COMBINATION OF IL15 / IL15Ralpha HETERODIMER Fc FUSION PROTEIN AND FcRH5XCD3 BISPECIFIC ANTIBODIES FOR THE TREATMENT OF HELLOGICAL CANCER

Abstract

The present disclosure provides methods of treating leukemia, such as multiple myeloma, by administering a heterodimeric protein, such as XmAb24306, comprising a first monomer comprising an IL15 protein-Fc domain fusion and a second monomer comprising an IL15R [alpha] protein-Fc domain fusion, in combination with an FcRH5xCD3 bispecific antibody, such as a civorestat monoclonal antibody.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 367,900, filed on July 7, 2022, and U.S. Provisional Application No. 63 / 504,524, filed on May 26, 2023, the contents of each of which are hereby incorporated by reference in their entirety. Technical Field

[0003] The present disclosure relates to the field of treating blood cancers, such as multiple myeloma, using a combination of IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody.

[0004] Sequence Listing

[0005] This application contains a sequence listing, which has been submitted electronically in XML format and is incorporated herein by reference in its entirety. The XML copy was created on July 6, 2023, is named 000218-0060-WO1_SL.xml, and is 31,425 bytes in size. Background Art

[0006] Most blood cancers (or hematologic cancers) begin in the bone marrow and are caused by the uncontrolled growth of abnormal blood cells, which interrupts the function of normal blood cells, which fight infection and produce new blood cells. Multiple myeloma (MM), a type of blood cancer, is an incurable tumor characterized by the proliferation and accumulation of malignant plasma cells in the bone marrow, which leads to overproduction of a monoclonal protein (M protein) that is detectable in the blood or urine of most subjects. Approximately 30,000 people are diagnosed with MM each year in the United States (Siegel et al. 2019) and approximately 160,000 people are diagnosed with MM each year worldwide (Bray et al. 2018). End-organ damage caused by MM includes hypercalcemia, renal insufficiency, anemia, and lytic bone lesions. Despite advances in treatment, MM remains incurable, with an estimated median survival of 8–10 years for standard-risk and 2–3 years for high-risk myeloma, even with aggressive treatment such as autologous stem cell transplantation (ASCT) (Mikhael et al. 2013). U.S. Package Insert [USPI]), proteasome inhibitors (PIs) such as lenalidomide (Revlimid Immunomodulatory drugs (IMiDs) such as USPI and daratumumab (Darzalex USPI,Darzalex-Faspro TMOther drugs with novel mechanisms of action that have been approved by the U.S. Food and Drug Administration for the treatment of MM include the nuclear export inhibitor selinexor (Xpovio TM USPI) and belantamab mofortin-bmlf (Blenrep USPI).

[0007] Despite significant advances in treatment options, the majority of MM patients eventually relapse. Relapsed / refractory multiple myeloma (R / R MM) remains a significant unmet medical need, with median overall survival of less than one year in subjects with disease that is refractory to anti-CD38 monoclonal antibodies (Chari et al. 2019; Ghandi et al. 2019). Several approaches to direct the body’s immune system to target and destroy malignant plasma cells are currently being explored in clinical settings, including T cell-engaging bispecific antibodies and chimeric antigen receptor [CAR] T cells. Emerging data from clinical studies using these agents suggest that manipulating a subject’s immune system is a potentially promising approach to treating R / R MM (Moreau et al. 2019; Caraccio et al. 2020). Summary of the invention

[0008] In a first aspect, the present disclosure provides a method of treating blood cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of (a) an IL15-IL15Rα heterodimeric Fc fusion protein and (b) a FcRH5xCD3 bispecific antibody or a fragment thereof that binds to two antigens.

[0009] In a second aspect, the present disclosure provides the use of a therapeutically effective amount of (a) an IL15-IL15Rα heterodimeric Fc fusion protein and (b) a FcRH5xCD3 bispecific antibody or fragment thereof that binds two antigens in the manufacture of one or more medicaments for treating blood cancer in a subject in need thereof.

[0010] In a third aspect, the present disclosure provides a therapeutically effective amount of (a) an IL15-IL15Rα heterodimeric Fc fusion protein and (b) a FcRH5xCD3 bispecific antibody or a fragment thereof that binds two antigens for use in treating blood cancer in a subject in need thereof.

[0011] 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 wherein the first Fc domain is a variant of a human IgG1 Fc domain; and (b) a second fusion protein comprising an IL-15 receptor α (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 wherein the second Fc domain is a variant of a human IgG1 Fc domain.

[0012] 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 wherein 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 α (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 wherein the second Fc domain comprises the amino acid sequence of SEQ ID NO:7.

[0013] 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.

[0014] 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 set forth in SEQ ID NO: 9; and a second monomer comprising the amino acid sequence set forth in SEQ ID NO: 10.

[0015] In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein is XmAb24306.

[0016] In some embodiments, the FcRH5xCD3 bispecific antibody or fragment thereof that binds two 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.

[0017] In some embodiments, the anti-FcRH5 light chain variable region comprises a light chain complementary 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 heavy chain complementary 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.

[0018] 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.

[0019] In some embodiments, the anti-CD3 light chain variable region comprises a light chain complementary 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; and the anti-CD3 heavy chain variable region comprises a heavy chain complementary 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.

[0020] 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.

[0021] 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; and the anti-CD3 heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 28.

[0022] 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; and the anti-CD3 heavy chain comprises the amino acid sequence of SEQ ID NO: 30.

[0023] In some embodiments, the FcRH5xCD3 bispecific antibody is cevostamab.

[0024] 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's lymphoma, B-cell non-Hodgkin's 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's lymphoma. In some embodiments, the blood cancer is chronic lymphocytic leukemia.

[0025] In some embodiments, the subject has previously been administered one or more prior therapies.

[0026] In some embodiments, the prior treatment of the present disclosure is an immunomodulatory drug, a proteasome inhibitor, or an anti-CD38 monoclonal antibody. In some embodiments, the immunomodulatory drug 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, mazetuzumab, and felzartamab.

[0027] In some embodiments, the IL15-IL15Rα heterodimeric 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 heterodimeric 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.

[0028] In some embodiments, the IL15-IL15Rα heterodimeric 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 heterodimeric Fc fusion protein (eg, 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.

[0029] 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 at a frequency of Q1W in one or more cycles. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at a frequency of Q2W in one or more cycles. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at a frequency of Q4W in one or more cycles.

[0030] In some embodiments, the IL15-IL15Rα heterodimeric Fc fusion protein (eg, XmAb24306) is administered intravenously.

[0031] In some embodiments, the IL15-IL15Rα heterodimeric Fc fusion protein (e.g., XmAb24306) and the FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or a fragment thereof that binds to two antigens are administered simultaneously. In some embodiments, the IL15-IL15Rα heterodimeric Fc fusion protein (e.g., XmAb24306) and the FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or a fragment thereof that binds to two antigens are administered sequentially.

[0032] In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or a fragment thereof that binds two antigens is administered at a frequency selected from the group consisting of: Q1W, Q2W, Q3W, Q4W, Q5W, and Q6W in one or more cycles. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or a fragment thereof that binds two antigens is administered at a frequency of Q2W in one or more cycles. In some embodiments, the IL15-IL15Rα heterodimeric Fc fusion protein (e.g., XmAb24306) is administered at a frequency of Q4W, and wherein the FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or a fragment thereof that binds two antigens is administered at a frequency of Q2W, which is performed in one or more cycles.

[0033] In some embodiments, each of the one or more cycles is a four-week cycle. In some embodiments, a FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or a fragment thereof that binds two antigens is administered Q2W for six four-week cycles, and is administered Q4W in the seventh and any subsequent four-week cycles. In some embodiments, a FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or a fragment thereof that binds two antigens is administered on days 1 and 15 for six four-week cycles, and is administered on day 1 in the seventh and any subsequent four-week cycles.

[0034] In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., Sivositumab) is administered at a dose of about 132 mg to about 198 mg. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., Sivositumab) is administered at a dose of about 132 mg. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., Sivositumab) is administered at a dose of about 132 mg at a frequency of Q2W in one or more 28-day cycles. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., Sivositumab) is administered at a dose of about 160 mg. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., Sivositumab) is administered at a dose of about 198 mg.

[0035] In some embodiments, one or more priming doses of a FcRH5xCD3 bispecific antibody (e.g., Sivositumab) or a fragment thereof binding to two antigens are administered to the subject during a pre-stage prior to the first treatment cycle. In some embodiments, the pre-stage is seven days. In some embodiments, the priming dose is about 3.6 mg of a FcRH5xCD3 bispecific antibody (e.g., Sivositumab). In some embodiments, two priming doses of a FcRH5xCD3 bispecific antibody (e.g., Sivositumab) or a fragment thereof binding to two antigens are administered to the subject. In some embodiments, two priming doses are administered together with about 3.6 mg of a FcRH5xCD3 bispecific antibody (e.g., Sivositumab) (i.e., the amount administered in the first priming dose and the amount administered in the second priming dose 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 day 2 and day 4 of the pre-stage. In some embodiments, the minimum interval between the end of the first priming dose and the beginning of the second priming dose is 20 hours. In some embodiments, the FcRH5xCD3 bispecific antibody (eg, silvostomumab) or a fragment thereof that binds two antigens is administered together in 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.

[0036] In some embodiments, the subject is administered a first priming dose of about 0.3 mg of the FcRH5xCD3 bispecific antibody (e.g., silvostomumab) on day 1 of the pre-phase, the subject is administered a second priming dose of about 3.3 mg of the FcRH5xCD3 bispecific antibody (e.g., silvostomumab) between days 2 and 4 of the pre-phase, and thereafter, the subject is administered a dose of about 132 mg of the FcRH5xCD3 bispecific antibody (e.g., silvostomumab) on day 1 for six four-week cycles and for the seventh and any subsequent four-week cycles.

[0037] In some embodiments, the FcRH5xCD3 bispecific antibody (eg, silvostomumab) is administered intravenously.

[0038] In some embodiments, the method further includes administering a therapeutically effective amount of Tocilizumab to the subject. In some embodiments, the subject has suffered a cytokine release syndrome (CRS) event. In some embodiments, Tocilizumab is administered to a subject who is still refractory to corticosteroids 24 hours after the first corticosteroid dose. In some embodiments, Tocilizumab is administered at a dosage of 8mg / kg. In some embodiments, if the subject's weight is ≥30kg, Tocilizumab is administered at a dosage of 8mg / kg. In some embodiments, Tocilizumab is administered at a dosage of 12mg / kg. In some embodiments, if the patient's weight is <30kg, Tocilizumab is administered at a dosage of 12mg / kg.

[0039] In some embodiments, tocilizumab is administered intravenously. In some embodiments, tocilizumab is administered every 8 hours.

[0040] A fourth aspect of the present disclosure provides 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 an amino acid sequence of SEQ ID NO: 9, and a second monomer comprising an amino acid sequence of SEQ ID NO: 10; and (b) sivosetumab, wherein sivosetumab comprises: an anti-FcRH5 light chain comprising an amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising an amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising an amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising an 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 sivosetumab is administered intravenously at a dose of about 132 mg.

[0041] A fifth aspect of the present disclosure provides for use of a therapeutically effective amount of the following in the manufacture of one or more medicaments for treating multiple myeloma in a subject in need thereof: (a) XmAb24306, wherein XmAb24306 comprises: a first monomer comprising an amino acid sequence of SEQ ID NO:9, and a second monomer comprising an amino acid sequence of SEQ ID NO:10; and (b) sivosetumab, wherein sivosetumab comprises: an anti-FcRH5 light chain comprising an amino acid sequence of SEQ ID NO:19, an anti-FcRH5 heavy chain comprising an amino acid sequence of SEQ ID NO:20, an anti-CD3 light chain comprising an amino acid sequence of SEQ ID NO:29, and an anti-CD3 heavy chain comprising an amino acid sequence of SEQ ID NO:30, wherein XmAb24306 is formulated for intravenous administration at a dose of about 0.02 mg / kg to about 0.06 mg / kg, and sivosetumab is formulated for intravenous administration at a dose of about 132 mg.

[0042] A sixth aspect of the present disclosure provides a therapeutically effective amount of (a) XmAb24306, wherein XmAb24306 comprises: a first monomer comprising an amino acid sequence of SEQ ID NO: 9, and a second monomer comprising an amino acid sequence of SEQ ID NO: 10; and (b) sivosetumab, wherein sivosetumab comprises: an anti-FcRH5 light chain comprising an amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising an amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising an amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising an amino acid sequence of SEQ ID NO: 30, for 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 sivosetumab is administered intravenously at a dose of about 132 mg.

[0043] In some embodiments, treatment further comprises administering one or more priming doses of silvositumab to the subject at a total dose of about 3.6 mg during a seven-day pre-stage prior to the first treatment cycle, wherein the priming dose is administered as a single dose. In some embodiments, treatment further comprises administering one or more priming doses of silvositumab to the subject at a total dose of about 3.6 mg during a seven-day pre-stage prior to the first treatment cycle, wherein the priming dose is administered in 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 wherein the second priming dose is administered on day 2, 3, or 4 of the pre-stage.

[0044] In some embodiments, XmAb24306 is administered at a frequency of Q4W for one or more cycles.

[0045] In some embodiments, silvostomumab is administered at a frequency of Q2W for one or more cycles. In some embodiments, silvostomumab is administered at a frequency of Q4W for one or more cycles.

[0046] In some embodiments, XmAb24306 is administered intravenously at a frequency of Q4W for at least seven four-week cycles, and wherein a first priming dose of 0.3 mg of silvositumab is administered intravenously on day 1 of the pre-phase, a second priming dose of 3.3 mg of silvositumab is administered intravenously between days 2 and 4 of the pre-phase, wherein the pre-phase is seven days, and thereafter, a dose of 132 mg of silvositumab is administered intravenously on days 1 and 15 for six four-week cycles and on day 1 for the seventh and any subsequent four-week cycles.

[0047] A seventh aspect of the present disclosure provides a method for 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 an amino acid sequence of SEQ ID NO: 9, and a second monomer comprising an amino acid sequence of SEQ ID NO: 10, and (b) sivosetumab, wherein sivosetumab comprises: an anti-FcRH5 light chain comprising an amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising an amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising an amino acid sequence of SEQ ID NO: 29, and a second monomer comprising an amino acid sequence of SEQ ID NO: 10. 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 seven four-week cycles, and wherein a first priming dose of 0.3 mg of silvositumomab is administered intravenously on day 1 of the pre-phase, a second priming dose of 3.3 mg of silvositumomab is administered intravenously between day 2 and day 4 of the pre-phase, wherein the pre-phase is seven days, and thereafter, a dose of 132 mg of silvositumomab is administered intravenously on day 1 and day 15 for six four-week cycles and on day 1 for the seventh and any subsequent four-week cycles.

