Combination of an IL15 / IL15R alpha heterodimeric Fc fusion protein and an FCRH5xCD3 bispecific antibody for the treatment of blood cancer

Abstract

The present disclosure provides a method of treating a blood cancer, such as multiple myeloma, by administering a combination of a heterodimeric protein (e.g., XmAb24306) comprising a first monomer comprising an IL15 protein-Fc domain fusion and a second monomer comprising an IL15Rα protein-Fc domain fusion, and an FcRH5xCD3 bispecific antibody (e.g., cevostamab).

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit and priority of U.S. Provisional Application No. 63 / 367,900, filed Jul. 7, 2022, and U.S. Provisional Application No. 63 / 504,524, filed May 26, 2023, the contents of each of which are hereby incorporated by reference in their entirety.

[0002] Technical Field The present disclosure relates to the field of treatment of blood cancers, such as multiple myeloma, using combinations of IL15 - IL15Rα heterodimer Fc fusion proteins and FcRH5xCD3 bispecific antibodies.

[0003] Sequence Listing This application includes a sequence listing that has been electronically submitted in XML format and is hereby incorporated by reference in its entirety. A copy of the XML was created on Jul. 6, 2023, named 000218 - 0060 - WO1_SL.xml, and is 31,425 bytes in size.

Background Art

[0004] Most blood cancers (or hematological cancers) begin in the bone marrow and result from abnormal blood cells that grow uncontrollably, interrupting the function of normal blood cells that fight infection and produce new blood cells. Multiple myeloma (MM), a type of blood cancer, is an incurable neoplasm characterized by the proliferation and accumulation of malignant plasma cells in the bone marrow, leading to the overproduction of detectable monoclonal protein (M protein) in the blood or urine of most patients. According to the diagnosis of MM, approximately 30,000 people are affected annually in the United States (Siegel et al. 2019), and approximately 160,000 people worldwide are diagnosed with MM each year (Bray et al. 2018). End-organ damage caused by MM includes hypercalcemia, renal insufficiency, anemia, and lytic bone lesions. MM remains incurable despite advances in treatment, and even with aggressive treatments such as autologous stem cell transplantation (ASCT), the median survival is estimated to be 8 - 10 years for standard-risk myeloma and 2 - 3 years for high-risk myeloma (Mikhael et al. 2013). The introduction of proteasome inhibitors (PIs) such as bortezomib (Velcade® U.S. Package Insert [USPI]), immunomodulatory drugs (IMiDs) such as lenalidomide (Revlimid® USPI), and monoclonal antibodies such as daratumumab (Darzalex® USPI, Darzalex-Faspro™ USPI) has achieved an extension of survival. Other drugs with novel mechanisms of action approved by the U.S. Food and Drug Administration for the treatment of MM include selinexor (Xpovio® USPI), a nuclear export inhibitor, and belantamab mafodotin-blmf (Blenrep USPI).

[0005] Despite significant advances in treatment options, most MM patients ultimately relapse. Relapsed / refractory multiple myeloma (R / R MM) still constitutes a major unmet medical need, and in subjects with disease refractory to anti-CD38 monoclonal antibodies, the median overall survival is less than 1 year (Chari et al. 2019; Ghandi et al. 2019). Several approaches that direct the human immune system to target and destroy malignant plasma cells are currently being investigated in clinical settings, including T cell-engaging bispecific antibodies and chimeric antigen receptor [CAR] T cells. New data from clinical trials using these agents suggest that manipulating the subject's immune system is a potentially promising approach for the treatment of R / R MM (Moreau et al. 2019; Caraccio et al. 2020).

Summary of the Invention

[0006] In a first aspect, the present disclosure provides a method of treating a blood cancer in a subject in need of treatment for a blood cancer, the method comprising administering to the subject a therapeutically effective amount of (a) an IL15-IL15Rα heterodimer Fc fusion protein and (b) an FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens.

[0007] In a second aspect, the present disclosure provides the use of a therapeutically effective amount of (a) an IL15-IL15Rα heterodimer Fc fusion protein and (b) an FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens in the manufacture of one or more medicaments for treating a blood cancer in a subject in need of treatment for a blood cancer.

[0008] In a third aspect, the present disclosure provides a therapeutically effective amount of (a) an IL15-IL15Rα heterodimer Fc fusion protein and (b) an FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens for use in treating a blood cancer in a subject in need of treatment for a blood cancer.

[0009] In some embodiments, the IL15-IL15Rα heterodimeric Fc fusion protein comprises: (a) a first fusion protein comprising an interleukin-15 (IL-15) protein covalently bound via a first domain linker to the N-terminus of a first Fc domain, wherein the IL-15 protein comprises the amino acid sequence of SEQ ID NO: 5 and the first Fc domain is a variant of the human IgG1 Fc domain; and (b) a second fusion protein comprising an IL-15 receptor alpha (IL-15Rα) protein fragment covalently bound via a second domain linker to the N-terminus of a second Fc domain, wherein the IL-15Rα protein comprises the amino acid sequence of SEQ ID NO: 4 and the second Fc domain is a variant of the human IgG1 Fc domain.

[0010] In some embodiments, the IL15-IL15Rα heterodimeric Fc fusion protein comprises: (a) a first fusion protein comprising an interleukin-15 (IL-15) protein covalently bound via a first domain linker to the N-terminus of a first Fc domain, wherein the IL-15 protein comprises the amino acid sequence of SEQ ID NO: 5 and the first Fc domain comprises the amino acid sequence of SEQ ID NO: 6; and (b) a second fusion protein comprising an IL-15 receptor alpha (IL-15Rα) protein fragment covalently bound via a second domain linker to the N-terminus of a second Fc domain, wherein the IL-15Rα protein comprises the amino acid sequence of SEQ ID NO: 4 and the second Fc domain comprises the amino acid sequence of SEQ ID NO: 7.

[0011] In some embodiments, the first domain linker comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, the second domain linker comprises the amino acid sequence of SEQ ID NO: 8.

[0012] In some embodiments, the first domain linker comprises the amino acid sequence of SEQ ID NO: 8, and the second domain linker comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first fusion protein comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments, the second fusion protein comprises the amino acid sequence of SEQ ID NO: 10. In some embodiments, the heterodimeric protein comprises a first monomer comprising the amino acid sequence shown in SEQ ID NO: 9 and a second monomer comprising the amino acid sequence shown in SEQ ID NO: 10.

[0013] In some embodiments, the IL15-IL15Rα heterodimeric Fc fusion protein is XmAb24306.

[0014] In some embodiments, the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens comprises an anti-FcRH5 light chain variable region, an anti-FcRH5 heavy chain variable region, an anti-CD3 light chain variable region, and an anti-CD3 heavy chain variable region.

[0015] In some embodiments, the anti-FcRH5 light chain variable region comprises complementarity-determining region-1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 11, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 12, and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 13; the anti-FcRH5 heavy chain variable region comprises complementarity-determining region-1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 14, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 15, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 16.

[0016] In some embodiments, the anti-FcRH5 light chain variable region comprises the amino acid sequence of SEQ ID NO: 17. In some embodiments, the anti-FcRH5 heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-FcRH5 light chain comprises the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-FcRH5 heavy chain comprises the amino acid sequence of SEQ ID NO: 20.

[0017] In some embodiments, the anti-CD3 light chain variable region comprises a light chain complementarity determining region-1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 21, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 22, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 23; the anti-CD3 heavy chain variable region comprises a heavy chain complementarity determining region-1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 24, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 25, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 26.

[0018] In some embodiments, the anti-CD3 light chain variable region comprises the amino acid sequence of SEQ ID NO: 27. In some embodiments, the anti-CD3 heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 28. In some embodiments, the anti-CD3 light chain comprises the amino acid sequence of SEQ ID NO: 29. In some embodiments, the anti-CD3 heavy chain comprises the amino acid sequence of SEQ ID NO: 30.

[0019] In some embodiments, the anti-FcRH5 light chain variable region comprises the amino acid sequence of SEQ ID NO: 17; the anti-FcRH5 heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 18; the anti-CD3 light chain variable region comprises the amino acid sequence of SEQ ID NO: 27; the anti-CD3 heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 28.

[0020] In some embodiments, the anti-FcRH5 light chain comprises the amino acid sequence of SEQ ID NO: 19; the anti-FcRH5 heavy chain comprises the amino acid sequence of SEQ ID NO: 20; the anti-CD3 light chain comprises the amino acid sequence of SEQ ID NO: 29; the anti-CD3 heavy chain comprises the amino acid sequence of SEQ ID NO: 30.

[0021] In some embodiments, the FcRH5xCD3 bispecific antibody is cevostamab.

[0022] In some embodiments, the blood cancer of the present disclosure is selected from the group consisting of leukemia, acute myeloid leukemia, adult acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, non-Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, and multiple myeloma. In some embodiments, the blood cancer is multiple myeloma. In some embodiments, the multiple myeloma is relapsed or refractory multiple myeloma. In some embodiments, the blood cancer is B-cell non-Hodgkin lymphoma. In some embodiments, the blood cancer is chronic lymphocytic leukemia.

[0023] In some embodiments, the subject has previously been administered one or more prior treatments.

[0024] In some embodiments, the prior treatment of the present disclosure is an immunomodulatory agent, a proteasome inhibitor, or an anti-CD38 monoclonal antibody. In some embodiments, the immunomodulatory agent is selected from the group consisting of lenalidomide, thalidomide, and pomalidomide. In some embodiments, the proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib, and ixazomib. In some embodiments, the anti-CD38 monoclonal antibody is selected from the group consisting of daratumumab, isatuximab, mezigitamab, and ferzalizumab.

[0025] In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at a dose selected from the group consisting of about 0.0025 mg / kg, about 0.005 mg / kg, about 0.01 mg / kg, about 0.015 mg / kg, about 0.02 mg / kg, about 0.025 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.08 mg / kg, about 0.1 mg / kg, about 0.12 mg / kg, about 0.16 mg / kg, about 0.2 mg / kg, about 0.24 mg / kg and about 0.32 mg / kg body weight. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at a dose selected from the group consisting of about 0.01 mg / kg, about 0.02 mg / kg, about 0.04 mg / kg, about 0.06 mg / kg, about 0.09 mg / kg, and about 0.12 mg / kg body weight.

[0026] In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at a dose selected from the group consisting of 0.0025 mg / kg, 0.005 mg / kg, 0.01 mg / kg, 0.015 mg / kg, 0.02 mg / kg, 0.025 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.08 mg / kg, 0.10 mg / kg, 0.16 mg / kg, 0.20 mg / kg, 0.24 mg / kg and 0.32 mg / kg body weight. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at a dose selected from the group consisting of 0.01 mg / kg, 0.02 mg / kg, 0.04 mg / kg, 0.06 mg / kg, 0.09 mg / kg, and 0.12 mg / kg body weight.

[0027] In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at a frequency selected from the group consisting of Q1W, Q2W, Q3W, Q4W, Q5W, and Q6W. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered for 1 cycle or more at the frequency of Q1W. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered for 1 cycle or more at the frequency of Q2W. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered for 1 cycle or more at the frequency of Q4W.

[0028] In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered intravenously.

[0029] In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) and the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens are administered simultaneously. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) and the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens are administered sequentially.

[0030] In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered for 1 cycle or more at a frequency selected from the group consisting of Q1W, Q2W, Q3W, Q4W, Q5W, and Q6W. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered for 1 cycle or more at a frequency of Q2W. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at a frequency of Q4W, and the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered for 1 cycle or more at a frequency of Q2W.

[0031] In some embodiments, each of 1 cycle or more is a 4-week cycle. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered 6 times in a 4-week cycle at Q2W, and is administered at the 7th time and subsequent 4-week cycles at Q4W. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered 6 times in a 4-week cycle on days 1 and 15, and is administered on the 1st day of the 7th and subsequent 4-week cycles.

[0032] In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is administered at a dose of about 132 mg to about 198 mg. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is administered at a dose of about 132 mg. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is administered at a dose of about 132 mg at a frequency of Q2W for 1 cycle or more of 28 days. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is administered at a dose of about 160 mg. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is administered at a dose of about 198 mg.

[0033] In some embodiments, one or more priming doses of an FcRH5xCD3 bispecific antibody (e.g., cevostamab) that binds to both antigens, or a fragment thereof, are administered to a subject during a pre-stage prior to the first treatment cycle. In some embodiments, the pre-stage is 7 days. In some embodiments, the priming dose is about 3.6 mg of an FcRH5xCD3 bispecific antibody (e.g., cevostamab). In some embodiments, two priming doses of an FcRH5xCD3 bispecific antibody (e.g., cevostamab) that binds to both antigens, or a fragment thereof, are administered to the subject. In some embodiments, about 3.6 mg of an FcRH5xCD3 bispecific antibody (e.g., cevostamab) is administered between the two priming doses (i.e., the amount administered in the first priming dose and the amount administered in the second priming dose together total about 3.6 mg). In some embodiments, the first priming dose is administered on day 1 of the pre-stage. In some embodiments, the second priming dose is administered between days 2 - 4 of the pre-stage. In some embodiments, the minimum interval between the end of the first priming dose and the start of the second priming dose is 20 hours. In some embodiments, an FcRH5xCD3 bispecific antibody (e.g., cevostamab) that binds to both antigens, or a fragment thereof, is administered between the two priming doses. In some embodiments, the first priming dose is about 0.3 mg and the second priming dose is about 3.3 mg.

[0034] In some embodiments, the subject is administered a first priming dose of about 0.3 mg of an FcRH5xCD3 bispecific antibody (e.g., cevostamab) on day 1 of the pre-stage, a second priming dose of about 3.3 mg of an FcRH5xCD3 bispecific antibody (e.g., cevostamab) between days 2 - 4 of the pre-stage, and thereafter, a dose of about 132 mg of an FcRH5xCD3 bispecific antibody (e.g., cevostamab) on days 1 and 15 for 6 times in a 4 - week cycle, as well as on day 1 of the 7th and subsequent 4 - week cycles.

[0035] In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is administered intravenously.

[0036] In some embodiments, the method further comprises administering to the subject a therapeutically effective amount of tocilizumab. In some embodiments, the subject is suffering from a cytokine release syndrome (CRS) event. In some embodiments, tocilizumab is administered to a subject who remains refractory to corticosteroids 24 hours after the first corticosteroid administration. In some embodiments, tocilizumab is administered at a dose of 8 mg / kg. In some embodiments, when the subject's body weight is ≥ 30 kg, tocilizumab is administered at a dose of 8 mg / kg. In some embodiments, tocilizumab is administered at a dose of 12 mg / kg. In some embodiments, when the subject's body weight is < 30 kg, tocilizumab is administered at a dose of 12 mg / kg.

[0037] In some embodiments, tocilizumab is administered intravenously. In some embodiments, tocilizumab is administered every 8 hours.

[0038] A fourth aspect of the present disclosure is a method of treating multiple myeloma in a subject in need of treatment for multiple myeloma, the method comprising administering to the subject a therapeutically effective amount of (a) XmAb24306 (wherein XmAb24306 comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10), and (b) cevostamab (wherein cevostamab comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30), wherein XmAb24306 is administered intravenously at a dose of about 0.02 mg / kg to about 0.06 mg / kg and cevostamab is administered intravenously at a dose of about 132 mg.

[0039] A fifth aspect of the present disclosure is the use of a therapeutically effective amount of (a) XmAb24306 (wherein XmAb24306 comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10), and (b) cevostamab (wherein cevostamab comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30) in the manufacture of one or more medicaments for treating multiple myeloma in a subject in need thereof, wherein XmAb24306 is formulated for intravenous administration at a dose of about 0.02 mg / kg to about 0.06 mg / kg, and cevostamab is formulated for intravenous administration at a dose of about 132 mg.

[0040] A sixth aspect of the present disclosure is a therapeutically effective amount of (a) XmAb24306 (wherein XmAb24306 comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10), and (b) cevostamab (wherein cevostamab comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30) for use in treating multiple myeloma in a subject in need thereof, wherein XmAb24306 is administered intravenously at a dose of about 0.02 mg / kg to about 0.06 mg / kg, and cevostamab is administered intravenously at a dose of about 132 mg, provided is XmAb24306 and cevostamab.

[0041] In some embodiments, the treatment further comprises administering to the subject one or more priming doses of sevosumab at a total dose of about 3.6 mg during a pre-stage of 7 days prior to the first treatment cycle, and the priming doses are administered as single doses. In some embodiments, the treatment further comprises administering to the subject one or more priming doses of sevosumab at a total dose of about 3.6 mg during a pre-stage of 7 days prior to the first treatment cycle, and the priming doses are administered as two doses. In some embodiments, the first priming dose is about 0.3 mg and the second priming dose is about 3.3 mg. In some embodiments, the first priming dose is administered on day 1 of the pre-stage, and the second priming dose is administered on day 2, 3, or 4 of the pre-stage.

[0042] In some embodiments, XmAb24306 is administered for one or more cycles at a frequency of Q4W.

[0043] In some embodiments, sevosumab is administered for one or more cycles at a frequency of Q2W. In some embodiments, sevosumab is administered for one or more cycles at a frequency of Q4W.

[0044] In some embodiments, XmAb24306 is administered intravenously at least 7 times in a 4-week cycle at a frequency of Q4W. The first priming dose of 0.3 mg of sevosumab is administered intravenously on day 1 of the pre-stage, and the second priming dose of 3.3 mg of sevosumab is administered intravenously between days 2 to 4 of the pre-stage. The pre-stage is 7 days. Thereafter, it is administered intravenously 6 times in a 4-week cycle on days 1 and 15, and on day 1 of the 7th and subsequent 4-week cycles at a dose of 132 mg of sevosumab.

[0045] A seventh aspect of the present disclosure is a method of treating multiple myeloma in a subject in need of treatment for multiple myeloma, the method comprising administering to the subject a therapeutically effective amount of (a) XmAb24306 (wherein XmAb24306 comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10), and (b) sevosumab (wherein sevosumab comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30), wherein XmAb24306 is administered intravenously at a dose of about 0.02 mg / kg to about 0.06 mg / kg, at a frequency of Q4W, for at least 7 times in a 4-week cycle, a first priming dose of 0.3 mg of sevosumab is administered intravenously on day 1 of the previous stage, a second priming dose of 3.3 mg of sevosumab is administered intravenously between days 2-4 of the previous stage, the previous stage is 7 days, and thereafter, at a dose of 132 mg of sevosumab, 6 times in a 4-week cycle on days 1 and 15, and on day 1 of the 7th and subsequent 4-week cycles, is provided.

