Therapeutic and diagnostic methods for treating cancer with Anti-fcrh5 / Anti-cd3 bispecific antibodies

Abstract

The present invention provides therapeutic and diagnostic methods for the treatment of cancer, such as multiple myeloma (MM), with an anti-crystallizable fragment receptor-like 5 (FcRH5) / anti-cluster of differentiation 3 (CD3) bispecific antibody.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480071932.7 (22) Application Date 2024.11.13 (30) Priority Data 63 / 598,887 2023.11.14 US (85) PCT International Application Entering National Phase Date 2026.05.12 (86) PCT International Application Application Data PCT / US2024 / 055624 2024.11.13 (87) PCT International Application Publication Data WO2025 / 106474 EN 2025.05.22 (71) Applicant Genentech Corporation Address California, USA (72) Inventors Teiko Sumiyoshi C.E. dos Santos H.R. Hamidi (74) Patent Agency Beijing Kunrui Law Firm 11494 Patent Attorney Feng Xinqin (51) Int.Cl. C07K 16 / 28 (2006.01) A61P 35 / 00 (2006.01) A61K 39 / 00 (2006.01) (54) Invention Title: Treatment and Diagnosis Method for Treating Cancer with Anti-FcRH5 / Anti-CD3 Bispecific Antibody (57) Abstract: This invention provides a treatment and diagnosis method for treating cancers such as multiple myeloma (MM) with a bispecific antibody against crystallizable fragment receptor-like 5 (FcRH5) / differentiation cluster 3 (CD3). Claims 15 pages, Description 144 pages, Sequence Listing (electronic publication), Drawings 37 pages, CN 122206702 A 2026.06.12 CN 1 22 20 67 02 A 1. A method of treating a subject with multiple myeloma (MM), the method comprising administering to the subject a bispecific antibody that binds to Fc receptor homolog 5 (FcRH5) and differentiation cluster 3 (CD3), wherein prior to administering the bispecific antibody: (a) a sample from the subject has been determined to have a level of one or more cell types listed in Table 3 that is lower than a reference level; (b) a sample from the subject has been determined to have a level of one or more cell types listed in Table 4 that is higher than a reference level; and / or (c) the subject has been determined to have a number of one or more of the characteristics listed in Table 5 that is lower than a reference number. 2. The method of claim 1, wherein: (a) the sample from the subject has been determined to have a reduced level of one or more cell types listed in Table 6 compared to the reference level; and / or (b) the sample from the subject has been determined to have an increased level of the cells listed in Table 7 compared to the reference level.3. The method of claim 1, wherein: (a) the sample from the subject has been determined to have a reduced level of one or more cell types listed in Table 8 compared to the reference level; and / or (b) the sample from the subject has been determined to have an increased level of one or more cell types listed in Table 9 compared to the reference level. 4. A method of treating a subject with multiple myeloma (MM), the method comprising: (I) determining: (a) levels of one or more cell types listed in Table 3 and / or Table 4 in a sample from the subject; and / or (b) one or more of the characteristics listed in Table 5 of the subject; (II) identifying the subject as a subject who would benefit from treatment comprising a bispecific antibody binding to FcRH5 and CD3, wherein: (a) the sample from the subject has a reduced level of one or more cell types listed in Table 3 compared to a reference level; (b) the sample from the subject has an increased level of one or more cell types listed in Table 4 compared to a reference level; and / or (c) the subject has a lower number of one or more of the characteristics listed in Table 5 compared to a reference number, thereby identifying the subject as a subject who would benefit from treatment comprising the bispecific antibody binding to FcRH5 and CD3; and (III) administering to the subject the bispecific antibody binding to FcRH5 and CD3. 5. The method of claim 4, wherein the method comprises: (I) determining the levels of one or more cell types listed in Table 6 and / or Table 7 in a sample from the subject; and (II) identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3, wherein: (a) the sample from the subject has a reduced level of one or more cell types listed in Table 6 compared to the reference level; and / or (b) the sample from the subject has an increased level of one or more cell types listed in Table 7 compared to the reference level, thereby identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3. 6. The method of claim 4, wherein the method comprises: (I) determining the levels of one or more cell types listed in Table 8 and / or Table 9 in a sample from the subject; and (II)The subject is identified as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3, wherein: (a) the sample from the subject has a reduced level of one or more cell types listed in Table 8 compared to the reference level; and / or (b) the sample from the subject has an increased level of one or more cell types listed in Table 9 compared to the reference level, thereby identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3. 7. A method for identifying a subject with MM as a subject who will benefit from treatment comprising a bispecific antibody binding to FcRH5 and CD3, the method comprising: (I) determining: (a) levels of one or more cell types listed in Table 3 and / or Table 4 in a sample from the subject; and / or (b) one or more of the characteristics listed in Table 5 of the subject; and (II) identifying the subject as a subject who will benefit from said treatment comprising the bispecific antibody binding to FcRH5 and CD3, wherein: (a) the sample from the subject has a reduced level of one or more cell types listed in Table 3 compared to a reference level; (b) the sample from the subject has an increased level of one or more cell types listed in Table 4 compared to a reference level; and / or (c) the subject has a lower number of one or more of the characteristics listed in Table 5 compared to a reference number, thereby identifying the subject as a subject who will benefit from treatment comprising the bispecific antibody binding to FcRH5 and CD3. 8. The method of claim 7, wherein the method comprises: (I) determining the levels of one or more cell types listed in Table 6 and / or Table 7 in a sample from the subject; and (II) identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3, wherein: (a) the sample from the subject has a reduced level of one or more cell types listed in Table 6 compared to the reference level; and / or (b) the sample from the subject has an increased level of one or more cell types listed in Table 7 compared to the reference level, thereby identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3. 9. The method of claim 7, wherein the method comprises: (I)(ii) Determining the levels of one or more cell types listed in Table 8 and / or Table 9 in a sample from the subject; and (ii) identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3, wherein: (a) the sample from the subject has a reduced level of one or more cell types listed in Table 8 compared to the reference level; and / or (b) the sample from the subject has an increased level of one or more cell types listed in Table 9 compared to the reference level, thereby identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3. 10. The method of any one of claims 7 to 9, wherein the method further comprises administering the treatment comprising the bispecific antibody binding to FcRH5 and CD3 to the subject. 11. The method of any one of claims 1, 2, 4, 5, 7, 8, and 10, wherein the sample from the subject is a bone marrow sample. 12. The method of any one of claims 1, 3, 4, 6, 7, 9, and 10, wherein the sample from the subject is a blood sample. 13. The method of any one of claims 4 to 12, wherein determining the level of the one or more cell types comprises flow cytometry (FC), mass spectrometry (MS), immunohistochemistry (IHC), DNA sequencing (DNA-seq), RNA sequencing (RNA-seq), quantitative PCR (qPCR), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), multiplex qPCR or RT-qPCR, microarray analysis, serial gene expression analysis (SAGE), MassARRAY® technology, in situ hybridization (ISH), or a combination thereof. 14. The method of any one of claims 4 to 13, wherein determining the level of the one or more cell types comprises FC. 15. The method of any one of claims 1 to 14, wherein the reference level is the mean Z-score of the one or more cell types in a population of subjects with the MM. 16. The method of any one of claims 1 to 15, wherein the reference number is the average of one or more characteristics listed in Table 5 in a population of subjects suffering from said MM. 17. The method of any one of claims 4 to 16, wherein benefit from said treatment includes a relative increase in overall survival (OS), objective response rate (ORR), progression-free survival (PFS), complete response (CR), partial response (PR), or a combination thereof.18. The method of claim 17, wherein the benefit from the treatment includes a relative increase in OS. Claims 3 / 15, page 4, CN 122206702 A 19. The method of any one of claims 1 to 18, wherein the MM is relapsed or refractory (R / R) MM. 20. The method according to any one of claims 1 to 19, wherein the bispecific antibody binding to FcRH5 and CD3 comprises an anti-FcRH5 arm containing a first binding domain comprising six hypervariable regions (HVRs): (a) HVR-H1 containing the amino acid sequence RFGVH (SEQ ID NO: 1); (b) HVR-H2 containing the amino acid sequence VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) HVR-H3 containing the amino acid sequence HYYGSSDYALDN (SEQ ID NO: 3); (d) HVR-L1 containing the amino acid sequence KASQDVRNLVV (SEQ ID NO: 4); (e) HVR-L2 containing the amino acid sequence SGSYRYS (SEQ ID NO: 5); and (f) HVR-L3 containing the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). 21. The method of any one of claims 1 to 20, wherein the bispecific antibody binding to FcRH5 and CD3 comprises an anti-FcRH5 arm containing a first binding domain, the first binding domain comprising (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 8; or (c) the VH domain as in (a) and the VL domain as in (b). 22. The method of claim 21, wherein the first binding domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 7; and a VL domain comprising the amino acid sequence of SEQ ID NO: 8. 23. The method according to any one of claims 1 to 22, wherein the bispecific antibody binding to FcRH5 and CD3 comprises an anti-CD3 arm containing a second binding domain, the second binding domain comprising six HVRs: (a) HVR-H1, which comprises(a) HVR-H2 containing the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) HVR-H2 containing the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) HVR-H3 containing the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11); (d) HVR-L1 containing the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 containing the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) HVR-L3 containing the amino acid sequence of KQSFILRT (SEQ ID NO: 14). 24. The method of any one of claims 1 to 23, wherein the bispecific antibody binding to FcRH5 and CD3 comprises an anti-CD3 arm containing a second binding domain, the second binding domain comprising (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 16; or (c) the VH domain as in (a) and the VL domain as in (b). 25. The method of claim 24, wherein the second binding domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 15; and a VL domain comprising the amino acid sequence of SEQ ID NO: 16. 26. The method according to any one of claims 1 to 25, wherein the bispecific antibody binding to FcRH5 and CD3 comprises: an anti-FcRH5 arm comprising a heavy chain polypeptide (H1) and a light chain polypeptide (L1); and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), wherein: (a) H1 comprises the amino acid sequence of SEQ ID NO: 35; (b) L1 comprises the amino acid sequence of SEQ ID NO: 36; (c) H2 comprises the amino acid sequence of SEQ ID NO: 37; and (d) L2 comprises the amino acid sequence of SEQ ID NO: 38. 27. The method according to any one of claims 1 to 26, wherein the bispecific antibody binding to FcRH5 and CD3 comprises a deglycosylation site mutation.28. The method of claim 27, wherein the deglycosylation site mutation reduces the effector function of the bispecific antibody. 29. The method of claim 27 or 28, wherein the deglycosylation site mutation is a substitution mutation. 30. The method of claim 29, wherein the bispecific antibody binding to FcRH5 and CD3 comprises a substitution mutation in the Fc region that reduces effector function. 31. The method of any one of claims 1 to 30, wherein the bispecific antibody binding to FcRH5 and CD3 is a monoclonal antibody. 32. The method of any one of claims 1 to 31, wherein the bispecific antibody binding to FcRH5 and CD3 is a chimeric antibody. 33. The method of any one of claims 1 to 32, wherein the bispecific antibody binding to FcRH5 and CD3 is a humanized antibody. 34. The method of any one of claims 1 to 25 and 27 to 33, wherein the bispecific antibody binding to FcRH5 and CD3 is an antibody fragment. 35. The method of claim 34, wherein the antibody fragment is selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments. 36. The method of any one of claims 1 to 33, wherein the bispecific antibody binding to FcRH5 and CD3 is a full-length antibody. 37. The method of any one of claims 1 to 33 and 36, wherein the bispecific antibody binding to FcRH5 and CD3 is an IgG antibody. 38. The method of claim 37, wherein the IgG antibody is an IgG1 antibody. 39. The method of any one of claims 1 to 33 and 36 to 38, wherein the bispecific antibody binding to FcRH5 and CD3 comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH11) domain, a first CH2 (CH21) domain, a first CH3 (CH31) domain, a second CH1 (CH12) domain, a second CH2 (CH22) domain, and a second CH3 (CH32) domain. 40. The method of claim 39, wherein at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. 41. The method of claim 39 or 40, wherein the CH31 domain and the CH32 domain...Each includes a protrusion or a cavity, and wherein the protrusion or cavity in the CH31 structural domain is respectively positioned within the cavity or protrusion in the CH32 structural domain. 42. The method of claim 41, wherein the CH31 structural domain and the CH32 structural domain are connected at the interface between the protrusion and the cavity. 43. The method of any one of claims 39 to 42, wherein the CH21 structural domain and the CH22 structural domain each include a protrusion or a cavity, and wherein the protrusion or cavity in the CH21 structural domain is respectively positioned within the cavity or protrusion in the CH22 structural domain. Claims 5 / 15, page 6, CN 122206702 A 44. The method of claim 43, wherein the CH21 structural domain and the CH22 structural domain are connected at the interface between the protrusion and the cavity. 45. The method of claim 42, wherein the anti-FcRH5 arm comprises the protrusion and the anti-CD3 arm comprises the cavity. 46. The method of claim 45, wherein the anti-FcRH5 arm comprises a protrusion containing a T366W amino acid substitution mutation (EU number), and the anti-CD3 arm comprises a cavity containing T366S, L368A, and Y407V amino acid substitution mutations (EU number). 47. The method of any one of claims 1 to 33 and 36 to 46, wherein the bispecific antibody binding to FcRH5 and CD3 is civastastat. 48. The method of any one of claims 1 to 47, wherein the bispecific antibody binding to FcRH5 and CD3 is administered to the subject as a single therapy. 49. The method of any one of claims 1 to 47, wherein the bispecific antibody binding to FcRH5 and CD3 is administered to the subject as a combination therapy. 50. The method of claim 49, wherein the bispecific antibody binding to FcRH5 and CD3 is administered to the subject simultaneously with one or more additional therapeutic agents. 51. The method of claim 49, wherein the bispecific antibody binding to FcRH5 and CD3 is administered to the subject prior to the administration of one or more additional therapeutic agents. 52. The method of claim 49, wherein the bispecific antibody binding to FcRH5 and CD3 is administered to the subject after the administration of one or more additional therapeutic agents. 53. The method of claim 52, wherein the one or more additional therapeutic agents comprise an effective amount of tortrol.54. The method of claim 53, wherein tocilizumab is administered to the subject via intravenous infusion. 55. The method of claim 53 or 54, wherein: (a) the subject weighs ≥ 100 kg and tocilizumab is administered to the subject at a dose of 800 mg; (b) the subject weighs ≥ 30 kg and < 100 kg and tocilizumab is administered to the subject at a dose of 8 mg / kg; or (c) the subject weighs < 30 kg and tocilizumab is administered to the subject at a dose of 12 mg / kg. 56. The method of any one of claims 53 to 55, wherein tocilizumab is administered to the subject 2 hours prior to administration of the bispecific antibody. 57. The method of any one of claims 50 to 52, wherein the one or more additional therapeutic agents comprise effective amounts of corticosteroids, analgesics and antipyretics, antihistamines, antimyeloma agents, PD-1 axis binding antagonists, antiCD38 therapeutic agents, immunomodulatory (IMiD) agents, cereblon E3 ligase modulators (CELMoD), proteasome inhibitors (PI), CAR-T therapy, antitumor agents, chemotherapeutic agents, growth inhibitors, antiangiogenic agents, radiotherapy, cytotoxic agents, cell-based therapies, or combinations thereof. 58. The method of any one of claims 1 to 57, wherein the bispecific antibody binding to FcRH5 and CD3 is administered to the subject via intravenous infusion. 59. The method of any one of claims 1 to 57, wherein the bispecific antibody binding to FcRH5 and CD3 is administered subcutaneously to the subject. 60. The method of any one of claims 1 to 59, wherein the subject has a cytokine release syndrome (CRS) event, and the method further comprises treating the symptoms of the CRS event while discontinuing treatment with the bispecific antibody binding to FcRH5 and CD3. 61. The method of claim 60, wherein the method further comprises administering an effective amount of tocilizumab to the subject to treat the CRS event. 62. The method of claim 61, wherein tocilizumab is administered intravenously to the subject in a single dose of about 8 mg / kg. 63. The method of claim 61 or 62, wherein the CRS event occurs within 24 hours of treating the symptoms of the CRS event.If the condition does not subside or worsen within hours, the method further includes administering one or more additional doses of tocilizumab to the subject to manage the CRS event. 64. The method of claim 63, wherein the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 8 mg / kg. 65. A method for classifying MM in a subject, the method comprising: (I) determining the levels of CD8+ T cells, Treg cells, and CD8+ TN cells in a sample from the subject; and (II) classifying the subject's MM into one of the following immune profiles based on the levels of the CD8+ T cells, Treg cells, and CD8+ TN cells: (a) an activated immune profile; (b) an inactivated immune profile; or (c) a suppressed immune profile, thereby classifying the subject's MM. 66. The method of claim 65, wherein: (I) the activated immune profile comprises, compared to a reference level, (a) an increased level of CD8+ T cells; (b) a decreased level of Treg cells; and (c) a decreased level of CD8+ TN cells; (II) the inactivated immune profile comprises, compared to a reference level, (a) a decreased level of CD8+ T cells; (b) an increased level of Treg cells; and (c) an increased level of CD8+ TN cells; or (III) the suppressed immune profile comprises, compared to a reference level, (a) an increased level of CD8+ T cells; (b) an increased level of Treg cells; and (c) a decreased level of CD8+ TN cells. 67. The method of claim 65 or 66, wherein the immune profile is assigned by similarity network fusion (SNF) analysis. 68. A bispecific antibody binding to FcRH5 and CD3, used to treat a subject with MM, wherein, prior to administration of the bispecific antibody, as stated in claim 7 / 15, page 8 CN 122206702 A: (a) a sample from the subject has been determined to have a level of one or more cell types listed in Table 1 that is lower than a reference level; (b) a sample from the subject has been determined to have a level of one or more cell types listed in Table 2 that is higher than a reference level; and / or (c) the subject has been determined to have a number of one or more of the characteristics listed in Table 3 that is lower than a reference number. 69. Claim 68The bispecific antibody binding to FcRH5 and CD3 used, wherein: (a) the sample from the subject has been determined to have a reduced level of one or more cell types listed in Table 4 compared to the reference level; and / or (b) the sample from the subject has been determined to have an increased level of one or more cell types listed in Table 5 compared to the reference level. 70. The bispecific antibody binding to FcRH5 and CD3 used according to claim 68, wherein: (a) the sample from the subject has been determined to have a reduced level of one or more cell types listed in Table 6 compared to the reference level; and / or (b) the sample from the subject has been determined to have an increased level of one or more cell types listed in Table 7 compared to the reference level. 71. A bispecific antibody binding to FcRH5 and CD3, used to treat a subject with multiple myeloma (MM), said treatment comprising: (I) determining: (a) levels of one or more cell types listed in Table 1 and / or Table 2 in a sample from said subject; and / or (b) one or more of the characteristics listed in Table 3 of said subject; (II) identifying said subject as a subject who would benefit from treatment comprising the bispecific antibody binding to FcRH5 and CD3, wherein: (a) said sample from said subject has a reduced level of one or more cell types listed in Table 1 compared to a reference level; (b) said sample from said subject has an increased level of one or more cell types listed in Table 2 compared to a reference level; and / or (c) said subject has a lower number of one or more of the characteristics listed in Table 3 compared to a reference number, thereby identifying said subject as a subject who would benefit from said treatment comprising the bispecific antibody binding to FcRH5 and CD3; and (III) The treatment comprising the bispecific antibody binding to FcRH5 and CD3 is administered to the subject. 72. The bispecific antibody binding to FcRH5 and CD3 used according to claim 71, wherein the treatment comprises: (I) determining the level of one or more cell types listed in Table 4 and / or Table 5 in a sample from the subject; and (II) identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3, wherein: (a) the sample from the subject has a reduced level compared to the reference level in Table 4.(a) The level of one or more cell types listed in Table 5; and / or (b) The sample from the subject has an increased level of one or more cell types listed in Table 5 compared to the reference level, thereby identifying the subject as a subject who will benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3. 73. The bispecific antibody binding to FcRH5 and CD3 used according to claim 71, wherein the treatment comprises: (I) determining the level of one or more cell types listed in Table 6 and / or Table 7 in a sample from the subject; and (II) identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3, wherein: (a) the sample from the subject has a reduced level of one or more cell types listed in Table 6 compared to the reference level; and / or (b) the sample from the subject has an increased level of one or more cell types listed in Table 7 compared to the reference level, thereby identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3. 74. A bispecific antibody binding to FcRH5 and CD3, used in a method for identifying a subject with MM as a subject who would benefit from treatment including the bispecific antibody binding to FcRH5 and CD3, the method comprising: (I) determining: (a) levels of one or more cell types listed in Table 1 and / or Table 2 in a sample from the subject; and / or (b) one or more of the characteristics listed in Table 3 of the subject; and (II) identifying the subject as a subject who would benefit from the treatment including the bispecific antibody binding to FcRH5 and CD3, wherein: (a) the sample from the subject has a reduced level of one or more cell types listed in Table 1 compared to a reference level; (b) the sample from the subject has an increased level of one or more cell types listed in Table 2 compared to a reference level; and / or (c) the subject has a lower number of one or more of the characteristics listed in Table 3 compared to a reference number. Thus, the subject is identified as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3. 75. The bispecific antibody binding to FcRH5 and CD3 used according to claim 74, wherein the method comprises: Claims 9 / 15 pages 10 CN 122206702 A (I)(i) Determine the levels of one or more cell types listed in Table 4 and / or Table 5 in samples from the subject; and (ii) identify the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3, wherein: (a) the sample from the subject has a reduced level of one or more cell types listed in Table 4 compared to the reference level; and / or (b) the sample from the subject has an increased level of one or more cell types listed in Table 5 compared to the reference level, thereby identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3. 76. The bispecific antibody binding to FcRH5 and CD3 used according to claim 74, wherein the method comprises: (I) determining the level of one or more cell types listed in Table 6 and / or Table 7 in a sample from the subject; and (II) identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3, wherein: (a) the sample from the subject has a reduced level of one or more cell types listed in Table 6 compared to the reference level; and / or (b) the sample from the subject has an increased level of one or more cell types listed in Table 7 compared to the reference level, thereby identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3. 77. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 74 to 76, wherein the method further comprises administering the treatment comprising the bispecific antibody binding to FcRH5 and CD3 to the subject. 78. A bispecific antibody binding to FcRH5 and CD3 used to treat a subject with MM, the treatment comprising the step of classifying the subject, the classification step comprising: (I) determining the levels of CD8+ T cells, Treg cells, and CD8+ TN cells in a sample from the subject, and (II) classifying the subject's MM to one of the following immune profiles based on the levels of the CD8+ T cells, Treg cells, and CD8+ TN cells: (a) an activated immune profile; (b) an inactivated immune profile; or (c) a suppressed immune profile, thereby classifying the subject's MM. 79. The bispecific antibody binding to FcRH5 and CD3 used according to claim 78.The combined bispecific antibody, wherein: (I) the activated immune profile includes, compared to a reference level, (a) an increased level of CD8+ T cells; (b) a decreased level of Treg cells; and (c) a decreased level of CD8+ TN cells; (II) the inactivated immune profile includes, compared to a reference level, (a) a decreased level of CD8+ T cells; (b) an increased level of Treg cells; and (c) an increased level of CD8+ TN cells; or (III) the inhibited immune profile includes, compared to a reference level, (a) an increased level of CD8+ T cells; (b) an increased level of Treg cells; and (c) a decreased level of CD8+ TN cells. 80. The bispecific antibody binding to FcRH5 and CD3 as described in claim 78 or 79, wherein the immune profile is distributed via SNF. 81. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68, 69, 71, 72, 74, 75, and 77 to 80, wherein the sample from the subject is a bone marrow sample. 82. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68, 69, 71, 72, 74, 75, and 77 to 80, wherein the sample from the subject is a blood sample. 83. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 69 to 82, wherein determining the level of the one or more cell types comprises flow cytometry (FC), mass spectrometry (MS), immunohistochemistry (IHC), DNA sequencing (DNA-seq), RNA sequencing (RNA-seq), quantitative PCR (qPCR), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), multiplex qPCR or RT-qPCR, microarray analysis, gene expression serial analysis (SAGE), MassARRAY® technology, in situ hybridization (ISH), or a combination thereof. 84. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 71 to 83, wherein determining the level of the one or more cell types comprises FC. 85. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 68 to 84.86. An antibody that binds to FcRH5 and CD3 as claimed in any one of claims 68 to 85, wherein the reference number is the average Z-score of one or more cell types in a population of subjects with said MM. 87. An antibody that binds to FcRH5 and CD3 as claimed in any one of claims 71 to 86, wherein benefit from said treatment includes a relative increase in overall survival (OS), objective response rate (ORR), progression-free survival (PFS), complete remission (CR), partial remission (PR), or a combination thereof. 88. An antibody that binds to FcRH5 and CD3 as claimed in claim 87, wherein benefit from said treatment includes a relative increase in OS. 89. An antibody that binds to FcRH5 and CD3 as claimed in any one of claims 68 to 88, wherein said MM is relapsed or refractory (R / R) MM. 90. The bispecific antibody binding to FcRH5 and CD3 as claimed in any one of claims 68 to 89, wherein the bispecific antibody binding to FcRH5 and CD3 comprises an anti-FcRH5 arm containing a first binding domain comprising the following six hypervariable regions (HVRs): (a) HVR-H1, comprising the amino acid sequence RFGVH (SEQ ID NO: 1); (b) HVR-H2, comprising the amino acid sequence VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) HVR-H3, comprising the amino acid sequence HYYGSSDYALDN (SEQ ID NO: 3); (d) HVR-L1, comprising the amino acid sequence KASQDVRNLVV (SEQ ID NO: 4); (e) HVR-L2, comprising SGSYRYS (SEQ ID NO: 4). 5) the amino acid sequence; and (f) HVR-L3, which contains the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6). 91. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 68 to 90, wherein the bispecific antibody binding to FcRH5 and CD3 comprises an anti-FcRH5 arm containing a first binding domain, the first binding domain comprising (a)(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 8; or (c) the VH domain as in (a) and the VL domain as in (b). 92. The bispecific antibody binding to FcRH5 and CD3 as claimed in claim 91, wherein the first binding domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 7; and a VL domain comprising the amino acid sequence of SEQ ID NO: 8. 93. The bispecific antibody binding to FcRH5 and CD3 as claimed in any one of claims 68 to 92, wherein the bispecific antibody binding to FcRH5 and CD3 comprises an anti-CD3 arm containing a second binding domain comprising the following six HVRs: (a) HVR-H1, comprising the amino acid sequence SYYIH (SEQ ID NO: 9); (b) HVR-H2, comprising the amino acid sequence WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) HVR-H3, comprising the amino acid sequence DGYSRYYFDY (SEQ ID NO: 11); (d) HVR-L1, comprising the amino acid sequence KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2, comprising the amino acid sequence WTSTRKS (SEQ ID NO: 13); and (f) HVR-L3, comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14). 94. The bispecific antibody binding to FcRH5 and CD3 as claimed in any one of claims 68 to 93, wherein the bispecific antibody binding to FcRH5 and CD3 comprises an anti-CD3 arm containing a second binding domain comprising (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 16; or (c) the VH domain as in (a) and the VL domain as in (b). 95. The bispecific antibody binding to FcRH5 and CD3 as claimed in claim 94.A bispecific antibody that binds to FcRH5 and CD3, wherein the second binding domain comprises: a VH domain containing the amino acid sequence of SEQ ID NO: 15; and a VL domain containing the amino acid sequence of SEQ ID NO: 16. 96. The bispecific antibody binding to FcRH5 and CD3 as claimed in any one of claims 68 to 95, wherein the bispecific antibody binding to FcRH5 and CD3 comprises: an anti-FcRH5 arm comprising a heavy chain polypeptide (H1) and a light chain polypeptide (L1); and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), wherein: (a) H1 comprises the amino acid sequence of SEQ ID NO: 35; (b) L1 comprises the amino acid sequence of SEQ ID NO: 36; (c) H2 comprises the amino acid sequence of SEQ ID NO: 37; and (d) L2 comprises the amino acid sequence of SEQ ID NO: 38. 97. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68 to 96, wherein the bispecific antibody binding to FcRH5 and CD3 comprises a deglycosylation site mutation. 98. The bispecific antibody binding to FcRH5 and CD3 as described in claim 97, wherein the deglycosylation site mutation reduces the effector function of the bispecific antibody. 99. The bispecific antibody binding to FcRH5 and CD3 as described in claim 97 or 98, wherein the deglycosylation site mutation is a substitution mutation. 100. The bispecific antibody binding to FcRH5 and CD3 as described in claim 99, wherein the bispecific antibody binding to FcRH5 and CD3 comprises a substitution mutation in the Fc region that reduces effector function. 101. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68 to 100, wherein the bispecific antibody binding to FcRH5 and CD3 is a monoclonal antibody. 102. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68 to 101, wherein the bispecific antibody binding to FcRH5 and CD3 is a chimeric antibody. 103. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68 to 102, wherein the bispecific antibody binding to FcRH5 and CD3 is a monoclonal antibody.104. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 68 to 95 and 97 to 103, wherein the bispecific antibody binding to FcRH5 and CD3 is an antibody fragment. 105. The bispecific antibody binding to FcRH5 and CD3 used according to claim 104, wherein the antibody fragment is selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments. 106. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 68 to 103, wherein the bispecific antibody binding to FcRH5 and CD3 is a full-length antibody. 107. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 68 to 103 and 106, wherein the bispecific antibody binding to FcRH5 and CD3 is an IgG antibody. 108. The bispecific antibody binding to FcRH5 and CD3 used according to claim 107, wherein the IgG antibody is an IgG1 antibody. 109. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 68 to 103 and 106 to 108, wherein the bispecific antibody binding to FcRH5 and CD3 comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH11) domain, a first CH2 (CH21) domain, a first CH3 (CH31) domain, a second CH1 (CH12) domain, a second CH2 (CH22) domain, and a second CH3 (CH32) domain. 110. The bispecific antibody binding to FcRH5 and CD3 as claimed in claim 109, wherein at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. 111. The bispecific antibody binding to FcRH5 and CD3 as claimed in claim 109 or 110, wherein the CH31 domain and the CH32 domain each comprise a protrusion or a cavity, and wherein the protrusion or cavity in the CH31 domain is respectively positioned within the cavity or protrusion in the CH32 domain. 112. The bispecific antibody binding to FcRH5 and CD3 as claimed in claim 111, wherein the claims...Page 13 / 15 14 CN 122206702 A The CH31 domain and the CH32 domain are connected at the interface between the protrusion and the cavity. 113. The bispecific antibody binding to FcRH5 and CD3 according to any one of claims 109 to 112, wherein the CH21 domain and the CH22 domain each comprise a protrusion or a cavity, and wherein the protrusion or the cavity in the CH21 domain is respectively positioned within the cavity or the protrusion in the CH22 domain. 114. The bispecific antibody binding to FcRH5 and CD3 according to claim 113, wherein the CH21 domain and the CH22 domain are connected at the interface between the protrusion and the cavity. 115. The bispecific antibody binding to FcRH5 and CD3 as described in claim 112, wherein the anti-FcRH5 arm comprises the protrusion and the anti-CD3 arm comprises the cavity. 116. The bispecific antibody binding to FcRH5 and CD3 as described in claim 115, wherein the anti-FcRH5 arm comprises a protrusion containing a T366W amino acid substitution mutation (EU number), and the anti-CD3 arm comprises a cavity containing T366S, L368A, and Y407V amino acid substitution mutations (EU number). 117. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68 to 103 and 106 to 116, wherein the bispecific antibody binding to FcRH5 and CD3 is civastastat. 118. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68 to 117, wherein the bispecific antibody binding to FcRH5 and CD3 is formulated for administration to the subject as a monotherapy. 119. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68 to 117, wherein the bispecific antibody binding to FcRH5 and CD3 is formulated for administration to the subject as a combination therapy. 120. The bispecific antibody binding to FcRH5 and CD3 as described in claim 119, wherein the bispecific antibody binding to FcRH5 and CD3 is formulated for simultaneous administration to the subject with one or more additional therapeutic agents. 121. The bispecific antibody binding to FcRH5 and CD3 as described in claim 119, wherein the bispecific antibody binding to FcRH5 and CD3 is formulated for administration to the subject with one or more additional therapeutic agents.122. The bispecific antibody binding to FcRH5 and CD3 as described in claim 119, wherein the bispecific antibody binding to FcRH5 and CD3 is formulated to be administered to the subject after administration of one or more additional therapeutic agents. 123. The bispecific antibody binding to FcRH5 and CD3 as described in claim 122, wherein the one or more additional therapeutic agents comprise an effective amount of tocilizumab. 124. The bispecific antibody binding to FcRH5 and CD3 as described in claim 123, wherein tocilizumab is administered to the subject via intravenous infusion. 125. The bispecific antibody binding to FcRH5 and CD3 as described in claim 123 or 124, wherein: (a) the subject weighs ≥ 100 kg and is administered to the subject at a dose of 800 mg; (b) the subject weighs ≥ 30 kg and < 100 kg and is administered to the subject at a dose of 8 mg / kg; or (c) the subject weighs < 30 kg and is administered to the subject at a dose of 12 mg / kg. 126. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 123 to 125, wherein the subject is administered to the subject 2 hours prior to administration of the bispecific antibody. 127. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 120 to 122, wherein the one or more additional therapeutic agents comprise effective amounts of corticosteroids, analgesics and antipyretics, antihistamines, antimyeloma agents, PD-1 axis binding antagonists, antiCD38 therapeutic agents, immunomodulatory (IMiD) agents, cereblon E3 ligase modulators (CELMoD), proteasome inhibitors (PI), CAR-T therapy, antitumor agents, chemotherapeutic agents, growth inhibitors, antiangiogenic agents, radiotherapy, cytotoxic agents, cell-based therapies, or combinations thereof. 128. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68 to 127, wherein the bispecific antibody binding to FcRH5 and CD3 is formulated for administration to the subject via intravenous infusion. 129. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68 to 127.130. A bispecific antibody binding to FcRH5 and CD3, wherein the bispecific antibody binding to FcRH5 and CD3 is formulated for subcutaneous administration to the subject. 131. A bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 68 to 129, wherein the subject has a cytokine release syndrome (CRS) event, and the method further comprises treating the symptoms of the CRS event while discontinuing treatment with the bispecific antibody binding to FcRH5 and CD3. 132. A bispecific antibody binding to FcRH5 and CD3 used according to claim 130, wherein the method further comprises administering an effective amount of tocilizumab to the subject to treat the CRS event. 133. A bispecific antibody binding to FcRH5 and CD3 used according to claim 131, wherein tocilizumab is administered intravenously to the subject in a single dose of about 8 mg / kg. 133. The bispecific antibody binding to FcRH5 and CD3 used according to claim 131 or 132, wherein the CRS event does not subside or worsen within 24 hours of treatment of the symptoms of the CRS event, the method further comprising administering one or more additional doses of tocilizumab to the subject to manage the CRS event. 134. The bispecific antibody binding to FcRH5 and CD3 used according to claim 133, wherein the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 8 mg / kg. Claims 15 / 15 pages 16 CN 122206702 A Treatment and diagnostic method for treating cancer with anti-FcRH5 / anti-CD3 bispecific antibody

[0001] Sequence Listing

[0002] 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 November 6, 2024, named 50474-340WO2_Sequence_Listing_11_6_24 and is 41,629 bytes in size. Technical Field

[0003] This invention relates to a treatment and diagnostic method for treating subjects with multiple myeloma (MM) with a bispecific antibody against crystallizable fragment receptor-like 5 (FcRH5) / differentiation cluster 3 (CD3). Background Art

[0004] Cancer remains one of the deadliest threats to human health. In the United States, cancer afflicts more than 1.7 million new cases annually.Patients with MM are the second leading cause of death after heart disease, accounting for approximately one-quarter of all cancer-related deaths.