[0048] An eighth aspect of the present disclosure provides a use of a therapeutically effective amount of the following in the manufacture of one or more medicaments for treating multiple myeloma in a subject in need thereof: (a) XmAb24306, wherein XmAb24306 comprises: a first monomer comprising an amino acid sequence of SEQ ID NO: 9, and a second monomer comprising an amino acid sequence of SEQ ID NO: 10; and (b) sivosetumab, wherein sivosetumab comprises: an anti-FcRH5 light chain comprising an amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising an amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising an amino acid sequence of SEQ ID NO: 29, and a second monomer comprising an amino acid sequence of SEQ ID NO: 10. NO:30, wherein XmAb24306 is formulated for intravenous administration at a dose of about 0.02 mg / kg to about 0.06 mg / kg at a frequency of Q4W for at least seven four-week cycles, wherein silvositumomab is formulated for intravenous administration at a dose of 132 mg on days 1 and 15 for six four-week cycles and on day 1 for the seventh and any subsequent four-week cycles; and wherein the treatment further comprises a seven-day pre-phase, wherein a first priming dose of silvositumomab of 0.3 mg is administered intravenously on day 1 of the pre-phase, and a second priming dose of silvositumomab of 3.3 mg is administered intravenously between days 2 and 4 of the pre-phase.

[0049] A ninth aspect of the present disclosure provides a therapeutically effective amount of (a) XmAb24306, wherein XmAb24306 comprises: a first monomer comprising an amino acid sequence of SEQ ID NO: 9, and a second monomer comprising an amino acid sequence of SEQ ID NO: 10; and (b) sivosetumab, wherein sivosetumab comprises: an anti-FcRH5 light chain comprising an amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising an amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising an amino acid sequence of SEQ ID NO: 29, and a second monomer comprising an amino acid sequence of SEQ ID NO: 10. An anti-CD3 heavy chain of the amino acid sequence of NO:30 for 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 at a frequency of Q4W for at least seven four-week cycles, and wherein a first starting dose of 0.3 mg of silvositumab is administered intravenously on day 1 of the pre-phase, a second starting dose of 3.3 mg of silvositumab is administered intravenously between day 2 and day 4 of the pre-phase, wherein the pre-phase is seven days, and thereafter, a dose of 132 mg of silvositumab is administered intravenously on day 1 and day 15 for six four-week cycles and on day 1 for the seventh and any subsequent four-week cycles. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figures 1A to 1B Graphs measuring the in vitro pharmacological activity of silvostomumab in combination with XmAb24306 in primary bone marrow mononuclear cells (BMMCs) from multiple myeloma (MM) subjects (ie, donors 1 to 3) are provided. Figure 1A The results show that CD8 + Plot of percent change in T cell numbers. Figure 1B Provides a demonstration of MM tumor cells (CD38 高 , CD138 + ) Graph of percent lysis. MM = multiple myeloma. Data are shown as mean ± SD of replicates. Statistical analysis was performed using paired t-test.

[0051] Figures 2A to 2C Provided are data showing that after silvostomumab treatment, CD69 ( Figure 2A )、CD25( Figure 2B ) and CD122 (IL-2R / IL-15Rb; Figure 2C ) in human CD4 + T cells, CD8 + Figure 3. In vitro expression levels in T cells and natural killer (NK) cells. Human PBMCs from three healthy donors were co-cultured with a multiple myeloma cell line (MOLP-2 cells) in the presence of 5000 pM silvostomumab or isotype control or without treatment for 30 minutes, 2 hours, 4 hours, 24 hours, and 48 hours. + T cells, CD8 + Measurement of CD69 on T cells and NK cells Figure 2A )、CD25( Figure 2B ) and CD122( Figure 2C ) level. Sivostomab induced CD4 + T cells and CD8 + Upregulation of CD69, CD25 and CD122 in T cells. Data are shown as mean ± SD of replicates. MFI = mean fluorescence intensity; NK = natural killer cell; TDB = T cell-dependent bispecific antibody.

[0052] Figure 3The amino acid sequences of XmAb24306 monomer 1 (SEQ ID NO: 9) and XmAb24306 monomer 2 (SEQ ID NO: 10) are provided. In the monomer 1 sequence, the IL15 portion is underlined, the linker is offset with a slash and bold and underlined, and the Fc portion follows the second slash and does not contain any formatting. In the monomer 2 sequence, the IL15Rα portion is underlined, the linker is offset with a slash and bold and underlined, and the Fc portion follows the second slash and does not contain any formatting.

[0053] Figure 4A and 4B Provided are the amino acid sequences of human IL-15 precursor protein (full-length human IL-15) (SEQ ID NO: 2), mature or truncated human IL-15 protein (SEQ ID NO: 1), full-length human IL-15Rα protein (SEQ ID NO: 3), the extracellular domain of human IL-15Rα protein (SEQ ID NO: 31), and the sushi domain of human IL-15Rα protein (SEQ ID NO: 4).

[0054] Figure 5 Representative treatment schedules for combination therapies comprising XmAb24306 and silvostomumab are provided. DLT = dose limiting toxicity.

[0055] Figure 6 Combination study protocol for IL15 / IL15Rα heterodimeric protein (e.g., XmAb24306) and cevos, showing subjects enrolled in two phases: a dose escalation phase and an expansion phase, and detailed information about the two phases. XmAb = IL15 / IL15Rα heterodimeric protein (e.g., XmAb24306); cevos = cevos; PK = pharmacokinetics; PD = pharmacodynamics.

[0056] Figure 7 Representative treatment schedules for silvostomumab monotherapy are provided. DLT = dose-limiting toxicity. DETAILED DESCRIPTION

[0057] conventional

[0058] Unless otherwise indicated, the practice of the methods disclosed herein and the preparation and use of the compositions employ conventional techniques in molecular biology, biochemistry, chromatin structure and analysis, computational chemistry, cell culture, recombinant DNA, and related fields within the skill of the art. Such techniques are fully described in the literature.

[0059] The term "herein" means the entire application.

[0060] It should be understood that any embodiment described herein, including embodiments described in different aspects of the present disclosure and in different parts of the specification (including embodiments described only in examples), can be combined with one or more other embodiments disclosed herein, unless explicitly stated to be denied or inappropriate. The combination of embodiments is not limited to these specific combinations claimed through multiple dependent claims.

[0061] Any publications, patents and published patent applications mentioned in this application are specifically incorporated herein by reference. In the event of any ambiguity, the present specification (including its specific definitions) shall prevail.

[0062] Throughout this specification, the word "comprise," which is synonymous with "including," "containing," or "characterized by," or variations such as "comprises" or "comprising," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.

[0063] Throughout the specification, where a composition is described as having, including or comprising (or variations thereof) a particular component, it is contemplated that the composition may also be substantially composed of or comprised of said component. Similarly, where a method or process is described as having, including or comprising a particular process step, the process may also be substantially composed of or comprised of said treatment step. In addition, it should be understood that the order of steps or the order in which certain actions are performed is not important, as long as the composition and method described herein remain operable. In addition, two or more steps or actions may be performed simultaneously.

[0064] The term "consisting of" excludes any elements, steps or ingredients not specifically listed.

[0065] The term "consisting essentially of" limits the scope of the present disclosure to the specified materials or steps, and those materials or steps that do not materially affect the basic and novel characteristics of the present disclosure.

[0066] The term "eg" or "for example" followed by any examples is not intended to be exhaustive or limiting.

[0067] As used herein, the articles "a," "an," and "the" may refer to one or more (ie, to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0068] As used herein, the term "about" for modifying the amount of a component, parameter, calculation or measurement in a composition used in the method of the present disclosure refers to, for example, a liquid handling procedure for preparing an isolated polypeptide or pharmaceutical composition in the real world through typical measurements and inadvertent errors in these procedures; through differences in the preparation, source or purity of the components used to prepare the composition or perform the method, etc., which may occur, without substantial effect on the chemical or physical properties of the composition or method of the present disclosure. Such variations can generally be within 10% of a given value or range, more usually within 5%. The term "about" also encompasses amounts that differ due to different equilibrium conditions of a composition produced by a particular initial mixture. Whether or not modified by the term "about", the paragraph includes equivalents of the amount. Mentioning "about" values ​​or parameters herein includes (and describes) embodiments involving the value or parameter itself. For example, a description involving "about X" includes a description of "X", and a numerical range includes numbers that define the range.

[0069] As used herein, the term "or" should be understood to mean "and / or" unless the context clearly indicates otherwise.

[0070] Although the numerical ranges and parameters setting forth the broad scope of the present disclosure are approximate, the numerical values ​​set forth in the specific examples are reported as accurately as possible. However, any numerical value inherently contains certain errors, which are necessarily caused by the standard deviation found in their respective test measurements. In addition, all ranges disclosed herein are understood to cover any and all subranges contained therein. For example, the range of "1 to 10" should be considered to include any and all subranges between (and including) a minimum value of 1 and a maximum value of 10; that is, all subranges start with a minimum value of 1 or greater, such as 1 to 6.1, and end with a maximum value of 10 or less, such as 5.5 to 10. The disclosure of a range should also be considered to be a disclosure of the endpoints of the range.

[0071] Exemplary methods and materials are described herein, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present application. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0072] definition

[0073] Unless otherwise indicated, the following terms shall be understood to have the following meanings:

[0074] As used herein, the term "ablation" refers to a reduction or removal of an activity. Thus, for example, "ablation of FcγR binding" means that the Fc region amino acid variant has less than 50% of the initial binding compared to the Fc region without the specific variant, wherein preferably less than 70%, less than 80%, less than 90%, less than 95% or less than 98% loss of activity, and generally wherein the activity is less than Detectable binding levels in the ELISA assay (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ). Unless otherwise stated, the Fc domains described herein retain binding to the FcRn receptor.

[0075] "Administering / administration of" a substance, compound, or agent to a subject refers to contact of the substance, compound, or agent with a subject or a cell, tissue, organ, or body fluid of the subject. For example, the compound or agent can be administered intravenously or subcutaneously. Administration can also be performed, for example, once, multiple times, and / or over one or more extended time 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 who administers a drug by another person and / or provides a drug prescription to a subject is administering a drug to a subject.

[0076] As used herein, the term "affinity" of a molecule refers to the strength of an interaction between a molecule and a binding partner (such as a receptor, ligand, or antigen). The affinity of a molecule for its binding partner is often expressed as the binding affinity equilibrium dissociation constant (KD) for a particular interaction, where the lower the KD, the higher the affinity. The KD binding affinity constant can be measured by surface plasmon resonance, for example using The KD can also be measured using the Pharmacia Biosensor AB system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ). See also 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. KD can also be measured using System (Sapidyne Instruments, Hanover, Germany and Boise, ID) for measurement. In some embodiments, the IL-15 variants of the heterodimeric protein described herein have a reduced binding affinity to the IL-2 / IL-15βγ receptor compared to wild-type IL-15. In some embodiments, the first Fc variant and / or the second Fc variant of the heterodimeric protein described herein have a reduced affinity to human, cynomolgus monkey and mouse Fcγ receptors. In some embodiments, the first Fc variant and / or the second Fc variant of the heterodimeric protein described herein do not bind to human, cynomolgus monkey and mouse Fcγ receptors.

[0077] As used herein, the terms "amino acid" and "amino acid identity" refer to one of the 20 naturally occurring amino acids encoded by DNA and RNA.

[0078] As used herein, the term "amino acid substitution" or "substitution" refers to replacing an amino acid at a specific position in a parent polypeptide sequence with a different amino acid. In particular, in some embodiments, substitution refers to a non-naturally occurring amino acid at a specific position, or an amino acid that does not occur naturally in an organism or in any organism. For example, the substitution E272Y refers to a variant polypeptide, in this case an Fc variant, in which the glutamic acid at position 272 is replaced by tyrosine. For clarity, a protein that has been engineered to change the nucleic acid coding sequence but does not change the starting amino acid (e.g., CGG (encoding arginine) is exchanged for CGA (still encoding arginine) to increase the expression level of the host organism) is not an "amino acid substitution"; that is, although a new gene encoding the same protein is generated, if the protein has the same amino acid at the specific position where it starts, it is not considered an amino acid substitution.

[0079] As used herein, the term "amino acid insertion", "amino acid addition" or "addition" or "insertion" refers to the addition of an amino acid sequence at a specific 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. In addition, -233ADE, -233ADE or 233ADE indicates the insertion of AlaAspGlu after position 233 and before position 234.

[0080] As used herein, the term "amino acid deletion" or "deletion" refers to the removal of an amino acid sequence at a specific position in a parent polypeptide sequence. For example, E233- or E233#, E233(), E233_ or E233del represents the deletion of glutamic acid at position 233. In addition, EDA233-, EDA233_ or EDA233# represents the deletion of the sequence GluAspAla starting at position 233.

[0081] As used herein, the term "antibody" or "Ab" refers to an immunoglobulin molecule (e.g., a complete antibody, an antibody fragment, or a modified antibody) that can recognize and bind to a specific target or antigen (such as a carbohydrate, a polynucleotide, a lipid, a polypeptide, etc.) through at least one antigen recognition site (located in the variable region of the immunoglobulin molecule). As used herein, the term "antibody" can encompass any type of antibody, including but not limited to the following antibodies that specifically bind to a given antigen: 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.). In some embodiments, "antibody" and / or "immunoglobulin" (Ig) refers to a polypeptide comprising at least two heavy (H) chains (about 50 kDa to 70 kDa) and two light (L) chains (about 25 kDa), which are optionally interconnected by disulfide bonds. There are two types of light chains: λ and κ. In humans, λ and κ light chains are similar, but only one type exists in each antibody. Heavy chains are classified as μ, δ, γ, α or ε, and define the isotype of the antibody as IgM, IgD, IgG, IgA and IgE, respectively. See generally Fundamental Immunology, Chapter 7 (Paul, W., ed., 2nd ed., Raven Press, NY (1989)) (incorporated by reference in its entirety). The methods, uses and compositions disclosed herein utilize IgG antibodies.

[0082] As used herein, the term "antigen-binding fragment" refers to a portion (or fragment) of an antibody that retains the binding specificity of the antibody. Thus, as used herein, an antigen-binding fragment retains the six CDRs of a reference antibody.

[0083] As used herein, the term "effector function" refers to a biochemical event caused by the interaction of an antibody Fc region with an Fc receptor or another effector molecule (e.g., Fc receptor-like (FcRL) molecules, complement component C1q, and protein 21 containing three motifs (TRIM21)). Effector functions include, but are not limited to, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and complement-dependent cellular cytotoxicity (CDC). As used herein, the term "ADCC" or "antibody-dependent cell-mediated cytotoxicity" refers to a cell-mediated reaction in which nonspecific cytotoxic cells expressing FcγR recognize bound antibodies on target cells and subsequently cause lysis of the target cells. ADCC is associated with binding to FcγRIIIa; increased binding to FcγRIIIa results in increased ADCC activity. As discussed herein, many embodiments of the present disclosure completely eliminate ADCC activity. As used herein, the term "ADCP" or "antibody-dependent cell-mediated phagocytosis" refers to a cell-mediated reaction in which nonspecific cytotoxic cells expressing FcγR recognize bound antibodies on target cells and subsequently cause phagocytosis of the target cells. As used herein, the term "CDC" or "complement-dependent cellular cytotoxicity" refers to effector functions leading to activation of the classical complement pathway, which is triggered by the binding of antibodies to antigens on target cells, which activates a series of cascade reactions containing complement-related protein groups in the blood.

