific antibody (C3D1); and / or (b) a fourth dosing cycle comprising a single dose of the bispecific antibody (C4D1). A method comprising:

20. 20. The method of claim 19, wherein the time after administration of the bispecific antibody is before administration of the C3D1 and / or C4D1.

21. 10. The method of any one of claims 1 to 9, wherein said administering of said bispecific antibody comprises: (a) a first dosing cycle comprising at least a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody; and (b) a second dosing cycle comprising a single dose of the bispecific antibody (C2D1). The method is carried out with a dosing regimen comprising:

22. 22. The method of claim 21 , wherein the time point after administration of the bispecific antibody is before administration of the C2D1.

23. 23. The method of claim 21 or 22, (a) the C1D1 is from about 0.01 mg to about 2.9 mg; (b) the C1D2 is from about 3 mg to about 19.9 mg; (c) the C1D3 is from about 20 mg to about 600 mg; and (d) the C2D1 is from about 20 mg to about 600 mg.

24. The method according to any one of claims 21 to 23, (a) the C1D1 is from about 0.2 mg to about 0.4 mg; (b) the C1D2 is from about 3.2 mg to about 10 mg; (c) the C1D3 is from about 80 mg to about 300 mg; and (d) the C2D1 is about 80 mg to about 300 mg.

25. The method according to any one of claims 21 to 24, (a) the C1D1 is about 0.3 mg; (b) the C1D2 is about 3.6 mg; (c) the C1D3 is about 160 mg; and (d) The method, wherein the C2D1 is about 160 mg.

26. 26. The method of any one of claims 21 to 25, wherein the first and second dosing cycles are 21 days in length.

27. 27. The method of claim 26, wherein the dosing regimen comprises administering the C1D1, C1D2, and C1D3 on or about days 1, 8, and 15 of the first dosing cycle, respectively, and administering the C2D1 on or about day 1 of the second dosing cycle.

28. 28. The method of any one of claims 21 to 27, wherein the dosing regimen comprises one or more additional dosing cycles.

29. 29. The method of any one of claims 28, wherein the dosing regimen comprises administering the bispecific antibody to the subject on or about day 1 of each of the additional dosing cycles.

30. 30. The method of claim 28 or 29, wherein the one or more additional dosing cycles comprise: (a) a third dosing cycle comprising a single dose of the bispecific antibody (C3D1); and / or (b) a fourth dosing cycle comprising a single dose of the bispecific antibody (C4D1). A method comprising:

31. 31. The method of claim 30, wherein the time after administration of the bispecific antibody is before administration of the C3D1 and / or C4D1.

32. 32. The method of any one of claims 1, 3, 5, 6, and 9-31, wherein the T cell proliferation marker is marker of proliferation Ki-67 (MKI67).

33. 33. The method of any one of claims 1, 3, 5, 6, and 9-32, wherein the level of the T cell proliferation marker is a protein level.

34. 34. The method of claim 33, wherein the protein levels are detected by flow cytometry (FC), Western blot, enzyme-linked immunosorbent assay (ELISA), mass spectrometry (MS), immunofluorescence (IF), or immunohistochemistry (IHC).

35. The method of claim 33 or 34, wherein the protein level is detected with an MKI67 antibody.

36. The method of claim 35, wherein the MKI67 antibody is a monoclonal Ki-67 or MIB-1 antibody.

37. The method of any one of claims 1, 3, 5, 6 and 9 to 32, wherein the level of the T cell proliferation marker is the mRNA level of MKI67.

38. 38. The method of claim 37, wherein the mRNA level is detected by polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), quantitative PCR (qPCR), microarray analysis, Northern blot, or RNA sequencing.

39. The method of any one of claims 1, 3, 5, 6 and 9-38, wherein the T cell proliferation marker is detected in T cells.

40. The T cells are MKI67 ＋ 40. The method of claim 39, wherein:

41. 41. The method of any one of claims 1, 3, 5, 6 and 9 to 40, wherein the reference level is the level of the T cell proliferation marker determined in a biological sample obtained from the subject prior to administering the bispecific antibody to the subject.

42. 42. The method of any one of claims 1, 3, 5, 6 and 9 to 41, wherein the reference level is the level of MKI67 determined in a biological sample obtained from the subject prior to administration of the bispecific antibody to the subject.

43. The method of any one of claims 2, 4 and 7 to 42, wherein the MKI67+ T cells are detected by FC, Western blot, ELISA, MS, IF or IHC.

44. The above MKI67 ＋ The method of any one of claims 2, 4 and 7 to 43, wherein the T cells are detected by an MKI67 antibody.