[0005] In particular, blood cancers are the second leading cause of cancer-related deaths. Blood cancers include multiple myeloma (MM), a tumor characterized by the proliferation and accumulation of malignant plasma cells. Approximately 110,000 people are diagnosed with MM each year worldwide. Despite advances in treatment, MM remains incurable, with an estimated median survival of 8 to 10 years for standard-risk myeloma and 2 to 3 years for high-risk disease, even with autologous stem cell transplantation. Although patient survival has improved significantly over the past 20 years, only 10% to 15% of patients achieve or exceed their expected survival compared to the matched general population. Survival extensions have been achieved through the introduction of proteasome inhibitors, immunomodulatory drugs (IMiDs), and monoclonal antibodies. However, most, if not all, patients eventually relapse, and patients with MM who become refractory or unsuitable for proteasome inhibitors or IMiDs have a rather poor outcome, surviving less than one year.

[0006] Therefore, the treatment of relapsed or refractory (R / R) MM continues to constitute a significant unmet medical need. For such patients, alternative or secondary treatment modalities, such as immunotherapy based on bispecific antibodies (e.g., anti-FcRH5 / anti-CD3 bispecific antibodies), may be particularly effective. However, the need in this field to identify R / R MM subjects most likely to respond to such treatments remains unmet.

[0007] In one aspect, the present disclosure is characterized by a method of treating a subject with multiple myeloma (MM), the method comprising administering to the subject a bispecific antibody that binds to Fc receptor homolog 5 (FcRH5) and differentiation cluster 3 (CD3), wherein prior to administering the bispecific antibody, (a) a sample from the subject has been determined to have a level of one or more cell types listed in Table 3 that is lower than a reference level, (b) a sample from the subject has been determined to have a level of one or more cell types listed in Table 4 that is higher than a reference level, and / or (c) a number of one or more of the characteristics listed in Table 5 that is lower than a reference level has been determined in the subject.

[0008] In some aspects, samples from subjects have been determined to have (a) levels of one or more cell types listed in Table 6 that are reduced compared to reference levels, and / or (b) samples from subjects have been determined to have levels of one or more cell types listed in Table 7 that are increased compared to reference levels as specified in document 1 / 144, page 17, CN 122206702 A.

[0009] In some respects, samples from subjects have been determined to have reduced levels of one or more cell types listed in Table 8 compared to reference levels, and optionally or alternatively, samples from subjects have been determined to have increased levels of one or more cell types listed in Table 9 compared to reference levels.

[0010] In another aspect, this disclosure is characterized by a method of treating a subject with MM, wherein the method comprises the steps of: (I) optionally, determining (a) the level of one or more cell types listed in Table 3 and / or Table 4 in a sample from the subject, and / or (b) one or more of the characteristics listed in Table 5 of the subject; (II) identifying the subject as a subject who will benefit from treatment comprising a bispecific antibody binding to FcRH5 and CD3, wherein: (a) the sample from the subject has a level of one or more cell types listed in Table 3 that is lower than a reference level; (b) the sample from the subject has a level of one or more cell types listed in Table 4 that is higher than a reference level; and / or (c) the subject has a number of one or more of the characteristics listed in Table 5 that is lower than a reference number, thereby identifying the subject as a subject who will benefit from treatment comprising a bispecific antibody binding to FcRH5 and CD3; and (III) administering to the subject a bispecific antibody binding to FcRH5 and CD3. Treatment with a bispecific antibody that binds to FcRH5 and CD3.

[0011] In some aspects, the method includes: (I) determining the level of one or more cell types listed in Table 6 and / or Table 7 in a sample from a subject; and (II) identifying the subject as a subject who will benefit from treatment including a bispecific antibody that binds to FcRH5 and CD3, wherein: (a) the sample from the subject has a reduced level of one or more cell types listed in Table 6 compared to a reference level, and / or (b) the sample from the subject has an increased level of one or more cell types listed in Table 7 compared to a reference level, thereby identifying the subject as a subject who will benefit from treatment including a bispecific antibody that binds to FcRH5 and CD3.

[0012] In some aspects, the method includes: (I) determining the levels of one or more cell types listed in Table 8 and / or Table 9 in a sample from a subject; and (II) identifying the subject as a subject who will benefit from treatment including a bispecific antibody binding to FcRH5 and CD3, wherein: (a) the sample from the subject has a reduced level of one or more cell types listed in Table 8 compared to a reference level, and / or (b) the sample from the subject has an increased level of one or more cell types listed in Table 9 compared to a reference level.The levels of one or more cell types listed in the study are used to identify subjects who will benefit from treatment including bispecific antibodies that bind to FcRH5 and CD3.

[0013] In another aspect, the present disclosure is characterized by a method for identifying a subject with MM as a subject who will benefit from treatment including a bispecific antibody binding to FcRH5 and CD3, the method comprising: (I) determining: (a) the level of one or more cell types listed in Table 3 and / or Table 4 in a sample from the subject, and / or (b) one or more of the characteristics listed in Table 5 of the subject; and (II) identifying the subject as a subject who will benefit from treatment including a bispecific antibody binding to FcRH5 and CD3, wherein: (a) the sample from the subject has a level of one or more cell types listed in Table 3 that is lower than a reference level; (b) the sample from the subject has a level of one or more cell types listed in Table 4 that is higher than a reference level; and / or (c) the subject has a number of one or more of the characteristics listed in Table 5 that is lower than a reference number, thereby identifying the subject as a subject who will benefit from treatment including a bispecific antibody binding to FcRH5 and CD3. Subjects treated with a bispecific antibody that binds to FcRH5 and CD3.

[0014] In some aspects, the method includes: (I) determining the levels of one or more cell types listed in Table 6 and / or Table 7 in a sample from a subject; and (II) identifying the subject as a subject who will benefit from treatment including a bispecific antibody that binds to FcRH5 and CD3, wherein: (a) the sample from the subject has a reduced level of one or more cell types listed in Table 6 compared to a reference level, and / or (b) the sample from the subject has an increased level of one or more cell types listed in Table 7 compared to a reference level, thereby identifying the subject as a subject who will benefit from treatment including a bispecific antibody that binds to FcRH5 and CD3.

[0015] In some aspects, the method includes: (I) determining the levels of one or more cell types listed in Table 8 and / or Table 9 in a sample from a subject; and (II) identifying the subject as a subject who will benefit from treatment including a bispecific antibody binding to FcRH5 and CD3, wherein: (a) the sample from the subject has a reduced level of one or more cell types listed in Table 8 compared to a reference level, and / or (b) the sample from the subject has an increased level of one or more cell types listed in Table 9 compared to a reference level, thereby identifying the subject as a subject who will benefit from treatment including a bispecific antibody binding to FcRH5 and CD3.Subjects treated with a CD3-binding bispecific antibody.

[0016] In another aspect, this disclosure features a method for classifying MM in a subject, the method comprising: (I) determining the levels of CD8+ T cells, Treg cells, and CD8+ TN cells in a sample from the subject, and (II) classifying the subject's MM into one of the following immune profiles based on the levels of CD8+ T cells, Treg cells, and CD8+ TN cells: (a) an activated immune profile; (b) an inactivated immune profile; or (c) a suppressed immune profile, thereby classifying the subject's MM. In some aspects, an activated immune profile includes: (a) increased CD8+ T cell levels, (b) decreased Treg cell levels, and (c) decreased CD8+ TN cell levels in a sample from the subject compared to reference levels. In some aspects, an inactivated immune profile includes, compared to a reference level, (a) decreased CD8+ T cell levels; (b) increased Treg cell levels; and (c) increased CD8+ TN cell levels. In some aspects, an inhibited immune profile includes, compared to a reference level, (a) increased CD8+ T cell levels; (b) increased Treg cell levels; and (c) decreased CD8+ TN cell levels. In some aspects, immune profiles are assigned via a similarity network fusion (SNF) algorithm / analysis. In some aspects, MM is classified as having either an activated or inactivated immune profile, which identifies subjects with MM as those who would benefit from treatment including bispecific antibodies binding to FcRH5 and CD3. In some aspects, MM is classified as having an immunosuppressive spectrum, which identifies subjects with MM as subjects who will not benefit from treatment including bispecific antibodies binding to FcRH5 and CD3.

[0017] In some aspects, the method further includes administering treatment to the subject including bispecific antibodies binding to FcRH5 and CD3.

[0018] In some aspects of any of the methods described herein, the sample from the subject is a bone marrow sample.

[0019] In some aspects of any of the methods described herein, the sample from the subject is a blood sample.

[0020] In some aspects, the sample from the subject is a baseline sample.

[0021] In some aspects of any of the methods described herein, determining the level of one or more cell types includes flow cytometry (FC), mass spectrometry (MS), immunohistochemistry (IHC), DNA sequencing (DNA-seq), RNA sequencing (RNA-seq), quantitative PCR.(qPCR), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), multiplex qPCR or RT-qPCR, microarray analysis, gene expression serial analysis (SAGE), MassARRAY® technology, in situ hybridization (ISH), or combinations thereof. In some aspects, determining the level of one or more cell types includes FC.

[0022] In some aspects of any of the methods described herein, the reference level is the mean Z-score of one or more cell types in a population of subjects with MM. In some aspects, the reference level is the median Z-score of one or more cell types in a population of subjects with MM. In some aspects, the reference level is the reference level assigned as listed in Table 14.

[0023] In some aspects of any of the methods described herein, the reference number is the mean of one or more characteristics listed in Table 5 in a population of subjects with MM. In some aspects, the reference number is the median of one or more characteristics listed in Table 5 in a population of subjects with MM. In some aspects, the reference number is the reference number of the allocation listed in Table 15.

[0024] In some aspects of any of the methods described herein, benefit from treatment includes a relative increase in overall survival (OS), objective response rate (ORR), progression-free survival (PFS), complete response (CR), partial response (PR), or a combination thereof. In some aspects, benefit from treatment includes a relative increase in OS. In some aspects, benefit from treatment includes a relative increase in ORR.

[0025] In some aspects of any of the methods described herein, MM is relapsed or refractory (R / R) MM.

[0026] In some aspects of any of the methods described herein, the bispecific antibody binding to FcRH5 and CD3 comprises an anti-FcRH5 arm having a first binding domain comprising the following six hypervariable regions (HVRs): (a) HVR-H1, comprising the amino acid sequence of RFGVH (SEQ ID NO: 1); (b) HVR-H2, comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) HVR-H3, comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO: 3); (d) HVR-L1, comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) HVR-L2, comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (f) HVR-L3, comprising QQHYSPPYT (SEQ ID NO: 5).The amino acid sequence of SEQ ID NO: 6). In some aspects, the bispecific antibody binding to FcRH5 and CD3 comprises an anti-FcRH5 arm having a first binding domain comprising (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 8; or (c) the VH domain as in (a) and the VL domain as in (b). In some aspects, the first binding domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 7 and a VL domain comprising the amino acid sequence of SEQ ID NO: 8. In some aspects, the bispecific antibody binding to FcRH5 and CD3 includes an anti-CD3 arm having a second binding domain comprising the following six HVRs: (a) HVR-H1 containing the amino acid sequence SYYIH (SEQ ID NO: 9); (b) HVR-H2 containing the amino acid sequence WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) HVR-H3 containing the amino acid sequence DGYSRYYFDY (SEQ ID NO: 11); (d) HVR-L1 containing the amino acid sequence KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 containing the amino acid sequence WTSTRKS (SEQ ID NO: 13); and (f) HVR-L3 containing the amino acid sequence KQSFILRT (SEQ ID NO: 14). In some aspects, the bispecific antibody binding to FcRH5 and CD3 includes an anti-CD3 arm having a second binding domain comprising (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 16; or (c) the VH domain as in (a) and the VL domain as in (b). In some aspects, the second binding domain comprises a VH domain having the amino acid sequence of SEQ ID NO: 15 and a VL domain comprising the amino acid sequence of SEQ ID NO: 16. In some aspects, withThe FcRH5 and CD3 binding bispecific antibody comprises: an anti-FcRH5 arm having a heavy chain polypeptide (H1) and a light chain polypeptide (L1); and an anti-CD3 arm having a heavy chain polypeptide (H2) and a light chain polypeptide (L2), wherein: (a) H1 comprises the amino acid sequence of SEQ ID NO: 35; (b) L1 comprises the amino acid sequence of SEQ ID NO: 36; (c) H2 comprises the amino acid sequence of SEQ ID NO: 37; and (d) L2 comprises the amino acid sequence of SEQ ID NO: 38.

[0027] In some aspects of any of the methods described herein, the FcRH5 and CD3 binding bispecific antibody comprises a deglycosylation site mutation. In some aspects, the deglycosylation site mutation reduces the effector function of the bispecific antibody. In some aspects, the deglycosylation site mutation is a substitution mutation. In some respects, bispecific antibodies binding to FcRH5 and CD3 include substitution mutations in the Fc region that reduce effector function. In some respects, bispecific antibodies binding to FcRH5 and CD3 (see page 4 / 144 of CN 122206702 A) are monoclonal antibodies. In some respects, bispecific antibodies binding to FcRH5 and CD3 are chimeric antibodies. In some respects, bispecific antibodies binding to FcRH5 and CD3 are humanized antibodies. In some respects, bispecific antibodies binding to FcRH5 and CD3 are antibody fragments binding to FcRH5 and CD3. In some respects, the antibody fragment is selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments. In some respects, bispecific antibodies binding to FcRH5 and CD3 are full-length antibodies. In some aspects, the bispecific antibody binding to FcRH5 and CD3 is an IgG antibody. In some aspects, the IgG antibody is an IgG1 antibody.

[0028] In some aspects of any of the methods described herein, the bispecific antibody binding to FcRH5 and CD3 includes one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH11) domain, a first CH2 (CH21) domain, a first CH3 (CH31) domain, a second CH1 (CH12) domain, a second CH2 (CH22) domain, and a second CH3 (CH32) domain. In some aspects, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. In some aspects, the CH31 domain and the CH32 domain each include a protrusion or a cavity, and wherein...The protrusions or cavities in the CH31 structural domain may be located within the cavities or protrusions in the CH32 structural domain. In some aspects, the CH31 and CH32 structural domains are connected at the interface between the protrusions and cavities. In some aspects, the CH21 and CH22 structural domains each include a protrusion or a cavity, and wherein the protrusions or cavities in the CH21 structural domain are located within the cavities or protrusions in the CH22 structural domain. In some aspects, the CH21 and CH22 structural domains meet at the interface between the protrusions and cavities. In some aspects, the anti-FcRH5 arm includes a protrusion, and the anti-CD3 arm includes a cavity. In some aspects, the CH3 domain of the anti-FcRH5 arm includes a protrusion containing a T366W amino acid substitution mutation (EU number), and the CH3 domain of the anti-CD3 arm includes a cavity containing T366S, L368A, and Y407V amino acid substitution mutations (EU number).

[0029] In some aspects of any of the methods described herein, the bispecific antibody binding to FcRH5 and CD3 is civastastatin.

[0030] In some aspects of any of the methods described herein, the bispecific antibody binding to FcRH5 and CD3 is administered to the subject as a monotherapy.

[0031] In some aspects of any of the methods described herein, the bispecific antibody binding to FcRH5 and CD3 is administered to the subject as a combination therapy. In some aspects, the bispecific antibody binding to FcRH5 and CD3 is administered to the subject concurrently with one or more additional therapeutic agents. In some aspects, a bispecific antibody binding to FcRH5 and CD3 is administered to the subject prior to administration of one or more additional therapeutic agents. In some aspects, a bispecific antibody binding to FcRH5 and CD3 is administered to the subject after administration of one or more additional therapeutic agents. In some aspects, one or more additional therapeutic agents comprise an effective amount of tocilizumab. In some aspects, tocilizumab is administered to the subject by intravenous infusion. In some aspects, (a) the subject weighs ≥ 100 kg and is administered to the subject at a dose of 800 mg; (b) the subject weighs ≥ 30 kg and < 100 kg and is administered to the subject at a dose of 8 mg / kg; or (c) the subject weighs < 30 kg and is administered to the subject at a dose of 12 mg / kg. In some aspects, tocilizumab is administered to the subject 2 hours prior to administration of the bispecific antibody binding to FcRH5 and CD3. In some respects, one or more additional therapeutic agents include effective amounts of corticosteroids, analgesics and antipyretics, antihistamines, antimyeloma agents, PD-1 inhibitors, etc.Axis-binding antagonists, anti-CD38 therapeutic agents, immunomodulatory (IMiD) agents, cereblon E3 ligase modulators (CELMoD), proteasome inhibitors (PI), CAR-T therapy, antitumor agents, chemotherapeutic agents, growth inhibitors, anti-angiogenic agents, radiotherapy, cytotoxic agents, cell-based therapies, or combinations thereof.

[0032] In some aspects of any of the methods described herein, a bispecific antibody binding to FcRH5 and CD3 is administered to the subject via intravenous infusion. Specification 5 / 144 pages 21 CN 122206702 A

[0033] In some aspects of any of the methods described herein, a bispecific antibody binding to FcRH5 and CD3 is administered subcutaneously to the subject.

[0034] In some aspects of any of the methods described herein, the subject has a cytokine release syndrome (CRS) event, and the method further includes treating the symptoms of the CRS event while discontinuing treatment with the bispecific antibody binding to FcRH5 and CD3. In some aspects, the method further includes administering an effective amount of tocilizumab to the subject to treat a CRS event. In some aspects, tocilizumab is administered intravenously to the subject in a single dose of about 8 mg / kg. In some aspects, the CRS event does not resolve or worsens within 24 hours of treatment of the symptoms of the CRS event, and the method further includes administering one or more additional doses of tocilizumab to the subject to manage the CRS event. In some aspects, one or more additional doses of tocilizumab are administered intravenously to the subject in a dose of about 8 mg / kg.

[0035] In some aspects, one or more additional therapeutic agents comprise an effective amount of a corticosteroid. In some aspects, a corticosteroid is administered intravenously to the subject. In some aspects, the corticosteroid is methylprednisolone. In some aspects, methylprednisolone is administered in a dose of about 80 mg. In some aspects, the corticosteroid is dexamethasone. In some aspects, dexamethasone is administered in a dose of about 20 mg. In some aspects, one or more additional therapeutic agents comprise an effective amount of acetaminophen or paracetamol. In some aspects, acetaminophen or paracetamol is administered at a dose between about 500 mg and about 1000 mg. In some aspects, acetaminophen or paracetamol is administered orally to the subject. In some aspects, one or more additional therapeutic agents include an effective amount of diphenhydramine. In some aspects, diphenhydramine is administered at a dose between about 25 mg and about 50 mg. In some aspects, diphenhydramine is administered orally to the subject.

[0036] Figure 1 is a schematic diagram illustrating omics and non-omics data types compiled and integrated into a single similarity network using similarity network fusion analysis (SNF).

[0037] FigureFigures 2A-2E are illustrative examples of the SNF steps. Figure 2A is a representation of the mRNA expression and DNA methylation datasets for the same patient cohort. Figure 2B shows the case-by-case patient similarity matrix for each data type. Figure 2C shows the case-by-case patient similarity network, which corresponds to the case-by-case patient data. Patients are represented by nodes, and pairwise similarities of patients are represented by edges. Figure 2D shows the network fusion generated by SNF, which iteratively updates each of these networks using information from other networks, making them more similar at each step. Figure 2E shows the convergence to the final fused network caused by iterative network fusion. Edge colors indicate the data types that contribute to a given similarity.

[0038] Figure 3A is a schematic diagram showing the data layers integrated using SNF.

[0039] Figure 3B is a heatmap showing clinical data (e.g., subject characteristics) and Z-scores of cell types isolated from bone marrow (BM) and / or blood. As determined by SNF, three clusters (“Cluster 1”, “Cluster 2”, and “Cluster 3”) were identified.

[0040] Figure 4 is a set of bar charts showing the responses of clusters 1, 2, and 3 according to the International Myeloma Working Group (IMWG) criteria. NR: No response; R: Response; sCR: Strict complete response; CR: Complete response; VGPR: Excellent partial response; PR: Partial response; MR: Minimal response; SD: Stable disease; PD: Disease progression.

[0041] Figure 5 is a set of Kaplan-Meier curves showing the probability of progression-free survival (PFS; left) or overall survival (OS; right) over time (days) for subjects in clusters 1 (responders to civastimab treatment with an activated immune profile), 2 (responders to civastimab treatment with an inactivated immune profile), and 3 (responders to civastimab treatment with an inhibited immune profile). Clusters were identified by similarity network fusion (SNF). Each curve is shown together with a table below showing the number of subjects at risk over time. Instructions for Use, Page 6 / 144, 22 CN 122206702 A

[0042] Figure 6 is a set of Kaplan-Meier curves showing the probability of PFS (left) or OS (right) for civasutamab treatment responders (clusters 1 and 2) or civasutamab treatment non-responders (cluster 3). Clusters were identified by SNF. Each curve is shown together with the table below, which shows the number of subjects at risk over time stratified by responder cluster or non-responder cluster.

[0043] Figure 7A is a set of bar graphs showing the probability of PFS (left) or OS (right) for civasutamab treatment responders (clusters 1 and 2) or civasutamab treatment non-responders (cluster 3).3) The percentage (left) and total (right) of the best overall response. SCR: Strict complete response; CR: Complete response; VGPR: Excellent partial response; PR: Partial response; MR: Minimal response; SD: Stable disease; PD: Disease progression.

[0044] Figure 7B is a set of bar charts showing the clinical response of civasutazumab responders (clusters 1 and 2) or civasutazumab non-responders (cluster 3) according to IMWG criteria.

[0045] Figure 8A is a heatmap of the clinical data layers for clusters 1, 2, and 3.

[0046] Figure 8B is a set of box-and-whisker plots showing the number of prior therapy lines (left), cellular ferritin level (middle), and soluble B cell maturation agent level (sBCMA; right) for subjects in clusters 1, 2, and 3.

[0047] Figure 9 is a heatmap showing the clinical data grouped by clusters 1, 2, and 3 and the Z-scores of cell types isolated from BM. The clinical data layer includes whether the subject had a response or no response (NR) to civasutazine® treatment, what the best overall response was (e.g., SCR: strict complete response; CR: complete response; VGPR: excellent partial response; PR: partial response; MR: minimal response; SD: stable disease; PD: disease progression), whether the subject had a prior line of therapy (e.g., BCMA, ADC, or CART), and whether the subject was a class III or class V refractory subject. The identified cell types include the percentages of CD8+ TN cells, Treg cells, CD8+ TCM cells, CD3- non-lymphocytes, CD4+PD1+OX40- T cells, CD4-PD1+ T cells, CD4+DR+PD1+ T cells, CD4+GzB+ T cells, CD8+GzB- T cells, CD8+GzB+TEM T cells, CD8+GzB+TEMRA T cells, CD8+DR+GzB+TEMRA T cells, CD8+DR+ T cells, CD8+DR+TEMRA T cells, CD8+DR+PD1+ T cells, CD8+PD1+GzB+ T cells, and CD8+DR+PD1+TEM cells.

[0048] Figure 10A is a set of box-and-whisker diagrams showing the levels of cell types isolated from BM grouped into clusters 1, 2, and 3. The representative cell types are CD8+ positive T cells, CD8+ naive T cells (CD8Tn), CD8+ central memory T cells (CD8Tcm), CD8+ effector memory T cells (CD8Tem), and CD8+ terminally differentiated effector memory T cells (CD8Temra).

[0049] FigureFigure 10B is a set of box-and-whisker diagrams showing the levels of cell types isolated from BM, grouped into clusters 1, 2, and 3. The representative cell types are regulatory T cells (Treg), CD8+ and granzyme B (GzB) positive effector memory T cells (CD8TemGzB), and CD8-positive and GzB-positive terminally differentiated effector memory T cells (CD8TemraGzB).

[0050] Figure 11 is a heatmap showing clinical data and Z-scores of cell types isolated from blood, grouped into clusters 1, 2, and 3.

[0051] Figure 12A is a set of box-and-whisker diagrams showing the levels of cell types isolated from blood, grouped into clusters 1, 2, and 3. The representative cell type is CD8-positive cells, further stratified into naive T cells (Tn), central memory T cells (Tcm), effector memory T cells (Tem), and terminally differentiated effector memory T cells (Temra).

[0052] Figure 12B is a set of box-and-whisker diagrams showing the levels of cell types isolated from blood, grouped into clusters 1, 2, and 3. The represented cell type is CD4 positive cells, which are further stratified into naive T cells (Tn), central memory T cells (Tcm), effector memory T cells (Tem), and terminally differentiated effector memory T cells (Temra).

[0053] Figure 13 is a set of box-and-whisker diagrams showing the levels of cell types, grouped into clusters 1, 2, and 3. The table on the left side of the diagram in the specification 7 / 144 page 23 CN 122206702 A shows the levels of regulatory T cells (Treg). The middle graph shows the levels of CD8 positive, programmed cell death protein 1 (PD1) positive (PD1+), T cell immune receptor (TIGIT) positive (TIGIT+) with immunoglobulin and immune receptor tyrosine inhibitory motif domains, and T cell immunoglobulin and mucin domain 3 (TIM3+) positive (TIM3+) cells. The right-hand graph shows the levels of PD1+, TIGIT+, and TIM3+ cells.

[0054] Figure 14A is a heatmap showing clinical data and Z-scores for cell types grouped into clusters 1, 2, and 3 in subjects who have received ≤5 prior lines of therapy.

[0055] Figure 14B is a heatmap showing clinical data and Z-scores for cell types grouped into clusters 1, 2, and 3 in subjects who have received >5 prior lines of therapy.

[0056] Figure 15A is a heatmap showing clinical data and Z-scores for cell types grouped into clusters 1, 2, and 3 in subjects who have received ≤3 prior lines of therapy.Heatmap of scores.

[0057] Figure 15B is a heatmap showing clinical data and Z-scores for cell types grouped by clusters 1, 2, and 3 in subjects who received >3 prior lines of therapy.

[0058] Figure 16 is a set of box-and-whisker plots showing the levels of cell types isolated from BM grouped by clusters 1, 2, and 3. The cell types represented are differentiation cluster 4 (CD4) positive and GzB positive cells (CD4GzB); CD4 positive, human leukocyte antigen-DR isotype (DR) positive and GzB positive cells (CD4DR+GzB+); CD8 positive and GzB positive effector memory T cells (CD8TemGzB); and CD8 positive, GzB positive terminally differentiated effector memory T cells (Cd8TemraGzB).

[0059] Figure 17A is a Kaplan-Meier curve showing the probability of PFS over time (days) for subjects treated with a bispecific antibody that binds to FcRH5 and CD3, where subjects received post-BCMA treatment (blue) or did not receive post-BCMA treatment (red). The graph below the curve shows the number of subjects at risk over time, stratified by treatment component.

[0060] Figure 17B is a Kaplan-Meier curve showing the probability of PFS over time (days) for subjects treated with a bispecific antibody that binds to FcRH5 and CD3, where subjects received prior anti-BCMA antibody treatment (blue) or did not receive prior anti-BCMA antibody treatment (red). The graph below the curve shows the number of subjects at risk over time, stratified by treatment component.

[0061] Figure 17C is a Kaplan-Meier curve showing the probability of PFS over time (days) for subjects treated with a bispecific antibody that binds to FcRH5 and CD3, where subjects either received prior anti-BCMA bispecific antibody treatment (blue) or not (red). The graph below the curve shows the number of subjects at risk over time, stratified by treatment component.

[0062] Figure 18A is a Kaplan-Meier curve showing the probability of PFS over time (days) for subjects treated with a bispecific antibody that binds to FcRH5 and CD3, where subjects either received prior anti-BCMA antibody and prior chimeric antigen receptor T-cell (CART) therapy (blue) or not.Therapy (red). The graph below the curve shows the number of subjects at risk over time by treatment component stratification.

[0063] Figure 18B is a Kaplan-Meier curve showing the probability of PFS over time (days) for subjects treated with a bispecific antibody binding to FcRH5 and CD3, where subjects received prior anti-BCMA antibody-drug conjugate (ADC) treatment (blue) or did not receive prior anti-BCMA antibody-drug conjugate (ADC) treatment (red). The graph below the curve shows the number of subjects at risk over time by treatment component stratification. Instructions for Use, Page 8 / 144, CN 122206702 A

[0064] Figure 18C is a Kaplan-Meier curve showing the probability of PFS over time (days) for subjects treated with bispecific antibodies that bind to FcRH5 and CD3, where subjects received prior anti-BCMA bispecific antibody treatment (blue) or did not receive prior anti-BCMA bispecific antibody treatment (red). The graph below the curve shows the number of subjects at risk over time by treatment group.

[0065] Figure 19 is a set of box-and-whisker plots showing the soluble levels of sBCMA (left) and interferon (IFN) (right) in blood samples grouped into clusters 1, 2, and 3.

[0066] Figure 20 is a set of box-and-whisker diagrams showing the levels of regulatory T cells (Treg) (left), CD4-positive naive T cells (CD4Tn) (middle), and CD8-positive naive T cells (CD8Tn) (right) in blood samples grouped into clusters 1, 2, and 3.

[0067] Figure 21 is a set of box-and-whisker diagrams showing the levels of regulatory T cells (Treg) (left), CD4-positive naive T cells (CD4Tn) (middle), and CD8-positive naive T cells (CD8Tn) (right) in BM samples grouped into clusters 1, 2, and 3.

[0068] Figure 22A is a set of box-and-whisker diagrams showing the levels of CD8-positive cells (left) and CD4-positive cells (right) in BM samples grouped into clusters 1, 2, and 3.

[0069] Figure 22B is a set of box-and-whisker plots showing the levels of CD8 positive cells (left) and CD4 positive cells (right) in blood samples grouped into clusters 1, 2, and 3.

[0070] Figure 23 is a heatmap showing clinical data (e.g., characteristics of the subjects) and Z-scores of the number of prior treatments in clusters 1, 2, and 3.

[0071] Figure 24A shows the levels of CD8 positive cells (left) and CD4 positive cells (right) in clusters 1, 2, and 3.A heatmap of grouped clinical data (e.g., subject characteristics) and Z-scores of cell types isolated from BM.

[0072] Figure 24B is a heatmap showing clinical data (e.g., subject characteristics) grouped by clusters 1, 2, and 3 and Z-scores of cell types isolated from blood. Detailed Description

[0073] I. Definitions

[0074] As used herein, the term “about” refers to a common range of error for a corresponding value that is readily known to those skilled in the art. References to “about” values ​​or parameters herein include (and describe) aspects relating to that value or parameter itself.

[0075] It should be understood that aspects of the invention described herein include aspects that “comprise,” “consist of,” and “substantially consist of.”

[0076] As used herein, the term “FcRH5” or “crystallizable fragment receptor-like 5” refers to any naturally occurring FcRH5 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise stated, and covers “full-length”, unprocessed FcRH5, as well as any form of FcRH5 produced through cellular processing. The term also covers naturally occurring variants of FcRH5, including, for example, splice variants or allele variants. FcRH5 includes, for example, the human FcRH5 protein (UniProtKB / Swiss-Prot ID: Q96RD9.3), which is 977 amino acids in length.

[0077] The terms “bispecific antibody binding to Fc receptor homology 5 (FcRH5) and differentiation cluster 3 (CD3)”, “bispecific anti-FcRH5 / anti-CD3 antibody”, and “anti-FcRH5 / anti-CD3 bispecific antibody” refer to antibodies capable of binding to FcRH5 and CD3 with sufficient affinity so that the antibody can be used as a therapeutic agent targeting FcRH5 and CD3. In one embodiment, the bispecific antibody binding to FcRH5 and CD3 binds to unrelated non-FcRH5 proteins and / or non-CD3 proteins to less than about 10% of the antibody binding to FcRH5 and / or CD3, as measured by, for example, radioimmunoassay (RIA). In some embodiments, the dissociation constant (KD) of the bispecific antibody binding to FcRH5 and CD3 with FcRH5 and / or CD3 is ≤ 1 μM, ≤ 250 nM, ≤ 100 nM, ≤ 15 nM, ≤ 10 nM, ≤ 6 nM, ≤ 4 nM, ≤ 2 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM.nM (e.g., 10⁻⁸ M or less, e.g., 10⁻⁸ M to 10⁻¹³ M, e.g., 10⁻⁹ M to 10⁻¹³ M). In some embodiments, the bispecific antibody binding to FcRH5 and CD3 binds to (i) a conserved FcRH5 epitope in FcRH5 from different species and / or (ii) a conserved CD3 epitope in CD3 from different species. In one embodiment, the bispecific antibody binding to FcRH5 and CD3 is civastastat.

[0078] Unless otherwise specified, the terms “differentiation cluster 3” or “CD3” as used herein refer to any natural CD3 from any vertebrate source, including primates (e.g., humans) and rodents (e.g., mice and rats), including, for example, CD3ε, CD3γ, CD3α, and CD3β chains. This term encompasses “full-length” unprocessed CD3 (e.g., unprocessed or unmodified CD3ε or CD3γ), as well as any form of CD3 produced through cellular processing. The term also covers naturally occurring variants of CD3, including, for example, splice variants or allelic variants. CD3 includes, for example, the 207-amino-acid human CD3ε protein (NCBI RefSeq No. NP_000724) and the 182-amino-acid human CD3γ protein (NCBI RefSeq No. NP_000064).

[0079] “Civoxetine”, also known as BFCR4350A or RO7187797, is an engineered, humanized, full-length non-glycosylated IgG1κ T cell-dependent bispecific antibody (TDB) that binds to FcRH5 and CD3 and contains an anti-FcRH5 arm containing the heavy chain polypeptide sequence of SEQ ID NO: 35 and the light chain polypeptide sequence of SEQ ID NO: 36, and an anti-CD3 arm containing the heavy chain polypeptide sequence of SEQ ID NO: 37 and the light chain polypeptide sequence of SEQ ID NO: 38. Civastastatin contains an amino acid substitution using EU numbers of amino acid residues in the Fc region at position 366 of the heavy chain of the anti-FcRH5 arm (T366W), representing a threonine to tryptophan substitution, and three amino acid substitutions using EU numbers of amino acid residues in the Fc region on the heavy chain of the anti-CD3 arm (Y407V, T366S, and L368A): a tyrosine to valine substitution at position 407, a threonine to serine substitution at position 366, and a leucine substitution at position 368.The substitution of alanine with an acid to drive heterodimerization of both arms (half antibody). Civastastat also contains an amino acid substitution (N297G) at position 297 on each heavy chain using the EU number of the amino acid residue in the Fc region, which results in minimal non-glycosylated antibody binding to the Fc (Fcγ) receptor and thus inhibits Fc effector function. Civastastat is also described in the following literature: WHO Drug Information (International Nonproprietary Name), Proposed INN: List 84, Volume 34, Issue 3, published in 2020 (see page 701).