[0084] As used herein, the terms "Fc", "Fc region" or "Fc domain" are used interchangeably herein and refer to a polypeptide comprising an antibody constant region, which in some cases does not include the first constant region immunoglobulin domain (e.g., CH1) or a portion thereof, and in some cases, is a portion of the hinge. For IgG, the Fc domain includes 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 a truncated CH1 domain, as well as CH2 and CH3 of an immunoglobulin. Although the boundaries of the Fc region may vary, the human IgG heavy chain Fc region is generally defined as including residues E216 or C226 or P230 to its carboxyl terminus, where numbering is according to EU numbering. In some embodiments, as described more fully herein, the Fc region is amino acid modified, for example to alter binding to one or more FcγR receptors or to an FcRn receptor. In some embodiments, the Fc domain is derived from a human IgG1 heavy chain Fc domain. In some embodiments, the Fc domain is derived from a human IgG2 heavy chain Fc domain. "EU format as described by Edelman" or "EU numbering" or "EU index" refers to the residue numbering of the human Fc domain as described by Edelman GM et al. (Proc. Natl. Acad. USA (1969), 63, 78-85, which is incorporated herein by reference in its entirety).

[0085] As used herein, the terms "Fc fusion protein" and "immunoadhesin" are used interchangeably and refer to a protein comprising an Fc region, typically linked (optionally via a linker moiety, as described herein) to a different protein (such as IL-15 and / or IL-15R, as described herein). In some cases, the two Fc fusion proteins may form a homodimeric Fc fusion protein or a heterodimeric Fc fusion protein, with the latter being preferred.

[0086] As used herein, the term "Fc variant" or "variant Fc" refers to a protein comprising amino acid modifications 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 parent Fc polypeptide, wherein the numbering is according to the EU index. Similarly, M428L / N434S defines an Fc variant having the substitutions M428L and N434S relative to the parent Fc polypeptide. For all positions discussed in the present invention relating to antibodies, unless otherwise stated, the amino acid position numbering is according to the EU index. Modifications can be additions, deletions or substitutions.

[0087] As used herein, the terms "Fcγ receptor," "FcγR," and "FcgammaR" are used interchangeably and refer to any member of the protein family that binds to the Fc region of an IgG antibody and is encoded by an FcγR gene. The FcγR can be 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) (Jefferis et al., 2002, Immunol Lett 82:57-65, incorporated by reference in its entirety), as well as any undiscovered human FcγR or FcγR isoform or allotype.

[0088] 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 can be from any organism. In some embodiments, FcRn is human FcRn. As known in the art, a functional FcRn protein comprises two polypeptides, commonly 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 FcRn heavy chain and beta-2-microglobulin. A variety of FcRn variants can be used to increase binding to the FcRn receptor, and in some cases to increase serum half-life. In general, unless otherwise specified, the Fc monomer disclosed herein retains binding to the FcRn receptor (and as described below, amino acid variants may be included to increase binding to the FcRn receptor).

[0089] As used herein, "IL-15", "IL15" or "interleukin 15" are used interchangeably and refer to a four-alpha-helical protein belonging to the cytokine family. IL-15 signals through a receptor complex composed of IL-2 / IL-15 receptor β (IL-15Rβ) (CD122) subunits. In some embodiments, the IL-15 protein comprises the polypeptide sequence shown in SEQ ID NO:2 (full-length human IL-15). In some embodiments, the IL-15 protein comprises the polypeptide sequence shown 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.

[0090] As used herein, "XENP24306", "XmAb306", "XmAb24306" are used interchangeably and refer to an IL15-IL15Rα heterodimeric Fc fusion protein, wherein 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.

[0091] As used herein, the term "modification" refers to an amino acid substitution, insertion and / or deletion in a polypeptide sequence, or a change in a portion chemically attached to a protein. For example, the modification can be an altered carbohydrate or PEG structure attached to a protein. "Amino acid modification" herein means an amino acid substitution, insertion and / or deletion in a polypeptide sequence. For clarity, unless otherwise indicated, amino acid modifications always refer to amino acids encoded by DNA, for example, the 20 amino acids with codons in DNA and RNA.

[0092] The terms "nucleic acid", "polynucleotide" and "oligonucleotide" are used interchangeably and refer to deoxyribonucleotide or ribonucleotide polymers in linear or circular conformations and in single-stranded or double-stranded form. For the purposes of this disclosure, these terms should not be construed as limiting the length of the polymer.

[0093] As used herein, the term "non-naturally occurring modification" refers to a non-isotypic amino acid modification. For example, since no IgG contains serine at position 434, the substitution 434S in IgG1, IgG2 or IgG4 (or a hybrid thereof) is considered a non-naturally occurring modification.

[0094] The terms "patient," "subject," and "individual" are used interchangeably herein and refer to a person in need of treatment. In some embodiments, the subject is in need of treatment for a blood cancer, such as multiple myeloma. As used herein, the terms "treating" or "treatment" refer to lessening the severity and / or frequency of symptoms, eliminating symptoms and / or underlying causes, preventing the occurrence of symptoms and / or their underlying causes, and ameliorating or repairing damage.

[0095] As used herein, the terms "polypeptide," "peptide," and "protein" are used interchangeably to refer to a polymer of amino acid residues. Expression of a fusion protein in a cell can be produced by delivering the fusion protein to the cell or by delivering a polynucleotide encoding the fusion protein to the cell, wherein the polynucleotide is transcribed and the transcript is translated to generate the fusion protein. Trans-splicing, polypeptide cleavage, and polypeptide ligation can also be involved in the expression of a protein in a cell. Methods for delivering polynucleotides and polypeptides to cells are known in the art.

[0096] As used herein, the term "position" refers to a position in a protein sequence. Positions can be numbered sequentially or according to a given format (e.g., the EU index for antibody numbering). Positions can be defined relative to a reference sequence. In such cases, a reference sequence is provided for comparison purposes, and the heterodimeric protein of the present disclosure (or a portion thereof) may include additional amino acid changes (e.g., substitutions, insertions, and deletions) relative to the reference sequence. In some embodiments, the heterodimeric protein of the present disclosure (or a portion thereof) does not include any additional amino acid changes relative to the reference sequence.

[0097] As used herein, the term "residue" refers to a position in a protein and its associated amino acid identity. For example, asparagine 297 (also known as Asn297 or N297) is the residue at position 297 in a particular protein.

[0098] 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, which will alleviate one or more of the symptoms of the condition being treated to some extent. In some embodiments, a therapeutically effective amount is an amount sufficient to achieve a beneficial or desired clinical outcome. With regard to the treatment of cancer, a therapeutically effective amount refers to an amount having at least one of the following effects: alleviating, improving, stabilizing, reversing, preventing, slowing down or delaying the progression of blood cancers such as multiple myeloma (and / or symptoms associated with the blood cancer). The effective amount that can be used for the present disclosure depends on the mode of administration, the age, weight and general health of the subject. Appropriate amounts and dosage regimens can be determined using conventional techniques in the art. For example, the International Myeloma Working Group (IMWG) unified response criteria can be used to determine efficacy.

[0099] 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 or is encoded by a nucleotide sequence that has not been intentionally modified.

[0100] Sequences cited herein are provided in Table 1 below. It is known in the art that during the processing and expression of Fc-containing proteins, the C-terminal lysine may be cleaved (also referred to in the art as C-terminal lysine shearing). Therefore, for each sequence disclosed herein containing a C-terminal lysine, a corresponding sequence that does not contain a C-terminal lysine (i.e., a C-terminal lysine cleavage product) is also contemplated. In some embodiments, the first monomer comprises a C-terminal lysine. In some embodiments, the first monomer lacks a C-terminal lysine. In some embodiments, the second monomer comprises a C-terminal lysine. In some embodiments, the second monomer lacks a C-terminal lysine.

[0101] It is also known in the art that the C-terminal cleavage process is imprecise and that additional C-terminal residues are cleaved. Therefore, for each sequence disclosed herein containing a C-terminal lysine, a corresponding sequence without two C-terminal residues is also contemplated. In some embodiments, for each sequence disclosed herein containing a C-terminal lysine, a corresponding sequence without three C-terminal residues is also contemplated. In some embodiments, for each sequence disclosed herein containing a C-terminal lysine, a corresponding sequence without four C-terminal residues is also contemplated. In some embodiments, for each sequence disclosed herein containing a C-terminal lysine, a corresponding sequence without five C-terminal residues is also contemplated. In some embodiments, for each sequence disclosed herein containing a C-terminal lysine, a corresponding sequence without six C-terminal residues is also contemplated. In some embodiments, for each sequence disclosed herein containing a C-terminal lysine, a corresponding sequence without seven C-terminal residues is also contemplated. In some embodiments, for each sequence disclosed herein containing a C-terminal lysine, a corresponding sequence without eight C-terminal residues is also contemplated. In some embodiments, for each sequence disclosed herein containing a C-terminal lysine, a corresponding sequence without nine C-terminal residues is also contemplated. In some embodiments, for each sequence containing C-terminal lysine disclosed herein, corresponding sequences without ten C-terminal residues are also envisioned. In some embodiments, for each sequence containing C-terminal lysine disclosed herein, corresponding sequences without eleven C-terminal residues are also envisioned. In some embodiments, for each sequence containing C-terminal lysine disclosed herein, corresponding sequences without twelve C-terminal residues are also envisioned. In some embodiments, for each sequence containing C-terminal lysine disclosed herein, corresponding sequences without thirteen C-terminal residues are also envisioned. In some embodiments, for each sequence containing C-terminal lysine disclosed herein, corresponding sequences without fourteen C-terminal residues are also envisioned. In some embodiments, for each sequence containing C-terminal lysine disclosed herein, corresponding sequences without fifteen C-terminal residues are also envisioned. In some embodiments, the C-terminal residue of deletion is the result of engineering (e.g., expressing a polynucleotide that lacks a nucleotide sequence encoding one or more C-terminal residues).

[0102] Table 1. Compilation of amino acid sequences described in the present disclosure.

[0103]

[0104]

[0105]

[0106]

[0107]

[0108] Methods of treating with IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody as combination therapy

[0109] The present disclosure relates to methods for treating blood cancer in a subject in need thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a heterodimeric Fc fusion protein comprising IL-15 and IL-15 receptor α (IL-15Rα) protein domains and a FcRH5xCD3 bispecific antibody. The present disclosure relates to methods for inducing CD8 + A method for proliferation of effector memory T cells, the method comprising administering to a subject an effective amount of a heterodimeric Fc fusion protein comprising IL-15 and IL-15 receptor α (IL-15Rα) protein domains and a FcRH5xCD3 bispecific antibody.

[0110] The first aspect of the present disclosure provides a method for treating a blood cancer as disclosed herein in a subject in need thereof, the method comprising administering to the subject an effective amount of (a) an IL15-IL15Rα heterodimer Fc fusion protein and (b) a FcRH5xCD3 bispecific antibody or a fragment thereof that binds two antigens. Without being bound by theory, the scientific rationale for this combination is that the T cell-mediated anti-tumor activity of the FcRH5xCD3 bispecific antibody can be enhanced by an increase in the proliferation, survival and / or effector function of T cells after exposure to an IL-15 agonist (such as the IL15-IL15Rα heterodimer Fc fusion protein disclosed herein, such as XmAb24306).

[0111] In a second aspect, the present disclosure provides the use of a therapeutically effective amount of (a) an IL15-IL15Rα heterodimeric Fc fusion protein and (b) a FcRH5xCD3 bispecific antibody or fragment thereof that binds two antigens in the manufacture of one or more medicaments for treating blood cancer in a subject in need thereof.

[0112] In a third aspect, the present disclosure provides a therapeutically effective amount of (a) an IL15-IL15Rα heterodimeric Fc fusion protein and (b) a FcRH5xCD3 bispecific antibody or a fragment thereof that binds two antigens for use in treating blood cancer in a subject in need thereof.

[0113] 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 wherein the first Fc domain is a variant of a human IgG1 Fc domain; and (b) a second fusion protein comprising an IL-15 receptor α (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 wherein the second Fc domain is a variant of a human IgG1 Fc domain.

[0114] Blood cancer refers to the abnormal or excessive production of blood cells (e.g., white blood cells). Examples of blood cancers to be treated by the methods and uses disclosed herein include, but are not limited to, leukemia, lymphoma, and myeloma. More specific non-limiting examples of such blood cancers include acute myeloid leukemia, adult acute lymphoblastic leukemia, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, B-cell non-Hodgkin's lymphoma, and multiple myeloma. In some embodiments, blood cancers are relapsed or refractory. In some embodiments, blood cancers are selected from the group consisting of: leukemia, acute myeloid leukemia, adult acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, non-Hodgkin's lymphoma, B-cell non-Hodgkin's lymphoma, and multiple myeloma. In some embodiments, blood cancers are 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's lymphoma, B-cell non-Hodgkin's 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's lymphoma. In some embodiments, the blood cancer is B-cell non-Hodgkin's lymphoma. In some embodiments, the blood cancer is multiple myeloma. In some embodiments, the blood cancer is relapsed or refractory multiple myeloma. In some embodiments, the blood cancer is a blood cancer for which standard therapy does not exist, has been proven to be ineffective or intolerable, or is considered inappropriate, or a blood cancer for which clinical trials of investigational agents are recognized standards of care.

[0115] Identifying a subject in need of such treatment can be in the judgment of the subject or a healthcare professional, and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method). Such treatment will be appropriately administered to a subject who has, has, is susceptible to, or is at risk of having a blood cancer.

[0116] IL15-IL15Rα heterodimer Fc fusion protein is known in the art. See, for example, WO 2018 / 071919, which is incorporated herein by reference. The use of IL15-IL15Rα heterodimer Fc fusion protein for treating cancer is also known in the art. See, for example, WO 2021 / 155042, which is incorporated herein by reference. XmAb24306 is an interleukin-15 (IL15) / IL15-receptor α (IL15Rα) fusion protein, which has a heterodimer Fc domain and a half-life extension mutation (IL15 / IL15Rα-Fc) after engineering. By making IL15 and IL15Rα (CD215) compound on the same Fc domain, XmAb24306 selectively engages IL2Rβ (CD122) and common γ-chain (γ) receptor (CD132), without engaging IL2Rα (CD25). Compared to IL2-based therapeutics, XmAb24306 is expected to selectively expand natural killer (NK) cells and CD8 T cells, and has minimal effect on the proliferation of regulatory T cells known to constitutively express IL2Rα. XmAb24306 has also been engineered to reduce affinity for the CD122 / CD132 receptor complex and extend half-life in vivo, thereby improving pharmacokinetics and prolonging pharmacodynamic response. In XmAb24306, the IL-15 variant was engineered to have reduced binding affinity for the IL-2 / IL-15βγ receptor complex (compared to wild-type IL-15) with the goal of improving tolerability by reducing acute toxicity and extending pharmacokinetics, and ultimately through CD8 + IL-15-mediated signaling on T cells and NK cells promotes anti-tumor immunity.

[0117] The IL-15Rα protein is a transmembrane protein with a very high affinity for IL-15, which can promote the transport of IL-15 from the endoplasmic reticulum (ER) across the cytoplasm and present the IL-15 / IL-15Rα complex on the cell surface. As used herein, the term "sushi domain of IL-15Rα" refers to a truncated extracellular region of IL-15Rα or recombinant human IL-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 (sushi domain of human IL-15Rα).

[0118] In some embodiments, 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, wherein the IL-15 protein comprises the amino acid sequence of SEQ ID NO: 5 and wherein 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 wherein 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.