[0046] The eighth aspect of the present disclosure is in the manufacture of one or more pharmaceutical products for treating multiple myeloma in a subject in need of treatment for multiple myeloma, a therapeutically effective amount of (a) XmAb24306 (wherein XmAb24306 comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10), and (b) cevostamab (wherein cevostamab comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30), wherein XmAb24306 is formulated to be administered intravenously at a dose of about 0.02 mg / kg to about 0.06 mg / kg, at a frequency of Q4W, for at least 7 times in a 4-week cycle, and cevostamab is formulated to be administered intravenously at a dose of 132 mg, 6 times in a 4-week cycle on days 1 and 15, and on the first day of the 7th and subsequent 4-week cycles; the treatment further comprises a 7-day pre-stage in which a first priming dose of 0.3 mg of cevostamab is administered intravenously on the first day of the pre-stage, and a second priming dose of 3.3 mg of cevostamab is administered intravenously between days 2 and 4 of the pre-stage, provided the use.

[0047] A ninth aspect of the present disclosure is a therapeutically effective amount of (a) XmAb24306 (wherein XmAb24306 comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10), and (b) cevostamab (wherein cevostamab comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30) for use in treating multiple myeloma in a subject in need thereof, wherein XmAb24306 is intravenously administered at a dose of about 0.02 mg / kg to about 0.06 mg / kg, at a frequency of Q4W, at least 7 times in a 4-week cycle, a first priming dose of 0.3 mg of cevostamab is intravenously administered on day 1 of the previous stage, a second priming dose of 3.3 mg of cevostamab is intravenously administered between days 2 to 4 of the previous stage, the previous stage is 7 days, and thereafter, at a dose of 132 mg of cevostamab, 6 times at weeks 1 and 15 in a 4-week cycle, and intravenously administered on day 1 of the 7th and subsequent 4-week cycles, provided are XmAb24306 and cevostamab.

Brief Description of the Drawings

[0048]

FIG. 1A-1B

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FIG. 2A-2C

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FIG. 3

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FIG. 4A-4B

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DETAILED DESCRIPTION OF THE INVENTION

[0055] General In the practice of the methods disclosed herein, as well as in the preparation and use of the compositions, unless otherwise indicated, conventional techniques in molecular biology, biochemistry, chromatin structure and analysis, computational chemistry, cell culture, recombinant DNA, and related fields such as are within the skill of the art are used. These techniques are well described in the literature.

[0056] The term "herein" means the entire application.

[0057] Any of the embodiments described in this specification can be combined with one or more other embodiments disclosed herein, including those described in different aspects of the present disclosure and different parts of the specification (including embodiments described only in the examples), unless explicitly negated or stated to be inappropriate in this specification. The combinations of embodiments are not limited to the specific combinations claimed by a plurality of dependent claims.

[0058] Any publications, patents, and published patent applications referred to in this application are specifically incorporated herein by reference. In case of any conflict, this specification, including specific definitions, shall prevail.

[0059] Throughout this specification, the word "comprise", or variations such as "comprises" or "comprising", is synonymous with "include", "contain" or "characterized by", and is inclusive or open-ended and does not exclude additional unrecited elements or method steps.

[0060] Throughout this specification, when a composition is described as having, including, or comprising (or a variation thereof) a particular component, it is contemplated that the composition may consist essentially of or consist of the recited components. Similarly, when a method or process is described as having, including, or comprising particular process steps, the process may consist essentially of or consist of the recited process steps. Furthermore, it should be understood that the order of steps or the order of performing a particular operation is not important as long as the compositions and methods described herein are operable. Additionally, two or more steps or operations can be performed simultaneously.

[0061] The term "consisting of" excludes elements, steps, or components not specifically recited.

[0062] The term "consisting essentially of" limits the scope of the present disclosure to the specified materials or steps and those that do not substantially affect the basic and novel characteristics of the present disclosure.

[0063] Any examples following the term "for example" are not meant to be exclusive or limiting.

[0064] The articles "a", "an", and "the" are used herein to refer to one or more (i.e., at least one) of the grammatical objects of the articles. By way of example, "an element" means one element or more than one element.

[0065] As used herein, the term "about", when modifying the amount of a component, parameter, calculation, or measurement value of a composition used in the methods of the present disclosure, can result, for example, from common measurements and liquid handling procedures used to make isolated polypeptides or pharmaceutical compositions in the real world; from inadvertent error in these procedures; from differences in the manufacture, source, or purity of the components used to make the composition or execute the method; etc., without substantially affecting the chemical or physical attributes of the compositions or methods of the present disclosure. Such variations can typically be within 10% of a given value or range, more typically within an additional 5%. The term "about" also encompasses amounts that vary depending on different equilibrium conditions of a composition resulting from a particular initial mixture. Whether or not modified by the term "about", that paragraph includes what corresponds to the amount. References to a value or parameter following "about" in this specification include (and describe) embodiments directed to that value or parameter itself. For example, a recitation of "about X" includes a recitation of "X". Numerical ranges include the numbers defining the range.

[0066] As used herein, the term "or" is to be understood as meaning "and / or" unless the context clearly dictates otherwise.

[0067] Numerical ranges and parameters setting forth the broad scope of the disclosure are approximations, however, the numerical values set forth in the specific examples are reported as precisely as possible. Nevertheless, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Further, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a range described as "1 to 10" includes any and all subranges between the minimum value of 1 and the maximum value of 10 (including the boundary values), that is, all subranges beginning with a minimum value of 1 or more, such as 1 to 6.1, and ending with a maximum value of 10 or less, such as 5.5 to 10). Also, the disclosure of a range is to be considered as the disclosure of the endpoints of that range.

[0068] Exemplary methods and materials are described below, but methods and materials similar or equivalent to those described herein can also be used in the practice or testing of this application. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0069] Definitions The following terms are to be understood to have the following meanings unless otherwise indicated:

[0070] As used herein, the term "ablation" refers to the reduction or removal of activity. Thus, for example, "ablating FcγR binding" means that an Fc region amino acid variant has less than 50% of the starting binding compared to an Fc region that does not contain the particular variant, with preferably less than 70%, less than 80%, less than 90%, less than 95% or less than 98% loss of activity, and generally, activity means below the level of binding detectable in a BIACORE® assay (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.). Unless otherwise specified, the Fc domains described herein retain binding to the FcRn receptor.

[0071] "Administering" a substance, compound or agent "to" a subject, or "administration" of a substance, compound or agent "to" a subject, refers to contact of that substance, compound or agent with the subject or the subject's cells, tissues, organs or body fluids. For example, a compound or agent can be administered intravenously or subcutaneously. Also, administration can be, for example, once, multiple times and / or over one or more extended periods. In some embodiments, administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug. For example, as used herein, a physician who instructs a subject to self-administer a drug or to have another person administer a drug to the subject, and / or a physician who provides a subject with a prescription for a drug, is administering the drug to the subject.

[0072] As used herein, the term "affinity" of a molecule refers to the strength of the interaction between the molecule and a binding partner, such as a receptor, ligand, or antigen. The affinity of a molecule for its binding partner is typically expressed as the binding affinity equilibrium dissociation constant (KD) of a particular interaction, and the lower the KD, the higher the affinity. The KD binding affinity constant can be measured by surface plasmon resonance, for example, using a BIACORE® system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.). See, for example, Jonsson et al., Ann. Biol. Clin. 51:19 26 (1993); Jonsson et al., Biotechniques 11:620 627 (1991); Jonsson et al., J. Mol. Recognit. 8:125 131 (1995); Johnsson et al., Anal. Biochem. 198:268 277 (1991); Hearty S et al., Methods Mol Biol. 907:411-42 (2012), each of which is incorporated herein by reference. The KD may be measured using a KinExA® system (Sapidyne Instruments, Hanover, Germany and Boise, ID). In some embodiments, the IL-15 variants of the heterodimeric proteins described herein have a reduced binding affinity for the IL-2 / IL-15βγ receptor compared to wild-type IL-15. In some embodiments, the first and / or second Fc variants of the heterodimeric proteins described herein have a reduced affinity for human, cynomolgus monkey, and mouse Fcγ receptors. In some embodiments, the first and / or second Fc variants of the heterodimeric proteins described herein do not bind to human, cynomolgus monkey, and mouse Fcγ receptors.

[0073] The terms "amino acid" and "amino acid identity" as used herein refer to one of the 20 naturally occurring amino acids encoded by DNA and RNA.

[0074] The terms "amino acid substitution" or "substitution", as used herein, refer to the replacement of an amino acid at a particular position in a parent polypeptide sequence with a different amino acid. In particular, in some embodiments, the substitution is with an amino acid that is not naturally present at the particular position and is not naturally present in vivo or in any organism. For example, the substitution E272Y refers to a variant polypeptide in which the glutamic acid at position 272 has been replaced with tyrosine, in this case an Fc variant. For clarity, a protein engineered to change the nucleic acid coding sequence but not change the starting amino acid (e.g., changing CGG (encoding arginine) to CGA (still encoding arginine) to increase the expression level in a host organism) is not an "amino acid substitution", i.e., if the protein has the same amino acid at a particular position that is the starting position, it is not considered an amino acid substitution even though a new gene encoding the same protein has been created.

[0075] The terms "amino acid insertion", "amino acid addition" or "addition" or "insertion", as used herein, refer to the addition of an amino acid sequence at a particular position in a parent polypeptide sequence. For example, -233E, _233E or 233E indicates the insertion of glutamic acid after position 233 and before position 234. Further, -233ADE, _233ADE or 233ADE indicates the insertion of AlaAspGlu after position 233 and before position 234.

[0076] The term "amino acid deletion" or "deletion", as used herein, refers to the removal of an amino acid sequence at a particular position in a parent polypeptide sequence. For example, E233- or E233#, E233(), E233_ or E233del indicates the deletion of glutamic acid at position 233. Further, EDA233-, EDA233_ or EDA233# indicates the deletion of the sequence GluAspAla starting at position 233.

[0077] As used herein, the term "antibody" or "Ab" refers to an immunoglobulin molecule (e.g., a full antibody, antibody fragment, or modified antibody) capable of recognizing and binding to a specific target or antigen located in the variable region of the immunoglobulin molecule, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., via at least one antigen recognition site. As used herein, the term "antibody" may encompass any type of antibody, including but not limited to monoclonal antibodies, polyclonal antibodies, human antibodies, engineered antibodies (including humanized antibodies, fully human antibodies, chimeric antibodies, single-chain antibodies, artificially selected antibodies, CDR-grafted antibodies, etc.), that specifically bind to a given antigen. In some embodiments, "antibody" and / or "immunoglobulin" (Ig) refers to a polypeptide comprising at least two heavy (H) chains (about 50-70 kDa) and two light (L) chains (about 25 kDa), optionally interconnected by disulfide bonds. There are two types of light chains, lambda and kappa. In humans, lambda and kappa light chains are similar, but only one type is present in each antibody. Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define the isotype of the antibody as IgM, IgD, IgG, IgA, and IgE, respectively. For an overview, see Fundamental Immunology Ch.7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989)), which is incorporated by reference in its entirety. The methods, uses, and compositions for use disclosed herein utilize IgG antibodies.

[0078] As used herein, the term "antigen-binding fragment" refers to a portion (or fragment) of an antibody that retains the antibody-binding specificity. Thus, as used herein, an antigen-binding fragment retains the six CDRs of the reference antibody.

[0079] As used herein, the term "effector function" refers to biochemical events resulting from the interaction of the Fc region of an antibody with an Fc receptor or another effector molecule (e.g., Fc receptor-like (FcRL) molecule, complement component C1q, and tripartite motif-containing protein 21 (TRIM21)). Effector functions include, but are not limited to, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). The term "ADCC" or "antibody-dependent cell-mediated cytotoxicity" as used herein refers to a cell-mediated reaction in which non-specific cytotoxic cells expressing FcγR recognize an antibody bound to a target cell and subsequently cause lysis of the target cell. ADCC correlates with binding to FcγRIIIa; increased binding to FcγRIIIa results in increased ADCC activity. As discussed herein, many embodiments of the present disclosure completely ablate ADCC activity. The term "ADCP" or "antibody-dependent cell-mediated phagocytosis" as used herein refers to a cell-mediated reaction in which non-specific cytotoxic cells expressing FcγR recognize an antibody bound to a target cell and subsequently cause phagocytosis of the target cell. The term "CDC" or "complement-dependent cytotoxicity" as used herein refers to an effector function that results in the activation of the classical complement pathway, which is induced by the binding of an antibody to an antigen on a target cell and activates a series of cascades containing complement-related proteins in the blood.

[0080] As used herein, the terms "Fc", "Fc region" or "Fc domain" are used interchangeably herein and, in some instances, refer to a polypeptide comprising the constant region of an antibody excluding the immunoglobulin domain of the first constant region (e.g., CH1) or a portion thereof, and in some instances refers to a portion of the hinge. In IgG, the Fc domain comprises the immunoglobulin domains Cγ2 and Cγ3 (Cγ2 and Cγ3) and the lower hinge region between Cγ1 (Cγ1) and Cγ2 (Cγ2). In some embodiments, Fc refers to the cleaved CH1 domain of an immunoglobulin, as well as CH2 and CH3. The boundaries of the Fc region can vary, but the human IgG heavy chain Fc region is typically defined to include residue E216 or C226 or P230 at its carboxyl terminus, and numbering follows EU numbering. In some embodiments, amino acid modifications are made to the Fc region, as described in more detail herein, for example to alter binding to one or more FcγR receptors or the FcRn receptor. In some embodiments, the Fc domain is derived from the human IgG1 heavy chain Fc domain. In some embodiments, the Fc domain is derived from the human IgG2 heavy chain Fc domain. "EU format as shown by Edelman" or "EU numbering" or "EU index" refers to the numbering of the residues of the human Fc domain as described in Edelman GM et al. (Proc. Natl. Acad. USA (1969), 63, 78-85, which is hereby incorporated by reference in its entirety).

[0081] As used herein, the terms "Fc fusion protein" and "immunoadhesin" are used interchangeably and generally refer to a protein comprising an Fc region linked to a different protein described herein, e.g., IL-15 and / or IL-15R, optionally via a linker portion described herein. In some instances, two Fc fusion proteins can form a homodimeric Fc fusion protein or a heterodimeric Fc fusion protein, with the latter being preferred.

[0082] As used herein, the terms "Fc variant" or "variant Fc" refer to a protein that contains an amino acid modification in the Fc domain. The Fc variants of the present invention are defined according to the amino acid modifications that constitute them. Thus, for example, N434S is an Fc variant having a substituted serine at position 434 relative to the parental Fc polypeptide, and the numbering follows the EU index. Similarly, M428L / N434S defines an Fc variant having substitutions M428L and N434S compared to the parental Fc polypeptide. For all positions discussed in the context of the present invention related to antibodies, unless otherwise specified, the numbering of amino acid positions follows the EU index. The modification can be an addition, deletion, or substitution.

[0083] The terms "Fc gamma receptor", "FcγR", and "Fc gamma R" are used interchangeably herein and refer to any member of a family of proteins that bind to the Fc region of an IgG antibody and are encoded by the FcγR gene. The FcγR may be derived from any organism. In some embodiments, the FcγR is a human FcγR. In humans, this family includes, but is not limited to, FcγRI (CD64) including isoforms FcγRIa, FcγRIb, and FcγRIc; FcγRII (CD32) including isoforms FcγRIIa (including allotypes H131 and R131), FcγRIIb (including FcγRIIb-1 and FcγRIIb-2), and FcγRIIc; and FcγRIII (CD16) including isoforms FcγRIIIa (including allotypes V158 and F158) and FcγRIIIb (including allotypes FcγRIIb-NA1 and FcγRIIb-NA2) (incorporated in its entirety by reference, Jefferis et al., 2002, Immunol Lett 82:57-65), as well as any undiscovered human FcγR or FcγR isoform or allotype.

[0084] As used herein, the term "FcRn" or "neonatal Fc receptor" refers to a protein that binds to the Fc region of an IgG antibody and is at least partially encoded by the FcRn gene. FcRn may be derived from any organism. In some embodiments, FcRn is human FcRn. As is known in the art, functional FcRn proteins often contain two polypeptides often referred to as a heavy chain and a light chain. The light chain is beta-2 microglobulin and the heavy chain is encoded by the FcRn gene. Unless otherwise specified herein, FcRn or FcRn protein refers to a complex of an FcRn heavy chain and beta-2 microglobulin. Various FcRn variants can be used to increase binding to the FcRn receptor and, in some cases, increase the serum half-life. Generally, unless otherwise specified, the Fc monomers disclosed herein retain binding to the FcRn receptor (and can include amino acid variants that increase binding to the FcRn receptor, as described below).

[0085] As used herein, "IL-15", "IL15" or "interleukin 15" may be used interchangeably and refers to a 4-α-helix protein belonging to the cytokine family. IL-15 signals through a receptor complex composed of the IL-2 / IL-15 receptor beta (IL-15Rβ) (CD122) subunit. In some embodiments, the IL-15 protein comprises the polypeptide sequence set forth in SEQ ID NO: 2 (full-length human IL-15). In some embodiments, the IL-15 protein comprises the polypeptide sequence set forth in SEQ ID NO: 1 (truncated or mature human IL-15). In some embodiments, the IL-15 protein comprises a polypeptide sequence selected from the group consisting of SEQ ID NO: 1 and SEQ ID NO: 2.

[0086] As used herein, "XENP24306", "XmAb306", and "XmAb24306" may be used interchangeably and refer to an IL15-IL15Rα heterodimer Fc fusion protein, where the first monomer comprises the amino acid sequence of SEQ ID NO: 9 and the second monomer comprises the amino acid sequence of SEQ ID NO: 10.

[0087] The term "modification", as used herein, refers to an amino acid substitution, insertion, and / or deletion in a polypeptide sequence or a change to a moiety chemically linked to a protein. For example, a modification can be an altered carbohydrate or PEG structure attached to a protein. As used herein, "amino acid modification" means an amino acid substitution, insertion, and / or deletion in a polypeptide sequence. For clarity, unless otherwise specified, amino acid modifications always refer to amino acids encoded by DNA, e.g., the 20 amino acids having codons in DNA and RNA.

[0088] The terms "nucleic acid", "polynucleotide", and "oligonucleotide" are used interchangeably and refer to a deoxyribonucleotide or ribonucleotide polymer in a linear or circular conformation, and in single-stranded or double-stranded form. For the purposes of the present disclosure, these terms should not be construed as limiting with respect to the length of the polymer.

[0089] The term "non-naturally occurring modification", as used herein, refers to an amino acid modification that is not an isotype. For example, since none of the IgGs contain serine at position 434, substitution 434S in IgG1, IgG2, or IgG4 (or hybrids thereof) is considered a non-naturally occurring modification.