[0080] The term “antibody” is used in the broadest sense and covers a variety of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments (e.g., dual Fab), as long as they exhibit the desired antigen-binding activity.

[0081] “Affinity” refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, “binding affinity” refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by conventional methods known in the art, including those described herein. Specific illustrative and exemplary aspects for measuring binding affinity are described below.

[0082] An “affinity-mature” antibody is an antibody having one or more alterations in one or more hypervariable regions (HVRs) that result in an improved affinity of the antibody for the antigen compared to a parent antibody without such alterations. Specification 10 / 144 pages 26 CN 122206702 A

[0083] The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used interchangeably herein to refer to an antibody having a structure substantially similar to that of a natural antibody or having a heavy chain containing an Fc region as defined herein.

[0084] An “antibody fragment” is a molecule other than an intact antibody that contains a portion of the intact antibody and binds to the antigen bound by the intact antibody. Examples of antibody fragments include, but are not limited to: double Fab; Fv; Fab; Fab, Fab'-SH; F(ab')2; bisomatic antibodies; linear antibodies; single-chain antibody molecules (e.g., scFv, ScFab); and multispecific antibodies formed from antibody fragments.

[0085] A “single-domain antibody” is an antibody fragment containing all or part of the variable domain of the heavy chain or all or part of the variable domain of the light chain of an antibody. In some respects, single-domain antibodies are human single-domain antibodies (see, for example, U.S. Patent).(No. 6,248,516 B1). Examples of single-domain antibodies include, but are not limited to, VHH.

[0086] The “Fab” fragment is an antigen-binding fragment produced by papain digestion of an antibody and consists of a complete L chain, a variable region domain (VH) of the H chain, and a first constant domain (CH1) of a heavy chain. Papain digestion of the antibody produces two identical Fab fragments. Pepsin treatment of the antibody produces a single large F(ab')2 fragment, which is roughly equivalent to two Fab fragments linked by disulfide bonds, having divalent antigen-binding activity and still capable of crosslinking antigens. The Fab' fragment differs from the Fab fragment in that the Fab' fragment has residues added to the carboxyl terminus of the CH1 domain, which contain one or more cysteine ​​residues from the hinge region of the antibody. Fab'-SH is the name used herein for Fab' in which the cysteine ​​residues of the constant domain have free thiol groups. The F(ab')2 antibody fragment was originally produced as a pair of Fab' fragments with hinge cysteine ​​residues in between. Other chemical conjugations of antibody fragments are also known.

[0087] “Fv” consists of a tight, non-covalently associated dimer of a heavy chain variable region domain and a light chain variable region domain. The folding of these two domains produces six hypervariable rings (three rings each from the H chain and the L chain), which contribute amino acid residues to achieve antigen binding, and thus the antibody has antigen-binding specificity. However, even a single variable domain (or half of Fv, containing only three antigen-specific CDRs) has the ability to recognize and bind antigens, although its affinity is often lower than that of the intact binding site.

[0088] The term “Fc region” used herein is used to define the C-terminal region of the immunoglobulin heavy chain, which includes the native sequence Fc region and variant Fc regions. Although the boundaries of the immunoglobulin heavy chain Fc region may vary, the human IgG heavy chain Fc region is generally defined as extending from the amino acid residue at position Cys226 or from Pro230 to the carboxyl terminus of the heavy chain. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) can be removed, for example, during antibody production or purification or by recombinantly designing nucleic acids encoding the antibody heavy chain. Therefore, compositions of intact antibodies may include antibody populations with all Lys447 residues removed, antibody populations with Lys447 residues not removed, and antibody populations having mixtures containing and without Lys447 residues.

[0089] The “natural sequence Fc region” contains the same amino acid sequence as the Fc region found in nature. The natural sequence human Fc region includes the natural sequence human IgG1 Fc region (non-A and A).Allotypes); natural sequence human IgG2 Fc region; natural sequence human IgG3 Fc region; and natural sequence human IgG4 Fc region and its naturally occurring variants.

[0090] A “variant Fc region” comprises an amino acid sequence different from that of the natural sequence Fc region, which is achieved by means of at least one amino acid modification, preferably one or more amino acid substitutions. Preferably, the variant Fc region has at least one amino acid substitution compared to the natural sequence Fc region or the Fc region of the parent polypeptide, for example, having about one to about ten amino acid substitutions in the natural sequence Fc region or the Fc region of the parent polypeptide, and preferably having about one to about five amino acid substitutions. The variant Fc region described herein preferably has at least about 80% homology with the natural sequence Fc region and / or with the Fc region of the parent polypeptide, preferably at least about 90% homology with it, or preferably at least about 95% homology with it.

[0091] The “hinge region” is generally defined as extending from approximately residue 216 to 230 of IgG (EU number), from approximately residue 226 to 243 of IgG (Kabat number), or from approximately residue 1 to 15 of IgG (IMGT unique number).

[0092] An “Fc receptor” or “FcR” refers to a receptor that binds to the Fc region of an antibody. Preferred FcRs are naturally occurring human FcRs. Furthermore, preferred FcRs are FcRs that bind to IgG antibodies (a type of γ receptor) and include receptors of the Fc γ RI, Fc γ RII, and Fc γ RIII subclasses, including allelic variants and alternative splicing forms of these receptors. Fc γ RII receptors include Fc γ RIIA (“activating receptor”) and Fc γ RIIB (“inhibitory receptor”), which have similar amino acid sequences and differ primarily in their cytoplasmic domains. The activating receptor FcγRIIA contains an activating motif (ITAM) based on the tyrosine residue of the immune receptor in its cytoplasmic domain. The repressive receptor FcγRIIB contains an repressive motif (ITIM) based on the tyrosine residue of the immune receptor in its cytoplasmic domain (see review in Daëron, Annu. Rev. Immunol. 15:203–234, 1997). Ravetch and Kinet, Annu. Rev. Immunol. 9:457–492 (1991); Capel et al., Immunomethods 4:25–34 (1994); and de Haas et al.,FcRs were reviewed in J. Lab. Clin. Med. 126:330-41 (1995). The term “FcR” as used herein encompasses other FcRs, including those to be identified in the future. The term also includes the neonatal receptor FcRn, which is responsible for transferring maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)).

[0093] As described herein, the term “knob-in-hole” or “KnH” technique refers to a technique that guides the pairing of two peptides together in vivo or in vitro by introducing a protrusion (knob) into one peptide and a cavity (cavity) into another peptide at their interacting interface. For example, KnH has been introduced into the Fc:Fc interaction interface, CL:CH1 interface, or VH / VL interface of antibodies (see, for example, US2007 / 0178552, WO 96 / 027011, WO 98 / 050431, and Zhu et al., 1997, Protein Science 6:781-788). This can be used in particular to drive two different heavy chains to pair together during the preparation of multispecific antibodies. For example, multispecific antibodies having KnH in their Fc region may further include a single variable domain linked to their respective Fc regions, or further include different heavy chain variable domains paired with the same, similar, or different light chain variable domains. KnH technology can also be used to pair together two different receptor extracellular domains or any other polypeptide sequences containing different target recognition sequences.

[0094] “Frame” or “FR” refers to variable domain residues other than hypervariable region (HVR) residues. The variable domain FR is typically composed of four FR domains: FR1, FR2, FR3, and FR4. Therefore, the HVR and FR sequences typically appear in VH (or VL) as follows: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0095] The “CH1 region” or “CH1 domain” comprises a segment of residues extending from approximately residues 118 to 215 of IgG (EU number), approximately residues 114 to 223 of IgG (Kabat number), or approximately residues 1.4 to 121 of IgG (IMGT unique number) (Lefranc M-P, Giudicelli V, Duroux P, Jabado-Michaloud J, Folch G, Aouinti S,Carillon E, Duvergey H, Houles A, Paysan-Lafosse T, Hadi-Saljoqi S, Sasorith S, Lefranc G, Kossida S. IMGT®, the international ImMunoGeneTics information system® 25 years on. Nucleic Acids Res. January 2015; 43 (Database issue): D413-22).

[0096] The “CH2 domain” of the human IgG Fc region typically extends from about 244 to about 360 (Kabat number) of IgG, from about 231 to about 340 (EU number) of IgG, or from about 1.6 to about 125 (IGMT unique number) of IgG. The CH2 domain is unique in that it is not tightly paired with another domain. Instead, two N-linked branched carbohydrate chains are located between the two CH2 domains of the intact natural IgG molecule. It is speculated that the carbohydrate compound, page 12 / 144, 28 CN 122206702 A, may provide alternatives for domain-domain pairing and help stabilize the CH2 domain. Burton, Molec. Immunol. 22: 161-206 (1985).

[0097] The “CH3 domain” contains a residue extending from the C-terminus of the CH2 domain in the Fc region (i.e., from about amino acid residue 361 to about amino acid residue 478 of IgG (Kabat number), from about amino acid residue 341 to about amino acid residue 447 of IgG (EU number), or from about amino acid residue 1.4 to about amino acid residue 130 of IgG (IGMT unique number)).

[0098] The “CL domain” or “constant light domain” contains a residue extending from the C-terminus of the light chain variable domain (VL). The light chain of an antibody can be a kappa (κ) (“Cκ”) or lambda (λ) (“Cλ”) light chain region. The Cκ region typically extends from approximately residue 108 to residue 214 of IgG (Kabat or EU number) or from approximately residue 1.4 to residue 126 of IgG (IMGT unique number). The Cλ residue typically extends from approximately residue 107a to residue 215 (Kabt number) or from approximately residue 1.5 to residue 127 (IMGT unique number) (Lefranc M-P, Giudicelli V,Duroux P, Jabado-Michaloud J, Folch G, Aouinti S, Carillon E, Duvergey H, Houles A, Paysan-Lafosse T, Hadi-Saljoqi S, Sasorith S, Lefranc G, Kossida S. IMGT®, the international ImMunoGeneTics information system® 25 years on. Nucleic Acids Res. January 2015; 43 (Database issue): D413-22).

[0099] Light chains (LC) derived from any vertebrate can be classified into one of two distinct types based on the amino acid sequence of their constant domain, referred to as κ and λ, respectively. Immunoglobulins can be classified into different classes or isotypes based on the amino acid sequence of their heavy chain constant domain (CH). There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, which have heavy chains referred to as α, δ, γ, ε, and μ, respectively. The γ and α classes are further subdivided into subclasses based on relatively small differences in CH sequence and function; for example, humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0100] The term "chimeric" antibody refers to an antibody in which a portion of the heavy chain and / or light chain originates from a particular source or species, while the remainder of the heavy chain and / or light chain originates from a different source or species.

[0101] The "class" of an antibody refers to the type of constant structural domain or constant region possessed by the heavy chain of the antibody. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these antibodies can be further subdivided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to different classes of immunoglobulins are respectively called α, δ, ε, γ, and μ.

[0102] A “human antibody” is an antibody having an amino acid sequence that corresponds to the amino acid sequence of an antibody produced by a human or human cell, or to an amino acid sequence derived from a non-human antibody using a complete library of human antibodies or other human antibody-encoding sequences. This definition of a human antibody specifically excludes humanized antibodies containing non-human antigen-binding residues. Human antibodies can be generated using various techniques known in the art, including phage display libraries. Hoogenboom and Winter J. Mol. Biol.227:381, 1991; Marks et al. J. Mol. Biol. 222:581, 1991. Methods for preparing human monoclonal antibodies can also be described as follows: Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(1):86–95, 1991. See also van Dijk and van de Winkel. Curr. Opin. Pharmacol. 5:368–74, 2001. Human antibodies can be prepared by administering antigens to transgenic animals that have been modified to produce such antibodies in response to antigen attack, but whose endogenous loci have been deactivated, for example, immunized xenogeneic mice (see, for example, U.S. Patent Nos. 6,075,181 and 6,150,584 concerning XENOMOUSE™ technology). See also, for example, Li et al., Proc. Natl. Acad. Sci. USA. 103:3557-3562, 2006, concerning human antibodies generated via human B-cell hybridoma technology. Specification 13 / 144 pages 29 CN 122206702 A

[0103] A “humanized” antibody is a chimeric antibody that comprises amino acid residues from a non-human HVR and amino acid residues from a human FR. In some respects, a humanized antibody will substantially contain at least one, typically two, variable domains, wherein all or substantially all of the HVRs (e.g., CDRs) correspond to the HVRs of the non-human antibody, and all or substantially all of the FRs correspond to the FRs of the human antibody. In which all or substantially all of the FRs of the humanized antibody correspond to certain aspects of the FRs of the human antibody, any FR of the humanized antibody may contain one or more amino acid residues from the non-human FR (e.g., one or more vernier position residues of the FR). A humanized antibody may optionally contain at least a portion of the antibody constant region derived from a human antibody. "Humanized form" antibodies, such as non-human antibodies, refer to antibodies that have undergone humanization.

[0104] The term "variable region" or "variable domain" refers to a domain of the antibody heavy or light chain involved in antibody-antigen binding. The variable domains (VH and VL, respectively) of the heavy and light chains of natural antibodies typically have similar structures, with each domain containing four conserved frame regions (FRs) and three hypervariable regions (HVRs). (See, for example, Kindt et al., Kuby Immunology, 6th ed., WH Freeman and...)Co., page 91 (2007). A single VH or VL domain may be sufficient to confer antigen binding specificity. In addition, antibodies binding to a specific antigen may be isolated using the VH or VL domains of the antibody binding that antigen to screen libraries of complementary VL or VH domains. See, for example, Portolano et al. J. Immunol. 150:880-887, 1993; Clarkson et al. Nature 352:624-628, 1991.

[0105] As used herein, the term “hypervariant region” or “HVR” refers to the individual regions (complementarity-determining regions or CDRs) in the variable domains of an antibody that are highly variable in sequence. Typically, an antibody contains six CDRs; three in VH (CDR-H1, CDR-H2, CDR-H3) and three in VL (CDR-L1, CDR-L2, CDR-L3). Exemplary CDRs in this article include:

[0106] (a) CDRs present at amino acid residues 26–32 (L1), 50–52 (L2), 91–96 (L3), 26–32 (H1), 53–55 (H2), and 96–101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901–917, 1987);

[0107] (b) CDRs present at amino acid residues 24–34 (L1), 50–56 (L2), 89–97 (L3), 31–35b (H1), 50–65 (H2), and 95–102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991)); and

[0108] (c) antigenic contact sites present at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al., J. Mol. Biol. 262: 732-745, 1996).

[0109] Unless otherwise specified, HVR residues and other residues (e.g., FR residues) in the variable domains are referenced herein according to Kabat et al., cited as above.

[0110] "Single-chain Fv", also abbreviated as "sFv" or "scFv", is an antibody fragment containing VH and VL antibody domains linked to a single polypeptide chain. Preferably, the scFv polypeptide further includes a polypeptide linker between the VH and VL domains, enabling the scFv to form the desired antigen-binding structure. For a review of scFv, see Pluckthun, The Pharmacology of Monoclonal Antibodies, Vol. 113, edited by Rosenburg and Moore, Springer-Verlag, New York, pp. 269–315 (1994); Malmborg et al., J. Immunol. Methods 183:7–13, 1995.

[0111] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous group of antibodies, i.e., individual antibodies comprising this group are identical and / or bind to the same epitopes, except for possible variant antibodies (e.g., those containing naturally occurring mutations or generated during the production of the monoclonal antibody formulation, typically present in small quantities as class A variants, as described on pages 14 / 144 of this specification, 30 CN 122206702). In contrast to polyclonal antibody formulations, which typically comprise different antibodies targeting different determinants (epitaxes), each monoclonal antibody in a monoclonal antibody formulation targets a single determinant on the antigen. Therefore, the modifier “monoclonal” indicates that the antibody is characterized by being obtained from a substantially homogeneous group of antibodies and should not be construed as requiring the antibody to be produced by any particular method. For example, monoclonal antibodies intended for use according to the invention can be prepared by a variety of techniques, including but not limited to hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for preparing monoclonal antibodies are described herein.

[0112] The term “multispecific antibody” is used in the broadest sense and specifically covers antibodies having multi-epitope specificity. In one aspect, a multispecific antibody binds to two different targets and is a “bispecific antibody.” Such multispecific antibodies include, but are not limited to, antibodies comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH / VL unit has multi-epitope specificity; antibodies having two or more VL and VH domains, wherein each VH / VL unit binds to a different epitope; antibodies having two or more single variable domains, wherein each single variable domain binds to a different epitope; full-length antibodies; antibody fragments such as Fab, Fv, dsFv, scFv, bispecific antibodies, and bispecific antibodies.Somatic antibodies and trisomatic antibodies, covalently or non-covalently linked antibody fragments. “Multi-epitope specificity” refers to the ability to specifically bind two or more different epitopes on the same or different target sites. “Monospecificity” refers to the ability to bind only one antigen. In one aspect, a monospecific bi-epitope antibody binds two different epitopes on the same target / antigen. In another aspect, a monospecific multi-epitope antibody binds to multiple different epitopes on the same target / antigen. According to one aspect, the multispecific antibody is an IgG antibody that binds to each epitope with an affinity of 5 μM to 0.001 pM, 3 μM to 0.001 pM, 1 μM to 0.001 pM, 0.5 μM to 0.001 pM, or 0.1 μM to 0.001 pM.

[0113] “Natural antibody” refers to a naturally occurring immunoglobulin molecule with a different structure. For example, a natural IgG antibody is a heterotetrameric glycoprotein of about 150,000 Daltons, consisting of two identical light chains and two identical heavy chains bound by disulfides. Each heavy chain has a variable region (VH), also called a variable heavy chain domain or heavy chain variable domain, from the N-terminus to the C-terminus, followed by three constant domains (CH1, CH2, and CH3). Similarly, each light chain has a variable region (VL), also called a variable light chain domain or light chain variable domain, from the N-terminus to the C-terminus, followed by a constant light chain (CL) domain. The light chains of an antibody, based on the amino acid sequence of their constant domains, can be classified into one of two types, referred to as kappa (κ) and lamuda (λ).

[0114] As used herein, the term “immunoadhesin” refers to a molecule that combines the binding specificity of a heterologous protein (“adhesin”) with the effector function of the constant domain of an immunoglobulin. Structurally, immunoadhesins comprise a fusion of an amino acid sequence having desired binding specificity with an immunoglobulin constant domain sequence (e.g., the CH2 and / or CH3 sequence of IgG), which is not an antigen recognition and binding site for the antibody (i.e., is "heterologous" compared to the constant region of the antibody). The adhesin and the immunoglobulin constant domain may optionally be separated by an amino acid spacer sequence. Exemplary adhesin sequences comprise a continuous amino acid sequence containing a portion of a receptor or ligand that binds to the target protein. Adhesin sequences may also be sequences that bind to the target protein but are not receptor or ligand sequences (e.g., adhesin sequences in peptide bodies). Such peptide sequences can be selected or identified by various methods, including phage display techniques and high-throughput sorting methods. The immunoglobulin constant domain sequence in the immunoadhesin can be derived from any immunoglobulin, such as IgG1, IgG2, IgG3, or IgG4 subtypes, IgA (including IgA1 and IgA2), IgE, IgD, or...IgM.

[0115] As used herein, the term "chemotherapeutic agent" refers to a compound that can be used to treat cancers such as multiple myeloma (MM, e.g., relapsed or refractory (R / R) MM). Examples of chemotherapeutic agents include EGFR inhibitors (including small molecule inhibitors such as erlotinib (TARCEVA®, Genentech / OSI Pharm.); PD 183805 (CI 1033, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholino)propoxy]-6-quinazolino]-2-acrylamide dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®). ), 4-(3'-chloro-4'-fluoroaniline)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 (6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimidino[5,4-d]pyrimidin-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3- Pyrimidine-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); and dual EGFR / HER2 tyrosine kinase inhibitors, such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5 [[[2-methylsulfonyl]ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine); tyrosine kinase inhibitors (e.g., EGFR inhibitors; small molecule HER2 tyrosine kinase inhibitors, such as TAK165 (Takeda); CP-724, 714, orally selective inhibitors of ErbB2 receptor tyrosine kinases (Pfizer and OSI); dual HER inhibitors, such as EKB-569 (available from Wyeth), which preferentially bind to EGFR).However, it inhibits both HER2 and EGFR overexpressing cells; PKI-166 (Novartis); pan-HER inhibitors, such as canatinib (CI-1033; Pharmacia); Raf-1 inhibitors, such as the antisense agent ISIS-5132 (ISIS Pharmaceuticals) that inhibits Raf-1 signaling; non-HER-targeting tyrosine kinase inhibitors, such as imatinib mesylate (GLEEVEC®, Glaxo SmithKline); multi-targeting tyrosine kinase inhibitors, such as sunitinib (SUTENT®, Pfizer); VEGF receptor tyrosine kinase inhibitors, such as vastatinib (PTK787 / ZK222584, Novartis / Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (Pharmacia); quinazoline derivatives, such as PD 153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; curcumin (diferoylmethane, 4,5-bis(4-fluoroanilino)phthalimide); tyrosine containing a nitrothiophene moiety; PD-0183805 (Warner-Lamber); antisense molecules (e.g., those that bind to HER-encoded nucleic acids); quinoxalines (US Patent No. 5,804,396); tryphostin (US Patent No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis / Schering AG); pan-HER Inhibitors, such as CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis / Lilly); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); INC-1C11 (Imclone); and rapamycin (sirolimus, RAPAMUNE®); proteasome inhibitors, such as bortezomib (VELCADE®, Millennium).Pharm); Disulfiram; Epigallocatechin gallate; Salsporamide A; Carfilzomib; 17-AAG (Geraldmycin); Rhizobacterium; Lactate dehydrogenase A (LDH-A); Flustifen (FASLODEX®, AstraZeneca); Letrozole (FEMARA®, Novartis); Finasalazine (VATALANIB®, Novartis); Oxaliplatin (ELOXATIN®, Sanofi); 5-FU (5-fluorouracil); Formosanoltetrahydrofolate; Rhonafami (SCH 66336); Sorafenib (NEXAVAR®, Bayer Labs); AG1478; Alkylating agents such as thiotepa and CYTOXAN® Cyclophosphamides; alkyl sulfonates such as busulfan, indomethacin, and piperosulfan; azircyclopropanes such as benzothiopena, carboquinone, metopepiphenate, and urotepiphenate; ethyleneimines and methylmelamines, including hexamethylmelamine, triethylmelamine, triethylphosphamide, triethylthiophosphamide, and tris(hydroxymethylmelamine); anthocyanins (especially bratasine and bratasineone); camptothecins (including topotecan and irinotecan); bryophytes; kalatatine; CC-1065 (including its synthetic analogues adolexin, calcexin, and bizelexin); nostocins (especially nostocin 1). [Note: The last part, "16 / 144 pages 32 CN 122206702 A," appears to be a separate, unrelated section and is not translated.] And candida albicans 8); corticosteroids (including prednisone and penicillin); cyproterone acetate; 5α-reductase, including finasteride and dutasteride); vorinostat, romidesin, pabistamine, valproic acid, moxinositamine, salinomycin; interleukin, talc docamycin (including synthetic analog KW-2189) And CB1-TM1); Acanthopanax senticosine; hygroscopic acid; spongein; spongin inhibitor; nitrogen mustards, such as chlorambucil chlorbutazone, naphthylmustine, chophosphatamide, estradiol, epoxetine, methyldi(chloroethyl)amine, methyldi(chloroethyl)amine oxide hydrochloride, mycoflam, neo-embezzin, benzylmustine cholesterol, prednimustine, trolophosphamide, uramustine; nitrosoureas, such as dichloroethylnitrosourea, chloramphenicol, formustine, lomustine, nimustine, and ramustine; antibiotics, such as enediyne antibiotics (e.g., calichimycin, especially calichimycin γ-1 and calichimycin ω-1); danendomycin, including danendomycin A; bisphosphonates, such as clophosphonates; esporomycin; and neo-carcinogen chromophores and related chromoprotein enediyne antibiotic chromophores), Aclarubicin, Actinomycin, Triamcinolone, Daseserine, Actinomycin, Calabexin, Olerimycin, CarcinomacinChromomycin, Actinomycin, Detoxin, 6-diazo-5-xyl-L-leucine, N-morpholino-doxamycin, Cyano-N-morpholino-doxamycin, 2-(N-pyrrololino)-doxamycin and Deoxydoxamycin), Epirubicin, Isorubicin, Idarubicin, Ephedrine, Mitomycin C, Mycophenolic acid, Nopramine, Olivamide, Pelomycin, Bofromycin, Purines, doxorubicin, rodobenzoin, streptomycin, streptozotocin, tuberculin, ubenimex, fenestrate, zolrubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as folate, methotrexate, pteroxate, trimethoprim; purine analogs, such as fludarabine, 6-mercaptopurine, thioguanine; pyrimidine analogs, such as azacitidine, azacitidine, 6-azouridine, carmoflurane, cytarabine, dideoxyuridine, deoxyfluorouridine. Enoxabine, fluorouracil; androgens such as calutosterone, drotartrate propionate, cyclothiosterol, meandrolone, testrolol; antiadrenergics such as aminoglutethimide, mitotane, troostanistan; folic acid supplements such as folinic acid; glucuronolactone; aldehyde phosphoramide glycoside; aminolevulinic acid; enuracil; acridine; amustine; bismuth subcitrate; edatrazine; dermaloplasmin; colchicine; irizoquinone; ileonisyl; eletate; epothilone; ethoxyphenidine; gallium nitrate; hydroxyurea; mushroom polysaccharides; lonidanin; maytansine compounds such as maytansine and anthraquinone; mitoxantrone; mitoxantrone; mupirocin; diaminonitroacin; pentostatin; benzylmethionine; pirarubicin; loxoantrone; podophyllotoxin; 2-ethylhydrazine; procarbazine; PSK® Polysaccharide complexes (JHS Natural Products); Razoxin; Lisol; Cizonan; Germonoxane; Alternaria solanilic acid; Triaminoquinone; 2,2',2''-Trichlorotriethylamine; Crescent toxins (especially T-2 toxin, wartycin A, baculosporin A, and serpentin); Urethane; Vinpocetine; Dacarbazine; Mannomustine; Dibromomannitol; Dibromoeugenol; Piperobromide; Garcitocin; Cytarabine (“Ara-C”); Thiotepa; Chlorisin; GEMZAR® (Gemcitabine); 6-Thioguanine; Mercaptopurine; Methotrexate; Doxorubicin (VP-16); Evoramide; Mitoxantrone; Mitoxantrone; Teniposide; Edatraxa; Donomycin; Methotrexate; Capecitabine (XELODA®) ); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid such as retinoic acid; and pharmaceutically acceptable salts, acids, prodrugs, and derivatives of any of the above.

[0116] Chemotherapy agents also include: (i)Antihormonal agents that regulate or inhibit the effects of hormones on tumors, such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene hydrochloride, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit aromatase, an enzyme that regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazole, aminoglutethimide, MEGASE® (medroxyprogesterone acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, and RIVISOR. ® (vorozole), FEMARA® (letrozole; Novartis) and ARIMIDEX (anastrozole; AstraZeneca) (see product information page 17 / 144, CN 122206702 A); (iii) antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, Premarin, fluoromethesterone, all trans-retinoic acid, fenretinide and trisatabolone (1,3-dioxolane-cytosine analogue); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) Antisense oligonucleotides, particularly those that inhibit gene expression in signaling pathways associated with abnormal cell proliferation, such as PKC-α, Ralf, and H-Ras; (vii) ribozymes, such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, such as ALLOVECTIN®, LEUVECTIN®, and VAXID®; (ix) growth inhibitors, including vinblastines (e.g., vincristine and vinblastine), NAVELBINE®, taxanes (e.g., paclitaxel, nab-paclitaxel, and docetaxel), and topoisomerase II.Inhibitors (e.g., doxorubicin, epirubicin, daunomycin, etoposide, and bleomycin) and DNA alkylating agents (e.g., tamoxifen, prednisone, dacarbazine, dichloromethyldiethylamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C); and (x) pharmaceutically acceptable salts, acids, prodrugs, and derivatives of any of the above.

[0117] As used herein, the term “cytotoxic agent” refers to a substance that inhibits or prevents cell function and / or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., radioactive isotopes of At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212, and Lu); chemotherapeutic agents or drugs (e.g., methotrexate, doxorubicin, vinblastine alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin, or other intercalating agents); growth inhibitors; enzymes and fragments thereof such as lysozymes; antibiotics; toxins such as small molecule toxins or enzyme-active toxins of bacterial, fungal, plant, or animal origin, including fragments and / or variants thereof; and various antitumor or anticancer drugs disclosed below.

[0118] “Disease” is any condition from which treatment will be beneficial, including, but not limited to, chronic and acute conditions or diseases, including those pathological conditions that make mammals susceptible to said conditions. In one aspect, a disease is cancer, such as multiple myeloma (MM).

[0119] The terms “cellular proliferative disorder” and “proliferative disorder” refer to disorders associated with a certain degree of abnormal cell proliferation. In one aspect, a cellular proliferative disorder is cancer. In another aspect, a cellular proliferative disorder is a tumor.

[0120] As used herein, the term “tumor” refers to all proliferative cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. The terms “cancer,” “cancerous,” “cellular proliferative disorder,” “proliferative disorder,” and “tumor” are not mutually exclusive herein.

[0121] The terms “cancer” and “cancerous” refer to or describe a physiological condition in mammals that is typically characterized by uncontrolled cell growth / proliferation. Cancer includes solid tumor cancers and non-solid tumor cancers. Examples of cancer include, but are not limited to, B-cell proliferative disorders such as multiple myeloma (MM), which can be relapsed or refractory MM. MMs can be, for example, typical MMs (e.g., immunoglobulin G (IgG) MMs, IgA MMs, IgD MMs, IgE MMs, or IgM MMs), light chain MMs (LC MMs) (e.g., λ light chain MMs or κ light chain MMs), or non-secretory MMs. MMs may possess one or more cytogenetic features.(For example, high-risk cytogenesis characteristics), such as t(4;14), t(11;14), t(14;16), and / or del(17p) (as described in Table 1 and the International Myeloma Working Group (IMWG) criteria provided in Sonneveld et al., Blood, 127(24): 2955–2962, 2016), and / or 1q21 (as described in Chang et al., Bone Marrow Transplantation, 45: 117–121, 2010). Cytogenesis characteristics can be detected, for example, using fluorescence in situ hybridization (FISH).

[0122] Table 1. Cellular Characteristics of MM Specification 18 / 144 pages 34 CN 122206702 A

[0123]

[0124] The terms “B-cell proliferative disorder” or “B-cell malignancy” refer to a disorder associated with some degree of abnormal B-cell proliferation and include, for example, lymphoma, leukemia, myeloma, and myelodysplastic syndromes. In one embodiment, a B-cell proliferative disorder is myeloma, such as multiple myeloma (MM).

[0125] “Effective function” refers to those biological activities attributable to the Fc region of an antibody that vary with antibody isotype. Examples of antibody effector functions include: C1q binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B-cell receptors); and B-cell activation.

[0126] "Complement-dependent cytotoxicity" or "CDC" refers to the lysis of target cells in the presence of complement. Activation of the classical complement pathway begins by the binding of the first component (C1q) of the complement system to an antibody (appropriate subclass) that binds to its homologous antigen. To assess complement activation, a CDC assay can be performed, for example, as described in Gazzano-Santoro et al. J. Immunol. Methods 202:163 (1996).

[0127] "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a form of cytotoxicity in which secreted Ig binds to Fc receptors (FcRs) present on certain cytotoxic cells (e.g., natural killer (NK) cells, neutrophils, and macrophages), causing these cytotoxic effector cells to specifically bind to target cells carrying antigens, which are then killed by a cytotoxic agent. Antibodies "arm" cytotoxic cells and are essential for this type of killing action. The main cells mediating ADCC, NK cells, express only FcγRIII, while monocytes express FcγRI and FcγRIII.RII and Fcγ RIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet. Annu. Rev. Immunol. 9:457-92, 1991. To assess the ADCC activity of the target molecule, in vitro ADCC assays can be performed, such as those described in U.S. Patent Nos. 5,500,362 or 5,821,337. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. Alternatively or additionally, the ADCC activity of the target molecule can be assessed in vivo, for example, in animal models, such as those disclosed in Clynes et al. Proc. Natl. Acad. Sci. USA. 95:652-656, 1998.

[0128] As used herein, “complex” or “composite” means the association of two or more molecules interacting with each other by non-peptide bonds and / or forces (e.g., van der Waals forces, hydrophobic forces, hydrophilic forces). In one aspect, the complex is a heteropolymer. It should be understood that, as used herein, the term “protein complex” or “peptide complex” includes complexes having a non-protein entity (e.g., including but not limited to chemical molecules, such as toxins or detection agents) conjugated to a protein complex.

[0129] As used herein, “delayed progression” of a condition or disease means delaying, hindering, mitigating, stabilizing, and / or postponing the development of a disease or condition (e.g., a proliferative condition, such as cancer). Such delay can have varying lengths of time, depending on medical history and / or the individual to be treated. It will be apparent to those skilled in the art that a sufficient or significant delay can effectively encompass prevention, as the individual will not develop the disease. For example, the development of advanced cancer, such as metastasis, may be delayed.

[0130] An “effective amount” of a compound (e.g., the anti-FcRH5 / anti-CD3 T cell-dependent bispecific antibody (TDB) described herein) or a combination thereof (e.g., a pharmaceutical composition) is at least the minimum amount required to achieve a desired therapeutic or preventive outcome, such as a measurable improvement or prevention of a particular disease (e.g., a proliferative disorder, such as cancer). An effective amount herein may vary depending on factors such as the patient’s disease state, age, sex, and weight, and the antibody’s ability to elicit the expected response in an individual. An effective amount is also the amount in which the beneficial therapeutic effect outweighs any toxic or adverse therapeutic effect. For preventive use, beneficial or anticipated outcomes include, for example, elimination or reduction of risk, mitigation of severity, or delay of disease onset.The effects of a drug include the biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that occur during the development of the disease. For therapeutic use, beneficial or anticipated outcomes include clinical results such as reducing one or more symptoms caused by the disease, improving the quality of life of the patient, reducing the dosage of other drugs required to treat the disease, and enhancing the effects of other drugs (such as by targeting, delaying disease progression, and / or prolonging survival). In the case of cancer or tumors, an effective amount of the drug may reduce the number of cancer cells; reduce tumor size; inhibit (i.e., to some extent slow or expect to stop) the infiltration of cancer cells into surrounding organs; inhibit (i.e., to some extent slow and expect to stop) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate one or more symptoms associated with the disease to some extent. An effective amount may be administered once or multiple times. For the purposes of this invention, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly prevent or treat the disease. As understood in a clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved when combined with another drug, compound, or pharmaceutical composition. Therefore, an “effective amount” can be considered when administering one or more therapeutic agents, and an effective amount of a single agent can be considered if the desired outcome can be obtained or achieved in combination with one or more other agents.

[0131] As used herein, “overall survival” or “OS” refers to the percentage of individuals in a group who are likely to survive after a specific time period.