[0119] The Fc receptor-like 5 (FcRH5, also known as FcRL5 or IRTA2) gene belongs to the six recently identified gene families in the immunoglobulin superfamily (IgSF). FcRH cDNA encodes a type I transmembrane glycoprotein with multiple Ig-like extracellular domains and cytoplasmic domains, which contains a consensus immunoreceptor tyrosine activation motif and / or inhibitory signaling motif. FcRH5 has been associated with enhanced proliferation and downstream isotype expression during antigen-induced B cell development (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 showed that FcRH5 expression was only expressed in the B cell lineage. The selective expression of B lineage cells and tissues indicates a good 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, indicating a prevalence of nearly 100% in MM. Overall, the high prevalence in MM, the predicted favorable safety profile, and overexpression in high-risk patients suggest that FcRH5 is a promising target for MM (Li et al. 2017).

[0120] CD3 (cluster of differentiation 3) is a protein complex and T cell co-receptor that is involved in the activation of cytotoxic T cells (CD8 + Naive T cells) and T helper cells (CD4 + CD3 is a protein that is involved in the production of MM cells. CD3 is a protein that is involved in the production of MM cells. CD3 is a protein that is involved in the production of MM cells. CD3 is a protein that is involved in the production of MM cells. CD3 is a protein that is involved in the production of MM cells. CD3 is a protein that is involved in the production of MM cells. CD3 is a protein that is involved in the production of MM cells. CD3 is a protein that is involved in the production of MM cells. CD3 is a protein that is involved in the production of MM cells. CD3 is a protein that is involved in the production of MM cells. CD3 is a protein that is involved in the production of MM cells. CD3 is a protein that is involved in the production of MM cells.

[0121] FcRH5xCD3 bispecific antibodies are known in the art. See, for example, WO2016 / 205520, which is incorporated herein by reference. The use of FcRH5xCD3 bispecific antibodies for treating cancer (including multiple myeloma) is also known in the art. See, for example, WO 2022 / 076462, which is incorporated herein by reference. In some embodiments, the FcRH5xCD3 bispecific antibody or fragment thereof that binds two 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.

[0122] In some embodiments, according to Kabat numbering, the anti-FcRH5 light chain variable region comprises a light chain complementary determining region-1 (CDR-L1) comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 11); a CDR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 12); and a CDR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 13); and the anti-FcRH5 heavy chain variable region comprises a CDR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 14); a CDR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 15); and a CDR-H3 comprising the amino acid sequence of 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).

[0123] In some embodiments, according to Kabat numbering, the anti-CD3 light chain variable region comprises a light chain complementary determining region-1 (CDR-L1) comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO:21); a CDR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO:22); and a CDR-L3 comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO:23); and the anti-CD3 heavy chain variable region comprises a CDR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO:24); a CDR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO:25); and a CDR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO:26). In some embodiments, the anti-CD3 light chain variable region comprises the amino acid sequence DIVMTQSPDSLAVSLGERATINCKSSQSLLNSRTRKNYLAWYQQKPGQSP KLLIYWTSTRKSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCKQSFILR TFGQGTKVEIK (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).

[0124] In some embodiments, the FcRH5xCD3 bispecific antibody is cevostamab. Cevostamab is described in the following documents: WHO Drug Information, Proposed INN: List 84, Volume 34, Issue 3, published on September 9, 2020 (see pages 701-703). Cevostamab, also known as BFCR4350A or RO7187797 in the art, is an Fc engineered, humanized, full-length non-glycosylated IgG1κT cell-dependent bispecific antibody (TDB) that binds to FcRH5 and CD3 and comprises an anti-FcRH5 arm containing a heavy chain polypeptide sequence of SEQ ID NO: 20 and a light chain polypeptide sequence of SEQ ID NO: 19, and an anti-CD3 arm containing a heavy chain polypeptide sequence of SEQ ID NO: 30 and a light chain polypeptide sequence of SEQ ID NO: 29. Sivositumab contains an amino acid substitution of threonine to tryptophan at position 366 of the anti-FcRH5 arm (T366W) using EU numbering of amino acid residues in the Fc region, and three amino acid substitutions on the heavy chain of the anti-CD3 arm (Y407V, T366S, and L368A) using EU numbering of amino acid residues in the Fc region (a tyrosine to valine substitution at position 407, a threonine to serine substitution at position 366, and a leucine to alanine substitution at position 368) to drive heterodimerization of the two arms (half antibody). Sivositumab also contains an amino acid substitution (N297G) at position 297 on each heavy chain using EU numbering of amino acid residues in the Fc region, which results in a minimal aglycosylated antibody that binds to Fc (Fcγ) receptors and thereby prevents Fc effector function.

[0125] In some embodiments, a FcRH5xCD3 bispecific antibody or fragment thereof that binds two antigens is administered in combination with XmAb24306. In some embodiments, silvositumumab is administered in combination with an IL15-IL15Rα heterodimer Fc fusion protein. In some embodiments, silvositumumab or fragment thereof that binds two antigens is administered in combination with an IL15-IL15Rα heterodimer Fc fusion protein. In some embodiments, silvositumumab is administered in combination with XmAb24306. In some embodiments, silvositumumab or fragment thereof that binds two antigens is administered in combination with XmAb24306.

[0126] The FcRH5xCD3 bispecific antibody (e.g., silvositumab) or a fragment thereof that binds two antigens can be administered by any suitable route. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvositumab) or a fragment thereof that binds two antigens is administered parenterally. In some embodiments, the FxRH5xCD3 bispecific antibody (e.g., silvositumab) or a fragment thereof that binds two antigens is administered intravenously. In some embodiments, the FxRH5xCD3 bispecific antibody (e.g., silvositumab) or a fragment thereof that binds two antigens is administered subcutaneously. In some embodiments, silvositumab is administered intravenously. In some embodiments, silvositumab is administered subcutaneously.

[0127] In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or fragment thereof that binds two antigens is administered systemically. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or fragment thereof that binds two 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 EW Martin. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or fragment thereof that binds two antigens is provided in a dosage form suitable for parenteral (e.g., intravenous) administration.

[0128] The amount of the FcRH5xCD3 bispecific antibody (e.g., sivosetumab) or fragment thereof that binds two antigens to be administered in combination with the heterodimeric protein (or combination thereof) of the present disclosure varies depending on the mode of administration, the age and weight of the patient, and the clinical symptoms of the cancer to be treated. A physician will be able to determine a sufficient dose of the FcRH5xCD3 bispecific antibody (e.g., sivosetumab) or fragment thereof that binds two antigens to be administered in combination with the heterodimeric protein of the present disclosure.

[0129] In some embodiments, the dose of the FcRH5xCD3 bispecific antibody (e.g., Sivosetumab) is about 0.15 mg to 198 mg. In some embodiments, the dose of the FcRH5xCD3 bispecific antibody (e.g., Sivosetumab) is about 132 mg to about 198 mg. In some embodiments, the dose of the FcRH5xCD3 bispecific antibody (e.g., Sivosetumab) is 132 mg to 198 mg. In some embodiments, the dose of the FcRH5xCD3 bispecific antibody (e.g., Sivosetumab) is about 132 mg. In some embodiments, the dose of the FcRH5xCD3 bispecific antibody (e.g., Sivosetumab) is about 132 mg per week. In some embodiments, the dose of the FcRH5xCD3 bispecific antibody (e.g., Sivosetumab) is about 132 mg every two weeks. In some embodiments, the dose of the FcRH5xCD3 bispecific antibody (e.g., Sivosetumab) is about 132 mg every three weeks. In some embodiments, the dose of the FcRH5xCD3 bispecific antibody (eg, silvostomumab) is about 132 mg every four weeks. In some embodiments, the dose of the FcRH5xCD3 bispecific antibody (eg, silvostomumab) is about 132 mg every five weeks.

[0130] In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) is 132 mg. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) is 132 mg per week. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) is 132 mg every two weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) is 132 mg every three weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) is 132 mg every four weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) is 132 mg every five weeks.

[0131] In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., Sivosetumab) is about 160 mg. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., Sivosetumab) is about 160 mg per week. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., Sivosetumab) is about 160 mg every two weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., Sivosetumab) is about 160 mg every three weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., Sivosetumab) is about 160 mg every four weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., Sivosetumab) is about 160 mg every five weeks.

[0132] In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) is 160 mg. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) is 160 mg per week. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) is 160 mg every two weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) is 160 mg every three weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) is 160 mg every four weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) is 160 mg every five weeks.

[0133] In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvostobin) is about 198 mg. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvostobin) is about 198 mg per week. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvostobin) is about 198 mg every two weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvostobin) is about 198 mg every three weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvostobin) is about 198 mg every four weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvostobin) is about 198 mg every five weeks.

[0134] In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) is 198 mg. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) is 198 mg per week. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) is 198 mg every two weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) is 198 mg every three weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) is 198 mg every four weeks. In some embodiments, the dosage of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) is 198 mg every five weeks.

[0135] In some embodiments, the dosage of silvositamab is about 0.15 mg to 198 mg. In some embodiments, the dosage of silvositamab is about 132 mg to about 198 mg. In some embodiments, the dosage of silvositamab is 132 mg to 198 mg. In some embodiments, the dosage of silvositamab is about 132 mg. In some embodiments, the dosage of silvositamab is about 132 mg per week. In some embodiments, the dosage of silvositamab is about 132 mg every two weeks. In some embodiments, the dosage of silvositamab is about 132 mg every three weeks. In some embodiments, the dosage of silvositamab is about 132 mg every four weeks. In some embodiments, the dosage of silvositamab is about 132 mg every five weeks.

[0136] In some embodiments, the dosage of silvosetumab is 132 mg. In some embodiments, the dosage of silvosetumab is 132 mg per week. In some embodiments, the dosage of silvosetumab is 132 mg every two weeks. In some embodiments, the dosage of silvosetumab is 132 mg every three weeks. In some embodiments, the dosage of silvosetumab is 132 mg every four weeks. In some embodiments, the dosage of silvosetumab is 132 mg every five weeks.

[0137] In some embodiments, the dosage of silvositumab is about 160 mg. In some embodiments, the dosage of silvositumab is about 160 mg per week. In some embodiments, the dosage of silvositumab is about 160 mg every two weeks. In some embodiments, the dosage of silvositumab is about 160 mg every three weeks. In some embodiments, the dosage of silvositumab is about 160 mg every four weeks. In some embodiments, the dosage of silvositumab is about 160 mg every five weeks.

[0138] In some embodiments, the dosage of silvosetumab is 160 mg. In some embodiments, the dosage of silvosetumab is 160 mg per week. In some embodiments, the dosage of silvosetumab is 160 mg every two weeks. In some embodiments, the dosage of silvosetumab is 160 mg every three weeks. In some embodiments, the dosage of silvosetumab is 160 mg every four weeks. In some embodiments, the dosage of silvosetumab is 160 mg every five weeks.

[0139] In some embodiments, the dosage of silvositumab is about 198 mg. In some embodiments, the dosage of silvositumab is about 198 mg per week. In some embodiments, the dosage of silvositumab is about 198 mg every two weeks. In some embodiments, the dosage of silvositumab is about 198 mg every three weeks. In some embodiments, the dosage of silvositumab is about 198 mg every four weeks. In some embodiments, the dosage of silvositumab is about 198 mg every five weeks.

[0140] In some embodiments, the dosage of silvosetumab is 198 mg. In some embodiments, the dosage of silvosetumab is 198 mg per week. In some embodiments, the dosage of silvosetumab is 198 mg every two weeks. In some embodiments, the dosage of silvosetumab is 198 mg every three weeks. In some embodiments, the dosage of silvosetumab is 198 mg every four weeks. In some embodiments, the dosage of silvosetumab is 198 mg every five weeks.

[0141] In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvostomat) or a fragment thereof that binds two antigens is administered daily, i.e., every 24 hours. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvostomat) or a fragment thereof that binds two antigens is administered weekly, i.e., once a week (Q1W). In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvostomat) or a fragment thereof that binds two antigens is administered once every two weeks, i.e., once every 14 days (Q2W). In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvostomat) or a fragment thereof that binds two antigens is administered once every three weeks, i.e., once every 21 days (Q3W). In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvostomat) or a fragment thereof that binds two antigens is administered once every four weeks, i.e., once every 28 days (Q4W). In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvositumab) or a fragment thereof that binds two antigens is administered once every five weeks (Q5W). In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvositumab) or a fragment thereof that binds two antigens is administered once every six weeks (Q6W). In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvositumab) or a fragment thereof that binds two antigens is administered once a month. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvositumab) or a fragment thereof that binds two antigens is administered intravenously according to the frequency disclosed herein.

[0142] In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvositumab) or a fragment thereof that binds two antigens is administered at any of the above frequencies in one or more cycles. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvositumab) or a fragment thereof that binds two antigens is administered at any of the above frequencies in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 cycles. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvositumab) or a fragment thereof that binds two antigens is administered at a frequency of Q1W in one or more cycles. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or a fragment thereof that binds two antigens is administered at a frequency of Q1W in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 cycles. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or a fragment thereof that binds two antigens is administered at a frequency of Q2W in one or more cycles. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or a fragment thereof that binds two antigens is administered at a frequency of Q1W for four cycles. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvositumab) or a fragment thereof that binds two antigens is administered at a frequency of Q2W in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 cycles. In some embodiments, the FcRH5xCD3 bispecific antibody is administered at a frequency of Q2W for six cycles. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvositumab) or a fragment thereof that binds two antigens is administered at a frequency of Q3W in one or more cycles. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvositumab) or a fragment thereof that binds two antigens is administered at a frequency of Q3W in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 cycles. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or a fragment thereof that binds two antigens is administered at a frequency of Q4W in one or more cycles. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or a fragment thereof that binds two antigens is administered at a frequency of Q4W in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 cycles. In some embodiments, each of the cycles is a 28-day cycle.

[0143] In some embodiments, one or more priming doses of a FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or a fragment thereof that binds two antigens is administered to the subject during a pre-phase prior to the first treatment cycle. In some embodiments, the pre-phase is seven days. See, e.g. Figure 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, two priming doses of a FcRH5xCD3 bispecific antibody (e.g., Sivositumab) or a fragment thereof that binds two antigens are administered to the subject. In some embodiments, two priming doses are administered together with 3.6 mg of a FcRH5xCD3 bispecific antibody (e.g., Sivositumab) or a fragment thereof that binds two antigens (i.e., the amount administered in the first priming dose and the amount administered in the second priming dose total 3.6 mg). In some embodiments, two priming doses are administered together with about 3.6 mg of a FcRH5xCD3 bispecific antibody (e.g., Sivositumab) (i.e., the amount administered in the first priming dose and the amount administered in the second priming dose 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 day 2 and day 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 FcRH5xCD3 bispecific antibody (e.g., sivostobin). In some embodiments, the first priming dose is about 0.3 mg FcRH5xCD3 bispecific antibody (e.g., sivostobin). In some embodiments, the second priming dose is 3.3 mg FcRH5xCD3 bispecific antibody (e.g., sivostobin). In some embodiments, the second priming dose is about 3.3 mg FcRH5xCD3 bispecific antibody (e.g., sivostobin). Without being bound by theory, splitting the 3.6 mg dose (0.3 mg and 3.3 mg) on ​​consecutive days is believed to reduce the overall cycle 1 risk of cytokine release syndrome (CRS) compared to the 3.6 mg dose in a single dose priming regimen.