[0090] The terms "patient", "subject", and "individual" are used interchangeably herein and refer to a human in need of treatment. In some embodiments, the subject is in need of treatment for a blood cancer such as multiple myeloma. The terms "treating" and "treatment" as used herein refer to a decrease in the severity and / or frequency of symptoms, elimination of symptoms and / or their cause, prevention of the occurrence of symptoms and / or their cause, and improvement or repair of damage.

[0091] As used herein, the terms "polypeptide", "peptide", and "protein" are used interchangeably and refer to a polymer of amino acid residues. Expression of a fusion protein in a cell can be caused by delivery of the fusion protein to the cell or by delivery of a polynucleotide encoding the fusion protein to the cell, where the polynucleotide is transcribed and the transcript is translated to produce the fusion protein. Trans-splicing, polypeptide cleavage, and polypeptide ligation may also be involved in the expression of a protein in a cell. Methods for polynucleotide and polypeptide delivery to cells are known in the prior art.

[0092] The term "position" as used herein refers to the positioning within the sequence of a protein. Positions can be numbered sequentially or according to a defined format, such as the EU index for antibody numbering. A position can be defined relative to a reference sequence. In such cases, the reference sequence is provided for comparison purposes and the heterodimeric protein (or a portion thereof) of the present disclosure may include additional amino acid changes (e.g., substitutions, insertions, and deletions) relative to the reference sequence. In some embodiments, the heterodimeric protein (or a portion thereof) of the present disclosure does not include any additional amino acid changes relative to the reference sequence.

[0093] As used herein, the term "residue" refers to a position in a protein and the amino acid identity associated therewith. For example, asparagine 297 (also referred to as Asn297 or N297) is the residue at position 297 in a particular protein.

[0094] The terms "therapeutically effective amount" and "effective amount" are used interchangeably herein and refer to the amount of a therapeutic agent administered as a single agent or in combination with one or more additional agents that will, to some extent, alleviate one or more of the symptoms of the condition being treated. In some embodiments, a therapeutically effective amount is an amount sufficient to produce an effective or desired clinical outcome. With respect to the treatment of cancer, a therapeutically effective amount refers to an amount having at least one of the effects of alleviating, ameliorating, stabilizing, reversing, preventing, retarding, or delaying the progression of a hematologic cancer such as multiple myeloma (and / or related symptoms). The effective amount that may be used in the present disclosure will vary depending on the mode of administration, the age, weight, and general health of the subject. Appropriate amounts and dosing regimens can be determined using ordinary skill in the art. For example, efficacy can be determined using the International Myeloma Working Group (IMWG) Uniform Response Criteria.

[0095] The terms "wild type" or "WT" are used interchangeably herein and refer to an amino acid sequence or nucleotide sequence found in nature, including allelic variants. A WT protein has an amino acid sequence that has not been intentionally modified or is encoded by a nucleotide sequence that has not been intentionally modified.

[0096] The sequences referred to in this specification are provided in Table 1 below. It is known in the art that the C-terminal lysine can be cleaved during processing and expression of the Fc-containing protein (also known in the art as C-terminal lysine clipping). Thus, for each sequence disclosed herein that contains a C-terminal lysine, the corresponding sequence that does not contain the C-terminal lysine (i.e., the C-terminal lysine cleavage product) is also contemplated. In some embodiments, the first monomer contains a C-terminal lysine. In some embodiments, the first monomer lacks a C-terminal lysine. In some embodiments, the second monomer contains a C-terminal lysine. In some embodiments, the second monomer lacks a C-terminal lysine.

[0097] It is also known in the art that the C-terminal cleavage process is inaccurate and additional C-terminal residues may be cleaved. Accordingly, for each sequence containing a C-terminal lysine disclosed herein, corresponding sequences that do not contain two C-terminal residues are contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, corresponding sequences that do not contain three C-terminal residues are contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, corresponding sequences that do not contain four C-terminal residues are contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, corresponding sequences that do not contain five C-terminal residues are contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, corresponding sequences that do not contain six C-terminal residues are contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, corresponding sequences that do not contain seven C-terminal residues are contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, corresponding sequences that do not contain eight C-terminal residues are contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, corresponding sequences that do not contain nine C-terminal residues are contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, corresponding sequences that do not contain ten C-terminal residues are contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, corresponding sequences that do not contain eleven C-terminal residues are contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, corresponding sequences that do not contain twelve C-terminal residues are contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, corresponding sequences that do not contain thirteen C-terminal residues are contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, corresponding sequences that do not contain fourteen C-terminal residues are contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, corresponding sequences that do not contain fifteen C-terminal residues are contemplated.In some embodiments, the missing C-terminal residue is the result of manipulation (e.g., expressing a polynucleotide lacking a nucleotide sequence encoding one or more C-terminal residues). [Table 1] TIFF2025522865000003.tif255170TIFF2025522865000004.tif248170TIFF2025522865000005.tif180170

[0098] Method of treatment with an IL15-IL15Rα heterodimer Fc fusion protein and an FcRH5xCD3 bispecific antibody as combination therapy The present disclosure relates to a method of treating a blood cancer in a subject in need thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a heterodimer Fc fusion protein comprising an IL-15 and an IL-15 receptor alpha (IL-15Rα) protein domain, and an FcRH5xCD3 bispecific antibody. The present disclosure relates to CD8 in a subject suffering from a blood cancer + A method for inducing the proliferation of effector memory T cells, the method comprising administering to a subject an effective amount of a heterodimer Fc fusion protein comprising an IL-15 and an IL-15 receptor alpha (IL-15Rα) protein domain, and an FcRH5xCD3 bispecific antibody.

[0099] A first aspect of the present disclosure is a method of treating a blood cancer in a subject in need of treatment for the blood cancer, the method comprising administering to the subject an effective amount of (a) an IL15-IL15Rα heterodimer Fc fusion protein and (b) an FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens. Without being bound by theory, the scientific rationale for this combination is that the T cell-mediated antitumor activity of the FcRH5xCD3 bispecific antibody can be enhanced by the increased proliferation, survival, and / or effector function of T cells when exposed to an IL-15 agonist disclosed herein, such as an IL15-IL15Rα heterodimer Fc fusion protein like XmAb24306.

[0100] In a second aspect, the present disclosure provides the use of a therapeutically effective amount of (a) an IL15-IL15Rα heterodimer Fc fusion protein and (b) an FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens in the manufacture of one or more medicaments for treating a blood cancer in a subject in need of treatment for the blood cancer.

[0101] In a third aspect, the present disclosure provides a therapeutically effective amount of (a) an IL15-IL15Rα heterodimer Fc fusion protein and (b) an FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens for use in treating a blood cancer in a subject in need of treatment for the blood cancer.

[0102] In some embodiments, the IL15-IL15Rα heterodimeric Fc fusion protein comprises: (a) a first fusion protein comprising an interleukin-15 (IL-15) protein covalently attached to the N-terminus of a first Fc domain via a first domain linker, wherein the IL-15 protein comprises the amino acid sequence of SEQ ID NO: 5 and the first Fc domain is a variant of the human IgG1 Fc domain; and (b) a second fusion protein comprising an IL-15 receptor alpha (IL-15Rα) protein fragment covalently attached to the N-terminus of a second Fc domain via a second domain linker, wherein the IL-15Rα protein comprises the amino acid sequence of SEQ ID NO: 4 and the second Fc domain is a variant of the human IgG1 Fc domain.

[0103] Blood cancer refers to the abnormal or excessive production of blood cells (e.g., white blood cells). Examples of blood cancers treated by the methods and uses disclosed herein include, but are not limited to, leukemia, lymphoma, and myeloma. More detailed non-limiting examples of such blood cancers include acute myeloid leukemia, adult acute lymphoblastic leukemia, chronic lymphocytic leukemia, non-Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, and multiple myeloma. In some embodiments, the blood cancer is recurrent or refractory. In some embodiments, the blood cancer is selected from the group consisting of leukemia, acute myeloid leukemia, adult acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, non-Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, and multiple myeloma. In some embodiments, the blood cancer is selected from the group consisting of leukemia, acute myeloid leukemia, adult acute lymphoblastic leukemia, chronic lymphocytic leukemia. In some embodiments, the blood cancer is selected from the group consisting of lymphoma, non-Hodgkin lymphoma, B-cell non-Hodgkin lymphoma. In some embodiments, the blood cancer is leukemia. In some embodiments, the blood cancer is acute myeloid leukemia. In some embodiments, the blood cancer is adult acute lymphoblastic leukemia. In some embodiments, the blood cancer is chronic lymphocytic leukemia. In some embodiments, the blood cancer is lymphoma. In some embodiments, the blood cancer is non-Hodgkin lymphoma. In some embodiments, the blood cancer is B-cell non-Hodgkin lymphoma. In some embodiments, the blood cancer is multiple myeloma. In some embodiments, the blood cancer is recurrent or refractory multiple myeloma. In some embodiments, the blood cancer is a blood cancer for which there is no standard treatment, or for which standard treatment has been proven ineffective or intolerable, or is considered inappropriate, or for which a clinical trial of an investigational drug is recognized as the standard treatment.

[0104] The identification of subjects in need of such treatment may be made at the discretion of the subject or a medical professional and may be subjective (e.g., an opinion) or objective (e.g., measurable by a test or diagnostic method). Such treatment is appropriately administered to subjects who have or are at risk of having a blood cancer, are susceptible to a blood cancer, or have a blood cancer.

[0105] IL15-IL15Rα heterodimer Fc fusion proteins are known in the art. See, for example, International Publication No. WO 2018 / 071919, which is incorporated herein by reference. The use of IL15-IL15Rα heterodimer Fc fusion proteins for treating cancer is also known in the art. See, for example, International Publication No. WO 2021 / 155042, which is incorporated herein by reference. XmAb24306 is an interleukin-15 (IL15) / IL15 receptor alpha (IL15Rα) fusion protein engineered with a heterodimeric Fc domain and a half-life extension mutation (IL15 / IL15Rα-Fc). By complexing IL15 and IL15Rα (CD215) on the same Fc domain, XmAb24306 selectively engages the common gamma chain (γ) receptor (CD132) with interleukin-2 receptor beta (IL2Rβ) without engaging interleukin-2 receptor alpha (IL2Rα) (CD25). Compared to IL2-based therapeutics, XmAb24306 is expected to selectively expand natural killer (NK) cells and CD8 T cells and minimize the effect on the proliferation of regulatory T cells, which are known to constitutively express IL2Rα. XmAb24306 has also been engineered to reduce its affinity for the CD122 / CD132 receptor complex, extend its in vivo half-life to improve pharmacokinetics, and extend the pharmacodynamic response. In XmAb24306, the IL-15 variant has a reduced binding affinity (compared to wild-type IL-15) for the IL-2 / IL-15βγ receptor complex, targeting to improve tolerability by reducing acute toxicity and expanding pharmacokinetics, and CD8 +It is engineered to ultimately promote anti-tumor immunity through IL-15-mediated signaling on T cells and NK cells.

[0106] The IL-15Rα protein is a transmembrane protein with extremely high affinity for IL-15 that facilitates the transport of IL-15 from the endoplasmic reticulum (ER) through the cytoplasm and the presentation of the IL-15 / IL-15Rα complex on the cell surface. As used herein, the term "succ domain of IL-15Rα" refers to the truncated extracellular region of IL-15Rα or recombinant human interleukin-15 receptor α. In some embodiments, the IL-15Rα protein comprises the polypeptide sequence of SEQ ID NO: 3 (full-length human IL-15Rα). In some embodiments, the IL-15Rα protein comprises the polypeptide sequence of SEQ ID NO: 4 (succ domain of human IL-15Rα).

[0107] In some embodiments, the IL15-IL15Rα heterodimeric Fc fusion protein comprises: a) a first fusion protein comprising an interleukin-15 (IL-15) protein covalently attached to the N-terminus of a first Fc domain via a first domain linker, wherein the IL-15 protein comprises the amino acid sequence of SEQ ID NO: 5 and the first Fc domain comprises the amino acid sequence of SEQ ID NO: 6; and b) a second fusion protein comprising an IL-15 receptor alpha (IL-15Rα) protein fragment covalently attached to the N-terminus of a second Fc domain via a second domain linker, wherein the IL-15Rα protein comprises the amino acid sequence of SEQ ID NO: 4 and the second Fc domain comprises the amino acid sequence of SEQ ID NO: 7. In some embodiments, the first domain linker comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, the second domain linker comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first domain linker comprises the amino acid sequence of SEQ ID NO: 8 and the second domain linker comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first fusion protein comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments, the second fusion protein comprises the amino acid sequence of SEQ ID NO: 10. In some embodiments, the heterodimeric protein comprises a first monomer comprising the amino acid sequence shown in SEQ ID NO: 9 and a second monomer comprising the amino acid sequence shown in SEQ ID NO: 10. In some embodiments, the IL15-IL15Rα heterodimeric Fc fusion protein is XmAb24306.

[0108] The Fc receptor-like 5 (FcRL5 or FcRH5, also known as IRTA2) gene belongs to a family of six recently identified genes of the immunoglobulin superfamily (IgSF). FcRH cDNA encodes a type I transmembrane glycoprotein having multiple Ig-like extracellular domains and a cytoplasmic domain containing consensus immunoreceptor tyrosine-based activation and / or inhibitory signaling motifs. FcRH5 is involved in the proliferation during the development of antigen-primed B cells and the enhancement of downstream isotype expression (Dement-Brown et al. J. Leukoc. Biol. 91:59-67, 2012). FcRH5 is selectively expressed in the B cell lineage starting from pre-B cells, but unlike most B cell markers, its expression is retained in plasma cells (Polson et al. 2006; Li et al. 2017). Analysis of FcRH5 RNA expression in 53 different normal human tissues demonstrated that FcRH5 expression is exclusively expressed in the B cell lineage. Selective expression for B lineage cells and tissues predicts a favorable safety profile for this target. Similar to its expression in normal plasma cells, FcRH5 is expressed by myeloma tumor cells. FcRH5 expression was detected in all patient-derived myeloma tumor cells, suggesting an almost 100% prevalence in MM. Overall, the high prevalence in MM, the predicted favorable safety profile, and the overexpression in high-risk patients indicate that FcRH5 is a promising target for MM (Li et al. 2017).

[0109] CD3 (cluster of differentiation 3) is a cell surface molecule expressed on cytotoxic T cells (CD8 + naïve T cells) and helper T cells (CD4 +It is a protein complex and a T cell co-receptor that plays a role in activating both naive T cells. CD3 contains four distinct chains: the CD3γ chain, the CD3δ chain, and two CD3ε chains. These chains associate with the T cell receptor (TCR) and the CD3-zeta (ζ chain) to generate activation signals in T lymphocytes. Therefore, T cells can be targeted to MM cells using an FcRH5xCD3 bispecific antibody (e.g., cevostamab).

[0110] FcRH5xCD3 bispecific antibodies are known in the art. See, for example, International Publication No. WO 2016 / 205520, which is incorporated herein by reference. The use of FcRH5xCD3 bispecific antibodies for treating cancers including multiple myeloma is also known in the art. See, for example, International Publication No. WO 2022 / 076462, which is incorporated herein by reference. In some embodiments, an FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens comprises an anti-FcRH5 light chain variable region, an anti-FcRH5 heavy chain variable region, an anti-CD3 light chain variable region, and an anti-CD3 heavy chain variable region.

[0111] In some embodiments, according to Kabat numbering, the anti-FcRH5 light chain variable region comprises a light chain complementarity determining region-1 (CDR-L1) comprising the amino acid sequence KASQDVRNLVV (SEQ ID NO: 11); a CDR-L2 comprising the amino acid sequence SGSYRYS (SEQ ID NO: 12); and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 13); the anti-FcRH5 heavy chain variable region comprises a CDR-H1 comprising the amino acid sequence RFGVH (SEQ ID NO: 14); a CDR-H2 comprising the amino acid sequence VIWRGGSTDYNAAFVS (SEQ ID NO: 15); and a CDR-H3 comprising the amino acid sequence HYYGSSDYALDN (SEQ ID NO: 16). In some embodiments, the anti-FcRH5 light chain variable region comprises the amino acid sequence DIQMTQSPSSLSASVGDRVTITCKASQDVRNLVVWFQQKPGKAPKLLIYSGSYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHYSPPYTFGQGTKVEIK (SEQ ID NO: 17). In some embodiments, the anti-FcRH5 heavy chain variable region comprises the amino acid sequence EVQLVESGPGLVKPSETLSLTCTVSGFSLTRFGVHWVRQPPGKGLEWLGVIWRGGSTDYNAAFVSRLTISKDNSKNQVSLKLSSVTAADTAVYYCSNHYYGSSDYALDNWGQGTLVTVSS (SEQ ID NO: 18). In some embodiments, the anti-FcRH5 light chain comprises the amino acid sequence DIQMTQSPSSLSASVGDRVTITCKASQDVRNLVVWFQQKPGKAPKLLIYSGSYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHYSPPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 19).In some embodiments, the anti-FcRH5 heavy chain comprises the amino acid sequence EVQLVESGPGLVKPSETLSLTCTVSGFSLTRFGVHWVRQPPGKGLEWLGVIWRGGSTDYNAAFVSRLTISKDNSKNQVSLKLSSVTAADTAVYYCSNHYYGSSDYALDNWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 20).

[0112] In some embodiments, according to Kabat numbering, the anti-CD3 light chain variable region comprises a light chain complementarity determining region-1 (CDR-L1) comprising the amino acid sequence KSSQSLLNSRTRKNYLA (SEQ ID NO: 21); a CDR-L2 comprising the amino acid sequence WTSTRKS (SEQ ID NO: 22); and a CDR-L3 comprising the amino acid sequence HYYGSSDYALDN (SEQ ID NO: 23); the anti-CD3 heavy chain variable region comprises a CDR-H1 comprising the amino acid sequence SYYIH (SEQ ID NO: 24); a CDR-H2 comprising the amino acid sequence WIYPENDNTKYNEKFKD (SEQ ID NO: 25); and a CDR-H3 comprising the amino acid sequence DGYSRYYFDY (SEQ ID NO: 26). In some embodiments, the anti-CD3 light chain variable region comprises the amino acid sequence DIVMTQSPDSLAVSLGERATINCKSSQSLLNSRTRKNYLAWYQQKPGQSPKLLIYWTSTRKSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCKQSFILRTFGQGTKVEIK (SEQ ID NO: 27). In some embodiments, the anti-CD3 heavy chain variable region comprises the amino acid sequence EVQLVQSGAEVKKPGASVKVSCKASGFTFTSYYIHWVRQAPGQGLEWIGWIYPENDNTKYNEKFKDRVTITADTSTSTAYLELSSLRSEDTAVYYCARDGYSRYYFDYWGQGTLVTVSS (SEQ ID NO: 28). In some embodiments, the anti-CD3 light chain comprises the amino acid sequence DIVMTQSPDSLAVSLGERATINCKSSQSLLNSRTRKNYLAWYQQKPGQSPKLLIYWTSTRKSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCKQSFILRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 29).In some embodiments, the anti-CD3 heavy chain comprises the amino acid sequence EVQLVQSGAEVKKPGASVKVSCKASGFTFTSYYIHWVRQAPGQGLEWIGWIYPENDNTKYNEKFKDRVTITADTSTSTAYLELSSLRSEDTAVYYCARDGYSRYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 30).