[0132] As used herein, “objective response rate” or “ORR” refers to the sum of rates of strict complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) as determined using the International Myeloma Working Group’s response criteria (Table 13; Kumar et al., Lancet. Oncol., 17:e328-346, 2019).

[0133] The term “epitope” refers to a specific site on an antigen molecule to which an antibody binds. In some aspects, a specific site on an antigen molecule to which an antibody binds is determined by hydroxyl radical footprinting. In some aspects, a specific site on an antigen molecule to which an antibody binds is determined by crystallography.

[0134] As used herein, “growth inhibitor” means a compound or composition that inhibits cell growth in vitro or in vivo. In one aspect, a growth inhibitor is a growth-inhibiting antibody that prevents or reduces the proliferation of cells expressing an antigen to which the antibody binds. In another aspect, a growth inhibitor can be an inhibitor that significantly reduces the percentage of cells in S phase. Aspects of growth inhibitors include agents that block cell cycle progression (at locations other than S phase), such as agents that induce G1 arrest and M phase arrest. Classical M phase arrestors include vinca (vincristine and vinblastine), taxanes, and topoisomerase II.Inhibitors (e.g., doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin). Agents that block G1 phase also spill over into S phase arrest, such as DNA alkylating agents like tamoxifen, prednisone, dacarbazine, nitrogen mustard, cisplatin, methotrexate, 5-fluorouracil, and ara-C. Further information can be found in Chapter 1, 20 / 144, 36 CN 122206702 A, of *The Molecular Basis of Cancer*, edited by Mendelsohn and Israel, entitled "Cell Cycle Regulation, Oncogenes, and Antitumor Drugs" (WBSaunders, Philadelphia, 1995), for example, page 13. Taxanes (paclitaxel and docetaxel) are both anticancer drugs derived from taxanes. Docetaxel (TAXOTERE®, Rhone-Poulenc Rorer) is derived from European yew and is a semi-synthetic analogue of paclitaxel (TAXOL®, Bristol-Myers Squibb). Paclitaxel and docetaxel promote the assembly of microtubules into tubulin dimers and stabilize microtubules by preventing depolymerization, thereby inhibiting cell mitosis.

[0135] An “immunomodulator” is an antibody conjugated to one or more heterologous molecules, including but not limited to cytotoxic agents.

[0136] The term “immunomodulator” refers to a class of molecules that alter the immune system response or immune system function. Immunomodulators include, but are not limited to, PD-1 axis binding antagonists, thalidomide (α-N-phthalimide-glutarimide) and its analogues, OTEZLA® (aplast), REVLIMID® (lenalidomide), and POMALYST® (pomalidomide) and their pharmaceutically acceptable salts or acids.

[0137] “Subject” or “Individual” is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., human and non-human primates, such as monkeys), rabbits, and rodents (e.g., mice and rats). In some respects, the subject or individual is a human.

[0138] “Isolated” protein or peptide is a protein or peptide that has been isolated from components of its natural environment. In some respects, the protein or peptide is purified to a purity greater than 95% or 99% by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reversed-phase HPLC).

[0139] “Isolated” nucleic acid refers to a nucleic acid molecule that has been isolated from components of its natural environment. Isolated nucleic acids includeSuch nucleic acid molecules are contained in cells that normally contain nucleic acid molecules, but are located outside the chromosome or at a chromosomal location different from their natural chromosomal location.

[0140] The term "PD-1 axis binding antagonist" refers to a molecule that inhibits the interaction between a PD-1 axis binding partner and one or more of its binding partners to eliminate T cell dysfunction caused by signal transduction on the PD-1 signaling axis, resulting in the restoration or enhancement of T cell function (e.g., proliferation, cytokine production, and / or target cell killing). As used herein, PD-1 axis binding antagonists include PD-L1 binding antagonists, PD-1 binding antagonists, and PD-L2 binding antagonists. In some cases, PD-1 axis binding antagonists include PD-L1 binding antagonists or PD-1 binding antagonists. In a preferred aspect, the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

[0141] The term “PD-L1 binding antagonist” refers to a molecule that reduces, blocks, inhibits, eliminates, or interferes with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners (such as PD-1 and / or B7-1). In some cases, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 with its binding partners. In one specific aspect, a PD-L1 binding antagonist inhibits the binding of PD-L1 with PD-1 and / or B7-1. In some cases, a PD-L1 binding antagonist includes anti-PD-L1 antibodies, their antigen-binding fragments, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, eliminate, or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners (such as PD-1 and / or B7-1). In one case, a PD-L1 binding antagonist reduces negative co-stimulatory signals mediated by PD-L1 signaling, either by or through cell surface proteins expressed on T lymphocytes, thereby reducing dysfunction of dysfunctional T cells (e.g., enhancing effector responses to antigen recognition). In some cases, the PD-L1 binding antagonist binds to PD-L1. In some cases, the PD-L1 binding antagonist is an anti-PD-L1 antibody (e.g., an anti-PD-L1 antagonist antibody). Exemplary anti-PD-L1 antagonist antibodies include atezolizumab, MDX-1105, MEDI4736 (dvorumab), MSB0010718C (avirumab), SHR-1316, CS1001, envorimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cochilimab, and lodalimab (instructions for use).Page 21 / 144, 37 CN 122206702 A (lodapolimab), FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636. In some aspects, anti-PD-L1 antibodies are atezolizumab, MDX-1105, MEDI4736 (dvorumab), or MSB0010718C (averumab). In one specific aspect, the PD-L1 binding antagonist is MDX-1105. In another specific aspect, the PD-L1 binding antagonist is MEDI4736 (dvorumab). In another specific aspect, the PD-L1 binding antagonist is MSB0010718C (averulimab). In other aspects, the PD-L1 binding antagonist may be a small molecule, such as GS-4224, INCB086550, MAX-10181, INCB090244, CA-170, or ABSK041, which in some cases can be administered orally. Other exemplary PD-L1 binding antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003, and JS-003. In a preferred aspect, the PD-L1 binding antagonist is atezolizumab.

[0142] The term “PD-1 binding antagonist” refers to a molecule that reduces, blocks, inhibits, eliminates, or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and / or PD-L2. PD-1 (programmed cell death 1) is also referred to in the art as “programmed cell death 1,” “PDCD1,” “CD279,” and “SLEB2.” Exemplary human PD-1 is shown in UniProtKB / Swiss-Prot accession number Q15116. In some cases, PD-1 binding antagonists are molecules that inhibit the binding of PD-1 to one or more of its binding partners. In one particular aspect, PD-1 binding antagonists inhibit the binding of PD-1 to PD-L1 and / or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies and their antigen-binding fragments, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, eliminate, or interfere with signaling generated by the interaction of PD-1 with PD-L1 and / or PD-L2. In one scenario, PD-1 binding antagonists reduce negative co-stimulatory signals mediated by PD-1 signaling, either directly or via cell surface proteins expressed on T lymphocytes, thereby impairing function.Less T cell dysfunction (e.g., enhanced effector response to antigen recognition). In some cases, PD-1 binding antagonists bind to PD-1. In some cases, PD-1 binding antagonists are anti-PD-1 antibodies (e.g., anti-PD-1 antagonist antibodies). Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartazumab), REGN2810 (cimiprizumab), BGB-108, palolizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dotalimab, rivanlimab, saxafenib, penaplimab, CS1003, HLX10, SCT-I10A, cepalimumab, batitilimab, jerolimab, BI 754091, cilimab, YBL-006, BAT1306, HX008, bouglimab, and AMG. 404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, and hAb21. In one specific aspect, the PD-1 binding antagonist is MDX-1106 (nivolumab). In another specific aspect, the PD-1 binding antagonist is MK-3475 (pembrolizumab). In yet another specific aspect, the PD-1 binding antagonist is a PD-L2 fusion protein, such as AMP-224. In yet another specific aspect, the PD-1 binding antagonist is MED1-0680. In yet another specific aspect, the PD-1 binding antagonist is PDR001 (spartazolizumab). In another specific aspect, the PD-1 binding antagonist is REGN2810 (cimiprimab). In another specific aspect, the PD-1 binding antagonist is BGB-108. In another specific aspect, the PD-1 binding antagonist is palolizumab. In another specific aspect, the PD-1 binding antagonist is camrelizumab. In another specific aspect, the PD-1 binding antagonist is sintilimab. In another specific aspect, the PD-1 binding antagonist is tislelizumab. In another specific aspect, the PD-1 binding antagonist is toripalimab. Other additional exemplary PD-1 binding antagonists include BION-004, CB201, AUNP-012, ADG104, and LBL-006.

[0143] The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, eliminates, or interferes with signal transduction resulting from the interaction of PD-L2 with one or more binding partners, such as PD-1. PD-L2 (programmed cell death ligand 2) is also referred to in the art as "programmed cell death 1 ligand".2, “PDCD1LG2”, “CD273”, “B7-DC”, “Btdc”, and “PDL2”. Exemplary human PD-L2 is shown in UniProtKB / Swiss-Prot Registry No. Q9BQ51. In some cases, PD-L2 binding antagonists are molecules that inhibit the binding of PD-L2 to one or more of its binding partners. In one specific aspect, PD-L2 binding antagonists inhibit the binding of PD-L2 to PD-1. Exemplary PD-L2 antagonists include anti-PD-L2 antibodies, their antigen-binding fragments, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, eliminate, or interfere with signaling generated by the interaction of PD-L2 with one or more of its binding partners (such as PD-1). In one aspect, PD-L2 binding antagonists reduce the signaling generated by the interaction of T Negative co-stimulatory signals mediated or expressed by cell surface proteins on lymphocytes, which, through PD-L2-mediated signaling, reduce dysfunction of dysfunctional T cells (e.g., enhance effector responses to antigen recognition). In some aspects, PD-L2 binding antagonists bind to PD-L2. In some aspects, PD-L2 binding antagonists are immunoadhesins. In other aspects, PD-L2 binding antagonists are anti-PD-L2 antagonist antibodies.

[0144] Unless otherwise specified, the term “protein” as used herein means any naturally occurring protein from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term includes “full-length” unprocessed proteins, as well as any form of protein produced through cellular processing. The term also covers naturally occurring protein variants, such as splice variants or allelic variants.

[0145] The "percentage of amino acid sequence identity (%)" relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in the candidate sequence that are identical to those in the reference polypeptide sequence after aligning the candidate sequence with the reference polypeptide sequence and introducing vacancies (if necessary) to achieve the maximum percentage of sequence identity, without considering any conserved substitutions as part of the sequence identity. Alignment used to determine the percentage of amino acid sequence identity can be performed in various ways within the scope of the art, such as using publicly available computer software, such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithm required to achieve maximum alignment across the full length of the sequences being compared. However, for the purposes of this study…The purpose of this paper is to use the sequence comparison computer program ALIGN-2 to generate values ​​for amino acid sequence identity % (%). The ALIGN-2 sequence comparison computer program was written by Genentech, Inc., and the source code has been submitted with user documentation to the US Copyright Office, Washington DC, 20559, where it is registered under US Copyright Registry No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc. (South San Francisco, California) or can be compiled from source code. The ALIGN-2 program should be compiled for use on UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and remain unchanged.

[0146] When using ALIGN-2 for amino acid sequence comparison, the amino acid sequence identity % between a given amino acid sequence A and a given amino acid sequence B (which can be alternatively expressed as a given amino acid sequence A having or containing an amino acid sequence identity % with a given amino acid sequence B) is calculated as follows:

[0147] 100 multiplied by a fraction X / Y

[0148] where X is the number of amino acid residues that are scored as identical matches by the sequence alignment program ALIGN-2 in the alignment of A and B, and where Y is the total number of amino acid residues in B. It should be understood that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, the amino acid sequence identity % between A and B will not be equal to the amino acid sequence identity % between B and A. Unless otherwise specifically indicated, all values ​​of amino acid sequence identity % used herein are obtained using the ALIGN-2 computer program as described in the preceding paragraph.

[0149] The term “pharmaceutical formulation” means a formulation in which the bioactive ingredient permitted to be contained is in an effective form and which does not contain any additional components that would have unacceptable toxicity to the subject to whom the formulation will be administered.

[0150] “Pharmaceuticalally acceptable carrier” means a component in a pharmaceutical formulation that is non-toxic to the subject other than the active ingredient. Pharmaceutical package insert 23 / 144 pages 39 CN 122206702 A Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0151] “Radiotherapy” refers to the use of directed gamma rays or beta rays to induce sufficient damage to cells, thereby limiting the cells’ ability to function normally or to completely destroy the cells. It will be understood that there will be many known methods in the art that canDetermine the dosage and duration of treatment. Typical treatment is a single administration, with typical dosages ranging from 10 to 200 units (Gray) per day.

[0152] As used herein, “treatment” (and its grammatical variations, such as “treat” or “treating”) refers to a clinical intervention that attempts to alter the natural course of the individual being treated, and may be for prevention or during the course of clinicopathological progression. The desired effects of treatment include, but are not limited to, preventing the onset or recurrence of disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, improving or alleviating the disease state, and mitigating or improving prognosis. In some respects, antibodies described herein (e.g., anti-FcRH5 / anti-CD3 bispecific antibodies) are used to delay the development of disease or slow the progression of disease.

[0153] “Reduce” or “inhibit” means the ability to cause an overall reduction, for example, an overall reduction of 20% or more, 50% or more, or 75%, 85%, 90%, 95% or more. In some respects, reduction or inhibition can refer to the effector function of an antibody mediated by the antibody Fc region, specifically including complement-dependent cytotoxicity (CDC), antibody-dependent cytotoxicity (ADCC), and antibody-dependent phagocytosis (ADCP).

[0154] According to the invention, the term "vaccine" refers to a pharmaceutical preparation (pharmaceutical composition) or product that, upon administration, induces an immune response, particularly a cellular immune response, that recognizes and attacks pathogens or diseased cells, such as cancer cells. Vaccines can be used to prevent or treat diseases. Vaccines can be cancer vaccines. As used herein, a "cancer vaccine" is a composition that stimulates an immune response in a subject against cancer. Cancer vaccines typically consist of cancer-related materials or cell (antigen) sources that may be autologous (from oneself) or allogeneic (from another person) to the subject, along with other components (e.g., adjuvants) to further stimulate and promote an immune response to the antigen. Cancer vaccines can cause stimulation of a subject's immune system to produce antibodies against one or more specific antigens, and / or to produce killer T cells to attack cancer cells that have those antigens.

[0155] As used herein, "administration" means a method of giving a subject a dose of a compound (e.g., an anti-FcRH5 / anti-CD3 bispecific antibody). In some aspects, the compositions used in the methods described herein are administered intravenously. The compositions used in the methods described herein can be, for example, intramuscularly, intravenously, subcutaneously, percutaneously, intra-arterially, intraperitoneally, intralesionally, intracranially, intra-articularly, intra-articularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally,The application can be administered vaginally, rectically, externally, on tumors, in the peritoneum, subcutaneously, subconjunctivally, in sacs, mucosally, in the pericardium, in the umbilicus, in the eye, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, by direct perfusion of target cells via local perfusion, via catheter, by perfusion, or in the form of an emulsion or lipid composition. The method of administration can vary depending on a variety of factors (e.g., the compound or composition to be administered and the severity of the condition, disease, or disorder to be treated).

[0156] As used herein, “CD38” refers to the CD38 glycoprotein found on the surface of many immune cells, including CD4+, CD8+, B lymphocytes, and natural killer (NK) cells, including any native CD38 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise stated. CD38 is expressed at higher and more uniform levels on myeloma cells compared to normal lymphoid and bone marrow cells. This term includes “full-length” unprocessed CD38, as well as any form of CD38 produced through cellular processing. The term also covers naturally occurring variants of CD38, such as splice variants or allelic variants. CD38 is also referred to in the art as differentiation cluster 38, ADP-ribosylcyclase 1, cADPr hydrolase 1, and cyclic ADP-ribosyl hydrolase 1. CD38 is encoded by the CD38 gene. An exemplary human CD38 nucleic acid sequence is shown in the following NCBI reference sequence: NM_001775.4 or in SEQ ID NO: 33. The amino acid sequence of an exemplary human CD38 protein encoded by CD38 is shown in UniProt accession number P28907 or SEQ ID NO: 34.

[0157] The term "anti-CD38 antibody" encompasses all antibodies that bind to CD38 with sufficient affinity to make the antibody usable as a therapeutic agent targeting cells expressing the antigen and that do not significantly cross-react with other proteins, such as negative control proteins, in the assays described below. For example, anti-CD38 antibodies can bind to CD38 on the surface of MM cells and mediate cell lysis by activating complement-dependent cytotoxicity, ADCC, antibody-dependent phagocytosis (ADCP), and Fc cross-linking-mediated apoptosis, leading to the consumption of malignant cells and a reduction in the overall cancer burden. Anti-CD38 antibodies can also modulate CD38 enzyme activity by inhibiting ribosylcyclase activity and stimulating the cyclic adenosine diphosphate ribose (cADPR) hydrolase activity of CD38. In some respects, anti-CD38 antibodies that bind to CD38...The dissociation constant (KD) of the antibody is ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM (e.g., 10⁻⁸ M or less, e.g., 10⁻⁸ M to 10⁻¹³ M, e.g., 10⁻⁹ M to 10⁻¹³ M). In some respects, anti-CD38 antibodies can bind to both human CD38 and chimpanzee CD38. Anti-CD38 antibodies also include anti-CD38 antagonist antibodies. Bispecific antibodies in which one arm of the antibody binds to CD38 are also considered. This definition of anti-CD38 antibody also includes the functional fragments of the aforementioned antibodies. Examples of antibodies that bind to CD38 include: daratumumab (DARZALEX®) (US Patent No. 7,829,673 and US Publication No. 20160067205 A1); “MOR202” (US Patent No. 8,263,746); and ixartuximab (SAR-650984).

[0158] As used herein, the term “relative increase” means, relative to a subject with MM whose baseline sample has been determined to have increased levels of one or more cell types listed in Table 3, decreased levels of one or more cell types listed in Table 4, higher numbers of one or more of the features listed in Table 5, increased levels of one or more cell types listed in Table 6, decreased levels of one or more cell types listed in Table 7, increased levels of one or more cell types listed in Table 8, or decreased levels of one or more cell types listed in Table 9, an increase in survival (e.g., as by progression-free survival (PFS)) compared to a subject whose baseline sample has been determined to have decreased levels of one or more cell types listed in Table 3, increased levels of one or more cell types listed in Table 4, lower numbers of one or more of the features listed in Table 5, decreased levels of one or more cell types listed in Table 6, increased levels of one or more cell types listed in Table 7, decreased levels of one or more cell types listed in Table 8, or increased levels of one or more cell types listed in Table 9. Or measured by overall survival (OS).

[0159] As used herein, the term “reference level” refers to the mean or median level (e.g., percentage, fold change, Z-score, etc.), pattern, quartile level, or pre-assigned value / level) of a given cell type in a population of subjects with MM. Exemplary reference levels for various cell types described herein (e.g., cell types in Tables 1, 2, 3, 4, 6, 7, 8, or 9) are provided in Table 14.

[0160] As used herein, the term "reference number" refers to the mean or median, pattern, quartile, or preassigned value of a given characteristic listed in Table 5 in a population of subjects with MM. Exemplary reference numbers for the given characteristics described herein (e.g., the characteristics in Table 5) are provided in Table 15.

[0161] As used herein, the term "group of subjects with MM" means a number of subjects of at least 10 (e.g., at least 10, at least 15, at least 20, at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, at least 228, at least 250, at least 275, at least 300, at least 325, at least 350, at least 375, at least 400, at least 425, at least 450, at least 475, at least 500, at least 525, at least 550, at least 575, at least 600, at least 625, at least 650, at least 675, at least 700, at least 725). A population of MM patients (at least 1,000, at least 750, at least 775, at least 800, at least 825, at least 850, at least 875, at least 900, at least 925, at least 950, at least 975, at least 1000 or more). For example, a population of subjects with MM can refer to a population of MM patients of size 228 subjects.

[0162] II. Treatment Methods

[0163] The present invention provides a method for treating subjects with MM who would benefit from treatment with a bispecific antibody that binds to crystallizable fragment receptor-like 5 (FcRH5) / antidifferentiation cluster 3 (CD3).

[0164] As described below, (i) measuring or determining the level of one or more cell types listed in Tables 3, 4, 6, 7, 8 and / or 9 in a sample from a subject or (ii) the number of one or more of the characteristics listed in Table 5 of a subject can be used to identify subjects with MM who will benefit from treatment with a bispecific antibody that binds to crystallizable fragment receptor-like 5 (FcRH5) / antidifferentiation cluster 3 (CD3).

[0165] The methods described herein may require identifying T cells (e.g., CD4+ or CD8+ T cells), T naïve (TN) cells, T central memory (TCM) cells, T effector memory cells, etc.The levels of TEM cells, terminally differentiated effector memory (TEMRA) cells, natural killer (NK) cells, natural killer T cells (NKT cells), T regulatory (Treg) cells, white blood cells (WBCs), non-lymphocytes (e.g., CD3- cells), or any combination thereof.

[0166] TN cells are circulating mature T cells that have never encountered or responded to their homologous antigens, thereby distinguishing them from effector cells and memory T cell subtypes. Upon activation, naïve CD8+ T cells can differentiate into cytotoxic T cells, and naïve CD4+ T cells can differentiate into helper T cells (e.g., TH1 or TH2 cells). TCM cells are memory T cells that are primarily confined to lymphoid organs and blood, providing immune surveillance due to their high sensitivity and rapid response to exposure to their homologous antigens. TEM cells are memory T cells that are primarily found in the peripheral circulation and tissues, rather than in lymphoid organs. TEM cells are persistent and can proliferate rapidly in large numbers upon re-exposure to their homologous antigens. TEMRA cells play a crucial role in humoral and cellular rejection. Compared to other effector or memory cells, TEMRA cells typically have a shorter lifespan and carry higher levels of cytotoxicity and exhaustion genes. NK cells are large granular lymphocytes that mediate innate immunity against tumors and pathogens and mediate antibody-dependent cell-mediated cytotoxicity (ADCC). Treg cells suppress or inhibit immune responses by secreting anti-inflammatory cytokines. Their role in immunosuppression maintains peripheral tolerance and helps prevent autoimmune or inflammatory diseases or conditions. Exemplary positive and negative markers that can be used to identify these cell types are described in Table 2.

[0167] Table 2. Exemplary cell markers for cell identification

[0168]

[0169] TN = T initial; TCM = T central memory; TEM = T effector memory; TEMRA = effector memory of terminal differentiation; Treg = T regulatory; NK = natural killer; NKT = natural killer T cell; CD8 = differentiation cluster 8; CD4 = differentiation cluster 4; CD16 = differentiation cluster 16; CD19 = differentiation cluster 19; CD56 = differentiation cluster 56; CD45RA = differentiation cluster RA45; CD45RO = differentiation cluster 45RO; GzB = granzyme B; CCR7 = c-c chemokine receptor type 7

[0170] Cell types associated with increased resistance to civastastatin

[0171] In some aspects of the invention, the methods described herein require determining the levels of one or more cell types listed in Table 3 in the subject. In other aspects of the invention, the methods described herein require that the levels of one or more cell types listed in Table 3 in the subject have been previously determined.

[0172] Generally, the sample (e.g., baseline sample) has one or more of the following increased levels compared to the reference level (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, eleven, twelve, thirteen, thirteen, thirteen, seventeen, eighteen, nineteen, twenty, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty ... MM subjects with a level (e.g., presence or percentage) of cell types (48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 or all 85) of cell types were more resistant to treatment with a bispecific antibody (e.g., civastanab) that binds to FcRH5 and CD3. For example, in samples from subjects, the levels of cell types in Table 3 could increase by approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, and so on, compared to reference levels.56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88% Approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, approximately 100%, approximately 101%, approximately 102%, approximately 103%, approximately 104%, approximately 105%, approximately 106%, approximately 107%, approximately 108%, approximately 109%, approximately 110%, approximately 111%, approximately 112%, approximately 113%, approximately 114%, approximately 115%, approximately 116%, approximately 117%. Approximately 118%, approximately 119%, approximately 120%, approximately 121%, approximately 122%, approximately 123%, approximately 124%, approximately 125%, approximately 126%, approximately 127%, approximately 128%, approximately 129%, approximately 130%, approximately 131%, approximately 132%, approximately 133%, approximately 134%, approximately 135%, approximately 136%, approximately 137%, approximately 138%, approximately 139%, approximately 140%, approximately 141%, approximately 142%, approximately 143%, approximately 144%, approximately 145%, approximately 146%, approximately 147%, approximately 148%, approximately 149%, approximately 150%, approximately 151%, approximately 152%, approximately 153%, approximately 154%, approximately 155% Approximately 156%, approximately 157%, approximately 158%, approximately 159%, approximately 160%, approximately 161%, approximately 162%, approximately 163%, approximately 164%, approximately 165%, approximately 166%, approximately 167%, approximately 168%, approximately 169%, approximately 170%, approximately 171%, approximately 172%, approximately 173%, approximately 174%, approximately 175%, approximately 176%, approximately 177%, approximately 178%, approximately 179%, approximately 180%, approximately 181%, approximately 182%, approximately 183%, approximately 184%, approximately 185%, approximately 186%, approximately 187%, approximately 188%, approximately 189%, approximately 190%, approximately 191%, approximately 192%, approximately 193%, approximately 194%, approximately 195%, approximately 196%, approximately 197%, approximately 198%, approximately 199%, or approximately 200%, indicating that the subject is unlikely to benefit from FcRH5.Treatment with bispecific antibodies that bind to CD3 (e.g., civastimab). Instructions for Use, 27 / 144, page 43, CN 122206702 A

[0173] Table 3. Cell types associated with increased resistance to civastastat

[0174]

[0175] CD = Differentiation cluster; DR = Human leukocyte antigen – DR isotype; Ki67 = Antigen Kiel 67; PD1 = Programmed cell death protein 1; GzB = Granulase B; TIGIT = T cell immune receptor with immunoglobulin and immunoreceptor tyrosine inhibitory motif domains; TIM3 = T cell immunoglobulin and mucin domain 3; TN cells = Naïve T cells; TCM cells = Central memory T cells; TEM cells = Effector memory T cells; TEMRA cells = Terminally differentiated effector memory T cells; Treg cells = Regulatory T cells; NK cells = Natural killer cells

[0176] Conversely, samples (e.g., baseline samples) exhibiting a reduction compared to the reference level of one or more of the substances listed in Table 3 (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty ... The levels of MM subjects with 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 or all 85) cell types (e.g., presence or percentage) were observed in subjects treated with FcRH5 and CD3. Treatment with a conjugated bispecific antibody (e.g., civasutazine) is generally more sensitive. For example, in samples from subjects, the levels of the cell types listed in Table 3 may be reduced by approximately 1%, approximately 2%, and approximately [missing information] compared to reference levels.3%, approximately 4%, approximately 5%, approximately 6%, approximately 7%, approximately 8%, approximately 9%, approximately 10%, approximately 11%, approximately 12%, approximately 13%, approximately 14%, approximately 15%, approximately 16%, approximately 17%, approximately 18%, approximately 19%, approximately 20%, approximately 21%, approximately 22%, approximately 23%, approximately 24%, approximately 25%, approximately 26%, approximately 27%, approximately 28%, approximately 29%, approximately 30%, approximately 31%, approximately 32%, approximately 33%, approximately 34%, approximately 35%, approximately 36%, approximately 37%, approximately 38%, approximately 39%, approximately 40%, approximately 41%, approximately 42%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54% Approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100%, indicating that the subject may benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., civastartrazine).

[0177] Cell Types Associated with Increased Sensitivity to Civasutazine

[0178] In some aspects of the invention, the methods described herein require determining the levels of one or more cell types listed in Table 4 in the subject. In some aspects of the invention, the methods described herein require that the levels of one or more cell types listed in Table 4 in the subject have been previously determined.

[0179] Generally, MM subjects with an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, or all eight) cell types listed in Table 4 in their sample (e.g., baseline sample) compared to a reference level are more sensitive to treatment with a bispecific antibody (e.g., civasutazine) that binds to FcRH5 and CD3. For example, in samples from subjects, the levels of cell types in Table 4 may increase by about 1%, about 2%, about 3%, about 4%, about 5%, or about [missing information] compared to a reference level.6%, approximately 7%, approximately 8%, approximately 9%, approximately 10%, approximately 11%, approximately 12%, approximately 13%, approximately 14%, approximately 15%, approximately 16%, approximately 17%, approximately 18%, approximately 19%, approximately 20%, approximately 21%, approximately 22%, approximately 23%, approximately 24%, approximately 25%, approximately 26%, approximately 27%, approximately 28%, approximately 29%, approximately 30%, approximately 31%, approximately 32%, approximately 33%, approximately 34%, approximately 35%, approximately 36%, approximately 37%, approximately 38%, approximately 39%, approximately 40%, approximately 41%, approximately 42%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64% Approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, approximately 100%, approximately 101%, approximately 102%, approximately 103%, approximately 104%, approximately 105%, approximately 106%, approximately 107%, approximately 108%, approximately 109%, approximately 110%, approximately 111%, approximately 112%, approximately 113%, approximately 114%, approximately 115%, approximately 116%. Approximately 117%, approximately 118%, approximately 119%, approximately 120%, approximately 121%, approximately 122%, approximately 123%, approximately 124%, approximately 125%, approximately 126%, approximately 127%, approximately 128%, approximately 129%, approximately 130%, approximately 131%, approximately 132%, approximately 133%, approximately 134%, approximately 135%, approximately 136%, approximately 137%, approximately 138%, approximately 139%, approximately 140%, approximately 141%, approximately 142%, approximately 143%, approximately 144%, approximately 145%, approximately 146%, approximately 147%, approximately 148%, approximately 149%, approximately 150%, approximately 151%, approximately 152%, approximately 153%, approximately 154%, approximately 155%, approximately 156%, approximately 157%, approximately 158%, approximately 159%, approximately 160%, approximately161%, approximately 162%, approximately 163%, approximately 164%, approximately 165%, approximately 166%, approximately 167%, approximately 168%, approximately 169%, approximately 170%, approximately 171%, approximately 172%, approximately 173%, approximately 174%, approximately 175%, approximately 176%, approximately 177%, approximately 178%, approximately 179%, approximately 180%, approximately 181%, approximately 182%, approximately 183%, approximately 184%, approximately 185%, approximately 186%, approximately 187%, approximately 188%, approximately 189%, approximately 190%, approximately 191%, approximately 192%, approximately 193%, approximately 194%, approximately 195%, approximately 196%, approximately 197%, approximately 198%, approximately 199%, or approximately 200%, indicating that the subject may benefit from the use of FcRH5 and CD3. Treatment with a bispecific antibody (e.g., civasutazumab) that binds to FcRH5 and CD3.

[0180] Table 4. Cell types associated with increased civasutazumab sensitivity

[0181]

[0182] CD = differentiated cluster; NK T cells = natural killer T cells; TN cells = naive T cells; TCM cells = central memory T cells; NK cells = natural killer cells

[0183] Conversely, MM subjects with a level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven or all eight) of the cell types listed in Table 4 that are reduced compared to reference levels in their samples (e.g., baseline samples) are generally more resistant to treatment with a bispecific antibody (e.g., civasutazumab) that binds to FcRH5 and CD3. For example, in samples from subjects, the levels of cell types in Table 4 may be reduced by approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, and so on, compared to reference levels.53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100%, indicating that the subject is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., civastartrazine).

[0184] Subject characteristics associated with increased resistance to civasutazumab

[0185] In some aspects of the invention, the methods described herein require identifying one or more of the characteristics listed in Table 5 in the subject. In some aspects of the invention, the methods described herein require that one or more of the characteristics listed in Table 5 in the subject have been previously identified.

[0186] Generally, MM subjects having a higher number of one or more of the characteristics listed in Table 5 (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or all fourteen) of characteristics compared to a reference number are more resistant to treatment with a bispecific antibody (e.g., civasutazumab) that binds to FcRH5 and CD3. For example, the number of one or more features in Table 5 may be higher than the reference number by one, two, three, four, five, six, seven, eight, nine, 10, 11, 12, 13, 14 or 15, which indicates that the subject is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., civastartrazine).

[0187] Table 5. Subject characteristics associated with civastastatin resistance 30 / 144 pages 46 CN 122206702 A

[0188]

[0189] PI = Proteasome inhibitor; IMID = Immunomodulatory agent; BCMA = B cell maturation antigen; CD = Differentiation cluster; CAR-T = Chimeric antigen receptor T cell

[0190] Conversely, having one or more of the following listed in Table 5 (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or all) compared to the reference number.MM subjects with a number of (14) traits are generally more sensitive to treatment with a bispecific antibody (e.g., civasutazumab) that binds to FcRH5 and CD3. For example, the number of one or more traits in Table 5 may be one, two, three, four, five, six, seven, eight, nine, 10, 11, 12, 13, 14, or 15 lower than the reference number, thereby indicating that the subject may benefit from treatment with a bispecific antibody (e.g., civasutazumab) that binds to FcRH5 and CD3.

[0191] Cell types in bone marrow associated with increased civasutazumab resistance

[0192] In some aspects of the invention, the methods described herein require determining the levels of one or more cell types listed in Table 6 in the subject's bone marrow. In some aspects of the invention, the methods described herein require that the levels of one or more cell types listed in Table 6 in the subject's bone marrow have been previously determined.