[0144] In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., sivositumumab) or a fragment thereof that binds two antigens is administered Q2W for the first 24 weeks, and then Q4W after the first 24 weeks. In some examples, each cycle is a 4-week cycle. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., sivositumumab) or a fragment thereof that binds two antigens is administered Q2W for six four-week cycles, and Q4W in the seventh and any subsequent four-week cycles. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., sivositumumab) or a fragment thereof that binds two antigens is administered on day 1 and day 15 for six four-week cycles, and on day 1 in the seventh and any subsequent four-week cycles. In some embodiments, the FcRH5xCD3 bispecific antibody (e.g., sivositumumab) or a fragment thereof that binds two antigens is administered at a dose of 132 mg. In some embodiments, the FcRH5xCD3 bispecific antibody (eg, silvostomumab) or a fragment thereof that binds two antigens is administered at a dose of about 132 mg.

[0145] In some embodiments, the patient is administered a first priming dose of a FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or a fragment thereof that binds two antigens on day 1 of the pre-stage, the patient is administered a second priming dose between days 2 to 4 of the pre-stage, and thereafter, the patient is administered Q2W for six four-week cycles and Q4W for the seventh and any subsequent four-week cycles. In some embodiments, the patient is administered a first priming dose of a FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or a fragment thereof that binds two antigens on day 1 of the pre-stage, the patient is administered a second priming dose between days 2 to 4 of the pre-stage, and thereafter, the patient is administered on days 1 and 15 for six four-week cycles and on day 1 for the seventh and any subsequent four-week cycles. In some embodiments, the patient is administered a first priming dose of 0.3 mg of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) on day 1 of the pre-phase, a second priming dose of 3.3 mg of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) is administered between day 2 and day 4 of the pre-phase, and thereafter, the patient is administered a 132 mg dose of the FcRH5xCD3 bispecific antibody (e.g., silvosetumab) on day 1 for six four-week cycles and for the seventh and any subsequent four-week cycles.

[0146] IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) can be administered by any suitable route. In some embodiments, IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered parenterally. In some embodiments, parenteral administration is intravenous. In some embodiments, XmAb24306 is administered intravenously.

[0147] In some embodiments, IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered systemically. In some embodiments, IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered as a composition comprising a pharmaceutically acceptable buffer. Suitable carriers and their preparations are described, for example, in Remington's Pharmaceutical Sciences by EW Martin. In some embodiments, the heterodimer protein is provided in a dosage form suitable for parenteral (e.g., intravenous) administration.

[0148] The amount of IL15-IL15Rα heterodimeric Fc fusion protein to be administered in combination with a FcRH5xCD3 bispecific antibody that binds two antigens (e.g., sivositumab) or a fragment thereof varies depending on the mode of administration, the age and weight of the patient, and the clinical symptoms of the cancer to be treated. A physician will be able to determine a sufficient dose of IL15-IL15Rα heterodimeric Fc fusion protein to be administered in combination with a FcRH5xCD3 bispecific antibody that binds two antigens (e.g., sivositumab) or a fragment thereof.

[0149] In certain embodiments, the dosage of IL15-IL15Rα heterodimeric Fc fusion protein (e.g., XmAb24306) can vary between about 0.0001 mg protein / kg body weight to about 5 mg protein / kg body weight; or between about 0.001 mg / kg body weight to about 4 mg / kg body weight or about 0.005 mg / kg body weight to about 1 mg / kg body weight or about 0.005 mg / kg body weight to about 0.3 mg / kg body weight or about 0.005 mg / kg body weight to about 0.2 mg / kg body weight or about 0.005 mg / kg body weight to about 0.02 mg / kg body weight. In some embodiments, such a dose of an 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 0.0 .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 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 IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.0025 mg / kg body weight. In some embodiments, the dose of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.01 mg / kg body weight. In some embodiments, the dose of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.015 mg / kg body weight. In some embodiments, the dose of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.02 mg / kg body weight.In some embodiments, the dosage of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.03 mg / kg body weight. In some embodiments, the dosage of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.04 mg / kg body weight. In some embodiments, the dosage of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.06 mg / kg body weight. In some embodiments, the dosage of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.08 mg / kg body weight. In some embodiments, the dosage of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.09 mg / kg body weight. In some embodiments, the dosage of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.12 mg / kg body weight. In some embodiments, the dosage of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.135 mg / kg body weight. In some embodiments, the dosage of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.16 mg / kg body weight. In some embodiments, the dosage of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.2025 mg / kg body weight. In some embodiments, the dosage of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.24 mg / kg body weight. In some embodiments, the dose of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is about 0.32 mg / kg body weight. In some embodiments, 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, 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 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. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered by IV infusion according to these doses.

[0150] In certain embodiments, the dosage of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) can vary between 0.0001 mg protein / kg body weight to 5 mg protein / kg body weight; or between 0.001 mg / kg body weight to 4 mg / kg body weight or 0.005 mg / kg body weight to 1 mg / kg body weight or 0.005 mg / kg body weight to 0.3 mg / kg body weight or 0.005 mg / kg body weight to 0.2 mg / kg body weight or 0.005 mg / kg body weight to 0.02 mg / kg body weight. In some embodiments, such a dosage of IL15-IL15Rα heterodimeric 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 dose of IL15-IL15Rα heterodimeric 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 dose of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.0025 mg / kg body weight. In some embodiments, the dose of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.01 mg / kg body weight. In some embodiments, the dose of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.015 mg / kg body weight. In some embodiments, the dose of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.02 mg / kg body weight. In some embodiments, the dose of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.03 mg / kg body weight.In some embodiments, the dose of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.04 mg / kg body weight. In some embodiments, the dose of IL15-IL15Rα heterodimer Fc fusion protein is 0.06 mg / kg body weight. In some embodiments, the dose of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.08 mg / kg body weight. In some embodiments, the dose of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.09 mg / kg body weight. In some embodiments, the dose of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.12 mg / kg body weight. In some embodiments, the dose of IL15-IL15Rα heterodimer Fc fusion protein is 0.135 mg / kg body weight. In some embodiments, the dose of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.16 mg / kg body weight. In some embodiments, the dose of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.2025 mg / kg body weight. In some embodiments, the dose of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is 0.24 mg / kg body weight. In some embodiments, the dose of 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 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, 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 doses.

[0151] 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 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. In some embodiments, XmAb24306 is administered by IV infusion according to these doses.

[0152] 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 doses.

[0153] 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 weekly, i.e., once a 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 (e.g., XmAb24306) of the present disclosure is administered by IV infusion according to the frequency disclosed herein.

[0154] In some embodiments, IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at any of the above frequencies in one or more cycles. In some embodiments, IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at any of the above frequencies in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 cycles. In some embodiments, IL15-IL15Rα heterodimer Fc fusion protein is administered at a frequency of Q1W in one or more cycles. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at a frequency of Q1W in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 cycles. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at a frequency of Q2W in one or more cycles. In some embodiments, the IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at a frequency of Q2W in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 cycles. In some embodiments, IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at a frequency of Q3W in one or more cycles. In some embodiments, IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at a frequency of Q3W in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 cycles. In some embodiments, IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at a frequency of Q4W in one or more cycles. In some embodiments, the IL15-IL15Rα heterodimeric Fc fusion protein (eg, XmAb24306) is administered at a frequency of Q4W for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 cycles.

[0155] The IL15-IL15Rα heterodimer Fc fusion protein disclosed herein (e.g., XmAb24306) can be administered Q4W. In some embodiments, the first dose of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered at least 24 hours after the first 1st cycle dose of FcRH5xCD3 bispecific antibody (e.g., sivostos monoclonal antibody) or a fragment thereof that binds two antigens. In some embodiments, the first dose of IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered between day 2 and day 4 of the 1st cycle. In some embodiments, IL15-IL15Rα heterodimer Fc fusion protein (e.g., XmAb24306) is administered on day 1 of the 2nd cycle and subsequent cycles.

[0156] A fourth aspect of the present disclosure provides 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 an amino acid sequence of SEQ ID NO: 9, and a second monomer comprising an amino acid sequence of SEQ ID NO: 10; and (b) sivosetumab, wherein sivosetumab comprises: an anti-FcRH5 light chain comprising an amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising an amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising an amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising an 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 sivosetumab is administered intravenously at a dose of about 132 mg.

[0157] A fifth aspect of the present disclosure provides for use of a therapeutically effective amount of the following in the manufacture of one or more medicaments for treating multiple myeloma in a subject in need thereof: (a) XmAb24306, wherein XmAb24306 comprises: a first monomer comprising an amino acid sequence of SEQ ID NO:9, and a second monomer comprising an amino acid sequence of SEQ ID NO:10; and (b) sivosetumab, wherein sivosetumab comprises: an anti-FcRH5 light chain comprising an amino acid sequence of SEQ ID NO:19, an anti-FcRH5 heavy chain comprising an amino acid sequence of SEQ ID NO:20, an anti-CD3 light chain comprising an amino acid sequence of SEQ ID NO:29, and an anti-CD3 heavy chain comprising an 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 sivosetumab is administered intravenously at a dose of about 132 mg.

[0158] A sixth aspect of the present disclosure provides a therapeutically effective amount of (a) XmAb24306, wherein XmAb24306 comprises: a first monomer comprising an amino acid sequence of SEQ ID NO: 9, and a second monomer comprising an amino acid sequence of SEQ ID NO: 10; and (b) sivosetumab, wherein sivosetumab comprises: an anti-FcRH5 light chain comprising an amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising an amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising an amino acid sequence of SEQ ID NO: 29, and an anti-CD3 heavy chain comprising an amino acid sequence of SEQ ID NO: 30, for 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 sivosetumab is administered intravenously at a dose of about 132 mg.

[0159] In some embodiments, the subject has previously been administered one or more priming doses of silvositumab for a total dose of about 3.6 mg, wherein the priming dose is administered as a single dose. In some embodiments, the subject has previously been administered one or more priming doses of silvositumab for a total dose of about 3.6 mg, wherein 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 wherein the second priming dose is administered on day 2, 3, or 4.

[0160] In some embodiments, XmAb24306 is administered at a frequency of Q4W for one or more cycles.

[0161] In some embodiments, silvostomumab is administered at a frequency of Q2W for one or more cycles. In some embodiments, silvostomumab is administered at a frequency of Q4W for one or more cycles.

[0162] In some embodiments, XmAb24306 is administered intravenously at a frequency of Q4W for at least seven four-week cycles, and wherein a first priming dose of 0.3 mg of silvositumab is administered intravenously on day 1 of the pre-phase, a second priming dose of 3.3 mg of silvositumab is administered intravenously between days 2 and 4 of the pre-phase, wherein the pre-phase is seven days, and thereafter, a dose of 132 mg of silvositumab is administered intravenously on days 1 and 15 for six four-week cycles and on day 1 for the seventh and any subsequent four-week cycles.

[0163] A seventh aspect of the present disclosure provides a method for 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 an amino acid sequence of SEQ ID NO: 9, and a second monomer comprising an amino acid sequence of SEQ ID NO: 10, and (b) sivosetumab, wherein sivosetumab comprises: an anti-FcRH5 light chain comprising an amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising an amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising an amino acid sequence of SEQ ID NO: 29, and a second monomer comprising an amino acid sequence of SEQ ID NO: 10. 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 seven four-week cycles, and wherein a first priming dose of 0.3 mg of silvositumomab is administered intravenously on day 1 of the pre-phase, a second priming dose of 3.3 mg of silvositumomab is administered intravenously between day 2 and day 4 of the pre-phase, wherein the pre-phase is seven days, and thereafter, a dose of 132 mg of silvositumomab is administered intravenously on day 1 and day 15 for six four-week cycles and on day 1 for the seventh and any subsequent four-week cycles.

[0164] An eighth aspect of the present disclosure provides a use of a therapeutically effective amount of the following in the manufacture of one or more medicaments for treating multiple myeloma in a subject in need thereof: (a) XmAb24306, wherein XmAb24306 comprises: a first monomer comprising an amino acid sequence of SEQ ID NO: 9, and a second monomer comprising an amino acid sequence of SEQ ID NO: 10; and (b) sivosetumab, wherein sivosetumab comprises: an anti-FcRH5 light chain comprising an amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising an amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising an amino acid sequence of SEQ ID NO: 29, and a second monomer comprising an amino acid sequence of SEQ ID NO: 10. 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 seven four-week cycles, and wherein a first priming dose of 0.3 mg of silvositumomab is administered intravenously on day 1 of the pre-phase, a second priming dose of 3.3 mg of silvositumomab is administered intravenously between day 2 and day 4 of the pre-phase, wherein the pre-phase is seven days, and thereafter, a dose of 132 mg of silvositumomab is administered intravenously on day 1 and day 15 for six four-week cycles and on day 1 for the seventh and any subsequent four-week cycles.

[0165] A ninth aspect of the present disclosure provides a therapeutically effective amount of (a) XmAb24306, wherein XmAb24306 comprises: a first monomer comprising an amino acid sequence of SEQ ID NO: 9, and a second monomer comprising an amino acid sequence of SEQ ID NO: 10; and (b) sivosetumab, wherein sivosetumab comprises: an anti-FcRH5 light chain comprising an amino acid sequence of SEQ ID NO: 19, an anti-FcRH5 heavy chain comprising an amino acid sequence of SEQ ID NO: 20, an anti-CD3 light chain comprising an amino acid sequence of SEQ ID NO: 29, and a second monomer comprising an amino acid sequence of SEQ ID NO: 10. An anti-CD3 heavy chain of the amino acid sequence of NO:30 for 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 at a frequency of Q4W for at least seven four-week cycles, and wherein a first starting dose of 0.3 mg of silvositumab is administered intravenously on day 1 of the pre-phase, a second starting dose of 3.3 mg of silvositumab is administered intravenously between day 2 and day 4 of the pre-phase, wherein the pre-phase is seven days, and thereafter, a dose of 132 mg of silvositumab is administered intravenously on day 1 and day 15 for six four-week cycles and on day 1 for the seventh and any subsequent four-week cycles.

[0166] In any of the above methods, the IL15-IL15Rα heterodimeric Fc fusion protein disclosed herein (e.g., XmAb24306) can be administered simultaneously or sequentially with a FcRH5xCD3 bispecific antibody (e.g., sivostobin) or a fragment thereof that binds two antigens. In some embodiments of any of the above methods, the IL15-IL15Rα heterodimeric Fc fusion protein disclosed herein (e.g., XmAb24306) and a FcRH5xCD3 bispecific antibody (e.g., sivostobin) or a fragment thereof that binds two antigens are administered simultaneously. In some embodiments of any of the above methods, the IL15-IL15Rα heterodimeric Fc fusion protein disclosed herein (e.g., XmAb24306) and a FcRH5xCD3 bispecific antibody (e.g., sivostobin) or a fragment thereof that binds two antigens are administered sequentially. In some embodiments of any of the above methods, a FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or a fragment thereof that binds two antigens is administered after administration of an IL15-IL15Rα heterodimeric Fc fusion protein (e.g., XmAb24306) disclosed herein. In some embodiments of any of the above methods, a FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or a fragment thereof that binds two antigens is administered before administration of an IL15-IL15Rα heterodimeric Fc fusion protein (e.g., XmAb24306) disclosed herein. In some embodiments of any of the above methods, an IL15-IL15Rα heterodimeric Fc fusion protein (e.g., XmAb24306) disclosed herein and a FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or a fragment thereof that binds two antigens are administered in the same composition. In some embodiments of any of the above methods, an IL15-IL15Rα heterodimeric Fc fusion protein disclosed herein (eg, XmAb24306) is administered in a different composition than a FcRH5xCD3 bispecific antibody (eg, sivostatin) or a fragment thereof that binds two antigens.