45. 45. The method of claim 44, wherein the MKI67 antibody is a monoclonal Ki-67 or MIB-1 antibody.

46. the reference number is MKI67 determined in a biological sample obtained from the subject prior to administration of the bispecific antibody to the subject; ＋ The method of any one of claims 2, 4, and 7 to 45, wherein the number of T cells.

47. The T cells are positive for differentiation antigen group 8 (CD8) (CD8 ＋ 47. The method of any one of claims 2, 4, and 7 to 46, wherein

48. 48. The method of any one of claims 2, 4, and 7-47, wherein the T cells are granzyme B (Gzb) positive (Gzb+).

49. The method of any one of claims 1 to 48, wherein the biological sample is blood, serum or plasma.

50. 50. The method of any one of claims 1 to 49, wherein the bispecific antibody comprises the following six hypervariable regions (HVRs): (a) HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) HVR-H3 comprising the amino acid sequence HYYGSSDYALDN (SEQ ID NO: 3); (d) HVR-L1 comprising the amino acid sequence KASQDVRNLVV (SEQ ID NO: 4); (e) HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (f) HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6) an anti-FcRH5 arm comprising a first binding domain comprising:

51. 51. The method of any one of claims 1 to 50, wherein the bispecific antibody comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8; or (c) an anti-FcRH5 arm comprising a first binding domain comprising the VH domain of (a) and the VL domain of (b).

52. 52. The method of claim 51 , 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.

53. 53. The method of any one of claims 1 to 52, wherein the bispecific antibody comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising the amino acid sequence WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) HVR-H3 comprising the amino acid sequence DGYSRYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising the amino acid sequence KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14) and an anti-CD3 arm comprising a second binding domain comprising:

54. 54. The method of any one of claims 1 to 53, wherein the bispecific antibody comprises an anti-CD3 arm comprising: (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16; or (c) a second binding domain comprising the VH domain of (a) and the VL domain of (b).

55. 55. The method of claim 54, 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.

56. 56. The method of any one of claims 1 to 55, wherein the bispecific antibody comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1) and a light chain polypeptide (L1), and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), (a) H1 comprises the amino acid sequence of SEQ ID NO: 35; (b) L1 comprises the amino acid sequence of SEQ ID NO: 36; (c) H2 comprises the amino acid sequence of SEQ ID NO: 37; and (d) the method, wherein L2 comprises the amino acid sequence of SEQ ID NO:

38.

57. 57. The method of any one of claims 1 to 56, wherein the bispecific antibody comprises an aglycosylation site mutation.

58. 58. The method of claim 57, wherein the aglycosylation site mutation reduces an effector function of the bispecific antibody.

59. 59. The method of claim 57 or 58, wherein the aglycosylation site mutation is a substitution mutation.

60. 60. The method of claim 59, wherein the bispecific antibody comprises a substitution mutation in the Fc region that reduces effector function.

61. The method of any one of claims 1 to 60, wherein the bispecific antibody is a monoclonal antibody.

62. The method of any one of claims 1 to 61, wherein the bispecific antibody is a humanized antibody.

63. The method of any one of claims 1 to 55 and 57 to 62, wherein the bispecific antibody is a chimeric antibody.

64. 64. The method of any one of claims 1 to 55 and 57 to 63, wherein the bispecific antibody is an antibody fragment that binds to FcRH5 and CD3.

65. The antibody fragments include Fab, Fab'-SH, Fv, scFv, and (Fab') ２ 65. The method of claim 64, wherein the fragment is selected from the group consisting of:

66. 64. The method of any one of claims 1 to 63, wherein the bispecific antibody is a full-length antibody.

67. 67. The method of any one of claims 1 to 63 and 66, wherein the bispecific antibody is an IgG antibody.

68. The IgG antibody is IgG １ 68. The method of claim 67, wherein the antibody is an antibody.

69. The bispecific antibody comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains comprise a first CH1 (CH1 １ ) domain, the first CH2 (CH2 １ ) domain, the first CH3 (CH3 １ ) domain, a second CH1 (CH1 ２ ) domain, the second CH2 (CH2 ２ ) domain, and a second CH3 (CH3 ２ 69. The method of any one of claims 1 to 55 and 57 to 68, wherein the domain is selected from the group consisting of:

70. 70. The method of claim 69, wherein at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

71. CH3 １ domain and the CH3 ２ Each domain has a protrusion or a cavity, and the CH3 １ The protrusion or cavity within the domain is ２ 71. The method of claim 69 or 70, wherein the cavity or protrusion, respectively, is positionable within the domain.