[0193] Generally, bone marrow samples (e.g., baseline bone marrow samples) contain an increase in one or more of the substances listed in Table 6 compared to the reference level (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, ten, eleven, twelve, thirteen ... MM subjects with levels (e.g., presence or percentage) of 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, or all 69) of cell types were more resistant to treatment with a bispecific antibody (e.g., civastastat) that binds to FcRH5 and CD3. For example, in some embodiments, the level of CD4+CD25-CD69+ T cells in samples from the subject (e.g., bone marrow) increased by about 27% to about 80% compared to a reference level (e.g., about 27% to about 54%, about 40% to about 60%, or about 54% to about 80%). In some embodiments, the level of CD4+DR+ T cells in samples from the subject (e.g., bone marrow) is increased by approximately 15% to approximately 44% compared to a reference level (e.g., approximately 15% to approximately 29%, approximately 22% to approximately 33%).Or about 29% to about 44%. In some embodiments, the level of CD4+DR+GzB+ T cells in samples from the subject (e.g., bone marrow) increases by about 17% to about 52% compared to a reference level (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 52%). In some embodiments, the level of CD4+DR+Ki67+ T cells in samples from the subject (e.g., bone marrow) increases by about 28% to about 83% compared to a reference level (e.g., about 28% to about 55%, about 42% to about 62%, or about 55% to about 83%). In some embodiments, the level of CD4+DR+PD1+ T cells in a sample (e.g., bone marrow) from a subject increases by about 26% to about 77% compared to a reference level (e.g., about 26% to about 51%, about 38% to about 58%, or about 51% to about 77%). In some embodiments, the level of CD4+Ki67+ T cells in a sample (e.g., bone marrow) from a subject increases by about 23% to about 68% compared to a reference level (e.g., about 23% to about 46%, about 34% to about 51%, or about 46% to about 68%). In some embodiments, the level of CD4+PD1+ T cells in a sample (e.g., bone marrow) from a subject increases by about 13% to about 40% compared to a reference level (e.g., about 13% to about 27%, about 20% to about 30%, or about 27% to about 40%). In some embodiments, the level of CD4+PD1+ T cells in a sample (e.g., bone marrow) from a subject increases by about 15% to about 45% compared to a reference level (e.g., about 15% to about 30%, about 22% to about 34%, or about 30% to about 45%). In some embodiments, the level of CD4+PD1+GzB+ T cells in a sample (e.g., bone marrow) from a subject increases by about 18% to about 55% compared to a reference level (e.g., about 18% to about 36%, about 27% to about 41%, or about 36% to about 55%). In some embodiments, the level of CD4+PD1+Ki67+ T cells in a sample (e.g., bone marrow) from a subject increases by about 30% to about 89% compared to a reference level (e.g., about 30% to about 59%, about 45% to about 67%, or about 59% to about 89%). In some embodiments, the level of CD4+PD1+OX40-T cells in samples from the subject (e.g., bone marrow) increased by approximately 12% compared to a reference level.The percentage is approximately 36% (e.g., approximately 12% to approximately 24%, approximately 18% to approximately 27%, or approximately 24% to approximately 36%). In some embodiments, the level of CD4+PD1+OX40+ T cells in a sample (e.g., bone marrow) from a subject increases by approximately 11% to approximately 34% compared to a reference level (e.g., approximately 11% to approximately 23%, approximately 17% to approximately 26%, or approximately 23% to approximately 34%). In some embodiments, the level of CD4+PD1-TIGIT+TIM3- T cells in a sample (e.g., bone marrow) from a subject increases by approximately 9% to approximately 26% compared to a reference level (e.g., approximately 9% to approximately 17%, approximately 13% to approximately 19%, or approximately 17% to approximately 26%). In some embodiments, the level of CD4+TIGIT+ T cells in a sample (e.g., bone marrow) from a subject increases by about 10% to about 31% compared to a reference level (e.g., about 10% to about 21%, about 16% to about 23%, or about 21% to about 31%). In some embodiments, the level of CD4+DR+ TCM cells in a sample (e.g., bone marrow) from a subject increases by about 23% to about 70% compared to a reference level (e.g., about 23% to about 47%, about 35% to about 53%, or about 47% to about 70%). In some embodiments, the level of CD4+DR+Ki67+ TCM cells in a sample (e.g., bone marrow) from a subject increases by about 30% to about 91% compared to a reference level (e.g., about 30% to about 61%, about 46% to about 68%, or about 61% to about 91%). In some embodiments, the level of CD4+DR+PD1+ TCM cells in a sample (e.g., bone marrow) from a subject increases by about 35% to about 104% compared to a reference level (e.g., about 35% to about 70%, about 52% to about 78%, or about 70% to about 104%). In some embodiments, the level of CD4+Ki67+ TCM cells in a sample (e.g., bone marrow) from a subject increases by about 23% to about 68% compared to a reference level (e.g., about 23% to about 45%, about 34% to about 51%, or about 45% to about 68%). In some embodiments, the level of CD4+PD1+ TCM cells in a sample (e.g., bone marrow) from a subject increases by about 17% to about 51% compared to a reference level (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 51%). In some embodiments, the level of CD4+PD1+OX40+ TCM cells in a sample (e.g., bone marrow) from a subject...The CD4+DR+ TEM cell levels in samples from the subject (e.g., bone marrow) increased by about 14% to about 42% compared to reference levels (e.g., about 14% to about 28%, about 21% to about 31%, or about 28% to about 42%). In some embodiments, the CD4+DR+ Ki67+ TEM cell levels in samples from the subject (e.g., bone marrow) increased by about 10% to about 31% compared to reference levels (e.g., about 10% to about 20%, about 15% to about 23%, or about 20% to about 31%). In some embodiments, the CD4+DR+ Ki67+ TEM cell levels in samples from the subject (e.g., bone marrow) increased by about 20% to about 59% compared to reference levels (e.g., about 20% to about 39%, about 30% to about 44%, or about 39% to about 59%). In some embodiments, the level of CD4+DR+PD1+ TEM cells in a sample (e.g., bone marrow) from a subject increases by about 17% to about 52% compared to a reference level (e.g., about 17% to about 35%, about 26% to about 39%, or about 35% to about 52%). In some embodiments, the level of CD4+Ki67+ TEM cells in a sample (e.g., bone marrow) from a subject increases by about 17% to about 52% compared to a reference level (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 52%). In some embodiments, the level of CD4+PD1+ TEM cells in a sample (e.g., bone marrow) from a subject increases by about 9% to about 27% compared to a reference level (e.g., about 9% to about 18%, about 14% to about 21%, or about 18% to about 27%). In some embodiments, the level of CD4+ TEM cells in a sample (e.g., bone marrow) from a subject increases by about 6% to about 19% compared to a reference level (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%). In some embodiments, the level of CD4+ TEM cells in a sample (e.g., bone marrow) from a subject increases by about 6% to about 18% compared to a reference level (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%). In some embodiments, the level of CD4+DR+ TEMRA cells in a sample (e.g., bone marrow) from a subject increases by about 10% to about 29% compared to a reference level (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 29%). In some embodiments, the sample from a subject...The levels of CD4+DR+GzB+TEMRA cells in the sample (e.g., bone marrow) increased by about 11% to about 32% compared to a reference level (e.g., about 11% to about 21%, about 16% to about 24%, or about 21% to about 32%). In some embodiments, the levels of CD4+DR+Ki67+TEMRA cells in the sample (e.g., bone marrow) from the subject increased by about 19% to about 56% compared to a reference level (e.g., about 19% to about 38%, about 28% to about 42%, or about 38% to about 56%). In some embodiments, the levels of CD4+DR+PD1+TEMRA cells in the sample (e.g., bone marrow) from the subject increased by about 17% to about 52% compared to a reference level (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 52%). In some embodiments, the level of CD4+Ki67+TEMRA cells in a sample (e.g., bone marrow) from a subject increases by about 17% to about 52% compared to a reference level (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 52%). In some embodiments, the level of CD4+PD1+TEMRA cells in a sample (e.g., bone marrow) from a subject increases by about 10% to about 29% compared to a reference level (e.g., about 10% to about 19%, about 15% to about 22%, or about 19% to about 29%). In some embodiments, the level of CD4+DR+Ki67+TN cells in a sample (e.g., bone marrow) from a subject increases by about 41% to about 124% compared to a reference level (e.g., about 41% to about 83%, about 62% to about 93%, or about 83% to about 124%). In some embodiments, the level of CD4+DR+PD1+ TN cells in a sample (e.g., bone marrow) from a subject increases by about 38% to about 113% compared to a reference level (e.g., about 38% to about 75%, about 56% to about 85%, or about 75% to about 113%). In some embodiments, the level of CD4+Ki67+ TN cells in a sample (e.g., bone marrow) from a subject increases by about 37% to about 110% compared to a reference level (e.g., about 37% to about 73%, about 55% to about 82%, or about 73% to about 110%). In some embodiments, the level of CD4+PD1+ TN cells in a sample (e.g., bone marrow) from a subject increases by about 22% to about 67% compared to a reference level (e.g., about 22% to about 45%, about 34% to about 50%, or about 45% to about 67%).67%. In some embodiments, the level of CD4+PD1+OX40+ TN cells in samples from the subject (e.g., bone marrow) increased by about 36% to about 107% compared to a reference level (e.g., about 36% to about 71%, about 53% to about 80%, or about 71% to about 107%). In some embodiments, the level of CD8+CD25-CD69+ T cells in samples from the subject (e.g., bone marrow) increased by about 10% to about 29% compared to a reference level (e.g., about 10% to about 19%, about 14% to about 21%, or about 19% to about 29%). In some embodiments, the level of CD8+DR+ T cells in samples from the subject (e.g., bone marrow) increased by about 6% to about 17% compared to a reference level (e.g., about 6% to about 11%, about 9% to about 13%, or about 11% to about 17%). In some embodiments, as described on pages 33 / 144 of CN 122206702 A, the level of CD8+DR+GzB+ T cells in a sample (e.g., bone marrow) from a subject increases by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%) compared to a reference level. In some embodiments, the level of CD8+DR+Ki67+ T cells in a sample (e.g., bone marrow) from a subject increases by about 24% to about 72% (e.g., about 24% to about 48%, about 36% to about 54%, or about 48% to about 72%) compared to a reference level. In some embodiments, the level of CD8+DR+PD1+ T cells in a sample (e.g., bone marrow) from a subject increases by about 11% to about 34% (e.g., about 11% to about 22%, about 17% to about 25%, or about 22% to about 34%) compared to a reference level. In some embodiments, the level of CD8+GzB+ T cells in a sample (e.g., bone marrow) from a subject increases by about 6% to about 19% compared to a reference level (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%). In some embodiments, the level of CD8+PD1+ T cells in a sample (e.g., bone marrow) from a subject increases by about 6% to about 19% compared to a reference level (e.g., about 6% to about 13%, about 9% to about 14%, or about 13% to about 19%). In some embodiments, the level of CD8+PD1+GzB+ T cells in a sample (e.g., bone marrow) from a subject increases by about 9% to about 27% compared to a reference level (e.g., about 9% to about 18%).13% to about 20% or about 18% to about 27%. In some embodiments, the level of CD8+PD1+OX40- T cells in a sample (e.g., bone marrow) from a subject increases by about 8% to about 23% compared to a reference level (e.g., about 8% to about 15%, about 11% to about 17%, or about 15% to about 23%). In some embodiments, the level of CD8+DR+GzB+ TCM cells in a sample (e.g., bone marrow) from a subject increases by about 21% to about 62% compared to a reference level (e.g., about 21% to about 42%, about 31% to about 47%, or about 42% to about 62%). In some embodiments, the level of CD8+DR+Ki67+ TCM cells in a sample (e.g., bone marrow) from a subject increases by about 26% to about 78% compared to a reference level (e.g., about 26% to about 52%, about 39% to about 59%, or about 52% to about 78%). In some embodiments, the level of CD8+DR+PD1+ TCM cells in a sample (e.g., bone marrow) from a subject increases by about 19% to about 56% compared to a reference level (e.g., about 19% to about 37%, about 28% to about 42%, or about 37% to about 56%). In some embodiments, the level of CD8+GzB+ TCM cells in a sample (e.g., bone marrow) from a subject increases by about 18% to about 54% compared to a reference level (e.g., about 18% to about 36%, about 27% to about 41%, or about 36% to about 54%). In some embodiments, the level of CD8+Ki67+ TCM cells in a sample (e.g., bone marrow) from a subject increases by about 21% to about 64% compared to a reference level (e.g., about 21% to about 42%, about 32% to about 48%, or about 42% to about 64%). In some embodiments, the level of CD8+PD1+ TCM cells in a sample (e.g., bone marrow) from a subject increases by about 10% to about 31% compared to a reference level (e.g., about 10% to about 21%, about 15% to about 23%, or about 21% to about 31%). In some embodiments, the level of CD8+DR+ TEM cells in a sample (e.g., bone marrow) from a subject increases by about 7% to about 21% compared to a reference level (e.g., about 7% to about 14%, about 11% to about 16%, or about 14% to about 21%). In some embodiments, the level of CD8+DR+GzB+ TEM cells in a sample (e.g., bone marrow) from a subject increases by about 9% to about 28% compared to a reference level (e.g., about 9% to about 19%).14% to about 21% or about 19% to about 28%. In some embodiments, the level of CD8+DR+Ki67+ TEM cells in a sample (e.g., bone marrow) from a subject increases by about 19% to about 56% compared to a reference level (e.g., about 19% to about 37%, about 28% to about 42%, or about 37% to about 56%). In some embodiments, the level of CD8+DR+PD1+ TEM cells in a sample (e.g., bone marrow) from a subject increases by about 11% to about 33% compared to a reference level (e.g., about 11% to about 22%, about 17% to about 25%, or about 22% to about 33%). In some embodiments, the level of CD8+GzB+ TEM cells in a sample (e.g., bone marrow) from a subject increases by about 7% to about 20% compared to a reference level (e.g., about 7% to about 13%, about 10% to about 15%, or about 13% to about 20%). In some embodiments, the level of CD8+PD1+ TEM cells in a sample (e.g., bone marrow) from a subject increases by about 6% to about 19% compared to a reference level (e.g., about 6% to about 13%, about 9% to about 14%, or about 13% to about 19%). In some embodiments, the level of CD8+DR+PD1+ TEMRA cells in a sample (e.g., bone marrow) from a subject increases by about 8% to about 23% compared to a reference level (e.g., about 8% to about 15%, about 11% to about 17%, or about 15% to about 23%). In some embodiments, the level of CD8+DR+ TN cells in a sample (e.g., bone marrow) from a subject increases by about 9% to about 27% compared to a reference level (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%). In some embodiments, the level of CD8+DR+GzB+ TN cells in a sample (e.g., bone marrow) from a subject increases by about 22% to about 65% compared to a reference level (e.g., about 22% to about 43%, about 32% to about 49%, or about 43% to about 65%). In some embodiments, the level of CD8+DR+Ki67+ TN cells in a sample (e.g., bone marrow) from a subject increases by about 30% to about 91% compared to a reference level (e.g., about 30% to about 61%, about 46% to about 69%, or about 61% to about 91%). In some embodiments, the level of CD8+DR+PD1 ...22% to about 65% (e.g., about 22% to about 43%, about 32% to about 49%, or about 61% to about 91%).Cell levels increased by approximately 20% to approximately 59% compared to reference levels (e.g., approximately 20% to approximately 39%, approximately 30% to approximately 44%, or approximately 39% to approximately 59%). In some embodiments, CD8+Ki67+ TN cell levels in samples from subjects (e.g., bone marrow) increased by approximately 28% to approximately 85% compared to reference levels (e.g., approximately 28% to approximately 57%, approximately 43% to approximately 64%, or approximately 57% to approximately 85%). In some embodiments, CD8+PD1+ TN cell levels in samples from subjects (e.g., bone marrow) increased by approximately 10% to approximately 29% compared to reference levels (e.g., approximately 10% to approximately 20%, approximately 15% to approximately 22%, or approximately 20% to approximately 29%). In some embodiments, the level of CD3-DR+ cells in a sample (e.g., bone marrow) from a subject increases by about 10% to about 30% compared to a reference level (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 30%). In some embodiments, the level of OX40+ Treg cells in a sample (e.g., bone marrow) from a subject increases by about 13% to about 38% compared to a reference level (e.g., about 13% to about 26%, about 19% to about 29%, or about 26% to about 38%). In some embodiments, the level of PD1+OX40+ Treg cells in a sample (e.g., bone marrow) from a subject increases by about 16% to about 48% compared to a reference level (e.g., about 16% to about 32%, about 24% to about 36%, or about 32% to about 48%). In some embodiments, the level of true NK cells in a sample (e.g., bone marrow) from a subject is increased by about 7% to about 22% compared to a reference level (e.g., about 7% to about 15%, about 11% to about 17%, or about 15% to about 22%).

[0194] Table 6. Cell types in bone marrow associated with increased resistance to civastastatin. (Document 35 / 144, Page 51, CN 122206702 A)

[0195]

[0196] CD = Differentiation cluster; DR = Human leukocyte antigen – DR isotype; Ki67 = Antigen Kiel 67; PD1 = Programmed cell death protein 1; GzB = Granulase B; TIGIT = T cell immune receptor with immunoglobulin and immunoreceptor tyrosine inhibitory motif domains; TIM3 = T cell immunoglobulin and mucin domain 3; TN cells = Naïve T cells; TCM cells = Central memory T cells; TEM cells = Effector memory T cells;TEMRA cells = terminally differentiated effector memory T cells; Treg cells = regulatory T cells; NK cells = natural killer cells

[0197] Conversely, bone marrow samples (e.g., baseline bone marrow samples) containing one or more of the following listed in Table 6 (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, ten, eleven, twelve, thirteen ... MM subjects with a level (e.g., presence or percentage) of cell types (40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, or all 69) of cell types are generally more sensitive to treatment with a bispecific antibody (e.g., civastanab) that binds to FcRH5 and CD3. For example, in some embodiments, the level of CD4+CD25-CD69+ T cells in a sample (e.g., bone marrow) from a subject is reduced by about 11% to about 32% compared to a reference level (e.g., about 11% to about 21%, about 16% to about 24%, or about 21% to about 32%). In some embodiments, the level of CD4+DR+ T cells in a sample (e.g., bone marrow) from a subject is reduced by about 6% to about 17% compared to a reference level (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 17%). In some embodiments, the level of CD4+DR+G2B+ T cells in a sample (e.g., bone marrow) from a subject is reduced by about 7% to about 21% compared to a reference level (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21%). In some embodiments, the level of CD4+DR+Ki67+ T cells in samples from the subject (e.g., bone marrow) is reduced by approximately 11% to approximately 33% compared to a reference level (e.g., approximately 11% to approximately 22%, approximately 17% to approximately 25%, or approximately 22% to approximately...).33%. In some embodiments, the level of CD4+DR+PD1+ T cells in samples (e.g., bone marrow) from the subject is reduced by about 10% to about 31% compared to a reference level (e.g., about 10% to about 20%, about 15% to about 23%, or about 20% to about 31%). In some embodiments, the level of CD4+Ki67+ T cells in samples (e.g., bone marrow) from the subject is reduced by about 9% to about 27% compared to a reference level (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%). In some embodiments, the level of CD4+PD1+ T cells in samples (e.g., bone marrow) from the subject is reduced by about 5% to about 16% compared to a reference level (e.g., about 5% to about 11%, about 8% to about 12%, or about 11% to about 16%). In some embodiments, the level of CD4+PD1+ T cells in a sample (e.g., bone marrow) from a subject is reduced by about 6% to about 18% compared to a reference level (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 18%). In some embodiments, the level of CD4+PD1+GzB+ T cells in a sample (e.g., bone marrow) from a subject is reduced by about 7% to about 22% compared to a reference level (e.g., about 7% to about 15%, about 11% to about 16%, or about 15% to about 22%). In some embodiments, the level of CD4+PD1+Ki67+ T cells in a sample (e.g., bone marrow) from a subject is reduced by about 12% to about 36% compared to a reference level (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%). In some embodiments, the level of CD4+PD1+OX40-T cells in a sample (e.g., bone marrow) from a subject is reduced by about 5% to about 14% compared to a reference level (e.g., about 5% to about 10%, about 7% to about 11%, or about 10% to about 14%). In some embodiments, the level of CD4+PD1+OX40+T cells in a sample (e.g., bone marrow) from a subject is reduced by about 5% to about 14% compared to a reference level (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%). In some embodiments, the level of CD4+PD1-TIGIT+TIM3-T cells in a sample (e.g., bone marrow) from a subject is reduced by about 3% to about 10% compared to a reference level (e.g., about 3% to about 7%, about 5% to about 8%, or about 7% to about 10%).10%. In some embodiments, the level of CD4+TIGIT+ T cells in samples (e.g., bone marrow) from the subject is reduced by about 4% to about 12% compared to a reference level (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%). In some embodiments, the level of CD4+DR+ TCM cells in samples (e.g., bone marrow) from the subject is reduced by about 9% to about 28% compared to a reference level (e.g., about 9% to about 19%, about 14% to about 21%, or about 19% to about 28%). In some embodiments, the level of CD4+DR+Ki67+ TCM cells in samples (e.g., bone marrow) from the subject is reduced by about 12% to about 36% compared to a reference level (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%). In some embodiments, the level of CD4+DR+PD1+ TCM cells in a sample (e.g., bone marrow) from a subject is reduced by about 14% to about 42% compared to a reference level (e.g., about 14% to about 28%, about 21% to about 31%, or about 28% to about 42%). In some embodiments, the level of CD4+Ki67+ TCM cells in a sample (e.g., bone marrow) from a subject is reduced by about 9% to about 27% compared to a reference level (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%). In some embodiments, the level of CD4+PD1+ TCM cells in a sample (e.g., bone marrow) from a subject is reduced by about 7% to about 21% compared to a reference level (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21%). In some embodiments, the level of CD4+PD1+OX40+ TCM cells in a sample (e.g., bone marrow) from a subject is reduced by about 6% to about 17% (e.g., about 6% to about 11%, about 8% to about 12%, or about 11% to about 17%) compared to a reference level. In some embodiments, the level of CD4+DR+TEM cells in a sample (e.g., bone marrow) from a subject is reduced by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%) compared to a reference level. In some embodiments, the level of CD4+DR+Ki67+ TEM cells in a sample (e.g., bone marrow) from a subject is reduced by about 8% to about 24% (e.g., about 8% to about 16%, about 12%) compared to a reference level.From about 18% or about 16% to about 24%. In some embodiments, the level of CD4+DR+PD1+ TEM cells in a sample (e.g., bone marrow) from a subject is reduced by about 7% to about 21% compared to a reference level (e.g., about 7% to about 14%, about 10% to about 16%, or about 14% to about 21%). In some embodiments, the level of CD4+Ki67+ TEM cells in a sample (e.g., bone marrow) from a subject is reduced by about 7% to about 21% compared to a reference level (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21%). In some embodiments, the level of CD4+PD1+ TEM cells in a sample (e.g., bone marrow) from a subject is reduced by about 4% to about 11% compared to a reference level (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%). In some embodiments, the level of CD4+ TEM cells in a sample (e.g., bone marrow) from a subject is reduced by about 2% to about 7% compared to a reference level (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%). In some embodiments, the level of CD4+ TEM cells in a sample (e.g., bone marrow) from a subject is reduced by about 2% to about 7% compared to a reference level (e.g., about 2% to about 5%, about 4% to about 5%, or about 5% to about 7%). In some embodiments, the level of CD4+ DR+ TEMRA cells in a sample (e.g., bone marrow) from a subject is reduced by about 4% to about 12% compared to a reference level (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%). In some embodiments, the level of CD4+DR+GzB+TEMRA cells in a sample (e.g., bone marrow) from a subject is reduced by about 4% to about 13% compared to a reference level (e.g., about 4% to about 9%, about 6% to about 10%, or about 9% to about 13%). In some embodiments, the level of CD4+DR+Ki67+TEMRA cells in a sample (e.g., bone marrow) from a subject is reduced by about 7% to about 22% compared to a reference level (e.g., about 7% to about 15%, about 11% to about 17%, or about 15% to about 22%). In some embodiments, the level of CD4+DR+PD1+TEMRA cells in a sample (e.g., bone marrow) from a subject is reduced by about 7% to about 21% compared to a reference level (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21%). In some embodimentsIn some embodiments, the level of CD4+Ki67+TEMRA cells in samples from subjects (e.g., bone marrow) is reduced by about 7% to about 21% compared to a reference level (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21%). In some embodiments, the level of CD4+PD1+TEMRA cells in samples from subjects (e.g., bone marrow) is reduced by about 4% to about 12% compared to a reference level (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%). In some embodiments, the level of CD4+DR+Ki67+TN cells in samples from subjects (e.g., bone marrow) is reduced by about 17% to about 50% compared to a reference level (e.g., about 17% to about 33%, about 25% to about 37%, or about 33% to about 50%). In some embodiments, the level of CD4+DR+PD1+ TN cells in a sample (e.g., bone marrow) from a subject is reduced by about 15% to about 45% compared to a reference level (e.g., about 15% to about 30%, about 22% to about 34%, or about 30% to about 45%). In some embodiments, the level of CD4+Ki67+ TN cells in a sample (e.g., bone marrow) from a subject is reduced by about 15% to about 44% compared to a reference level (e.g., about 15% to about 29%, about 22% to about 33%, or about 29% to about 44%). In some embodiments, the level of CD4+PD1+ TN cells in a sample (e.g., bone marrow) from a subject is reduced by about 9% to about 27% compared to a reference level (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 27%). In some embodiments, the level of CD4+PD1+OX40+ TN cells in a sample (e.g., bone marrow) from a subject is reduced by about 14% to about 42% (e.g., about 14% to about 28%, about 21% to about 32%, or about 28% to about 42%) compared to a reference level. In some embodiments, the level of CD8+CD25-CD69+ T cells in a sample (e.g., bone marrow) from a subject is reduced by about 4% to about 11% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 11%) compared to a reference level. In some embodiments, the level of CD8+DR+ T cells in a sample (e.g., bone marrow) from a subject is reduced by about 2% to about 7% (e.g., about 2% to about 5%, about 3% to about 5%, or about 5% to about 7 .... In some embodiments, the level of CD8+PD1+OX40+ TN cells in a sample (e.g., bone marrow) from a subject is reduced by about 14% to about 42% (e.g., about 14% to about 28%, about 21% to about 32%, or about 28% to about 42%) compared to a reference level.CD8+DR+ Specification 38 / 144 pages 54 CN 122206702 A GzB+ T cell levels are reduced by about 3% to about 10% compared to reference levels (e.g., about 3% to about 7%, about 5% to about 8%, or about 7% to about 10%). In some embodiments, CD8+DR+ Ki67+ T cell levels in samples from subjects (e.g., bone marrow) are reduced by about 10% to about 29% compared to reference levels (e.g., about 10% to about 19%, about 14% to about 22%, or about 19% to about 29%). In some embodiments, CD8+DR+ PD1+ T cell levels in samples from subjects (e.g., bone marrow) are reduced by about 4% to about 13% compared to reference levels (e.g., about 4% to about 9%, about 7% to about 10%, or about 9% to about 13%). In some embodiments, the level of CD8+GzB+ T cells in a sample (e.g., bone marrow) from a subject is reduced by about 2% to about 7% compared to a reference level (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%). In some embodiments, the level of CD8+PD1+ T cells in a sample (e.g., bone marrow) from a subject is reduced by about 3% to about 8% compared to a reference level (e.g., about 3% to about 5%, about 4% to about 6%, or about 5% to about 8%). In some embodiments, the level of CD8+PD1+GzB+ T cells in a sample (e.g., bone marrow) from a subject is reduced by about 4% to about 11% compared to a reference level (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%). In some embodiments, the level of CD8+PD1+OX40-T cells in samples from subjects (e.g., bone marrow) is reduced by about 3% to about 9% compared to a reference level (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%). In some embodiments, the level of CD8+DR+GzB+ TCM cells in samples from subjects (e.g., bone marrow) is reduced by about 8% to about 25% compared to a reference level (e.g., about 8% to about 17%, about 12% to about 19%, or about 17% to about 25%). In some embodiments, the level of CD8+DR+Ki67+ TCM cells in samples from subjects (e.g., bone marrow) is reduced by about 10% to about 31% compared to a reference level (e.g., about 10% to about 21%, about 16% to about 23%, or about 21% to about 31%). In some embodiments, the level of CD8+PD1+OX40-T cells in samples from subjects (e.g., bone marrow) is reduced by about 3% to about 9% compared to a reference level.The CD8+DR+PD1+ TCM cell level is reduced by about 7% to about 22% compared to a reference level (e.g., about 7% to about 15%, about 11% to about 17%, or about 15% to about 22%). In some embodiments, the CD8+GzB+ TCM cell level in a sample (e.g., bone marrow) from a subject is reduced by about 7% to about 22% compared to a reference level (e.g., about 7% to about 14%, about 11% to about 16%, or about 14% to about 22%). In some embodiments, the CD8+Ki67+ TCM cell level in a sample (e.g., bone marrow) from a subject is reduced by about 8% to about 25% compared to a reference level (e.g., about 8% to about 17%, about 13% to about 19%, or about 17% to about 25%). In some embodiments, the level of CD8+PD1+ TCM cells in a sample (e.g., bone marrow) from a subject is reduced by about 4% to about 12% compared to a reference level (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%). In some embodiments, the level of CD8+DR+ TEM cells in a sample (e.g., bone marrow) from a subject is reduced by about 3% to about 9% compared to a reference level (e.g., about 3% to about 6%, about 4% to about 6%, or about 6% to about 9%). In some embodiments, the level of CD8+DR+GzB+ TEM cells in a sample (e.g., bone marrow) from a subject is reduced by about 4% to about 11% compared to a reference level (e.g., about 4% to about 8%, about 6% to about 8%, or about 8% to about 11%). In some embodiments, the level of CD8+DR+Ki67+ TEM cells in a sample (e.g., bone marrow) from a subject is reduced by about 7% to about 22% compared to a reference level (e.g., about 7% to about 15%, about 11% to about 17%, or about 15% to about 22%). In some embodiments, the level of CD8+DR+PD1+ TEM cells in a sample (e.g., bone marrow) from a subject is reduced by about 4% to about 13% compared to a reference level (e.g., about 4% to about 9%, about 7% to about 10%, or about 9% to about 13%). In some embodiments, the level of CD8+GzB+ TEM cells in a sample (e.g., bone marrow) from a subject is reduced by about 3% to about 8% compared to a reference level (e.g., about 3% to about 5%, about 4% to about 6%, or about 5% to about 8%). In some embodiments, the level of CD8+PD1+ TEM cells in a sample (e.g., bone marrow) from a subject is reduced by about 2% to about 13% compared to a reference level.7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%). In some embodiments, the level of CD8+DR+PD1+TEMRA cells in a sample (e.g., bone marrow) from a subject is reduced by about 3% to about 9% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%) compared to a reference level. In some embodiments, the level of CD8+DR+TN cells in a sample (e.g., bone marrow) from a subject is reduced by about 4% to about 11% (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%) compared to a reference level. In some embodiments, the level of CD8+DR+GzB+ TN cells in a sample (e.g., bone marrow) from a subject is reduced by about 9% to about 26% compared to a reference level (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%). In some embodiments, the level of CD8+DR+Ki67+ TN cells in a sample (e.g., bone marrow) from a subject is reduced by about 12% to about 36% compared to a reference level (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%). In some embodiments, the level of CD8+DR+PD1+ TN cells in a sample (e.g., bone marrow) from a subject is reduced by about 8% to about 24% compared to a reference level (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%). In some embodiments, the level of CD8+Ki67+ TN cells in a sample (e.g., bone marrow) from a subject is reduced by about 11% to about 34% compared to a reference level (e.g., about 11% to about 23%, about 17% to about 25%, or about 23% to about 34%). In some embodiments, the level of CD8+PD1+ TN cells in a sample (e.g., bone marrow) from a subject is reduced by about 4% to about 12% compared to a reference level (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%). In some embodiments, the level of CD3-DR+ cells in a sample (e.g., bone marrow) from a subject is reduced by about 4% to about 12% compared to a reference level (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%). In some embodiments, the level of OX40+ Treg cells in a sample (e.g., bone marrow) from a subject is reduced by about 5% to about 12% compared to a reference level.15% (e.g., about 5% to about 10%, about 8% to about 11%, or about 10% to about 15%). In some embodiments, the PD1+OX40+ Treg cell level in a sample (e.g., bone marrow) from a subject is reduced by about 6% to about 19% (e.g., about 6% to about 13%, about 9% to about 14%, or about 13% to about 19%) compared to a reference level. In some embodiments, the true NK cell level in a sample (e.g., bone marrow) from a subject is reduced by about 3% to about 9% (e.g., about 3% to about 6%, about 4% to about 7%, or about 6% to about 9%) compared to a reference level.

[0198] Cell types in bone marrow associated with increased civastastatin sensitivity

[0199] In some aspects of the invention, the methods described herein require determining the levels of one or more cell types listed in Table 7 in the bone marrow of a subject. In some aspects of the invention, the methods described herein require that the levels of one or more cell types listed in Table 7 in the bone marrow of a subject have been previously determined.

[0200] Generally, MM subjects with increased levels (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, or all eight) cell types listed in Table 7 in their bone marrow samples (e.g., baseline bone marrow samples) compared to reference levels are more sensitive to treatment with a bispecific antibody (e.g., civastastat) that binds to FcRH5 and CD3. For example, in some embodiments, the CD4+ T cell level in a sample (e.g., bone marrow) from the subject is increased by about 4% to about 12% compared to reference levels (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%). In some embodiments, the CD4+CD25+CD69- T cell level in a sample (e.g., bone marrow) from the subject is increased by about 3% to about 10% compared to reference levels (e.g., about 3% to about 7%, about 5% to about 7%, or about 7% to about 10%). In some embodiments, the CD4+ T cell level in a sample (e.g., bone marrow) from a subject increases by about 3% to about 10% compared to a reference level (e.g., about 3% to about 7%, about 5% to about 8%, or about 7% to about 10%). In some embodiments, the CD4+ T cell level in a sample (e.g., bone marrow) from a subject increases by about 5% to about 14% compared to a reference level (e.g., about 5% to about 9%, about 7% to about 11%, or about 9% to about 14%). In some embodiments, the CD4+ T cell level in a sample (e.g., bone marrow) from a subject increases by about 3% to about 10% compared to a reference level (e.g., about 3% to about 7%, about 5% to about 11%, or about 9% to about 14%).The cell levels increase by about 4% to about 12% compared to a reference level (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%). In some embodiments, the CD4+ TCM cell levels in samples from the subject (e.g., bone marrow) increase by about 4% to about 11% compared to a reference level (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%). In some embodiments, the CD4+ TCM cell levels in samples from the subject (e.g., bone marrow) increase by about 4% to about 11% compared to a reference level (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%). In some embodiments, the level of CD8+CD25+CD69- T cells in samples from the subject (e.g., bone marrow) increases by about 11% to about 33% compared to a reference level (e.g., about 11% to about 22%, about 17% to about 25%, or about 22% to about 33%). In some embodiments, the level of CD8+NK T cells in samples from the subject (e.g., bone marrow) increases by about 3% to about 9% compared to a reference level (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%). In some embodiments, the level of CD8+ TCM cells in samples from the subject (e.g., bone marrow) increases by about 8% to about 25% compared to a reference level (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 25%). In some embodiments, the level of CD8+ TCM cells in a sample (e.g., bone marrow) from a subject increases by about 9% to about 26% compared to a reference level (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%). In some embodiments, the level of CD8+ TN cells in a sample (e.g., bone marrow) from a subject increases by about 6% to about 19% compared to a reference level (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%). In some embodiments, the level of CD8+ TN cells in a sample (e.g., bone marrow) from a subject increases by about 8% to about 23% compared to a reference level (e.g., about 8% to about 15%, about 11% to about 17%, or about 15% to about 23%). In some embodiments, the level of CD25+CD69-NK cells in a sample (e.g., bone marrow) from a subject increases by about 5% to about 15% compared to a reference level (e.g., about 5% to about 26%).10%, about 8% to about 11% or about 10% to about 15%.