[0167] In some embodiments of any of the above methods, the IL15-IL15Rα heterodimeric Fc fusion protein disclosed herein (e.g., XmAb24306) and the FcRH5xCD3 bispecific antibody (e.g., silvostomumab) or a fragment thereof that binds two antigens can act synergistically. In some embodiments of any of the above methods, the IL15-IL15Rα heterodimeric Fc fusion protein (e.g., XmAb24306) can 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., silvostomumab) or a fragment thereof that binds two antigens can be administered at a dose less than its therapeutically effective dose when administered as a monotherapy.

[0168] In some embodiments of any one of the above methods, the method further includes administering a corticosteroid to the subject. In certain embodiments, a corticosteroid is administered to a subject with signs or symptoms of CRS. CRS symptoms may be progressive, must include fever at the beginning, and may include hypotension, capillary leakage (hypoxia), and end-organ dysfunction. Fever should result in a temperature of ≥38°C (100.4°F) and may last for a long time (e.g., greater than 4 hours, such as greater than 6 hours). In certain embodiments, corticosteroids are administered intravenously. In certain embodiments, the corticosteroid is dexamethasone. In certain embodiments, dexamethasone is administered at a dose of 10 mg. In certain embodiments, 10 mg dexamethasone is administered intravenously every six hours.

[0169] In some embodiments of any of the methods above, the method further comprises administering a therapeutically effective amount of tocilizumab. is a recombinant humanized anti-human monoclonal antibody directed against soluble and membrane-bound IL-6R that inhibits IL-6-mediated signaling. Emerging evidence suggests that IL-6 acts as a central mediator in CRS. Without being bound by theory, blocking the inflammatory effects of IL-6 using tocilizumab may therefore represent an effective approach to treating CRS. In fact, the U.S. Food and Drug Administration has approved tocilizumab for the treatment of severe or life-threatening CAR T cell-induced CRS in adult patients and pediatric patients aged ≥2 years. However, recent literature supports the use of tocilizumab in all grades of CRS (Neelapu et al., 2018; Riegler et al., 2019). Therefore, patients who develop CRS treated with FcRH5xCD3 bispecific antibodies (e.g., silvostomumab) may benefit from tocilizumab therapy.

[0170] In some embodiments of any one of the above methods, Tocilizumab is administered to a subject experiencing a CRS event. In some embodiments of any one of the above methods, Tocilizumab is administered to a subject who is still refractory to corticosteroids 24 hours after the first corticosteroid dose. In some embodiments of any one of the above methods, Tocilizumab is administered at a dosage of 8mg / kg. In some embodiments of any one of the above methods, Tocilizumab is administered at a dosage of 12mg / kg. In some embodiments of any one of the above methods, if the patient's weight is ≥30kg, Tocilizumab is administered at a dosage of 8mg / kg. In some embodiments of any one of the above methods, if the patient's weight is <30kg, Tocilizumab is administered at a dosage of 12mg / kg. In some embodiments of any one of the above methods, Tocilizumab is administered intravenously. In some embodiments, Tocilizumab is administered every 8 hours.

[0171] In some embodiments of any of the above methods, the subject has previously been administered an agent for treating a blood cancer. In some embodiments of any of the above methods, the subject has previously been administered one or more previous treatments for treating a blood cancer. In some embodiments of any of the above methods, the subject has previously been administered one previous treatment. In some embodiments of any of the above methods, the subject has previously been administered two previous treatments. In some embodiments of any of the above methods, the subject has previously been administered three previous treatments. In some embodiments of any of the above methods, the subject has previously been administered four previous treatments. In some embodiments, the subject has previously been administered five previous treatments. In some embodiments of any of the above methods, the previous treatment administered to the subject is an immunomodulatory drug, 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 previous treatments, including at least one immunomodulatory drug, 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 previous treatments, including at least one immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. In some embodiments, the previous treatment administered to the subject is an immunomodulatory drug. In some embodiments of any of the above methods, the immunomodulatory drug is selected from the group consisting of: lenalidomide, thalidomide, and pomalidomide. In some embodiments of any of the above methods, the immunomodulatory drug is lenalidomide. In some embodiments of any of the above methods, the immunomodulatory drug is thalidomide. In some embodiments of any of the above methods, the immunomodulatory drug is pomalidomide. In some embodiments of any of the above methods, the previous treatment 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 previous treatment 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, mazetuzumab (TAK-079), and furezetuzumab (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 mazetuzumab. In some embodiments of any of the above methods, the anti-CD38 monoclonal antibody is fezetuzumab.

[0172] Exemplary Embodiments

[0173] Specific embodiments of the present disclosure are set forth in the following numbered paragraphs:

[0174] 1. A method for treating 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) a FcRH5xCD3 bispecific antibody or a fragment thereof that binds to two antigens.

[0175] 2. Use of a therapeutically effective amount of (a) an IL15-IL15Rα heterodimeric Fc fusion protein and (b) a FcRH5xCD3 bispecific antibody or a fragment thereof that binds two antigens in the manufacture of one or more medicaments for treating blood cancer in a subject in need thereof.

[0176] 3. A therapeutically effective amount of (a) an IL15-IL15Rα heterodimeric Fc fusion protein and (b) a FcRH5xCD3 bispecific antibody or a fragment thereof that binds two antigens, for use in treating blood cancer in a subject in need thereof.

[0177] 4. The method according to embodiment 1, the use according to embodiment 2, or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 3, 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 wherein the first Fc domain is a variant of a human IgG1 Fc domain; and (b) a second fusion protein comprising an IL-15 receptor α (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 wherein the second Fc domain is a variant of a human IgG1 Fc domain.

[0178] 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-

[0179] The 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 wherein 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 α (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 wherein the second Fc domain comprises the amino acid sequence of SEQ ID NO:7.

[0180] 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.

[0181] 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.

[0182] 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 heterodimeric 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.

[0183] 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.

[0184] 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.

[0185] 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 a 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.

[0186] 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.

[0187] 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 two 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.

[0188] 14. The method, use, or IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to Example 13, wherein the anti-FcRH5 light chain variable region comprises a light chain complementary 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 heavy chain complementary 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.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] 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.

[0193] 19. The method, use, or IL15-IL15Rα heterodimeric 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 a light chain complementary 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; and the anti-CD3 heavy chain variable region comprises a heavy chain complementary 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.

[0194] 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.

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 24. The method, use or IL15-IL15Rα heterodimeric 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.

[0199] 25. The method, use or IL15-IL15Rα heterodimeric 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.

[0200] 26. The method, the use or the IL15-IL15Rα heterodimer Fc fusion protein and the FcRH5xCD3 bispecific antibody or a fragment thereof according to any one of embodiments 19 to 25, wherein the FcRH5xCD3 bispecific antibody is sivostatin.

[0201] 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 heterodimeric 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's lymphoma, B-cell non-Hodgkin's lymphoma and multiple myeloma.

[0202] 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.

[0203] 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.

[0204] 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 heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 29, wherein the subject has previously been administered one or more prior treatments.

[0205] 31. The method, use or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 30, wherein the previous treatment is an immunomodulatory drug, a proteasome inhibitor or an anti-CD38 monoclonal antibody.

[0206] 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 drug is selected from the group consisting of: lenalidomide, thalidomide and pomalidomide.

[0207] 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.

[0208] 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, mazetuzumab and furezetuzumab.

[0209] 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 g, 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.

[0210] 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.

[0211] 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 heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 36, wherein the IL15-IL15Rα heterodimeric 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.

[0212] 38. The method, use or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 36, 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.

[0213] 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 heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 38, wherein the IL15-IL15Rα heterodimeric Fc fusion protein is administered at a frequency selected from the group consisting of: Q1W, Q2W, Q3W, Q4W, Q5W and Q6W.

[0214] 40. The method, the use or the IL15-IL15Rα heterodimer Fc fusion protein and the FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 39, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered at a frequency of Q1W in one or more cycles.

[0215] 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 a frequency of Q2W in one or more cycles.

[0216] 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 a frequency of Q4W in one or more cycles.

[0217] 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 heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 42, wherein the IL15-IL15Rα heterodimeric Fc fusion protein is administered intravenously.

[0218] 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 heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 43, wherein the IL15-IL15Rα heterodimeric Fc fusion protein and the FcRH5xCD3 bispecific antibody or fragment thereof that binds to two antigens are administered simultaneously.

[0219] 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 heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 43, wherein the IL15-IL15Rα heterodimeric Fc fusion protein and the FcRH5xCD3 bispecific antibody or fragment thereof that binds to two antigens are administered sequentially.

[0220] 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 two antigens is administered in one or more cycles at a frequency selected from the group consisting of: Q1W, Q2W, Q3W, Q4W, Q5W and Q6W.

[0221] 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 binding to two antigens is administered at a frequency of Q2W in one or more cycles.

[0222] 48. The method, use or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 47, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered at a frequency of Q4W, and wherein the FcRH5xCD3 bispecific antibody or fragment thereof that binds to two antigens is administered at a frequency of Q2W, and the administration is performed in one or more cycles.

[0223] 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 binding to two antigens is administered at a frequency of Q4W in one or more cycles.

[0224] 50. The method, the use or the 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 said one or more cycles is a four week cycle.

[0225] 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 binding to two antigens is administered Q2W for six four-week cycles and Q4W in the seventh and any subsequent four-week cycles.

[0226] 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 binding to two antigens is administered on day 1 and day 15 for six four-week cycles, and on day 1 in the seventh and any subsequent four-week cycles.

[0227] 53. The method according to any one of embodiments 1 and 4 to 52, the use according to any one of embodiments 2 and 4 to 52, or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or a fragment thereof according to any one of embodiments 3 to 52, wherein the FcRH5xCD3 bispecific antibody is administered at a dose of about 132 mg to about 198 mg.

[0228] 54. The method, the use or the IL15-IL15Rα heterodimer Fc fusion protein and the FcRH5xCD3 bispecific antibody or a fragment thereof according to embodiment 53, wherein the FcRH5xCD3 bispecific antibody is administered at a dose of about 132 mg.

[0229] 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 in one or more 28-day cycles.

[0230] 56. The method, the use or the IL15-IL15Rα heterodimer Fc fusion protein and the FcRH5xCD3 bispecific antibody or a fragment thereof according to embodiment 53, wherein the FcRH5xCD3 bispecific antibody is administered at a dose of about 160 mg.

[0231] 57. The method, the use or the IL15-IL15Rα heterodimer Fc fusion protein and the FcRH5xCD3 bispecific antibody or a fragment thereof according to embodiment 53, wherein the FcRH5xCD3 bispecific antibody is administered at a dose of about 198 mg.

[0232] 58. The method, use or IL15-IL15Rα heterodimeric 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 binding to two antigens is administered to the subject during a preliminary period prior to the first treatment cycle.

[0233] 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-phase is seven days.

[0234] 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.

[0235] 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 two antigens are administered to the subject.

[0236] 62. The method, the use or the IL15-IL15Rα heterodimeric 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-phase.

[0237] 63. The method, the use or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 62, wherein the second priming dose is administered between day 2 and day 4 of the pre-phase.

[0238] 64. The method, use or IL15-IL15Rα heterodimeric 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.

[0239] 65. The method, the use or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 61 to 64, wherein the two priming doses are administered together with about 3.6 mg of the FcRH5xCD3 bispecific antibody.

[0240] 66. The method, use or IL15-IL15Rα heterodimeric 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.

[0241] 67. The method according to any one of embodiments 1 and 4 to 55 and 58 to 66, the use according to any one of embodiments 2 and 4 to 55 and 58 to 66, or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 55 and 58 to 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 preliminary period, the subject is administered a second priming dose of about 3.3 mg of the FcRH5xCD3 bispecific antibody between day 2 and day 4 of the preliminary period, and thereafter, the subject is administered a dose of about 132 mg of the FcRH5xCD3 bispecific antibody on day 1 and day 15 for six four-week cycles and on day 1 for the seventh and any subsequent four-week cycles.

[0242] 68. The method according to any one of embodiments 1 and 4 to 67, the use according to any one of embodiments 2 and 4 to 67, or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or a fragment thereof according to any one of embodiments 3 to 67, wherein the FcRH5xCD3 bispecific antibody is administered intravenously.

[0243] 69. The method according to any one of embodiments 1 and 4 to 68, the use according to any one of embodiments 2 and 4 to 68, or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 3 to 68, wherein the method further comprises administering a therapeutically effective amount of tocilizumab to the subject.

[0244] 70. The method, the use or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 69, wherein the subject has suffered a cytokine release syndrome (CRS) event.

[0245] 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 the tocilizumab is administered to a subject who is refractory to corticosteroids 24 hours after the first corticosteroid dose.

[0246] 72. The method, the use or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 69 to 71, wherein tocilizumab is administered at a dose of 8 mg / kg.

[0247] 73. The method, use or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 72, wherein if the subject weighs ≥30 kg, the tocilizumab is administered at a dose of 8 mg / kg.

[0248] 74. The method, the use or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 69 to 71, wherein tocilizumab is administered at a dose of 12 mg / kg.

[0249] 75. The method, use or IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to embodiment 74, wherein if the patient weighs <30 kg, the tocilizumab is administered at a dose of 12 mg / kg.

[0250] 76. The method, the use or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 69 to 75, wherein the tocilizumab is administered intravenously.

[0251] 77. The method, the use or the IL15-IL15Rα heterodimer Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of embodiments 69 to 76, wherein the tocilizumab is administered every 8 hours.

[0252] 78. 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) silvositumomab, wherein silvositumomab 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 silvositumomab is administered intravenously at a dose of about 132 mg.

[0253] 79. Use of a therapeutically effective amount of the following in the manufacture of one or more medicaments for treating multiple myeloma in a subject in need thereof: (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) sivosetumab, wherein sivosetumab 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 for intravenous administration at a dose of about 0.02 mg / kg to about 0.06 mg / kg, and sivosetumab is formulated for intravenous administration at a dose of about 132 mg.

[0254] 80. 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) sivosetumab, wherein sivosetumab 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 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 sivosetumab is administered intravenously at a dose of about 132 mg.

[0255] 81. The method of embodiment 78, the use of embodiment 79, or XmAb24306 and silvostomumab of embodiment 80, wherein the treatment further comprises administering to the subject one or more priming doses of silvostomumab at a total dose of about 3.6 mg during a seven-day pre-phase prior to the first treatment cycle, wherein the priming dose is administered as a single dose.

[0256] 82. The method of embodiment 78, the use of embodiment 79, or XmAb24306 and silvostomumab of embodiment 80, wherein the treatment further comprises administering to the subject one or more priming doses of silvostomumab at a total dose of about 3.6 mg during a seven-day pre-phase prior to the first treatment cycle, wherein the priming dose is administered in two doses.

[0257] 83. The method, the use, or XmAb24306 and silvostomumab according to embodiment 82, wherein the first priming dose is about 0.3 mg and the second priming dose is about 3.3 mg.

[0258] 84. The method, the use, or XmAb24306 and silvostomumab according to embodiment 83, wherein the first priming dose is administered on day 1 of the pre-period, and wherein the second priming dose is administered on day 2, 3, or 4 of the pre-period.

[0259] 85. The method according to any one of embodiments 78 and 81 to 84, the use according to any one of embodiments 79 and 81 to 84, or XmAb24306 and sivostatin according to any one of embodiments 80 to 84, wherein XmAb24306 is administered at a frequency of Q4W for one or more cycles.