[0113] In some embodiments, the FcRH5xCD3 bispecific antibody is cevostamab. Cevostamab is described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Recommended INN: List 84, Vol. 34, No. 3, published September 9, 2020 (see pages 701 - 703). Cevostamab is also known in the art as BFCR4350A or RO7187797, and binds to FcRH5 and CD3, and comprises an anti - FcRH5 arm comprising the heavy - chain polypeptide sequence of SEQ ID NO: 20 and the light - chain polypeptide sequence of SEQ ID NO: 19, and an anti - CD3 arm comprising the heavy - chain polypeptide sequence of SEQ ID NO: 30 and the light - chain polypeptide sequence of SEQ ID NO: 29. It is an Fc - engineered humanized full - length non - glycosylated IgG1 kappa T - cell - dependent bispecific antibody (TDB). Cevostamab contains an amino - acid substitution from threonine to tryptophan (T366W) at position 366 of the heavy chain of the anti - FcRH5 arm using the EU numbering of Fc - region amino - acid residues, and three amino - acid substitutions (from tyrosine to valine at position 407, from threonine to serine at position 366, and from leucine to alanine at position 368) (Y407V, T366S, and L368A) of the heavy chain of the anti - CD3 arm using the EU numbering of Fc - region amino - acid residues, which drive the heterodimerization of the two arms (half - antibodies). Cevostamab also contains an amino - acid substitution (from asparagine to glycine) (N297G) at position 297 of each heavy chain using the EU numbering of Fc - region amino - acid residues, resulting in a non - glycosylated antibody with minimal binding to Fc (Fcγ) receptors and thus interfering with Fc effector functions.

[0114] In some embodiments, an FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens is administered in combination with XmAb24306. In some embodiments, cevostamab is administered in combination with an IL15-IL15Rα heterodimer Fc fusion protein. In some embodiments, cevostamab or a fragment thereof that binds to both antigens is administered in combination with an IL15-IL15Rα heterodimer Fc fusion protein. In some embodiments, cevostamab is administered in combination with XmAb24306. In some embodiments, cevostamab or a fragment thereof that binds to both antigens is administered in combination with XmAb24306.

[0115] An FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens can be administered by any suitable route. In some embodiments, an FxRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered parenterally. In some embodiments, an FxRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered intravenously. In some embodiments, an FxRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered subcutaneously. In some embodiments, cevostamab is administered intravenously. In some embodiments, cevostamab is administered subcutaneously.

[0116] In some embodiments, an FcRH5xCD3 bispecific antibody (e.g., cevostamab) or a fragment thereof that binds to both antigens is administered systemically. In some embodiments, an FcRH5xCD3 bispecific antibody (e.g., cevostamab) or a fragment thereof that binds to both antigens is administered as a composition comprising a pharmaceutically acceptable buffer. Suitable carriers and their formulations are described, for example, in Remington’s Pharmaceutical Sciences by E.W. Martin. In some embodiments, an FcRH5xCD3 bispecific antibody (e.g., cevostamab) or a fragment thereof that binds to both antigens is provided in a dosage form suitable for parenteral (e.g., intravenous) administration.

[0117] The amount of an FcRH5xCD3 bispecific antibody (e.g., cevostamab) or a fragment thereof that binds to both antigens administered in combination with the heterodimeric proteins (or combinations thereof) of the present disclosure will vary depending on the mode of administration, the age and weight of the patient, and the clinical condition of the cancer being treated. A physician can determine the appropriate dosage of an FcRH5xCD3 bispecific antibody (e.g., cevostamab) or a fragment thereof that binds to both antigens for administration in combination with the heterodimeric proteins of the present disclosure.

[0118] In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is from about 0.15 mg to 198 mg. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is from about 132 mg to about 198 mg. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is 132 mg to 198 mg. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is about 132 mg. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is about 132 mg per week. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is about 132 mg every two weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is about 132 mg every three weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is about 132 mg every four weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is about 132 mg every five weeks.

[0119] In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is 132 mg. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is 132 mg per week. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is 132 mg every two weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is 132 mg every three weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is 132 mg every four weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is 132 mg every five weeks.

[0120] In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is about 160 mg. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is about 160 mg per week. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is about 160 mg every two weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is about 160 mg every three weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is about 160 mg every four weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is about 160 mg every five weeks.

[0121] In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is 160 mg. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is 160 mg per week. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is 160 mg every two weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is 160 mg every three weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is 160 mg every four weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is 160 mg every five weeks.

[0122] In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is about 198 mg. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is about 198 mg per week. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is about 198 mg every two weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is about 198 mg every three weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is about 198 mg every four weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is about 198 mg every five weeks.

[0123] In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is 198 mg. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is 198 mg per week. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is 198 mg every two weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is 198 mg every three weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is 198 mg every four weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) is 198 mg every five weeks.

[0124] In some embodiments, the dosage of sevosetamab is from about 0.15 mg to 198 mg. In some embodiments, the dosage of sevosetamab is from about 132 mg to about 198 mg. In some embodiments, the dosage of sevosetamab is 132 mg to 198 mg. In some embodiments, the dosage of sevosetamab is about 132 mg. In some embodiments, the dosage of sevosetamab is about 132 mg per week. In some embodiments, the dosage of sevosetamab is about 132 mg every two weeks. In some embodiments, the dosage of sevosetamab is about 132 mg every three weeks. In some embodiments, the dosage of sevosetamab is about 132 mg every four weeks. In some embodiments, the dosage of sevosetamab is about 132 mg every five weeks.

[0125] In some embodiments, the dosage of sevosetamab is 132 mg. In some embodiments, the dosage of sevosetamab is 132 mg per week. In some embodiments, the dosage of sevosetamab is 132 mg every two weeks. In some embodiments, the dosage of sevosetamab is 132 mg every three weeks. In some embodiments, the dosage of sevosetamab is 132 mg every four weeks. In some embodiments, the dosage of sevosetamab is 132 mg every five weeks.

[0126] In some embodiments, the dosage of sevosetamab is about 160 mg. In some embodiments, the dosage of sevosetamab is about 160 mg per week. In some embodiments, the dosage of sevosetamab is about 160 mg every two weeks. In some embodiments, the dosage of sevosetamab is about 160 mg every three weeks. In some embodiments, the dosage of sevosetamab is about 160 mg every four weeks. In some embodiments, the dosage of sevosetamab is about 160 mg every five weeks.

[0127] In some embodiments, the dosage of sevosumab is 160 mg. In some embodiments, the dosage of sevosumab is 160 mg per week. In some embodiments, the dosage of sevosumab is 160 mg every two weeks. In some embodiments, the dosage of sevosumab is 160 mg every three weeks. In some embodiments, the dosage of sevosumab is 160 mg every four weeks. In some embodiments, the dosage of sevosumab is 160 mg every five weeks.

[0128] In some embodiments, the dosage of sevosumab is about 198 mg. In some embodiments, the dosage of sevosumab is about 198 mg per week. In some embodiments, the dosage of sevosumab is about 198 mg every two weeks. In some embodiments, the dosage of sevosumab is about 198 mg every three weeks. In some embodiments, the dosage of sevosumab is about 198 mg every four weeks. In some embodiments, the dosage of sevosumab is about 198 mg every five weeks.

[0129] In some embodiments, the dosage of sevosumab is 198 mg. In some embodiments, the dosage of sevosumab is 198 mg per week. In some embodiments, the dosage of sevosumab is 198 mg every two weeks. In some embodiments, the dosage of sevosumab is 198 mg every three weeks. In some embodiments, the dosage of sevosumab is 198 mg every four weeks. In some embodiments, the dosage of sevosumab is 198 mg every five weeks.

[0130] In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered daily, i.e., every 24 hours. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered weekly, i.e., once a week (Q1W). In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered once every two weeks, i.e., once every 14 days (Q2W). In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered once every three weeks, i.e., once every 21 days (Q3W). In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered once every four weeks, i.e., once every 28 days (Q4W). In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered once every five weeks (Q5W). In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered once every six weeks (Q6W). In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered once a month. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered intravenously according to the frequencies disclosed herein.

[0131] In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered for 1 cycle or more at any of the above frequencies. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 cycles at any of the above frequencies. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered for 1 cycle or more at a Q1W frequency. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 cycles at a Q1W frequency. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered for 1 cycle or more at a Q2W frequency. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered at 4 cycles at a Q1W frequency. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 cycles at a Q2W frequency. In some embodiments, the FcRH5xCD3 bispecific antibody is administered at 6 cycles at a Q2W frequency. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered for 1 cycle or more at a Q3W frequency. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 cycles at a Q3W frequency.In some embodiments, an FcRH5xCD3 bispecific antibody (e.g., cevostamab) or a fragment thereof that binds to both antigens is administered for one or more cycles at a frequency of Q4W. In some embodiments, an FcRH5xCD3 bispecific antibody (e.g., cevostamab) or a fragment thereof that binds to both antigens is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 cycles at a frequency of Q4W. In some embodiments, each of the cycles is a 28-day cycle.

[0132] In some embodiments, the subject will be administered one or more priming doses of an FcRH5xCD3 bispecific antibody (e.g., cevostamab) or a fragment thereof that binds to both antigens during a pre-stage period prior to the first treatment cycle. In some embodiments, the pre-stage is 7 days. See, for example, FIG. 5. In some embodiments, the priming dose is 3.6 mg. In some embodiments, the priming dose is about 3.6 mg. In some embodiments, the subject is administered two priming doses of an FcRH5xCD3 bispecific antibody (e.g., cevostamab) or a fragment thereof that binds to both antigens. In some embodiments, 3.6 mg of an FcRH5xCD3 bispecific antibody (e.g., cevostamab) or a fragment thereof that binds to both antigens is administered between two priming doses (i.e., the sum of the amount administered in the first priming dose and the amount administered in the second priming dose is 3.6 mg). In some embodiments, about 3.6 mg of an FcRH5xCD3 bispecific antibody (e.g., cevostamab) is administered between two priming doses (i.e., the sum of the amount administered in the first priming dose and the amount administered in the second priming dose is about 3.6 mg). In some embodiments, the first priming dose is administered on day 1 of the pre-stage. In some embodiments, the second priming dose is administered between days 2-4 of the pre-stage. In some embodiments, the minimum interval between the end of the first priming dose and the start of the second priming dose is 20 hours. In some embodiments, the first priming dose is 0.3 mg of an FcRH5xCD3 bispecific antibody (e.g., cevostamab). In some embodiments, the first priming dose is about 0.3 mg of an FcRH5xCD3 bispecific antibody (e.g., cevostamab). In some embodiments, the second priming dose is 3.3 mg of an FcRH5xCD3 bispecific antibody (e.g., cevostamab). In some embodiments, the second priming dose is about 3.3 mg of an FcRH5xCD3 bispecific antibody (e.g., cevostamab).Although not bound by theory, dividing the 3.6 mg dose over consecutive days (0.3 mg and 3.3 mg) is thought to reduce the overall risk of cytokine release syndrome (CRS) during cycle 1 compared to a 3.6 mg dose in a single-dose priming regimen.

[0133] In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered Q2W for the first 24 weeks and then Q4W after the first 24 weeks. In some embodiments, each cycle is a 4-week cycle. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered 6 times in 4-week cycles Q2W and then at the 7th and subsequent 4-week cycles Q4W. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered 6 times in 4-week cycles on days 1 and 15 and then on day 1 of the 7th and subsequent 4-week cycles. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered at a dose of 132 mg. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens is administered at a dose of approximately 132 mg.

[0134] In some embodiments, the patient is administered a first priming dose of an FcRH5xCD3 bispecific antibody (e.g., cevostamab) or a fragment thereof that binds to both antigens on day 1 of the pre-phase, a second priming dose between days 2 - 4 of the pre-phase, and then six times in a 4-week cycle Q2W, as well as on the 7th and subsequent 4-week cycles Q4W. In some embodiments, the patient is administered a first priming dose of an FcRH5xCD3 bispecific antibody (e.g., cevostamab) or a fragment thereof that binds to both antigens on day 1 of the pre-phase, a second priming dose between days 2 - 4 of the pre-phase, and then six times in a 4-week cycle on days 1 and 15, as well as on the 7th and subsequent 4-week cycles on day 1. In some embodiments, the patient is administered a first priming dose of 0.3 mg of an FcRH5xCD3 bispecific antibody (e.g., cevostamab) on day 1 of the pre-phase, a second priming dose of 3.3 mg of an FcRH5xCD3 bispecific antibody (e.g., cevostamab) between days 2 - 4 of the pre-phase, and then a dose of 132 mg of an FcRH5xCD3 bispecific antibody (e.g., cevostamab) six times in a 4-week cycle on days 1 and 15, as well as on the 7th and subsequent 4-week cycles on day 1.

[0135] The IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) can be administered by any suitable route. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered parenterally. In some embodiments, parenteral administration is intravenous administration. In some embodiments, XmAb24306 is administered intravenously.

[0136] In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered systemically. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered as a composition comprising a pharmaceutically acceptable buffer. Suitable carriers and their formulations are described, for example, in Remington’s Pharmaceutical Sciences by E.W. Martin. In some embodiments, the heterodimeric protein is provided in a dosage form suitable for parenteral (e.g., intravenous) administration.

[0137] The amount of IL15-IL15Rα heterodimer Fc fusion protein administered in combination with an FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens will vary depending on the mode of administration, the age and weight of the patient, and the clinical condition of the cancer being treated. A physician will be able to determine the appropriate dosage of the IL15-IL15Rα heterodimer Fc fusion protein to administer in combination with an FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens.

[0138] In certain embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) can vary between about 0.0001 mg of protein / kg to about 5 mg of protein / kg; or about 0.001 mg / kg to about 4 mg / kg, or about 0.005 mg / kg to about 1 mg / kg, or about 0.005 mg / kg to about 0.3 mg / kg, or about 0.005 mg / kg to about 0.2 mg / kg, or about 0.005 mg / kg to about 0.02 mg / kg body weight. In some embodiments, this dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) can be about 0.0001, about 0.00025, about 0.0003, about 0.0005, about 0.001, about 0.003, about 0.005, about 0.008, about 0.01, about 0.015, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 0.12, about 0.135, about 0.15, about 0.16, about 0.2, about 0.2025, about 0.24, about 0.25, about 0.3, about 0.32, about 0.35, about 0.4, about 0.45, about 0.5, about 0.55 or about 0.6 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.0025 mg / kg, about 0.005 mg / kg, about 0.01 mg / kg, about 0.015 mg / kg, about 0.02 mg / kg, about 0.025 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.08 mg / kg, about 0.1 mg / kg, about 0.12 mg / kg, about 0.16 mg / kg, about 0.2 mg / kg, about 0.24 mg / kg and about 0.32 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.0025 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.01 mg / kg body weight.In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.015 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.02 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.03 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.04 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.06 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.08 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.09 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.12 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.135 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.16 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.2025 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.24 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.32 mg / kg body weight.In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at a dosage selected from the group consisting of about 0.01 mg / kg, about 0.02 mg / kg, about 0.04 mg / kg, about 0.06 mg / kg, about 0.09 mg / kg, about 0.135 mg / kg and about 0.2025 mg / kg body weight. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at a dosage selected from the group consisting of about 0.01 mg / kg, about 0.02 mg / kg, about 0.04 mg / kg, about 0.06 mg / kg, about 0.09 mg / kg and about 0.12 mg / kg body weight. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered by IV infusion according to these dosages.

[0139] In certain embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) can vary between 0.0001 mg of protein / kg to 5 mg of protein / kg or 0.001 mg / kg to 4 mg / kg, or 0.005 mg / kg to 1 mg / kg, or 0.005 mg / kg to 0.3 mg / kg, or 0.005 mg / kg to 0.2 mg / kg, or 0.005 mg / kg to 0.02 mg / kg body weight. In some embodiments, this dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) can be 0.0001, 0.0003, 0.0005, 0.001, 0.003, 0.005, 0.008, 0.01, 0.015, 0.02, 0.03, 0.05, 0.08, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55 or 0.6 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is selected from the group consisting of 0.0025 mg / kg, 0.005 mg / kg, 0.01 mg / kg, 0.015 mg / kg, 0.02 mg / kg, 0.025 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.10 mg / kg, 0.12 mg / kg, 0.135 mg / kg, 0.16 mg / kg, 0.20 mg / kg, 0.2025 mg / kg, 0.24 mg / kg and 0.32 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.0025 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.01 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.015 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.02 mg / kg body weight.In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.03 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.04 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein is 0.06 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.08 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.09 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.12 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein is 0.135 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.16 mg / kg. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.2025 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.24 mg / kg body weight. In some embodiments, the dosage of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.32 mg / kg body weight. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at a dosage selected from the group consisting of 0.01 mg / kg, 0.02 mg / kg, 0.04 mg / kg, 0.06 mg / kg, 0.09 mg / kg, 0.135 mg / kg and 0.2025 mg / kg body weight.In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at a dose selected from the group consisting of 0.01 mg / kg, 0.02 mg / kg, 0.04 mg / kg, 0.06 mg / kg, 0.09 mg / kg and 0.12 mg / kg body weight. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered by IV infusion according to these dosages.

[0140] Optionally, the IL15-IL15Rα heterodimer Fc fusion protein is XmAb24306. In some embodiments, the dosage of XmAb24306 is about 0.0025 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is about 0.01 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is about 0.015 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is about 0.02 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is about 0.03 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is about 0.04 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is about 0.06 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is about 0.08 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is about 0.09 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is about 0.12 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is about 0.135 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is about 0.16 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is about 0.2025 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is about 0.24 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is about 0.32 mg / kg body weight. In some embodiments, XmAb24306 is administered at a dosage selected from the group consisting of about 0.01 mg / kg, about 0.02 mg / kg, about 0.04 mg / kg, about 0.06 mg / kg, about 0.09 mg / kg, about 0.135 mg / kg and about 0.2025 mg / kg body weight. In some embodiments, XmAb24306 is administered at a dosage selected from the group consisting of about 0.01 mg / kg, about 0.02 mg / kg, about 0.04 mg / kg, about 0.06 mg / kg, about 0.09 mg / kg and about 0.12 mg / kg body weight. In some embodiments, XmAb24306 is administered by intravenous infusion according to these dosages.