[0201] Table 7. Cell types in bone marrow associated with increased sensitivity to civasutazine

[0202]

[0203] CD = differentiated cluster; NK T cells = natural killer T cells; TN cells = naive T cells; TCM cells = central memory T cells; NK cells = natural killer cells

[0204] Conversely, MM subjects with a reduced level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven or all eight) cell types listed in Table 7 compared to reference levels in bone marrow samples (e.g., baseline bone marrow samples) were more resistant to treatment with a bispecific antibody (e.g., civasutazine) that binds to FcRH5 and CD3. For example, in some embodiments, the level of CD4+ T cells in a sample (e.g., bone marrow) from a subject is reduced by about 10% to about 29% compared to a reference level (e.g., about 10% to about 19%, about 15% to about 22%, or about 19% to about 29%). In some embodiments, the level of CD4+CD25+CD69- T cells in a sample (e.g., bone marrow) from a subject is reduced by about 8% to about 25% compared to a reference level (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 25%). In some embodiments, the level of CD4+ T cells in a sample (e.g., bone marrow) from a subject is reduced by about 9% to about 26% compared to a reference level (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%). In some embodiments, the CD4+ T cell level in a sample (e.g., bone marrow) from a subject is reduced by about 12% to about 36% compared to a reference level (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%). In some embodiments, the CD4+ T cell level in a sample (e.g., bone marrow) from a subject is reduced by about 10% to about 31% compared to a reference level (e.g., about 10% to about 21%, about 16% to about 23%, or about 21% to about 31%). In some embodiments, the CD4+ TCM cell level in a sample (e.g., bone marrow) from a subject is reduced by about 9% to about 27% compared to a reference level (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 36%).27%. In some embodiments, the level of CD4+ TCM cells in samples (e.g., bone marrow) from the subject is reduced by about 9% to about 27% compared to a reference level (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%). In some embodiments, the level of CD8+CD25+CD69- T cells in samples (e.g., bone marrow) from the subject is reduced by about 28% to about 83% compared to a reference level (e.g., about 28% to about 55%, about 41% to about 62%, or about 55% to about 83%). In some embodiments, the level of CD8+NK T cells in samples (e.g., bone marrow) from the subject is reduced by about 8% to about 23% compared to a reference level (e.g., about 8% to about 16%, about 12% to about 17%, or about 16% to about 23%). In some embodiments, the level of CD8+ TCM cells in a sample (e.g., bone marrow) from a subject is reduced by about 20% to about 61% compared to a reference level (e.g., about 20% to about 41%, about 31% to about 46%, or about 41% to about 61%). In some embodiments, the level of CD8+ TCM cells in a sample (e.g., bone marrow) from a subject is reduced by about 21% to about 64% compared to a reference level (e.g., about 21% to about 43%, about 32% to about 48%, or about 43% to about 64%). In some embodiments, the level of CD8+ TN cells in a sample (e.g., bone marrow) from a subject is reduced by about 16% to about 47% compared to a reference level (e.g., about 16% to about 31%, about 23% to about 35%, or about 31% to about 47%). In some embodiments, the level of CD8+ TN cells in a sample (e.g., bone marrow) from a subject is reduced by about 19% to about 57% (e.g., about 19% to about 38%, about 29% to about 43%, or about 38% to about 57%) compared to a reference level. In some embodiments, the level of CD25+CD69-NK cells in a sample (e.g., bone marrow) from a subject is reduced by about 13% to about 38% (e.g., about 13% to about 25%, about 19% to about 29%, or about 25% to about 38%) compared to a reference level.

[0205] Cell types in blood associated with increased civastastatin resistance

[0206] In some aspects of the invention, the methods described herein require determining the levels of one or more cell types listed in Table 8 in the blood (e.g., whole blood, serum, or plasma) of a subject. In some aspects of the invention, the methods described herein require prior determination of the levels of one or more cell types listed in Table 8 in the blood of a subject.Levels of one or more cell types listed in 8.

[0207] Generally, a blood sample (e.g., baseline blood sample) contains an increase compared to a reference level of one or more of the substances listed in Table 8 (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, ten, eleven, twelve, thirteen ... MM subjects with a level (e.g., presence or percentage) of cell types (47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or all 80) of cell types were more resistant to treatment with a bispecific antibody (e.g., civastanab) that binds to FcRH5 and CD3. For example, in some embodiments, the level of CD8+DR+ TCM cells in a sample (e.g., bone marrow) from a subject increases by about 14% to about 43% compared to a reference level (e.g., about 14% to about 29%, about 22% to about 32%, or about 29% to about 43%). In some embodiments, the level of CD4+DR+ T cells in a sample (e.g., blood) from a subject increases by about 19% to about 57% compared to a reference level (e.g., about 19% to about 38%, about 28% to about 42%, or about 38% to about 57%). In some embodiments, the level of CD4+DR+G2B+ T cells in a sample (e.g., blood) from a subject increases by about 17% to about 51% compared to a reference level (e.g., about 17% to about 34%, about 26% to about 38%, or about 34% to about 51%). In some embodiments, the CD4+DR+Ki67+ T cell levels in samples (e.g., blood) from a subject are increased by approximately 24% to approximately 73% compared to a reference level (e.g., approximately 24% to approximately 49%, approximately 37% to approximately 55%, or approximately...).49% to about 73%. In some embodiments, the level of CD4+DR+PD1+ T cells in a sample (e.g., blood) from a subject increases by about 26% to about 79% compared to a reference level (e.g., about 26% to about 53%, about 39% to about 59%, or about 53% to about 79%). In some embodiments, the level of CD4+Ki67+ T cells in a sample (e.g., blood) from a subject increases by about 22% to about 65% compared to a reference level (e.g., about 22% to about 43%, about 32% to about 48%, or about 43% to about 65%). In some embodiments, the level of CD4+PD1+ T cells in a sample (e.g., blood) from a subject increases by about 13% to about 38% compared to a reference level (e.g., about 13% to about 26%, about 19% to about 29%, or about 26% to about 38%). In some embodiments, the level of CD4+PD1+ T cells in a sample (e.g., blood) from a subject increases by about 14% to about 41% compared to a reference level (e.g., about 14% to about 27%, about 21% to about 31%, or about 27% to about 41%). In some embodiments, the level of CD4+PD1+Ki67+ T cells in a sample (e.g., blood) from a subject increases by about 26% to about 77% compared to a reference level (e.g., about 26% to about 52%, about 39% to about 58%, or about 52% to about 77%). In some embodiments, the level of CD4+PD1+OX40- T cells in a sample (e.g., blood) from a subject increases by about 5% to about 15% compared to a reference level (e.g., about 5% to about 10%, about 7% to about 11%, or about 10% to about 15%). In some embodiments, the level of CD4+PD1+OX40+ T cells in samples (e.g., blood) from a subject increases by about 11% to about 34% compared to a reference level (e.g., about 11% to about 23%, about 17% to about 26%, or about 23% to about 34%). In some embodiments, the level of CD4+PD1-TIGIT+TIM3- T cells in samples (e.g., blood) from a subject increases by about 12% to about 35% compared to a reference level (e.g., about 12% to about 23%, about 17% to about 26%, or about 23% to about 35%). In some embodiments, the level of CD4+PDL1+ T cells in samples (e.g., blood) from a subject increases by about 15% to about 45% compared to a reference level (e.g., about 15% to about 30%, about 23% to about 34%).Or about 30% to about 45%. In some embodiments, the level of CD4+TIGIT+ T cells in a sample (e.g., blood) from a subject increases by about 11% to about 34% compared to a reference level (e.g., about 11% to about 23%, about 17% to about 26%, or about 23% to about 34%). In some embodiments, the level of CD4+DR+ TCM cells in a sample (e.g., blood) from a subject increases by about 26% to about 77% compared to a reference level (e.g., about 26% to about 52%, about 39% to about 58%, or about 52% to about 77%). In some embodiments, the level of CD4+DR+Ki67+ TCM cells in a sample (e.g., blood) from a subject increases by about 25% to about 74% compared to a reference level (e.g., about 25% to about 49%, about 37% to about 55%, or about 49% to about 74%). In some embodiments, the level of CD4+DR+PD1+ TCM cells in a sample (e.g., blood) from a subject increases by about 34% to about 102% compared to a reference level (e.g., about 34% to about 68%, about 51% to about 76%, or about 68% to about 102%). In some embodiments, the level of CD4+Ki67+ TCM cells in a sample (e.g., blood) from a subject increases by about 19% to about 57% compared to a reference level (e.g., about 19% to about 38%, about 28% to about 43%, or about 38% to about 57%). In some embodiments, the level of CD4+PD1+ TCM cells in a sample (e.g., blood) from a subject increases by about 15% to about 46% compared to a reference level (e.g., about 15% to about 31%, about 23% to about 35%, or about 31% to about 46%). In some embodiments, the level of CD4+PD1+OX40+ TCM cells in samples (e.g., blood) from a subject increases by about 12% to about 37% compared to a reference level (e.g., about 12% to about 25%, about 18% to about 28%, or about 25% to about 37%). In some embodiments, the level of CD4+DR+TEM cells in samples (e.g., blood) from a subject increases by about 13% to about 38% compared to a reference level (e.g., about 13% to about 26%, about 19% to about 29%, or about 26% to about 38%). In some embodiments, the level of CD4+DR+Ki67+ TEM cells in samples (e.g., blood) from a subject increases by about 19% to about 57% compared to a reference level (e.g., about 19% to about 38%, about 28%).(Approximately 43% or approximately 38% to approximately 57%). In some embodiments, as described on pages 43 / 144 of CN 122206702 A, the level of CD4+DR+PD1+ TEM cells in a sample (e.g., blood) from a subject increases by approximately 18% to approximately 53% compared to a reference level (e.g., approximately 18% to approximately 35%, approximately 27% to approximately 40%, or approximately 35% to approximately 53%). In some embodiments, the level of CD4+Ki67+ TEM cells in a sample (e.g., blood) from a subject increases by approximately 18% to approximately 53% compared to a reference level (e.g., approximately 18% to approximately 35%, approximately 27% to approximately 40%, or approximately 35% to approximately 53%). In some embodiments, the level of CD4+PD1+ TEM cells in a sample (e.g., blood) from a subject increases by about 8% to about 24% compared to a reference level (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%). In some embodiments, the level of CD4+PD1+OX40+ TEM cells in a sample (e.g., blood) from a subject increases by about 8% to about 23% compared to a reference level (e.g., about 8% to about 15%, about 11% to about 17%, or about 15% to about 23%). In some embodiments, the level of CD4+DR+ TEMRA cells in a sample (e.g., blood) from a subject increases by about 15% to about 46% compared to a reference level (e.g., about 15% to about 31%, about 23% to about 35%, or about 31% to about 46%). In some embodiments, the level of CD4+DR+GzB+TEMRA cells in a sample (e.g., blood) from a subject increases by about 14% to about 41% compared to a reference level (e.g., about 14% to about 27%, about 20% to about 31%, or about 27% to about 41%). In some embodiments, the level of CD4+DR+Ki67+TEMRA cells in a sample (e.g., blood) from a subject increases by about 23% to about 68% compared to a reference level (e.g., about 23% to about 46%, about 34% to about 51%, or about 46% to about 68%). In some embodiments, the level of CD4+DR+PD1+TEMRA cells in a sample (e.g., blood) from a subject increases by about 21% to about 63% compared to a reference level (e.g., about 21% to about 42%, about 31% to about 47%, or about 42% to about 63%). In some embodiments, CD4+Ki67+ TEMRA in samples (e.g., blood) from the subjectCell levels increased by approximately 21% to approximately 63% compared to reference levels (e.g., approximately 21% to approximately 42%, approximately 32% to approximately 47%, or approximately 42% to approximately 63%). In some embodiments, CD4+PD1+TEMRA cell levels in samples (e.g., blood) from the subject increased by approximately 9% to approximately 28% compared to reference levels (e.g., approximately 9% to approximately 19%, approximately 14% to approximately 21%, or approximately 19% to approximately 28%). In some embodiments, CD4+PD1+OX40+TEMRA cell levels in samples (e.g., blood) from the subject increased by approximately 10% to approximately 29% compared to reference levels (e.g., approximately 10% to approximately 20%, approximately 15% to approximately 22%, or approximately 20% to approximately 29%). In some embodiments, the level of CD4+DR+TN cells in a sample (e.g., blood) from a subject increases by about 19% to about 58% compared to a reference level (e.g., about 19% to about 39%, about 29% to about 44%, or about 39% to about 58%). In some embodiments, the level of CD4+DR+Ki67+TN cells in a sample (e.g., blood) from a subject increases by about 38% to about 114% compared to a reference level (e.g., about 38% to about 76%, about 57% to about 85%, or about 76% to about 114%). In some embodiments, the level of CD4+DR+PD1+TN cells in a sample (e.g., blood) from a subject increases by about 53% to about 160% compared to a reference level (e.g., about 53% to about 107%, about 80% to about 120%, or about 107% to about 160%). In some embodiments, the level of CD4+ Ki67+ TN cells in a sample (e.g., blood) from a subject increases by about 27% to about 81% compared to a reference level (e.g., about 27% to about 54%, about 41% to about 61%, or about 54% to about 81%). In some embodiments, the level of CD4+ PD1+ TN cells in a sample (e.g., blood) from a subject increases by about 19% to about 58% compared to a reference level (e.g., about 19% to about 39%, about 29% to about 44%, or about 39% to about 58%). In some embodiments, the level of CD4+ PD1+ OX40+ TN cells in a sample (e.g., blood) from a subject increases by about 18% to about 54% compared to a reference level (e.g., about 18% to about 36%, about 27% to about 41%, or about 36% to about 54 ...The CD8+DR+ T cell level increases by about 8% to about 25% compared to a reference level (e.g., about 8% to about 17%, about 13% to about 19%, or about 17% to about 25%). In some embodiments, the CD8+DR+GzB+ T cell level in a sample (e.g., blood) from a subject increases by about 9% to about 28% compared to a reference level (e.g., about 9% to about 18%, about 14% to about 21%, or about 18% to about 28%). In some embodiments, the CD8+DR+Ki67+ T cell level in a sample (e.g., blood) from a subject increases by about 25% to about 74% compared to a reference level (e.g., about 25% to about 49%, about 37% to about 56%, or about 49% to about 74%). In some embodiments, the level of CD8+DR+PD1+ T cells in a sample (e.g., blood) from a subject increases by about 15% to about 44% compared to a reference level (e.g., about 15% to about 29%, about 22% to about 33%, or about 29% to about 44%). In some embodiments, the level of CD8+G2B+ T cells in a sample (e.g., blood) from a subject increases by about 6% to about 18% compared to a reference level (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%). In some embodiments, the level of CD8+Ki67+ T cells in a sample (e.g., blood) from a subject increases by about 22% to about 67% compared to a reference level (e.g., about 22% to about 45%, about 34% to about 50%, or about 45% to about 67%). In some embodiments, the CD8+PD1+ T cell level in a sample (e.g., blood) from a subject increases by about 9% to about 26% compared to a reference level (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 26%). In some embodiments, the CD8+PD1+ T cell level in a sample (e.g., blood) from a subject increases by about 8% to about 24% compared to a reference level (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%). In some embodiments, the CD8+PD1+G2B+ T cell level in a sample (e.g., blood) from a subject increases by about 11% to about 34% compared to a reference level (e.g., about 11% to about 23%, about 17% to about 26%, or about 23% to about 24%).34%. In some embodiments, the level of CD8+PD1+Ki67+ T cells in samples (e.g., blood) from the subject increases by about 26% to about 78% compared to a reference level (e.g., about 26% to about 52%, about 39% to about 59%, or about 52% to about 78%). In some embodiments, the level of CD8+DR+ TCM cells in samples (e.g., blood) from the subject increases by about 14% to about 43% compared to a reference level (e.g., about 14% to about 28%, about 21% to about 32%, or about 28% to about 43%). In some embodiments, the level of CD8+DR+GzB+ TCM cells in samples (e.g., blood) from the subject increases by about 20% to about 61% compared to a reference level (e.g., about 20% to about 41%, about 31% to about 46%, or about 41% to about 61%). In some embodiments, the level of CD8+DR+Ki67+ TCM cells in a sample (e.g., blood) from a subject increases by about 18% to about 54% compared to a reference level (e.g., about 18% to about 36%, about 27% to about 40%, or about 36% to about 54%). In some embodiments, the level of CD8+DR+PD1+ TCM cells in a sample (e.g., blood) from a subject increases by about 17% to about 51% compared to a reference level (e.g., about 17% to about 34%, about 25% to about 38%, or about 34% to about 51%). In some embodiments, the level of CD8+GzB+ TCM cells in a sample (e.g., blood) from a subject increases by about 18% to about 55% compared to a reference level (e.g., about 18% to about 37%, about 27% to about 41%, or about 37% to about 55%). In some embodiments, the level of CD8+Ki67+ TCM cells in a sample (e.g., blood) from a subject increases by about 16% to about 49% compared to a reference level (e.g., about 16% to about 33%, about 25% to about 37%, or about 33% to about 49%). In some embodiments, the level of CD8+PD1+ TCM cells in a sample (e.g., blood) from a subject increases by about 11% to about 34% compared to a reference level (e.g., about 11% to about 23%, about 17% to about 25%, or about 23% to about 34%). In some embodiments, the level of CD8+PD1+OX40+ TCM cells in a sample (e.g., blood) from a subject increases by about 14% to about 43% compared to a reference level (e.g., about 14% to about 28%, about 21% to about 49%).32% or about 28% to about 43%. In some embodiments, the level of CD8+DR+TEM cells in a sample (e.g., blood) from a subject increases by about 7% to about 22% compared to a reference level (e.g., about 7% to about 15%, about 11% to about 17%, or about 15% to about 22%). In some embodiments, the level of CD8+DR+GzB+TEM cells in a sample (e.g., blood) from a subject increases by about 8% to about 24% compared to a reference level (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%). In some embodiments, the level of CD8+DR+Ki67+ TEM cells in a sample (e.g., blood) from a subject increases by about 18% to about 55% (e.g., about 18% to about 36%, about 27% to about 41%, or about 36% to about 55%) compared to a reference level. In some embodiments, the level of CD8+DR+PD1+ TEM cells in a sample (e.g., blood) from a subject increases by about 11% to about 34% (e.g., about 11% to about 23%, about 17% to about 26%, or about 23% to about 34%) compared to a reference level. In some embodiments, the level of CD8+GzB+ TEM cells in a sample (e.g., blood) from a subject increases by about 6% to about 17% (e.g., about 6% to about 11%, about 8% to about 13%, or about 11% to about 17%) compared to a reference level. In some embodiments, the level of CD8+Ki67+ TEM cells in a sample (e.g., blood) from a subject increases by about 16% to about 47% compared to a reference level (e.g., about 16% to about 31%, about 23% to about 35%, or about 31% to about 47%). In some embodiments, the level of CD8+PD1+ TEM cells in a sample (e.g., blood) from a subject increases by about 6% to about 18% compared to a reference level (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%). In some embodiments, the level of CD8+DR+ TEMRA cells in a sample (e.g., blood) from a subject increases by about 5% to about 16% compared to a reference level (e.g., about 5% to about 11%, about 8% to about 12%, or about 11% to about 16%). In some embodiments, the level of CD8+DR+Ki67+TEMRA cells in samples (e.g., blood) from the subject increased by approximately 23% to approximately [missing value].69% (e.g., about 23% to about 46%, about 34% to about 52%, or about 46% to about 69%). In some embodiments, the level of CD8+DR+PD1+TEMRA cells in a sample (e.g., blood) from a subject increases by about 11% to about 34% compared to a reference level (e.g., about 11% to about 23%, about 17% to about 26%, or about 23% to about 34%). In some embodiments, the level of CD8+GzB+TEMRA cells in a sample (e.g., blood) from a subject increases by about 3% to about 8% compared to a reference level (e.g., about 3% to about 5%, about 4% to about 6%, or about 5% to about 8%). In some embodiments, the level of CD8+Ki67+TEMRA cells in a sample (e.g., blood) from a subject increases by about 22% to about 65% compared to a reference level (e.g., about 22% to about 43%, about 32% to about 48%, or about 43% to about 65%). In some embodiments, the level of CD8+PD1+TEMRA cells in a sample (e.g., blood) from a subject increases by about 7% to about 21% compared to a reference level (e.g., about 7% to about 14%, about 11% to about 16%, or about 14% to about 21%). In some embodiments, the level of CD8+DR+TN cells in a sample (e.g., blood) from a subject increases by about 15% to about 46% compared to a reference level (e.g., about 15% to about 31%, about 23% to about 35%, or about 31% to about 46%). In some embodiments, the level of CD8+DR+GzB+ TN cells in a sample (e.g., blood) from a subject increases by about 27% to about 80% compared to a reference level (e.g., about 27% to about 53%, about 40% to about 60%, or about 53% to about 80%). In some embodiments, the level of CD8+DR+Ki67+ TN cells in a sample (e.g., blood) from a subject increases by about 39% to about 116% compared to a reference level (e.g., about 39% to about 77%, about 58% to about 87%, or about 77% to about 116%). In some embodiments, the level of CD8+DR+PD1+ TN cells in a sample (e.g., blood) from a subject increases by about 27% to about 82% compared to a reference level (e.g., about 27% to about 54%, about 41% to about 61%, or about 54% to about 82%). In some embodiments, the level of CD8+G2B+TN cells in samples (e.g., blood) from the subject increased by approximately 23% compared to a reference level.The percentage is approximately 69% (e.g., approximately 23% to approximately 46%, approximately 34% to approximately 52%, or approximately 46% to approximately 69%). In some embodiments, the level of CD8+Ki67+ TN cells in a sample (e.g., blood) from a subject increases by approximately 34% to approximately 103% compared to a reference level (e.g., approximately 34% to approximately 69%, approximately 51% to approximately 77%, or approximately 69% to approximately 103%). In some embodiments, the level of CD8+PD1+ TN cells in a sample (e.g., blood) from a subject increases by approximately 11% to approximately 32% compared to a reference level (e.g., approximately 11% to approximately 21%, approximately 16% to approximately 24%, or approximately 21% to approximately 32%). In some embodiments, the level of CD8+PD1+OX40+ TN cells in a sample (e.g., blood) from a subject increases by about 12% to about 37% (e.g., about 12% to about 25%, about 18% to about 28%, or about 25% to about 37%) compared to a reference level. In some embodiments, the level of CD3-DR+ cells in a sample (e.g., blood, see page 46 / 144 of the specification, CN 122206702 A) increases by about 8% to about 23% (e.g., about 8% to about 15%, about 11% to about 17%, or about 15% to about 23%) compared to a reference level. In some embodiments, the level of OX40+ Treg cells in a sample (e.g., blood) from a subject increases by about 9% to about 28% (e.g., about 9% to about 19%, about 14% to about 21%, or about 19% to about 28%) compared to a reference level. In some embodiments, the PD1+OX40+ Treg cell level in a sample (e.g., blood) from a subject increases by about 13% to about 38% compared to a reference level (e.g., about 13% to about 25%, about 19% to about 29%, or about 25% to about 38%). In some embodiments, the true NK cell level in a sample (e.g., blood) from a subject increases by about 6% to about 18% compared to a reference level (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 18%). In some embodiments, the white blood cell level in a sample (e.g., blood) from a subject increases by about 2% to about 5% compared to a reference level (e.g., about 2% to about 3%, about 3% to about 4%, or about 3% to about 5%). In some embodiments, the white blood cell level in a sample (e.g., blood) from a subject increases by about 2% to about 5% compared to a reference level (e.g., about 2% to about 3%, about 2% to about 3%).4% or about 3% to about 5%. In some embodiments, the white blood cell level in a sample (e.g., blood) from the subject increases by about 2% to about 7% compared to a reference level (e.g., about 2% to about 5%, about 3% to about 5%, or about 5% to about 7%). In some embodiments, the white blood cell level in a sample (e.g., blood) from the subject increases by about 2% to about 5% compared to a reference level (e.g., about 2% to about 4%, about 3% to about 4%, or about 4% to about 5%).

[0208] Table 8. Cell types associated with increased resistance to civastastat in blood

[0209] Specification 47 / 144 pages 63 CN 122206702 A

[0210] CD = Differentiation cluster; DR = Human leukocyte antigen – DR isotype; Ki67 = Antigen Kiel 67; PD1 = Programmed cell death protein 1; GzB = Granulase B; TIGIT = T cell immune receptor with immunoglobulin and immunoreceptor tyrosine inhibitory motif domains; TIM3 = T cell immunoglobulin and mucin domain 3; TN cells = Naïve T cells; TCM cells = Central memory T cells; TEM cells = Effector memory T cells; TEMRA cells = Terminally differentiated effector memory T cells; Treg cells = Regulatory T cells; NK cells = Natural killer cells

[0211] Conversely, blood samples (e.g., baseline blood samples) exhibiting a decrease compared to reference levels of one or more of the substances listed in Table 8 (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, eleven, twelve, thirteen ... 48 kinds, 49 kinds, 50 kinds, 51 kinds, 52 kinds, 53 kinds, 54 kinds, 55 kinds, 56 kinds, 57 kinds, 58 kinds, 59 kinds, 60 kinds, 61 kinds, 62 kinds, 63 kinds, 64 kinds, 65 kinds, 66 kinds, 67 kinds, 68 kinds, 69 kinds, 70 kinds, 71 kinds, 72 kinds, 73 kinds, 74 kinds, 75 kinds, 76 kinds, 77 kinds, 78 kinds, 79 kinds, or all 80Multiphasic disease (MM) subjects with a certain level (e.g., presence or percentage) of cell types are generally more sensitive to treatment with a bispecific antibody (e.g., civastastat) that binds to FcRH5 and CD3. For example, in some embodiments, the level of CD8+DR+ TCM cells in a sample (e.g., bone marrow) from the subject is reduced by about 6% to about 17% compared to a reference level (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 17%). In some embodiments, the level of CD4+DR+ T cells in a sample (e.g., blood) from the subject is reduced by about 8% to about 23% compared to a reference level (e.g., about 8% to about 15%, about 11% to about 17%, or about 15% to about 23%). In some embodiments, the level of CD4+DR+GzB+ T cells in a sample (e.g., blood) from a subject is reduced by about 7% to about 20% compared to a reference level (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 20%). In some embodiments, the level of CD4+DR+Ki67+ T cells in a sample (e.g., blood) from a subject is reduced by about 10% to about 29% compared to a reference level (e.g., about 10% to about 19%, about 15% to about 22%, or about 19% to about 29%). In some embodiments, the level of CD4+DR+PD1+ T cells in a sample (e.g., blood) from a subject is reduced by about 11% to about 32% compared to a reference level (e.g., about 11% to about 21%, about 16% to about 24%, or about 21% to about 32%). In some embodiments, the level of CD4+ Ki67+ T cells in a sample (e.g., blood) from a subject is reduced by about 9% to about 26% compared to a reference level (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%). In some embodiments, the level of CD4+ PD1+ T cells in a sample (e.g., blood) from a subject is reduced by about 5% to about 15% compared to a reference level (e.g., about 5% to about 10%, about 8% to about 11%, or about 10% to about 15%). In some embodiments, the level of CD4+ PD1+ T cells in a sample (e.g., blood) from a subject is reduced by about 5% to about 16% compared to a reference level (e.g., about 5% to about 11%, about 8% to about 12%, or about 11% to about 16%). In some embodiments, the level of CD4+ PD1+ Ki67+ T cells in a sample (e.g., blood) from a subject is reduced by about 10% compared to a reference level.The percentage is approximately 31% (e.g., approximately 10% to approximately 21%, approximately 15% to approximately 23%, or approximately 21% to approximately 31%). In some embodiments, the level of CD4+PD1+OX40- T cells in a sample (e.g., blood) from a subject is reduced by approximately 2% to approximately 6% compared to a reference level (e.g., approximately 2% to approximately 4%, approximately 3% to approximately 4%, or approximately 4% to approximately 6%). In some embodiments, the level of CD4+PD1+OX40+ T cells in a sample (e.g., blood) from a subject is reduced by approximately 5% to approximately 14% compared to a reference level (e.g., approximately 5% to approximately 9%, approximately 7% to approximately 10%, or approximately 9% to approximately 14%). In some embodiments, the level of CD4+PD1-TIGIT+TIM3- T cells in a sample (e.g., blood) from a subject is reduced by about 5% to about 14% compared to a reference level (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%). In some embodiments, the level of CD4+PDL1+ T cells in a sample (e.g., blood) from a subject is reduced by about 6% to about 18% compared to a reference level (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 18%). In some embodiments, the level of CD4+TIGIT+ T cells in a sample (e.g., blood) from a subject is reduced by about 5% to about 14% compared to a reference level (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%). In some embodiments, the level of CD4+DR+ TCM cells in a sample (e.g., blood) from a subject is reduced by about 10% to about 31% (e.g., about 10% to about 21%, about 15% to about 23%, or about 21% to about 31%) compared to a reference level. In some embodiments, the level of CD4+DR+Ki67+ TCM cells in a sample (e.g., blood) from a subject is reduced by about 10% to about 29% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 29%) compared to a reference level. In some embodiments, the level of CD4+DR+PD1+ TCM cells in a sample (e.g., blood) from a subject is reduced by about 14% to about 41% (e.g., about 14% to about 27%, about 20% to about 30%, or about 27% to about 41%) compared to a reference level. In some embodiments, the level of CD4+Ki67+ TCM cells in a sample (e.g., blood) from a subject is reduced by about 14% to about 41% (e.g., about 14% to about 27%, about 20% to about 30%, or about 27% to about 41%). In some embodiments, the level of CD4+Ki67+ TCM cells in a sample (e.g., blood) from a subject is reduced by about 14% to about 41% compared to a reference level.The TCM cell level is reduced by about 8% to about 23% compared to a reference level (e.g., about 8% to about 15%, about 11% to about 17%, or about 15% to about 23%). In some embodiments, the CD4+PD1+ TCM cell level in a sample (e.g., blood) from a subject is reduced by about 6% to about 19% compared to a reference level (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%). In some embodiments, the CD4+PD1+OX40+ TCM cell level in a sample (e.g., blood) from a subject is reduced by about 5% to about 15% compared to a reference level (e.g., about 5% to about 10%, about 7% to about 11%, or about 10% to about 15%). In some embodiments, the level of CD4+DR+ TEM cells in a sample (e.g., blood) from a subject is reduced by about 5% to about 15% compared to a reference level (e.g., about 5% to about 10%, about 8% to about 11%, or about 10% to about 15%). In some embodiments, the level of CD4+DR+Ki67+ TEM cells in a sample (e.g., blood) from a subject is reduced by about 8% to about 23% compared to a reference level (e.g., about 8% to about 15%, about 11% to about 17%, or about 15% to about 23%). In some embodiments, the level of CD4+DR+PD1+ TEM cells in a sample (e.g., blood) from a subject is reduced by about 7% to about 21% compared to a reference level (e.g., about 7% to about 14%, about 11% to about 16%, or about 14% to about 21%). In some embodiments, the level of CD4+ Ki67+ TEM cells in a sample (e.g., blood) from a subject is reduced by about 7% to about 21% compared to a reference level (e.g., about 7% to about 14%, about 11% to about 16%, or about 14% to about 21%). In some embodiments, the level of CD4+ PD1+ TEM cells in a sample (e.g., blood) from a subject is reduced by about 3% to about 10% compared to a reference level (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 10%). In some embodiments, the level of CD4+ PD1+ OX40+ TEM cells in a sample (e.g., blood) from a subject is reduced by about 3% to about 9% compared to a reference level (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%). In some embodiments, the level of CD4+ DR+ TEMRA cells in a sample (e.g., blood) from a subject is reduced by about 6% to about 9% compared to a reference level.18% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%). In some embodiments, the level of CD4+DR+GzB+TEMRA cells in a sample (e.g., blood) from a subject is reduced by about 5% to about 16% compared to a reference level (e.g., about 5% to about 11%, about 8% to about 12%, or about 11% to about 16%). In some embodiments, the level of CD4+DR+Ki67+TEMRA cells in a sample (e.g., blood) from a subject is reduced by about 9% to about 27% compared to a reference level (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%). In some embodiments, the level of CD4+DR+PD1+TEMRA cells in a sample (e.g., blood) from a subject is reduced by about 8% to about 25% (e.g., about 8% to about 17%, about 13% to about 19%, or about 17% to about 25%) compared to a reference level. In some embodiments, the level of CD4+Ki67+TEMRA cells in a sample (e.g., blood) from a subject is reduced by about 8% to about 25% (e.g., about 8% to about 17%, about 13% to about 19%, or about 17% to about 25%) compared to a reference level. In some embodiments, the level of CD4+PD1+TEMRA cells in a sample (e.g., blood) from a subject is reduced by about 4% to about 11% (e.g., about 4% to about 7%, about 6% to about 8%, or about 7% to about 11%) compared to a reference level. In some embodiments, the level of CD4+PD1+OX40+TEMRA cells in a sample (e.g., blood) from a subject is reduced by about 4% to about 12% compared to a reference level (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%). In some embodiments, the level of CD4+DR+TN cells in a sample (e.g., blood) from a subject is reduced by about 8% to about 23% compared to a reference level (e.g., about 8% to about 16%, about 12% to about 17%, or about 16% to about 23%). In some embodiments, the level of CD4+DR+Ki67+TN cells in a sample (e.g., blood) from a subject is reduced by about 15% to about 45% compared to a reference level (e.g., about 15% to about 30%, about 23% to about 34%, or about 30% to about 45%). In some embodiments, the level of CD4+PD1+OX40+TEMRA cells in a sample (e.g., blood) from a subject is reduced by about 4% to about 12% compared to a reference level (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%).The CD4+DR+PD1+ TN cell level is reduced by about 21% to about 64% compared to a reference level (e.g., about 21% to about 43%, about 32% to about 48%, or about 43% to about 64%). In some embodiments, the CD4+Ki67+ TN cell level in a sample (e.g., blood) from a subject is reduced by about 11% to about 32% compared to a reference level (e.g., about 11% to about 22%, about 16% to about 24%, or about 22% to about 32%). In some embodiments, the CD4+PD1+ TN cell level in a sample (e.g., blood) from a subject is reduced by about 8% to about 23% compared to a reference level (e.g., about 8% to about 15%, about 12% to about 17%, or about 15% to about 23%). In some embodiments, the level of CD4+PD1+OX40+ TN cells in a sample (e.g., blood) from a subject is reduced by about 7% to about 22% compared to a reference level (e.g., about 7% to about 14%, about 11% to about 16%, or about 14% to about 22%). In some embodiments, the level of CD8+DR+ T cells in a sample (e.g., blood) from a subject is reduced by about 3% to about 10% compared to a reference level (e.g., about 3% to about 7%, about 5% to about 8%, or about 7% to about 10%). In some embodiments, the level of CD8+DR+GzB+ T cells in a sample (e.g., blood) from a subject is reduced by about 4% to about 11% compared to a reference level (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%). In some embodiments, the level of CD8+DR+Ki67+ T cells in a sample (e.g., blood) from a subject is reduced by about 10% to about 30% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 30%) compared to a reference level. In some embodiments, the level of CD8+DR+PD1+ T cells in a sample (e.g., blood) from a subject is reduced by about 6% to about 17% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 17%) compared to a reference level. In some embodiments, the level of CD8+GzB+ T cells in a sample (e.g., blood) from a subject is reduced by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%) compared to a reference level. In some embodiments, the level of CD8+Ki67+ T cells in a sample (e.g., blood) from a subject is reduced by about 9% to about 30% compared to a reference level.27% (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 27%). In some embodiments, the CD8+PD1+ T cell level in a sample (e.g., blood) from a subject is reduced by about 4% to about 11% compared to a reference level (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%). In some embodiments, the CD8+PD1+ T cell level in a sample (e.g., blood) from a subject is reduced by about 3% to about 10% compared to a reference level (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 10%). In some embodiments, the CD8+PD1+G2B+ T cell level in a sample (e.g., blood) from a subject is reduced by about 5% to about 14% compared to a reference level (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%). In some embodiments, the level of CD8+PD1+Ki67+ T cells in a sample (e.g., blood) from a subject is reduced by about 10% to about 31% (e.g., about 10% to about 21%, about 16% to about 23%, or about 21% to about 31%) compared to a reference level. In some embodiments, the level of CD8+DR+ TCM cells in a sample (e.g., blood) from a subject is reduced by about 6% to about 17% (e.g., about 6% to about 11%, about 8% to about 13%, or about 11% to about 17%) compared to a reference level. In some embodiments, the level of CD8+DR+ GzB+ TCM cells in a sample (e.g., blood) from a subject is reduced by about 8% to about 25% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 25%) compared to a reference level. In some embodiments, the level of CD8+DR+Ki67+ TCM cells in samples (e.g., blood) from a subject is reduced by about 7% to about 21% compared to a reference level (e.g., about 7% to about 14%, about 11% to about 16%, or about 14% to about 21%). In some embodiments, the level of CD8+DR+PD1+ TCM cells in samples (e.g., blood) from a subject is reduced by about 7% to about 20% compared to a reference level (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 20%). In some embodiments, the level of CD8+GzB+ TCM cells in samples (e.g., blood) from a subject is reduced by about 7% compared to a reference level.The level of CD8+Ki67+ TCM cells in a sample (e.g., blood) from a subject is reduced by about 7% to about 20% compared to a reference level (e.g., about 7% to about 13%, about 10% to about 15%, or about 13% to about 20%). In some embodiments, the level of CD8+PD1+ TCM cells in a sample (e.g., blood) from a subject is reduced by about 4% to about 13% compared to a reference level (e.g., about 4% to about 9%, about 7% to about 10%, or about 9% to about 13%). In some embodiments, the level of CD8+PD1+OX40+ TCM cells in a sample (e.g., blood) from a subject is reduced by about 6% to about 17% compared to a reference level (e.g., about 6% to about 11%, about 9% to about 13%, or about 11% to about 17%). In some embodiments, the level of CD8+DR+ TEM cells in a sample (e.g., blood) from a subject is reduced by about 3% to about 9% compared to a reference level (e.g., about 3% to about 6%, about 4% to about 7%, or about 6% to about 9%). In some embodiments, the level of CD8+DR+GzB+ TEM cells in a sample (e.g., blood) from a subject is reduced by about 3% to about 10% compared to a reference level (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 10%). In some embodiments, the level of CD8+DR+Ki67+ TEM cells in a sample (e.g., blood) from a subject is reduced by about 7% to about 22% compared to a reference level (e.g., about 7% to about 15%, about 11% to about 16%, or about 15% to about 22%). In some embodiments, the level of CD8+DR+PD1+ TEM cells in a sample (e.g., blood) from a subject is reduced by about 5% to about 14% compared to a reference level (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%). In some embodiments, the level of CD8+GzB+ TEM cells in a sample (e.g., blood) from a subject is reduced by about 2% to about 7% compared to a reference level (e.g., about 2% to about 4%, about 3% to about 5%, or about 4% to about 7%). In some embodiments, the level of CD8+Ki67+ TEM cells in a sample (e.g., blood) from a subject is reduced by about 6% to about 19% compared to a reference level (e.g., about 6% to about 12%, about 9% to about 14%).14% or about 12% to about 19%. In some embodiments, the level of CD8+PD1+ TEM cells in a sample (e.g., blood) from a subject is reduced by about 2% to about 7% compared to a reference level (e.g., about 2% to about 5%, about 4% to about 5%, or about 5% to about 7%). In some embodiments, the level of CD8+DR+ TEMRA cells in a sample (e.g., blood) from a subject is reduced by about 2% to about 7% compared to a reference level (e.g., about 2% to about 4%, about 3% to about 5%, or about 4% to about 7%). In some embodiments, the level of CD8+DR+Ki67+ TEMRA cells in a sample (e.g., blood) from a subject is reduced by about 9% to about 27% compared to a reference level (e.g., about 9% to about 18%, about 14% to about 21%, or about 18% to about 27%). In some embodiments, the level of CD8+DR+PD1+TEMRA cells in a sample (e.g., blood) from a subject is reduced by about 5% to about 14% compared to a reference level (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%). In some embodiments, the level of CD8+GzB+TEMRA cells in a sample (e.g., blood) from a subject is reduced by about 1% to about 3% compared to a reference level (e.g., about 1% to about 2%, about 2% to about 2%, or about 2% to about 3%). In some embodiments, the level of CD8+Ki67+TEMRA cells in a sample (e.g., blood) from a subject is reduced by about 9% to about 26% compared to a reference level (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%). In some embodiments, the level of CD8+PD1+TEMRA cells in a sample (e.g., blood) from a subject is reduced by about 3% to about 9% compared to a reference level (e.g., about 3% to about 6%, about 4% to about 6%, or about 6% to about 9%). In some embodiments, the level of CD8+DR+TN cells in a sample (e.g., blood) from a subject is reduced by about 6% to about 18% compared to a reference level (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%). In some embodiments, the level of CD8+DR+G2B+TN cells in a sample (e.g., blood) from a subject is reduced by about 11% to about 32% compared to a reference level (e.g., about 11% to about 21%, about 16%).From about 24% or about 21% to about 32%. In some embodiments, the level of CD8+DR+Ki67+ TN cells in a sample (e.g., blood) from a subject is reduced by about 15% to about 46% compared to a reference level (e.g., about 15% to about 31%, about 23% to about 35%, or about 31% to about 46%). In some embodiments, the level of CD8+DR+PD1+ TN cells in a sample (e.g., blood) from a subject is reduced by about 11% to about 33% compared to a reference level (e.g., about 11% to about 22%, about 16% to about 24%, or about 22% to about 33%). In some embodiments, the level of CD8+GzB+ TN cells in a sample (e.g., blood) from a subject is reduced by about 9% to about 27% compared to a reference level (e.g., about 9% to about 18%, about 14% to about 21%, or about 18% to about 27%). In some embodiments, the level of CD8+Ki67+ TN cells in a sample (e.g., blood) from a subject is reduced by about 14% to about 41% compared to a reference level (e.g., about 14% to about 27%, about 21% to about 31%, or about 27% to about 41%). In some embodiments, the level of CD8+PD1+ TN cells in a sample (e.g., blood) from a subject is reduced by about 4% to about 13% compared to a reference level (e.g., about 4% to about 8%, about 6% to about 10%, or about 8% to about 13%). In some embodiments, the level of CD8+PD1+OX40+ TN cells in a sample (e.g., blood) from a subject is reduced by about 5% to about 15% compared to a reference level (e.g., about 5% to about 10%, about 7% to about 11%, or about 10% to about 15%). In some embodiments, the level of CD3-DR+ cells in a sample (e.g., blood) from a subject is reduced by about 3% to about 9% compared to a reference level (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%). In some embodiments, the level of OX40+ Treg cells in a sample (e.g., blood) from a subject is reduced by about 4% to about 11% compared to a reference level (e.g., about 4% to about 7%, about 6% to about 8%, or about 7% to about 11%). In some embodiments, the level of PD1+OX40+ Treg cells in a sample (e.g., blood) from a subject is reduced by about 5% to about 15% compared to a reference level (e.g., about 5% to about 10%, about 8% to about 11%, or about 10% to about 15%).15%). In some embodiments, the level of true NK cells in a sample (e.g., blood) from a subject is reduced by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 5%, or about 5% to about 7%) compared to a reference level. In some embodiments, the level of white blood cells in a sample (e.g., blood) from a subject is reduced by about 1% to about 3% compared to a reference level.