72. CH3 １ domain and the CH3 ２ 72. The method of claim 71, wherein the domains associate at the interface between the protrusion and the cavity.

73. CH2 １ domain and the CH2 ２ Each domain contains a protrusion or a cavity, and the CH2 １ The protrusion or cavity of the domain is ２ 73. The method of any one of claims 69 to 72, wherein the domain is positionable in the cavity or protrusion, respectively.

74. CH2 １ domain and the CH2 ２ 74. The method of claim 73, wherein the domains associate at the interface between the protrusion and the cavity.

75. 73. The method of claim 72, wherein the anti-FcRH5 arm comprises the protrusion and the anti-CD3 arm comprises the cavity.

76. 76. The method of claim 75, wherein the CH3 domain of the anti-FcRH5 arm comprises a protrusion comprising a T366W amino acid substitution mutation (EU numbering), and the CH3 domain of the anti-CD3 arm comprises a cavity comprising T366S, L368A, and Y407V amino acid substitution mutations (EU numbering).

77. 77. The method of any one of claims 1 to 76, wherein the bispecific antibody is administered to the subject as monotherapy.

78. 77. The method of any one of claims 1 to 76, wherein the bispecific antibody is administered to the subject as a combination therapy.

79. 79. The method of claim 78, wherein the bispecific antibody is administered to the subject concomitantly with one or more additional therapeutic agents.

80. 79. The method of claim 78, wherein the bispecific antibody is administered to the subject prior to administration of one or more additional therapeutic agents.

81. 79. The method of claim 78, wherein the bispecific antibody is administered to the subject after administration of one or more additional therapeutic agents.

82. 82. The method of claim 81, wherein the one or more additional therapeutic agents comprises an effective amount of tocilizumab.

83. 83. The method of claim 82, wherein tocilizumab is administered to the subject by intravenous infusion.

84. 84. The method of claim 82 or 83, (a) the subject weighs 100 kg or more and tocilizumab is administered to the subject at a dose of 800 mg; (b) the subject weighs greater than or equal to 30 kg and less than 100 kg, and tocilizumab is administered to the subject at a dose of 8 mg / kg; or (c) the subject weighs less than 30 kg and tocilizumab is administered to the subject at a dose of 12 mg / kg.

85. 85. The method of any one of claims 82 to 84, wherein tocilizumab is administered to the subject 2 hours prior to administration of the bispecific antibody.

86. 82. The method of any one of claims 79-81, wherein the one or more additional therapeutic agents comprise an effective amount of an IMiD, daratumumab, or a B-cell maturation antigen (BCMA) directed therapy.

87. 87. The method of any one of claims 1 to 86, wherein the bispecific antibody is administered to the subject by intravenous infusion.

88. 87. The method of any one of claims 1 to 86, wherein the bispecific antibody is administered subcutaneously to the subject.

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

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

91. 91. The method of claim 90, wherein tocilizumab is administered intravenously to the subject as a single dose of about 8 mg / kg.

92. 92. The method of claim 90 or 91, wherein the CRS event does not resolve or worsens within 24 hours of treating the symptoms of the CRS event, and the method further comprises administering one or more additional doses of tocilizumab to the subject to manage the CRS event.

93. 93. The method of claim 92, wherein the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 8 mg / kg.

94. 82. The method of claim 81, wherein the one or more additional therapeutic agents comprises an effective amount of a corticosteroid.

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

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

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

98. 96. The method of claim 94 or 95, wherein the corticosteroid is dexamethasone.

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

100. 100. The method of any one of claims 81 and 94-99, wherein the one or more additional therapeutic agents comprises an effective amount of acetaminophen or paracetamol.

101. 101. The method of claim 100, wherein the acetaminophen or paracetamol is administered in a dose of about 500 mg to about 1000 mg.

102. 102. The method of claim 100 or 101, wherein acetaminophen or paracetamol is administered orally to the subject.

103. 103. The method of any one of claims 81 and 94-102, wherein the one or more additional therapeutic agents comprises an effective amount of diphenhydramine.

104. 104. The method of claim 103, wherein diphenhydramine is administered in a dose of about 25 mg to about 50 mg.

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

106. The method of any one of claims 1 to 105, wherein the MM is relapsed or refractory (R / R) MM.

107. 107. The method of claim 106, wherein the individual has received at least three prior lines of treatment for the MM.

108. 108. The method of claim 107, wherein the individual has received at least four prior lines of treatment for the MM.