[0141] In some embodiments, the dosage of XmAb24306 is 0.0025 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is 0.01 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is 0.015 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is 0.02 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is 0.03 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is 0.04 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is 0.06 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is 0.08 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is 0.09 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is 0.12 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is 0.135 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is 0.16 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is 0.2025 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is 0.24 mg / kg body weight. In some embodiments, the dosage of XmAb24306 is 0.32 mg / kg body weight. In some embodiments, XmAb24306 is administered at a dosage selected from the group consisting of 0.01 mg / kg, 0.02 mg / kg, 0.04 mg / kg, 0.06 mg / kg, 0.09 mg / kg, 0.135 mg / kg and 0.2025 mg / kg body weight. In some embodiments, XmAb24306 is administered at a dosage selected from the group consisting of 0.01 mg / kg, 0.02 mg / kg, 0.04 mg / kg, 0.06 mg / kg, 0.09 mg / kg and 0.12 mg / kg body weight. In some embodiments, XmAb24306 is administered by IV infusion according to these dosages.

[0142] In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered daily, i.e., every 24 hours. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered once a week, i.e., once every week (Q1W). In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered once every two weeks, i.e., once every 14 days (Q2W). In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered once every three weeks, i.e., once every 21 days (Q3W). In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered once every four weeks, i.e., once every 28 days (Q4W). In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered once every five weeks (Q5W). In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered once every six weeks (Q6W). In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered once a month. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein of the present disclosure (e.g., XmAb24306) is administered by intravenous infusion according to the frequencies disclosed herein.

[0143] In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered one or more cycles at any of the above frequencies. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 cycles at any of the above frequencies. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein is administered one or more cycles at a frequency of Q1W. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 cycles at a frequency of Q1W. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered one or more cycles at a frequency of Q2W. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 cycles at a frequency of Q2W. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered one or more cycles at a frequency of Q3W. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 cycles at a frequency of Q3W. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered one or more cycles at a frequency of Q4W. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 cycles at a frequency of Q4W.

[0144] The IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) disclosed in this specification can be administered Q4W. In some embodiments, the first dose of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at least 24 hours after the first dose of the first cycle of the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or a fragment thereof that binds to both antigens. In some embodiments, the first dose of the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered between the second and fourth days of cycle 1. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered on the first day of cycle 2 and subsequent cycles.

[0145] A fourth aspect of the present disclosure is a method of treating multiple myeloma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of (a) XmAb24306 (wherein XmAb24306 comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10), and (b) cevostamab (wherein cevostamab comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30), wherein XmAb24306 is administered intravenously at a dose of about 0.02 mg / kg to about 0.06 mg / kg, and cevostamab is administered intravenously at a dose of about 132 mg.

[0146] A fifth aspect of the present disclosure is for the manufacture of one or more medicaments for treating multiple myeloma in a subject in need of treatment for multiple myeloma, a therapeutically effective amount of (a) XmAb24306 (wherein XmAb24306 comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10), and (b) cevostamab (wherein cevostamab comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30), wherein XmAb24306 is administered intravenously at a dose of about 0.02 mg / kg to about 0.06 mg / kg and cevostamab is administered intravenously at a dose of about 132 mg, provided.

[0147] A sixth aspect of the present disclosure is a therapeutically effective amount of (a) XmAb24306 (wherein XmAb24306 comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10), and (b) cevostamab (wherein cevostamab comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30) for use in treating multiple myeloma in a subject in need of treatment for multiple myeloma, wherein XmAb24306 is administered intravenously at a dose of about 0.02 mg / kg to about 0.06 mg / kg and cevostamab is administered intravenously at a dose of about 132 mg, providing XmAb24306 and cevostamab.

[0148] In some embodiments, the subject has been previously administered one or more priming doses of sevosumab at a total dose of about 3.6 mg, and the priming dose is administered as a single dose. In some embodiments, the subject has been previously administered one or more priming doses of sevosumab at a total dose of about 3.6 mg, and the priming dose is administered as two doses. In some embodiments, the first priming dose is about 0.3 mg and the second priming dose is about 3.3 mg. In some embodiments, the first priming dose is administered on day 1 and the second priming dose is administered on day 2, 3, or 4.

[0149] In some embodiments, XmAb24306 is administered for one or more cycles at a frequency of Q4W.

[0150] In some embodiments, sevosumab is administered for one or more cycles at a frequency of Q2W. In some embodiments, sevosumab is administered for one or more cycles at a frequency of Q4W.

[0151] In some embodiments, XmAb24306 is administered intravenously at least 7 times in a 4-week cycle at a frequency of Q4W. The first priming dose of 0.3 mg of sevosumab is administered intravenously on day 1 of the previous stage. The second priming dose of 3.3 mg of sevosumab is administered intravenously between days 2 and 4 of the previous stage. The previous stage is 7 days. Thereafter, it is administered intravenously at a dose of 132 mg of sevosumab 6 times in a 4-week cycle on days 1 and 15, and on day 1 of the 7th and subsequent 4-week cycles.

[0152] A seventh aspect of the present disclosure is a method of treating multiple myeloma in a subject in need of treatment for multiple myeloma, the method comprising administering to the subject a therapeutically effective amount of (a) XmAb24306 (wherein XmAb24306 comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10), and (b) sevosumab (wherein sevosumab comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30), wherein XmAb24306 is intravenously administered at a dose of about 0.02 mg / kg to about 0.06 mg / kg, at a frequency of Q4W, for at least 7 times in a 4-week cycle, a first priming dose of 0.3 mg of sevosumab is intravenously administered on day 1 of the previous stage, a second priming dose of 3.3 mg of sevosumab is intravenously administered between days 2 to 4 of the previous stage, the previous stage is 7 days, and thereafter, at a dose of 132 mg of sevosumab, it is intravenously administered 6 times in a 4-week cycle on days 1 and 15, and on day 1 of the 7th and subsequent 4-week cycles, thereby providing a method.

[0153] The eighth aspect of the present disclosure is the use of a therapeutically effective amount of (a) XmAb24306 (wherein XmAb24306 comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10), and (b) cevostamab (wherein cevostamab comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30) in the manufacture of one or more medicaments for treating multiple myeloma in a subject in need of treatment for multiple myeloma, wherein XmAb24306 is intravenously administered at a dose of about 0.02 mg / kg to about 0.06 mg / kg, at a frequency of Q4W, for at least 7 times in a 4-week cycle, a first priming dose of 0.3 mg of cevostamab is intravenously administered on day 1 of the previous stage, a second priming dose of 3.3 mg of cevostamab is intravenously administered between days 2 to 4 of the previous stage, the previous stage is 7 days, and thereafter, at a dose of 132 mg of cevostamab, it is intravenously administered 6 times in a 4-week cycle on days 1 and 15, and on day 1 of the 7th and subsequent 4-week cycles, to provide the use.

[0154] A ninth aspect of the present disclosure is a therapeutically effective amount of (a) XmAb24306 (wherein XmAb24306 comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10), and (b) cevostamab (wherein cevostamab comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30) for use in treating multiple myeloma in a subject in need of treatment for multiple myeloma, wherein XmAb24306 is administered intravenously at a dose of about 0.02 mg / kg to about 0.06 mg / kg, at a frequency of Q4W, for at least 7 times in a 4-week cycle, a first priming dose of 0.3 mg of cevostamab is administered intravenously on day 1 of the previous stage, a second priming dose of 3.3 mg of cevostamab is administered intravenously between days 2 to 4 of the previous stage, the previous stage is 7 days, and thereafter, at a dose of 132 mg of cevostamab, 6 times in a 4-week cycle on days 1 and 15, and on day 1 of the 7th and subsequent 4-week cycles, is provided with XmAb24306 and cevostamab.

[0155] In any of the above methods, the IL15-IL15Rα heterodimer Fc fusion protein disclosed herein (e.g., XmAb24306) can be administered simultaneously or sequentially with an FcRH5xCD3 bispecific antibody (e.g., cevostamab) that binds to both antigens or a fragment thereof. In some embodiments of any of the above methods, the IL15-IL15Rα heterodimer Fc fusion protein disclosed herein (e.g., XmAb24306) and an FcRH5xCD3 bispecific antibody (e.g., cevostamab) that binds to both antigens or a fragment thereof are administered simultaneously. In some embodiments of any of the above methods, the IL15-IL15Rα heterodimer Fc fusion protein disclosed herein (e.g., XmAb24306) and an FcRH5xCD3 bispecific antibody (e.g., cevostamab) that binds to both antigens or a fragment thereof are administered sequentially. In some embodiments of any of the above methods, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) that binds to both antigens or a fragment thereof is administered after the IL15-IL15Rα heterodimer Fc fusion protein disclosed herein (e.g., XmAb24306) has been administered. In some embodiments of any of the above methods, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) that binds to both antigens or a fragment thereof is administered before the IL15-IL15Rα heterodimer Fc fusion protein disclosed herein (e.g., XmAb24306) is administered. In some embodiments of any of the above methods, the IL15-IL15Rα heterodimer Fc fusion protein disclosed herein (e.g., XmAb24306) and an FcRH5xCD3 bispecific antibody (e.g., cevostamab) that binds to both antigens or a fragment thereof are administered in the same composition. In some embodiments of any of the above methods, the IL15-IL15Rα heterodimer Fc fusion protein disclosed herein (e.g., XmAb24306) is administered in a composition different from the FcRH5xCD3 bispecific antibody (e.g., cevostamab) that binds to both antigens or a fragment thereof.

[0156] In some embodiments of any of the above methods, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) disclosed herein and the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens may act synergistically. In some embodiments of any of the above methods, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) may be administered at a dose less than its therapeutically effective dose when administered as a monotherapy. In some embodiments of any of the above methods, the FcRH5xCD3 bispecific antibody (e.g., cevostamab) or fragment thereof that binds to both antigens may be administered at a dose less than its therapeutically effective dose when administered as a monotherapy.

[0157] In some embodiments of any of the above methods, the method further comprises administering a corticosteroid to the subject. In some embodiments, the corticosteroid is administered to a subject having signs or symptoms of CRS. CRS symptoms can be progressive and must include fever at onset, and can include hypotension, capillary leak (hypoxia), and end-organ dysfunction. Fever should cause a temperature of 38°C or higher (100.4°F) and can be prolonged (e.g., for more than 4 hours, e.g., more than 6 hours). In some embodiments, the corticosteroid is administered intravenously. In some embodiments, the corticosteroid is dexamethasone. In some embodiments, dexamethasone is administered at a dose of 10 mg. In some embodiments, 10 mg of dexamethasone is administered intravenously every 6 hours.

[0158] In some embodiments of any of the above methods, the method further comprises administering a therapeutically effective amount of tocilizumab. Tocilizumab (Actemra® / RoActemra®) is a recombinant humanized anti-human monoclonal antibody against soluble and membrane-bound IL-6R that inhibits IL-6-mediated signaling. New evidence implicates IL-6 as a central mediator of CRS. Thus, without being bound by theory, using tocilizumab to block the inflammatory effects of IL-6 represents an effective approach for the treatment of CRS. Indeed, the US Food and Drug Administration has approved tocilizumab for the treatment of severe or life-threatening CAR-T cell-induced CRS in adult and pediatric patients 2 years of age and older. However, recent literature supports the use of tocilizumab in all grades of CRS (Neelapu et al. 2018; Riegler et al. 2019). Thus, patients treated with an FcRH5xCD3 bispecific antibody (e.g., cevostamab) who develop CRS may benefit from tocilizumab therapy.

[0159] In some embodiments of any of the above methods, tocilizumab is administered to a subject who has experienced a CRS event. In some embodiments of any of the above methods, tocilizumab is administered to a subject who remains refractory to corticosteroids 24 hours after the first corticosteroid administration. In some embodiments of any of the above methods, tocilizumab is administered at a dose of 8 mg / kg. In some embodiments of any of the above methods, tocilizumab is administered at a dose of 12 mg / kg. In some embodiments of any of the above methods, tocilizumab is administered at a dose of 8 mg / kg if the patient's weight is ≥30 kg. In some embodiments of any of the above methods, tocilizumab is administered at a dose of 12 mg / kg if the patient's weight is less than 30 kg. In some embodiments of any of the above methods, tocilizumab is administered intravenously. In some embodiments, tocilizumab is administered every 8 hours.

[0160] In some embodiments of any of the above methods, the subject has previously been administered an agent for the treatment of a blood cancer. In some embodiments of any of the above methods, the subject has previously been administered one or more pretreatment regimens for the treatment of a blood cancer. In some embodiments of any of the above methods, the subject has previously been administered one pretreatment regimen. In some embodiments of any of the above methods, the subject has previously been administered two pretreatment regimens. In some embodiments of any of the above methods, the subject has previously been administered three pretreatment regimens. In some embodiments of any of the above methods, the subject has previously been administered four pretreatment regimens. In some embodiments, the subject has previously been administered five pretreatment regimens. In some embodiments of any of the above methods, the pretreatment regimen administered to the subject is an immunomodulatory agent, a proteasome inhibitor, an anti-CD38 monoclonal antibody, or a combination thereof. In some embodiments of any of the above methods, the subject has previously been administered at least three pretreatment regimens comprising at least one immunomodulatory agent, a proteasome inhibitor, or an anti-CD38 monoclonal antibody. In some embodiments of any of the above methods, the subject has previously been administered at least three pretreatment regimens comprising at least one immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. In some embodiments, the pretreatment regimen administered to the subject is an immunomodulatory agent. In some embodiments of any of the above methods, the immunomodulatory agent is selected from the group consisting of lenalidomide, thalidomide, and pomalidomide. In some embodiments of any of the above methods, the immunomodulatory agent is lenalidomide. In some embodiments of any of the above methods, the immunomodulatory agent is thalidomide. In some embodiments of any of the above methods, the immunomodulatory agent is pomalidomide. In some embodiments of any of the above methods, the pretreatment regimen administered to the subject is a proteasome inhibitor. In some embodiments of any of the above methods, the proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib, and ixazomib.In some embodiments of any of the above methods, the proteasome inhibitor is selected from the group consisting of bortezomib. In some embodiments of any of the above methods, the proteasome inhibitor is selected from the group consisting of carfilzomib. In some embodiments of any of the above methods, the proteasome inhibitor is selected from the group consisting of ixazomib. In some embodiments of any of the above methods, the pretreatment administered to the subject is an anti-CD38 monoclonal antibody. In some embodiments of any of the above methods, the anti-CD38 monoclonal antibody is selected from the group consisting of daratumumab, isatuximab, mezigitamab (TAK-079), and felzartamab (MOR202). In some embodiments of any of the above methods, the anti-CD38 monoclonal antibody is daratumumab. In some embodiments of any of the above methods, the anti-CD38 monoclonal antibody is isatuximab. In some embodiments of any of the above methods, the anti-CD38 monoclonal antibody is mezigitamab. In some embodiments of any of the above methods, the anti-CD38 monoclonal antibody is felzartamab.