[0260] 86. The method according to any one of embodiments 78 and 81 to 85, the use according to any one of embodiments 79 and 81 to 85, or XmAb24306 according to any one of embodiments 80 to 85 and silvositumomab, wherein silvositumomab is administered at a frequency of Q2W for one or more cycles.

[0261] 87. The method according to any one of embodiments 78 and 81 to 86, the use according to any one of embodiments 79 and 81 to 86, or XmAb24306 according to any one of embodiments 80 to 86 and silvositumomab, wherein silvositumomab is administered at a frequency of Q4W for one or more cycles.

[0262] 88. The method according to any one of embodiments 78 and 81 to 87, the use according to any one of embodiments 79 and 81 to 87, or XmAb24306 and silvositumomab according to any one of embodiments 80 to 87, wherein XmAb24306 is administered intravenously at a frequency of Q4W for at least seven four-week cycles, and wherein a first priming dose of silvositumomab of 0.3 mg is administered intravenously on day 1 of a pre-phase, a second priming dose of silvositumomab of 3.3 mg is administered intravenously between day 2 and day 4 of a pre-phase, wherein the pre-phase is seven days, and thereafter, a dose of 132 mg of silvositumomab is administered intravenously on day 1 and day 15 for six four-week cycles and on day 1 for the seventh and any subsequent four-week cycles.

[0263] 89. A method for 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) sivosetumab, wherein sivosetumab 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 a second monomer comprising the amino acid sequence of SEQ ID NO: 10. 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 seven four-week cycles, and wherein a first priming dose of 0.3 mg of silvositumomab is administered intravenously on day 1 of the pre-phase, a second priming dose of 3.3 mg of silvositumomab is administered intravenously between day 2 and day 4 of the pre-phase, wherein the pre-phase is seven days, and thereafter, a dose of 132 mg of silvositumomab is administered intravenously on day 1 and day 15 for six four-week cycles and on day 1 for the seventh and any subsequent four-week cycles.

[0264] 90. Use of a therapeutically effective amount of the following in the manufacture of one or more medicaments for treating multiple myeloma in a subject in need thereof: (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) sivosetumab, wherein sivosetumab 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 a second monomer comprising the amino acid sequence of SEQ ID NO: 10. NO:30, wherein XmAb24306 is formulated for intravenous administration at a dose of about 0.02 mg / kg to about 0.06 mg / kg at a frequency of Q4W for at least seven four-week cycles, wherein silvositumomab is formulated for intravenous administration at a dose of 132 mg on days 1 and 15 for six four-week cycles and on day 1 for the seventh and any subsequent four-week cycles; and wherein the treatment further comprises a seven-day pre-phase, wherein a first priming dose of silvositumomab of 0.3 mg is administered intravenously on day 1 of the pre-phase, and a second priming dose of silvositumomab of 3.3 mg is administered intravenously between days 2 and 4 of the pre-phase.

[0265] 91. 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) sivosetumab, wherein sivosetumab 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 a second monomer comprising the amino acid sequence of SEQ ID NO: 10. An anti-CD3 heavy chain of the amino acid sequence of NO:30 for 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 at a frequency of Q4W for at least seven four-week cycles, and wherein a first priming dose of 0.3 mg of silvositumab is administered intravenously on day 1 of the pre-phase, a second priming dose of 3.3 mg of silvositumab is administered intravenously between day 2 and day 4 of the pre-phase, wherein the pre-phase is seven days, and thereafter, a dose of 132 mg of silvositumab is administered intravenously on day 1 and day 15 for six four-week cycles and on day 1 for the seventh and any subsequent four-week cycles.

[0266] Examples

[0267] Example 1: In vitro pharmacological activity of the combination therapy of silvostomumab and XmAb24306

[0268] Bone marrow mononuclear cells (BMMC) cryopreserved vials from multiple myeloma subjects were purchased from Discovery Life Sciences. Samples were thawed according to the manufacturer's instructions. Samples were cultured overnight in RPMI containing 10% fetal calf serum (FCS) and 100 ng / mL recombinant human IL-6. Viable BMMCs were isolated by Ficoll density gradient centrifugation. 3 x 10 5 Live cells were pretreated with 10 mg / mL XmAb24306 for 24 hours, followed by the addition of 15 ng / mL silvostomumab for combination treatment or medium addition as single agent treatment in 96-well plates. Treatment continued for another 72 hours. At the end of treatment, cells were collected and myeloma cell lysis was quantified by flow cytometric analysis. TM Absolute cell counts were quantified using Absolute Counting Beads (ThermoFisher Scientific, #C36950). Multiple myeloma tumor cells were defined as CD38 高 CD138 + The killing activity was calculated as follows: {(untreated live target cell number - treated live target cell number) / (untreated live target cell number)}×100%.

[0269] The in vitro pharmacological activity of silvostomumab in combination with XmAb24306 was evaluated. Primary BMMCs from multiple myeloma (MM) subjects (n=3) were treated with autologous CD8 + The ratio of T cells:tumor cells varied from 0.1:1 to 2:1. The effects of treatment with XmAb24306 alone or silvosetumab alone were compared to the effects of treatment with a combination of XmAb24306a and silvosetumab. Sivosetumab alone at 15 ng / mL showed 10% to 40% tumor cell lysis ( Figure 1B ) and does not change CD8 + T cell count ( Figure 1A Treatment with 10 mg / mL XmAb24306 slightly increased CD8 + T cell count ( Figure 1A ), while tumor cell lysis is minimal ( Figure 1B Co-treatment of XmAb24306 and silvostomumab synergistically increased CD8 + T cell count ( Figure 1A) and synergistically enhanced the target cell killing effect mediated by silvostomumab ( Figure 1B ).

[0270] Human peripheral blood mononuclear cells (PBMC) were isolated from whole blood of healthy donors by Ficoll gradient. In the presence or absence of 5000pM silvostamab, PBMC and multiple myeloma cell lines (e.g., MOLP-2 cells) were prepared in 96-well plates at a ratio of 3:1 for 30 minutes, 2 hours, 4 hours, 24 hours, and 48 hours. At the end of incubation, cells were collected and stained with the following surface markers: CD3-BV421, CD4-APC-Cy7, CD8-BUV395, CD56-APC, CD122-PE, CD25-FITC, and CD69-PE-Cy7. CD4 was analyzed by flow cytometry. + T cells, CD8 + Expression levels of CD69, CD25, and CD122 on T cells and NK cells.

[0271] CD69, CD25, and CD122 expression on T cells and natural killer (NK) cells after silvostomumab treatment was assessed by co-culturing human PBMCs and MOLP-2 cells in the presence or absence of silvostomumab. Figures 2A to 2C MOLP-2 was identified as a benchmark cell line expressing FcRH5 at similar levels to plasma cells and MM tumor cells (Li et al. 2017). At 4 hours of silvostomumab treatment, CD4 + T cells and CD8 + CD69 (an early T cell activation marker) was detected on all T cells and reached a peak level within 24 hours. Figure 2A ). After 24 hours of treatment, CD4 + T cells and CD8 + CD25 expression levels in T cells increased ( Figure 2B No significant changes in CD69 or CD25 were observed in NK cells after treatment ( Figure 2A and 2B ). CD122 in unstimulated peripheral blood CD4 + T cells and CD8 + It is expressed at low levels in T cells. Stimulation of T cells with 5000 pM silvostomumab induced CD4 + T cells and CD8 + CD122 expression on T cells but had little effect on NK cells, which expressed high levels of CD122 at baseline ( Figure 2C ).

[0272] Example 2: Combination therapy of XmAb24306 and silvostomomab, open-label, multicenter, global, dose-escalation study

[0273] A combination therapy, open-label, multicenter, global, dose-escalation study will be conducted to evaluate the safety, tolerability, pharmacokinetics, and activity of the FcRH5xCD3 bispecific antibody silvostomumab alone or in combination with XmAb24306 in subjects with blood cancers (e.g., relapsed or refractory multiple myeloma (R / R MM)) who have received at least three prior lines of therapy including at least one immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody.

[0274] The study consisted of a screening period of up to 28 days, a treatment period (up to 1 year or longer), and a minimum follow-up period of 90 days after treatment.

[0275] Subjects will be recruited for the combination study arm in two phases: a dose escalation phase and an expansion phase.

[0276] Cohorts of 3 to 9 subjects with blood cancer (e.g., R / R MM) will be enrolled in the dose escalation phase of the combination therapy portion of the study. Increasing doses of XmAb24306 will be administered by IV infusion and in a 3+3+3 design ( Figure 6 ) was administered 132 mg of silvosetumab intravenously to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of the combination of XmAb24306 and silvosetumab.

[0277] Sivoduzumab will initially be administered using a split-dose priming schedule. Two priming doses of sivoduzumab will be administered during the pre-phase cycle, with the first priming dose (0.3 mg) administered on Day 1 and until resolution of infusion-related events including cytokine release syndrome (CRS), and the second priming dose (3.3 mg) administered on Day 2, 3, or 4, with at least 20 hours between the end of the first priming dose of sivoduzumab and the start of the second priming dose. Thereafter, the target sivoduzumab dose (132 mg) will be administered every 2 weeks (on Days 1 and 15) in Cycles 1 to 6, and every 4 weeks (on Day 1) in Cycles 7 and beyond (see Figure 5 ).

[0278] The starting dose of XmAb24306 is 0.02 mg / kg, administered IV. Once the subject has resolved safety parameters, the first dose of XmAb24306 will be administered at least 24 hours after the first target dose of silvostomumab on Day 2 to Day 4 of Cycle 1. Thereafter, XmAb24306 will be administered every 4 weeks on Day 1 of Cycle 2 and each subsequent cycle (see Figure 5 ). During dose escalation, the DLT assessment window was defined as Day 1 to Day 28 of Cycle 1.

[0279] The silvostomumab monotherapy arm will enroll approximately 20 subjects and provide concurrent comparative data for the above combination therapies. If recruitment to the combination arm is restricted to a specific population of interest, the same restrictions may apply to recruitment to the monotherapy arm.

[0280] The silvostomumab dosing schedule in the monotherapy arm will be a split-dose priming schedule, with two ascending silvostomumab priming doses to be administered during the pre-phase, with 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 and 4, and a target dose of 132 mg administered every 2 weeks (on Days 1 and 15) in Cycles 1 to 6 and every 4 weeks (on Day 1) in Cycle 7 and thereafter (see Figure 7 ).

[0281] Subjects who were initially treated with silvosetumab monotherapy, have received at least 1 cycle of treatment and whose disease response was assessed as stable disease (SD) or better, but then progressed during the study treatment period may benefit from the combination of XmAb24306 and silvosetumab. Therefore, such subjects may be eligible to cross over into the combination arm of the trial. Without being bound by theory, the rationale for this crossover design is that adding XmAb24306 to silvosetumab can increase CD8 + The XmAb24306 and silvostomumab combination therapy may be used to treat T cells and / or T cells, thereby enhancing anti-tumor activity compared to single-agent silvostomumab. Subjects who cross over from silvostomumab monotherapy to the XmAb24306 and silvostomumab combination therapy may receive combination therapy for up to 12 months or longer.

[0282] Subjects who experience disease progression and / or no longer obtain clinical benefit on silvostomumab as a single agent may be eligible to receive XmAb24306 in combination with silvostomumab if the following criteria are met:

[0283] ● Prior to progression during the study treatment period, the subject must have received at least 1 cycle of treatment in the silvostomumab monotherapy arm with disease response assessed as stable disease (SD) or better;

[0284] ● Treatment with XmAb24306 and silvostomomab after progression on single-agent XmAb24306 must be considered acceptable after careful assessment and discussion of the benefit-risk balance;

[0285] ●The subjects must meet all inclusion and exclusion criteria;

[0286] ●Patients must have documented disease progression by IMWG uniform response criteria;

[0287] ● The subject must not experience toxicity during the final dose of study treatment with silvostomumab monotherapy that would prevent combination treatment with XmAb24306 and silvostomumab;

[0288] Any adverse event related to silvostomumab must have resolved to ≤ Grade 1 or baseline and / or met the protocol-specified dosing criteria for the specific adverse event on or before the first day of treatment in the combination study (ie, Example 2). Exceptions may be permitted.

[0289] For subjects eligible for crossover, the time between the last dose of silvostomumab monotherapy administered and the first dose of silvostomumab planned to be administered in combination therapy with XmAb24306 (i.e., Example 2) must be ≥ 2 weeks. Subjects will also repeat the pre-stage prior to Cycle 1, depending on the length of this interval, as follows:

[0290] If the interval between the final dose of silvostomumab monotherapy and the planned first dose of silvostomumab and XmAb24306 combination therapy is ≥2 weeks but <6 weeks, the subject will restart treatment with the combination therapy on Cycle 1 Day 1, and the silvostomumab target dose will be administered on Day 1 and XmAb24306 will be administered between Days 2 and 4.

[0291] If the interval between the final dose of silvostomumab monotherapy and the initial dose of silvostomumab in combination with XmAb24306 is 8 weeks or more, the pre-phase dosing must be repeated.

[0292] If the interval between the final dose of the silvosetumab monotherapy arm and the initial dose of the combination therapy of silvosetumab and XmAb24306 is at least 6 weeks but < 8 weeks, the need to repeat the pre-phase dosing before cycle 1 will be determined.

[0293] All subjects in both trial arms will be closely monitored for adverse events throughout the study and for at least 90 days after the last dose of study treatment. All adverse events, including serious adverse events and adverse events of special concern, will continue to be reported until 90 days after the final dose of study treatment or until new systemic anticancer therapy is started (whichever occurs first). Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0), with the exception of CRS, which will be graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) cytokine release syndrome consensus grade. For treatment-emergent CRS, tocilizumab will be administered as appropriate. Tocilizumab will be administered IV at a dose of 8 mg / kg (8 mg / kg only for patients weighing ≥30 kg; 12 mg / kg for patients weighing <30 kg; not to exceed a dose of 800 mg per infusion) and repeated every 8 hours as needed (up to a maximum of four doses).

[0294] During the study, subjects in both arms will receive disease assessments at screening (baseline) and at regular intervals, which will be assessed according to the International Myeloma Working Group [IMWG] Uniform Response Criteria. Subjects with acceptable toxicity and evidence of clinical benefit may continue to receive XmAb24306 and silvostomumab for up to 12 months or until disease progression (as determined by IMWG criteria) or unacceptable toxicity occurs, whichever occurs first. After completing 12 months of study treatment, patients who have not experienced disease progression may continue study treatment if they consent to a bone marrow aspirate / biopsy and their overall IMWG disease assessment does not indicate a stringent complete response (sCR). If a bone marrow assessment is not performed, or if the bone marrow shows an sCR, the patient will no longer be able to continue study treatment. Patients who initially respond to study treatment but then relapse or have disease progression after completing therapy or after a dose delay of more than 28 days (i.e., no study treatment for >42 to 56 days, depending on when the delay occurred during study treatment) may be eligible for retreatment.

[0295] Subjects who complete study treatment will continue to receive tumor and other assessments until disease progression, initiation of new anticancer therapy, or withdrawal from study participation, whichever occurs first.

[0296] Subjects who permanently discontinue XmAb24306 and silvostomumab will return to the clinic for a treatment discontinuation visit within 30 days of the last dose of study treatment or initiation of another systemic anticancer therapy, whichever occurs first. The visit at which response assessments show disease progression may serve as the treatment discontinuation visit.