[0212] Cell types in blood associated with increased civastastatin sensitivity

[0213] In some aspects of the invention, the methods described herein require determining the levels of one or more cell types listed in Table 9 in the blood (e.g., whole blood, serum, or plasma) of a subject. In some aspects of the invention, the methods described herein require that the levels of one or more cell types listed in Table 9 in the blood of a subject have been previously determined.

[0214] Typically, MM subjects having increased levels (e.g., presence or percentage) of one or more (e.g., one, two, three, four, or all five) cell types listed in Table 9 compared to reference levels are more sensitive to treatment with a bispecific antibody (e.g., civastastat) that binds to FcRH5 and CD3. For example, in some embodiments, CD4+ T cell levels in samples (e.g., blood) from the subject are increased by about 4% to about 11% (e.g., about 4% to about 7%, about 6% to about 8%, or about 7% to about 11%) compared to reference levels. In some embodiments, CD4+ T cell levels in samples (e.g., blood) from the subject are increased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%) compared to reference levels. In some embodiments, the CD4+ T cell level in a sample (e.g., blood) from the subject's instructions (page 52 / 144, 68 CN 122206702 A) increases by about 4% to about 11% (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%) compared to a reference level. In some embodiments, the CD4+ T cell level in a sample (e.g., blood) from the subject increases by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%) compared to a reference level. In some embodiments, the CD8+CD25+CD69- T cell level in a sample (e.g., blood) from the subject increases by about 9% to about 28% (e.g., about 9% to about 18%, about 14% to about 21%, or about 18% to about 28%) compared to a reference level. In some embodiments, the CD8+CD25+CD69- T cell level in a sample (e.g., blood) from the subject...CD8+ NK T cell levels increase by about 2% to about 6% compared to reference levels (e.g., about 2% to about 4%, about 3% to about 5%, or about 4% to about 6%). In some embodiments, CD8+ TCM cell levels in samples (e.g., blood) from a subject increase by about 7% to about 20% compared to reference levels (e.g., about 7% to about 13%, about 10% to about 15%, or about 13% to about 20%). In some embodiments, CD8+ TN cell levels in samples (e.g., blood) from a subject increase by about 5% to about 16% compared to reference levels (e.g., about 5% to about 11%, about 8% to about 12%, or about 11% to about 16%). In some embodiments, CD8+ TN cell levels in samples (e.g., blood) from a subject increase by about 6% to about 17% compared to reference levels (e.g., about 6% to about 11%, about 8% to about 13%, or about 11% to about 17%).

[0215] Table 9. Cell types in blood associated with increased sensitivity to civasutazine

[0216]

[0217] CD = Differentiation cluster; NK T cells = Natural killer T cells; TN cells = Naïve T cells; TCM cells = Central memory T cells

[0218] Conversely, MM subjects with reduced levels (e.g., presence or percentage) of one or more (e.g., one, two, three, four, or all five) cell types listed in Table 9 compared to reference levels are more resistant to treatment with a bispecific antibody (e.g., civasutazine) that binds to FcRH5 and CD3. For example, in some embodiments, the level of CD4+ T cells in samples (e.g., blood) from the subject is reduced by about 9% to about 28% (e.g., about 9% to about 19%, about 14% to about 21%, or about 19% to about 28%) compared to reference levels. In some embodiments, the CD4+ T cell level in a sample (e.g., blood) from a subject is reduced by about 6% to about 19% compared to a reference level (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%). In some embodiments, the CD4+ T cell level in a sample (e.g., blood) from a subject is reduced by about 9% to about 27% compared to a reference level (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 27%). In some embodiments, the CD4+ T cell level in a sample (e.g., blood) from a subject is reduced by about 10% to about 30% compared to a reference level (e.g., about 10%).From about 20%, about 15%, about 22%, or about 20% to about 30%. In some embodiments, the level of CD8+CD25+CD69- T cells in a sample (e.g., blood) from a subject is reduced by about 23% to about 69% compared to a reference level (e.g., about 23% to about 46%, about 35% to about 52%, or about 46% to about 69%). In some embodiments, the level of CD8+NK T cells in a sample (e.g., blood) from a subject is reduced by about 5% to about 15% compared to a reference level (e.g., about 5% to about 10%, about 8% to about 11%, or about 10% to about 15%). In some embodiments, the level of CD8+ TCM cells in a sample (e.g., blood) from a subject is reduced by approximately 16% to approximately 49% compared to a reference level (e.g., approximately 16% to approximately 33%, approximately 25% to approximately 37%, or approximately 33% to approximately 49%). In some embodiments, the level of CD8+ TN cells in a sample (e.g., blood) from a subject is reduced by approximately 13% to approximately 40% compared to a reference level (e.g., approximately 13% to approximately 26%, approximately 20% to approximately 30%, or approximately 26% to approximately 40%). In some embodiments, the level of CD8+ TN cells in a sample (e.g., blood) from a subject is reduced by approximately 14% to approximately 42% compared to a reference level (e.g., approximately 14% to approximately 28%, approximately 21% to approximately 32%, or approximately 28% to approximately 42%).

[0219] A. Treatment Method

[0220] In some aspects, the present invention is characterized by a method of treating a subject with MM. The method may include administering to the subject a bispecific antibody (e.g., civastastatin) that binds to FcRH5 and CD3. Prior to administering the bispecific antibody, it may have been previously determined that the sample from the subject has a reduced level of one or more cell types listed in Tables 3, 6, and / or 8 compared to a reference level. Prior to administering the bispecific antibody, it may have been previously determined that the sample from the subject has an increased level of one or more cell types listed in Tables 4, 7, and / or 9 compared to a reference level. The sample from the subject may be derived from the subject's bone marrow and / or blood. Prior to administering the bispecific antibody, it may have been previously determined that the subject has a lower number of one or more of the characteristics listed in Table 5 compared to a reference number. In some aspects, the reference level is the reference level assigned as listed in Table 14. In some aspects, the reference number is the reference number assigned as listed in Table 15.

[0221] Flow cytometry (FC), mass spectrometry (MS), immunohistochemistry (IHC), DNA sequencing (DNA-seq), RNA sequencing (RNA-seq), quantitative PCR (qPCR), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), multiplex qPCR or RT-qPCR, microarray analysis, gene expression serial analysis (SAGE), MassARRAY® technology, in situ hybridization (ISH), or combinations thereof can be used to determine the levels of one or more cell types in a sample (e.g., BM or blood).

[0222] Prior to administration of bispecific antibodies, samples from the subject's bone marrow may have been previously determined to have reduced levels of one or more cell types listed in Tables 3 and / or 6 compared to reference levels. Prior to administration of bispecific antibodies, samples from the subject's bone marrow may have been previously determined to have increased levels of one or more cell types listed in Tables 4 and / or 7 compared to reference levels.

[0223] Prior to administering the bispecific antibody, it may have been previously determined that a sample from the subject's blood (e.g., whole blood, plasma, or serum) has a reduced level of one or more cell types listed in Tables 3 and / or 8 compared to a reference level. Prior to administering the bispecific antibody, it may have been previously determined that a sample from the subject's blood (e.g., whole blood, plasma, or serum) has an increased level of one or more cell types listed in Tables 4 and / or 9 compared to a reference level.

[0224] In some aspects, the present invention provides a method for treating a subject with MM, wherein the method may optionally include the step of determining the level of one or more cell types listed in Tables 3 and / or 4 in a sample from the subject. The sample from the subject may be from the subject's bone marrow and / or blood. In some aspects of the invention, the method may or may not include the step of determining one or more of the characteristics listed in Table 5.

[0225] A method of treating a subject with MM may include the following steps: prior to administration of a bispecific antibody, identifying the subject as a subject who will benefit from treatment comprising a bispecific antibody binding to FcRH5 and CD3. Subjects may benefit from treatment based on a relative increase in overall survival (OS), objective response rate (ORR), progression-free survival (PFS), complete response (CR), partial response (PR), or a combination thereof.

[0226] Subjects who will benefit from treatment comprising a bispecific antibody binding to FcRH5 and CD3 may be identified as having: a decrease in the level of one or more cell types listed in Table 3 compared to a reference level; an increase in the level of one or more cell types listed in Table 4 compared to a reference level; and / or an increase in the level of a reference number of cell types.Page 54 / 144 of the document, 70 CN 122206702 A, compared to the number of one or more of the features listed in Table 5. A method of treating a subject with MM may further include the step of administering a treatment comprising a bispecific antibody (e.g., civastastatin) binding to FcRH5 and CD3 to an identified subject.

[0227] In some aspects of the invention, the sample is derived from the subject's bone marrow and has a reduced level of one or more cell types listed in Tables 3 and / or 6 compared to a reference level. In some aspects of the invention, the sample is derived from the subject's bone marrow and has an increased level of one or more cell types listed in Tables 4 and / or 7 compared to a reference level.

[0228] In some aspects of the invention, the sample is derived from the subject's blood (e.g., whole blood, plasma, or serum) and has a reduced level of one or more cell types listed in Tables 3 and / or 8 compared to a reference level. In some aspects of the invention, the sample is derived from the subject's blood (e.g., whole blood, plasma, or serum) and has increased levels of one or more cell types listed in Tables 4 and / or 9 compared to reference levels.

[0229] In some aspects of the invention, the method may include measuring or determining one or more (e.g., 1 to 85), two or more (e.g., 2 to 85), three or more (e.g., 3 to 85), four or more (e.g., 4 to 85), five or more (e.g., 5 to 85), six or more (e.g., 6 to 85), seven or more (e.g., 7 to 85), eight or more (e.g., 8 to 85), nine or more (e.g., 9 to 85), ten or more (e.g., 10 to 85), eleven or more (e.g., 11 to 85), twelve or more (e.g., 12 to 85), thirteen or more (e.g., 13 to 85), and fourteen or more of the cell types listed in Table 3. 14 or more (e.g., 14 to 85), 15 or more (e.g., 15 to 85), 16 or more (e.g., 16 to 85), 17 or more (e.g., 17 to 85), 18 or more (e.g., 18 to 85), 19 or more (e.g., 19 to 85), 20 or more (e.g., 20 to 85), 21 or more (e.g., 21 to 85), 22 or more (e.g., 22 to 85), 23 or more (e.g., 23 to 85), 2424 to 85 people, 25 to 85 people, 26 to 85 people, 27 to 85 people, 28 to 85 people, 29 to 85 people, 30 to 85 people, 31 to 85 people, 32 to 85 people, 33 to 85 people, 34 to 85 people, 35 to 85 people, 36 to 85 people, 37 to 85 people 38 or more (e.g., 38 to 85), 39 or more (e.g., 39 to 85), 40 or more (e.g., 40 to 85), 41 or more (e.g., 41 to 85), 42 or more (e.g., 42 to 85), 43 or more (e.g., 43 to 85), 44 or more (e.g., 44 to 85), 45 or more (e.g., 45 to 85), 46 or more (e.g., 46 to 85), 47 or more (e.g., 47 to 85), 48 or more (e.g., 48 to 85), 49 or more (e.g., 49 to 85), 50 or more (e.g., 50 to 85), 51 51 to 85, 52 to 85, 53 to 85, 54 to 85, 55 to 85, 56 to 85, 57 to 85, 58 to 85, 59 to 85, 60 to 85, 61 to 85, 62 to 85, 63 to 85, 64 to 85, 64 to 85. (e.g., 65 to 85), 65 or more (e.g., 65 to 85), 66 or more, 55 / 144 pages, 71 CN122206702 A More than 66 (e.g., 66 to 85), 67 or more (e.g., 67 to 85), 68 or more (e.g., 68 to 85), 69 or more (e.g., 69 to 85), 70 or more (e.g., 70 to 85), 71 or more (e.g., 71 to 85), 72 or more (e.g., 72 to 85), 73 or more (e.g., 73 to 85), 74 or more (e.g., 74 to 85), 75 or more (e.g., 75 to 85), 76 or more (e.g., 76 to 85), 77 or more (e.g., 77 to 85), 78 or more (e.g., 78 to 85), 79 The steps are at the level of 89 or more (e.g., 79 to 85), 80 or more (e.g., 80 to 85), 81 or more (e.g., 81 to 85), 82 or more (e.g., 82 to 85), 83 or more (e.g., 83 to 85), 84 or more (e.g., 84 to 85), or 85.

[0230] In some aspects of the invention, the method may include the step of measuring or determining the level of 1 or more (e.g., 1 to 8), 2 or more (e.g., 2 to 8), 3 or more (e.g., 3 to 8), 4 or more (e.g., 4 to 8), 5 or more (e.g., 5 to 8), 6 or more (e.g., 6 to 8), 7 or more (e.g., 7 to 8), or 8 of the cell types listed in Table 4.

[0231] In some aspects of the invention, the method may include measuring or determining one or more of the features listed in Table 5 (e.g., 1 to 15), two or more (e.g., 2 to 15), three or more (e.g., 3 to 15), four or more (e.g., 4 to 15), five or more (e.g., 5 to 15), six or more (e.g., 6 to 15), seven or more (e.g., 7 to 15), eight or more (e.g., 8 to 15), nine or more (e.g., 9 to 15), ten or more (e.g., 10 to 15), eleven or more (e.g., 11 to 15), twelve or more (e.g., 12 to 15), thirteen or more (e.g., 13 to 15), 14 One or more (e.g., 14 toThe steps for 15 people or 15 people.

[0232] In some aspects of the invention, the method may include measuring or determining one or more (e.g., 1 to 69), two or more (e.g., 2 to 69), three or more (e.g., 3 to 69), four or more (e.g., 4 to 69), five or more (e.g., 5 to 69), six or more (e.g., 6 to 69), seven or more (e.g., 7 to 69), eight or more (e.g., 8 to 69), nine or more (e.g., 9 to 69), ten or more (e.g., 10 to 69), eleven or more (e.g., 11 to 69), twelve or more (e.g., 12 to 69), thirteen or more (e.g., 13 to 69), 14 14 or more (e.g., 14 to 69), 15 or more (e.g., 15 to 69), 16 or more (e.g., 16 to 69), 17 or more (e.g., 17 to 69), 18 or more (e.g., 18 to 69), 19 or more (e.g., 19 to 69), 20 or more (e.g., 20 to 69), 21 or more (e.g., 21 to 69), 22 or more (e.g., 22 to 69), 23 or more (e.g., 23 to 69), 24 or more (e.g., 24 to 69), 25 or more (e.g., 25 to 69), 26 or more (e.g., 26 to 69), 27 or more (e.g., 27... 28 to 69, 28 or more (e.g., 28 to 69), 29 or more (e.g., 29 to 69), 30 or more (e.g., 30 to 69), 31 or more (e.g., 31 to 69), 32 or more (e.g., 32 to 69), 33 or more (e.g., 33 to 69), 34 or more (e.g., 34 to 69), 35 or more (e.g., 35 to 69), 36 or more (e.g., 36 to 69), 37 or more (e.g., 37 to 69), 38 or more (e.g., 38 to 69), 39 or more (e.g., 39 to 69), 40 or more (e.g., 40 to 69), 41 Those with 41 or more (e.g., 41 to 69), 42 or moreMultiple (e.g., 42 to 69), 43 or more (e.g., 43 to 69), 44 or more (e.g., 44 to 69), 45 or more (e.g., 45 to 69), 46 or more (e.g., 46 to 69), 47 or more (e.g., 47 to 69), 48 or more (e.g., 48 to 69), 49 or more (e.g., 49 to 69), 50 or more (e.g., 50 to 69), 51 or more (e.g., 51 to 69), 52 or more (e.g., 52 to 69), 53 or more (e.g., 53 to 69), 54 54 to 69 people, 55 to 69 people, 56 to 69 people, 57 to 69 people, 58 to 69 people, 59 to 69 people, 60 to 69 people, 61 to 69 people, 62 to 69 people, 63 to 69 people, 64 to 69 people, 65 to 69 people, 66 to 69 people, 67 ...9 to 69 people, 66 to 69 people, 67 to 69 people, 68 to 69 people, 59 to 69 people, 69 to 69 people, 69 to 69 people, 67 to 69 people, 69 to 69 people, 69 to 69 people, 69 to 69 people, 69 to 69 people, 69 to 69 people, 69 to 69 people, 69 to 69 people, 69 to 69 people, 69 to 69 people, 69 to 69 people, 69 to 69 people, 69 to 69 people, 69 to 69 people, 69 to 69 people, 69 to 69 people, 69 to 69 people, 69 to 69 people, 69 to 69 people, 69 to 69 people, 69 to 69 people, 69 to 69 The steps of measuring or determining the levels of 1 or more (e.g., 1 to 8), 2 or more (e.g., 2 to 8), 3 or more (e.g., 3 to 8), 4 or more (e.g., 4 to 8), 5 or more (e.g., 5 to 8), 6 or more (e.g., 6 to 8), 7 or more (e.g., 7 to 8), or 8 of the cell types listed in Table 7.

[0234] In some aspects of the invention, the method may include measuring or determining one or more (e.g., 1 to 80), two or more (e.g., 2 to 80), three or more (e.g., 3 to 80), four or more (e.g., 4 to 80), five or more of the cell types listed in Table 8.10 or more (e.g., 5 to 80), 6 or more (e.g., 6 to 80), 7 or more (e.g., 7 to 80), 8 or more (e.g., 8 to 80), 9 or more (e.g., 9 to 80), 10 or more (e.g., 10 to 80), 11 or more (e.g., 11 to 80), 12 or more (e.g., 12 to 80), 13 or more (e.g., 13 to 80), 14 or more (e.g., 14 to 80), 15 or more (e.g., 15 to 80), 16 or more (e.g., 16 to 80), 17 or more (e.g., 17 to 80), 18 or more (e.g., 18 to 80), 19 20 or more (e.g., 19 to 80), 21 or more (e.g., 21 to 80), 22 or more (e.g., 22 to 80), 23 or more (e.g., 23 to 80), 24 or more (e.g., 24 to 80), 25 or more (e.g., 25 to 80), 26 or more (e.g., 26 to 80), 27 or more (e.g., 27 to 80), 28 or more (e.g., 28 to 80), 29 or more (e.g., 29 to 80), 30 or more (e.g., 30 to 80), 31 or more (e.g., 31 to 80), 32 or more (e.g., 32 to 80). 33 to 80, 34 to 80, 35 to 80, 36 to 80, 37 to 80, 38 to 80, 39 to 80, 40 to 80, 41 to 80, 42 to 80, 43 to 80, 44 to 80, 45 to 80, 46 ...6 to 80, 37 to 80, 38 to 80, 39 to 80, 46 to 80, 46 to 80, 37 to 80, 38 to 80, 39 to 80, 49 to 80, 46 to 80, 46 to 80, 46 to 80 47 or more (e.g., 46 to 80), 47 or more (e.g., 47 to 80), 48 or more (e.g., 48 to80), 49 or more (e.g., 49 to 80), 50 or more (e.g., 50 to 80), 51 or more (e.g., 51 to 80), 52 or more (e.g., 52 to 80), 53 or more (e.g., 53 to 80), 54 or more (e.g., 54 to 80), 55 or more (e.g., 55 to 80), 56 or more (e.g., 56 to 80), 57 or more (e.g., 57 to 80), 58 or more (e.g., 58 to 80), 59 or more (e.g., 59 to 80), 60 or more (e.g., 60 to 80). 61 or more (e.g., 61 to 80), 62 or more (e.g., 62 to 80), 63 or more (e.g., 63 to 80), 64 or more (e.g., 64 to 80), 65 or more (e.g., 65 to 80), 66 or more (e.g., 66 to 80), 67 or more (e.g., 67 to 80), 68 or more (e.g., 68 to 80), 69 or more (e.g., 69 to 80), 70 or more (e.g., 70 to 80), 71 or more (e.g., 71 to 80), 72 or more (e.g., 72 to 80), 73 or more (e.g., 73 to 80), 74 The steps of measuring or determining the levels of 1 or more (e.g., 74 to 80), 75 or more (e.g., 75 to 80), 76 or more (e.g., 76 to 80), 77 or more (e.g., 77 to 80), 78 or more (e.g., 78 to 80), 79 or more (e.g., 79 to 80), or 80.

[0235] In some aspects of the invention, the method may include the steps of measuring or determining the levels of 1 or more (e.g., 1 to 8), 2 or more (e.g., 2 to 8), 3 or more (e.g., 3 to 8), 4 or more (e.g., 4 to 8), or 5 of the cell types listed in Table 9.

[0236] In some aspects of the invention, subjects have previously been treated for MM (e.g., R / R MM). In some respects, the subjects have received treatment for MM (e.g., R / R).The subject has received at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more than fifteen lines of treatment for MM (e.g., 2L+, 3L+, 4L+, 5L+, 6L+, 7L+, 8L+, 9L+, 10L+, 11L+, 12L+, 13L+, 14L+, or 15L+. In some respects, the subject has received at least three prior lines of treatment for MM (e.g., R / R MM), for example, 4L+, or for example, has received three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more than fifteen lines of treatment.

[0237] In some aspects, prior lines of treatment include one or more of the following: proteasome inhibitors (PIs), such as bortezomib, carfilzomib, or ixazomib; immunomodulatory drugs (IMiDs), such as thalidomide, lenalidomide, or pomalidomide; autologous stem cell transplantation (ASCT); anti-CD38 agents, such as daratumumab (DARZALEX®) (US Patent No. 7,829,673 and US Publication No. 20160067205 A1), “MOR202” (US Patent No. 8,263,746), ixazomib (SAR-650984); CAR-T therapy; therapies comprising bispecific antibodies; anti-SLAMF7 therapeutic agents (e.g., anti-SLAMF7 antibodies, such as elotuzumab); nuclear export inhibitors (e.g., selinexor); and histone deacetylases (HDACs). Inhibitors (e.g., panobinostat). In some aspects, prior lines of treatment include antibody-drug conjugates (ADCs). In some aspects, prior lines of treatment include B-cell maturation antigen (BCMA)-targeted therapies, such as BCMA-ADCs targeting BCMA.

[0238] In some aspects, prior lines of treatment include proteasome inhibitors (PIs), IMiDs, and anti-CD38 agents (e.g., daratumumab).

[0239] In some aspects, MM is refractory to treatment lines, for example, to one or more of the following: daratumumab, PIs, IMiDs, ASCTs, anti-CD38 agents, CAR-T therapy, therapies containing bispecific antibodies, anti-SLAMF7 therapies, nuclear export inhibitors, HDAC inhibitors, ADCs, or BCMA-targeted therapies. In some aspects, B-cell proliferative disorders (e.g., MM) are refractory to daratumumab.

[0240] The step of administering a bispecific antibody (e.g., civastastatin) that binds to FcRH5 and CD3 can makeThe administration regimen described herein shall be used.

[0241] III. Diagnostic Methods

[0242] The present invention provides a method for diagnosing (e.g., identifying or classifying) a subject suffering from MM who will benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3. This invention is based in part on the following findings: (i) the presence of certain levels of one or more specific cell types in a sample (e.g., bone marrow or blood) from the subject and / or (ii) the presence of certain clinical characteristics of the subject (e.g., the number of prior lines of treatment) can be used to (i) identify the subject as a subject who will benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 and / or (ii) classify the subject into one of three immune profiles: 1) an activated immune profile; 2) an inactivated immune profile; or 3) an inhibited immune profile, thereby finding that subjects classified as having an activated or inactivated immune profile benefit from treatment with a bispecific antibody compared to subjects classified as having an inhibited immune profile.

[0243] A. Identification Method

[0244] In some aspects, the present invention provides a method for identifying a subject with MM as a subject who will benefit from treatment comprising a bispecific antibody that binds to FcRH5 and CD3. Subjects may benefit from treatment when they exhibit a relative increase in overall survival (OS), objective response rate (ORR), progression-free survival (PFS), complete response (CR), partial response (PR), or a combination thereof. The method optionally includes the steps of determining the level of one or more cell types listed in Tables 3, 4, 6, 7, 8, and / or 9 in a sample from the subject and / or determining one or more of the characteristics listed in Table 5. The sample from the subject may be from the subject's bone marrow and / or blood.

[0245] Flow cytometry (FC), mass spectrometry (MS), immunohistochemistry (IHC), DNA sequencing (DNA-seq), RNA sequencing (RNA-seq), quantitative PCR (qPCR), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), multiplex qPCR or RT-qPCR, microarray analysis, gene expression serial analysis (SAGE), MassARRAY® technology, in situ hybridization (ISH), or a combination thereof may be used to determine the level of one or more cell types in a sample (e.g., bone marrow or blood).

[0246] The identification method may include the step of identifying a subject as a subject who will benefit from treatment comprising a bispecific antibody that binds to FcRH5 and CD3. If the subject has reduced levels compared to reference levels (Tables 3 and 6)A subject may be identified as a subject who will benefit from treatment comprising a bispecific antibody binding to FcRH5 and CD3 if the level of one or more cell types listed in Table 8 and / or Table 9 is increased compared to a reference level; and / or the number of one or more of the characteristics listed in Table 5 is lower compared to a reference number. In some aspects, the reference level is the pre-assigned reference level listed in Table 14. In some aspects, the reference number is the pre-assigned reference number listed in Table 15.

[0247] In some aspects of the invention, a subject may be identified as a subject who will benefit from treatment comprising a bispecific antibody binding to FcRH5 and CD3 if a sample from the subject's bone marrow has a decreased level of one or more cell types listed in Table 3 and / or Table 6 compared to a reference level. In some aspects of the invention, if a sample from a subject's bone marrow has an increased level of one or more cell types listed in Tables 4 and / or 7 compared to a reference level, the subject may be identified as a subject who will benefit from treatment comprising a bispecific antibody binding to FcRH5 and CD3.

[0248] In some aspects of the invention, if a sample from a subject's blood (e.g., whole blood, plasma, or serum) has a decreased level of one or more cell types listed in Tables 3 and / or 8 compared to a reference level, the subject may be identified as a subject who will benefit from treatment comprising a bispecific antibody binding to FcRH5 and CD3. In some aspects of the invention, if a sample from a subject's blood (e.g., whole blood, plasma, or serum) has an increased level of one or more cell types listed in Tables 4 and / or 9 compared to a reference level, the subject may be identified as a subject who will benefit from treatment comprising a bispecific antibody binding to FcRH5 and CD3.

[0249] The sample (e.g., baseline sample) has one or more of the following increased levels compared to the reference level: one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen ... 43 species, 44 species, 45 species, 46 species, 47 species, 48 ​​speciesSubjects with MM (multiple, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, or all 85) cell types at a level (e.g., presence or percentage) can be identified as subjects unlikely to benefit from treatment with a bispecific antibody (e.g., civastanab) that binds to FcRH5 and CD3. For example, in samples from subjects, the levels of the cell types listed in Table 3 may increase by approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, and 57% compared to reference levels. Approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, approximately 100%, approximately 101%, approximately 102%, approximately 103%, approximately 104%, approximately 105%, approximately 106%, approximately 107%, approximately 108%, approximately 109%, approximately 110%, approximately 111%, approximately 112%, approximately 113%, approximately114%, approximately 115%, approximately 116%, approximately 117%, approximately 118%, approximately 119%, approximately 120%, approximately 121%, approximately 122%, approximately 123%, approximately 124%, approximately 125%, approximately 126%, approximately 127%, approximately 128%, approximately 129%, approximately 130%, approximately 131%, approximately 132%, approximately 133%, approximately 134%, approximately 135%, approximately 136%, approximately 137%, approximately 138%, approximately 139%, approximately 140%, approximately 141%, approximately 142%, approximately 143%, approximately 144%, approximately 145%, approximately 146%, approximately 147%, approximately 148%, approximately 149%, approximately 150%, approximately 151%, approximately 152%. Approximately 153%, approximately 154%, approximately 155%, approximately 156%, approximately 157%, approximately 158%, approximately 159%, approximately 160%, approximately 161%, approximately 162%, approximately 163%, approximately 164%, approximately 165%, approximately 166%, approximately 167%, approximately 168%, approximately 169%, approximately 170%, approximately 171%, approximately 172%, approximately 173%, approximately 174%, approximately 175%, approximately 176%, approximately 177%, approximately 178%, approximately 179%, approximately 180%, approximately 181%, approximately 182%, approximately 183%, approximately 184%, approximately 185%, approximately 186%, approximately 187%, approximately 188%, approximately 189%, approximately 190%, approximately 191%, approximately 192%, approximately 193%, approximately 194%, approximately 195%, approximately 196%, approximately 197%, approximately 198%, approximately 199% Or approximately 200%, suggesting that the subject is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., civastimab).