[0161] Exemplary embodiments Certain embodiments of the present disclosure are set forth in the paragraphs numbered below. 1. A method of treating a blood cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of (a) an IL15-IL15Rα heterodimer Fc fusion protein and (b) an FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens. 2. Use of a therapeutically effective amount of (a) an IL15-IL15Rα heterodimer Fc fusion protein and (b) an FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens in the manufacture of one or more medicaments for treating a blood cancer in a subject in need thereof. 3. A therapeutically effective amount of (a) an IL15-IL15Rα heterodimer Fc fusion protein and (b) an FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens for use in the treatment of blood cancer in a subject in need of treatment for blood cancer. 4. The method according to embodiment 1, the use according to embodiment 2, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 3, wherein the IL15-IL15Rα heterodimer Fc fusion protein comprises: (a) a first fusion protein comprising an interleukin-15 (IL-15) protein covalently attached to the N-terminus of a first Fc domain via a first domain linker, the IL-15 protein comprising the amino acid sequence of SEQ ID NO: 5, and the first Fc domain being a variant of the human IgG1 Fc domain; and (b) a second fusion protein comprising an IL-15 receptor alpha (IL-15Rα) protein fragment covalently attached to the N-terminus of a second Fc domain via a second domain linker, the IL-15Rα protein comprising the amino acid sequence of SEQ ID NO: 4, and the second Fc domain being a variant of the human IgG1 Fc domain. 5. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 4, wherein the IL15-IL15Rα heterodimer Fc fusion protein comprises: (a) a first fusion protein comprising an interleukin-15 (IL-15) protein covalently attached to the N-terminus of a first Fc domain via a first domain linker, the IL-15 protein comprising the amino acid sequence of SEQ ID NO: 5, and the first Fc domain comprising the amino acid sequence of SEQ ID NO: 6; and (b) a second fusion protein comprising an IL-15 receptor alpha (IL-15Rα) protein fragment covalently attached to the N-terminus of a second Fc domain via a second domain linker, the IL-15Rα protein comprising the amino acid sequence of SEQ ID NO: 4, and the second Fc domain comprising the amino acid sequence of SEQ ID NO: 7. 6. The method according to any one of embodiments 4 to 5, the use according to any one of embodiments 4 to 5, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 4 to 5, wherein the first domain linker comprises the amino acid sequence of SEQ ID NO: 8. 7. The method according to any one of embodiments 4 to 6, the use according to any one of embodiments 4 to 6, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 4 to 6, wherein the second domain linker comprises the amino acid sequence of SEQ ID NO: 8. 8. The method according to any one of embodiments 4 to 7, the use according to any one of embodiments 4 to 7, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 4 to 7, wherein the first domain linker comprises the amino acid sequence of SEQ ID NO: 8 and the second domain linker comprises the amino acid sequence of SEQ ID NO: 8. 9. The method according to any one of embodiments 4 to 8, the use according to any one of embodiments 4 to 8, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 4 to 8, wherein the first fusion protein comprises the amino acid sequence of SEQ ID NO: 9. 10. The method according to any one of embodiments 4 to 9, the use according to any one of embodiments 4 to 9, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 4 to 9, wherein the second fusion protein comprises the amino acid sequence of SEQ ID NO: 10. 11. The method according to any one of embodiments 1 and 4 to 10, the use according to any one of embodiments 2 and 4 to 10, or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 10, wherein the heterodimeric protein comprises a first fusion protein comprising the amino acid sequence shown in SEQ ID NO: 9 and a second fusion protein comprising the amino acid sequence shown in SEQ ID NO: 10. 12. The method according to any one of embodiments 1 and 4 to 11, the use according to any one of embodiments 2 and 4 to 11, or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 11, wherein the IL15-IL15Rα heterodimeric Fc fusion protein is XmAb24306. 13. The method according to any one of embodiments 1 and 4 to 12, the use according to any one of embodiments 2 and 4 to 12, or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 12, wherein the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens comprises an anti-FcRH5 light chain variable region, an anti-FcRH5 heavy chain variable region, an anti-CD3 light chain variable region, and an anti-CD3 heavy chain variable region. 14. The method, use, or IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 13, wherein the anti-FcRH5 light chain variable region comprises a complementarity-determining region-1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 11, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 12, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 13; and the anti-FcRH5 heavy chain variable region comprises a complementarity-determining region-1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 14, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 16. 15. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 13 or 14, wherein the anti-FcRH5 light chain variable region comprises the amino acid sequence of SEQ ID NO: 17. 16. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 13 to 15, wherein the anti-FcRH5 heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 18. 17. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 13 to 16, wherein the anti-FcRH5 light chain comprises the amino acid sequence of SEQ ID NO: 19. 18. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 13 to 17, wherein the anti-FcRH5 heavy chain comprises the amino acid sequence of SEQ ID NO: 20. 19. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 13 to 18, wherein the anti-CD3 light chain variable region comprises complementarity-determining region-1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 21, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 22, and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 23; and the anti-CD3 heavy chain variable region comprises complementarity-determining region-1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 24, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 25, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 26. 20. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 19, wherein the anti-CD3 light chain variable region comprises the amino acid sequence of SEQ ID NO: 27. 21. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 19 or 20, wherein the anti-CD3 heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 28. 22. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 19 to 21, wherein the anti-CD3 light chain comprises the amino acid sequence of SEQ ID NO: 29. 23. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 19 to 22, wherein the anti-CD3 heavy chain comprises the amino acid sequence of SEQ ID NO: 30. 24. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 19 to 23, wherein the anti-FcRH5 light chain variable region comprises the amino acid sequence of SEQ ID NO: 17; the anti-FcRH5 heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 18; the anti-CD3 light chain variable region comprises the amino acid sequence of SEQ ID NO: 27; and the anti-CD3 heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 28. 25. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 19 to 24, wherein the anti-FcRH5 light chain comprises the amino acid sequence of SEQ ID NO: 19; the anti-FcRH5 heavy chain comprises the amino acid sequence of SEQ ID NO: 20; the anti-CD3 light chain comprises the amino acid sequence of SEQ ID NO: 29; and the anti-CD3 heavy chain comprises the amino acid sequence of SEQ ID NO: 30. 26. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 19 to 25, wherein the FcRH5xCD3 bispecific antibody is cevostamab. 27. The method according to any one of embodiments 1 and 4 to 26, the use according to any one of embodiments 2 and 4 to 26, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 26, wherein the blood cancer is selected from the group consisting of leukemia, acute myeloid leukemia, adult acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, non-Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, and multiple myeloma. 28. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 27, wherein the blood cancer is multiple myeloma. 29. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 28, wherein the multiple myeloma is relapsed or refractory multiple myeloma. 30. The method according to any one of embodiments 1 and 4 to 29, the use according to any one of embodiments 2 and 4 to 29, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 29, wherein the subject has been previously administered one or more prior treatments. 31. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 30, wherein the prior treatment is an immunomodulatory agent, a proteasome inhibitor, or an anti-CD38 monoclonal antibody. 32. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 31, wherein the immunomodulatory agent is selected from the group consisting of lenalidomide, thalidomide, and pomalidomide. 33. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 31, wherein the proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib, and ixazomib. 34. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 31, wherein the anti-CD38 monoclonal antibody is selected from the group consisting of daratumumab, isatuximab, mezigitamab, and ferzalizumab. 35. The method according to any one of embodiments 1 and 4 to 33, the use according to any one of embodiments 2 and 4 to 34, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 34, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered at a dose selected from the group consisting of about 0.0025 mg / kg, about 0.005 mg / kg, about 0.01 mg / kg, about 0.015 mg / kg, about 0.02 mg / kg, about 0.025 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.08 mg / kg, about 0.1 mg / kg, about 0.12 mg / kg, about 0.16 mg / kg, about 0.2 mg / kg, about 0.24 mg / kg, and about 0.32 mg / kg body weight. 36. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 35, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered at a dose selected from the group consisting of about 0.01 mg / kg, about 0.02 mg / kg, about 0.04 mg / kg, about 0.06 mg / kg, about 0.09 mg / kg, and about 0.12 mg / kg body weight. 37. The method according to any one of embodiments 1 and 4 to 36, the use according to any one of embodiments 2 and 4 to 36, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 36, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered at a dose selected from the group consisting of 0.0025 mg / kg, 0.005 mg / kg, 0.01 mg / kg, 0.015 mg / kg, 0.02 mg / kg, 0.025 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.08 mg / kg, 0.10 mg / kg, 0.16 mg / kg, 0.20 mg / kg, 0.24 mg / kg and 0.32 mg / kg body weight. 38. The method, use according to embodiment 36, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 38, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered at a dose selected from the group consisting of 0.01 mg / kg, 0.02 mg / kg, 0.04 mg / kg, 0.06 mg / kg, 0.09 mg / kg and 0.12 mg / kg body weight. 39. The method according to any one of embodiments 1 and 4 to 38, the use according to any one of embodiments 2 and 4 to 38, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 38, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered at a frequency selected from the group consisting of Q1W, Q2W, Q3W, Q4W, Q5W and Q6W. 40. The method, use according to embodiment 39, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered at a frequency of Q1W for one or more cycles. 41. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 39, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered at least one cycle at a frequency of Q2W. 42. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 39, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered at least one cycle at a frequency of Q4W. 43. The method according to any one of embodiments 1 and 4 to 42, the use according to any one of embodiments 2 and 4 to 42, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 42, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered intravenously. 44. The method according to any one of embodiments 1 and 4 to 43, the use according to any one of embodiments 2 and 4 to 43, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 43, wherein the IL15-IL15Rα heterodimer Fc fusion protein and the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens are administered simultaneously. 45. The method according to any one of embodiments 1 and 4 to 43, the use according to any one of embodiments 2 and 4 to 43, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 43, wherein the IL15-IL15Rα heterodimer Fc fusion protein and the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens are administered continuously. 46. The method according to any one of embodiments 1 and 4 to 45, the use according to any one of embodiments 2 and 4 to 43, or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 43, wherein the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens is administered one or more cycles at a frequency selected from the group consisting of Q1W, Q2W, Q3W, Q4W, Q5W and Q6W. 47. The method, use, or IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 46, wherein the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens is administered one or more cycles at a frequency of Q2W. 48. The method, use, or IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 47, wherein the IL15-IL15Rα heterodimeric Fc fusion protein is administered at a frequency of Q4W, and the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens is administered one or more cycles at a frequency of Q2W. 49. The method, use, or IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 46, wherein the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens is administered one or more cycles at a frequency of Q4W. 50. The method, use, or IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 40 to 49, wherein each of one or more cycles is a 4-week cycle. 51. The method, use, or IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 50, wherein the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens is administered in 6 four-week cycles at Q2W and in the 7th and subsequent four-week cycles at Q4W. 52. The method, use, or IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 51, wherein the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens is administered 6 times at 4-week cycles on days 1 and 15, and on the 7th day and the 1st day of subsequent 4-week cycles. 53. The method according to any one of embodiments 1 and 4-52, the use according to any one of embodiments 2 and 4-52, or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3-52, wherein the FcRH5xCD3 bispecific antibody is administered at a dose of about 132 mg to about 198 mg. 54. The method, use, or IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 53, wherein the FcRH5xCD3 bispecific antibody is administered at a dose of about 132 mg. 55. The method, use, or IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 54, wherein the FcRH5xCD3 bispecific antibody is administered at a dose of about 132 mg at a frequency of Q2W for one or more 28-day cycles. 56. The method, use, or IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 53, wherein the FcRH5xCD3 bispecific antibody is administered at a dose of about 160 mg. 57. The method, use, or IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 53, wherein the FcRH5xCD3 bispecific antibody is administered at a dose of about 198 mg. 58. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 46 to 57, wherein one or more priming doses of the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens are administered to the subject during a pre-stage prior to the first treatment cycle. 59. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 58, wherein the pre-stage is 7 days. 60. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 58 or 59, wherein the priming dose of the FcRH5xCD3 bispecific antibody is about 3.6 mg. 61. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 58 to 60, wherein two priming doses of the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens are administered to the subject. 62. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 61, wherein the first priming dose is administered on day 1 of the pre-stage. 63. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 62, wherein the second priming dose is administered between days 2 to 4 of the pre-stage. 64. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 61 to 63, wherein the minimum interval between the end of the first priming dose and the start of the second priming dose is 20 hours. 65. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 61-64, wherein an FcRH5xCD3 bispecific antibody of about 3.6 mg is administered between two priming doses. 66. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 65, wherein the first priming dose is about 0.3 mg and the second priming dose is about 3.3 mg. 67. The method according to any one of embodiments 1 and 4-55 and 58-66, the use according to any one of embodiments 2 and 4-55 and 58-66, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3-55 and 58-66, wherein the subject is administered a first priming dose of about 0.3 mg of the FcRH5xCD3 bispecific antibody on day 1 of the previous stage, a second priming dose of about 3.3 mg of the FcRH5xCD3 bispecific antibody between days 2-4 of the previous stage, and then a dose of about 132 mg of the FcRH5xCD3 bispecific antibody on days 1 and 15 of 6 four-week cycles, and on day 1 of the 7th and subsequent four-week cycles. 68. The method according to any one of embodiments 1 and 4-67, the use according to any one of embodiments 2 and 4-67, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3-67, wherein the FcRH5xCD3 bispecific antibody is administered intravenously. 69. The method according to any one of embodiments 1 and 4-68, the use according to any one of embodiments 2 and 4-68, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3-68, wherein the method further comprises administering to the subject a therapeutically effective amount of tocilizumab. 70. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 69, wherein the subject is suffering from a cytokine release syndrome (CRS) event. 71. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 69 or 70, wherein tocilizumab is administered to a subject who remains refractory to corticosteroids 24 hours after the first corticosteroid administration. 72. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 69-71, wherein tocilizumab is administered at a dose of 8 mg / kg. 73. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 72, wherein tocilizumab is administered at a dose of 8 mg / kg when the subject's weight is ≧30 kg. 74. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 69-71, wherein tocilizumab is administered at a dose of 12 mg / kg. 75. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 74, wherein tocilizumab is administered at a dose of 12 mg / kg when the patient's weight is <30 kg. 76. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 69-75, wherein tocilizumab is administered intravenously. 77. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 69 to 76, wherein tocilizumab is administered every 8 hours. 78. A method of treating multiple myeloma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of (a) XmAb24306 (wherein XmAb24306 comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10), and (b) sevosumab (wherein sevosumab comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30), wherein XmAb24306 is administered intravenously at a dose of about 0.02 mg / kg to about 0.06 mg / kg, and sevosumab is administered intravenously at a dose of about 132 mg. 79. Use of a therapeutically effective amount of (a) XmAb24306 (wherein XmAb24306 comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10), and (b) sevosumab (wherein sevosumab comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30) in the manufacture of one or more medicaments for treating multiple myeloma in a subject in need thereof, wherein XmAb24306 is formulated to be administered intravenously at a dose of about 0.02 mg / kg to about 0.06 mg / kg, and sevosumab is formulated to be administered intravenously at a dose of about 132 mg. 80. For use in treating multiple myeloma in a subject in need of treatment for multiple myeloma, a therapeutically effective amount of (a) XmAb24306 (wherein XmAb24306 comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10), and (b) cevostamab (wherein cevostamab comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30), wherein XmAb24306 is administered intravenously at a dose of about 0.02 mg / kg to about 0.06 mg / kg, and cevostamab is administered intravenously at a dose of about 132 mg, XmAb24306 and cevostamab. 81. The method according to embodiment 78, the use according to embodiment 79, or XmAb24306 and cevostamab according to embodiment 80, wherein the treatment further comprises administering to the subject one or more priming doses of cevostamab at a total dose of about 3.6 mg during the pre-phase of 7 days before the first treatment cycle, and the priming dose is administered as a single dose. 82. The method according to embodiment 78, the use according to embodiment 79, or XmAb24306 and cevostamab according to embodiment 80, wherein the treatment further comprises administering to the subject one or more priming doses of cevostamab at a total dose of about 3.6 mg during the pre-phase of 7 days before the first treatment cycle, and the priming dose is administered as two doses. 83. The method, use or XmAb24306 and cevostamab according to embodiment 82, wherein the first priming dose is about 0.3 mg and the second priming dose is about 3.3 mg. 84. The method, use or XmAb24306 and cevostamab according to embodiment 83, wherein the first priming dose is administered on day 1 of the pre-phase and the second priming dose is administered on day 2, 3 or 4 of the pre-phase. 85. The method according to any one of embodiments 78 and 81-84, the use according to any one of embodiments 79 and 81-84, or XmAb24306 and cevostamab according to any one of embodiments 80-84, wherein XmAb24306 is administered at a frequency of Q4W for one or more cycles. 86. The method according to any one of embodiments 78 and 81-85, the use according to any one of embodiments 79 and 81-85, or XmAb24306 and cevostamab according to any one of embodiments 80-85, wherein cevostamab is administered at a frequency of Q2W for one or more cycles. 87. The method according to any one of embodiments 78 and 81-86, the use according to any one of embodiments 79 and 81-86, or XmAb24306 and cevostamab according to any one of embodiments 80-86, wherein cevostamab is administered at a frequency of Q4W for one or more cycles. 88. The method according to any one of embodiments 78 and 81-87, the use according to any one of embodiments 79 and 81-87, or XmAb24306 and cevostamab according to any one of embodiments 80-87, wherein XmAb24306 is administered intravenously at a frequency of Q4W for at least 7 four-week cycles, the first priming dose of 0.3 mg of cevostamab is administered intravenously on the first day of the previous stage, the second priming dose of 3.3 mg of cevostamab is administered intravenously between the 2nd and 4th days of the previous stage, the previous stage is 7 days, and thereafter, at a dose of 132 mg of cevostamab, it is administered intravenously on days 1 and 15 of 6 four-week cycles, on the 7th day and the first day of subsequent four-week cycles. 89. A method of treating multiple myeloma in a subject in need of treatment for multiple myeloma, the method comprising administering to the subject a therapeutically effective amount of (a) XmAb24306 (wherein XmAb24306 comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10), and (b) cevostamab (wherein cevostamab comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30), wherein XmAb24306 is administered intravenously at a dose of about 0.02 mg / kg to about 0.06 mg / kg, at a frequency of Q4W, in at least 7 four-week cycles, a first priming dose of 0.3 mg of cevostamab is administered intravenously on day 1 of the previous stage, a second priming dose of 3.3 mg of cevostamab is administered intravenously between days 2 to 4 of the previous stage, the previous stage is 7 days, and thereafter, at a dose of 132 mg of cevostamab, on days 1 and 15 of 6 four-week cycles, and on day 1 of the 7th and subsequent four-week cycles, intravenously administered. 90. Use of a therapeutically effective amount of (a) XmAb24306 (wherein XmAb24306 comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10), and (b) cevostamab (wherein cevostamab comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30) in the manufacture of one or more medicaments for treating multiple myeloma in a subject in need thereof, wherein XmAb24306 is formulated to be administered intravenously at a dose of about 0.02 mg / kg to about 0.06 mg / kg, at a frequency of Q4W, in at least 7 four-week cycles, and cevostamab is formulated to be administered intravenously at a dose of 132 mg on days 1 and 15 of 6 four-week cycles, and on day 1 of the 7th and subsequent four-week cycles; the treatment further comprising a 7-day pre-phase in which a first priming dose of 0.3 mg of cevostamab is administered intravenously on day 1 of the pre-phase, and a second priming dose of 3.3 mg of cevostamab is administered intravenously between days 2 and 4 of the pre-phase. For use in treating multiple myeloma in a subject in need of treatment for multiple myeloma, a therapeutically effective amount of (a) XmAb24306 (wherein XmAb24306 comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10), and (b) cevostamab (wherein cevostamab comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30), wherein XmAb24306 is intravenously administered at a dose of about 0.02 mg / kg to about 0.06 mg / kg, at a frequency of Q4W, for at least 7 times in a 4-week cycle, a first priming dose of 0.3 mg of cevostamab is intravenously administered on day 1 of the previous stage, a second priming dose of 3.3 mg of cevostamab is intravenously administered between days 2 to 4 of the previous stage, the previous stage is 7 days, and thereafter, at a dose of 132 mg of cevostamab, it is intravenously administered 6 times at a 4-week cycle on days 1 and 15, and on day 1 of the 7th and subsequent 4-week cycles, XmAb24306 and cevostamab.

Example

[0162] Example 1: In vitro pharmacological activity of the combination therapy of cevostamab with XmAb24306 Frozen vials of bone marrow mononuclear cells (BMMCs) from subjects with multiple myeloma were purchased from Discovery Life Sciences. The samples were thawed according to the manufacturer's instructions. The samples were cultured overnight in RPMI containing 10% fetal calf serum (FCS) containing 100 ng / mL of recombinant human IL-6. Viable BMMCs were isolated by Ficoll density gradient centrifugation. 3×10 5Individual viable cells were pretreated with 10 mg / mL of XmAb24306 for 24 hours, and then 15 ng / mL of sevastamab was added for combination treatment, or medium as a single-agent treatment in a 96-well plate. The treatment was continued for an additional 72 hours. At the end of the treatment, the cells were harvested and myeloma cell lysis was quantified by flow cytometry analysis. Quantification of the absolute cell number was determined using CountBright™ Absolute Counting Beads (ThermoFisher Scientific, #C36950). Multiple myeloma tumor cells were defined as CD38 高 CD138 + . The killing activity was calculated as follows: {(number of live target cells without treatment - number of live target cells with treatment) / (number of live target cells without treatment)} × 100%.