109. 109. The method of any one of claims 106 to 108, wherein the individual has been exposed to a prior treatment comprising a proteasome inhibitor, an immunomodulatory drug (IMiD) and / or an anti-CD38 therapeutic agent.

110. 110. The method of claim 109, wherein the proteasome inhibitor is bortezomib, carfilzomib, or ixazomib.

111. 110. The method of claim 109, wherein the IMiD is thalidomide, lenalidomide, or pomalidomide.

112. 110. The method of claim 109, wherein the anti-CD38 therapeutic agent is an anti-CD38 antibody.

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

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

115. 115. The method of any one of claims 106-114, wherein the individual has been exposed to a prior treatment comprising an anti-SLAMF7 therapeutic, a nuclear export inhibitor, a histone deacetylase (HDAC) inhibitor, autologous stem cell transplant (ASCT), a bispecific antibody, an antibody-drug conjugate (ADC), a CAR-T cell therapy, or a BCMA-directed therapy.

116. 116. The method of claim 115, wherein the anti-SLAMF7 therapeutic agent is an anti-SLAMF7 antibody.

117. 117. The method of claim 116, wherein the anti-SLAMF7 antibody is elotuzumab.

118. 116. The method of claim 115, wherein the nuclear export inhibitor is selinexol.

119. 116. The method of claim 115, wherein the HDAC inhibitor is panobinostat.

120. 116. The method of claim 115, wherein the BCMA-directed therapy is an antibody-drug conjugate that targets BCMA.

121. 1. A bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, said treatment comprising: (a) determining the level of a T cell proliferation marker in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; (b) comparing the level of the T cell proliferation marker in the biological sample with a reference level, wherein an increased level of the T cell proliferation marker in the biological sample compared to the reference level identifies the subject as one that is responsive to the bispecific antibody; and (c) continuing to administer the bispecific antibody to the subject if the level of the T cell proliferation marker is increased compared to the reference level. A bispecific antibody comprising:

122. 1. A bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, said treatment comprising: (a) detecting proliferation Ki-67 positivity (MKI67) in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; ＋ ) determining the number of T cell markers; (b) MKI67 in the biological sample ＋ comparing the number of T cells to a reference number, and determining whether MKI67 in the biological sample is increased compared to the reference number. ＋ comparing, where an increased number of T cells identifies the subject as responding to the bispecific antibody; and (c) MKI67 in a biological sample from the subject. ＋ if the number of T cells is increased compared to the reference number, continuing to administer the bispecific antibody to the subject. A bispecific antibody comprising:

123. 1. A bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, said treating comprising monitoring said subject's response to treatment, said monitoring comprising: (a) determining the level of a T cell proliferation marker in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; and (b) comparing the level of the T cell proliferation marker in the biological sample with a reference level, wherein an increased level of the T cell proliferation marker in the biological sample compared to the reference level identifies the subject as one that is responsive to the bispecific antibody. Including, A bispecific antibody, thereby monitoring the subject's response to treatment with the bispecific antibody.

124. 1. A bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, said treating comprising monitoring said subject's response to treatment, said monitoring comprising: (a) detecting MKI67 in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; ＋ Determining the number of T cells; and (b) MKI67 in the biological sample ＋ comparing the number of T cells to a reference number, and determining whether MKI67 in the biological sample is increased compared to the reference number. ＋ an increased number of T cells identifies the subject as responding to the bispecific antibody. Including, A bispecific antibody, thereby monitoring the subject's response to treatment with the bispecific antibody.

125. 1. A bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, said treating comprising assessing the subject's response to treatment, said assessing comprising: (a) determining the level of a T cell proliferation marker in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; and (b) maintaining, adjusting, or stopping said treatment of said subject based on a comparison of said level of said T cell proliferation marker in said biological sample to a reference level. Including, a change in the level of said T cell proliferation marker in said biological sample compared to said reference level is indicative of a response to treatment with said bispecific antibody.

126. 1. A bispecific antibody that binds FcRH5 and CD3 for use in treating a subject with MM, said treating comprising assessing the subject's response to treatment, said assessing comprising: (a) detecting MKI67 in a biological sample obtained from the subject at a time point after administration of the bispecific antibody; ＋ Determining the number of T cells; and (b) MKI67 in the biological sample ＋ maintaining, adjusting, or stopping said treatment of said subject based on a comparison of said number of T cells to a reference number. Including, the MKI67 in the biological sample compared to the reference number ＋ A bispecific antibody, wherein a change in said number of T cells indicates a response to treatment with said bispecific antibody.

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