[0297] To characterize the pharmacokinetics, immunogenic response, and PD properties of XmAb24306 and / or silvostomumab, blood samples will be collected at various time points before and after dosing.

[0298] The safety objectives of this study were to evaluate the safety and tolerability of the combination of XmAb24306 and silvostomomab based on the following endpoints:

[0299] The incidence and severity of adverse events, where severity was determined according to the NCI CTCAE v5.0 and ASTCT cytokine release syndrome consensus grading;

[0300] ■Changes in target vital signs from baseline;

[0301] ■Changes from baseline in target clinical laboratory test results; and

[0302] ■Changes in ECG parameters from baseline.

[0303] The pharmacokinetic (PK) objectives of this study were to characterize the PK profile of the combination of XmAb24306 and silvostomumab based on the following endpoints:

[0304] ■Serum concentrations of silvostomumab at specified time points;

[0305] ■Serum concentration of XmAb24306 at the indicated time points;

[0306] ■PK parameters of silvostomumab; and

[0307] ■PK parameters of XmAb24306.

[0308] The exploratory PK objectives of this study are as follows:

[0309] ■ To evaluate the potential relationship between serum concentrations or PK parameters of XmAb24306 and / or silvostomumab and PD biomarkers (including but not limited to cytokine release, T cell numbers, and T cell activation status); and

[0310] ■ To evaluate the potential relationship between selected covariates and PK parameter serum concentrations of XmAb24306 and / or silvostomumab to study treatment.

[0311] The activity objectives of this study are to provide a preliminary assessment of the activity of XmAb24306 when administered in combination with silvostomomab based on the following endpoints:

[0312] Objective response rate (ORR), defined as the proportion of patients with a best overall response of sCR, complete response (CR), very good partial response (VGPR), or partial response (PR) as determined by the investigator according to the International Myeloma Working Group (IMWG) criteria

[0313] CR / sCR ratio, defined as the proportion of patients who achieved two consecutive CRs or sCRs as determined by the investigator

[0314] VGPR or better rate, defined as the proportion of patients who achieved two consecutive VGPR or better as determined by the investigator

[0315] The exploratory activity objectives of this study are to conduct a preliminary assessment of the activity of XmAb24306 when administered in combination with silvostomomab based on the following endpoints:

[0316] Duration of response (DOR), defined as the time from the first documented confirmed objective response (sCR, CR, VGPR, or PR) to disease progression during the study (defined as within 30 days after the last dose of study drug) or death from any cause as determined by the investigator according to IMWG criteria

[0317] Progression-free survival (PFS), defined as the time from the first study treatment to the first occurrence of disease progression during the study (defined as within 30 days after the last dose of study drug) or death from any cause, whichever occurs first, as determined by the investigator according to IMWG criteria

[0318] Time to first response (for patients who achieved a PR or better), defined as the time from the start of study treatment to the achievement of a confirmed PR or better

[0319] Time to best response (for patients who achieve PR or better)

[0320] Minimal residual disease (MRD) negativity rate (for patients who achieve a CR or sCR response), defined as the proportion of patients who achieve MRD negativity as determined by next-generation sequencing (NGS) on bone marrow aspirates

[0321] ■Overall survival (OS), defined as the time from the start of study treatment to death from any cause

[0322] For subjects treated with tocilizumab, an additional exploratory active objective of this study was to conduct a preliminary assessment of the efficacy of tocilizumab in improving symptoms of cytokine release syndrome (CRS) following study treatment based on the following endpoints:

[0323] ■Outcome of CRS after administration of tocilizumab.

[0324] The safety objectives of this study are to evaluate the immune response to the combination of XmAb24306 and silvostomomab based on the following endpoints:

[0325] The incidence of anti-drug antibodies (ADA) to silvostomumab at baseline and during the study

[0326] ■ The incidence of anti-drug antibodies (ADA) to XmAb24306 at baseline and the incidence of ADA to XmAb24306 during the study.

[0327] The exploratory immunogenicity objectives of this study were to evaluate the potential efficacy of ADA based on the following endpoints:

[0328] ■ Relationship between ADA status against silvostomumab and safety, PK, or activity endpoints

[0329] ■ Relationship between ADA status against XmAb24306 and safety, PK or activity endpoints.

[0330] The exploratory biomarker objectives of this study are as follows:

[0331] ■To evaluate the activity of the study treatment in driving patients with R / R MM to MRD negativity based on the following endpoints:

[0332] ○ MRD-negative in first CR; and

[0333] ○MRD negativity after 12 months of study treatment.

[0334] ■ To identify and / or evaluate biomarkers that predict response to XmAb24306 and silvostomumab (i.e., predictive biomarkers), serve as early surrogates of activity, correlate with progression to a more severe disease state (i.e., prognostic biomarkers), are associated with acquired resistance to XmAb24306 and / or silvostomumab, are associated with susceptibility to adverse events or may lead to improved monitoring or investigation of adverse events (i.e., safety biomarkers), provide evidence of activity of XmAb24306 and / or silvostomumab (i.e., pharmacodynamic (PD) biomarkers), or may increase knowledge and understanding of disease biology and drug safety:

[0335] o Relationship between biomarkers in blood and bone marrow aspirate / biopsy and safety, PK, activity, immunogenicity, or other biomarker endpoints.

Claims

1. A method for treating 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) a FcRH5xCD3 bispecific antibody or a fragment thereof that binds to two antigens.

2. Use of a therapeutically effective amount of (a) an IL15-IL15Rα heterodimeric Fc fusion protein and (b) a FcRH5xCD3 bispecific antibody or a fragment thereof that binds two antigens in the manufacture of one or more medicaments for treating blood cancer in a subject in need thereof.

3. A therapeutically effective amount of (a) an IL15-IL15Rα heterodimeric Fc fusion protein and (b) a FcRH5xCD3 bispecific antibody or a fragment thereof that binds two antigens, for use in treating blood cancer in a subject in need thereof.

4. The method according to claim 1, the use according to claim 2, or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 3, 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 wherein the first Fc domain is a variant of a human IgG1 Fc domain; and (b) a second fusion protein comprising an IL-15 receptor α (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 wherein the second Fc domain is a variant of a human IgG1 Fc domain.

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 wherein 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 α (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 wherein 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 heterodimer 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 heterodimer 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 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 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 heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or a fragment thereof according to any one of claims 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 claims 1 and 4 to 11, the use according to any one of claims 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 claims 3 to 11, wherein the IL15-IL15Rα heterodimeric 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 heterodimeric Fc fusion protein and 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 two 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 claim 13, wherein the anti-FcRH5 light chain variable region comprises a light chain complementary 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 heavy chain complementary 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 claim 13 , 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 claims 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 claims 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 claims 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 heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 13 to 18, wherein the anti-CD3 light chain variable region comprises a light chain complementary 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; and the anti-CD3 heavy chain variable region comprises a heavy chain complementary 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.

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

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 heterodimeric 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's lymphoma, B-cell non-Hodgkin's 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 heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 3 to 29, wherein the subject has previously been 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 claim 30, wherein the previous treatment is an immunomodulatory drug, 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 drug 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, mazetuzumab and furezetuzumab.

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 heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 3 to 34, wherein the IL15-IL15Rα heterodimeric 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 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 claims 1 and 4 to 36, the use according to any one of claims 2 and 4 to 36, or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 3 to 36, wherein the IL15-IL15Rα heterodimeric 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 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 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 claims 1 and 4 to 38, the use according to any one of claims 2 and 4 to 38, or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 3 to 38, wherein the IL15-IL15Rα heterodimeric Fc fusion protein is administered at a frequency selected from the group consisting of: Q1W, Q2W, Q3W, Q4W, Q5W and Q6W.

40. The method, the use or the IL15-IL15Rα heterodimer Fc fusion protein and the FcRH5xCD3 bispecific antibody or fragment thereof according to claim 39, wherein the IL15-IL15Rα heterodimer Fc fusion protein is administered at a frequency of Q1W in one or more cycles.

41. The method, the use, or the 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 at a frequency of Q2W in one or more cycles.

42. The method, the use, or the 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 at a frequency of Q4W in one or more cycles.

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 heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 3 to 42, wherein the IL15-IL15Rα heterodimeric 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 heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 3 to 43, wherein the IL15-IL15Rα heterodimeric Fc fusion protein and the FcRH5xCD3 bispecific antibody or fragment thereof that binds two 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 heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 3 to 43, wherein the IL15-IL15Rα heterodimeric Fc fusion protein and the FcRH5xCD3 bispecific antibody or fragment thereof that binds to two antigens are administered sequentially.

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 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 two antigens is administered in 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 binding to two antigens is administered at a frequency of Q2W in one or more cycles.

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

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 binding to two antigens is administered at a frequency of Q4W in one or more cycles.

50. The method, the use or the 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 four 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 binding to two antigens is administered Q2W for six four-week cycles and Q4W in the seventh and any subsequent four-week cycles.

52. The method, use or IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 51, wherein the FcRH5xCD3 bispecific antibody or fragment thereof binding to two antigens is administered on day 1 and day 15 for six four-week cycles and on day 1 in the seventh and any 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 heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or a 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, the use or the IL15-IL15Rα heterodimeric 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, the use or the IL15-IL15Rα heterodimeric 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 at a frequency of Q2W in one or more 28-day cycles.

56. The method, the use or the IL15-IL15Rα heterodimeric 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, the use or the 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 heterodimeric 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 binding to two antigens are administered to the subject during a preliminary period prior to the first treatment cycle.

59. The method, the use or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 58, wherein the pre-phase is seven days.

60. The method, use or IL15-IL15Rα heterodimeric 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 heterodimeric 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 binding to two antigens are administered to the subject.

62. The method, the use or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 61, wherein the first priming dose is administered on day 1 of the pre-phase.

63. The method, the use or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to claim 62, wherein the second priming dose is administered between day 2 and day 4 of the pre-phase.

64. The method, use or IL15-IL15Rα heterodimeric 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, the use or the IL15-IL15Rα heterodimeric 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, the use or the IL15-IL15Rα heterodimeric 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 according to any one of claims 1 and 4 to 55 and 58 to 66, the use according to any one of claims 2 and 4 to 55 and 58 to 66, or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 3 to 55 and 58 to 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 preliminary period, the subject is administered a second priming dose of about 3.3 mg of the FcRH5xCD3 bispecific antibody between day 2 and day 4 of the preliminary period, and thereafter, the subject is administered a dose of about 132 mg of the FcRH5xCD3 bispecific antibody on day 1 and day 15 for six four-week cycles and on day 1 for the seventh and any subsequent four-week cycles.

68. The method according to any one of claims 1 and 4 to 67, the use according to any one of claims 2 and 4 to 67, or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or a fragment thereof according to any one of claims 3 to 67, wherein the FcRH5xCD3 bispecific antibody is administered intravenously.

69. The method according to any one of claims 1 and 4 to 68, the use according to any one of claims 2 and 4 to 68, or the IL15-IL15Rα heterodimeric Fc fusion protein and FcRH5xCD3 bispecific antibody or fragment thereof according to any one of claims 3 to 68, wherein the method further comprises administering a therapeutically effective amount of tocilizumab to the subject.

70. The method of claim 69, wherein the subject has suffered a cytokine release syndrome (CRS) event.

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

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

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

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

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

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

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

78. 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) silvositumomab, wherein silvositumomab 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 silvositumomab is administered intravenously at a dose of about 132 mg.

79. Use of a therapeutically effective amount of the following in the manufacture of one or more medicaments for treating multiple myeloma in a subject in need thereof: (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) sivosetumab, wherein sivosetumab 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 for intravenous administration at a dose of about 0.02 mg / kg to about 0.06 mg / kg, and sivosetumab is formulated for intravenous administration at a dose of about 132 mg.

80. 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) sivosetumab, wherein sivosetumab 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 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 sivosetumab is administered intravenously at a dose of about 132 mg.

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

82. The method of claim 78, the use of claim 79, or XmAb24306 and silvostomumab according to claim 80, wherein the treatment further comprises administering to the subject one or more priming doses of silvostomumab at a total dose of about 3.6 mg during a seven-day pre-phase prior to the first treatment cycle, wherein the priming dose is administered in two doses.

83. The method, the use, or XmAb24306 and silvostomumab 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, the use, or XmAb24306 and silvostomumab according to claim 83, wherein the first priming dose is administered on day 1 of the pre-period, and wherein the second priming dose is administered on day 2, 3, or 4 of the pre-period.

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

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

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

88. 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 silvositumab according to any one of claims 80 to 87, wherein XmAb24306 is administered intravenously at a frequency of Q4W for at least seven four-week cycles, and wherein a first priming dose of silvositumab of 0.3 mg is administered intravenously on day 1 of a pre-phase, a second priming dose of silvositumab of 3.3 mg is administered intravenously between day 2 and day 4 of a pre-phase, wherein the pre-phase is seven days, and thereafter, a dose of 132 mg of silvositumab is administered intravenously on day 1 and day 15 for six four-week cycles and on day 1 for the seventh and any subsequent four-week cycles.

89. A method for 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) sivosetumab, wherein sivosetumab 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 a second monomer comprising the amino acid sequence of SEQ ID NO:

10. 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 seven four-week cycles, and wherein a first priming dose of 0.3 mg of silvositumomab is administered intravenously on day 1 of the pre-phase, a second priming dose of 3.3 mg of silvositumomab is administered intravenously between day 2 and day 4 of the pre-phase, wherein the pre-phase is seven days, and thereafter, a dose of 132 mg of silvositumomab is administered intravenously on day 1 and day 15 for six four-week cycles and on day 1 for the seventh and any subsequent four-week cycles.

90. Use of a therapeutically effective amount of the following in the manufacture of one or more medicaments for treating multiple myeloma in a subject in need thereof: (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) sivosetumab, wherein sivosetumab 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 a second monomer comprising the amino acid sequence of SEQ ID NO:

10. NO:30, wherein XmAb24306 is formulated for intravenous administration at a dose of about 0.02 mg / kg to about 0.06 mg / kg at a frequency of Q4W for at least seven four-week cycles, wherein silvositumomab is formulated for intravenous administration at a dose of 132 mg on days 1 and 15 for six four-week cycles and on day 1 for the seventh and any subsequent four-week cycles; and wherein the treatment further comprises a seven-day pre-phase, wherein a first priming dose of silvositumomab of 0.3 mg is administered intravenously on day 1 of the pre-phase, and a second priming dose of silvositumomab of 3.3 mg is administered intravenously between days 2 and 4 of the pre-phase.

91. A therapeutically effective amount of (a) XmAb24306, wherein XmAb24306 comprises: A first monomer having an amino acid sequence of SEQ ID NO: 9, and a second monomer having an amino acid sequence of SEQ ID NO: 10; and (b) sivosetumab, wherein sivosetumab comprises: an anti-FcRH5 light chain having an 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 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 at a frequency of Q4W for at least seven four-week cycles, and wherein a first priming dose of 0.3 mg of silvositumomab is administered intravenously on day 1 of a pre-phase, a second priming dose of 3.3 mg of silvositumomab is administered intravenously between day 2 and day 4 of a pre-phase, wherein the pre-phase is seven days, and thereafter, a dose of 132 mg of silvositumomab is administered intravenously on day 1 and day 15 for six four-week cycles and on day 1 for the seventh and any subsequent four-week cycles.

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