[0163] The in vitro pharmacological activity of the combination of sevastamab with XmAb24306 was evaluated. Primary BMMCs from multiple myeloma (MM) subjects (n = 3) with a ratio of autologous CD8 + T cells: tumor cells varying from 0.1:1 to 2:1 were treated. The effect of treatment with either XmAb24306 alone or sevastamab alone was compared with the effect of treatment with the combination of XmAb24306a and sevastamab. Treatment with sevastamab alone showed 10% - 40% tumor cell lysis (Figure 1B) without changing the number of CD8 + T cells (Figure 1A) at 15 ng / mL. Treatment with 10 mg / mL of XmAb24306 slightly increased the number of CD8 + T cells (Figure 1A) with minimal tumor cell lysis (Figure 1B). Concurrent treatment with both XmAb24306 and sevastamab synergistically increased the number of CD8 + T cells (Figure 1A), resulting in a synergistic enhancement of sevastamab-mediated target cell killing (Figure 1B).

[0164] Human peripheral blood mononuclear cells (PBMCs) were isolated from the whole blood of healthy donors by Ficoll gradient. Co-cultures of PBMCs and multiple myeloma cell lines (e.g., MOLP-2 cells) were prepared at a ratio of 3:1 in 96-well plates in the presence or absence of 5000 pM of sevosetamab for 30 minutes, 2 hours, 4 hours, 24 hours, and 48 hours. At the end of the incubation, the cells were harvested and stained with surface markers as follows: CD3-BV421, CD4-APC-Cy7, CD8-BUV395, CD56-APC, CD122-PE, CD25-FITC, and CD69-PE-Cy7. CD4 + T cells, CD8 + The expression levels of CD69, CD25, and CD122 on CD4

[0165] The expression of CD69, CD25, and CD122 on T cells and natural killer (NK) cells upon sevosetamab treatment was evaluated by co-culturing human PBMCs and MOLP-2 cells in the presence or absence of sevosetamab (Figures 2A - 2C). MOLP-2 was identified as a benchmark cell line that expresses FcRH5 at levels similar to plasma cells and MM tumor cells (Li et al. 2017). The expression of CD69 (an early T cell activation marker) was detectable on both CD4 + T cells and CD8 + T cells after 4 hours of sevosetamab treatment and reached peak levels at 24 hours (Figure 2A). The CD25 expression level increased in both CD4 + T cells and CD8 + T cells after 24 hours of treatment (Figure 2B). No significant changes in CD69 or CD25 were observed in NK cells after treatment (Figures 2A and 2B). CD122 was expressed at low levels in unstimulated peripheral blood CD4 + T cells and CD8 + T cells. Stimulation of T cells with 5000 pM of sevosetamab increased CD122 expression in both CD4 + T cells and CD8 +The expression of CD122 was induced on T cells for 24 - 48 hours, but it had little effect on NK cells that express high levels of CD122 at baseline (Figure 2C).

[0166] Example 2: A non - blinded, multi - center, global, dose - escalation study of the combination therapy of XmAb24306 and cevostamab A combination therapy, non - blinded, multi - center, global, dose - escalation study to evaluate the safety, tolerability, pharmacokinetics, and activity of cevostamab alone or in combination with XmAb24306, which is an FcRH5xCD3 bispecific antibody, will be conducted in subjects with hematological malignancies (e.g., relapsed or refractory multiple myeloma (R / R MM)) who have received at least three prior treatment lines, including at least one immunomodulatory drug (IMiD), one proteasome inhibitor (PI), and one anti - CD38 monoclonal antibody.

[0167] The study consists of a screening period of up to 28 days, a treatment period (up to 1 year or more), and a minimum follow - up period of 90 days after treatment.

[0168] Subjects in the combination - treatment arms will be enrolled in two stages: a dose - escalation stage and an expansion stage.

[0169] A cohort of 3 - 9 subjects with hematological malignancies (e.g., R / R MM) will be enrolled in the dose - escalation stage of the combination - therapy part of the study. To determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of XmAb24306 in combination with cevostamab, escalating doses of XmAb24306 will be administered by IV infusion, followed by intravenous administration of 132 mg of cevostamab after a 3 + 3 + 3 design (Figure 6).

[0170] Sevostamab is first administered using a divided-dose priming schedule. The first priming dose (0.3 mg) is administered on Day 1, and the second priming dose (3.3 mg) is administered on Day 2, 3, or 4 to withhold the resolution of infusion-related events including cytokine release syndrome (CRS), with a minimum interval of 20 hours from the end of the first sevostamab priming dose infusion to the start of the second priming dose, and two sevostamab priming doses are administered during the pre-cycle period. Thereafter, the sevostamab target dose (132 mg) is administered every two weeks (on Day 1 and Day 15) in Cycles 1-6 and every four weeks (on Day 1) from Cycle 7 onwards (see Figure 5).

[0171] The starting dose of XmAb24306 is 0.02 mg / kg administered IV. The first dose of XmAb24306 is administered at least 24 hours after the first target dose of sevostamab on Days 2-4 of Cycle 1 after the subject has cleared the safety parameters. Thereafter, XmAb24306 is administered every four weeks on Day 1 of each cycle from Cycle 2 onwards (see Figure 5). In dose escalation, the DLT evaluation window is defined as Days 1-28 of Cycle 1.

[0172] The sevostamab monotherapy arm enrolls approximately 20 subjects and provides contemporaneous comparative data for the combination therapy described above. If enrollment in the combination therapy arm is restricted to a specific population of interest, the same restrictions may apply to enrollment in the monotherapy arm.

[0173] The sevostamab dosing schedule in the monotherapy arm is a divided-dose priming schedule with two escalating sevostamab priming doses administered during the pre-cycle period using a first priming dose of 0.3 mg administered on Day 1 and a second priming dose of 3.3 mg administered between Days 2-4, and a target dose of 132 mg is administered every two weeks (on Day 1 and Day 15) in Cycles 1-6 and every four weeks (on Day 1) from Cycle 7 onwards (see Figure 7).

[0174] Subjects who were initially treated with sevastamab monotherapy and received at least 1 cycle of treatment in a stable disease (SD) or greater disease response assessment but subsequently progressed during the study treatment may benefit from treatment with XmAb24306 in combination with sevastamab. Thus, such subjects may be eligible to crossover to the combination arm of the trial. Without being bound by theory, the rationale for this crossover design is that the addition of XmAb24306 to sevastamab may increase the proliferation, survival and / or cytotoxicity of CD8 + T cells, resulting in enhanced antitumor activity compared to single-agent sevastamab. Subjects who crossover from sevastamab monotherapy to XmAb24306 and sevastamab combination therapy may receive combination therapy for up to 12 months or more.

[0175] Subjects treated with sevastamab as a single agent who develop progressive disease and / or are no longer deriving a clinical benefit may be eligible to receive treatment with XmAb24306 in combination with sevastamab if the following criteria are met. · The subject must have received at least 1 cycle of treatment in the sevastamab monotherapy arm and have had a stable disease (SD) or better disease response assessment prior to proceeding to the study treatment. · Treatment with XmAb24306 and sevastamab after progression must be considered acceptable as determined after a careful assessment and consideration of the benefit-risk balance for single-agent XmAb24306. · The patient must meet all inclusion and exclusion criteria. · Disease progression must be documented according to the IMWG uniform response criteria. · The subject must not have experienced toxicity during the final dose of the sevastamab monotherapy study treatment that would preclude treatment with the combination of XmAb24306 and sevastamab. ·Any cevostamab-related adverse event must resolve to Grade ≤1 or baseline grade on or before the first day of treatment in the combination trial (i.e., Example 2), and / or must not meet the protocol-specified criteria for dosing for a specific adverse event. Exceptions may be allowed.

[0176] Subjects eligible for crossover must have a time interval of at least 2 weeks between the last dose of the single-agent cevostamab treatment administered and the planned first dose of cevostamab in the combination treatment with XmAb24306 (i.e., Example 2). Depending on the length of this interval, subjects also repeat the pre-phase as follows before Cycle 1. ·If the interval between the last dose of the single-agent cevostamab treatment and the planned first dose of cevostamab in the combination treatment with XmAb24306 is ≥2 weeks but less than 6 weeks, the subject resumes treatment on Day 1 of Cycle 1 for the combination treatment, the target dose of cevostamab is administered on Day 1, and XmAb24306 is administered between Days 2 and 4. ·If the interval between the last dose of the single-agent cevostamab treatment and the first dose of cevostamab in the combination treatment with XmAb24306 is 8 weeks or more, repeated pre-phase dosing is required.

[0177] When the interval between the last dose of the single-agent cevostamab treatment arm and the initial dose of cevostamab in the combination treatment with XmAb24306 is at least 6 weeks but less than 8 weeks, it is determined whether repeated pre-phase dosing is required before Cycle 1.

[0178] All subjects in both arms of the trial are closely monitored for adverse events throughout the study and for at least 90 days after the final dose of the study treatment. All adverse events, including serious adverse events and particularly adverse events of interest, are reported up to 90 days after the final dose of the study treatment or earlier of the start of a new systemic anticancer therapy. Adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0), except for CRS which is graded according to the consensus grading for cytokine release syndrome by the American Society for Transplantation and Cellular Therapy (ASTCT). Tocilizumab is appropriately administered for CRS manifested by the treatment. Tocilizumab is administered at a dose of 8 mg / kg IV (8 mg / kg only for patients with a body weight of 30 kg or more; 12 mg / kg for patients with a body weight of less than 30 kg; dose not exceeding 800 mg per infusion) and repeated every 8 hours as needed (up to a maximum of 4 doses).

[0179] Subjects in both arms of the trial will undergo disease assessments at screening (baseline) and at regular intervals during the trial, which will be evaluated according to the International Myeloma Working Group [IMWG] Uniform Response Criteria. Subjects with evidence of acceptable toxicity and clinical benefit may continue treatment with XmAb24306 and cevostamab for up to 12 months or until disease progression (determined according to IMWG criteria) or unacceptable toxicity occurs, whichever comes first. After completion of 12 months of trial treatment, patients who have not experienced disease progression may consent to bone marrow aspiration / biopsy and may continue trial treatment if the overall IMWG disease assessment does not show stringent complete response (sCR). If bone marrow evaluation is not performed or if the bone marrow demonstrates sCR, the patient can no longer continue trial treatment. Patients who initially respond to trial treatment but then develop recurrent or progressive disease either after completion of treatment or after a dose delay of more than 28 days (i.e., there is no trial treatment beyond 42 - 56 days depending on when the delay occurs during the trial treatment) may be eligible for retreatment.

[0180] Subjects who complete trial treatment will continue to receive tumor and additional evaluations until either disease progression, initiation of a new anticancer therapy, or discontinuation from the trial occurs first.

[0181] Subjects who permanently discontinue XmAb24306 and cevostamab will return to the clinic for a treatment discontinuation visit within 30 days of either the last dose of trial treatment or the initiation of another systemic anticancer therapy, whichever is earlier. A visit at which the response assessment shows progressive disease may be used as a treatment discontinuation visit.

[0182] Blood samples will be collected at various time points before and after dosing to characterize the pharmacokinetics, immunogenic response, and PD properties of XmAb24306 and / or cevostamab.

[0183] The safety objective of this trial is to evaluate the safety and tolerability of the combination of XmAb24306 and sevastamab based on the following endpoints. · Incidence and severity of adverse events with severity determined according to NCI CTCAE v5.0 and ASTCT Consensus Grading for Cytokine Release Syndrome; · Changes from baseline in target vital signs; · Changes from baseline in target clinical laboratory results; and · Changes from baseline in ECG parameters.

[0184] The pharmacokinetic (PK) objective of this trial is to characterize the PK profile of XmAb24306 in combination with sevastamab based on the following endpoints. · Serum concentration of sevastamab at specific time points; · Serum concentration of XmAb24306 at specific time points; · PK parameters of sevastamab; and · PK parameters of XmAb24306.

[0185] The exploratory PK objective of this trial is as follows. · To evaluate potential relationships between serum concentrations or PK parameters for XmAb24306 and / or sevastamab and PD biomarkers, including but not limited to cytokine release, T cell numbers, and T cell activation status; and · To evaluate potential relationships between selected covariates and serum concentrations of PK parameters of XmAb24306 and / or sevastamab for the study treatment.

[0186] The efficacy objective of this trial is to perform a preliminary evaluation of the activity of XmAb24306 when administered in combination with sevastamab based on the following endpoints. ·The objective response rate (ORR), determined by the principal investigator in accordance with the criteria of the International Myeloma Working Group (IMWG), defined as the proportion of patients with the best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR) ·The proportion of CR / sCR, determined by the principal investigator in two consecutive instances, defined as the proportion of patients who achieved CR or sCR ·The proportion of VGPR or higher, determined by the principal investigator in two consecutive instances, defined as the proportion of patients who achieved VGPR or higher

[0187] The exploratory objective of this study is to perform a preliminary assessment of the activity of XmAb24306 when administered in combination with sevostamab based on the following endpoints. ·Duration of response (DOR), defined as the time from the first occurrence of a documented objective response (sCR, CR, VGPR or PR) to disease progression or death from any cause during the study period, determined by the principal investigator in accordance with the IMWG criteria (defined as within 30 days after the last dose of study drug) ·Progression-free survival (PFS), defined as the time from the first study treatment to the first occurrence of disease progression or death from any cause during the study (defined as within 30 days after the last dose of study drug), determined by the principal investigator in accordance with the IMWG criteria, whichever occurs earlier ·Time to first response, defined as the time from the start of study treatment until the achievement of a confirmed PR or better (for patients who achieved a PR or better response) ·Time to best response (for patients who achieved a response of PR or better) ·Minimal residual disease (MRD) negativity rate, determined using next-generation sequencing (NGS) on bone marrow aspirate (for patients who achieved a CR or sCR response), defined as the proportion of patients who achieved MRD negativity ·Overall survival (OS), defined as the time from the start of study treatment to death from any cause

[0188] For subjects treated with tocilizumab, the purpose of this additional investigational activity of the study is to perform a preliminary evaluation of the effectiveness of tocilizumab in improving the symptoms of cytokine release syndrome (CRS) after administration of the study treatment, based on the following endpoints. · Results of CRS after administration of tocilizumab

[0189] The immunogenicity objective of this trial is to evaluate the immune response to XmAb24306 in combination with cevostamab, based on the following endpoints. · Prevalence of anti-drug antibodies (ADA) to cevostamab at baseline and incidence of ADA to cevostamab during the trial · Prevalence of anti-drug antibodies (ADA) to XmAb24306 at baseline and incidence of ADA to XmAb24306 during the trial

[0190] The objective of exploratory immunogenicity for this study is to evaluate the potential effects of ADA, based on the following endpoints. · Relationship between the status of ADA to cevostamab and safety, PK or active endpoints · Relationship between the status of ADA to XmAb24306 and safety, PK or active endpoints

[0191] The objectives of exploratory biomarkers for this study are as follows. · Evaluate the activity of the study treatment in driving MRD negativity in patients with R / R MM, based on the following endpoints: o MRD negativity at first CR; and o MRD negativity after 12 months of study treatment. ·Predict the response to XmAb24306 and cevostamab (i.e., predictive biomarker), be an early surrogate of activity, be related to progression to a more severe disease state (i.e., prognostic biomarker), be related to acquired resistance to XmAb24306 and / or cevostamab, be related to susceptibility to the occurrence of adverse events, or be able to provide evidence of XmAb24306 and / or cevostamab activity (i.e., pharmacodynamic (PD) biomarker), or identify and / or evaluate biomarkers that can enhance knowledge and understanding of disease biology and drug safety based on the following endpoints: o The relationship between biomarkers in blood and bone marrow aspirate / biopsy and safety, PK, activity, immunogenicity, or other biomarker endpoints.

Claims

**Claim 1** A method of treating blood cancer in a subject in need of treatment for blood cancer, the method comprising administering to the subject a therapeutically effective amount of (a) an IL15-IL15Rα heterodimer Fc fusion protein and (b) an FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens. **Claim 2** Use of a therapeutically effective amount of (a) an IL15-IL15Rα heterodimer Fc fusion protein and (b) an FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens in the manufacture of one or more medicaments for treating blood cancer in a subject in need of treatment for blood cancer. **Claim 3** A therapeutically effective amount of (a) an IL15-IL15Rα heterodimer Fc fusion protein and (b) an FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens for use in treating blood cancer in a subject in need of treatment for blood cancer. **Claim 4** The method according to claim 1, the use according to claim 2, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 3, wherein the IL15-IL15Rα heterodimer Fc fusion protein comprises: (a) a first fusion protein comprising an interleukin-15 (IL-15) protein covalently bound to the N-terminus of a first Fc domain via a first domain linker, wherein the IL-15 protein comprises the amino acid sequence of SEQ ID NO: 5 and the first Fc domain is a variant of the human IgG1 Fc domain; and (b) a second fusion protein comprising an IL-15 receptor alpha (IL-15Rα) protein fragment covalently bound to the N-terminus of a second Fc domain via a second domain linker, wherein the IL-15Rα protein comprises the amino acid sequence of SEQ ID NO: 4 and the second Fc domain is a variant of the human IgG1 Fc domain. **Claim 5** The method, use, or IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 4, wherein the IL15-IL15Rα heterodimeric Fc fusion protein comprises: (a) a first fusion protein comprising an interleukin-15 (IL-15) protein covalently attached to the N-terminus of a first Fc domain via a first domain linker, wherein the IL-15 protein comprises the amino acid sequence of SEQ ID NO: 5 and the first Fc domain comprises the amino acid sequence of SEQ ID NO: 6; and (b) a second fusion protein comprising an IL-15 receptor alpha (IL-15Rα) protein fragment covalently attached to the N-terminus of a second Fc domain via a second domain linker, wherein the IL-15Rα protein comprises the amino acid sequence of SEQ ID NO: 4 and the second Fc domain comprises the amino acid sequence of SEQ ID NO:

7.

6. The method according to any one of claims 4 to 5, the use according to any one of claims 4 to 5, or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 4 to 5, wherein the first domain linker comprises the amino acid sequence of SEQ ID NO:

8.

7. The method according to any one of claims 4 to 6, the use according to any one of claims 4 to 6, or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 4 to 6, wherein the second domain linker comprises the amino acid sequence of SEQ ID NO:

8.

8. The method according to any one of claims 4 to 7, the use according to any one of claims 4 to 7, or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 4 to 7, wherein the first domain linker comprises the amino acid sequence of SEQ ID NO: 8 and the second domain linker comprises the amino acid sequence of SEQ ID NO:

8.

9. The method according to any one of claims 4 to 8, the use according to any one of claims 4 to 8, or the IL15-IL15Rα heterodimer Fc fusion protein and the FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 4 to 8, wherein the first fusion protein comprises the amino acid sequence of SEQ ID NO:

9.

10. The method according to any one of claims 4 to 9, the use according to any one of claims 4 to 9, or the IL15-IL15Rα heterodimer Fc fusion protein and the FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 4 to 9, wherein the second fusion protein comprises the amino acid sequence of SEQ ID NO:

10.