[0250] The sample (e.g., baseline sample) has one or more of the following reduced levels compared to the reference level (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, eleven, twelve, thirteen, thirteen, seventeen, eighteen, nineteen, ten, eleven, eleven, thirteen ... 48 kinds, 49 kinds, 50 kinds, 51 kinds, 52 kinds, 53 kinds, 54 kinds, 55 kinds, 56 kinds, 57 kinds, 58 kinds, 59 kindsSubjects with MM at levels (e.g., presence or percentage) of cell types (60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, or all 85) can be identified as subjects who may benefit from treatment with a bispecific antibody binding to FcRH5 and CD3 (e.g., civastimab). For example, in samples from subjects, Table 3 The levels of cell types may be reduced by approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, and so on, compared to reference levels. 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99% Or approximately 100%, thus indicating that the subject may benefit from treatment with a bispecific antibody (e.g., civastanab) that binds to FcRH5 and CD3.

[0251] The sample (e.g., baseline sample) has an increase in one or more of the levels listed in Table 4 compared to the reference level.Subjects with a certain level (e.g., presence or percentage) of MM cell types (e.g., one, two, three, four, five, six, seven, or all eight) can be identified as subjects who may benefit from treatment with a bispecific antibody (e.g., civastastatab) that binds to FcRH5 and CD3. For example, in samples from subjects, the levels of cell types in Table 4 may be increased by approximately 1%, approximately 2%, approximately 3%, approximately 4%, approximately 5%, approximately 6%, and approximately 7% compared to reference levels. Approximately 8%, approximately 9%, approximately 10%, approximately 11%, approximately 12%, approximately 13%, approximately 14%, approximately 15%, approximately 16%, approximately 17%, approximately 18%, approximately 19%, approx...

Claims

1. A method of treating a subject with multiple myeloma (MM), the method comprising administering to the subject a bispecific antibody that binds to Fc receptor homolog 5 (FcRH5) and differentiation cluster 3 (CD3), wherein prior to administering the bispecific antibody: (a) Samples from the subject have been determined to have reduced levels of one or more cell types listed in Table 3 compared to reference levels; (b) Samples from the subject have been determined to have increased levels of one or more cell types listed in Table 4 compared to reference levels; and / or (c) It has been determined that the subject has a lower number of one or more of the characteristics listed in Table 5 compared to the reference number.

2. The method according to claim 1, wherein: (a) The sample from the subject has been determined to have a reduced level of one or more cell types listed in Table 6 compared to the reference level; and / or (b) The sample from the subject has been determined to have increased levels of one or more cell types listed in Table 7 compared to the reference level.

3. The method according to claim 1, wherein: (a) The sample from the subject has been determined to have a reduced level of one or more cell types listed in Table 8 compared to the reference level; and / or (b) The sample from the subject has been determined to have increased levels of one or more cell types listed in Table 9 compared to the reference level.

4. A method for treating a subject suffering from MM, the method comprising: (I) Determine: (a) Levels of one or more cell types listed in Table 3 and / or Table 4 in samples from the subjects; and / or (b) One or more of the characteristics listed in Table 5 of the subject; (II) Identify the subjects as those who will benefit from treatment including a bispecific antibody binding to FcRH5 and CD3, wherein: (a) The sample from the subject had a reduced level of one or more cell types listed in Table 3 compared to the reference level; (b) The sample from the subject has an increased level of one or more cell types listed in Table 4 compared to the reference level; and / or (c) The subject has a lower number of one or more of the characteristics listed in Table 5 compared to the reference number. This identifies the subjects as those who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3; and (III) Administer the treatment to the subject comprising the bispecific antibody that binds to FcRH5 and CD3.

5. The method according to claim 4, wherein the method comprises: (I) Determine the levels of one or more cell types listed in Table 6 and / or Table 7 in samples from the subject; as well as (II) Identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3, wherein: (a) The sample from the subject has a reduced level of one or more cell types listed in Table 6 compared to the reference level; and / or (b) The sample from the subject had an increased level of one or more cell types listed in Table 7 compared to the reference level. Thus, the subject was identified as a subject who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3.

6. The method of claim 4, wherein the method comprises: (I) Determine the levels of one or more cell types listed in Table 8 and / or Table 9 in samples from the subject; as well as (II) Identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3, wherein: (a) The sample from the subject has a reduced level of one or more cell types listed in Table 8 compared to the reference level; and / or (b) The sample from the subject had increased levels of one or more cell types listed in Table 9 compared to the reference level. Thus, the subject was identified as a subject who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3.

7. A method for identifying a subject with MM as a subject who will benefit from treatment comprising a bispecific antibody binding to FcRH5 and CD3, the method comprising: (I) Determine: (a) Levels of one or more cell types listed in Table 3 and / or Table 4 in samples from the subjects; and / or (b) One or more of the characteristics listed in Table 5 of the subject; and (II) Identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3, wherein: (a) The sample from the subject had a reduced level of one or more cell types listed in Table 3 compared to the reference level; (b) The sample from the subject has an increased level of one or more cell types listed in Table 4 compared to the reference level; and / or (c) The subject has a lower number of one or more of the characteristics listed in Table 5 compared to the reference number. Thus, the subject was identified as a subject who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3.

8. The method of claim 7, wherein the method comprises: (I) Determine the levels of one or more cell types listed in Table 6 and / or Table 7 in samples from the subject; as well as (II) Identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3, wherein: (a) The sample from the subject has a reduced level of one or more cell types listed in Table 6 compared to the reference level; and / or (b) The sample from the subject had an increased level of one or more cell types listed in Table 7 compared to the reference level. Thus, the subject was identified as a subject who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3.

9. The method of claim 7, wherein the method comprises: (I) Determine the levels of one or more cell types listed in Table 8 and / or Table 9 in samples from the subject; as well as (II) Identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3, wherein: (a) The sample from the subject has a reduced level of one or more cell types listed in Table 8 compared to the reference level; and / or (b) The sample from the subject had increased levels of one or more cell types listed in Table 9 compared to the reference level. Thus, the subject was identified as a subject who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3.

10. The method according to any one of claims 7 to 9, wherein the method further comprises administering the treatment comprising the bispecific antibody binding to FcRH5 and CD3 to the subject.

11. The method according to any one of claims 1, 2, 4, 5, 7, 8 and 10, wherein the sample from the subject is a bone marrow sample.

12. The method according to any one of claims 1, 3, 4, 6, 7, 9 and 10, wherein the sample from the subject is a blood sample.

13. The method according to any one of claims 4 to 12, wherein determining the level of one or more cell types comprises flow cytometry (FC), mass spectrometry (MS), immunohistochemistry (IHC), DNA sequencing (DNA-seq), RNA sequencing (RNA-seq), quantitative PCR (qPCR), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), multiplex qPCR or RT-qPCR, microarray analysis, gene expression serial analysis (SAGE), MassARRAY® technology, in situ hybridization (ISH), or a combination thereof.

14. The method according to any one of claims 4 to 13, wherein determining the level of the one or more cell types includes FC.

15. The method according to any one of claims 1 to 14, wherein the reference level is the mean Z-score of one or more cell types in a population of subjects with the MM.

16. The method according to any one of claims 1 to 15, wherein the reference number is the average of one or more characteristics listed in Table 5 in a population of subjects suffering from the MM.

17. The method according to any one of claims 4 to 16, wherein benefit from the treatment includes a relative increase in overall survival (OS), objective response rate (ORR), progression-free survival (PFS), complete response (CR), partial response (PR), or a combination thereof.

18. The method of claim 17, wherein the benefit from the treatment includes a relative increase in OS.

19. The method according to any one of claims 1 to 18, wherein the MM is relapsed or refractory (R / R) MM.

20. The method according to any one of claims 1 to 19, wherein the bispecific antibody binding to FcRH5 and CD3 comprises an anti-FcRH5 arm containing a first binding domain comprising six hypervariable regions (HVRs): (a) HVR-H1, which contains the amino acid sequence of RFGVH (SEQ ID NO: 1); (b) HVR-H2, which contains the amino acid sequence VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) HVR-H3, which contains the amino acid sequence of HYYGSSDYALDN (SEQ ID NO:3); (d) HVR-L1, which contains the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) HVR-L2, which contains the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (f) HVR-L3, which contains the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6).

21. The method according to any one of claims 1 to 20, wherein the bispecific antibody binding to FcRH5 and CD3 comprises an anti-FcRH5 arm containing a first binding domain, the first binding domain comprising (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 8; or (c) the VH domain as in (a) and the VL domain as in (b).

22. The method of claim 21, wherein the first binding domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 7; and a VL domain comprising the amino acid sequence of SEQ ID NO:

8.

23. The method according to any one of claims 1 to 22, wherein the bispecific antibody binding to FcRH5 and CD3 comprises an anti-CD3 arm containing a second binding domain, the second binding domain comprising the following six HVRs: (a) HVR-H1, which contains the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) HVR-H2, which contains the amino acid sequence WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) HVR-H3, which contains the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11); (d) HVR-L1, which contains the amino acid sequence KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2, which contains the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) HVR-L3, which contains the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

24. The method according to any one of claims 1 to 23, wherein the bispecific antibody binding to FcRH5 and CD3 comprises an anti-CD3 arm containing a second binding domain comprising (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 16; or (c) the VH domain as in (a) and the VL domain as in (b).

25. The method of claim 24, wherein the second binding domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 15; and a VL domain comprising the amino acid sequence of SEQ ID NO:

16.

26. The method according to any one of claims 1 to 25, wherein the bispecific antibody binding to FcRH5 and CD3 comprises: an anti-FcRH5 arm comprising a heavy chain polypeptide (H1) and a light chain polypeptide (L1); and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), wherein: (a) H1 contains the amino acid sequence of SEQ ID NO: 35; (b) L1 contains the amino acid sequence of SEQ ID NO: 36; (c) H2 contains the amino acid sequence of SEQ ID NO: 37; and (d) L2 contains the amino acid sequence of SEQ ID NO:

38.

27. The method according to any one of claims 1 to 26, wherein the bispecific antibody binding to FcRH5 and CD3 comprises a deglycosylation site mutation.

28. The method of claim 27, wherein the deglycosylation site mutation reduces the effector function of the bispecific antibody.

29. The method according to claim 27 or 28, wherein the deglycosylation site mutation is a substitution mutation.

30. The method of claim 29, wherein the bispecific antibody binding to FcRH5 and CD3 comprises a substitution mutation in the Fc region that reduces effector function.

31. The method according to any one of claims 1 to 30, wherein the bispecific antibody binding to FcRH5 and CD3 is a monoclonal antibody.

32. The method according to any one of claims 1 to 31, wherein the bispecific antibody binding to FcRH5 and CD3 is a chimeric antibody.

33. The method according to any one of claims 1 to 32, wherein the bispecific antibody binding to FcRH5 and CD3 is a humanized antibody.

34. The method according to any one of claims 1 to 25 and 27 to 33, wherein the bispecific antibody binding to FcRH5 and CD3 is an antibody fragment.

35. The method of claim 34, wherein the antibody fragment is selected from the group consisting of: Fab, Fab'-SH, Fv, scFv and (Fab')2 fragments.

36. The method according to any one of claims 1 to 33, wherein the bispecific antibody binding to FcRH5 and CD3 is a full-length antibody.

37. The method according to any one of claims 1 to 33 and 36, wherein the bispecific antibody binding to FcRH5 and CD3 is an IgG antibody.

38. The method of claim 37, wherein the IgG antibody is an IgG1 antibody.

39. The method according to any one of claims 1 to 33 and 36 to 38, wherein the bispecific antibody binding to FcRH5 and CD3 comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH11) domain, a first CH2 (CH21) domain, a first CH3 (CH31) domain, a second CH1 (CH12) domain, a second CH2 (CH22) domain, and a second CH3 (CH32) domain.

40. The method of claim 39, wherein at least one of the one or more heavy chain constant structural domains is paired with another heavy chain constant structural domain.

41. The method according to claim 39 or 40, wherein the CH31 structural domain and the CH32 structural domain each include a protrusion or a cavity, and wherein the protrusion or the cavity in the CH31 structural domain is respectively positioned in the cavity or the protrusion in the CH32 structural domain.

42. The method of claim 41, wherein the CH31 structural domain and the CH32 structural domain are connected at the interface between the protrusion and the cavity.

43. The method according to any one of claims 39 to 42, wherein the CH21 structural domain and the CH22 structural domain each comprise a protrusion or a cavity, and wherein the protrusion or the cavity in the CH21 structural domain is respectively positioned in the cavity or the protrusion in the CH22 structural domain.

44. The method of claim 43, wherein the CH21 structural domain and the CH22 structural domain are connected at the interface between the protrusion and the cavity.

45. The method of claim 42, wherein the anti-FcRH5 arm includes the protrusion and the anti-CD3 arm includes the cavity.

46. ​​The method of claim 45, wherein the anti-FcRH5 arm comprises a protrusion containing a T366W amino acid substitution mutation (EU number), and the anti-CD3 arm comprises a cavity containing T366S, L368A, and Y407V amino acid substitution mutations (EU number).

47. The method according to any one of claims 1 to 33 and 36 to 46, wherein the bispecific antibody binding to FcRH5 and CD3 is civastana monoclonal antibody.

48. The method according to any one of claims 1 to 47, wherein the bispecific antibody binding to FcRH5 and CD3 is administered to the subject as a single therapy.

49. The method according to any one of claims 1 to 47, wherein the bispecific antibody binding to FcRH5 and CD3 is administered to the subject as a combination therapy.

50. The method of claim 49, wherein the bispecific antibody binding to FcRH5 and CD3 is administered to the subject simultaneously with one or more additional therapeutic agents.

51. The method of claim 49, wherein the bispecific antibody binding to FcRH5 and CD3 is administered to the subject prior to administration of one or more additional therapeutic agents.

52. The method of claim 49, wherein the bispecific antibody binding to FcRH5 and CD3 is administered to the subject after administration of one or more additional therapeutic agents.

53. The method of claim 52, wherein the one or more additional therapeutic agents comprise an effective amount of tocilizumab.

54. The method of claim 53, wherein tocilizumab is administered to the subject via intravenous infusion.

55. The method according to claim 53 or 54, wherein: (a) The subject weighed ≥ 100 kg and was administered tocilizumab at a dose of 800 mg; (b) The subject weighed ≥ 30 kg and < 100 kg, and tocilizumab was administered to the subject at a dose of 8 mg / kg; or (c) The subject weighs < 30 kg and is given tocilizumab at a dose of 12 mg / kg.

56. The method according to any one of claims 53 to 55, wherein tocilizumab is administered to the subject 2 hours prior to administration of the bispecific antibody.

57. The method according to any one of claims 50 to 52, wherein the one or more additional therapeutic agents comprise effective amounts of corticosteroids, analgesics and antipyretics, antihistamines, antimyeloma agents, PD-1 axis binding antagonists, antiCD38 therapeutic agents, immunomodulatory (IMiD) agents, cereblon E3 ligase modulators (CELMoD), proteasome inhibitors (PI), CAR-T therapy, antitumor agents, chemotherapeutic agents, growth inhibitors, antiangiogenic agents, radiotherapy, cytotoxic agents, cell-based therapies, or combinations thereof.

58. The method according to any one of claims 1 to 57, wherein the bispecific antibody binding to FcRH5 and CD3 is administered to the subject via intravenous infusion.

59. The method according to any one of claims 1 to 57, wherein the bispecific antibody binding to FcRH5 and CD3 is administered subcutaneously to the subject.

60. The method of any one of claims 1 to 59, wherein the subject has a cytokine release syndrome (CRS) event, and the method further comprises treating the symptoms of the CRS event while discontinuing treatment with the bispecific antibody binding to FcRH5 and CD3.

61. The method of claim 60, wherein the method further comprises administering an effective amount of tocilizumab to the subject to treat the CRS event.

62. The method of claim 61, wherein tocilizumab is administered intravenously to the subject in a single dose of about 8 mg / kg.

63. The method of claim 61 or 62, wherein the CRS event does not subside or worsen within 24 hours of treatment of the symptoms of the CRS event, the method further comprising administering one or more additional doses of tocilizumab to the subject to manage the CRS event.

64. The method of claim 63, wherein the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 8 mg / kg.

65. A method for classifying the multiple myelodysplastic syndrome (MM) of a subject, the method comprising: (I) Determine the levels of CD8+ T cells, Treg cells, and CD8+ TN cells in samples from the subjects, and (II) Based on the levels of the CD8+ T cells, Treg cells, and CD8+ TN cells, the subject's MM is assigned to one of the following immune profiles: (a) Activated immune profile; (b) Inactivated immune profile; or (c) Suppressed immune spectrum, The subject's MM was thus classified.

66. The method of claim 65, wherein: (I) The activated immune spectrum includes: In the samples from the subjects, compared with reference levels, (a) there was an increase in CD8+ T cell levels; (b) Decreased Treg cell levels; and (c) Decreased CD8+ TN cell levels, (II) The inactivated immune spectrum includes: In the samples from the subjects, compared with reference levels, (a) the level of CD8+ T cells was reduced; (b) Increased Treg cell levels; and (c) Increased CD8+ TN cell levels; or (III) The suppressed immune spectrum includes: In the samples from the subjects, compared with reference levels, (a) there was an increase in CD8+ T cell levels; (b) Increased Treg cell levels; and (c) Decreased CD8+ TN cell levels.

67. The method of claim 65 or 66, wherein the immune spectrum is assigned via similarity network fusion (SNF) analysis.

68. A bispecific antibody that binds to FcRH5 and CD3, used to treat a subject with MM, wherein prior to administration of said bispecific antibody: (a) Samples from the subject have been determined to have reduced levels of one or more cell types listed in Table 1 compared to reference levels; (b) Samples from the subject have been determined to have increased levels of one or more cell types listed in Table 2 compared to reference levels; and / or (c) It has been determined that the subject has a lower number of one or more of the characteristics listed in Table 3 compared to the reference number.

69. The bispecific antibody binding to FcRH5 and CD3 as described in claim 68, wherein: (a) The sample from the subject has been determined to have a reduced level of one or more cell types listed in Table 4 compared to the reference level; and / or (b) The sample from the subject has been determined to have increased levels of one or more cell types listed in Table 5 compared to the reference level.

70. The bispecific antibody binding to FcRH5 and CD3 as described in claim 68, wherein: (a) The sample from the subject has been determined to have a reduced level of one or more cell types listed in Table 6 compared to the reference level; and / or (b) The sample from the subject has been determined to have increased levels of one or more cell types listed in Table 7 compared to the reference level.

71. A bispecific antibody that binds to FcRH5 and CD3, used to treat a subject with multiple myeloma (MM), said treatment comprising: (I) Determine: (a) Levels of one or more cell types listed in Table 1 and / or Table 2 in samples from the subject; and / or (b) One or more of the characteristics listed in Table 3 of the subject; (II) Identify the subjects as those who will benefit from treatment including a bispecific antibody binding to FcRH5 and CD3, wherein: (a) The sample from the subject had a reduced level of one or more cell types listed in Table 1 compared to a reference level; (b) The sample from the subject has an increased level of one or more cell types listed in Table 2 compared to the reference level; and / or (c) The subject has a lower number of one or more of the characteristics listed in Table 3 compared to the reference number. This identifies the subjects as those who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3; and (III) Administer the treatment to the subject comprising the bispecific antibody that binds to FcRH5 and CD3.

72. The bispecific antibody binding to FcRH5 and CD3 as described in claim 71, wherein the treatment comprises: (I) Determine the levels of one or more cell types listed in Table 4 and / or Table 5 in samples from the subject; as well as (II) Identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3, wherein: (a) The sample from the subject has a reduced level of one or more cell types listed in Table 4 compared to the reference level; and / or (b) The sample from the subject had an increased level of one or more cell types listed in Table 5 compared to the reference level. Thus, the subject was identified as a subject who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3.

73. The bispecific antibody binding to FcRH5 and CD3 as described in claim 71, wherein the treatment comprises: (I) Determine the levels of one or more cell types listed in Table 6 and / or Table 7 in samples from the subject; as well as (II) Identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3, wherein: (a) The sample from the subject has a reduced level of one or more cell types listed in Table 6 compared to the reference level; and / or (b) The sample from the subject had an increased level of one or more cell types listed in Table 7 compared to the reference level. Thus, the subject was identified as a subject who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3.

74. A bispecific antibody binding to FcRH5 and CD3, used in a method for identifying a subject with MM as a subject who would benefit from treatment including the bispecific antibody binding to FcRH5 and CD3, the method comprising: (I) Determine: (a) Levels of one or more cell types listed in Table 1 and / or Table 2 in samples from the subject; and / or (b) One or more of the characteristics listed in Table 3 of the subject; and (II) Identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3, wherein: (a) The sample from the subject had a reduced level of one or more cell types listed in Table 1 compared to a reference level; (b) The sample from the subject has an increased level of one or more cell types listed in Table 2 compared to the reference level; and / or (c) The subject has a lower number of one or more of the characteristics listed in Table 3 compared to the reference number. Thus, the subject was identified as a subject who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3.

75. The bispecific antibody binding to FcRH5 and CD3 as described in claim 74, wherein the method comprises: (I) Determine the levels of one or more cell types listed in Table 4 and / or Table 5 in samples from the subject; as well as (II) Identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3, wherein: (a) The sample from the subject has a reduced level of one or more cell types listed in Table 4 compared to the reference level; and / or (b) The sample from the subject had an increased level of one or more cell types listed in Table 5 compared to the reference level. Thus, the subject was identified as a subject who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3.

76. The bispecific antibody binding to FcRH5 and CD3 as described in claim 74, wherein the method comprises: (I) Determine the levels of one or more cell types listed in Table 6 and / or Table 7 in samples from the subject; as well as (II) Identifying the subject as a subject who will benefit from the treatment comprising the bispecific antibody binding to FcRH5 and CD3, wherein: (a) The sample from the subject has a reduced level of one or more cell types listed in Table 6 compared to the reference level; and / or (b) The sample from the subject had an increased level of one or more cell types listed in Table 7 compared to the reference level. Thus, the subject was identified as a subject who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3.

77. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 74 to 76, wherein the method further comprises administering the treatment comprising the bispecific antibody binding to FcRH5 and CD3 to the subject.

78. A bispecific antibody that binds to FcRH5 and CD3, used to treat a subject with MM, said treatment comprising the step of classifying said subject, said classification step comprising: (I) Determine the levels of CD8+ T cells, Treg cells, and CD8+ TN cells in samples from the subjects, and (II) Based on the levels of the CD8+ T cells, Treg cells, and CD8+ TN cells, the subject's MM is assigned to one of the following immune profiles: (a) Activated immune profile; (b) Inactivated immune profile; or (c) Suppressed immune spectrum, The subject's MM was thus classified.

79. The bispecific antibody binding to FcRH5 and CD3 as described in claim 78, wherein: (I) The activated immune spectrum includes: In the samples from the subjects, compared with reference levels, (a) there was an increase in CD8+ T cell levels; (b) Decreased Treg cell levels; and (c) Decreased CD8+ TN cell levels, (II) The inactivated immune spectrum includes: In the samples from the subjects, compared with reference levels, (a) the level of CD8+ T cells was reduced; (b) Increased Treg cell levels; and (c) Increased CD8+ TN cell levels; or (III) The suppressed immune spectrum includes: In the samples from the subjects, compared with reference levels, (a) there was an increase in CD8+ T cell levels; (b) Increased Treg cell levels; and (c) Decreased CD8+ TN cell levels.

80. The bispecific antibody binding to FcRH5 and CD3 as described in claim 78 or 79, wherein the immune spectrum is distributed via SNF.

81. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 68, 69, 71, 72, 74, 75 and 77 to 80, wherein the sample from the subject is a bone marrow sample.

82. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 68, 69, 71, 72, 74, 75 and 77 to 80, wherein the sample from the subject is a blood sample.

83. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 69 to 82, wherein determining the level of the one or more cell types comprises flow cytometry (FC), mass spectrometry (MS), immunohistochemistry (IHC), DNA sequencing (DNA-seq), RNA sequencing (RNA-seq), quantitative PCR (qPCR), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), multiplex qPCR or RT-qPCR, microarray analysis, gene expression serial analysis (SAGE), MassARRAY® technology, in situ hybridization (ISH), or a combination thereof.

84. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 71 to 83, wherein determining the level of the one or more cell types includes FC.

85. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 68 to 84, wherein the reference level is the mean Z-score of one or more cell types in a population of subjects with said MM.

86. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 68 to 85, wherein the reference number is the average of one or more characteristics listed in Table 3 in a population of subjects with said MM.

87. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 71 to 86, wherein benefit from said treatment includes a relative increase in overall survival (OS), objective response rate (ORR), progression-free survival (PFS), complete response (CR), partial response (PR), or a combination thereof.

88. The bispecific antibody binding to FcRH5 and CD3 as described in claim 87, wherein the benefit from the treatment includes a relative increase in OS.

89. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 68 to 88, wherein the MM is relapsed or refractory (R / R) MM.

90. The bispecific antibody binding to FcRH5 and CD3 as claimed in any one of claims 68 to 89, wherein the bispecific antibody binding to FcRH5 and CD3 comprises an anti-FcRH5 arm containing a first binding domain comprising six hypervariable regions (HVRs): (a) HVR-H1, which contains the amino acid sequence of RFGVH (SEQ ID NO: 1); (b) HVR-H2, which contains the amino acid sequence VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) HVR-H3, which contains the amino acid sequence of HYYGSSDYALDN (SEQ ID NO:3); (d) HVR-L1, which contains the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) HVR-L2, which contains the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (f) HVR-L3, which contains the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6).

91. The bispecific antibody binding to FcRH5 and CD3 as claimed in any one of claims 68 to 90, wherein the bispecific antibody binding to FcRH5 and CD3 comprises an anti-FcRH5 arm containing a first binding domain comprising (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:8; or (c) the VH domain as in (a) and the VL domain as in (b).

92. The bispecific antibody binding to FcRH5 and CD3 as claimed in claim 91, wherein the first binding domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 7; and a VL domain comprising the amino acid sequence of SEQ ID NO:

8.

93. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68 to 92, wherein the bispecific antibody binding to FcRH5 and CD3 comprises an anti-CD3 arm containing a second binding domain comprising six HVRs: (a) HVR-H1, which contains the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) HVR-H2, which contains the amino acid sequence WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) HVR-H3, which contains the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11); (d) HVR-L1, which contains the amino acid sequence KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2, which contains the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) HVR-L3, which contains the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

94. The bispecific antibody binding to FcRH5 and CD3 as claimed in any one of claims 68 to 93, wherein the bispecific antibody binding to FcRH5 and CD3 comprises an anti-CD3 arm containing a second binding domain comprising (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 16; or (c) the VH domain as in (a) and the VL domain as in (b).

95. The bispecific antibody binding to FcRH5 and CD3 as described in claim 94, wherein the second binding domain comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 15; and a VL domain comprising the amino acid sequence of SEQ ID NO:

16.

96. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68 to 95, wherein the bispecific antibody binding to FcRH5 and CD3 comprises: an anti-FcRH5 arm comprising a heavy chain polypeptide (H1) and a light chain polypeptide (L1); and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), and wherein: (a) H1 contains the amino acid sequence of SEQ ID NO: 35; (b) L1 contains the amino acid sequence of SEQ ID NO: 36; (c) H2 contains the amino acid sequence of SEQ ID NO: 37; and (d) L2 contains the amino acid sequence of SEQ ID NO:

38.

97. The bispecific antibody binding to FcRH5 and CD3 as claimed in any one of claims 68 to 96, wherein the bispecific antibody binding to FcRH5 and CD3 comprises a deglycosylation site mutation.

98. The bispecific antibody binding to FcRH5 and CD3 as described in claim 97, wherein the deglycosylation site mutation reduces the effector function of the bispecific antibody.

99. The bispecific antibody binding to FcRH5 and CD3 as described in claim 97 or 98, wherein the deglycosylation site mutation is a substitution mutation.

100. The bispecific antibody binding to FcRH5 and CD3 as described in claim 99, wherein the bispecific antibody binding to FcRH5 and CD3 comprises a substitution mutation in the Fc region that reduces effector function.

101. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68 to 100, wherein the bispecific antibody binding to FcRH5 and CD3 is a monoclonal antibody.

102. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68 to 101, wherein the bispecific antibody binding to FcRH5 and CD3 is a chimeric antibody.

103. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68 to 102, wherein the bispecific antibody binding to FcRH5 and CD3 is a humanized antibody.

104. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 68 to 95 and 97 to 103, wherein the bispecific antibody binding to FcRH5 and CD3 is an antibody fragment.

105. The bispecific antibody binding to FcRH5 and CD3 as described in claim 104, wherein the antibody fragment is selected from the group consisting of: Fab, Fab'-SH, Fv, scFv and (Fab')2 fragments.

106. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68 to 103, wherein the bispecific antibody binding to FcRH5 and CD3 is a full-length antibody.

107. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 68 to 103 and 106, wherein the bispecific antibody binding to FcRH5 and CD3 is an IgG antibody.

108. The bispecific antibody binding to FcRH5 and CD3 as described in claim 107, wherein the IgG antibody is an IgG1 antibody.

109. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 68 to 103 and 106 to 108, wherein the bispecific antibody binding to FcRH5 and CD3 comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH11) domain, a first CH2 (CH21) domain, a first CH3 (CH31) domain, a second CH1 (CH12) domain, a second CH2 (CH22) domain, and a second CH3 (CH32) domain.

110. The bispecific antibody for binding to FcRH5 and CD3 as described in claim 109, wherein at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

111. The bispecific antibody binding to FcRH5 and CD3 as claimed in claim 109 or 110, wherein the CH31 domain and the CH32 domain each comprise a protrusion or a cavity, and wherein the protrusion or cavity in the CH31 domain is respectively positioned within the cavity or protrusion in the CH32 domain.

112. The bispecific antibody binding to FcRH5 and CD3 as claimed in claim 111, wherein the CH31 domain and the CH32 domain are connected at the interface between the protrusion and the cavity.

113. The bispecific antibody binding to FcRH5 and CD3 as claimed in any one of claims 109 to 112, wherein the CH21 domain and the CH22 domain each comprise a protrusion or a cavity, and wherein the protrusion or cavity in the CH21 domain is respectively positioned within the cavity or protrusion in the CH22 domain.

114. The bispecific antibody binding to FcRH5 and CD3 as claimed in claim 113, wherein the CH21 domain and the CH22 domain are connected at the interface between the protrusion and the cavity.

115. The bispecific antibody binding to FcRH5 and CD3 as described in claim 112, wherein the anti-FcRH5 arm includes the protrusion and the anti-CD3 arm includes the cavity.

116. The bispecific antibody for binding to FcRH5 and CD3 as claimed in claim 115, wherein the anti-FcRH5 arm comprises a protrusion containing a T366W amino acid substitution mutation (EU number), and the anti-CD3 arm comprises a cavity containing T366S, L368A, and Y407V amino acid substitution mutations (EU number).

117. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 68 to 103 and 106 to 116, wherein the bispecific antibody binding to FcRH5 and CD3 is civastastat.

118. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68 to 117, wherein the bispecific antibody binding to FcRH5 and CD3 is formulated for administration to the subject as a single therapy.

119. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68 to 117, wherein the bispecific antibody binding to FcRH5 and CD3 is formulated for administration to the subject as a combination therapy.

120. The bispecific antibody binding to FcRH5 and CD3 as described in claim 119, wherein the bispecific antibody binding to FcRH5 and CD3 is formulated to be administered to the subject simultaneously with one or more additional therapeutic agents.

121. The bispecific antibody binding to FcRH5 and CD3 as described in claim 119, wherein the bispecific antibody binding to FcRH5 and CD3 is formulated to be administered to the subject prior to administration of one or more additional therapeutic agents.

122. The bispecific antibody binding to FcRH5 and CD3 as described in claim 119, wherein the bispecific antibody binding to FcRH5 and CD3 is formulated to be administered to the subject after administration of one or more additional therapeutic agents.

123. The bispecific antibody binding to FcRH5 and CD3 as described in claim 122, wherein the one or more additional therapeutic agents comprise an effective amount of tocilizumab.

124. The bispecific antibody binding to FcRH5 and CD3 as described in claim 123, wherein tocilizumab is administered to the subject via intravenous infusion.

125. The bispecific antibody binding to FcRH5 and CD3 as described in claim 123 or 124, wherein: (a) The subject weighed ≥ 100 kg and was administered tocilizumab at a dose of 800 mg; (b) The subject weighed ≥ 30 kg and < 100 kg, and tocilizumab was administered to the subject at a dose of 8 mg / kg; or (c) The subject weighs < 30 kg and is given tocilizumab at a dose of 12 mg / kg.

126. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 123 to 125, wherein tocilizumab is administered to the subject 2 hours prior to administration of the bispecific antibody.

127. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 120 to 122, wherein the one or more additional therapeutic agents comprise effective amounts of corticosteroids, analgesics and antipyretics, antihistamines, antimyeloma agents, PD-1 axis binding antagonists, antiCD38 therapeutic agents, immunomodulatory (IMiD) agents, cereblon E3 ligase modulators (CELMoD), proteasome inhibitors (PI), CAR-T therapy, antitumor agents, chemotherapeutic agents, growth inhibitors, antiangiogenic agents, radiotherapy, cytotoxic agents, cell-based therapies, or combinations thereof.

128. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68 to 127, wherein the bispecific antibody binding to FcRH5 and CD3 is formulated for administration to the subject by intravenous infusion.

129. The bispecific antibody binding to FcRH5 and CD3 as described in any one of claims 68 to 127, wherein the bispecific antibody binding to FcRH5 and CD3 is formulated for subcutaneous administration to the subject.

130. The bispecific antibody binding to FcRH5 and CD3 used according to any one of claims 68 to 129, wherein the subject has a cytokine release syndrome (CRS) event, and the method further comprises treating the symptoms of the CRS event while discontinuing treatment with the bispecific antibody binding to FcRH5 and CD3.

131. The bispecific antibody binding to FcRH5 and CD3 as described in claim 130, wherein the method further comprises administering an effective amount of tocilizumab to the subject to treat the CRS event.

132. The bispecific antibody binding to FcRH5 and CD3 as described in claim 131, wherein tocilizumab is administered intravenously to the subject at a single dose of about 8 mg / kg.

133. The bispecific antibody binding to FcRH5 and CD3 used according to claim 131 or 132, wherein the CRS event does not subside or worsen within 24 hours of treatment of the symptoms of the CRS event, the method further comprising administering one or more additional doses of tocilizumab to the subject to manage the CRS event.

134. The bispecific antibody binding to FcRH5 and CD3 as described in claim 133, wherein the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 8 mg / kg.

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