11. The method according to any one of claims 1 and 4 to 10, the use according to any one of claims 2 and 4 to 10, or the IL15-IL15Rα heterodimer Fc fusion protein and the FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 3 to 10, wherein the heterodimer protein comprises a first fusion protein comprising the amino acid sequence shown in SEQ ID NO: 9 and a second fusion protein comprising the amino acid sequence shown in SEQ ID NO:

10.

12. The method according to any one of claims 1 and 4 to 11, the use according to any one of claims 2 and 4 to 11, or the IL15-IL15Rα heterodimer Fc fusion protein and the FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 3 to 11, wherein the IL15-IL15Rα heterodimer Fc fusion protein is XmAb24306.

13. The method according to any one of claims 1 and 4 to 12, the use according to any one of claims 2 and 4 to 12, or the IL15-IL15Rα heterodimer Fc fusion protein and the FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 3 to 12, wherein the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens comprises an anti-FcRH5 light chain variable region, an anti-FcRH5 heavy chain variable region, an anti-CD3 light chain variable region, and an anti-CD3 heavy chain variable region.

14. The anti-FcRH5 light chain variable region comprises complementarity-determining region-1 (CDR-L1) containing the amino acid sequence of SEQ ID NO: 11, CDR-L2 containing the amino acid sequence of SEQ ID NO: 12, and CDR-L3 containing the amino acid sequence of SEQ ID NO: 13; the anti-FcRH5 heavy chain variable region comprises heavy chain complementarity-determining region-1 (CDR-H1) containing the amino acid sequence of SEQ ID NO: 14, CDR-H2 containing the amino acid sequence of SEQ ID NO: 15, and CDR-H3 containing the amino acid sequence of SEQ ID NO: 16, the method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 13.

15. The anti-FcRH5 light chain variable region contains the amino acid sequence of SEQ ID NO: 17, the method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 13 or 14.

16. The anti-FcRH5 heavy chain variable region contains the amino acid sequence of SEQ ID NO: 18, the method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 13 to 15.

17. The anti-FcRH5 light chain contains the amino acid sequence of SEQ ID NO: 19, the method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 13 to 16.

18. The anti-FcRH5 heavy chain contains the amino acid sequence of SEQ ID NO: 20, the method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 13 to 17.

19. The anti-CD3 light chain variable region comprises complementarity-determining region-1 (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 21, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 22, and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 23; the anti-CD3 heavy chain variable region comprises heavy chain complementarity-determining region-1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 24, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 25, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 26, the method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 13 to 18.

20. The anti-CD3 light chain variable region comprises the amino acid sequence of SEQ ID NO: 27, the method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 19.

21. The anti-CD3 heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 28, the method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 19 or 20.

22. The anti-CD3 light chain comprises the amino acid sequence of SEQ ID NO: 29, the method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 19 to 21.

23. The anti-CD3 heavy chain comprises the amino acid sequence of SEQ ID NO: 30, the method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 19 to 22.

24. The anti-FcRH5 light chain variable region comprises the amino acid sequence of SEQ ID NO: 17; the anti-FcRH5 heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 18; the anti-CD3 light chain variable region comprises the amino acid sequence of SEQ ID NO: 27; the anti-CD3 heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 28, the method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 19 to 23.

25. The anti-FcRH5 light chain comprises the amino acid sequence of SEQ ID NO: 19; the anti-FcRH5 heavy chain comprises the amino acid sequence of SEQ ID NO: 20; the anti-CD3 light chain comprises the amino acid sequence of SEQ ID NO: 29; the anti-CD3 heavy chain comprises the amino acid sequence of SEQ ID NO: 30, the method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 19 to 24.

26. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 19 to 25, wherein the FcRH5xCD3 bispecific antibody is cevostamab.

27. The method according to any one of claims 1 and 4 to 26, the use according to any one of claims 2 and 4 to 26, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 3 to 26, wherein the blood cancer is selected from the group consisting of leukemia, acute myeloid leukemia, adult acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, non-Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, and multiple myeloma.

28. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 27, wherein the blood cancer is multiple myeloma.

29. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 28, wherein the multiple myeloma is relapsed or refractory multiple myeloma.

30. The method according to any one of claims 1 and 4 to 29, the use according to any one of claims 2 and 4 to 29, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 3 to 29, wherein one or more prior treatments have been administered to the subject.

31. The method, use or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 30, wherein the pretreatment is an immunomodulatory agent, a proteasome inhibitor, or an anti-CD38 monoclonal antibody.

32. The method, use or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 31, wherein the immunomodulatory agent is selected from the group consisting of lenalidomide, thalidomide, and pomalidomide.

33. The method, use or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 31, wherein the proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib, and ixazomib.

34. The method, use or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 31, wherein the anti-CD38 monoclonal antibody is selected from the group consisting of daratumumab, isatuximab, mezigitamab, and ferzalizumab.

35. The method according to any one of claims 1 and 4 to 33, the use according to any one of claims 2 and 4 to 34, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 3 to 34, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered at a dose selected from the group consisting of about 0.0025 mg / kg, about 0.005 mg / kg, about 0.01 mg / kg, about 0.015 mg / kg, about 0.02 mg / kg, about 0.025 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.08 mg / kg, about 0.1 mg / kg, about 0.12 mg / kg, about 0.16 mg / kg, about 0.2 mg / kg, about 0.24 mg / kg and about 0.32 mg / kg body weight.

36. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCd3 bispecific antibody or fragment thereof according to claim 35, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered at a dosage selected from the group consisting of about 0.01 mg / kg, about 0.02 mg / kg, about 0.04 mg / kg, about 0.06 mg / kg, about 0.09 mg / kg, and about 0.12 mg / kg body weight.

37. The method according to any one of claims 1 and 4 to 36, the use according to any one of claims 2 and 4 to 36, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCd3 bispecific antibody or fragment thereof according to any one of claims 3 to 36, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered at a dosage selected from the group consisting of 0.0025 mg / kg, 0.005 mg / kg, 0.01 mg / kg, 0.015 mg / kg, 0.02 mg / kg, 0.025 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.08 mg / kg, 0.10 mg / kg, 0.16 mg / kg, 0.20 mg / kg, 0.24 mg / kg, and 0.32 mg / kg body weight.

38. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCd3 bispecific antibody or fragment thereof according to claim 36, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered at a dosage selected from the group consisting of 0.01 mg / kg, 0.02 mg / kg, 0.04 mg / kg, 0.06 mg / kg, 0.09 mg / kg, and 0.12 mg / kg body weight.

39. The method according to any one of claims 1 and 4 to 38, the use according to any one of claims 2 and 4 to 38, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCd3 bispecific antibody or fragment thereof according to any one of claims 3 to 38, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered at a frequency selected from the group consisting of Q1W, Q2W, Q3W, Q4W, Q5W, and Q6W.

40. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCd3 bispecific antibody or fragment thereof according to claim 39, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered one or more cycles at a frequency of Q1W.

41. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCd3 bispecific antibody or fragment thereof according to claim 39, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered one or more cycles at a frequency of Q2W.

42. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCd3 bispecific antibody or fragment thereof according to claim 39, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered one or more cycles at a frequency of Q4W.

43. The method according to any one of claims 1 and 4 to 42, the use according to any one of claims 2 and 4 to 42, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCd3 bispecific antibody or fragment thereof according to any one of claims 3 to 42, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered intravenously.

44. The method according to any one of claims 1 and 4 to 43, the use according to any one of claims 2 and 4 to 43, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCd3 bispecific antibody or fragment thereof according to any one of claims 3 to 43, wherein the IL15-IL15Rα heterodimer Fc fusion protein and the FcRH5xCd3 bispecific antibody or fragment thereof that binds to both antigens are administered simultaneously.

45. The method according to any one of claims 1 and 4 to 43, the use according to any one of claims 2 and 4 to 43, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCd3 bispecific antibody or fragment thereof according to any one of claims 3 to 43, wherein the IL15-IL15Rα heterodimer Fc fusion protein and the FcRH5xCd3 bispecific antibody or fragment thereof that binds to both antigens are administered continuously.

46. The method according to any one of claims 1 and 4 to 45, the use according to any one of claims 2 and 4 to 43, or the IL15-IL15Rα heterodimeric Fc fusion protein and the FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 3 to 43, wherein the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens is administered one or more cycles at a frequency selected from the group consisting of Q1W, Q2W, Q3W, Q4W, Q5W and Q6W.

47. The method, use, or IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 46, wherein the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens is administered one or more cycles at a frequency of Q2W.

48. The method, use, or IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 47, wherein the IL15-IL15Rα heterodimeric Fc fusion protein is administered at a frequency of Q4W, and the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens is administered one or more cycles at a frequency of Q2W.

49. The method, use, or IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 46, wherein the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens is administered one or more cycles at a frequency of Q4W.

50. The method, use, or IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 40 to 49, wherein each of the one or more cycles is a 4-week cycle.

51. The method, use, or IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 50, wherein the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens is administered in 6 four-week cycles at Q2W and in the 7th and subsequent four-week cycles at Q4W.

52. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 51, wherein the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens is administered on days 1 and 15 of 6 four-week cycles, and on day 1 of the 7th and subsequent four-week cycles.

53. The method according to any one of claims 1 and 4 to 52, the use according to any one of claims 2 and 4 to 52, or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 3 to 52, wherein the FcRH5xCD3 bispecific antibody is administered at a dose of about 132 mg to about 198 mg.

54. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 53, wherein the FcRH5xCD3 bispecific antibody is administered at a dose of about 132 mg.

55. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 54, wherein the FcRH5xCD3 bispecific antibody is administered at a dose of about 132 mg in one or more 28-day cycles at a frequency of Q2W.

56. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 53, wherein the FcRH5xCD3 bispecific antibody is administered at a dose of about 160 mg.

57. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 53, wherein the FcRH5xCD3 bispecific antibody is administered at a dose of about 198 mg.

58. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 46 to 57, wherein one or more priming doses of the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens are administered to the subject during a pre-treatment phase before the first treatment cycle.

59. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 58, wherein the prior stage is 7 days.

60. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 58 or 59, wherein the priming dose of the FcRH5xCD3 bispecific antibody is about 3.6 mg.

61. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 58 to 60, wherein two priming doses of the FcRH5xCD3 bispecific antibody or fragment thereof that binds to both antigens are administered to the subject.

62. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 61, wherein the first priming dose is administered on the first day of the prior stage.

63. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 62, wherein the second priming dose is administered between the 2nd and 4th days of the prior stage.

64. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 61 to 63, wherein the minimum interval between the end of the first priming dose and the start of the second priming dose is 20 hours.

65. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 61 to 64, wherein about 3.6 mg of the FcRH5xCD3 bispecific antibody is administered between the two priming doses.

66. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 65, wherein the first priming dose is about 0.3 mg and the second priming dose is about 3.3 mg.

67. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 1 and 4-55 and 58-66, wherein the subject is administered a first priming dose of about 0.3 mg of the FcRH5xCD3 bispecific antibody on day 1 of the previous stage, a second priming dose of about 3.3 mg of the FcRH5xCD3 bispecific antibody between days 2-4 of the previous stage, and thereafter at a dose of about 132 mg of the FcRH5xCD3 bispecific antibody on days 1 and 15 of 6 four-week cycles, and on day 1 of the 7th and subsequent four-week cycles.

68. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 1 and 4-67, wherein the FcRH5xCD3 bispecific antibody is administered intravenously.

69. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 1 and 4-68, further comprising administering to the subject a therapeutically effective amount of tocilizumab.

70. The method according to claim 69, wherein the subject is suffering from a cytokine release syndrome (CRS) event.

71. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 69 or 70, wherein the tocilizumab is administered 24 hours after the first corticosteroid administration to a subject remaining resistant to corticosteroids.

72. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 69-71, wherein the tocilizumab is administered at a dose of 8 mg / kg.

73. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 72, wherein when the weight of the subject is ≧ 30 kg, tocilizumab is administered at a dose of 8 mg / kg.

74. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 69 to 71, wherein tocilizumab is administered at a dose of 12 mg / kg.

75. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 74, wherein when the weight of the patient is < 30 kg, tocilizumab is administered at a dose of 12 mg / kg.

76. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 69 to 75, wherein tocilizumab is administered intravenously.

77. The method, use, or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 69 to 76, wherein tocilizumab is administered every 8 hours.

78. A method of treating multiple myeloma in a subject in need of treatment for multiple myeloma, the method comprising administering to the subject a therapeutically effective amount of (a) XmAb24306, which comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10, and (b) cevostamab, which comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30, wherein XmAb24306 is administered intravenously at a dose of about 0.02 mg / kg to about 0.06 mg / kg and cevostamab is administered intravenously at a dose of about 132 mg.

79. In the manufacture of one or more pharmaceutical products for treating multiple myeloma in a subject in need thereof, a therapeutically effective amount of (a) XmAb24306, which comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10, and (b) cevostamab, which comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30, wherein XmAb24306 is formulated to be administered intravenously at a dose of about 0.02 mg / kg to about 0.06 mg / kg and cevostamab is formulated to be administered intravenously at a dose of about 132 mg.

80. For use in treating multiple myeloma in a subject in need thereof, a therapeutically effective amount of (a) XmAb24306, which comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10, and (b) cevostamab, which comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30, wherein XmAb24306 is administered intravenously at a dose of about 0.02 mg / kg to about 0.06 mg / kg and cevostamab is administered intravenously at a dose of about 132 mg, a therapeutically effective amount of XmAb24306 and cevostamab.

81. The method according to claim 78, the use according to claim 79, or XmAb24306 and cevostamab according to claim 80, wherein the treatment further comprises administering to the subject one or more priming doses of cevostamab at a total dose of about 3.6 mg during a pre-stage of 7 days before the first treatment cycle, and the priming dose is administered as a single dose.

82. The treatment further comprises administering to the subject one or more priming doses of sevastamab at a total dose of about 3.6 mg during the pre-stage for 7 days before the first treatment cycle, wherein the priming dose is administered as two doses. The method according to claim 78, the use according to claim 79, or XmAb24306 and sevastamab according to claim 80.

83. The method, use, or XmAb24306 and sevastamab according to claim 82, wherein the first priming dose is about 0.3 mg and the second priming dose is about 3.3 mg.

84. The method, use, or XmAb24306 and sevastamab according to claim 83, wherein the first priming dose is administered on the first day of the pre-stage, and the second priming dose is administered on the second, third, or fourth day of the pre-stage.

85. The method according to any one of claims 78 and 81 - 84, the use according to any one of claims 79 and 81 - 84, or XmAb24306 and sevastamab according to any one of claims 80 - 84, wherein XmAb24306 is administered for one or more cycles at a frequency of Q4W.

86. The method according to any one of claims 78 and 81 - 85, the use according to any one of claims 79 and 81 - 85, or XmAb24306 and sevastamab according to any one of claims 80 - 85, wherein sevastamab is administered for one or more cycles at a frequency of Q2W.

87. The method according to any one of claims 78 and 81 - 86, the use according to any one of claims 79 and 81 - 86, or XmAb24306 and sevastamab according to any one of claims 80 - 86, wherein sevastamab is administered for one or more cycles at a frequency of Q4W.

88. XmAb24306 is intravenously administered at a frequency of Q4W for at least 7 four-week cycles, the first priming dose of 0.3 mg of cevostamab is intravenously administered on day 1 of the previous stage, the second priming dose of 3.3 mg of cevostamab is intravenously administered on days 2 to 4 of the previous stage, the previous stage is 7 days, and then at a dose of 132 mg of cevostamab, on days 1 and 15 of 6 four-week cycles, and on day 1 of the 7th and subsequent four-week cycles, intravenously administered, the method according to any one of claims 78 and 81 to 87, the use according to any one of claims 79 and 81 to 87, or XmAb24306 and cevostamab according to any one of claims 80 to 87.

89. A method of treating multiple myeloma in a subject in need of treatment for multiple myeloma, the method comprising administering to the subject a therapeutically effective amount of: (a) XmAb24306, which comprises a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10, and (b) cevostamab, which comprises an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30, wherein XmAb24306 is intravenously administered at a dose of about 0.02 mg / kg to about 0.06 mg / kg at a frequency of Q4W for at least 7 four-week cycles, the first priming dose of 0.3 mg of cevostamab is intravenously administered on day 1 of the previous stage, the second priming dose of 3.3 mg of cevostamab is intravenously administered between days 2 to 4 of the previous stage, the previous stage is 7 days, and then at a dose of 132 mg of cevostamab, on days 1 and 15 of 6 four-week cycles, and on day 1 of the 7th and subsequent four-week cycles, intravenously administered.

90. In the manufacture of one or more pharmaceutical products for treating multiple myeloma in a subject in need of treatment for multiple myeloma, the use of a therapeutically effective amount of: (a) XmAb24306, comprising a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10, and (b) cevostamab, comprising an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30, wherein XmAb24306 is formulated to be administered intravenously at a dose of about 0.02 mg / kg to about 0.06 mg / kg, at a frequency of Q4W, for at least 7 four-week cycles, and cevostamab is formulated to be administered intravenously at a dose of 132 mg on days 1 and 15 of 6 four-week cycles, and on day 1 of the 7th and subsequent four-week cycles; said treatment further comprising a 7-day pre-phase in which a first priming dose of 0.3 mg of cevostamab is administered intravenously on day 1 of the pre-phase and a second priming dose of 3.3 mg of cevostamab is administered intravenously between days 2 and 4 of the pre-phase.

91. For use in the treatment of multiple myeloma in a subject in need thereof, a therapeutically effective amount of: (a) XmAb24306, comprising a first monomer comprising the amino acid sequence of SEQ ID NO: 9 and a second monomer comprising the amino acid sequence of SEQ ID NO: 10; and (b) cevostamab, comprising an anti-FcRH5 light chain comprising the amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising the amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising the amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising the amino acid sequence of SEQ ID NO: 30, wherein XmAb24306 is intravenously administered at a dose of about 0.02 mg / kg to about 0.06 mg / kg, at a frequency of Q4W, in at least 7 four-week cycles, a first priming dose of 0.3 mg of cevostamab is intravenously administered on day 1 of the previous stage, a second priming dose of 3.3 mg of cevostamab is intravenously administered between days 2 to 4 of the previous stage, the previous stage being 7 days, and thereafter, at a dose of 132 mg of cevostamab, on days 1 and 15 of 6 four-week cycles, and on day 1 of the 7th and subsequent four-week cycles, a therapeutically effective amount of XmAb24306 and cevostamab.

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